JP4322208B2 - Pyrimidine derivatives - Google Patents

Description

  The present invention relates to a pyrimidine derivative having a fibrinolysis promoting action and useful as a thrombolytic agent or an antithrombotic agent.

In order to dissolve the thrombus, a therapy in which plasminogen activator (PA) is administered, that is, a thrombolytic therapy (fibrinolytic therapy) is currently widely performed. Activation of the fibrinolytic system is initiated by the activation of plasminogen, which is a precursor of the blood fibrinolytic regulator, by plasmin, and the resulting plasmin develops an enzymatic action to produce fibrin, a constituent of thrombus. The thrombolysis proceeds by decomposing. Currently, thrombolytic agents used in this fibrinolytic therapy include in vivo substances such as urokinase (UK), tissue plasminogen activator (t-PA), streptokinase (SK), staphylokinase (SAK) and the like. Fungus-producing substances and their gene recombinants are known. However, since all these existing thrombolytic drugs are protein preparations, the blood half-life is short, they are rapidly metabolized in the liver, and there are inhibitors in the body, so thrombus in the area where thrombus occurs. Large doses are required to develop a lytic effect. In clinical practice, it has been reported that the higher the dose, the higher the reperfusion rate. However, the transient large-scale administration of such a thrombolytic agent significantly increases the thrombolytic activity systemically and reduces the thromboembolic site. While it is expected to be opened, severe bleeding symptoms are observed as a side effect. Moreover, even if the embolization site is temporarily opened by administration of these thrombolytic agents, it is a big problem that re-occlusion is likely to occur.
An object of the present invention is to provide a pharmaceutical composition having a thrombolytic action and an antithrombotic action that does not have the above-mentioned drawbacks.

［式中、
（１）ａは、
（ｉ）ａ１−低級アルキレン基−Ｙ−……（２）
（ここで、
▲１▼ａ１は、
１．カルボキシ基
２．ジカルボキシメチル基
３．ハロゲン
４．フェニル基
（ここで、フェニル基は、メチル基、シアノ基、
メトキシ基、ハロゲン、ニトロ基、カルボキシ
基、低級アルコキシカルボニル基で置換されて
良いフェニル基を意味する）
５．４−モルホリニル基
６．４−ピリジニル基
７．ジメチルアミノ基
８．低級アルコキシカルボニル基
９．（フェニルメトキシ）カルボニル基
（ここで、フェニルは、ハロゲンで置換されて
良いフェニルを意味する）
１０．ジ（低級アルコキシカルボニル）メチル基
▲２▼Ｙは、

（ここで、Ｙ１は、水素、カルボキシメチル基、（低級
アルコキシカルボニル）メチル基を意味する）
２．−Ｏ−アリーレン基− ……（４）
（ここで、アリーレン基は、１，４−フェニレン基、
２，６−ナフタレンジイル基、［１，１’−ビフェニル］−
４，４’−ジイル基を意味する）
を意味する）
（ｉｉ）３−ピリジニル基、４−（トリフルオロメチル）フェニル基、
４−ヒドロキシフェニル基、４’−ヒドロキシ［１，１’−ビフェニ
ル］−４−イル基、６−ヒドロキシ−２−ナフタレニル基、２−ナフ
タレニル基
（ｉｉｉ）（カルボキシフェニルメチル）アミノ基
（ここで、フェニルは、水酸基で置換されて良い
フェニルを意味する）
（２）ｂは、
（ｉ）水酸基
（ｉｉ）ｂ１−低級アルキレン基−Ｏ− ……（５）
（ここで、ｂ１は、
▲１▼カルボキシ基
▲２▼ジカルボキシメチル基
▲３▼ハロゲン
▲４▼フェニル基
（ここで、フェニル基は、メチル基、シアノ基、
メトキシ基、ハロゲン、ニトロ基、カルボキ
シ基、低級アルコキシカルボニル基、アセト
キシ基で置換されて良いフェニル基を意味する）
▲５▼シクロヘキシル基
▲６▼４−モルホリニル基
▲７▼ピリジニル基
▲８▼低級アルコキシカルボニル基
▲９▼ジ（低級アルコキシカルボニル）メチル基

を意味する）
（３）ｃは、
▲１▼フェニル基
（ここで、フェニル基は、アミノ基、ニトロ基、メトキシ基
で置換されて良いフェニル基を意味する）
▲２▼第三級ブチル基
▲３▼トリフルオロメチル基
▲４▼ｃ１−Ｏ−ＣＯ− ……（７）
（ここで、ｃ１は、水素、（低級アルコキシカルボ
ニル）低級アルキル基を意味する）
▲５▼３−フラニル基
▲６▼ホルミル基
▲７▼ジメトキシメチル基
▲８▼ピリミジン環の５位炭素と一緒になってシクロペンタン環
を形成する
▲９▼メチル基
（但し、
（１）ｃが、メチル基である場合、ａは、
（ｉ）ａ１−低級アルキレン基−Ｙ− ……（２）
（ここで、
▲１▼ａ１は、
１．カルボキシ基
２．低級アルコキシカルボニル基
▲２▼Ｙは、

（ここで、Ｙ１は、水素）
２．−Ｏ−アリーレン基− ……（４）
（ここで、アリーレン基は、［１，１’−ビフェニル］−
４，４’−ジイル基を意味する）
を意味する）
（ｉｉ）３−ピリジニル基
（ｉｉｉ）４−（トリフルオロメチル）フェニル基
（ｉｖ）（カルボキシフェニルメチル）アミノ基
（ここで、フェニルは、水酸基で置換されて良いフェニル
を意味する）
（ｖ）４’−ヒドロキシ［１，１’−ビフェニル］−４−イル基
（２）ｃが、第三級ブチル基である場合、ａは、
（ｉ）ａ１−低級アルキレン基−Ｙ− ……（２）
（ここで、
▲１▼ａ１は、
１．カルボキシ基
２．低級アルコキシカルボニル基
３．４−モルホリニル基
▲２▼Ｙは、
１．−Ｏ−アリーレン基− ……（４）
（ここで、アリーレン基は、１，４−フェニレン基を
意味する）
を意味する）
（ｉｉ）４−ヒドロキシフェニル基
を意味する）
を意味する］
で表される化合物又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物を含む血栓症を治療するための医薬組成物。
［２］医薬組成物が血栓溶解剤である、前記［１］の医薬組成物。
［３］医薬組成物が抗血栓剤である、前記［１］の医薬組成物。
［４］医薬組成物として使用するための前記［１］の式（１）で示される化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。
［５］血栓症を治療するための医薬組成物を製造するための前記［１］の式（１）で示される化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物の使用。
［６］前記［１］の式（１）で示される化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物の有効量を対象に投与することからなる血栓症を治療する方法。
［７］前記式（１）に於いて、ｃが、フェニル基（ここで、フェニル基は、アミノ基、ニトロ基、メトキシ基で置換されて良いフェニル基を意味する）、第三級ブチル基、及びトリフルオロメチル基である化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。
［ここで、
（１）ａは、
（ｉ）ａ１−低級アルキレン基−Ｙ− ……（２）
（ここで、
▲１▼ａ１は、
１．カルボキシ基
２．ジカルボキシメチル基
３．ハロゲン
４．フェニル基
（ここで、フェニル基は、メチル基、シアノ基、
メトキシ基、ハロゲン、ニトロ基、カルボキシ
基、低級アルコキシカルボニル基で置換されて
良いフェニル基を意味する）
５．４−モルホリニル基
６．４−ピリジニル基
７．ジメチルアミノ基
８．低級アルコキシカルボニル基
９．（フェニルメトキシ）カルボニル基
（ここで、フェニルは、ハロゲンで置換されて良い
フェニルを意味する）
１０．ジ（低級アルコキシカルボニル）メチル基
▲２▼Ｙは、

（ここで、Ｙ１は、水素、カルボキシメチル基、（低級
アルコキシカルボニル）メチル基を意味する）
２．−Ｏ−アリーレン基− ……（４）
（ここで、アリーレン基は、１，４−フェニレン基、
２，６−ナフタレンジイル基、［１，１’−ビフェニル］−
４，４’−ジイル基を意味する）
を意味する）
（ｉｉ）３−ピリジニル基、４−（トリフルオロメチル）フェニル基、
４−ヒドロキシフェニル基、４’−ヒドロキシ［１，１’−ビフェニ
ル］−４−イル基、６−ヒドロキシ−２−ナフタレニル基、２−ナフ
タレニル基
（ｉｉｉ）（カルボキシフェニルメチル）アミノ基
（ここで、フェニルは、水酸基で置換されて良いフェニル
を意味する）
（２）ｂは、
（ｉ）水酸基
（ｉｉ）ｂ１−低級アルキレン基−Ｏ− ……（５）
（ここで、ｂ１は、
▲１▼カルボキシ基
▲２▼ジカルボキシメチル基
▲３▼ハロゲン
▲４▼フェニル基
（ここで、フェニル基は、メチル基、シアノ基、
メトキシ基、ハロゲン、ニトロ基、カルボキシ
基、低級アルコキシカルボニル基、アセトキシ基
で置換されて良いフェニル基を意味する）
▲５▼シクロヘキシル基
▲６▼４−モルホリニル基
▲７▼ピリジニル基
▲８▼低級アルコキシカルボニル基
▲９▼ジ（低級アルコキシカルボニル）メチル基
を意味する）
（但し、
（１）６−フェニル−２−［４−（トリフルオロメチル）フェニル］−
４（１Ｈ）−ピリミジノンは除く
（２）ｃが、第三級ブチル基である場合、ａは、
（ｉ）ａ１−低級アルキレン基−Ｙ− ……（２）
（ここで、
▲１▼ａ１は、
１．カルボキシ基
２．低級アルコキシカルボニル基
３．４−モルホリニル基
▲２▼Ｙは、
１．−Ｏ−アリーレン基− ……（４）
（ここで、アリーレン基は、１，４−フェニレン基を
意味する）
を意味する）
（ｉｉ）４−ヒドロキシフェニル基
を意味する）
を意味する］
［８］前記式（１）に於いて、ｃが、
▲１▼ｃ１−Ｏ−ＣＯ− ……（７）
（ここで、ｃ１は、水素、（低級アルコキシカルボニル）低級アル
キル基を意味する）
▲２▼３−フラニル基
▲３▼ホルミル基
▲４▼ジメトキシメチル基
である化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。
［ここで、
（１）ａは、
（ｉ）ａ１−低級アルキレン基−Ｙ− ……（２）
（ここで、
▲１▼ａ１は、
１．カルボキシ基
２．低級アルコキシカルボニル基
３．フェニル基
▲２▼Ｙは、−Ｏ−アリーレン基− ……（４）
（ここで、アリーレン基は２，６−ナフタレンジ
イル基を意味する）
を意味する）
（ｉｉ）６−ヒドロキシ−２−ナフタレニル基
（２）ｂは、
（ｉ）水酸基
（ｉｉ）ｂ１−低級アルキレン基−Ｏ− ……（５）
（ここで、ｂ１は、カルボキシ基、低級アルコキシ
カルボニル基を意味する）
を意味する］
［９］前記一般式（１）に於いて、ｃが、ピリミジン環の５位炭素と一緒になってシクロペンタン環を形成した化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。
［ここで、
（１）ａは、
（ｉ）ａ１−低級アルキレン基−Ｙ− ……（２）
（ここで、
▲１▼ａ１は、
１．カルボキシ基
２．低級アルコキシカルボニル基
▲２▼Ｙは、−Ｏ−アリーレン基− ……（４）
（ここで、アリーレン基は、２，６−ナフタレン
ジイル基を意味する）
を意味する）
（ｉｉ）６−ヒドロキシ−２−ナフタレニル基
（２）ｂは、
（ｉ）水酸基
（ｉｉ）ｂ１−低級アルキレン基−Ｏ− ……（５）
（ここで、ｂ１は、カルボキシ基、低級アルコキシ
カルボニル基を意味する）
を意味する］
［１０］前記一般式（１）に於いて、ｃが、メチル基である化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。
［ここで、
（１）ａは、
（ｉ）ａ１−低級アルキレン基−Ｙ− ……（２）
（ここで、
▲１▼ａ１は、
１．カルボキシ基
２．低級アルコキシカルボニル基
▲２▼Ｙは、

（ここで、Ｙ１は、水素を意味する）
２．−Ｏ−アリーレン基− ……（４）
（ここで、アリーレン基は、［１，１’−ビフェニ
ル］−４，４’−ジイル基を意味する）
を意味する）
（ｉｉ）３−ピリジニル基
（ｉｉｉ）４−（トリフルオロメチル）フェニル基
（ｉｖ）（カルボキシフェニルメチル）アミノ基
（ここで、フェニルは、水酸基で置換されて良いフェニル
を意味する）
（ｖ）４’−ヒドロキシ［１，１’−ビフェニル］−４−イル基
（２）ｂは、
（ｉ）水酸基
（ｉｉ）ｂ１−低級アルキレン基−Ｏ− ……（５）
（ここで、ｂ１は、
１．カルボキシ基
２．低級アルコキシカルボニル基

を意味する）
（但し、Ｎ−（１，４−ジヒドロ−６−メチル−４−オキソ−２−ピリミジニル）グリシン、６−メチル−２−（３−ピリジニル）−４（１Ｈ）−ピリミジノン、６−メチル−２−［４−（トリフルオロメチル）フェニル］−４（１Ｈ）−ピリミジノンは除く）
を意味する］
［１１］以下の化合物群から選ばれる化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。
６−フェニル−２−（３−ピリジニル）−４（１Ｈ）−ピリミジノンナトリウム塩、［［６−フェニル−２−［４−（トリフルオロメチル）フェニル］−４−ピリミジニル］オキシ］酢酸メチルエステル、［［６−フェニル−２−［４−（トリフルオロメチル）フェニル］−４−ピリミジニル］オキシ］酢酸、６−［［６−フェニル−２−［４−（トリフルオロメチル）フェニル］−４−ピリミジニル］オキシ］ヘキサン酸、［５−［［６−フェニル−２−［４−（トリフルオロメチル）フェニル］−４−ピリミジニル］オキシ］ペンチル］プロパン二酸、２−（４−ヒドロキシフェニル）−６−フェニル−４（１Ｈ）−ピリミジノン、［［２−［４−（２−メトキシ−２−オキソエトキシ）フェニル］−６−フェニル−４−ピリミジニル］オキシ］酢酸メチルエステル、［［２−［４−（カルボキシメトキシ）フェニル］−６−フェニル−４−ピリミジニル］オキシ］酢酸、４−［４−フェニル−６−（フェニルメトキシ）−２−ピリミジニル］フェノール、［４−［４−フェニル−６−（フェニルメトキシ）−２−ピリミジニル］フェノキシ］酢酸ナトリウム塩、［４−（１，４−ジヒドロ−４−オキソ−６−フェニル−２−ピリミジニル）フェノキシ］酢酸、［４−［４−［（２−クロロフェニル）メトキシ］−６−フェニル−２−ピリミジニル］フェノキシ］酢酸ナトリウム塩、４−［４−［４−フェニル−６−（フェニルメトキシ）−２−ピリミジニル］フェノキシ］ブタン酸エチルエステル、４−［４−［４−フェニル−６−（フェニルメトキシ）−２−ピリミジニル］フェノキシ］ブタン酸ナトリウム塩、４−［４−（１，４−ジヒドロ−４−オキソ−６−フェニル−２−ピリミジニル）フェノキシ］ブタン酸エチルエステル、４−［４−（１，４−ジヒドロ−４−オキソ−６−フェニル−２−ピリミジニル）フェノキシ］ブタン酸、４−［４−［４−［（２−クロロフェニル）メトキシ］−６−フェニル−２−ピリミジニル］フェノキシ］ブタン酸ナトリウム塩、４−［４−［４−［（２−フルオロフェニル）メトキシ］−６−フェニル−２−ピリミジニル］フェノキシ］ブタン酸ナトリウム塩、４−［４−［４−（シクロヘキシルメトキシ）−６−フェニル−２−ピリミジニル］フェノキシ］ブタン酸ナトリウム塩、６−［４−［４−フェニル−６−（フェニルメトキシ）−２−ピリミジニル］フェノキシ］ヘキサン酸、６−［４−（１，４−ジヒドロ−４−オキソ−６−フェニル−２−ピリミジニル）フェノキシ］ヘキサン酸、［３−［４−［４−フェニル−６−（フェニルメトキシ）−２−ピリミジニル］フェノキシ］プロピル］プロパン二酸ジエチルエステル、［３−［４−［４−フェニル−６−（フェニルメトキシ）−２−ピリミジニル］フェノキシ］プロピル］プロパン二酸、［３−［４−［４−［（２−フルオロフェニル）メトキシ］−６−フェニル−２−ピリミジニル］フェノキシ］プロピル］プロパン二酸、［３−［４−［４−（シクロヘキシルメトキシ）−６−フェニル−２−ピリミジニル］フェノキシ］プロピル］プロパン二酸、４−［２−［４−［４−フェニル−６−（フェニルメトキシ）−２−ピリミジニル］フェノキシ］エチル］モルホリン塩酸塩、２−［４−［２−（４−モルホリニル）エトキシ］フェニル］−６−フェニル−４（１Ｈ）−ピリミジノン、４−［２−［４−［４−［（２−フルオロフェニル）メトキシ］−６−フェニル−２−ピリミジニル］フェノキシ］エチル］モルホリン、４−［２−［４−［４−（シクロヘキシルメトキシ）−６−フェニル−２−ピリミジニル］フェノキシ］エチル］モルホリン、２−（４’−ヒドロキシ［１，１’−ビフェニル］−４−イル）−６−フェニル−４（１Ｈ）−ピリミジノン、［［２−［４’−（２−メトキシ−２−オキソエトキシ）［１，１’−ビフェニル］−４−イル］−６−フェニル−４−ピリミジニル］オキシ］酢酸メチルエステル、［［２−［４’−（カルボキシメトキシ）［１，１’−ビフェニル］−４−イル］−６−フェニル−４−ピリミジニル］オキシ］酢酸、Ｎ−［１，４−ジヒドロ−４−オキソ−６−フェニル−２−ピリミジニル］グリシン、Ｎ−（カルボキシメチル）−Ｎ−［４−（２−エトキシ−２−オキソエトキシ）−６−フェニル−２−ピリミジニル］グリシンエチルエステル、Ｎ−［４−（カルボキシメトキシ）−６−フェニル−２−ピリミジニル］−Ｎ−（カルボキシメチル）グリシン二ナトリウム塩、α−［（１，４−ジヒドロ−４−オキソ−６−フェニル−２−ピリミジニル）アミノ］−４−ヒドロキシベンゼン酢酸、２−（２−ナフタレニル）−６−フェニル−４（１Ｈ）−ピリミジノン、２−（６−ヒドロキシ−２−ナフタレニル）−６−（４−ニトロフェニル）−４（１Ｈ）−ピリミジノン、２−（６−ヒドロキシ−２−ナフタレニル）−６−（３−ニトロフェニル）−４（１Ｈ）−ピリミジノン、６−（４−アミノフェニル）−２−（６−ヒドロキシ−２−ナフタレニル）−４（１Ｈ）−ピリミジノン塩酸塩、６−（３−アミノフェニル）−２−（６−ヒドロキシ−２−ナフタレニル）−４（１Ｈ）−ピリミジノン、２−（６−ヒドロキシ−２−ナフタレニル）−６−（４−メトキシフェニル）−４（１Ｈ）−ピリミジノン、２−（６−ヒドロキシ−２−ナフタレニル）−６−フェニル−４（１Ｈ）−ピリミジノン、［［２−（６−ヒドロキシ−２−ナフタレニル）−６−（４−ニトロフェニル）−４−ピリミジニル］オキシ］酢酸メチルエステル、［［２−（６−ヒドロキシ−２−ナフタレニル）−６−（４−ニトロフェニル）−４−ピリミジニル］オキシ］酢酸、［［２−（６−ヒドロキシ−２−ナフタレニル）−６−（３−ニトロフェニル）−４−ピリミジニル］オキシ］酢酸メチルエステル、［［２−（６−ヒドロキシ−２−ナフタレニル）−６−（３−ニトロフェニル）−４−ピリミジニル］オキシ］酢酸、［［６−（４−アミノフェニル）−２−（６−ヒドロキシ−２−ナフタレニル）−４−ピリミジニル］オキシ］酢酸メチルエステル塩酸塩、［［６−（４−アミノフェニル）−２−（６−ヒドロキシ−２−ナフタレニル）−４−ピリミジニル］オキシ］酢酸、［［６−（３−アミノフェニル）−２−（６−ヒドロキシ−２−ナフタレニル）−４−ピリミジニル］オキシ］酢酸メチルエステル、［［６−（３−アミノフェニル）−２−（６−ヒドロキシ−２−ナフタレニル）−４−ピリミジニル］オキシ］酢酸、［［２−（６−ヒドロキシ−２−ナフタレニル）−６−フェニル−４−ピリミジニル］オキシ］酢酸メチルエステル、［［２−（６−ヒドロキシ−２−ナフタレニル）−６−フェニル−４−ピリミジニル］オキシ］酢酸エチルエステル、［［２−（６−ヒドロキシ−２−ナフタレニル）−６−フェニル−４−ピリミジニル］オキシ］酢酸、６−フェニル−２−［６−（フェニルメトキシ）−２−ナフタレニル］−４（１Ｈ）−ピリミジノン、４−［［６−フェニル−２−［６−（フェニルメトキシ）−２−ナフタレニル］−４−ピリミジニル］オキシ］ブタン酸エチルエステル、４−［［６−フェニル−２−［６−（フェニルメトキシ）−２−ナフタレニル］−４−ピリミジニル］オキシ］ブタン酸ナトリウム塩、４−［［２−（６−ヒドロキシ−２−ナフタレニル）−６−フェニル−４−ピリミジニル］オキシ］ブタン酸エチルエステル、４−［［２−（６−ヒドロキシ−２−ナフタレニル）−６−フェニル−４−ピリミジニル］オキシ］ブタン酸二ナトリウム塩、６−［４−［（２−フルオロフェニル）メトキシ］−６−（４−ニトロフェニル）−２−ピリミジニル］−２−ナフタレノール、６−［４−［（２−フルオロフェニル）メトキシ］−６−（３−ニトロフェニル）−２−ピリミジニル］−２−ナフタレノール、６−［４−［（２−フルオロフェニル）メトキシ］−６−（４−メトキシフェニル）−２−ピリミジニル］−２−ナフタレノール、６−［４−［（２−フルオロフェニル）メトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレノール、６−［４−フェニル−６−（フェニルメトキシ）−２−ピリミジニル］−２−ナフタレノール、４−［２−［［６−フェニル−２−［６−（フェニルメトキシ）−２−ナフタレニル］−４−ピリミジニル］オキシ］エチル］モルホリン塩酸塩、６−［４−［２−（４−モルホリニル）エトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレノール塩酸塩、［［２−［６−（２−クロロエトキシ）−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］酢酸ナトリウム塩、［［２−［６−（３−クロロプロポキシ）−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］酢酸ナトリウム塩、［［２−［６−（２−メトキシ−２−オキソエトキシ）−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］酢酸メチルエステル、［［２−［６−（カルボキシメトキシ）−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］酢酸、［［６−（１，４−ジヒドロ−４−オキソ−６−フェニル−２−ピリミジニル）−２−ナフタレニル］オキシ］酢酸、［［２−［６−（２−メトキシ−２−オキソエトキシ）−２−ナフタレニル］−６−（４−ニトロフェニル）−４−ピリミジニル］オキシ］酢酸メチルエステル、［［２−［６−（カルボキシメトキシ）−２−ナフタレニル］−６−（４−ニトロフェニル）−４−ピリミジニル］オキシ］酢酸、［［６−［１，４−ジヒドロ−６−（４−ニトロフェニル）−４−オキソ−２−ピリミジニル］−２−ナフタレニル］オキシ］酢酸、［［２−［６−（２−メトキシ−２−オキソエトキシ）−２−ナフタレニル］−６−（３−ニトロフェニル）−４−ピリミジニル］オキシ］酢酸メチルエステル、［［２−［６−（カルボキシメトキシ）−２−ナフタレニル］−６−（３−ニトロフェニル）−４−ピリミジニル］オキシ］酢酸、［［６−［１，４−ジヒドロ−６−（３−ニトロフェニル）−４−オキソ−２−ピリミジニル］−２−ナフタレニル］オキシ］酢酸、［［６−［６−（４−アミノフェニル）−１，４−ジヒドロ−４−オキソ−２−ピリミジニル］−２−ナフタレニル］オキシ］酢酸、［［６−［６−（３−アミノフェニル）−１，４−ジヒドロ−４−オキソ−２−ピリミジニル］−２−ナフタレニル］オキシ］酢酸、［［６−（４−アミノフェニル）−２−［６−（２−メトキシ−２−オキソエトキシ）−２−ナフタレニル］−４−ピリミジニル］オキシ］酢酸メチルエステル、［［６−（４−アミノフェニル）−２−［６−（カルボキシメトキシ）−２−ナフタレニル］−４−ピリミジニル］オキシ］酢酸、［［６−（３−アミノフェニル）−２−［６−（２−メトキシ−２−オキソエトキシ）−２−ナフタレニル］−４−ピリミジニル］オキシ］酢酸メチルエステル、［［６−（３−アミノフェニル）−２−［６−（カルボキシメトキシ）−２−ナフタレニル］−４−ピリミジニル］オキシ］酢酸、［［６−［４−（２−メトキシ−２−オキソエトキシ）−６−（４−メトキシフェニル）−２−ピリミジニル］−２−ナフタレニル］オキシ］酢酸メチルエステル、［［６−［４−（カルボキシメトキシ）−６−（４−メトキシフェニル）−２−ピリミジニル］−２−ナフタレニル］オキシ］酢酸、４−［［２−［６−（カルボキシメトキシ）−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］ブタン酸二ナトリウム塩、［［６−［４−フェニル−６−（フェニルメトキシ）−２−ピリミジニル］−２−ナフタレニル］オキシ］酢酸、［［６−［４−［（２−フルオロフェニル）メトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］酢酸、［［６−［４−［（２−フルオロフェニル）メトキシ］−６−（４−ニトロフェニル）−２−ピリミジニル］−２−ナフタレニル］オキシ］酢酸ナトリウム塩、［［６−［４−［（２−フルオロフェニル）メトキシ］−６−（３−ニトロフェニル）−２−ピリミジニル］−２−ナフタレニル］オキシ］酢酸ナトリウム塩、［［６−［４−［（２−フルオロフェニル）メトキシ］−６−（４−メトキシフェニル）−２−ピリミジニル］−２−ナフタレニル］オキシ］酢酸、［［６−［４−［２−（４−モルホリニル）エトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］酢酸エチルエステル、［［６−［４−［２−（４−モルホリニル）エトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］酢酸ナトリウム塩、４−［［６−［４−フェニル−６−（フェニルメトキシ）−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸エチルエステル、４−［［６−［４−フェニル−６−（フェニルメトキシ）−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、４−［［６−（１，４−ジヒドロ−４−オキソ−６−フェニル−２−ピリミジニル）−２−ナフタレニル］オキシ］ブタン酸エチルエステル、４−［［６−（１，４−ジヒドロ−４−オキソ−６−フェニル−２−ピリミジニル）−２−ナフタレニル］オキシ］ブタン酸、４−［［６−［４−（カルボキシメトキシ）−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸二ナトリウム塩、４−［［２−［６−（３−カルボキシプロポキシ）−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］ブタン酸、４−［［６−［４−［２−（４−モルホリニル）エトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸、４−［［６−［４−フェニル−６−［（３−ピリジニル）メトキシ］−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸、４−［［６−［４−フェニル−６−［（４−ピリジニル）メトキシ］−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸、４−［［［２−［６−（３−カルボキシプロポキシ）−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］メチル］安息香酸、４−［［６−［４−［（２−クロロフェニル）メトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、４−［［６−［４−［（３−クロロフェニル）メトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、４−［［６−［４−［（４−クロロフェニル）メトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、４−［［６−［４−［（２，６−ジクロロフェニル）メトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、４−［［６−［４−［（２−フルオロフェニル）メトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、４−［［６−［４−［（３−フルオロフェニル）メトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、４−［［６−［４−［（４−フルオロフェニル）メトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、４−［［６−［４−［（２，６−ジフルオロフェニル）メトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、４−［［６−［４−［（２，４−ジフルオロフェニル）メトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、４−［［６−［４−［（ペンタフルオロフェニル）メトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、４−［［６−［４−［（２−ブロモフェニル）メトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、４−［［６−［４−［（４−ブロモフェニル）メトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、４−［［６−［４−［（２−フルオロフェニル）メトキシ］−６−（４−ニトロフェニル）−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、４−［［６−［４−［（２−フルオロフェニル）メトキシ］−６−（３−ニトロフェニル）−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、４−［［６−［４−［（２−フルオロフェニル）メトキシ］−６−（４−メトキシフェニル）−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、４−［［６−［４−［（２−メチルフェニル）メトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、４−［［６−［４−［（２−ニトロフェニル）メトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、４−［［６−［４−［（２−シアノフェニル）メトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、４−［［６−［４−［（２−メトキシフェニル）メトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、４−［［６−［４−［［２−（アセチルオキシ）フェニル］メトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸エチルエステル、４−［［６−［４−（３−クロロプロポキシ）−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、５−［［６−［４−フェニル−６−（フェニルメトキシ）−２−ピリミジニル］−２−ナフタレニル］オキシ］ペンタン酸、５−［［６−（１，４−ジヒドロ−４−オキソ−６−フェニル−２−ピリミジニル）−２−ナフタレニル］オキシ］ペンタン酸、５−［［２−［６−［（５−エトキシ−５−オキソペンチル）オキシ］−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］ペンタン酸エチルエステル、５−［［２−［６−（４−カルボキシブトキシ）−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］ペンタン酸、６−［［６−［４−フェニル−６−（フェニルメトキシ）−２−ピリミジニル］−２−ナフタレニル］オキシ］ヘキサン酸、６−［［６−（１，４−ジヒドロ−４−オキソ−６−フェニル−２−ピリミジニル）−２−ナフタレニル］オキシ］ヘキサン酸、６−［［２−［６−［（５−カルボキシペンチル）オキシ］−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］ヘキサン酸、６−［［６−［４−［（２−フルオロフェニル）メトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］ヘキサン酸ナトリウム塩、６−［［６−［４−［（２−フルオロフェニル）メトキシ］−６−（４−ニトロフェニル）−２−ピリミジニル］−２−ナフタレニル］オキシ］ヘキサン酸ナトリウム塩、６−［［６−［４−［（２−フルオロフェニル）メトキシ］−６−（３−ニトロフェニル）−２−ピリミジニル］−２−ナフタレニル］オキシ］ヘキサン酸ナトリウム塩、６−［［６−［４−［（２−フルオロフェニル）メトキシ］−６−（４−メトキシフェニル）−２−ピリミジニル］−２−ナフタレニル］オキシ］ヘキサン酸ナトリウム塩、７−［［６−［４−フェニル−６−（フェニルメトキシ）−２−ピリミジニル］−２−ナフタレニル］オキシ］ヘプタン酸ナトリウム塩、７−［［６−（１，４−ジヒドロ−４−オキソ−６−フェニル−２−ピリミジニル）−２−ナフタレニル］オキシ］ヘプタン酸、［３−［［６−［４−［（２−フルオロフェニル）メトキシ］−６−フェニル−２−ピリミジニル］−２−ナフタレニル］オキシ］プロピル］プロパン二酸、［３−［［６−［４−［（２−フルオロフェニル）メトキシ］−６−（４−メトキシフェニル）−２−ピリミジニル］−２−ナフタレニル］オキシ］プロピル］プロパン二酸、［５−［［６−［４−フェニル−６−（フェニルメトキシ）−２−ピリミジニル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸、［５−［［６−（１，４−ジヒドロ−４−オキソ−６−フェニル−２−ピリミジニル）−２−ナフタレニル］オキシ］ペンチル］プロパン二酸、［５−［［２−［６−［（６，６−ジカルボキシヘキシル）オキシ］−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］ペンチル］プロパン二酸、［［６−フェニル−２−［６−（フェニルメトキシ）−２−ナフタレニル］−４−ピリミジニル］オキシ］酢酸カリウム塩、［［２−［６−［（２−メチルフェニル）メトキシ］−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］酢酸ナトリウム塩、［［２−［６−［（２−シアノフェニル）メトキシ］−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］酢酸ナトリウム塩、［［２−［６−［（２−メトキシフェニル）メトキシ］−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］酢酸ナトリウム塩、［［２−［６−［（２−クロロフェニル）メトキシ］−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］酢酸ナトリウム塩、［［２−［６−［（２−フルオロフェニル）メトキシ］−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］酢酸ナトリウム塩、［［２−［６−［（２，６−ジフルオロフェニル）メトキシ］−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］酢酸ナトリウム塩、４−［［２−［６−［（２，６−ジフルオロフェニル）メトキシ］−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］ブタン酸ナトリウム塩、４−［２−［［２−［６−［（２，６−ジフルオロフェニル）メトキシ］−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］エチル］モルホリン塩酸塩、［［２−［６−［（２−ニトロフェニル）メトキシ］−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］酢酸ナトリウム塩、４−［［［６−［４−フェニル−６−（フェニルメトキシ）−２−ピリミジニル］−２−ナフタレニル］オキシ］メチル］安息香酸、４−［２−［［６−［４−フェニル−６−（フェニルメトキシ）−２−ピリミジニル］−２−ナフタレニル］オキシ］エチル］モルホリン、２−［６−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］−６−フェニル−４（１Ｈ）−ピリミジノン塩酸塩、４−［２−［［６−［４−［（２−フルオロフェニル）メトキシ］−６−（４−ニトロフェニル）−２−ピリミジニル］−２−ナフタレニル］オキシ］エチル］モルホリン、６−（４−アミノフェニル）−２−［６−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］−４（１Ｈ）−ピリミジノン二塩酸塩、４−［２−［［６−［４−［（２−フルオロフェニル）メトキシ］−６−（４−メトキシフェニル）−２−ピリミジニル］−２−ナフタレニル］オキシ］エチル］モルホリン塩酸塩、６−（４−メトキシフェニル）−２−［６−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］−４（１Ｈ）−ピリミジノン塩酸塩、４−［２−［［６−［４−［（２−フルオロフェニル）メトキシ］−６−（３−ニトロフェニル）−２−ピリミジニル］−２−ナフタレニル］オキシ］エチル］モルホリン塩酸塩、６−（３−アミノフェニル）−２−［６−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］−４（１Ｈ）−ピリミジノン二塩酸塩、［［２−［６−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］酢酸エチルエステル塩酸塩、［［２−［６−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］酢酸、４−［［２−［６−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］ブタン酸ナトリウム塩、４−［２−［［２−［６−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］−６−フェニル−４−ピリミジニル］オキシ］エチル］モルホリン二塩酸塩、４−フェニル−６−（フェニルメトキシ）−２−［６−［（４−ピリジニル）メトキシ］−２−ナフタレニル］ピリミジン塩酸塩、Ｎ，Ｎ−ジメチル−３−［［６−［４−フェニル−６−（フェニルメトキシ）−２−ピリミジニル］−２−ナフタレニル］オキシ］−１−プロパンアミン塩酸塩、２−［６−［３−（ジメチルアミノ）プロポキシ］−２−ナフタレニル］−６−フェニル−４（１Ｈ）−ピリミジノン塩酸塩、２−（４−ヒドロキシフェニル）−６−（１，１−ジメチルエチル）−４（１Ｈ）−ピリミジノン、４−［４−［４−（１，１−ジメチルエチル）−６−（フェニルメトキシ）−２−ピリミジニル］フェノキシ］ブタン酸、４−［４−［６−（１，１−ジメチルエチル）−１，４−ジヒドロ−４−オキソ−２−ピリミジニル］フェノキシ］ブタン酸エチルエステル、４−［４−［４−（１，１−ジメチルエチル）−６−［（２−フルオロフェニル）メトキシ］−２−ピリミジニル］フェノキシ］ブタン酸、４−［４−［４−（シクロヘキシルメトキシ）−６−（１，１−ジメチルエチル）−２−ピリミジニル］フェノキシ］ブタン酸、４−［２−［４−［４−（１，１−ジメチルエチル）−６−（フェニルメトキシ）−２−ピリミジニル］フェノキシ］エチル］モルホリン塩酸塩、６−（１，１−ジメチルエチル）−２−［４−［２−（４−モルホリニル）エトキシ］フェニル］−４（１Ｈ）−ピリミジノン、４−［２−［４−［４−（１，１−ジメチルエチル）−６−［（２−フルオロフェニル）メトキシ］−２−ピリミジニル］フェノキシ］エチル］モルホリン塩酸塩、４−［２−［４−［４−（シクロヘキシルメトキシ）−６−（１，１−ジメチルエチル）−２−ピリミジニル］フェノキシ］エチル］モルホリン塩酸塩、２−（４−ヒドロキシフェニル）−６−（トリフルオロメチル）−４（１Ｈ）−ピリミジノン、４−［４−（フェニルメトキシ）−６−（トリフルオロメチル）−２−ピリミジニル］フェノール、４−［４−［４−（フェニルメトキシ）−６−（トリフルオロメチル）−２−ピリミジニル］フェノキシ］ブタン酸エチルエステル、４−［４−［１，４−ジヒドロ−４−オキソ−６−（トリフルオロメチル）−２−ピリミジニル］フェノキシ］ブタン酸エチルエステル、４−［４−［４−（シクロヘキシルメトキシ）−６−（トリフルオロメチル）−２−ピリミジニル］フェノキシ］ブタン酸ナトリウム塩、［３−［４−［４−（フェニルメトキシ）−６−（トリフルオロメチル）−２−ピリミジニル］フェノキシ］プロピル］プロパン二酸ジエチルエステル、［３−［４−［１，４−ジヒドロ−４−オキソ−６−（トリフルオロメチル）−２−ピリミジニル］フェノキシ］プロピル］プロパン二酸ジエチルエステル、［３−［４−［４−（シクロヘキシルメトキシ）−６−（トリフルオロメチル）−２−ピリミジニル］フェノキシ］プロピル］プロパン二酸、４−［２−［４−［４−（フェニルメトキシ）−６−（トリフルオロメチル）−２−ピリミジニル］フェノキシ］エチル］モルホリン塩酸塩、４−［２−［４−［４−（シクロヘキシルメトキシ）−６−（トリフルオロメチル）−２−ピリミジニル］フェノキシ］エチル］モルホリン、２−（６−ヒドロキシ−２−ナフタレニル）−６−（トリフルオロメチル）−４（１Ｈ）−ピリミジノン、［［２−（６−ヒドロキシ−２−ナフタレニル）−６−（トリフルオロメチル）−４−ピリミジニル］オキシ］酢酸メチルエステル、［［２−（６−ヒドロキシ−２−ナフタレニル）−６−（トリフルオロメチル）−４−ピリミジニル］オキシ］酢酸、６−［４−（フェニルメトキシ）−６−（トリフルオロメチル）−２−ピリミジニル］−２−ナフタレノール、［［２−［６−（２−メトキシ−２−オキソエトキシ）−２−ナフタレニル］−６−（トリフルオロメチル）−４−ピリミジニル］オキシ］酢酸メチルエステル、［［２−［６−（カルボキシメトキシ）−２−ナフタレニル］−６−（トリフルオロメチル）−４−ピリミジニル］オキシ］酢酸、［［６−［４−（フェニルメトキシ）−６−（トリフルオロメチル）−２−ピリミジニル］−２−ナフタレニル］オキシ］酢酸エチルエステル、［［６−［４−（フェニルメトキシ）−６−（トリフルオロメチル）−２−ピリミジニル］−２−ナフタレニル］オキシ］酢酸ナトリウム塩、［［６−［１，４−ジヒドロ−４−オキソ−６−（トリフルオロメチル）−２−ピリミジニル］−２−ナフタレニル］オキシ］酢酸エチルエステル、［［６−［１，４−ジヒドロ−４−オキソ−６−（トリフルオロメチル）−２−ピリミジニル］−２−ナフタレニル］オキシ］酢酸、［［６−［４−［（２−フルオロフェニル）メトキシ］−６−（トリフルオロメチル）−２−ピリミジニル］−２−ナフタレニル］オキシ］酢酸、４−［［６−［４−（フェニルメトキシ）−６−（トリフルオロメチル）−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸エチルエステル、４−［［６−［１，４−ジヒドロ−４−オキソ−６−（トリフルオロメチル）−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸エチルエステル、４−［［６−［１，４−ジヒドロ−４−オキソ−６−（トリフルオロメチル）−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸、４−［［６−［４−［（２−フルオロフェニル）メトキシ］−６−（トリフルオロメチル）−２−ピリミジニル］−２−ナフタレニル］オキシ］ブタン酸ナトリウム塩、６−［［６−［１，４−ジヒドロ−４−オキソ−６−（トリフルオロメチル）−２−ピリミジニル］−２−ナフタレニル］オキシ］ヘキサン酸エチルエステル、６−［［６−［１，４−ジヒドロ−４−オキソ−６−（トリフルオロメチル）−２−ピリミジニル］−２−ナフタレニル］オキシ］ヘキサン酸、［５−［［６−［１，４−ジヒドロ−４−オキソ−６−（トリフルオロメチル）−２−ピリミジニル］−２−ナフタレニル］オキシ］ペンチル］プロパン二酸、４−［２−［［６−［４−（フェニルメトキシ）−６−（トリフルオロメチル）−２−ピリミジニル］−２−ナフタレニル］オキシ］エチル］モルホリン、２−［６−［２−（４−モルホリニル）エトキシ］−２−ナフタレニル］−６−（トリフルオロメチル）−４（１Ｈ）−ピリミジノン、４−［２−［［６−［４−［（２−フルオロフェニル）メトキシ］−６−（トリフルオロメチル）−２−ピリミジニル］−２−ナフタレニル］オキシ］エチル］モルホリン、６−（ジメトキシメチル）−２−［６−（フェニルメトキシ）−２−ナフタレニル］−４（１Ｈ）−ピリミジノン、１，６−ジヒドロ−６−オキソ−２−［６−（フェニルメトキシ）−２−ナフタレニル］−４−ピリミジンカルボキシアルデヒド、１，６−ジヒドロ−６−オキソ−２−［６−（フェニルメトキシ）−２−ナフタレニル］−４−ピリミジンカルボン酸、１，６−ジヒドロ−２−（６−ヒドロキシ−２−ナフタレニル）−６−オキソ−４−ピリミジンカルボン酸、６−（２−メトキシ−２−オキソエトキシ）−２−［６−（２−メトキシ−２−オキソエトキシ）−２−ナフタレニル］−４−ピリミジンカルボン酸２−メトキシ−２−オキソエチルエステル、６−（２−メトキシ−２−オキソエトキシ）−２−［６−（フェニルメトキシ）−２−ナフタレニル］−４−ピリミジンカルボン酸２−メトキシ−２−オキソエチルエステル、６−（カルボキシメトキシ）−２−［６−（カルボキシメトキシ）−２−ナフタレニル］−４−ピリミジンカルボン酸、６−（カルボキシメトキシ）−２−（６−ヒドロキシ−２−ナフタレニル）−４−ピリミジンカルボン酸、６−（３−フラニル）−２−（６−ヒドロキシ−２−ナフタレニル）−４（１Ｈ）−ピリミジノン、［［６−（３−フラニル）−２−［６−（２−メトキシ−２−オキソエトキシ）−２−ナフタレニル］−４−ピリミジニル］オキシ］酢酸メチルエステル、［［６−［４−（カルボキシメトキシ）−６−（３−フラニル）−２−ピリミジニル］−２−ナフタレニル］オキシ］酢酸、１，５，６，７−テトラヒドロ−２−（６−ヒドロキシ−２−ナフタレニル）−４Ｈ−シクロペンタピリミジン−４−オン、［［６−［６，７−ジヒドロ−４−（２−メトキシ−２−オキソエトキシ）−５Ｈ−シクロペンタピリミジン−２−イル］−２−ナフタレニル］オキシ］酢酸メチルエステル、［［６−［４−（カルボキシメトキシ）−６，７−ジヒドロ−５Ｈ−シクロペンタピリミジン−２−イル］−２−ナフタレニル］オキシ］酢酸、Ｎ−［４−（２−エトキシ−２−オキソエトキシ）−６−メチル−２−ピリミジニル］グリシン、Ｎ−［４−（カルボキシメトキシ）−６−メチル−２−ピリミジニル］グリシン、［［６−メチル−２−（３−ピリジニル）−４−ピリミジニル］オキシ］酢酸メチルエステル、［［６−メチル−２−（３−ピリジニル）−４−ピリミジニル］オキシ］酢酸、［［６−メチル−２−［４−（トリフルオロメチル）フェニル］−４−ピリミジニル］オキシ］酢酸メチルエステル、［［６−メチル−２−［４−（トリフルオロメチル）フェニル］−４−ピリミジニル］オキシ］酢酸、６−［［６−メチル−２−［４−（トリフルオロメチル）フェニル］−４−ピリミジニル］オキシ］ヘキサン酸ナトリウム塩、４−［４−（１−シクロヘキシル−１Ｈ−テトラゾール−５−イル）ブトキシ］−６−メチル−２−［４−（トリフルオロメチル）フェニル］ピリミジン、α−［（１，４−ジヒドロ−６−メチル−４−オキソ−２−ピリミジニル）アミノ］−４−ヒドロキシベンゼン酢酸、２−（４’−ヒドロキシ［１，１’−ビフェニル］−４−イル）−６−メチル−４（１Ｈ）−ピリミジノン、［［２−（４’−ヒドロキシ［１，１’−ビフェニル］−４−イル）−６−メチル−４−ピリミジニル］オキシ］酢酸メチルエステル、［［２−（４’−ヒドロキシ［１，１’−ビフェニル］−４−イル）−６−メチル−４−ピリミジニル］オキシ］酢酸、［［２−［４’−（２−メトキシ−２−オキソエトキシ）［１，１’−ビフェニル］−４−イル］−６−メチル−４−ピリミジニル］オキシ］酢酸メチルエステル、［［２−［４’−（カルボキシメトキシ）［１，１’−ビフェニル］−４−イル］−６−メチル−４−ピリミジニル］オキシ］酢酸
［１２］医薬組成物として使用するための前記［７］〜［１１］のいずれかに記載の化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。
［１３］血栓溶解剤又は抗血栓剤として使用するための前記［７］〜［１１］のいずれかに記載の化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。
［１４］血栓症を治療するための医薬組成物を製造するための前記［７］〜［１１］のいずれかに記載の化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。
［１５］前記［７］〜［１１］のいずれかに記載の化合物、又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物の有効量を対象に投与することからなる血栓症を治療する方法。
［１６］血栓溶解剤又は抗血栓剤として使用するための以下の化合物群から選ばれる化合物又は医薬的に許容し得るそれらの塩化合物若しくはそれらの溶媒和物。
６−フェニル−２−［４−（トリフルオロメチル）フェニル］−４（１Ｈ）−ピリミジノン、Ｎ−（１，４−ジヒドロ−６−メチル−４−オキソ−２−ピリミジニル）グリシン、６−メチル−２−（３−ピリジニル）−４（１Ｈ）−ピリミジノン、６−メチル−２−［４−（トリフルオロメチル）フェニル］−４（１Ｈ）−ピリミジノンBy inhibiting plasminogen activator inhibitor (PAI-1), which is a potent inhibitor of PA, we can maintain the activity of PA and reduce the incidence of thrombosis or reocclusion. As a result of diligent research focusing on the fact that it can be made, it was found that the following pyrimidine derivatives or pharmaceutically acceptable salt compounds or solvates thereof meet the above purpose.
The present invention has been made based on such findings, and has excellent PA activity promoting action and PAI-1 inhibitory activity, and can be administered orally, and has a fibrinolysis promoting action, a thrombolytic action and an antithrombotic action. A composition is provided.
That is, the present invention relates to the following inventions.
[1] As an active ingredient, the general formula (1)

[Where:
(1) a is
(I) a1-lower alkylene group -Y- (2)
(here,
▲ 1 ▼ a1 is
1. Carboxy group
2. Dicarboxymethyl group
3. halogen
4). Phenyl group
(Here, the phenyl group is a methyl group, a cyano group,
Methoxy group, halogen, nitro group, carboxy
Substituted with a lower alkoxycarbonyl group
Means a good phenyl group)
5. 4-morpholinyl group
6.4-pyridinyl group
7). Dimethylamino group
8). Lower alkoxycarbonyl group
9. (Phenylmethoxy) carbonyl group
(Where phenyl is substituted with halogen
Means good phenyl)
10. Di (lower alkoxycarbonyl) methyl group
(2) Y is

(Where Y1 is hydrogen, a carboxymethyl group, (lower
Alkoxycarbonyl) means methyl group)
2. -O-arylene group- (4)
(Here, the arylene group is a 1,4-phenylene group,
2,6-naphthalenediyl group, [1,1′-biphenyl]-
4,4'-diyl group)
Means)
(Ii) 3-pyridinyl group, 4- (trifluoromethyl) phenyl group,
4-hydroxyphenyl group, 4′-hydroxy [1,1′-biphenyl
Ru] -4-yl group, 6-hydroxy-2-naphthalenyl group, 2-naphth
Talenyl group
(Iii) (Carboxyphenylmethyl) amino group
(Wherein phenyl may be substituted with a hydroxyl group
Means phenyl)
(2) b is
(I) Hydroxyl group
(Ii) b1-lower alkylene group -O- (5)
(Where b1 is
(1) Carboxy group
(2) Dicarboxymethyl group
(3) Halogen
(4) Phenyl group
(Here, the phenyl group is a methyl group, a cyano group,
Methoxy group, halogen, nitro group, carboxyl
Si group, lower alkoxycarbonyl group, aceto
Meaning a phenyl group which may be substituted with a xy group)
(5) Cyclohexyl group
(6) 4-morpholinyl group
(7) Pyridinyl group
(8) Lower alkoxycarbonyl group
(9) Di (lower alkoxycarbonyl) methyl group

Means)
(3) c is
(1) Phenyl group
(Here, phenyl group is amino group, nitro group, methoxy group
Meaning a phenyl group which may be substituted with
(2) Tertiary butyl group
(3) Trifluoromethyl group
(4) c1-O-CO- (7)
(Where c1 is hydrogen, (lower alkoxycarbo
Nyl) means lower alkyl)
(5) 3-furanyl group
(6) Formyl group
(7) Dimethoxymethyl group
(8) Cyclopentane ring together with 5-position carbon of pyrimidine ring
Form
▲ 9 ▼ Methyl group
(However,
(1) When c is a methyl group, a is
(I) a1-lower alkylene group -Y- (2)
(here,
▲ 1 ▼ a1 is
1. Carboxy group
2. Lower alkoxycarbonyl group
(2) Y is

(Where Y1 is hydrogen)
2. -O-arylene group- (4)
(Wherein the arylene group is [1,1′-biphenyl]-
4,4'-diyl group)
Means)
(Ii) 3-pyridinyl group
(Iii) 4- (trifluoromethyl) phenyl group
(Iv) (Carboxyphenylmethyl) amino group
(Here, phenyl is phenyl which may be substituted with a hydroxyl group.
Means)
(V) 4′-hydroxy [1,1′-biphenyl] -4-yl group
(2) When c is a tertiary butyl group, a is
(I) a1-lower alkylene group -Y- (2)
(here,
▲ 1 ▼ a1 is
1. Carboxy group
2. Lower alkoxycarbonyl group
3.4-morpholinyl group
(2) Y is
1. -O-arylene group- (4)
(Here, the arylene group is a 1,4-phenylene group.
means)
Means)
(Ii) 4-hydroxyphenyl group
Means)
Means]
Or a pharmaceutically acceptable salt compound thereof or a solvate thereof, a pharmaceutical composition for treating thrombosis.
[2] The pharmaceutical composition according to the above [1], wherein the pharmaceutical composition is a thrombolytic agent.
[3] The pharmaceutical composition according to the above [1], wherein the pharmaceutical composition is an antithrombotic agent.
[4] A compound represented by the formula (1) of the above [1] for use as a pharmaceutical composition, or a pharmaceutically acceptable salt compound thereof or a solvate thereof.
[5] A compound represented by the formula (1) of [1], or a pharmaceutically acceptable salt compound or a solvate thereof for producing a pharmaceutical composition for treating thrombosis use.
[6] Treating thrombosis comprising administering to a subject an effective amount of the compound represented by formula (1) of [1] above, or a pharmaceutically acceptable salt compound thereof, or a solvate thereof. Method.
[7] In the formula (1), c is a phenyl group (wherein the phenyl group means a phenyl group which may be substituted with an amino group, a nitro group or a methoxy group), a tertiary butyl group And a compound which is a trifluoromethyl group, or a pharmaceutically acceptable salt compound or a solvate thereof.
[here,
(1) a is
(I) a1-lower alkylene group -Y- (2)
(here,
▲ 1 ▼ a1 is
1. Carboxy group
2. Dicarboxymethyl group
3. halogen
4). Phenyl group
(Here, the phenyl group is a methyl group, a cyano group,
Methoxy group, halogen, nitro group, carboxy
Substituted with a lower alkoxycarbonyl group
Means a good phenyl group)
5. 4-morpholinyl group
6.4-pyridinyl group
7). Dimethylamino group
8). Lower alkoxycarbonyl group
9. (Phenylmethoxy) carbonyl group
(Wherein phenyl may be substituted with halogen
Means phenyl)
10. Di (lower alkoxycarbonyl) methyl group
(2) Y is

(Where Y1 is hydrogen, a carboxymethyl group, (lower
Alkoxycarbonyl) means methyl group)
2. -O-arylene group- (4)
(Here, the arylene group is a 1,4-phenylene group,
2,6-naphthalenediyl group, [1,1′-biphenyl]-
4,4'-diyl group)
Means)
(Ii) 3-pyridinyl group, 4- (trifluoromethyl) phenyl group,
4-hydroxyphenyl group, 4′-hydroxy [1,1′-biphenyl
Ru] -4-yl group, 6-hydroxy-2-naphthalenyl group, 2-naphth
Talenyl group
(Iii) (Carboxyphenylmethyl) amino group
(Here, phenyl is phenyl which may be substituted with a hydroxyl group.
Means)
(2) b is
(I) Hydroxyl group
(Ii) b1-lower alkylene group -O- (5)
(Where b1 is
(1) Carboxy group
(2) Dicarboxymethyl group
(3) Halogen
(4) Phenyl group
(Here, the phenyl group is a methyl group, a cyano group,
Methoxy group, halogen, nitro group, carboxy
Group, lower alkoxycarbonyl group, acetoxy group
Meaning a phenyl group which may be substituted with
(5) Cyclohexyl group
(6) 4-morpholinyl group
(7) Pyridinyl group
(8) Lower alkoxycarbonyl group
(9) Di (lower alkoxycarbonyl) methyl group
Means)
(However,
(1) 6-phenyl-2- [4- (trifluoromethyl) phenyl]-
Excludes 4 (1H) -pyrimidinone
(2) When c is a tertiary butyl group, a is
(I) a1-lower alkylene group -Y- (2)
(here,
▲ 1 ▼ a1 is
1. Carboxy group
2. Lower alkoxycarbonyl group
3.4-morpholinyl group
(2) Y is
1. -O-arylene group- (4)
(Here, the arylene group is a 1,4-phenylene group.
means)
Means)
(Ii) 4-hydroxyphenyl group
Means)
Means]
[8] In the formula (1), c is
(1) c1-O-CO- (7)
(Where c1 is hydrogen, (lower alkoxycarbonyl) lower al
Means a kill group)
(2) 3-furanyl group
(3) Formyl group
(4) Dimethoxymethyl group
Or a pharmaceutically acceptable salt compound or a solvate thereof.
[here,
(1) a is
(I) a1-lower alkylene group -Y- (2)
(here,
▲ 1 ▼ a1 is
1. Carboxy group
2. Lower alkoxycarbonyl group
3. Phenyl group
(2) Y is —O-arylene group— (4)
(Wherein the arylene group is 2,6-naphthalene
Meaning yl group)
Means)
(Ii) 6-hydroxy-2-naphthalenyl group
(2) b is
(I) Hydroxyl group
(Ii) b1-lower alkylene group -O- (5)
(Where b1 is a carboxy group, lower alkoxy
Means carbonyl group)
Means]
[9] A compound in which, in the general formula (1), c forms a cyclopentane ring together with the 5-position carbon of the pyrimidine ring, or a pharmaceutically acceptable salt compound thereof or a solvent thereof Japanese products.
[here,
(1) a is
(I) a1-lower alkylene group -Y- (2)
(here,
▲ 1 ▼ a1 is
1. Carboxy group
2. Lower alkoxycarbonyl group
(2) Y is —O-arylene group— (4)
(Here, the arylene group is 2,6-naphthalene.
Meaning diyl group)
Means)
(Ii) 6-hydroxy-2-naphthalenyl group
(2) b is
(I) Hydroxyl group
(Ii) b1-lower alkylene group -O- (5)
(Where b1 is a carboxy group, lower alkoxy
Means carbonyl group)
Means]
[10] A compound in which c is a methyl group in the general formula (1), or a pharmaceutically acceptable salt compound or a solvate thereof.
[here,
(1) a is
(I) a1-lower alkylene group -Y- (2)
(here,
▲ 1 ▼ a1 is
1. Carboxy group
2. Lower alkoxycarbonyl group
(2) Y is

(Where Y1 means hydrogen)
2. -O-arylene group- (4)
(Wherein the arylene group is [1,1′-biphenyl
L] -4,4′-diyl group)
Means)
(Ii) 3-pyridinyl group
(Iii) 4- (trifluoromethyl) phenyl group
(Iv) (Carboxyphenylmethyl) amino group
(Here, phenyl is phenyl which may be substituted with a hydroxyl group.
Means)
(V) 4′-hydroxy [1,1′-biphenyl] -4-yl group
(2) b is
(I) Hydroxyl group
(Ii) b1-lower alkylene group -O- (5)
(Where b1 is
1. Carboxy group
2. Lower alkoxycarbonyl group

Means)
(However, N- (1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl) glycine, 6-methyl-2- (3-pyridinyl) -4 (1H) -pyrimidinone, 6-methyl-2) -[4- (trifluoromethyl) phenyl] -4 (1H) -pyrimidinone is excluded)
Means]
[11] A compound selected from the following group of compounds, or a pharmaceutically acceptable salt compound thereof or a solvate thereof.
6-phenyl-2- (3-pyridinyl) -4 (1H) -pyrimidinone sodium salt, [[6-Phenyl-2- [4- (trifluoromethyl) phenyl] -4-pyrimidinyl] oxy] acetic acid methyl ester, [[6-phenyl-2- [4- (trifluoromethyl) phenyl] -4-pyrimidinyl] oxy] acetic acid, 6-[[6-phenyl-2- [4- (trifluoromethyl) phenyl] -4-pyrimidinyl] oxy] hexanoic acid, [5-[[6-phenyl-2- [4- (trifluoromethyl) phenyl] -4-pyrimidinyl] oxy] pentyl] propanedioic acid, 2- (4-hydroxyphenyl) -6-phenyl-4 (1H) -pyrimidinone, [[2- [4- (2-methoxy-2-oxoethoxy) phenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid methyl ester, [[2- [4- (carboxymethoxy) phenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid, 4- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenol, [4- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] acetic acid sodium salt, [4- (1, 4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) phenoxy] acetic acid, [4- [4-[(2-chlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] phenoxy] acetic acid sodium salt, 4- [4- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] butanoic acid ethyl ester, 4- [4- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] butanoic acid sodium salt, 4- [4- (1, 4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) phenoxy] butanoic acid ethyl ester, 4- [4- (1, 4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) phenoxy] butanoic acid, 4- [4- [4-[(2-chlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] phenoxy] butanoic acid sodium salt, 4- [4- [4-[(2-fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] phenoxy] butanoic acid sodium salt, 4- [4- [4- (cyclohexylmethoxy) -6-phenyl-2-pyrimidinyl] phenoxy] butanoic acid sodium salt, 6- [4- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] hexanoic acid, 6- [4- (1, 4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) phenoxy] hexanoic acid, [3- [4- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] propyl] propanedioic acid diethyl ester, [3- [4- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] propyl] propanedioic acid, [3- [4- [4-[(2-fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] phenoxy] propyl] propanedioic acid, [3- [4- [4- (cyclohexylmethoxy) -6-phenyl-2-pyrimidinyl] phenoxy] propyl] propanedioic acid, 4- [2- [4- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] ethyl] morpholine hydrochloride, 2- [4- [2- (4-morpholinyl) ethoxy] phenyl] -6-phenyl-4 (1H) -pyrimidinone, 4- [2- [4- [4-[(2-fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] phenoxy] ethyl] morpholine, 4- [2- [4- [4- (cyclohexylmethoxy) -6-phenyl-2-pyrimidinyl] phenoxy] ethyl] morpholine, 2- (4′-hydroxy [1, 1'-biphenyl] -4-yl) -6-phenyl-4 (1H) -pyrimidinone, [[2- [4 ′-(2-methoxy-2-oxoethoxy) [1, 1′-biphenyl] -4-yl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid methyl ester, [[2- [4 ′-(carboxymethoxy) [1, 1′-biphenyl] -4-yl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid, N- [1, 4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl] glycine, N- (carboxymethyl) -N- [4- (2-ethoxy-2-oxoethoxy) -6-phenyl-2-pyrimidinyl] glycine ethyl ester, N- [4- (carboxymethoxy) -6-phenyl-2-pyrimidinyl] -N- (carboxymethyl) glycine disodium salt, α-[(1, 4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) amino] -4-hydroxybenzeneacetic acid, 2- (2-naphthalenyl) -6-phenyl-4 (1H) -pyrimidinone, 2- (6-hydroxy-2-naphthalenyl) -6- (4-nitrophenyl) -4 (1H) -pyrimidinone, 2- (6-hydroxy-2-naphthalenyl) -6- (3-nitrophenyl) -4 (1H) -pyrimidinone, 6- (4-aminophenyl) -2- (6-hydroxy-2-naphthalenyl) -4 (1H) -pyrimidinone hydrochloride, 6- (3-aminophenyl) -2- (6-hydroxy-2-naphthalenyl) -4 (1H) -pyrimidinone, 2- (6-hydroxy-2-naphthalenyl) -6- (4-methoxyphenyl) -4 (1H) -pyrimidinone, 2- (6-hydroxy-2-naphthalenyl) -6-phenyl-4 (1H) -pyrimidinone, [[2- (6-hydroxy-2-naphthalenyl) -6- (4-nitrophenyl) -4-pyrimidinyl] oxy] acetic acid methyl ester, [[2- (6-Hydroxy-2-naphthalenyl) -6- (4-nitrophenyl) -4-pyrimidinyl] oxy] acetic acid, [[2- (6-hydroxy-2-naphthalenyl) -6- (3-nitrophenyl) -4-pyrimidinyl] oxy] acetic acid methyl ester, [[2- (6-Hydroxy-2-naphthalenyl) -6- (3-nitrophenyl) -4-pyrimidinyl] oxy] acetic acid, [[6- (4-aminophenyl) -2- (6-hydroxy-2-naphthalenyl) -4-pyrimidinyl] oxy] acetic acid methyl ester hydrochloride, [[6- (4-aminophenyl) -2- (6-hydroxy-2-naphthalenyl) -4-pyrimidinyl] oxy] acetic acid, [[6- (3-aminophenyl) -2- (6-hydroxy-2-naphthalenyl) -4-pyrimidinyl] oxy] acetic acid methyl ester, [[6- (3-aminophenyl) -2- (6-hydroxy-2-naphthalenyl) -4-pyrimidinyl] oxy] acetic acid, [[2- (6-Hydroxy-2-naphthalenyl) -6-phenyl-4-pyrimidinyl] oxy] acetic acid methyl ester, [[2- (6-hydroxy-2-naphthalenyl) -6-phenyl-4-pyrimidinyl] oxy] acetic acid ethyl ester, [[2- (6-hydroxy-2-naphthalenyl) -6-phenyl-4-pyrimidinyl] oxy] acetic acid, 6-phenyl-2- [6- (phenylmethoxy) -2-naphthalenyl] -4 (1H) -pyrimidinone, 4-[[6-phenyl-2- [6- (phenylmethoxy) -2-naphthalenyl] -4-pyrimidinyl] oxy] butanoic acid ethyl ester, 4-[[6-phenyl-2- [6- (phenylmethoxy) -2-naphthalenyl] -4-pyrimidinyl] oxy] butanoic acid sodium salt, 4-[[2- (6-hydroxy-2-naphthalenyl) -6-phenyl-4-pyrimidinyl] oxy] butanoic acid ethyl ester, 4-[[2- (6-hydroxy-2-naphthalenyl) -6-phenyl-4-pyrimidinyl] oxy] butanoic acid disodium salt, 6- [4-[(2-fluorophenyl) methoxy] -6- (4-nitrophenyl) -2-pyrimidinyl] -2-naphthalenol, 6- [4-[(2-fluorophenyl) methoxy] -6- (3-nitrophenyl) -2-pyrimidinyl] -2-naphthalenol, 6- [4-[(2-fluorophenyl) methoxy] -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenol, 6- [4-[(2-fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenol, 6- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenol, 4- [2-[[6-phenyl-2- [6- (phenylmethoxy) -2-naphthalenyl] -4-pyrimidinyl] oxy] ethyl] morpholine hydrochloride, 6- [4- [2- (4-morpholinyl) ethoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenol hydrochloride, [[2- [6- (2-chloroethoxy) -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid sodium salt, [[2- [6- (3-chloropropoxy) -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid sodium salt, [[2- [6- (2-methoxy-2-oxoethoxy) -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid methyl ester, [[2- [6- (carboxymethoxy) -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid, [[6- (1, 4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] acetic acid, [[2- [6- (2-methoxy-2-oxoethoxy) -2-naphthalenyl] -6- (4-nitrophenyl) -4-pyrimidinyl] oxy] acetic acid methyl ester, [[2- [6- (carboxymethoxy) -2-naphthalenyl] -6- (4-nitrophenyl) -4-pyrimidinyl] oxy] acetic acid, [[6- [1, 4-dihydro-6- (4-nitrophenyl) -4-oxo-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid, [[2- [6- (2-methoxy-2-oxoethoxy) -2-naphthalenyl] -6- (3-nitrophenyl) -4-pyrimidinyl] oxy] acetic acid methyl ester, [[2- [6- (carboxymethoxy) -2-naphthalenyl] -6- (3-nitrophenyl) -4-pyrimidinyl] oxy] acetic acid, [[6- [1, 4-dihydro-6- (3-nitrophenyl) -4-oxo-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid, [[6- [6- (4-aminophenyl) -1, 4-dihydro-4-oxo-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid, [[6- [6- (3-Aminophenyl) -1, 4-dihydro-4-oxo-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid, [[6- (4-aminophenyl) -2- [6- (2-methoxy-2-oxoethoxy) -2-naphthalenyl] -4-pyrimidinyl] oxy] acetic acid methyl ester, [[6- (4-aminophenyl) -2- [6- (carboxymethoxy) -2-naphthalenyl] -4-pyrimidinyl] oxy] acetic acid, [[6- (3-aminophenyl) -2- [6- (2-methoxy-2-oxoethoxy) -2-naphthalenyl] -4-pyrimidinyl] oxy] acetic acid methyl ester, [[6- (3-aminophenyl) -2- [6- (carboxymethoxy) -2-naphthalenyl] -4-pyrimidinyl] oxy] acetic acid, [[6- [4- (2-methoxy-2-oxoethoxy) -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid methyl ester, [[6- [4- (carboxymethoxy) -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid, 4-[[2- [6- (carboxymethoxy) -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] butanoic acid disodium salt, [[6- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid, [[6- [4-[(2-fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid, [[6- [4-[(2-fluorophenyl) methoxy] -6- (4-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid sodium salt, [[6- [4-[(2-fluorophenyl) methoxy] -6- (3-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid sodium salt, [[6- [4-[(2-fluorophenyl) methoxy] -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid, [[6- [4- [2- (4-morpholinyl) ethoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid ethyl ester, [[6- [4- [2- (4-morpholinyl) ethoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid sodium salt, 4-[[6- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[6- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 4-[[6- (1, 4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[6- (1, 4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] butanoic acid, 4-[[6- [4- (carboxymethoxy) -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid disodium salt, 4-[[2- [6- (3-carboxypropoxy) -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] butanoic acid, 4-[[6- [4- [2- (4-morpholinyl) ethoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid, 4-[[6- [4-phenyl-6-[(3-pyridinyl) methoxy] -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid, 4-[[6- [4-phenyl-6-[(4-pyridinyl) methoxy] -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid, 4-[[[2- [6- (3-carboxypropoxy) -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] methyl] benzoic acid, 4-[[6- [4-[(2-chlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 4-[[6- [4-[(3-chlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 4-[[6- [4-[(4-chlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 4-[[6- [4-[(2, 6-dichlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 4-[[6- [4-[(2-fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 4-[[6- [4-[(3-fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 4-[[6- [4-[(4-fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 4-[[6- [4-[(2, 6-difluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 4-[[6- [4-[(2, 4-difluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 4-[[6- [4-[(pentafluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 4-[[6- [4-[(2-bromophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 4-[[6- [4-[(4-bromophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 4-[[6- [4-[(2-fluorophenyl) methoxy] -6- (4-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 4-[[6- [4-[(2-fluorophenyl) methoxy] -6- (3-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 4-[[6- [4-[(2-fluorophenyl) methoxy] -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 4-[[6- [4-[(2-methylphenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 4-[[6- [4-[(2-nitrophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 4-[[6- [4-[(2-cyanophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 4-[[6- [4-[(2-methoxyphenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 4-[[6- [4-[[2- (acetyloxy) phenyl] methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[6- [4- (3-chloropropoxy) -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 5-[[6- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] pentanoic acid, 5-[[6- (1, 4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] pentanoic acid, 5-[[2- [6-[(5-ethoxy-5-oxopentyl) oxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] pentanoic acid ethyl ester, 5-[[2- [6- (4-carboxybutoxy) -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] pentanoic acid, 6-[[6- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid, 6-[[6- (1, 4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] hexanoic acid, 6-[[2- [6-[(5-carboxypentyl) oxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] hexanoic acid, 6-[[6- [4-[(2-fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt, 6-[[6- [4-[(2-fluorophenyl) methoxy] -6- (4-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt, 6-[[6- [4-[(2-fluorophenyl) methoxy] -6- (3-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt, 6-[[6- [4-[(2-fluorophenyl) methoxy] -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt, 7-[[6- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] heptanoic acid sodium salt, 7-[[6- (1, 4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] heptanoic acid, [3-[[6- [4-[(2-fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] propyl] propanedioic acid, [3-[[6- [4-[(2-fluorophenyl) methoxy] -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] propyl] propanedioic acid, [5-[[6- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, [5-[[6- (1, 4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid, [5-[[2- [6-[(6, 6-dicarboxyhexyl) oxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] pentyl] propanedioic acid, [[6-Phenyl-2- [6- (phenylmethoxy) -2-naphthalenyl] -4-pyrimidinyl] oxy] acetic acid potassium salt, [[2- [6-[(2-methylphenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid sodium salt, [[2- [6-[(2-cyanophenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid sodium salt, [[2- [6-[(2-methoxyphenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid sodium salt, [[2- [6-[(2-chlorophenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid sodium salt, [[2- [6-[(2-fluorophenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid sodium salt, [[2- [6-[(2, 6-difluorophenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid sodium salt, 4-[[2- [6-[(2, 6-difluorophenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] butanoic acid sodium salt, 4- [2-[[2- [6-[(2, 6-difluorophenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] ethyl] morpholine hydrochloride, [[2- [6-[(2-nitrophenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid sodium salt, 4-[[[6- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] methyl] benzoic acid, 4- [2-[[6- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] ethyl] morpholine, 2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-phenyl-4 (1H) -pyrimidinone hydrochloride, 4- [2-[[6- [4-[(2-fluorophenyl) methoxy] -6- (4-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] ethyl] morpholine, 6- (4-aminophenyl) -2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -4 (1H) -pyrimidinone dihydrochloride, 4- [2-[[6- [4-[(2-fluorophenyl) methoxy] -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] ethyl] morpholine hydrochloride, 6- (4-methoxyphenyl) -2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -4 (1H) -pyrimidinone hydrochloride, 4- [2-[[6- [4-[(2-fluorophenyl) methoxy] -6- (3-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] ethyl] morpholine hydrochloride, 6- (3-aminophenyl) -2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -4 (1H) -pyrimidinone dihydrochloride, [[2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid ethyl ester hydrochloride, [[2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid, 4-[[2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] butanoic acid sodium salt, 4- [2-[[2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] ethyl] morpholine dihydrochloride, 4-phenyl-6- (phenylmethoxy) -2- [6-[(4-pyridinyl) methoxy] -2-naphthalenyl] pyrimidine hydrochloride, N, N-dimethyl-3-[[6- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] -1-propanamine hydrochloride, 2- [6- [3- (dimethylamino) propoxy] -2-naphthalenyl] -6-phenyl-4 (1H) -pyrimidinone hydrochloride, 2- (4-Hydroxyphenyl) -6- (1, 1-dimethylethyl) -4 (1H) -pyrimidinone, 4- [4- [4- (1, 1-dimethylethyl) -6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] butanoic acid, 4- [4- [6- (1, 1-dimethylethyl) -1, 4-dihydro-4-oxo-2-pyrimidinyl] phenoxy] butanoic acid ethyl ester, 4- [4- [4- (1, 1-dimethylethyl) -6-[(2-fluorophenyl) methoxy] -2-pyrimidinyl] phenoxy] butanoic acid, 4- [4- [4- (cyclohexylmethoxy) -6- (1, 1-dimethylethyl) -2-pyrimidinyl] phenoxy] butanoic acid, 4- [2- [4- [4- (1, 1-dimethylethyl) -6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] ethyl] morpholine hydrochloride, 6- (1, 1-dimethylethyl) -2- [4- [2- (4-morpholinyl) ethoxy] phenyl] -4 (1H) -pyrimidinone, 4- [2- [4- [4- (1, 1-dimethylethyl) -6-[(2-fluorophenyl) methoxy] -2-pyrimidinyl] phenoxy] ethyl] morpholine hydrochloride, 4- [2- [4- [4- (cyclohexylmethoxy) -6- (1, 1-dimethylethyl) -2-pyrimidinyl] phenoxy] ethyl] morpholine hydrochloride, 2- (4-hydroxyphenyl) -6- (trifluoromethyl) -4 (1H) -pyrimidinone, 4- [4- (phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] phenol, 4- [4- [4- (phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] butanoic acid ethyl ester, 4- [4- [1, 4-dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] butanoic acid ethyl ester, 4- [4- [4- (cyclohexylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] butanoic acid sodium salt, [3- [4- [4- (phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] propyl] propanedioic acid diethyl ester, [3- [4- [1, 4-dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] propyl] propanedioic acid diethyl ester, [3- [4- [4- (cyclohexylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] propyl] propanedioic acid, 4- [2- [4- [4- (phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] ethyl] morpholine hydrochloride, 4- [2- [4- [4- (cyclohexylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] ethyl] morpholine, 2- (6-hydroxy-2-naphthalenyl) -6- (trifluoromethyl) -4 (1H) -pyrimidinone, [[2- (6-hydroxy-2-naphthalenyl) -6- (trifluoromethyl) -4-pyrimidinyl] oxy] acetic acid methyl ester, [[2- (6-hydroxy-2-naphthalenyl) -6- (trifluoromethyl) -4-pyrimidinyl] oxy] acetic acid, 6- [4- (phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenol, [[2- [6- (2-methoxy-2-oxoethoxy) -2-naphthalenyl] -6- (trifluoromethyl) -4-pyrimidinyl] oxy] acetic acid methyl ester, [[2- [6- (carboxymethoxy) -2-naphthalenyl] -6- (trifluoromethyl) -4-pyrimidinyl] oxy] acetic acid, [[6- [4- (phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid ethyl ester, [[6- [4- (phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid sodium salt, [[6- [1, 4-dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid ethyl ester, [[6- [1, 4-dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid, [[6- [4-[(2-fluorophenyl) methoxy] -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid, 4-[[6- [4- (phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[6- [1, 4-dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester, 4-[[6- [1, 4-dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid, 4-[[6- [4-[(2-fluorophenyl) methoxy] -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt, 6-[[6- [1, 4-dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester, 6-[[6- [1, 4-dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid, [5-[[6- [1, 4-dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, 4- [2-[[6- [4- (phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] ethyl] morpholine, 2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6- (trifluoromethyl) -4 (1H) -pyrimidinone, 4- [2-[[6- [4-[(2-fluorophenyl) methoxy] -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] ethyl] morpholine, 6- (dimethoxymethyl) -2- [6- (phenylmethoxy) -2-naphthalenyl] -4 (1H) -pyrimidinone, 1, 6-dihydro-6-oxo-2- [6- (phenylmethoxy) -2-naphthalenyl] -4-pyrimidinecarboxaldehyde, 1, 6-dihydro-6-oxo-2- [6- (phenylmethoxy) -2-naphthalenyl] -4-pyrimidinecarboxylic acid, 1, 6-dihydro-2- (6-hydroxy-2-naphthalenyl) -6-oxo-4-pyrimidinecarboxylic acid, 6- (2-methoxy-2-oxoethoxy) -2- [6- (2-methoxy-2-oxoethoxy) -2-naphthalenyl] -4-pyrimidinecarboxylic acid 2-methoxy-2-oxoethyl ester, 6- (2-methoxy-2-oxoethoxy) -2- [6- (phenylmethoxy) -2-naphthalenyl] -4-pyrimidinecarboxylic acid 2-methoxy-2-oxoethyl ester, 6- (carboxymethoxy) -2- [6- (carboxymethoxy) -2-naphthalenyl] -4-pyrimidinecarboxylic acid, 6- (carboxymethoxy) -2- (6-hydroxy-2-naphthalenyl) -4-pyrimidinecarboxylic acid, 6- (3-furanyl) -2- (6-hydroxy-2-naphthalenyl) -4 (1H) -pyrimidinone, [[6- (3-furanyl) -2- [6- (2-methoxy-2-oxoethoxy) -2-naphthalenyl] -4-pyrimidinyl] oxy] acetic acid methyl ester, [[6- [4- (carboxymethoxy) -6- (3-furanyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid, 1, 5, 6, 7-tetrahydro-2- (6-hydroxy-2-naphthalenyl) -4H-cyclopentapyrimidin-4-one, [[6- [6, 7-dihydro-4- (2-methoxy-2-oxoethoxy) -5H-cyclopentapyrimidin-2-yl] -2-naphthalenyl] oxy] acetic acid methyl ester, [[6- [4- (carboxymethoxy) -6,6 7-dihydro-5H-cyclopentapyrimidin-2-yl] -2-naphthalenyl] oxy] acetic acid, N- [4- (2-ethoxy-2-oxoethoxy) -6-methyl-2-pyrimidinyl] glycine, N- [4- (carboxymethoxy) -6-methyl-2-pyrimidinyl] glycine, [[6-Methyl-2- (3-pyridinyl) -4-pyrimidinyl] oxy] acetic acid methyl ester, [[6-Methyl-2- (3-pyridinyl) -4-pyrimidinyl] oxy] acetic acid, [[6-Methyl-2- [4- (trifluoromethyl) phenyl] -4-pyrimidinyl] oxy] acetic acid methyl ester, [[6-Methyl-2- [4- (trifluoromethyl) phenyl] -4-pyrimidinyl] oxy] acetic acid, 6-[[6-Methyl-2- [4- (trifluoromethyl) phenyl] -4-pyrimidinyl] oxy] hexanoic acid sodium salt, 4- [4- (1-cyclohexyl-1H-tetrazol-5-yl) butoxy] -6-methyl-2- [4- (trifluoromethyl) phenyl] pyrimidine, α-[(1, 4-dihydro-6-methyl-4-oxo-2-pyrimidinyl) amino] -4-hydroxybenzeneacetic acid, 2- (4′-hydroxy [1, 1'-biphenyl] -4-yl) -6-methyl-4 (1H) -pyrimidinone, [[2- (4′-hydroxy [1, 1′-biphenyl] -4-yl) -6-methyl-4-pyrimidinyl] oxy] acetic acid methyl ester, [[2- (4′-hydroxy [1, 1′-biphenyl] -4-yl) -6-methyl-4-pyrimidinyl] oxy] acetic acid, [[2- [4 ′-(2-methoxy-2-oxoethoxy) [1, 1′-biphenyl] -4-yl] -6-methyl-4-pyrimidinyl] oxy] acetic acid methyl ester, [[2- [4 ′-(carboxymethoxy) [1, 1′-biphenyl] -4-yl] -6-methyl-4-pyrimidinyl] oxy] acetic acid
[12] The compound according to any one of [7] to [11], or a pharmaceutically acceptable salt compound or a solvate thereof, for use as a pharmaceutical composition.
[13] The compound according to any one of [7] to [11], or a pharmaceutically acceptable salt compound or solvate thereof for use as a thrombolytic agent or antithrombotic agent.
[14] The compound according to any one of the above [7] to [11] for producing a pharmaceutical composition for treating thrombosis, or a pharmaceutically acceptable salt compound thereof or a solvate thereof object.
[15] Thrombosis comprising administering to a subject an effective amount of the compound according to any of [7] to [11] above, or a pharmaceutically acceptable salt compound thereof, or a solvate thereof How to treat.
[16] A compound selected from the following group of compounds for use as a thrombolytic agent or antithrombotic agent, or a pharmaceutically acceptable salt compound thereof, or a solvate thereof.
6-phenyl-2- [4- (trifluoromethyl) phenyl] -4 (1H) -pyrimidinone, N- (1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl) glycine, 6-methyl -2- (3-pyridinyl) -4 (1H) -pyrimidinone, 6-methyl-2- [4- (trifluoromethyl) phenyl] -4 (1H) -pyrimidinone

［式中，ａ，ｂ，ｃは前記の通りである。］
以下に、本発明化合物の代表的製造方法を示す。但し、これらは例であり、その他の既知の方法を用いる事も出来る。
ピリミジン誘導体の一般的な合成法として、［Ｇ．Ｗ．Ｋｅｎｎｅｒ，”Ｐｙｒｉｍｉｄｉｎｅ ａｎｄ Ｉｔｓ Ｄｅｒｉｖａｔｉｖｅｓ”，ｉｎ Ｒ．Ｃ．Ｅｌｄｅｒｆｉｅｌｄ，”Ｈｅｔｅｒｏｃｙｃｌｉｃ ｃｏｍｐｏｕｎｄ”，６，２３４．，Ｊｏｈｎ Ｗｉｌｌｅｙ（１９５７）］が知られているが、下記スキームＡにより示す事が出来る。

［式中、Ａ，Ｃは本発明の前記した置換基ａ，ｃ自体を，或いはこれらａ，ｃに変換出来得る置換基である事をそれぞれ意味する。点線の半弧は環を形成しても良い事を意味する。Ｗは結合，又は

を意味する。Ｒは低級アルキル基を意味する。］
式（８）で示されるアミジン又はグアニジン若しくは其れ等の酸塩と、式（９）で示されるβ−ケトエステル、或いは其れ等の等価体を溶媒中、或いは無溶媒で、適当な塩基の存在下、室温から１５０℃で反応させる事により、式（１０）で示されるピリミジン誘導体を製造する事ができる。溶媒として、例えばメタノール、エタノール、或いはアセトニトリルなどが挙げられる。又、塩基として、ナトリウム、アルコキシアルカリ金属（例えばナトリウムメトキシド）或いは、炭酸カリウム、炭酸ナトリウム、水酸化ナトリウムなどの無機塩基、或いはトリエチルアミン、ピリジン、ピペリジンなどの有機塩基が挙げられる。
式（１０）で示される化合物はピリミジノール体として表記されているが、このものはピリミジノン体と互変異性の関係にあり、特に断らない限り本発明において互変異性体の両方を示し、いずれの異性体も本発明の範囲に含まれる。
前記式（１０）に於いて、ｃがカルボキシ基である化合物は、下記スキームＢに従って合成することも出来る。

［式中，Ａ，Ｗは前記した通りである。Ｒ，Ｒ１は低級アルキル基をそれ
ぞれ意味する。］
式（１３）で示されるピリミジン誘導体を塩酸、蟻酸等の酸で処理し式（１４）で示されるアルデヒド体に転化した後、過マンガン酸塩等の酸化剤を用いて酸化する事によって式（１０−１）で示される化合物が製造できる。
スキームＡ、Ｂに於いて式（８）で示される原料化合物は、下記スキームＣに示す公知方法によって製造できる。

［式中，Ａは前記した通りである。］
式（８−１）で示されるアミジノ化合物はＰｉｎｎｅｒ反応によって合成される。つまり、式（１５）で示されるニトリル体を塩化水素等の酸の存在下、低級アルコールと反応させ、イミノエーテル化した後、アンモニアで処理する事によって、または同様に、ニトリル体をナトリウムメトキシド等の塩基を触媒として、低級アルコールと反応させた後、塩化アンモニウムを作用させる事によっても合成する事ができる。ここで、出発物質となるニトリル体は、対応するジアゾニウム塩或いは、ハロゲン化体とシアン化銅とから（Ｊ．Ｏ．Ｃ．１９４７，１６０^〜等）或いは、対応するカルボン酸アミドの塩化チオニルや無水酢酸等による脱水等から合成出来る。式（１６）で示されるアミン化合物からは、シアナミドとの反応（特開昭５７−１７９１４６，米国特許３４０６１８５号）等から式（８−２）で示されるグアニジノ化合物が得られる。シアナミドの代わりにＯ−アルキルイソ尿素等を使用する事もできる。
（ＳＫＷ Ｔｒｏｓｔｂｅｒｇ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ；”ＣＹＡＮＡＭＩＤＥ：Ｎｅｕｅｒｅ Ｂｅｉｓｐｉｅｌｅ ｆｕｒ ｄｉｅ Ｓｙｎｔｈｅｓｅｒｅａｋｔｉｖｅｒ Ｚｗｉｓｃｈｅｎｐｒｏｄｕｃｔｅ ｕｎｄ ｂｉｏｌｏｇｉｓｃｈＡｋｔｉｖｅｒ Ｓｕｂｓｔａｎｚｅｎ”）
前記した式（１０）で示される化合物のピリミジン環上及び、側鎖Ａ中の水酸基は下記スキームＤに従って他の官能基に変換することが出来る。

［式中，ａ２，ｂ２は本発明の前記した置換基ａ１，ｂ１自体を，
或いはこれらａ１，ｂ１に変換出来得る置換基であることをそれ
ぞれ意味し，Ｃは前記した通りである。Ｗは結合を意味し，Ａｌｋは低
級アルキレン基を意味する。Ｘ，Ｘ１はハロゲンをそれぞれ意味
する。点線の半弧は環を形成しても良い事を意味する。Ａ’は前
記したＡの残基である。］
式（１０−２）で示される化合物を、ＤＭＦ等の非プロトン性極性溶媒中で、炭酸アルカリ等の塩基の存在下、式（１７）で示されるハロゲン化体と室温下、或いは加温下で反応させ、式（１８）で示される化合物に誘導する事が出来る。式（２０）で示される化合物も式（１８）で示される化合物と式（１９）で示されるハロゲン化体から同様にして得る事が出来る。官能基の変換を位置特異的に行う場合は、保護基を使用し、下記スキームＥに従って行う。

［式中，Ｐｒｏは保護基を示し，Ａ’，Ａｌｋ，ａ２，ｂ２，点線の
半弧は前記した通りである。］
式（２４）で示される化合物は、式（２１）で示される水酸基を有するシアノ体を予め、ベンジル基等により保護した後、前記したＰｉｎｎｅｒ反応につぐピリミジンの合成法に処する事により得られる。式（２８）で示される化合物から式（２６）、式（３１）でそれぞれ示される化合物への変換は、何れも１当量のアルキル化剤、若しくは保護化剤を使用し行われる。式（２８）で示される化合物を２当量のアルキル化剤と反応させると、式（２９）で示される化合物が得られる。式（３１）で示される化合物にアルキル化剤を反応させた後、脱保護し式（３３）で示される化合物が得られ、式（２４）で示される化合物から式（２６）で示される化合物の合成も同様に成される。得られたいずれの化合物からも、式（３０）で示される二つの異なる官能基が導入された化合物を合成することが出来る。保護基の導入及び脱離は、例えば、Ｔ．Ｗ．Ｇｒｅｅｎ，”Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ，２ｎｄ Ｅｄ．”，Ｊｏｈｎ Ｗｉｌｌｅｙ ＆ Ｓｏｎｓ，１９９１に方法が記載されており、これらの常法に従って行われる。
式（２９）で示される化合物が、下記式（２９’）

［式中，Ａ’，Ｃは前記した通りである。］
で示される化合物である場合、この化合物の加水分解を、高温且つ長時間行う事によって、下記式（３４）で示される化合物への変換も可能である。

［式中，Ａ’，Ｃは前記した通りである。］
例えば、式（２９’）で示されるジエステル体をメタノール、若しくはエタノール溶媒中でアルカリ加水分解し、ジカルボン酸体を生成させた後、溶媒を留去し、水酸化ナトリウム水溶液を加え、９０℃で数日間再び反応させるか、或いはメタノール中、水酸化ナトリウム水溶液と共に数時間、還流する事により達成される。
式（３３）で示される化合物が、下記式（３３’）

［式中，Ａｌｋ，Ａ’，Ｃ，Ｒは前記した通りである。］
で示される化合物である場合は下記スキームＦに示される官能基変換が可能である。

［式中，Ａｌｋ，Ａ’，Ｃ，Ｒ，Ｘは前記した通りである。］
また、ピリミジン環上にカルボキシ基がある場合にも、下記スキームＧに従った官能基変換が同様に行われる。

［式中，Ｐｒｏ，Ａ’，Ａｌｋ，ａ２，は前記した通りである。］
具体的には、下記スキームＨに従った変換が可能である。

［式中，Ａ’，Ｒは前記した通りである。］
前記一般式（１）で示される化合物の置換基ａ、ｂ又はｃ中に存在するカルボン酸エステルは常法に従い、アルカリ加水分解等により、カルボン酸のアルカリ塩に、若しくは生成したアルカリ塩を酸析する事で遊離カルボン酸に変換することが出来る。得られた遊離カルボン酸は水酸化ナトリウム等によってナトリウム塩等のアルカリ金属塩にすることも出来る。前記一般式（１）で示される化合物中に、低級アルコキシカルボニル基が存在する場合、それ自体、本発明の医薬組成物を構成するひとつの形態を成すものであるが、この様にして、本発明のもう一つの形態である対応するカルボン酸及びそのアルカリ塩に変換する事が出来る。
一般式（１）で示される化合物の塩酸等による酸付加塩も本発明の医薬組成物を構成する一つの形態であり、これらは常法に従い、例えば、対応する遊離体を水、或いは水性アルコール、水性アセトンの如き溶媒中で当量の塩酸等で処理する事によって得られる。
このようにして製造される一般式（１）で表わされるピリミジン誘導体若しくはそれらの塩化合物あるいはそれらの溶媒和物を有効成分とする医薬は、通常、哺乳類（ヒト患者を含む）に対し、錠剤、カプセル剤、散剤、細粒剤、シロップ剤等の経口投与剤、直腸投与剤、あるいは注射剤として投与することができる。また、本発明化合物は１個の治療剤として、あるいは他の治療剤との混合物として投与することができる。それらは単体で投与しても良いが、一般的には医薬組成物の形態で投与する。それらの製剤は薬理学的、製剤学的に許容し得る添加物を加え、常法により製造することができる。すなわち、経口剤には、通常の賦形剤、滑沢剤、結合剤、崩壊剤、湿潤剤、コーティング剤等の添加剤を用いることができる。経口用液剤は、水性または油性懸濁液、溶液、乳濁液、シロップ、エリキシル等の形態であっても良く、あるいは使用前水または他の適当な溶媒で調製するドライシロップとして供されても良い。前記の液剤は、懸濁化剤、香料、希釈剤あるいは乳化剤のような通常の添加剤を含有できる。直腸内投与する場合は、坐剤として投与することができる。坐剤は、カカオ脂、ラウリン脂、マクロゴール、グリセロゼラチン、ウィテップゾール、ステアリン酸ナトリウムまたはそれらの混合物など、適当な物質を基剤とし、必要に応じて乳化剤、懸濁化剤、保存剤等を加えることができる。注射剤は、水性あるいは用時溶解型剤形を構成し得る注射用蒸留水、生理食塩水、５％ブドウ糖溶液、プロピレングリコール等の溶解剤ないし溶解補助剤、ｐＨ調節剤、等張化剤、安定化剤等の製剤成分が使用される。上記組成物で用いられる賦形剤等の具体例を以下に挙げる。
賦形剤：リン酸水素カルシウム、合成ケイ酸アルミニウム、メタケイ酸アルミン酸マグネシウム、水酸化アルミニウム・マグネシウム、ケイ酸マグネシウム、炭酸カルシウム、炭酸マグネシウム、リン酸水素カルシウム、軽質無水ケイ酸、無水ケイ酸、アビセル、各種デンプン、デキストリン、カルボキシメチルスターチ（ＣＭＳ）、乳糖等。
結合剤：エチルセルロース（ＥＣ）、カルボキシメチルセルロースＮａ（ＣＭＣ−Ｎａ）、低置換度ヒドロキシプロピルセルロース（Ｌ−ＨＰＣ）、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）、メチルセルロース（ＭＣ）、ヒドロキシプロピルセルロース（ＨＰＣ）、各種デンブン、デキストリン、アルギン酸ナトリウム、ゼラチン、ポリビニルアルコール（ＰＶＡ）、ポリビニルピロリドン（ＰＶＰ）等。
崩壊剤：合成ケイ酸アルミニウム、メタケイ酸アルミン酸マグネシウム、ＣＭＣ−Ｃａ、ＣＭＣ、アビセル、Ｌ−ＨＰＣ、ＨＰＭＣ、ＭＣ、各種デンプン、ＣＭＳ、ヒドロキシプロピルスターチ（ＣＰＳ）等。
固化防止剤：軽質無水ケイ酸、合成ケイ酸アルミニウム等。
滑沢剤：合成ケイ酸アルミニウム、無水ケイ酸、タルク、アビセル等。
矯味剤：マンニトール、クエン酸、クエン酸Ｎａ、砂糖等。
乳化剤：ゼラチン、クエン酸、クエン酸Ｎａ、ポリオキシエチレン硬化ヒマシ油、マクロゴール（ＰＥＧ）、プロピレングリコール脂肪酸エステル、ポリオキシエチレンポリオキシプロピレングリコール、プロピレングリコール、ラウリル硫酸Ｎａ、リン脂質等。
安定化剤：亜硫酸水素ナトリウム、ポリオキシエチレン硬化ヒマシ油、ＰＥＧ、プロピレングリコール脂肪酸エステル、ポリオキシエチレンポリオキシプロピレングリコール、プロピレングリコール、ラウリル硫酸Ｎａ、各種天然・合成シクロデキストリン、リン脂質等。
吸収促進剤：ポリオキシエチレン硬化ヒマシ油、ＰＥＧ、プロピレングリコール脂肪酸エステル、ポリオキシエチレンポリオキシプロピレングリコール、プロピレングリコール、ラウリル硫酸Ｎａ、各種天然・合成シクロデキストリン、中鎖脂肪酸トリグリセリド等。
溶解補助剤：エタノール、ポリオキシエチレン硬化ヒマシ油、ＰＥＧ、プロピレングリコール脂肪酸エステル、ポリオキシエチレンポリオキシプロピレングリコール、プロピレングリコール、ラウリル硫酸Ｎａ、各種天然・合成シクロデキストリン等。
懸濁化剤：ＣＭＣ−Ｎａ、ＨＰＭＣ、ＭＣ、ＨＰＣ、アルギン酸ナトリウム、ゼラチン、プロピレングリコール、ラウリル硫酸Ｎａ等。
被覆剤：ＥＣ、ケイ酸マグネシウム、タルク、酸化チタン、炭酸カルシウム、トリアセチン、カルボキシメチルエチルセルロース（ＣＭＥＣ）、酢酸フタル酸セルロース（ＣＡＰ）、ＨＰＭＣ、ヒドロキシプロピルメチルセルロースフタレート（ＨＰＭＣＰ）、ＭＣ、ＨＰＣ、アルギン酸ナトリウム、ポリビニルアセタールジエチルアミノアセテート、ポリアクリル酸Ｎａ、各種アクリル酸メタクリル酸誘導体のコポリマー、ポリグリコール酸Ｎａ等。
着色剤：酸化チタン、タール色素、カラメル等。
本発明化合物をヒトに投与する場合の投与量は、患者の年齢、症状等により異なるが、通常成人の場合、経口剤あるいは直腸内投与剤で１ｍｇ〜１０００ｍｇ／人／日程度、注射剤で０．１〜５００ｍｇ／人／日程度である。しかし、これらの数値はあくまでも例示であり、投与量は患者の症状等種々の条件によって適宜増減される。In the present specification, the “lower alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, and specifically includes a methyl group, an ethyl group, a propyl group, an isopropyl group, Examples thereof include a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, and a hexyl group. The “lower alkylene group” means a linear or branched alkylene group having 1 to 6 carbon atoms, such as methylene group, ethanediyl group, propanediyl group, pentanediyl group, hexanediyl group, and the like. The “lower alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, Examples thereof include a sec-butoxy group, a tert-butoxy group, a pentyloxy group, and a hexyloxy group. The “lower alkoxycarbonyl group” means an alkoxycarbonyl group having a lower alkoxy group having 1 to 6 carbon atoms as described above, and examples thereof include a methoxycarbonyl group and an ethoxycarbonyl group. The compound represented by the above formula (1) of the present invention can be converted into a pharmacologically acceptable salt as necessary, or the formed salt can be converted into a free acid or an ester. Further, these compounds can be solvated. Examples of the salt include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine salts, and amino acid addition salts. Specifically, examples of the acid addition salt include inorganic acid salts such as hydrochloride, phosphate, and sulfate, and organic acid salts such as acetate, citrate, and methanesulfonate. Examples include alkali metals such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts, etc., ammonium salts include salts such as ammonium, and organic amine salt addition salts. Addition salts such as morpholine and piperidine, and amino acid addition salts include addition salts such as glycine and lysine. Examples of solvates include hydrates. Examples of esters include lower alkyl esters.
Among the compounds of the present invention, 6-phenyl-2- [4- (trifluoromethyl) phenyl] -4 (1H) -pyrimidinone, N- (1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl) Glycine, 6-methyl-2- (3-pyridinyl) -4 (1H) -pyrimidinone, 6-methyl-2- [4- (trifluoromethyl) phenyl] -4 (1H) -pyrimidinone are known compounds. However, nothing is known about their fibrinolysis-promoting action, thrombolytic action, and antithrombotic action.
The compound represented by the formula (1) of the present invention can be represented by the following formulas (1-1) and (1-2), and both can be produced by a known method.

[Wherein, a, b and c are as described above. ]
Below, the typical manufacturing method of this invention compound is shown. However, these are examples, and other known methods can also be used.
As a general synthesis method of pyrimidine derivatives, [G. W. Kenner, “Pyrimidine and Its Derivatives”, in R.M. C. Elderfield, “Heterocyclic compound”, 6,234. John Willey (1957)] is known, and can be represented by the following scheme A.

[Wherein, A and C mean the substituents a and c themselves of the present invention or substituents that can be converted into a and c, respectively. The dotted half arc means that a ring may be formed. W is a bond, or

Means. R means a lower alkyl group. ]
Amidine or guanidine represented by the formula (8) or an acid salt thereof and a β-ketoester represented by the formula (9) or an equivalent thereof in a solvent or without a solvent may be prepared with an appropriate base. By reacting at room temperature to 150 ° C. in the presence, a pyrimidine derivative represented by the formula (10) can be produced. Examples of the solvent include methanol, ethanol, or acetonitrile. Examples of the base include sodium, an alkoxy alkali metal (for example, sodium methoxide), an inorganic base such as potassium carbonate, sodium carbonate, and sodium hydroxide, or an organic base such as triethylamine, pyridine, and piperidine.
The compound represented by the formula (10) is represented as a pyrimidinol form, which is in a tautomeric relationship with the pyrimidinone form, and unless otherwise specified, shows both tautomeric forms in the present invention. Isomers are also included within the scope of the present invention.
In the formula (10), the compound in which c is a carboxy group can also be synthesized according to the following scheme B.

[Wherein, A and W are as described above. R and R1 each represent a lower alkyl group. ]
The pyrimidine derivative represented by the formula (13) is treated with an acid such as hydrochloric acid or formic acid to convert it to an aldehyde compound represented by the formula (14), and then oxidized using an oxidizing agent such as permanganate to formula (13) The compound shown by 10-1) can be produced.
In the schemes A and B, the raw material compound represented by the formula (8) can be produced by a known method shown in the following scheme C.

[Wherein A is as described above. ]
The amidino compound represented by formula (8-1) is synthesized by the Pinner reaction. That is, the nitrile compound represented by the formula (15) is reacted with a lower alcohol in the presence of an acid such as hydrogen chloride, iminoetherified, and then treated with ammonia, or similarly, the nitrile compound is treated with sodium methoxide. It can also be synthesized by reacting with a lower alcohol using a base such as a catalyst and then reacting with ammonium chloride. Here, nitrile as a starting material, the corresponding diazonium salt or a halogen embodying and copper cyanide (J.O.C.1947,160 ^~ etc.) or thionyl chloride of the corresponding carboxylic acid amide Ya It can be synthesized from dehydration with acetic anhydride or the like. From the amine compound represented by the formula (16), a guanidino compound represented by the formula (8-2) is obtained from a reaction with cyanamide (Japanese Patent Laid-Open No. 57-179146, US Pat. No. 3,406,185). O-alkylisourea or the like can be used in place of cyanamide.
(SKW Trostberg Aktiengesellschaft; “CYANAMIDE: Neue Beispiele fur die Syntheseeraktiver Zwishen produced undibioschutiver Aktivers”)
The hydroxyl group on the pyrimidine ring of the compound represented by the formula (10) and in the side chain A can be converted into another functional group according to the following scheme D.

[Wherein, a2 and b2 represent the substituents a1 and b1 themselves of the present invention,
Alternatively, it means that these are substituents that can be converted into a1 and b1, and C is as described above. W means a bond, and Alk means a lower alkylene group. X and X1 each mean halogen. The dotted half arc means that a ring may be formed. A ′ is the residue of A described above. ]
The compound represented by formula (10-2) is mixed with a halogenated compound represented by formula (17) at room temperature or under heating in an aprotic polar solvent such as DMF in the presence of a base such as alkali carbonate. To obtain a compound represented by the formula (18). The compound represented by the formula (20) can also be obtained in the same manner from the compound represented by the formula (18) and the halide represented by the formula (19). When the functional group is converted in a position-specific manner, a protective group is used, and is performed according to the following scheme E.

[In the formula, Pro represents a protecting group, and A ′, Alk, a2, b2 and the dotted half-arc are as described above. ]
The compound represented by the formula (24) can be obtained by preliminarily protecting the cyano compound having the hydroxyl group represented by the formula (21) with a benzyl group or the like and then subjecting it to the pyrimidine synthesis method followed by the Pinner reaction. The conversion from the compound represented by the formula (28) to the compound represented by each of the formula (26) and the formula (31) is performed using 1 equivalent of an alkylating agent or a protecting agent. When a compound represented by the formula (28) is reacted with 2 equivalents of an alkylating agent, a compound represented by the formula (29) is obtained. The compound represented by the formula (31) is reacted with an alkylating agent and then deprotected to obtain a compound represented by the formula (33). From the compound represented by the formula (24), a compound represented by the formula (26) Is synthesized in the same manner. From any of the obtained compounds, a compound into which two different functional groups represented by formula (30) are introduced can be synthesized. The introduction and removal of protecting groups is described in, for example, W. The method is described in Green, "Protective Groups in Organic Synthesis, 2nd Ed.", John Willy & Sons, 1991, and is performed according to these conventional methods.
The compound represented by the formula (29) is represented by the following formula (29 ′)

[Wherein A ′ and C are as described above. ]
In the case of a compound represented by the formula, the compound can be converted to a compound represented by the following formula (34) by performing hydrolysis of the compound at a high temperature for a long time.

[Wherein A ′ and C are as described above. ]
For example, the diester compound represented by the formula (29 ′) is alkali-hydrolyzed in methanol or an ethanol solvent to form a dicarboxylic acid compound, and then the solvent is distilled off, an aqueous sodium hydroxide solution is added, and the mixture is heated at 90 ° C. This can be accomplished by reacting again for several days or by refluxing for several hours with aqueous sodium hydroxide in methanol.
The compound represented by the formula (33) is represented by the following formula (33 ′)

[Wherein, Alk, A ′, C and R are as described above. ]
In the case of a compound represented by the formula, functional group conversion shown in the following scheme F is possible.

[Wherein, Alk, A ′, C, R, and X are as described above. ]
Also, when there is a carboxy group on the pyrimidine ring, functional group conversion according to the following scheme G is similarly performed.

[Wherein, Pro, A ′, Alk, a2, are as described above. ]
Specifically, conversion according to the following scheme H is possible.

[Wherein, A ′ and R are as described above. ]
The carboxylic acid ester present in the substituent a, b or c of the compound represented by the general formula (1) is converted into an alkali salt of carboxylic acid or an alkali salt formed by acid hydrolysis according to a conventional method. It can be converted to free carboxylic acid by analyzing. The obtained free carboxylic acid can be converted to an alkali metal salt such as sodium salt with sodium hydroxide or the like. When a lower alkoxycarbonyl group is present in the compound represented by the general formula (1), the compound itself constitutes one form constituting the pharmaceutical composition of the present invention. Another form of the invention can be converted to the corresponding carboxylic acid and its alkali salts.
Acid addition salts of the compound represented by the general formula (1) with hydrochloric acid or the like are also one form constituting the pharmaceutical composition of the present invention, and these are prepared according to a conventional method, for example, the corresponding free form is water or aqueous alcohol. Or by treatment with an equivalent amount of hydrochloric acid or the like in a solvent such as aqueous acetone.
A medicament containing the pyrimidine derivative represented by the general formula (1) or a salt compound thereof or a solvate thereof thus produced as an active ingredient is usually used for a mammal (including a human patient), It can be administered as oral preparations such as capsules, powders, fine granules, syrups, rectal preparations, or injections. The compound of the present invention can be administered as a single therapeutic agent or as a mixture with other therapeutic agents. They may be administered alone, but are generally administered in the form of a pharmaceutical composition. These preparations can be produced by a conventional method with addition of pharmacologically and pharmaceutically acceptable additives. That is, additives such as ordinary excipients, lubricants, binders, disintegrants, wetting agents, and coating agents can be used for the oral preparations. Oral solutions may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc., or may be provided as dry syrups prepared in water or other suitable solvent prior to use. . The liquid preparation can contain conventional additives such as suspending agents, perfumes, diluents or emulsifiers. When administered rectally, it can be administered as a suppository. The suppository is based on a suitable substance such as cacao butter, lauric fat, macrogol, glycerogelatin, witepsol, sodium stearate or a mixture thereof, and if necessary an emulsifier, suspending agent, preservative. Etc. can be added. Injections include aqueous or injectable distilled water, physiological saline, 5% glucose solution, propylene glycol and other solubilizers or solubilizers, pH adjusters, isotonic agents, Pharmaceutical ingredients such as stabilizers are used. Specific examples of excipients used in the above composition are listed below.
Excipients: calcium hydrogen phosphate, synthetic aluminum silicate, magnesium metasilicate aluminate, aluminum hydroxide / magnesium, magnesium silicate, calcium carbonate, magnesium carbonate, calcium hydrogen phosphate, light anhydrous silicic acid, anhydrous silicic acid, Avicel, various starches, dextrin, carboxymethyl starch (CMS), lactose, etc.
Binders: Ethylcellulose (EC), carboxymethylcellulose Na (CMC-Na), low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), hydroxypropylcellulose (HPC), various denbuns , Dextrin, sodium alginate, gelatin, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP) and the like.
Disintegrants: synthetic aluminum silicate, magnesium aluminate metasilicate, CMC-Ca, CMC, Avicel, L-HPC, HPMC, MC, various starches, CMS, hydroxypropyl starch (CPS) and the like.
Anti-caking agent: light anhydrous silicic acid, synthetic aluminum silicate, etc.
Lubricant: Synthetic aluminum silicate, silicic anhydride, talc, Avicel, etc.
Flavoring agents: mannitol, citric acid, sodium citrate, sugar and the like.
Emulsifiers: gelatin, citric acid, sodium citrate, polyoxyethylene hydrogenated castor oil, macrogol (PEG), propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, propylene glycol, lauryl sulfate Na, phospholipid and the like.
Stabilizer: Sodium bisulfite, polyoxyethylene hydrogenated castor oil, PEG, propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, propylene glycol, sodium lauryl sulfate, various natural and synthetic cyclodextrins, phospholipids, and the like.
Absorption accelerators: polyoxyethylene hydrogenated castor oil, PEG, propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, propylene glycol, sodium lauryl sulfate, various natural and synthetic cyclodextrins, medium chain fatty acid triglycerides, and the like.
Solubilizing agents: ethanol, polyoxyethylene hydrogenated castor oil, PEG, propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, propylene glycol, sodium lauryl sulfate, various natural and synthetic cyclodextrins, and the like.
Suspending agent: CMC-Na, HPMC, MC, HPC, sodium alginate, gelatin, propylene glycol, sodium lauryl sulfate and the like.
Coating agent: EC, magnesium silicate, talc, titanium oxide, calcium carbonate, triacetin, carboxymethyl ethyl cellulose (CMEC), cellulose acetate phthalate (CAP), HPMC, hydroxypropyl methylcellulose phthalate (HPMCP), MC, HPC, sodium alginate , Polyvinyl acetal diethylaminoacetate, polyacrylic acid Na, copolymers of various acrylic acid methacrylic acid derivatives, polyglycolic acid Na and the like.
Colorant: Titanium oxide, tar pigment, caramel, etc.
The dosage when the compound of the present invention is administered to humans varies depending on the age, symptoms, etc. of the patient, but in the case of an adult, it is usually about 1 mg to 1000 mg / person / day for oral or rectal administration, and 0 for injection. About 1 to 500 mg / person / day. However, these numerical values are merely examples, and the dosage is appropriately increased or decreased depending on various conditions such as patient symptoms.

  Next, although manufacture of the compound of this invention and a test example are given and this invention is demonstrated concretely, this invention is not limited by these examples.

Preparation of 6-Phenyl-2- (3-pyridinyl) -4 (1H) -pyrimidinone (Compound 1) and its sodium salt (Compound 1 • Na) To 3-cyanopyridine (10.4 g) in methanol (100 ml) Sodium methoxide (0.54 g) was added and stirred at room temperature for 20 hours, then ammonium chloride (5.99 g) was added and stirred under reflux for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethanol (120 ml), and then the extract was concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from ethanol (60 ml) to obtain 3-pyridinecarboximidamide hydrochloride (5.54 g) as a white solid as an intermediate.
1H-NMR (DMSO-d6 / TMS):
δ = 7.54-7.75 (1H, m) 8.19-8.36 (1H, m) 8.83-9.17 (2H, m) 9.34 (3H, br s)
Sodium methoxide (238 mg) and ethyl benzoyl acetate (461 mg) were added to 3-pyridinecarboximidoamide hydrochloride (315 mg) in methanol (10 ml), and the mixture was stirred for 20 hours under reflux. The reaction solution was concentrated under reduced pressure, and water (20 ml) and 1N hydrochloric acid (1.8 ml) were added to the residue for acid precipitation, followed by filtration to obtain a crude product. The crude product was recrystallized with 70% aqueous ethanol (50 ml) to obtain Compound 1 (141 mg) as a white solid.
Compound 1 (49.9 mg), 1N sodium hydroxide (0.2 ml) were dissolved in water (200 ml) by heating and filtered, and then the filtrate was lyophilized to obtain Compound 1 • Na as a white solid. .
1H-NMR (DMSO-d6 / TMS):
δ = 6.38 (1H, s) 7.38-7.52 (4H, m) 8.01-8.16 (2H, m) 8.55-8.75 (2H, m) 9.54 ( 1H, s)

Preparation of 6-phenyl-2- [4- (trifluoromethyl) phenyl] -4 (1H) -pyrimidinone (compound 2) and its sodium salt (compound 2 • Na) Methanol (3.84 g) in ethyl ether (200 ml) ), Hydrochloric acid gas (54 g) was dissolved under cooling, 4-trifluoromethylbenzonitrile (17.1 g) was added, and the mixture was allowed to stand at 5 ° C. for 7 days. The precipitated imino ether was collected by filtration. The imino ether was added to a saturated ammonia gas-methanol solution (200 ml), allowed to stand at 5 ° C. for 4 days, and then concentrated under reduced pressure to obtain a crude product. 35% hydrochloric acid (5 drops) was added to the crude product and recrystallized from water (200 ml) to obtain 4- (trifluoromethyl) benzenecarboximidoamide hydrochloride (17.25 g) as a white solid as an intermediate. .
1H-NMR (DMSO-d6 / TMS):
δ = 8.04 (4H, s) 9.58 (3H, br s)
Sodium methoxide (1.19 g) and ethyl benzoyl acetate (2.31 g) were added to 4- (trifluoromethyl) benzenecarboximidamide hydrochloride (2.25 g) in methanol (30 ml), and the mixture was stirred for 7 hours under reflux. did. The reaction solution was concentrated under reduced pressure, and water (50 ml) and 35% hydrochloric acid (2 ml) were added to the residue for acid precipitation, followed by filtration to obtain a crude product. The crude product was recrystallized with ethanol (400 ml) to obtain Compound 2 (1.25 g) as a white solid.
1H-NMR (DMSO-d6 / TMS):
δ = 7.05 (1H, s) 7.49-7.60 (3H, m) 7.93 (2H, d, J = 8 Hz) 8.14-8.30 (2H, m) 8.51 ( 2H, d, J = 8Hz)
Compound 2 (158 mg), 1N sodium hydroxide (0.5 ml) were dissolved in methanol (150 ml) and filtered, and then the filtrate was concentrated under reduced pressure to obtain Compound 2 · Na as a white solid.

[[6-Phenyl-2- [4- (trifluoromethyl) phenyl] -4-pyrimidinyl] oxy] acetic acid methyl ester (Compound 3Me), [[6-Phenyl-2- [4- (trifluoromethyl) phenyl ] -4-Pyrimidinyl] oxy] acetic acid (Compound 3) and its sodium salt (Compound 3 • Na) In DMF (20 ml), Compound 2 (633 mg) obtained in Example 2 was added to potassium carbonate (553 mg), Methyl bromoacetate (367 mg) was added, and the mixture was stirred at room temperature for 5 hours. Water (200 ml) was added to the reaction solution for crystallization. The precipitated crystals were collected by filtration and dried to give white solid compound 3Me (667 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 3.75 (3H, s) 5.19 (2H, s) 7.54-7.65 (4H, m) 7.94 (2H, d, J = 8 Hz) 8.28-8.39 ( 2H, m) 8.63 (2H, d, J = 8 Hz)
1N sodium hydroxide (1.8 ml) was added to compound 3Me (583 mg) in methanol (15 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was concentrated under reduced pressure, and water (50 ml) and 1N hydrochloric acid (1.8 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to give Compound 3 (465 mg) as a white solid.
1H-NMR (DMSO-d6 / TMS):
δ = 5.10 (2H, s) 7.54-7.62 (4H, m) 7.93 (2H, d, J = 8 Hz) 8.29-8.43 (2H, m) 8.66 ( 2H, d, J = 8Hz)
Compound 3 (187 mg) and 0.1N sodium hydroxide (5 ml) were dissolved in water (50 ml) by heating, and then concentrated under reduced pressure. The residue was washed with cold water (20 ml) and then dried to obtain a white solid compound 3 • Na.

6-[[6-Phenyl-2- [4- (trifluoromethyl) phenyl] -4-pyrimidinyl] oxy] hexanoic acid ethyl ester (Compound 4Et), 6-[[6-Phenyl-2- [4- ( Preparation of (trifluoromethyl) phenyl] -4-pyrimidinyl] oxy] hexanoic acid (compound 4) and its sodium salt (compound 4 • Na) In DMF (10 ml), compound 2 (474 mg) obtained in Example 2 Potassium carbonate (415 mg) and ethyl 6-bromohexanoate (402 mg) were added, and the mixture was stirred at room temperature for 20 hours and further at 80 ° C. for 1 hour. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain oily compound 4Et. 1N sodium hydroxide (2.1 ml) was added to compound 4Et in ethanol (15 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (50 ml), and then activated carbon (0.1 g) was added and filtered. 1N Hydrochloric acid (2.1 ml) was added to the filtrate and acidified, and then filtered to obtain a crude product. The crude product was recrystallized with 67% aqueous ethanol (30 ml) to obtain Compound 4 (329 mg) as a white solid.
1H-NMR (DMSO-d6 / TMS):
δ = 1.4-2.27 (8H, m) 4.54 (2H, t, J = 6 Hz) 7.46-7.63 (4H, m) 7.91 (2H, d, J = 8 Hz) 8.25-8.41 (2H, m) 8.70 (2H, d, J = 8 Hz)
Compound 4 (215 mg), 1N sodium hydroxide (0.5 ml) was dissolved in (50 ml) by heating and filtered, and then the filtrate was lyophilized to obtain Compound 4 • Na as a white solid.

[5-[[6-Phenyl-2- [4- (trifluoromethyl) phenyl] -4-pyrimidinyl] oxy] pentyl] propanedioic acid diethyl ester (Compound 5Et), [5-[[6-Phenyl-2 Preparation of-[4- (trifluoromethyl) phenyl] -4-pyrimidinyl] oxy] pentyl] propanedioic acid (compound 5) and its disodium salt (compound 5 · 2Na) Example 2 in DMF (10 ml) To the obtained compound 2 (633 mg) were added potassium carbonate (553 mg) and diethyl 5-bromopentylmalonate (742 mg), and the mixture was stirred at room temperature for 20 hours, and further diethyl 5-bromopentylmalonate (124 mg) was added. , And stirred at 80 ° C. for 3 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain oily compound 5Et. 1N sodium hydroxide (7 ml) was added to compound 5Et in ethanol (20 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzate was concentrated under reduced pressure, and the residue was dissolved in water (50 ml) by heating, and then activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (7 ml) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 5 (971 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 1.9-19-199 (8H, m) 3.24 (1H, t, J = 7 Hz) 4.54 (2H, t, J = 6 Hz) 7.47-7.75 (4H, m) 7.92 (2H, d, J = 9 Hz) 8.26-8.40 (2H, m) 8.69 (2H, d, J = 9 Hz) 12.23-13.05 (2H, br)
Compound 5 (971 mg), 1N sodium hydroxide (4 ml) was dissolved in water (50 ml) by heating and filtered, and then the filtrate was lyophilized to give Compound 5.2Na as a white solid.

Preparation of 2- (4-hydroxyphenyl) -6-phenyl-4 (1H) -pyrimidinone (Compound 6) and its disodium salt (Compound 6 · 2Na) 4-Amidinophenol hydrochloride (1) in methanol (50 ml) Sodium methoxide (2.38 g) and ethyl benzoyl acetate (2.11 g) were added to .73 g), and the mixture was stirred for 20 hours under reflux. Sodium methoxide (1.19 g) was further added, and the mixture was stirred at the same temperature for 2 hours. Stir. The reaction solution was concentrated under reduced pressure, and water (30 ml) and 35% hydrochloric acid (3.5 ml) were added to the residue for acid precipitation, followed by filtration to obtain a crude product. The crude product was recrystallized from ethanol (150 ml) to obtain a white solid compound 6 (1.12 g).
1H-NMR (DMSO-d6 / TMS):
δ = 6.81 (1H, s) 6.93 (2H, d, J = 9 Hz) 7.47-7.57 (3H, m) 8.12-8.26 (4H, m) 9.19- 11.20 (1H, br) 11.41-13.46 (1H, br)
Compound 6 (132 mg), 1N sodium hydroxide (1 ml) was dissolved in water (50 ml) and filtered, and then the filtrate was lyophilized to obtain Compound 6 · 2Na as a yellow solid.

[[2- [4- (2-methoxy-2-oxoethoxy) phenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid methyl ester (compound 7Me), [[2- [4- (carboxymethoxy) phenyl ] -6-Phenyl-4-pyrimidinyl] oxy] acetic acid (Compound 7) and its disodium salt (Compound 7 • 2Na) Potassium (829 mg) and methyl bromoacetate (673 mg) were added, and the mixture was stirred at room temperature for 20 hours. Water (100 ml) was added to the reaction solution for crystallization. The precipitated crystals were collected by filtration and dried to obtain white solid compound 7Me (689 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 3.74 (6H, s) 4.92 (2H, s) 5.13 (2H, s) 7.11 (2H, d, J = 9 Hz) 7.49-7.62 (4H, m) 8.31-8.46 (4H, m)
1N sodium hydroxide (3.3 ml) was added to compound 7Me (613 mg) in methanol (15 ml) and hydrolyzed at room temperature for 1 hour. The hydrolyzed solution was concentrated under reduced pressure, and water (50 ml) and 1N hydrochloric acid (3.3 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 7 (498 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 4.80 (2H, s) 5.04 (2H, s) 7.09 (2H, d, J = 9 Hz) 7.45-7.62 (4H, m) 8.34-8.49 ( 4H, m) 12.35-13.87 (1H, br)
Compound 7 (190 mg), 1N sodium hydroxide (10 ml) was dissolved in water (50 ml) and concentrated under reduced pressure. The residue was washed with acetone (20 ml) and then dried to obtain a white solid compound 7.2N.

Preparation of 4- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenol (Compound 8) and its sodium salt (Compound 8 • Na) Compound 6 obtained in Example 6 in DMF (130 ml) Potassium carbonate (13.5 g) and benzyl bromide (10.1 g) were added to (12.9 g), and the mixture was stirred at room temperature for 18 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column (n-hexane-chloroform) to obtain Compound 8 (9.2 g).
1H-NMR (DMSO-d6-D20 / TMS):
δ = 5.61 (2H, s) 6.97 (2H, d, J = 8 Hz) 7.18-7.62 (9H, m) 8.21-8.48 (4H, m)
Compound 8 (177 mg), 1N sodium hydroxide (0.6 ml) were dissolved in water (200 ml), and then lyophilized to obtain Compound 8 • Na.

Preparation of [4- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] acetic acid (Compound 9) and its sodium salt (Compound 9 • Na) Obtained in Example 8 in DMF (20 ml). To compound 8 (2.13 g) were added potassium carbonate (1.66 g) and ethyl bromoacetate (1.10 g), and the mixture was stirred at room temperature for 3 days. The reaction was filtered, the filtrate was concentrated under reduced pressure, and n-hexane (100 ml) was added to the residue for crystallization. The precipitate was collected by filtration and dried to obtain a reaction product (3.38 g).
To the reaction product (1.32 g) was added 1N sodium hydroxide (4.5 ml) in ethanol (60 ml), and the mixture was hydrolyzed under reflux for 2.5 hours. The hydrolyzed solution was concentrated under reduced pressure, and water (150 ml) and 1N hydrochloric acid (4.5 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to give compound 9 (883 mg).
Compound 9 (206 mg), 1N sodium hydroxide (1.0 ml) were dissolved in water (200 ml), and then lyophilized to obtain Compound 9 • Na.
1H-NMR (Methanol-d4-D20 / TMS):
δ = 4.26 (2H, s) 5.60 (2H, s) 6.93-7.71 (11H, m) 8.02-8.32 (2H, m) 8.46 (2H, d, J = 9Hz)

Preparation of [4- (1,4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) phenoxy] acetic acid (compound 10) and its disodium salt (compound 10.2Na) Examples in DMF (20 ml) To compound 8 (2.13 g) obtained in 8 was added potassium carbonate (1.66 g) and ethyl bromoacetate (1.10 g), and the mixture was stirred at room temperature for 3 days. The reaction was filtered, the filtrate was concentrated under reduced pressure, and n-hexane (100 ml) was added to the residue for crystallization. The precipitate was collected by filtration and dried to obtain a reaction product (3.38 g).
Toluene (100 ml) in methanol (400 ml) was added to the reaction product (1.54 g), dissolved by heating, 5% palladium carbon (0.5 g) was added, and the mixture was added at 40-50 ° C. in a hydrogen stream. Stir for hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain a debenzylated product. To the debenzylated product, 1N sodium hydroxide (4.8 ml) and methanol (50 ml) were added in ethanol (300 ml) and hydrolyzed under reflux for 2.5 hours. The hydrolyzed solution was concentrated under reduced pressure, and water (120 ml) and 1N hydrochloric acid (4.8 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to give compound 10 (640 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 4.59 (2H, s) 6.83 (1H, s) 7.03 (2H, d, J = 9 Hz) 7.46-7.56 (3H, m) 8.10-8.31 ( 4H, m)
Compound 10 (193 mg), 1N sodium hydroxide (1.8 ml) were dissolved in water (200 ml), and then lyophilized to obtain compound 10.2Na.

[4- [4-[(2-chlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] phenoxy] acetic acid 2-chlorobenzyl ester (Compound 11Be), [4- [4-[(2-chlorophenyl) methoxy] Preparation of −6-phenyl-2-pyrimidinyl] phenoxy] acetic acid (Compound 11) and its sodium salt (Compound 11 • Na) In DMF (20 ml), Compound 10 (419 mg) obtained in Example 10 was added to potassium carbonate (419 mg). 539 mg) and 2-chlorobenzyl bromide (801 mg) were added, and the mixture was stirred at 80-90 ° C. for 24 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain Compound 11Be (1.47 g).
1N Sodium hydroxide (1.5 ml) and methanol (30 ml) were added to compound 11Be (1.47 g) in ethanol (70 ml) and hydrolyzed under reflux for 2 hours. The hydrolyzed solution was concentrated under reduced pressure, and water (150 ml) and 1N hydrochloric acid (1.6 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to give compound 11 (489 mg).
Compound 11 (223 mg), 1N sodium hydroxide (1.0 ml) were dissolved in water (250 ml) and then lyophilized to obtain Compound 11 • Na.
1H-NMR (DMSO-d6 / TMS):
δ = 4.19 (2H, s) 5.71 (2H, s) 6.96 (2H, d, J = 9 Hz) 7.31-7.71 (8H, m) 8.24-8.48 ( 4H, m)

4- [4- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] butanoic acid ethyl ester (Compound 12Et), 4- [4- [4-Phenyl-6- (phenylmethoxy) -2 Preparation of -pyrimidinyl] phenoxy] butanoic acid (compound 12) and its sodium salt (compound 12 · Na) In DMF (100 ml), compound 8 (3.54 g) obtained in Example 8 was added to potassium carbonate (2.76 g). ), Ethyl 4-bromo-n-butyrate (2.34 g) was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and n-hexane (100 ml) was added to the residue for crystallization. The precipitated crystals were collected by filtration, washed with water, and dried to give compound 12Et (4.18 g).
1H-NMR (Chloroform-d / TMS):
δ = 1.27 (3H, t, J = 7 Hz) 1.94-2.70 (4H, m) 4.00-4.35 (4H, m) 5.61 (2H, s) 6.92- 7.07 (3H, m) 7.26-7.70 (8H, m) 8.08-8.24 (2H, m) 8.54 (2H, d, J = 9 Hz)
To DMF (20 ml), potassium carbonate (1.66 g) and ethyl 4-bromo-n-butyrate (1.29 g) were added to compound 8 (2.13 g) obtained in Example 8 and stirred at room temperature for 2 days. did. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Then, n-hexane (80 ml) was added to the residue for crystallization. The precipitate was collected by filtration and washed with water to obtain Compound 12Et. 1N sodium hydroxide (9.0 ml) was added to compound 12Et in ethanol (70 ml) and hydrolyzed under reflux for 2 hours. The hydrolyzed solution was concentrated under reduced pressure, and water (200 ml) and 1N hydrochloric acid (9.0 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 12 (2.2 g).
Compound 12 (220 mg), 1N sodium hydroxide (0.8 ml) were dissolved in water (150 ml), and then lyophilized to obtain Compound 12 · Na.
1H-NMR (Methanol-d4-D20 / TMS):
δ = 2.02-2.50 (4H, m) 4.10 (2H, t, J = 6 Hz) 5.55 (2H, s) 6.95-7.10 (3H, m) 7.25- 7.55 (8H, m) 7.9-8.22 (2H, m) 8.43 (2H, d, J = 9 Hz)

4- [4- (1,4-Dihydro-4-oxo-6-phenyl-2-pyrimidinyl) phenoxy] butanoic acid ethyl ester (compound 13Et), 4- [4- (1,4-dihydro-4-oxo Preparation of -6-phenyl-2-pyrimidinyl) phenoxy] butanoic acid (Compound 13) and its disodium salt (Compound 13.2Na) Compound 12Et (3.98 g) obtained in Example 12 was added to methanol (1000 ml). After dissolution, 5% palladium carbon (1.0 g) was added, and the mixture was stirred in a hydrogen stream at 40-50 ° C. for 2 hours. Methanol (1000 ml) and toluene (300 ml) were added to the reaction solution and refluxed. After filtration, the filtrate was concentrated under reduced pressure to obtain Compound 13Et (2.87 g).
1H-NMR (Chloroform-d / TMS):
δ = 1.27 (3H, t, J = 7 Hz) 2.05-2.69 (4H, m) 4.03-4.36 (4H, m) 6.86 (1H, s) 7.06 ( 2H, d, J = 9 Hz) 7.45-7.55 (3H, m) 8.06-8.42 (4H, m) 11.06-14.04 (1H, br)
Compound 12 (1.98 g) obtained in Example 12 was dissolved in methanol (500 ml), 5% palladium carbon (0.5 g) was added, and the mixture was stirred in a hydrogen stream at room temperature for 2.5 hours. Acetone (800 ml) was added to the reaction solution and the mixture was heated and filtered, and then the filtrate was concentrated under reduced pressure to obtain Compound 13 (1.54 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.87−2.54 (4H, m) 4.11 (2H, t, J = 6 Hz) 6.84 (1H, s) 7.10 (2H, d, J = 9 Hz) 7.40− 7.58 (3H, m) 8.05-8.41 (4H, m)
Compound 13 (175 mg), 1N sodium hydroxide (1.5 ml) were dissolved in water (250 ml), and then lyophilized to obtain compound 13.2Na.

4- [4- [4-[(2-chlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] phenoxy] butanoic acid 2-chlorobenzyl ester (Compound 14Be), 4- [4- [4-[(2 Preparation of -Chlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] phenoxy] butanoic acid (Compound 14) and its sodium salt (Compound 14 · Na) Compound 13 (Example 13) obtained in Example 13 in DMF (10 ml) 0.53 g) was added with potassium carbonate (0.41 g) and 2-chlorobenzyl bromide (0.92 g), and further added with 2-chlorobenzyl bromide (0.31 g) at room temperature for 22 hours. After stirring for 3 hours at 80 to 90 ° C., potassium carbonate (0.21 g) was added, and the mixture was stirred at the same temperature for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and then water (100 ml) was added to the residue for crystallization. The precipitated crystals were collected by filtration, washed with n-hexane (30 ml), and then dried to obtain Compound 14Be (652 mg).
1N Sodium hydroxide (1.35 ml) was added to compound 14Be (540 mg) in ethanol (50 ml) and hydrolyzed under reflux for 3.5 hours. The hydrolyzed solution was concentrated under reduced pressure, and water (150 ml) and 1N hydrochloric acid (1.35 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to give compound 14 (419 mg).
Compound 14 (237 mg), 1N sodium hydroxide (1.0 ml) were dissolved in water (250 ml) and then lyophilized to obtain Compound 14 • Na.
1H-NMR (Methanol-d4-D20 / TMS):
δ = 1.92−2.56 (4H, m) 4.10 (2H, t, J = 6 Hz) 5.67 (2H, s) 6.94-7.73 (10H, m) 8.03- 8.36 (2H, m) 8.47 (2H, d, J = 9 Hz)

4- [4- [4-[(2-Fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] phenoxy] butanoic acid ethyl ester (compound 15Et), 4- [4- [4-[(2-fluoro Phenyl) methoxy] -6-phenyl-2-pyrimidinyl] phenoxy] butanoic acid sodium salt (compound 15 · Na) In 13 ml of DMF (40 ml), potassium carbonate was added to (829 mg) and 2-fluorobenzyl bromide (851 mg) were added, and the mixture was stirred at room temperature for 16 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain Compound 15Et. 1N sodium hydroxide (3.3 ml) was added to compound 15Et in ethanol (30 ml), and 1N sodium hydroxide (1.2 ml) was further added under reflux for 3 hours, followed by hydrolysis at the same temperature for 1 hour. . The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and then dried to obtain Compound 15 • Na (1.30 g).
1H-NMR (Methanol-d4 / TMS):
δ = 1.90-2.49 (4H, m) 4.11 (2H, t, J = 6 Hz) 5.65 (2H, s) 6.95-7.75 (10H, m) 8.11- 8.27 (2H, m) 8.48 (2H, d, J = 9 Hz)

4- [4- [4- (cyclohexylmethoxy) -6-phenyl-2-pyrimidinyl] phenoxy] butanoic acid ethyl ester (Compound 16Et), 4- [4- [4- (cyclohexylmethoxy) -6-phenyl-2 -Pyrimidinyl] phenoxy] butanoic acid sodium salt (compound 16 · Na) In DMF (40 ml), compound 13Et (1.14 g) obtained in Example 13 was added to potassium carbonate (829 mg) and bromomethylcyclohexane (797 mg). And stirred at room temperature for 17 hours and further at 90-100 ° C. for 4.5 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain Compound 16Et. 1N sodium hydroxide (4.5 ml) was added to compound 16Et in ethanol (30 ml) and hydrolyzed under reflux for 2 hours. The hydrolyzed solution was cooled, and the precipitated crystals were collected by filtration and dried to obtain Compound 16 • Na (493 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 0.95−2.54 (15H, m) 4.00−4.35 (4H, m) 6.94−7.09 (3H, m) 7.44−7.54 (3H, m) 8.09-8.32 (2H, m) 8.44 (2H, d, J = 9 Hz)

Preparation of 6- [4- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] hexanoic acid (Compound 17) Compound 8 (2.13 g) obtained in Example 8 in DMF (20 ml). ) Were added potassium carbonate (1.66 g) and ethyl 6-bromohexanoate (1.47 g), and the mixture was stirred at room temperature for 3 days. The reaction was filtered, the filtrate was concentrated under reduced pressure, and n-hexane (100 ml) was added to the residue for crystallization. The precipitate was collected by filtration and dried to obtain a reaction product (2.8 g).
To the reaction product (1.24 g) was added 1N sodium hydroxide (3.8 ml) in ethanol (50 ml), and the mixture was hydrolyzed under reflux for 2.5 hours. The hydrolyzed solution was concentrated under reduced pressure, and water (100 ml) and 1N hydrochloric acid (3.8 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 17 (504 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 1.56−1.86 (6H, m) 2.25 (2H, t, J = 6 Hz) 4.08 (2H, t, J = 6 Hz) 5.62 (2H, s) 7.09 ( 2H, d, J = 9 Hz) 7.32-7.61 (9H, m) 8.25-8.55 (4H, m)

Preparation of 6- [4- (1,4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) phenoxy] hexanoic acid (Compound 18) Compound 8 (Example 8) obtained in Example 8 in DMF (20 ml) To 2.13 g) were added potassium carbonate (1.66 g) and ethyl 6-bromohexanoate (1.47 g), and the mixture was stirred at room temperature for 3 days. The reaction was filtered, the filtrate was concentrated under reduced pressure, and n-hexane (100 ml) was added to the residue for crystallization. The precipitate was collected by filtration and dried to obtain a reaction product (2.8 g).
The reaction product (1.45 g) was dissolved in methanol (350 ml), 5% palladium carbon (0.5 g) was added, and the mixture was stirred in a hydrogen stream at room temperature for 2.5 hours. Acetone (150 ml) was added to the reaction solution to reflux and filtered, and then the filtrate was concentrated under reduced pressure to obtain a debenzylated product. To the debenzylated product, 1N sodium hydroxide (4.9 ml) was added in ethanol (400 ml) and hydrolyzed under reflux for 2 hours. The hydrolyzed solution was concentrated under reduced pressure, and water (200 ml) and 1N hydrochloric acid (4.9 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to give compound 18 (603 mg).
1H-NMR (DMSO-d6-D20 / TMS):
δ = 1.2-2.45 (8H, m) 4.08 (2H, t, J = 6 Hz) 6.82 (1H, s) 7.09 (2H, d, J = 9 Hz) 7.54- 7.59 (3H, m) 8.10-8.54 (4H, m)

[3- [4- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] propyl] propanedioic acid diethyl ester (Compound 19Et), [3- [4- [4-Phenyl-6- ( Preparation of (phenylmethoxy) -2-pyrimidinyl] phenoxy] propyl] propanedioic acid (compound 19) and its disodium salt (compound 19.2Na) Compound 8 (3.3) obtained in Example 8 in DMF (100 ml). 54 g) were added potassium carbonate (2.76 g) and diethyl (3-chloropropyl) malonate (3.55 g), and the mixture was stirred at 80 to 90 ° C. for 11 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column (toluene-ethyl acetate) to obtain Compound 19Et (4.16 g).
1H-NMR (Chloroform-d / TMS):
δ = 1.28 (6H, t, J = 7 Hz) 1.78-2.23 (4H, m) 3.45 (1H, t, J = 7 Hz) 4.00-4.40 (6H, m) 5.61 (2H, s) 6.92-7.06 (3H, m) 7.26-7.54 (8H, m) 8.09-8.24 (2H, m) 8.54 (2H, d, J = 9Hz)
1N sodium hydroxide (3.9 ml) was added to compound 19Et (721 mg) in ethanol (30 ml) and hydrolyzed under reflux for 2 hours. The hydrolyzed solution was cooled, and the precipitated crystals were collected by filtration and dried to obtain Compound 19.2Na (644 mg). Compound 19.2Na was acidified with 1N hydrochloric acid to give compound 19.
1H-NMR (DMSO-d6 / TMS):
δ = 1.85-2.02 (4H, m) 3.35 (1H, t, J = 7 Hz) 4.10 (2H, t, J = 6 Hz) 5.63 (2H, s) 7.10 ( 2H, d, J = 9 Hz) 7.33-7.61 (9H, m) 8.23-8.56 (4H, m)

[3- [4- [1,4-Dihydro-4-oxo-6-phenyl-2-pyrimidinyl] phenoxy] propyl] propanedioic acid diethyl ester (Compound 20H), [3- [4- [4-[( 2-Fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] phenoxy] propyl] propanedioic acid diethyl ester (compound 20Et), [3- [4- [4-[(2-fluorophenyl) methoxy] -6 Preparation of -phenyl-2-pyrimidinyl] phenoxy] propyl] propanedioic acid (compound 20) and its disodium salt (compound 20 · 2Na) Compound 19Et obtained in Example 19 (3.33 g) in methanol (600 ml) Was dissolved by heating, 5% palladium carbon (1.0 g) was added, and the mixture was stirred in a hydrogen stream at 40-50 ° C. for 2.5 hours. Toluene (300 ml) was added to the reaction solution and the mixture was heated and filtered, and then the filtrate was concentrated under reduced pressure to obtain Compound 20H (2.6 g).
To compound 20H (1.16 g) in DMF (40 ml) were added potassium carbonate (691 mg) and 2-fluorobenzyl bromide (709 mg), and the mixture was stirred at room temperature for 17 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain Compound 20Et. 1N sodium hydroxide (7.5 ml) was added to compound 20Et in ethanol (25 ml) and hydrolyzed under reflux for 1.5 hours. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and then dried to obtain Compound 20.2Na (1.21 g).
Compound 20 · 2Na was acidified with 1N hydrochloric acid to obtain Compound 20.
1H-NMR (DMSO-d6 / TMS):
δ = 1.60-2.17 (4H, m) 3.37 (1H, t, J = 6 Hz) 4.10 (2H, t, J = 6 Hz) 5.68 (2H, s) 7.03- 7.77 (10H, m) 8.24-8.56 (4H, m)

[3- [4- [4- (cyclohexylmethoxy) -6-phenyl-2-pyrimidinyl] phenoxy] propyl] propanedioic acid diethyl ester (compound 21Et), [3- [4- [4- (cyclohexylmethoxy)- 6-Phenyl-2-pyrimidinyl] phenoxy] propyl] propanedioic acid (Compound 21) and its disodium salt (Compound 21.2Na).
Potassium carbonate (608 mg) and (bromomethyl) cyclohexane (584 mg) were added to compound 20H (1.02 g) obtained in Example 20 in DMF (40 ml), and the mixture was added at room temperature for 17 hours and further at 100-120 ° C. for 6 hours. Stir. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain Compound 21Et. 1N sodium hydroxide (6.6 ml) was added to compound 21Et in ethanol (20 ml) and hydrolyzed under reflux for 2.5 hours, and then the hydrolyzed solution was cooled. The precipitated crystals were collected by filtration, washed with methanol (15 ml), and dried to give compound 21.2Na (884 mg). Compound 21 · 2Na was acidified with 1N hydrochloric acid to obtain compound 21.
1H-NMR (DMSO-d6 / TMS):
δ = 0.80-2.07 (15H, m) 3.27 (1H, t, J = 6 Hz) 4.09 (2H, t, J = 6 Hz) 4.33 (2H, d, J = 6 Hz) 7.08 (2H, d, J = 9 Hz) 7.29 (1H, s) 7.50-7.60 (3H, m) 8.22-8.51 (4H, m)

Preparation of 4- [2- [4- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] ethyl] morpholine (Compound 22) and its hydrochloride (Compound 22 • HCl) in DMF (80 ml) Potassium carbonate (4.42 g) and 4- (2-chloroethyl) morpholine hydrochloride (1.79 g) were added to compound 8 (2.84 g) obtained in Example 8, and the mixture was stirred at 80-90 ° C. for 6 hours. Further, potassium iodide (664 mg) was added, and the mixture was stirred at the same temperature for 5 hours. Then, potassium iodide (664 mg) and 4- (2-chloroethyl) morpholine hydrochloride (447 mg) were added, and the mixture was stirred at the same temperature for 4.5 hours. 4- (2-chloroethyl) morpholine hydrochloride (1.49 g) was added again, and the mixture was stirred at the same temperature for 12 hours and then at 120 to 130 ° C. for 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column (chloroform), and n-hexane (30 ml) was added to the obtained oily substance for crystallization. The precipitated crystals were collected by filtration and dried to obtain Compound 22 (2.10 g).
Compound 22 (140 mg) was dissolved in methanol (100 ml) by adding 1N hydrochloric acid (0.3 ml), and concentrated under reduced pressure to give compound 22 · HCl.
1H-NMR (DMSO-d6 / TMS):
δ = 3.16-4.15 (10H, m) 4.59 (2H, t, J = 6 Hz) 5.64 (2H, s) 7.12-7.77 (11H, m) 8.27- 8.60 (4H, m)

Preparation of 2- [4- [2- (4-morpholinyl) ethoxy] phenyl] -6-phenyl-4 (1H) -pyrimidinone (Compound 23) Compound 22 (Example 22) obtained in Example 22 in methanol (500 ml). Toluene (100 ml) was added to 1.87 g) and dissolved by heating, 5% palladium carbon (1.0 g) was added, and the mixture was stirred in a hydrogen stream at 40-50 ° C. for 2.5 hours. Toluene (100 ml) was added to the reaction solution and the mixture was heated and filtered, and then the filtrate was concentrated under reduced pressure to obtain Compound 23 (1.17 g).
1H-NMR (DMSO-d6 / TMS):
δ = 2.49 (4H, t, J = 4 Hz) 2.73 (2H, t, J = 6 Hz) 3.60 (4H, t, J = 4 Hz) 4.21 (2H, t, J = 6 Hz) 6.84 (1H, s) 7.11 (2H, d, J = 9 Hz) 7.47-7.58 (3H, m) 8.11-8.35 (4H, m)

4- [2- [4- [4-[(2-Fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] phenoxy] ethyl] morpholine (Compound 24) and its hydrochloride (Compound 24 • HCl) Potassium carbonate (332 mg) and 2-fluorobenzyl bromide (340 mg) were added to compound 23 (453 mg) obtained in Example 23 in DMF (15 ml), and the mixture was stirred at room temperature for 17 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Diisopropyl ether (10 ml) was added to the residue for crystallization. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 24 (496 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 2.50 (4H, t, J = 4 Hz) 2.74 (2H, t, J = 6 Hz) 3.60 (4H, t, J = 4 Hz) 4.20 (2H, t, J = 6 Hz) 5.68 (2H, s) 7.04-7.81 (10H, m) 8.16-8.56 (4H, m)
Compound 24 (194 mg) was dissolved in methanol (100 ml) by adding 1N hydrochloric acid (0.4 ml), and then concentrated under reduced pressure to obtain compound 24 • HCl.

Preparation of 4- [2- [4- [4- (cyclohexylmethoxy) -6-phenyl-2-pyrimidinyl] phenoxy] ethyl] morpholine (compound 25) and its hydrochloride (compound 25 · HCl) in DMF (15 ml) To the compound 23 (453 mg) obtained in Example 23, potassium carbonate (332 mg) and (bromomethyl) cyclohexane (319 mg) were added, followed by stirring at 90-100 ° C. for 17 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Diisopropyl ether (10 ml) was added to the residue for crystallization. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 25 (447 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 1.5-1.88 (11H, m) 2.50 (4H, t, J = 4 Hz) 2.73 (2H, t, J = 6 Hz) 3.60 (4H, t, J = 4 Hz) 4.10-4.39 (4H, m) 7.10 (2H, d, J = 9 Hz) 7.30 (1H, s) 7.51-7.61 (3H, m) 8.24-8. 52 (4H, m)
Compound 25 (189 mg) was dissolved in methanol (100 ml) by adding 1N hydrochloric acid (0.4 ml), and concentrated under reduced pressure to give compound 25 · HCl.

Preparation of 2- (4′-hydroxy [1,1′-biphenyl] -4-yl) -6-phenyl-4 (1H) -pyrimidinone (Compound 26) and its disodium salt (Compound 26.2Na) Methanol ( 200 ml) was dissolved in hydrochloric acid gas (112 g) under cooling, 4′-hydroxy (1,1′-biphenyl) -4-carbonitrile (19.5 g) was added, and the mixture was stirred at room temperature for 20 hours, then cooled. The precipitated iminoether was collected by filtration. The imino ether was added to a saturated ammonia gas-methanol solution (300 ml), stirred at room temperature for 20 hours, cooled, and the precipitate was collected by filtration. Water (70 ml) and 35% hydrochloric acid (7 g) were added to the obtained crystals for acid precipitation, followed by filtration to obtain a crude product. 35% hydrochloric acid (5 drops) was added to the crude product, recrystallized with water (150 ml), and 4′-hydroxy (1,1′-biphenyl) -4-carboximidamide hydrochloride (Yellow solid as an intermediate) 10.16 g) was obtained.
1H-NMR (DMSO-d6 / TMS):
δ = 6.93 (2H, d, J = 9 Hz) 7.65 (2H, d, J = 9 Hz) 7.89 (4H, s) 9.43 (4H, br s)
Sodium methoxide (333 mg) and ethyl benzoyl acetate (646 mg) were added to 4′-hydroxy (1,1′-biphenyl) -4-carboximidohydrochloride (696 mg) in methanol (14 ml) and refluxed for 20 hours. Stir. The reaction mixture was concentrated under reduced pressure, and water (20 ml) and 1N hydrochloric acid (6 ml) were added to the residue for acid precipitation, followed by filtration to obtain a crude product. The crude product was recrystallized from ethanol (320 ml) to obtain Compound 26 as a white solid (312 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 6.83-6.97 (3H, m) 7.57-7.86 (7H, m) 8.14-8.42 (4H, m) 8.94-10.38 (1H, br) 11.82-13.46 (1H, br)
Compound 26 (68.1 mg), 1N sodium hydroxide (1 ml) was dissolved in water (100 ml) by heating and filtered, and then the filtrate was freeze-dried to obtain a white solid compound 26.2Na.

[[2- [4 ′-(2-methoxy-2-oxoethoxy) [1,1′-biphenyl] -4-yl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid methyl ester (compound 27Me), [[2- [4 ′-(Carboxymethoxy) [1,1′-biphenyl] -4-yl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid (Compound 27) and its disodium salt (Compound 27 2Na) In DMF (2 ml), potassium carbonate (207 mg) and methyl bromoacetate (168 mg) were added to compound 26 (170 mg) obtained in Example 26 and stirred at room temperature for 20 hours. Water (20 ml) was added to the reaction solution for crystallization. The precipitated crystals were collected by filtration and dried to obtain white solid compound 27Me (213 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 3.74 (6H, s) 4.87 (2H, s) 5.17 (2H, s) 7.07 (2H, d, J = 8 Hz) 7.55-7.89 (8H, m) 8.28-8.56 (4H, m)
1N sodium hydroxide (0.88 ml) was added to compound 27Me (194 mg) in methanol (4 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was concentrated under reduced pressure, and water (8 ml) and 1N hydrochloric acid (0.88 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain yellow solid compound 27 (163 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 4.74 (2H, s) 5.07 (2H, s) 7.04 (2H, d, J = 9 Hz) 7.51-7.87 (8H, m) 8.27-8.59 ( 4H, m)
Compound 27 (114 mg) and 0.1N sodium hydroxide (5 ml) were dissolved in water (50 ml) and concentrated under reduced pressure. The residue was washed with acetone (20 ml) and then dried to obtain a green solid compound 27.2Na.

Preparation of N- [1,4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl] glycine (Compound 28) and its sodium salt (Compound 28 · Na) In methanol (600 ml), guanidinoacetic acid (30 g) was prepared. A 28% sodium methoxide-methanol solution (108.7 g) and ethyl benzoyl acetate (59.7 g) were added, and the mixture was stirred under reflux for 24 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure. The residue was dissolved in water (200 ml), washed with n-hexane (100 ml), and acidified by adding 35% hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to obtain a crude product. The crude product was recrystallized from ethanol (350 ml) to obtain Compound 28 (1.79 g).
1H-NMR (DMSO-d6 / TMS):
δ = 4.09 (2H, d, J = 6 Hz) 6.20 (1H, s) 6.76 (1H, t, J = 6 Hz) 7.39-7.50 (3H, m) 7.84− 8.15 (2H, m) 11.11-12.60 (2H, br)
Compound 28 was dissolved in 0.05% aqueous sodium hydroxide solution (60 ml), activated carbon was added and filtered, and the filtrate was lyophilized to obtain Compound 28 • Na (180 mg).

N- (carboxymethyl) -N- [4- (2-ethoxy-2-oxoethoxy) -6-phenyl-2-pyrimidinyl] glycine ethyl ester (Compound 29Et), N- [4- (carboxymethoxy) -6 -Phenyl-2-pyrimidinyl] -N- (carboxymethyl) glycine (Compound 29) and its disodium salt (Compound 29 • 2Na) Compound 28 obtained in Example 28 (0. 98 g) were added potassium carbonate (2.44 g) and ethyl bromoacetate (2.21 g), and the mixture was stirred at 60 ° C. for 5 hours and further at room temperature overnight. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column (toluene-ethyl acetate-formic acid) and then recrystallized from ethanol (5 ml) to obtain compound 29Et (0.35 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.17 (3H, t, J = 7 Hz) 1.21 (3H, t, J = 7 Hz) 3.96-4.33 (6H, m) 4.71 (2H, s) 4.93 ( 2H, s) 6.77 (1H, s) 7.44-7.71 (3H, m) 8.01-8.17 (2H, m)
16% aqueous sodium hydroxide solution (1 ml) was added to compound 29Et (150 mg) in ethanol (5 ml) and hydrolyzed overnight at room temperature. After concentrating the hydrolyzed solution under reduced pressure, the residue was dissolved in water (5 ml) and acidified by adding 35% hydrochloric acid. The precipitated crystals were filtered, washed with water, and dried to obtain Compound 29 (93 mg).
Compound 29 (92.8 mg) was dissolved in 0.23% aqueous sodium hydroxide solution (10 ml), activated carbon was added and filtered, and the filtrate was freeze-dried to obtain compound 29.2Na.
1H-NMR (DMSO-d6 / TMS):
δ = 4.03 (2H, s) 4, 80 (4H, s) 6.58 (1H, s) 7.38-7.48 (3H, m) 7.93-8.03 (2H, m)

Preparation of α-[(1,4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) amino] -4-hydroxybenzeneacetic acid (Compound 30) 5 in α-amino-4-hydroxybenzeneacetic acid (30 g) Aqueous ammonia solution (251 ml) and cyanamide (18 g) were added, and the mixture was stirred at room temperature for 50 hr. The reaction solution was acidified by adding 35% hydrochloric acid. The precipitated crystals were filtered, washed with water, and dried to obtain α-[(aminoiminomethyl) amino] -4-hydroxybenzeneacetic acid (13.6 g) as an intermediate.
Sodium methoxide (4.3 g) and ethyl benzoyl acetate (5.5 g) were added to α-[(aminoiminomethyl) amino] -4-hydroxybenzeneacetic acid (5 g) in methanol (100 ml) and refluxed overnight. Stir. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in water (100 ml), and activated carbon (0.5 g) was added and filtered. Methanesulfonic acid was added to the filtrate and acidified. The precipitated crystals were collected by filtration to obtain a crude product (4.6 g). The crude product was subjected to silica gel or ram (chloroform-methanol) to obtain compound 30.
1H-NMR (DMSO-d6 / TMS):
δ = 5.41 (1H, d, J = 6 Hz) 6.23 (1H, s) 6.80 (2H, d, J = 9 Hz) 7.07-7.50 (5H, m) 7.92− 7.97 (2H, m)

Preparation of 2- (2-naphthalenyl) -6-phenyl-4 (1H) -pyrimidinone (Compound 31) and its sodium salt (Compound 31 · Na) In methanol (500 ml), 2-naphthalenecarboximidamide (5 g) Sodium methoxide (2.9 g) and ethyl benzoyl acetate (5.6 g) were added, and the mixture was stirred for 12 hours under reflux. The reaction solution was concentrated under reduced pressure, and water (200 ml) and 35% hydrochloric acid were added to the residual acid for acid precipitation. The precipitated crystals were filtered, washed with water, and dried to obtain a crude product. The crude product was recrystallized from 1,4-dioxane to obtain Compound 31 (4.04 g).
1H-NMR (DMSO-d6 / TMS):
δ = 6.97 (1H, s) 7.51-8.50 (11H, m) 8.91 (1H, s) 11.91-13.61 (1H, br)
Compound 31 (500 mg), 1% aqueous sodium hydroxide solution (6.7 ml) was dissolved in methanol (25 ml) with heating and then concentrated under reduced pressure to obtain compound 31 • Na.

Preparation of 2- (6-hydroxy-2-naphthalenyl) -6- (4-nitrophenyl) -4 (1H) -pyrimidinone (Compound 32) 6-Hydroxy-2-naphthalenecarboximidomethane in methanol (300 ml) Sodium methoxide (5.94 g) and ethyl 4-nitrobenzoyl acetate (14.2 g) were added to the sulfonate (14.1 g), and the mixture was stirred for 20 hours under reflux. The reaction solution was cooled, and the precipitate was collected by filtration. Water (100 ml) and 35% hydrochloric acid (3 drops) were added to the obtained crystals for acid precipitation. The precipitated crystals were collected by filtration, washed with acetone (50 ml), and then dried to obtain a yellow solid compound 32 (4.91 g).
1H-NMR (DMSO-d6 / TMS):
δ = 7.08-7.25 (3H, m) 7.76-8.01 (2H, m) 8.23-8.59 (5H, m) 8.78 (1H, s) 10.14 ( 1H, br s) 12.23-13.46 (1H, br)

Preparation of 2- (6-hydroxy-2-naphthalenyl) -6- (3-nitrophenyl) -4 (1H) -pyrimidinone (Compound 33) 6-Hydroxy-2-naphthalenecarboximidomethane in methanol (300 ml) Sodium methoxide (5.94 g) and ethyl 3-nitrobenzoyl acetate (14.2 g) were added to the sulfonate (14.1 g), and the mixture was stirred for 20 hours under reflux. The reaction solution was cooled, and the precipitate was collected by filtration. Water (50 ml) and 35% hydrochloric acid (3 drops) were added to the obtained crystals for acid precipitation. The precipitated crystals were collected by filtration, washed with acetone (50 ml), and then dried to obtain a yellow solid compound 33 (5.12 g).
1H-NMR (DMSO-d6 / TMS):
δ = 7.09 (1H, s) 7.15-7.25 (2H, m) 7.69-8.01 (3H, m) 8.21-8.76 (4H, m) 8.98 ( 1H, s) 9.43-10.89 (1H, br)

Preparation of 6- (4-aminophenyl) -2- (6-hydroxy-2-naphthalenyl) -4 (1H) -pyrimidinone hydrochloride (compound 34 · HCl) and disodium salt (compound 34.2Na) Methanol ( 60 ml), 1N sodium hydroxide (0.8 ml) was added to and dissolved in the compound 32 (144 mg) obtained in Example 32, 5% palladium on carbon (150 mg) was added, and the mixture was heated in a hydrogen stream at room temperature. Stir for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water (8 ml) and 1N hydrochloric acid (12 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 34 · HCl (58 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 6.78 (1H, s) 7.04-7.26 (4H, m) 7.75-8.35 (5H, m) 8.77 (1H, s)
In methanol (60 ml), 1N sodium hydroxide (0.8 ml) was added to and dissolved in compound 32 (144 mg) obtained in Example 32, 5% palladium on carbon (150 mg) was added, and hydrogen stream was added. Stir at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water (60 ml) and filtered, and then the filtrate was lyophilized to obtain Compound 34.2Na (146 mg) as a yellow solid.

Preparation of 6- (3-aminophenyl) -2- (6-hydroxy-2-naphthalenyl) -4 (1H) -pyrimidinone (compound 35) and its disodium salt (compound 35.2Na) in methanol (60 ml) 1N Sodium hydroxide (0.8 ml) was added to and dissolved in compound 33 (144 mg) obtained in Example 33, 5% palladium carbon (150 mg) was added, and the mixture was stirred in a hydrogen stream at room temperature for 3 hours. . The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water (8 ml) and 1N hydrochloric acid (0.8 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 35 (102 mg) as a yellow solid.
1H-NMR (DMSO-d6 / TMS):
δ = 4.22-6.27 (1H, br) 6.69-6.78 (2H, m) 7.18-7.47 (5H, m) 7.76-8.01 (2H, m) 8.29 (1H, d, J = 9 Hz) 8.77 (1H, s) 10.10 (1H, s) 11.61-13.66 (1H, br)
In methanol (60 ml), 1N sodium hydroxide (0.8 ml) was added to and dissolved in compound 33 (144 mg) obtained in Example 33, 5% palladium on carbon (150 mg) was added, and hydrogen stream was added. Stir at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water (60 ml) and filtered, and then the filtrate was lyophilized to obtain Compound 35.2Na (114 mg) as a yellow solid.

Preparation of 2- (6-hydroxy-2-naphthalenyl) -6- (4-methoxyphenyl) -4 (1H) -pyrimidinone (compound 36) and its disodium salt (compound 36.2Na) in methanol (300 ml) Sodium methoxide (5.94 g) and ethyl 4-methoxybenzoyl acetate (13.3 g) were added to 6-hydroxy-2-naphthalenecarboximidamide methanesulfonate (14.1 g), and the mixture was stirred under reflux for 2 days. The reaction solution was concentrated under reduced pressure, and water (500 ml) and 35% hydrochloric acid (6 ml) were added to the residue for acid precipitation, followed by filtration to obtain a crude product. The crude product was recrystallized from ethanol (800 ml) to obtain a yellow solid compound 36 (5.82 g).
1H-NMR (DMSO-d6 / TMS):
δ = 3.85 (3H, s) 6.81 (1H, s) 7.01-7.25 (4H, m) 7.75-8.37 (5H, m) 8.77 (1H, s)
Compound 36 (344 mg), 1N sodium hydroxide (2 ml) was dissolved in water (50 ml), filtered, and the filtrate was lyophilized to give Compound 36.2Na as a white solid.

Preparation of 2- (6-hydroxy-2-naphthalenyl) -6-phenyl-4 (1H) -pyrimidinone (Compound 37) 6-hydroxy-2-naphthalenecarboximidamide methanesulfonate (6 g) in methanol (30 ml) , Sodium methoxide (3.2 g) and ethyl benzoyl acetate (5.9 g) were added and the mixture was heated to reflux for 12 hours. The reaction mixture was concentrated under reduced pressure, water (200 ml) was added to the residue and dissolved by heating, and 35% hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration to obtain a crude product. The crude product was recrystallized from 1,4-dioxane to obtain a white solid compound 37 (6.0 g).
1H-NMR (DMSO-d6 / TMS):
δ = 6.90-8.80 (12H, m) 10.20 (1H, br) 12.60 (1H, br)

[[2- (6-Hydroxy-2-naphthalenyl) -6- (4-nitrophenyl) -4-pyrimidinyl] oxy] acetic acid methyl ester (compound 38Me), [[2- (6-hydroxy-2-naphthalenyl) Preparation of -6- (4-nitrophenyl) -4-pyrimidinyl] oxy] acetic acid (Compound 38) and its sodium salt (Compound 38 · Na) Compound 32 (2) obtained in Example 32 in DMF (80 ml) Potassium carbonate (2.21 g) and methyl bromoacetate (1.53 g) were added to .87 g), and the mixture was stirred at room temperature for 4 hours. The precipitate in the reaction solution was collected by filtration to obtain a crude product. The crude product was applied to a silica gel column (chloroform), and methanol (10 ml) was added to the obtained oily substance for crystallization. The precipitated crystals were collected by filtration and dried to obtain white solid compound 38Me (1.11 g).
1H-NMR (DMSO-d6 / TMS):
δ = 3.78 (3H, s) 5.21 (2H, s) 7.12-7.23 (2H, m) 7.69 (1H, s) 7.75-8.03 (2H, m) 8.30-8.71 (5H, m) 8.87 (1H, s) 9.34-10.94 (1H, br)
1N sodium hydroxide (4.5 ml) was added to compound 38Me (647 mg) in methanol (15 ml) and hydrolyzed at room temperature for 1 hour. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (30 ml), and then activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (4.5 ml) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 38 (561 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 5.11 (2H, s) 7.11-7.23 (2H, m) 7.64 (1H, s) 7.74-8.02 (2H, m) 8.30-8.70 ( 5H, m) 8.91 (1H, s)
Compound 38 (209 mg), 1N sodium hydroxide (0.5 ml) were dissolved in water (50 ml), filtered, and the filtrate was lyophilized to obtain Compound 38 · Na as a white solid.

[[2- (6-Hydroxy-2-naphthalenyl) -6- (3-nitrophenyl) -4-pyrimidinyl] oxy] acetic acid methyl ester (Compound 39Me), [[2- (6-Hydroxy-2-naphthalenyl) Preparation of -6- (3-nitrophenyl) -4-pyrimidinyl] oxy] acetic acid (Compound 39) and its sodium salt (Compound 39 · Na) Compound 33 (2) obtained in Example 33 in DMF (80 ml) Potassium carbonate (2.21 g) and methyl bromoacetate (1.53 g) were added to .87 g), and the mixture was stirred at room temperature for 20 hours. The precipitate in the reaction solution was collected by filtration to obtain a crude product. The crude product was applied to a silica gel column (n-hexane-chloroform), and methanol (200 ml) was added to the obtained oily substance for crystallization. The precipitated crystals were collected by filtration and dried to obtain white solid compound 39Me (1.60 g).
1H-NMR (DMSO-d6 / TMS):
δ = 3.78 (3H, s) 5.20 (2H, s) 7.12-7.23 (2H, m) 7.71 (1H, s) 7.76-7.99 (3H, m) 8.35-8.49 (2H, m) 8.72-8.85 (2H, m) 9.09 (1H, s) 10.04 (1H, s)
1N sodium hydroxide (4.5 ml) was added to compound 39Me (647 mg) in methanol (15 ml) and hydrolyzed at room temperature for 2 hours. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (30 ml), and then activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (4.5 ml) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 39 (512 mg) as a yellow solid.
1H-NMR (DMSO-d6 / TMS):
δ = 5.12 (2H, s) 7.11-7.23 (2H, m) 7.69 (1H, s) 7.74-8.01 (3H, m) 8.37-8.52 ( 2H, m) 8.73-8.89 (2H, m) 9.10 (1H, s)
Compound 39 (209 mg), 1N sodium hydroxide (0.5 ml) were dissolved in water (50 ml), filtered, and the filtrate was lyophilized to give Compound 39 • Na as a white solid.

[[6- (4-Aminophenyl) -2- (6-hydroxy-2-naphthalenyl) -4-pyrimidinyl] oxy] acetic acid methyl ester hydrochloride (compound 40Me · HCl), [[6- (4-aminophenyl ) -2- (6-Hydroxy-2-naphthalenyl) -4-pyrimidinyl] oxy] acetic acid (Compound 40) 1N hydroxylated compound 38Me (151 mg) obtained in Example 38 in methanol (60 ml). Sodium (0.35 ml) was added and dissolved, 5% palladium carbon (150 g) was added, and the mixture was stirred in a hydrogen stream at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water (8 ml) and 1N hydrochloric acid (0.7 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain a white solid compound 40Me.HCl (103 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 3.76 (3H, s) 5.13 (2H, s) 6.80 (2H, d, J = 8 Hz) 7.11-7.24 (3H, m) 7.73-8.48 ( 5H, m) 8.85 (1H, s)
The compound 38 (146 mg) obtained in Example 38 was dissolved in methanol (60 ml), 5% palladium carbon (150 mg) was added, and the mixture was stirred in a hydrogen stream at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and dried to obtain Compound 40 (46 mg) as a yellow solid.
1H-NMR (DMSO-d6 / TMS):
δ = 5.02 (2H, s) 6.71 (2H, d, J = 8 Hz) 7.10-7.18 (3H, m) 7.71-8.17 (4H, m) 8.45 ( 1H, d, J = 9 Hz) 8.89 (1H, s)

[[6- (3-aminophenyl) -2- (6-hydroxy-2-naphthalenyl) -4-pyrimidinyl] oxy] acetic acid methyl ester (compound 41Me), [[6- (3-aminophenyl) -2- Preparation of (6-hydroxy-2-naphthalenyl) -4-pyrimidinyl] oxy] acetic acid (Compound 41) Compound 39Me (151 mg) obtained in Example 39 in methanol (60 ml) was mixed with 1 N sodium hydroxide (0. 35 ml) was added and dissolved, 5% palladium carbon (150 mg) was added, and the mixture was stirred in a hydrogen stream at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water (8 ml) and 1N hydrochloric acid (0.35 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to give a brown solid compound 41Me (103 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 3.77 (3H, s) 5.17 (2H, s) 6.79 (1H, d, J = 7 Hz) 7.11-8.03 (8H, m) 8.45 (1H, d, J = 9 Hz) 8.87 (1H, s) 10.01 (1H, s)
The compound 39 (146 mg) obtained in Example 39 was dissolved in methanol (60 ml), 5% palladium carbon (150 mg) was added, and the mixture was stirred in a hydrogen stream at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and dried to give brown solid compound 41 (78 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 5.07 (2H, s) 6.77 (1H, d, J = 8 Hz) 7.11-8.02 (8H, m) 8.47 (1H, d, J = 9 Hz) 8.91 ( 1H, s)

[[2- (6-Hydroxy-2-naphthalenyl) -6-phenyl-4-pyrimidinyl] oxy] acetic acid methyl ester (compound 42Me), [[2- (6-hydroxy-2-naphthalenyl) -6-phenyl- 4-Pyrimidinyl] oxy] acetic acid ethyl ester (Compound 42Et), [[2- (6-Hydroxy-2-naphthalenyl) -6-phenyl-4-pyrimidinyl] oxy] acetic acid (Compound 42) and its disodium salt (Compound 42.2Na) Compound 37 (2.5 g) obtained in Example 37 was dissolved in DMF (30 ml), potassium carbonate (3 g) and methyl bromoacetate (1.6 g) were added, and the mixture was stirred overnight at room temperature. did. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column (chloroform) to obtain white solid compound 42Me (0.39 g).
1H-NMR (DMSO-d6 / TMS):
δ = 3.78 (3H, s) 5.19 (2H, s) 7.08-8.89 (12H, s) 10.01 (1H, s)
In DMF (200 ml), potassium carbonate (11.1 g) and ethyl bromoacetate (6.68 g) were added to compound 37 (12.6 g) obtained in Example 37, and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column (chloroform), and the obtained solid was recrystallized from isopropyl alcohol (70 ml) to obtain a pink solid compound 42Et (8.24 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.24 (3H, t, J = 7 Hz) 4.24 (2H, q, J = 7 Hz) 5.16 (2H, s) 7.12-7.24 (2H, m) 7.53- 8.04 (6H, m) 8.31-8.54 (3H, m) 8.91 (1H, s) 10.02 (1H, s)
1N sodium hydroxide (1.1 ml) was added to compound 42Et (200 mg) in ethanol (5 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was concentrated under reduced pressure, and water (20 ml) and 1N hydrochloric acid (1.1 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain yellow solid compound 42 (171 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 5.10 (2H, s) 7.09-7.23 (2H, m) 7.37-8.55 (9H, m) 8.92 (1H, s) 9.35-10.79 ( 1H, br)
Compound 42 (149 mg), 1N sodium hydroxide (0.8 ml) was dissolved in water (50 ml) by heating and filtered, and the filtrate was lyophilized to give compound 42.2Na as a yellow solid.

Preparation of 6-phenyl-2- [6- (phenylmethoxy) -2-naphthalenyl] -4 (1H) -pyrimidinone (compound 43) To 6-cyano-2-naphthol (42.3 g) in DMF (500 ml). Potassium carbonate (138.2 g) and benzyl bromide (51.4 g) were added, and the mixture was stirred for 18 hours under water cooling. The reaction solution was added to water (4000 ml) and crystallized. The precipitated crystals were collected by filtration, washed successively with water and n-hexane (400 g), and dried to give 6- (phenylmethoxy) -2-naphthalenecarbonitrile (64.6 g).
6- (Phenylmethoxy) -2-naphthalenecarbonitrile (51.9 g) was added to a saturated hydrochloric acid-methanol solution (1500 ml) and stirred at room temperature for 4 days, and the precipitated iminoether was collected by filtration. The imino ether was added to a saturated ammonia-methanol solution (3700 ml), stirred for 7 days, concentrated under reduced pressure, and 1.35% hydrochloric acid (540 g) was added to the residue for acid precipitation. The precipitated crystals were collected by filtration and washed with water to obtain a crude product. The crude product was recrystallized with 50% aqueous ethanol (74 ml) to obtain 6- (phenylmethoxy) -2-naphthalenecarboximidohydrochloride (50.7 g) as an intermediate.
1H-NMR (DMSO-d6 / TMS):
δ = 5.29 (2H, s) 7.48-8.11 (10H, m) 8.52 (1H, s) 9.44 (3H, br s)
Sodium methoxide (4.16 g) and ethyl benzoyl acetate (8.07 g) were added to 6- (phenylmethoxy) -2-naphthalenecarboximido hydrochloride (10.9 g) in methanol (200 ml), and the mixture was refluxed for 20 Stirring was continued for further time, methanol (100 ml) and sodium methoxide (4.16 g) were further added, and the mixture was stirred at the same temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and water (300 ml) and 35% hydrochloric acid (13 g) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration, washed successively with 67% aqueous methanol (900 ml), methanol (300 ml), and acetone (100 ml), and then dried to obtain Compound 43 (7.63 g) as a white solid.
1H-NMR (DMSO-d6 / TMS):
δ = 5.29 (2H, s) 6.92 (1H, s) 7.08-7.60 (10H, m) 7.88-8.46 (5H, m) 8.83 (1H, s)

4-[[6-Phenyl-2- [6- (phenylmethoxy) -2-naphthalenyl] -4-pyrimidinyl] oxy] butanoic acid ethyl ester (Compound 44Et), 4-[[6-Phenyl-2- [6 Preparation of-(phenylmethoxy) -2-naphthalenyl] -4-pyrimidinyl] oxy] butanoic acid sodium salt (Compound 44 · Na) In DMF (50 ml), compound 43 (2.02 g) obtained in Example 43 was added. Potassium carbonate (1.38 g) and ethyl 4-bromo-n-butyrate (1.27 g) were added, and the mixture was stirred at room temperature for 20 hours and further at 80 ° C. for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (50 ml) was added to the residue for crystallization. The precipitated crystals were collected by filtration, washed with water, and then dried to obtain white solid compound 44Et (2.50 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.18 (3H, t, J = 7 Hz) 2.01-2.66 (4H, m) 4.10 (2H, q, J = 7 Hz) 4.63 (2H, t, J = 6 Hz) 5.28 (2H, s) 7.22-7.63 (11H, m) 7.87-8.66 (5H, m) 9.02 (1H, s)
1N sodium hydroxide (0.6 ml) was added to compound 44Et (259 mg) in ethanol (5 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was cooled, and the precipitated crystals were collected by filtration and then dried to obtain a white solid compound 44 • Na (141 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 2.18-2.41 (4H, m) 4.60 (2H, t, J = 6 Hz) 5.19 (2H, s) 7.11-7.99 (13H, m) 8.16- 8.30 (2H, m) 8.57 (1H, d, J = 8 Hz) 8.93 (1H, s)

4-[[2- (6-Hydroxy-2-naphthalenyl) -6-phenyl-4-pyrimidinyl] oxy] butanoic acid ethyl ester (compound 45Et), 4-[[2- (6-hydroxy-2-naphthalenyl) Preparation of -6-phenyl-4-pyrimidinyl] oxy] butanoic acid (Compound 45) and its disodium salt (Compound 45 · 2Na) Compound 44Et obtained in Example 44 (2.18 g) in acetone (100 ml) Then, methanol (300 ml) and 5% palladium carbon (0.5 g) were added, and the mixture was stirred in a hydrogen stream at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized with 80% aqueous ethanol (30 ml) to obtain compound 45Et (1.33 g) as a white solid.
1H-NMR (DMSO-d6 / TMS):
δ = 1.18 (3H, t, J = 7 Hz) 2.02-2.65 (4H, m) 4.10 (2H, q, J = 7 Hz) 4.62 (2H, t, J = 6 Hz) 7.11-8.09 (8H, m) 8.28-8.61 (3H, m) 8.98 (1H, s) 10.00 (1H, br s)
1N sodium hydroxide (1.2 ml) was added to compound 45Et (214 mg) in ethanol (5 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was concentrated under reduced pressure, and water (20 ml) and 1N hydrochloric acid (1.2 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to give a yellow solid compound 45 (165 mg).
Compound 45 (120 mg), 1N sodium hydroxide (0.6 ml) was dissolved in water (50 ml) by heating and filtered, and the filtrate was freeze-dried to obtain yellow solid compound 45.2Na.
1H-NMR (Methanol-d4 / TMS):
δ = 2.19-2.42 (4H, m) 4.63 (2H, t, J = 6 Hz) 6.97-7.14 (3H, m) 7.47-7.80 (5H, m) 8.16-8.47 (3H, m) 8.82 (1H, s)

Preparation of 6- [4-[(2-fluorophenyl) methoxy] -6- (4-nitrophenyl) -2-pyrimidinyl] -2-naphthalenol (Compound 46) Obtained from Example 32 in DMF (100 ml). To compound 32 (3.59 g) were added potassium carbonate (2.76 g) and 2-fluorobenzyl bromide (1.89 g), and the mixture was stirred at room temperature for 3 days. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column (toluene-chloroform), and the obtained solid was recrystallized from toluene (350 ml) to obtain a yellow solid compound 46 (2.94 g).
1H-NMR (DMSO-d6 / TMS):
δ = 5.76 (2H, s) 7.13-8.54 (14H, m) 9.01 (1H, s) 10.06 (1H, br s)

Preparation of 6- [4-[(2-fluorophenyl) methoxy] -6- (3-nitrophenyl) -2-pyrimidinyl] -2-naphthalenol (Compound 47) Obtained from Example 33 in DMF (50 ml). To compound 33 (3.59 g) were added potassium carbonate (2.76 g) and 2-fluorobenzyl bromide (2.27 g), and the mixture was stirred at room temperature for 18 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column (toluene-chloroform) and then recrystallized from toluene (200 ml) to obtain Compound 47 (3.25 g).
1H-NMR (DMSO-d6 / TMS):
δ = 5.76 (2H, s) 7.12-8.12 (10H, m) 8.35-9.10 (5H, m) 10.05 (1H, br s)

Preparation of 6- [4-[(2-fluorophenyl) methoxy] -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenol (Compound 48) Obtained from Example 36 in DMF (200 ml). To compound 36 (6.89 g) were added potassium carbonate (5.53 g) and 2-fluorobenzyl bromide (3.78 g), and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column (toluene-chloroform-methanol) and then recrystallized from toluene (40 ml) to obtain an amber solid compound 48 (5.96 g).
1H-NMR (DMSO-d6 / TMS):
δ = 3.86 (3H, s) 5.73 (2H, s) 7.04-8.62 (14H, m) 8.99 (1H, s) 10.01 (1H, s)

Preparation of 6- [4-[(2-fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenol (Compound 49) Compound 37 (7) obtained in Example 37 in DMF (125 ml) Potassium carbonate (6.91 g) and 2-fluorobenzyl bromide (5.67 g) were added to .86 g), and the mixture was stirred at room temperature for 21 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column (n-hexane-toluene) and then recrystallized from toluene (10 ml) to obtain Compound 49 (5.51 g).
1H-NMR (DMSO-d6 / TMS):
δ = 5.75 (2H, s) 7.13-8.64 (15H, m) 9.01 (1H, s) 10.02 (1H, s)

Preparation of 6- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenol (Compound 50) Compound 37 (12.6 g) obtained in Example 37 was carbonated in DMF (200 ml). Potassium (11.1 g) and benzyl bromide (6.84 g) were added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column (toluene-ethyl acetate) to obtain a brown solid compound 50 (11.1 g).
1H-NMR (DMSO-d6 / TMS):
δ = 5.68 (2H, s) 7.11-8.62 (16H, m) 8.98 (1H, s)

Preparation of 4- [2-[[6-phenyl-2- [6- (phenylmethoxy) -2-naphthalenyl] -4-pyrimidinyl] oxy] ethyl] morpholine hydrochloride (Compound 51.HCl) in DMF (100 ml) To the compound 43 (4.04 g) obtained in Example 43, potassium carbonate (5.53 g), 4- (2-chloroethyl) morpholine hydrochloride (2.42 g) and potassium iodide (0.83 g) were added. , And stirred at 80 ° C. for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (100 ml), collected by filtration, and washed with water to obtain a crude product. 35% hydrochloric acid (2 ml) was added to the crude product, and then recrystallized with 78% aqueous methanol (230 ml) to obtain Compound 51 • HCl (4.40 g) as a white solid.
1H-NMR (DMSO-d6-D20 / TMS):
δ = 3.40-4.09 (10H, m) 4.92-5.10 (2H, m) 5.29 (2H, s) 7.34-8.70 (16H, m) 9.04 ( 1H, s)

Preparation of 6- [4- [2- (4-morpholinyl) ethoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenol hydrochloride (Compound 52 • HCl) Obtained in Example 51 in methanol (600 ml). Compound 51 · HCl (4.21 g) was dissolved, 5% palladium carbon (1 g) was added, and the mixture was stirred in a hydrogen stream at 45 ° C. for 20 hours. Methanol (1000 ml) was added to the reaction solution and refluxed, and the filtrate was concentrated under reduced pressure. The residue was washed with methanol (100 ml) and then dried to obtain a white solid compound 52.HCl (3.23 g).
1H-NMR (DMSO-d6-D20 / TMS):
δ = 3.56-4.00 (10H, m) 4.97-5.11 (2H, m) 7.15-7.27 (2H, m) 7.44-8.12 (6H, m) 8.28-8.65 (3H, m) 9.01 (1H, s)

[[2- [6- (2-Chloroethoxy) -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid ethyl ester (Compound 53Et), [[2- [6- (2-Chloroethoxy)] Preparation of 2-Naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid sodium salt (Compound 53 · Na) Compound 42Et (400 mg) obtained in Example 42 in potassium carbonate (276 mg) in DMF (15 ml) ), 1,2-bromochloroethane (186 mg) was added, and the mixture was stirred at room temperature for 20 hours. Potassium carbonate (1.2 g) and 1,2-bromochloroethane (1.25 g) were further added, and the mixture was stirred at the same temperature for 20 hours. Stir for hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (15 ml), collected by filtration, and washed with water to obtain a white solid compound 53Et. 1N sodium hydroxide (0.8 ml) was added to compound 53Et in ethanol (10 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and dried to obtain a white solid compound 53 • Na (251 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 3.92 (2H, t, J = 5 Hz) 4.40 (2H, t, J = 5 Hz) 4.96 (2H, s) 7.14-7.27 (3H, m) 7.48- 7.58 (3H, m) 7.75-8.03 (2H, m) 8.18-8.33 (2H, m) 8.61 (1H, d, J = 9 Hz) 8.98 (1H, s)

[[2- [6- (3-Chloropropoxy) -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid ethyl ester (Compound 54Et), [[2- [6- (3-Chloropropoxy) Preparation of 2-Naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid sodium salt (Compound 54 • Na) Compound 42Et (400 mg) obtained in Example 42 was added to potassium carbonate (276 mg) in DMF (15 ml). ), 1,3-bromochloropropane (205 mg) was added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (15 ml), collected by filtration, and washed with water to obtain a white solid compound 54Et. 1N sodium hydroxide (1 ml) was added to compound 54Et in ethanol (7.5 ml) and hydrolyzed under reflux for 1 hour. After cooling the hydrolyzate, the precipitate was collected by filtration to obtain a crude product. The crude product was recrystallized with 50% aqueous ethanol (10 ml) to obtain Compound 54 • Na (144 mg) as a white solid.
1H-NMR (Methanol-d4 / TMS):
δ = 2.19−2.51 (2H, m) 3.82 (2H, t, J = 6 Hz) 4.28 (2H, t, J = 5 Hz) 4.96 (2H, s) 7.12- 7.25 (3H, m) 7.37-7.58 (3H, m) 7.70-8.02 (2H, m) 8.19-8.34 (2H, m) 8.61 (1H, d, J = 10 Hz) 8.97 (1H, s)

[[2- [6- (2-methoxy-2-oxoethoxy) -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid methyl ester (compound 55Me), [[2- [6- (carboxyl Preparation of (methoxy) -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid (Compound 55) Compound 37 (2.5 g) obtained in Example 37 was dissolved in DMF (30 ml), and potassium carbonate was added. (3 g) and methyl bromoacetate (1.6 g) were added, and the mixture was stirred overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column (chloroform) to obtain a white solid compound 55Me (1.7 g).
1H-NMR (DMSO-d6 / TMS):
δ = 3.77 (6H, s) 4.98 (2H, s) 5.20 (2H, s) 7.24-8.94 (12H, m)
As described in Example 42, compound 42Me was obtained as a by-product in this reaction.
To compound 55Me (1.0 g), 1,4-dioxane (50 ml) in methanol (50 ml) was added and dissolved by heating. Then, 12% aqueous sodium hydroxide solution (4.54 g) was added, Hydrolyzed for minutes. The hydrolyzed solution was concentrated under reduced pressure, the residue was dissolved in water (40 ml), and diluted hydrochloric acid was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain a yellowish white solid compound 55 (700 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 4.87 (2H, s) 5.12 (2H, s) 7.24-8.99 (12H, m)

[[6- (1,4-Dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] acetic acid (Compound 56) and its sodium salt (Compound 56 · Na) and disodium salt ( Compound 56.2Na) 1M sodium hydroxide (2 ml) was added to methanol 55 (458 mg) obtained in Example 55 in methanol (10 ml), hydrolyzed under reflux for 1 hour, and concentrated under reduced pressure to give a residue. Water (10 ml) and 1N sodium hydroxide (13 ml) were added to the mixture, and the mixture was stirred at 90 ° C. for 5 days. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water (20 ml), and activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (15 ml) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain a green solid compound 56 (271 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 4.87 (2H, s) 6.92 (1H, s) 7.26-7.59 (5H, m) 7.89-8.45 (5H, m) 8.84 (1H, s) 11.82-13.87 (1H, br)
Compound 56 (186 mg) and 0.1N sodium hydroxide (5 ml) were dissolved in water (100 ml), filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with acetone (30 ml) and then dried to obtain a green solid compound 56 · Na.
Compound 56 • Na (79 mg) and 0.1N sodium hydroxide (2 ml) were dissolved in water (50 ml), filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with acetone (20 ml) and then dried to obtain a green solid compound 56.2Na.

[[2- [6- (2-methoxy-2-oxoethoxy) -2-naphthalenyl] -6- (4-nitrophenyl) -4-pyrimidinyl] oxy] acetic acid methyl ester (compound 57Me), [[2- Preparation of [6- (carboxymethoxy) -2-naphthalenyl] -6- (4-nitrophenyl) -4-pyrimidinyl] oxy] acetic acid (Compound 57) and its disodium salt (Compound 57.2Na) DMF (30 ml) Medium, potassium carbonate (1.24 g) and methyl bromoacetate (1.05 g) were added to compound 32 (1.08 g) obtained in Example 32, and the mixture was stirred at room temperature for 4 hours. The precipitate in the reaction solution was collected by filtration, washed successively with water (60 ml) and methanol (10 ml), and then dried to obtain white solid compound 57Me (1.15 g).
1H-NMR (DMSO-d6 / TMS):
δ = 3.77 (6H, s) 4.98 (2H, s) 5.22 (2H, s) 7.25-7.39 (2H, m) 7.72 (1H, s) 7.87- 8.13 (2H, m) 8.30-8.72 (5H, m) 8.93 (1H, s)
1N Sodium hydroxide (4.5 ml) was added to compound 57Me (755 mg) in methanol (15 ml) and hydrolyzed at room temperature for 1 hour, water (10 ml) was added, and the mixture was refluxed for 1 hour. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (30 ml), and then activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (4.5 ml) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 57 (358 mg) as a white solid.
1H-NMR (DMSO-d6 / TMS):
δ = 4.83 (2H, s) 5.12 (2H, s) 7.21-7.34 (2H, m) 7.66 (1H, s) 7.83-8.10 (2H, m) 8.30-8.71 (5H, m) 8.96 (1H, s)
Compound 57 (238 mg), 1N sodium hydroxide (0.9 ml) was dissolved in water (25 ml), filtered, and the filtrate was lyophilized to obtain Compound 57.2Na as a yellow solid.

[[6- [1,4-Dihydro-6- (4-nitrophenyl) -4-oxo-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid (Compound 58) and its disodium salt (Compound 58.2Na The compound 57Me (2.01 g) obtained in Example 57 was added to 1N sodium hydroxide (200 ml) and hydrolyzed under reflux for 15 hours. The hydrolyzate was cooled and the precipitate was collected by filtration. The obtained crystals were dissolved in water (100 ml), activated carbon (0.1 g) was added and filtered. The filtrate was acidified by adding 35% hydrochloric acid (1 ml). The precipitated crystals were collected by filtration and dried to obtain yellow solid compound 58 (0.82 g).
1H-NMR (DMSO-d6 / TMS):
δ = 4.87 (2H, s) 7.10 (1H, s) 7.26-7.39 (2H, m) 7.88-8.08 (2H, m) 8.29-8.59 ( 5H, m) 8.83 (1H, s) 12.23-13.87 (1H, br)
Compound 58 (417 mg), 1N sodium hydroxide (2 ml) was dissolved in water (50 ml), filtered, and the filtrate was lyophilized to obtain Compound 58.2Na as a yellow solid.

[[2- [6- (2-methoxy-2-oxoethoxy) -2-naphthalenyl] -6- (3-nitrophenyl) -4-pyrimidinyl] oxy] acetic acid methyl ester (compound 59Me), [[2- Preparation of [6- (carboxymethoxy) -2-naphthalenyl] -6- (3-nitrophenyl) -4-pyrimidinyl] oxy] acetic acid (compound 59) and its disodium salt (compound 59 · 2Na) DMF (30 ml) In the mixture, potassium carbonate (1.24 g) and methyl bromoacetate (1.05 g) were added to compound 33 (1.08 g) obtained in Example 33, and the mixture was stirred at room temperature for 20 hours. Water (300 ml) was added to the reaction solution for crystallization, followed by filtration to obtain a crude product. The crude product was recrystallized from acetone (120 ml) to obtain white solid compound 59Me (0.84 g).
1H-NMR (DMSO-d6 / TMS):
δ = 3.77 (6H, s) 4.98 (2H, s) 5.22 (2H, s) 7.25-7.39 (2H, m) 7.74 (1H, s) 7.88- 8.10 (3H, m) 8.40-8.57 (2H, m) 8.73-8.90 (2H, m) 9.10 (1H, s)
1N sodium hydroxide (3 ml) was added to compound 59Me (503 mg) in methanol (20 ml) and hydrolyzed at room temperature for 2 hours. Water (20 ml) was added to the hydrolyzed solution and refluxed, followed by concentration under reduced pressure. The residue was dissolved in water (30 ml), and activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (3 ml) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain green solid compound 59 (385 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 4.85 (2H, s) 5.12 (2H, s) 7.23-7.36 (2H, m) 7.70 (1H, s) 7.87-8.09 (3H, m) 8.36-8.94 (4H, m) 9.09 (1H, s)
Compound 59 (238 mg), 1N sodium hydroxide (0.9 ml) were dissolved in water (25 ml), filtered, and the filtrate was lyophilized to obtain Compound 59.2Na as a yellow solid.

[[6- [1,4-Dihydro-6- (3-nitrophenyl) -4-oxo-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid (compound 60) and its disodium salt (compound 60 2Na The compound 59Me (503 mg) obtained in Example 59 was added to 1N sodium hydroxide (30 ml) and hydrolyzed under reflux for 20 hours. Activated carbon (0.1 g) was added to the hydrolyzate and filtered. 35% hydrochloric acid (2.5 ml) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 60 (407 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 4.84 (2H, s) 7.12 (1H, s) 7.25-7.39 (2H, m) 7.83-8.03 (2H, m) 8.26-8.98 ( 6H, m)
Compound 60 (209 mg), 1N sodium hydroxide (1 ml) was dissolved in water (50 ml) and filtered, and then the filtrate was freeze-dried to obtain compound 60.2Na as a white solid.

[[6- [6- (4-Aminophenyl) -1,4-dihydro-4-oxo-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid (Compound 61) and its disodium salt (Compound 61.2Na The compound 58.2Na (231 mg) obtained in Example 58 was dissolved in methanol (70 ml), 5% palladium carbon (200 mg) was added, and the mixture was stirred in a hydrogen stream at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water (50 ml) and filtered, and then the filtrate was freeze-dried to obtain white solid compound 61.2Na (210 mg). Compound 61.2Na was acidified with 0.1N hydrochloric acid to obtain white solid compound 61.
1H-NMR (DMSO-d6 / TMS):
δ = 4.86 (2H, s) 6.63-6.75 (3H, m) 7.25-7.39 (2H, m) 7.90-8.03 (4H, m) 8.35 ( 1H, d, J = 9 Hz) 8.80 (1H, s)

[[6- [6- (3-Aminophenyl) -1,4-dihydro-4-oxo-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid (Compound 62) and its disodium salt (Compound 6 2Na ) In methanol (70 ml), 1N sodium hydroxide (0.8 ml) was added to and dissolved in compound 60 (167 mg) obtained in Example 60, 5% palladium on carbon (200 mg) was added, and hydrogen was added. The mixture was stirred for 20 hours at room temperature in an air stream. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water (50 ml), and the filtrate was freeze-dried to obtain white solid compound 62.2Na (97 mg). Compound 62.2Na was acidified with 0.1 N hydrochloric acid to obtain white solid compound 62.
1H-NMR (DMSO-d6 / TMS):
δ = 4.75 (2H, s) 4.99-6.48 (2H, br) 6.62-7.58 (7H, m) 7.86-8.07 (2H, m) 8.33 ( 1H, d, J = 8 Hz) 8.80 (1H, s)

[[6- (4-Aminophenyl) -2- [6- (2-methoxy-2-oxoethoxy) -2-naphthalenyl] -4-pyrimidinyl] oxy] acetic acid methyl ester (Compound 63Me), [[6- Preparation of (4-Aminophenyl) -2- [6- (carboxymethoxy) -2-naphthalenyl] -4-pyrimidinyl] oxy] acetic acid (Compound 63) and its disodium salt (Compound 63.2Na) Methanol (60 ml) In this, 5% palladium carbon (150 mg) was added to compound 57Me (151 mg) obtained in Example 57, and the mixture was stirred in a hydrogen stream at room temperature for 20 hours. Acetone (120 ml) was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and dried to obtain white solid compound 63Me (85 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 3.76 (6H, s) 4.98 (2H, s) 5.14 (2H, s) 5.74 (2H, br s) 6.72 (2H, d, J = 9 Hz) 7.25 −7.38 (3H, m) 7.85-8.19 (4H, m) 8.50 (1H, d, J = 9 Hz) 8.92 (1H, s)
The compound 57.2Na (104 mg) obtained in Example 57 was dissolved in methanol (60 ml), 5% palladium carbon (150 g) was added, and the mixture was stirred in a hydrogen stream at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water (8 ml) and 1N hydrochloric acid (0.4 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain a green solid compound 63 (42 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 4.86 (2H, s) 5.05 (2H, s) 6.76 (2H, d, J = 8 Hz) 7.19-7.36 (3H, m) 7.84-8.21 ( 4H, m) 8.52 (1H, d, J = 8 Hz) 8.96 (1H, s)
Compound 63 (22.3 mg) and 0.1 N sodium hydroxide (1 ml) were dissolved in water (30 ml), filtered, and the filtrate was lyophilized to obtain Compound 63.2Na as a white solid.

[[6- (3-Aminophenyl) -2- [6- (2-methoxy-2-oxoethoxy) -2-naphthalenyl] -4-pyrimidinyl] oxy] acetic acid methyl ester (Compound 64Me), [[6- Preparation of (3-aminophenyl) -2- [6- (carboxymethoxy) -2-naphthalenyl] -4-pyrimidinyl] oxy] acetic acid (Compound 64) and its disodium salt (Compound 64.2Na) Methanol (60 ml) In this, 5% palladium carbon (150 mg) was added to the compound 59Me (151 mg) obtained in Example 59, and the mixture was stirred in a hydrogen stream at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water and dried to obtain white solid compound 64Me (67 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 3.77 (6H, s) 4.99 (2H, s) 5.19 (2H, s) 5.32 (2H, br s) 6.78 (1H, d, J = 8 Hz) 7.10 -7.63 (6H, m) 7.88-8.11 (2H, m) 8.51 (1H, d, J = 9 Hz) 8.92 (1H, s)
The compound 59.2Na (104 mg) obtained in Example 59 was dissolved in methanol (60 ml), 5% palladium carbon (150 g) was added, and the mixture was stirred in a hydrogen stream at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water (8 ml) and 1N hydrochloric acid (0.4 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain a green solid compound 64 (72 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 4.87 (2H, s) 5.09 (2H, s) 6.79 (1H, d, J = 8 Hz) 7.11-7.64 (6H, m) 7.88-8.11 ( 2H, m) 8.53 (1H, d, J = 9 Hz) 8.96 (1H, s)
Compound 64 (22.3 mg) and 0.1N sodium hydroxide (1 ml) were dissolved in water (30 ml) and filtered, and then the filtrate was lyophilized to obtain Compound 64.2Na as a white solid.

[[6- [4- (2-Methoxy-2-oxoethoxy) -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid methyl ester (compound 65Me), [[6- Preparation of [4- (carboxymethoxy) -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid (compound 65) and its disodium salt (compound 65 · 2Na) DMF (50 ml) Among these, potassium carbonate (4.15 g) and methyl bromoacetate (3.37 g) were added to compound 36 (3.44 g) obtained in Example 36, and the mixture was stirred at room temperature for 20 hours. Water (500 ml) was added to the reaction solution for crystallization. The precipitated crystals were collected by filtration and dried to obtain white solid compound 65Me (4.23 g).
1H-NMR (DMSO-d6 / TMS):
δ = 3.77 (6H, s) 3.87 (3H, s) 4.98 (2H, s) 5.17 (2H, s) 7.07-7.46 (5H, m) 7.87- 8.13 (2H, m) 8.29-8.58 (3H, m) 8.93 (1H, s)
1N sodium hydroxide (17.6 ml) was added to compound 65Me (3.91 g) in methanol (80 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzate was concentrated under reduced pressure, and the residue was dissolved in water (200 ml), and then activated carbon (0.5 g) was added and filtered. 1N hydrochloric acid (18 ml) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain yellow solid compound 65 (3.49 g).
1H-NMR (DMSO-d6 / TMS):
δ = 3.87 (3H, s) 4.86 (2H, s) 5.09 (2H, s) 7.06-7.42 (5H, m) 7.86-8.12 (2H, m) 8.29-8.61 (3H, m) 8.97 (1H, s)
Compound 65 (230 mg), 1N sodium hydroxide (1 ml) was dissolved in water (50 ml), filtered, and the filtrate was lyophilized to obtain white solid compound 65.2Na.

4-[[2- [6- (carboxymethoxy) -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] butanoic acid ethyl ester (compound 66Et), 4-[[2- [6- (carboxymethoxy ) -2-Naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] butanoic acid (Compound 66) and its disodium salt (Compound 66 2Na) The compound obtained in Example 45 in DMF (10 ml) To 45 Et (214 mg) were added potassium carbonate (138 mg) and ethyl bromoacetate (109 mg), and the mixture was stirred at room temperature for 2 days. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain an oily compound 66Et. 1N sodium hydroxide (1.2 ml) was added to compound 66Et in ethanol (5 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (20 ml), and then activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (1.2 ml) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 66 (88 mg).
Compound 66 (69 mg), 1N sodium hydroxide (0.3 ml) was dissolved in water (50 ml) by heating and filtered, and then the filtrate was lyophilized to obtain Compound 66.2Na as a white solid.
1H-NMR (Methanol-d4 / TMS):
δ = 2.19-2.42 (4H, m) 4.56-4.80 (4H, m) 7.14-7.59 (6H, m) 7.76-8.03 (2H, m) 8.17-8.34 (2H, m) 8.59 (1 H, d, J = 9 Hz) 8.98 (1 H, s)

[[6- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid methyl ester (Compound 67Me), [[6- [4-Phenyl-6- (phenylmethoxy) Preparation of 2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid (Compound 67) and its sodium salt (Compound 67 · Na) Potassium carbonate was added to Compound 50 (404 mg) obtained in Example 50 in DMF (10 ml). (276 mg) and methyl bromoacetate (184 mg) were added, and the mixture was stirred at room temperature for 20 hours. Water (200 ml) was added to the reaction solution for crystallization, and then the product was collected by filtration to obtain Compound 67Me. 1N sodium hydroxide (2 ml) was added to compound 67Me in methanol (20 ml) and hydrolyzed under reflux for 2 hours. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (50 ml) by heating, and then activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (2 ml) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 67 (111 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 4.86 (2H, s) 5.70 (2H, s) 7.23-7.64 (11H, m) 7.88-8.20 (2H, m) 8.29-8.70 ( 3H, m) 9.05 (1H, s)
Compound 67 (92.5 mg), 1N sodium hydroxide (0.4 ml) was dissolved in water (100 ml) by heating and filtered, and the filtrate was freeze-dried to obtain white solid compound 67 · Na. .

[[6- [4-[(2-Fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid ethyl ester (Compound 68Et), [[6- [4-[(2 Preparation of -fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid (Compound 68) and its sodium salt (Compound 68 Na) Obtained in Example 49 in DMF (15 ml). To the obtained compound 49 (422 mg) were added potassium carbonate (276 mg) and ethyl bromoacetate (200 mg), and the mixture was stirred at room temperature for 18 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (20 ml) was added to the residue for crystallization. The precipitate was collected by filtration to obtain Compound 68Et. 1N sodium hydroxide (1.1 ml) was added to compound 68Et in ethanol (50 ml) and hydrolyzed under reflux for 1.5 hours. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and dried to obtain Compound 68 • Na (413 mg). Compound 68 · Na was acidified with 1N hydrochloric acid to obtain Compound 68.
1H-NMR (DMSO-d6 / TMS):
δ = 4.87 (2H, s) 5.75 (2H, s) 7.12-8.71 (15H, m) 9.06 (1H, s)

[[6- [4-[(2-Fluorophenyl) methoxy] -6- (4-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid ethyl ester (Compound 69Et), [[6- [ Preparation of 4-[(2-fluorophenyl) methoxy] -6- (4-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid sodium salt (Compound 69 · Na) Performed in DMF (10 ml) To compound 46 (467 mg) obtained in Example 46 were added potassium carbonate (276 mg) and ethyl bromoacetate (200 mg), and the mixture was stirred at room temperature for 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (10 ml) was added to the residue for crystallization. The precipitate was collected by filtration, washed with water, and dried to give a yellow solid compound 69Et (472 mg).
1N sodium hydroxide (1 ml) was added to compound 69Et (472 mg) in ethanol (10 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was cooled, and the precipitated crystals were collected by filtration and dried to obtain a yellow solid compound 69 • Na (436 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 4.28 (2H, s) 5.77 (2H, s) 7.18-8.75 (14H, m) 9.03 (1H, s)

[[6- [4-[(2-Fluorophenyl) methoxy] -6- (3-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid ethyl ester (Compound 70Et), [[6- [ Preparation of 4-[(2-fluorophenyl) methoxy] -6- (3-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid sodium salt (Compound 70 · Na) Performed in DMF (10 ml) To compound 47 (467 mg) obtained in Example 47 were added potassium carbonate (276 mg) and ethyl bromoacetate (200 mg), and the mixture was stirred at room temperature for 17 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (20 ml) was added to the residue for crystallization. The precipitate was collected by filtration, washed with water, and dried to give compound 70Et (492 mg).
1N sodium hydroxide (1.1 ml) was added to compound 70Et (492 mg) in ethanol (25 ml) and hydrolyzed under reflux for 1.5 hours. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and dried to obtain Compound 70 • Na (419 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 4.32 (2H, s) 5.75 (2H, s) 7.19-8.08 (10H, m) 8.35-9.17 (5H, m)

[[6- [4-[(2-Fluorophenyl) methoxy] -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid ethyl ester (Compound 71Et), [[6- [ Preparation of 4-[(2-fluorophenyl) methoxy] -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid (Compound 71) and its sodium salt (Compound 71 · Na) DMF (10 ml), potassium carbonate (276 mg) and ethyl bromoacetate (200 mg) were added to compound 48 (452 mg) obtained in Example 48, and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (10 ml) was added to the residue for crystallization. The precipitate was collected by filtration, washed with water, and dried to give a yellow solid compound 71Et (415 mg).
1N sodium hydroxide (1 ml) was added to compound 71Et (415 mg) in ethanol (10 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and dried to obtain white solid compound 71 • Na (381 mg). Compound 71 · Na was acidified with 0.1N hydrochloric acid to obtain Compound 71 as a white solid.
1H-NMR (DMSO-d6 / TMS):
δ = 3.87 (3H, s) 4.86 (2H, s) 5.74 (2H, s) 7.05-8.68 (14H, m) 9.05 (1H, s)

[[6- [4- [2- (4-morpholinyl) ethoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid ethyl ester (Compound 72Et), [[6- [4- [2 -(4-Morpholinyl) ethoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid ethyl ester hydrochloride (compound 72 Et.HCl), [[6- [4- [2- (4-morpholinyl) ) Ethoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid sodium salt (compound 72 · Na) Compound 52 · HCl (464 mg) obtained in Example 52 in DMF (10 ml) To the mixture were added potassium carbonate (553 mg) and ethyl bromoacetate (217 mg), and the mixture was stirred at room temperature for 4 days. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (20 ml) was added to the residue for crystallization. The precipitated crystals were collected by filtration, washed with water, and recrystallized from ethanol (10 ml) to obtain white solid compound 72Et (311 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 1.25 (3H, t, J = 7 Hz) 2.54 (4H, t, J = 5 Hz) 2.82 (2H, t, J = 6 Hz) 3.60 (4H, t, J = 5 Hz) 4.23 (2H, q, J = 7 Hz) 4.72 (2H, t, J = 6 Hz) 4.96 (2H, s) 7.24-7.64 (6H, m) 7.88-8. 69 (5H, m) 9.04 (1H, s)
Compound 72Et (77 mg), 1N hydrochloric acid (0.2 ml) were dissolved in ethanol (20 ml), and concentrated under reduced pressure to obtain yellow solid compound 72Et.HCl.
1N sodium hydroxide (0.5 ml) was added to compound 72Et (205 mg) in ethanol (4 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was cooled, and the precipitated crystals were collected by filtration and dried to obtain a white solid compound 72 • Na (111 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 2.59-2.93 (6H, m) 3.73-3.77 (4H, m) 4.57-4.75 (4H, m) 7.02-8.59 (11H, m) 8.87 (1H, s)

4-[[6- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 73Et), 4-[[6- [4-Phenyl-6 -(Phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid (Compound 73) and its sodium salt (Compound 73 · Na) Compound 50 obtained in Example 50 in DMF (40 ml) To (2.0 g), potassium carbonate (1.35 g) and ethyl 4-bromo-n-butyrate (1.15 g) were added, and the mixture was stirred at room temperature for 22 hours and further at 70-75 ° C. for 2.5 hours. The reaction solution was cooled, and the precipitate was collected by filtration. The obtained crystals were washed with water and dried to give compound 73Et (1.96 g).
1H-NMR (Chloroform-d / TMS):
δ = 1.27 (3H, t, J = 7 Hz) 1.95-2.73 (4H, m) 4.00-4.36 (4H, m) 5.67 (2H, s) 7.08- 8.29 (15H, m) 8.67 (1H, d, J = 9 Hz) 9.02 (1H, s)
1N sodium hydroxide (4.2 ml) was added to compound 73Et (1.82 g) in ethanol (40 ml) and hydrolyzed under reflux for 5.5 hours. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (100 ml) by heating, and then activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (4.2 ml) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 73 (1.62 g).
Compound 73 (245 mg), 1N sodium hydroxide (0.5 ml) was dissolved in water (30 ml) by heating and then freeze-dried to obtain compound 73 • Na.
1H-NMR (Methanol-d4 / TMS):
δ = 2.5-2.56 (4H, m) 4.14 (2H, t, J = 6 Hz) 5.59 (2H, s) 7.10-8.26 (15H, m) 8.52 ( 1H, d, J = 9 Hz) 8.89 (1H, s)

4-[[6- (1,4-Dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester (compound 74Et), 4-[[6- (1, Preparation of 4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] butanoic acid (Compound 74) and its disodium salt (Compound 74.2Na) Example 73 in toluene (700 ml) The compound 73Et (11.1 g) obtained in 1 was dissolved, ethanol (700 ml) and 5% palladium carbon (3 g) were added, and the mixture was stirred in a hydrogen stream at 55-60 ° C. for 20 hours. The reaction solution was refluxed and filtered, and then the filtrate was cooled. The precipitated crystals were collected by filtration and dried to obtain white solid compound 74Et (6.93 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.20 (3H, t, J = 7 Hz) 1.95-2.66 (4H, m) 3.93-4.28 (4H, m) 6.93 (1H, s) 7.17- 7.60 (5H, m) 7.92-8.43 (5H, m) 8.83 (1H, s) 12.73 (1H, br s)
In methanol (200 ml), 1N sodium hydroxide (4.0 ml) was added to and dissolved in compound 73 (981 mg) obtained in Example 73, 5% palladium on carbon (245 mg) was added, and in a hydrogen stream, Stir overnight at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water (60 ml) and 1N hydrochloric acid (4.0 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 74 (702 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 1.92−2.51 (4H, m) 4.18 (2H, t, J = 6 Hz) 6.92 (1H, s) 7.18-7.60 (5H, m) 7.92− 8.45 (5H, m) 8.81 (1H, s) 11.48-13.19 (2H, br)
Compound 74 (200 mg), 1N sodium hydroxide (1 ml) was dissolved in water (30 ml) by heating and then freeze-dried to obtain compound 74.2Na.

4-[[6- [4- (2-Ethoxy-2-oxoethoxy) -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 75Et), 4-[[6- Preparation of [4- (Carboxymethoxy) -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid disodium salt (Compound 75 • 2Na) Compound obtained in Example 74 in DMF (10 ml) To 74 Et (214 mg) were added potassium carbonate (138 mg) and ethyl bromoacetate (100 mg), and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (20 ml), collected by filtration, and then washed with water to obtain a white solid compound 75Et. 1N sodium hydroxide (1 ml) was added to compound 75Et in ethanol (10 ml) and hydrolyzed under reflux for 2 hours. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and then dried to obtain white solid compound 75.2Na (164 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 2.03-2.40 (4H, m) 4.18 (2H, t, J = 6 Hz) 4.97 (2H, s) 7.12-7.26 (3H, m) 7.50- 7.59 (3H, m) 7.76-8.01 (2H, m) 8.21-8.35 (2H, m) 8.61 (1H, d, J = 9 Hz) 8.98 (1H, s)

4-[[2- [6- (4-Ethoxy-4-oxobutoxy) -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] butanoic acid ethyl ester (Compound 76Et), 4-[[2- [ 6- (3-Carboxypropoxy) -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] butanoic acid (Compound 76) and its disodium salt (Compound 76.2Na) Implementation in DMF (50 ml) Potassium carbonate (5.53 g) and ethyl 4-bromo-n-butyrate (4.68 g) were added to compound 37 (3.14 g) obtained in Example 37, and the mixture was stirred at room temperature for 20 hours and further at 75 ° C. for 2 hours. did. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was partitioned with chloroform (150 ml) -water (150 ml). The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain an oily compound 76Et. 1N sodium hydroxide (30 ml) was added to compound 76Et in ethanol (50 ml) and hydrolyzed under reflux for 2 hours. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (150 ml), and then activated carbon (0.1 g) was added and filtered. 35% hydrochloric acid (3.2 g) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 76 (4.31 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.95-2.48 (8H, m) 4.17 (2H, t, J = 6 Hz) 4.61 (2H, t, J = 6 Hz) 7.17-7.63 (6H, m) 7.87-8.15 (2H, m) 8.30-8.66 (3H, m) 9.02 (1H, s) 12.16 (1H, br s)
Compound 76 (487 mg), 1N sodium hydroxide (2 ml) was dissolved in water (100 ml) and filtered, and then the filtrate was lyophilized to obtain Compound 76.2Na as a white solid.

4-[[6- [4- [2- (4-morpholinyl) ethoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 77Et), 4-[[6- Preparation of [4- [2- (4-morpholinyl) ethoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid (Compound 77) and its hydrochloride (Compound 77 · HCl) DMF (7 ml ), Potassium carbonate (387 mg), 4- (2-chloroethyl) morpholine hydrochloride (156 mg) and potassium iodide (58 mg) were added to compound 74Et (300 mg) obtained in Example 74, and the mixture was added at 80 ° C. for 2 hours. Stir. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (20 ml), collected by filtration, and then washed with water to obtain a white solid compound 77Et. 1N sodium hydroxide (0.9 ml) was added to compound 77Et in ethanol (10 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was concentrated under reduced pressure, and water (20 ml) and 1N hydrochloric acid (0.9 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 77 (204 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 1.94-2.50 (4H, m) 2.83-3.86 (10H, m) 4.19 (2H, t, J = 6 Hz) 4.86 (2H, t, J = 6 Hz) 7.42-8.70 (11H, m) 9.03 (1H, s)
Compound 77 (180 mg), 1N hydrochloric acid (0.35 ml) was dissolved in methanol (15 ml) by heating, and then concentrated under reduced pressure to obtain compound 77 • HCl as a yellow solid.

4-[[6- [4-Phenyl-6-[(3-pyridinyl) methoxy] -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 78Et), 4-[[6- [4 Preparation of -phenyl-6-[(3-pyridinyl) methoxy] -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid (Compound 78) and its sodium salt (Compound 78 Na) Implementation in DMF (30 ml) Potassium carbonate (829 mg) and 3- (bromomethyl) pyridine hydrobromide (607 mg) were added to compound 74Et (857 mg) obtained in Example 74, and the mixture was stirred at room temperature for 20 hours and further at 80 ° C. for 1 hour, Potassium carbonate (829 mg) and 3- (bromomethyl) pyridine hydrobromide (405 mg) were added, and the mixture was stirred at the same temperature for 2 hours. Water (300 ml) and potassium carbonate (30 g) were added to the reaction solution for crystallization, and the precipitate was collected by filtration. The obtained crystals were recrystallized from ethanol (200 ml) to obtain white solid compound 78Et (622 mg).
1N sodium hydroxide (2 ml) was added to compound 78Et (520 mg) in ethanol (20 ml) and hydrolyzed under reflux for 30 minutes. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (50 ml), and then activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (2 ml) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 78 (374 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 1.90-2.48 (4H, m) 4.18 (2H, t, J = 6 Hz) 5.74 (2H, s) 7.19-7.57 (7H, m) 7.89- 8.68 (7H, m) 8.87 (1H, s) 9.03 (1H, s) 12.13 (1H, br s)
Compound 78 (245 mg), 1N sodium hydroxide (0.5 ml) were dissolved in water (50 ml), and then lyophilized to obtain Compound 78 · Na as a white solid.

4-[[6- [4-Phenyl-6-[(4-pyridinyl) methoxy] -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester hydrochloride (Compound 79Et.HCl), 4-[[ Preparation of 6- [4-phenyl-6-[(4-pyridinyl) methoxy] -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid (Compound 79) and its sodium salt (Compound 79 · Na) DMF (15 ml ), Potassium carbonate (829 mg) and 4- (chloromethyl) pyridine hydrochloride (394 mg) were added to compound 74Et (857 mg) obtained in Example 74, and the mixture was stirred at 80 ° C. for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water (50 ml) was added to the residue for crystallization, and the precipitate was collected by filtration. The obtained crystals were dissolved by heating in acetone (100 ml), and activated carbon (0.1 g) was added and filtered. The filtrate was acidified by adding 35% hydrochloric acid (0.5 ml), collected by filtration and dried to obtain a yellow solid compound 79Et.HCl (699 mg).
To the compound 79Et.HCl (556 mg), 1N sodium hydroxide (3 ml) was added in ethanol (30 ml) and hydrolyzed under reflux for 3 hours. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (70 ml), and then activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (2 ml) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain gray solid compound 79 (326 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 1.94−2.51 (4H, m) 4.18 (2H, t, J = 6 Hz) 5.75 (2H, s) 7.19-7.64 (8H, m) 7.86− 8.13 (2H, m) 8.33-8.69 (5H, m) 8.97 (1H, s) 11.46-12.84 (1H, br)
Compound 79 (245 mg), 1N sodium hydroxide (0.5 ml) were dissolved in water (50 ml), filtered, and the filtrate was lyophilized to obtain Compound 79 • Na as a white solid.

4-[[[2- [6- (4-Ethoxy-4-oxobutoxy) -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] methyl] benzoic acid methyl ester (compound 80Me), 4- [ [[2- [6- (3-Carboxypropoxy) -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] methyl] benzoic acid (Compound 80) and its disodium salt (Compound 80 · 2Na) In DMF (15 ml), potassium carbonate (415 mg) and methyl 4- (bromomethyl) benzoate (412 mg) were added to the compound 74Et obtained in Example 74 (643 mg) and stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed successively with methanol (30 ml) and water (10 ml) and then dried to obtain white solid compound 80Me (0.8 g).
1N sodium hydroxide (3.9 ml) was added to compound 80Me (750 mg) in ethanol (40 ml) and hydrolyzed under reflux for 2 hours. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (100 ml), and then activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (4 ml) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 80 (559 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 1.95-2.50 (4H, m) 4.17 (2H, t, J = 6 Hz) 5.77 (2H, s) 7.14-8.67 (15H, m) 9.00 ( 1H, s) 11.61-13.25 (1H, br)
Compound 80 (267 mg), 1N sodium hydroxide (1 ml) were dissolved in water (50 ml) and then lyophilized to obtain white solid compound 80.2Na.

4-[[6- [4-[(2-Chlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 81Et), 4-[[6- [4 Preparation of-[(2-chlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 81 · Na) Obtained in Example 74 in DMF (15 ml). To compound 74Et (643 mg) were added potassium carbonate (415 mg) and 2-chlorobenzyl bromide (370 mg), and the mixture was stirred at room temperature for 20 hours. Water (150 ml) was added to the reaction solution for crystallization, and the residue was collected by filtration and dried to obtain white solid compound 81Et (748 mg).
1N sodium hydroxide (2.6 ml) was added to compound 81Et (719 mg) in ethanol (30 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and then dried to obtain white solid compound 81 • Na (559 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 2.2-2.41 (4H, m) 4.16 (2H, t, J = 6 Hz) 5.72 (2H, s) 7.11-7.94 (12H, m) 8.16- 8.32 (2H, m) 8.54 (1H, d, J = 8 Hz) 8.89 (1H, s)

4-[[6- [4-[(3-Chlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 82Et), 4-[[6- [4 Preparation of-[(3-Chlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 82 Na) Obtained in Example 74 in DMF (8 ml). To compound 74Et (171 mg) were added potassium carbonate (111 mg) and 3-chlorobenzyl bromide (99 mg), and the mixture was stirred at room temperature for 26 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (20 ml) was added to the residue for crystallization. The precipitate was collected by filtration to obtain Compound 82Et. 1N sodium hydroxide (0.8 ml) was added to compound 82Et in ethanol (10 ml) and hydrolyzed under reflux for 2.5 hours. The hydrolyzed solution was cooled, and the precipitated crystals were collected by filtration and dried to obtain Compound 82 • Na (171 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 2.02-2.50 (4H, m) 4.15 (2H, t, J = 6 Hz) 5.54 (2H, s) 7.05-8.59 (15H, m) 8.87 ( 1H, s)

4-[[6- [4-[(4-Chlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 83Et), 4-[[6- [4 Preparation of-[(4-chlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (compound 83.Na) Obtained in Example 74 in DMF (8 ml). To compound 74Et (171 mg) were added potassium carbonate (111 mg) and 4-chlorobenzyl bromide (99 mg), and the mixture was stirred at room temperature for 27 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (20 ml) was added to the residue for crystallization. The precipitate was collected by filtration to obtain Compound 83Et. 1N sodium hydroxide (0.8 ml) was added to compound 83Et in ethanol (10 ml) and hydrolyzed under reflux for 2 hours. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and dried to obtain Compound 83 • Na (158 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 1.98-2.58 (4H, m) 4.14 (2H, t, J = 6 Hz) 5.53 (2H, s) 7.10-8.58 (15H, m) 8.87 ( 1H, s)

4-[[6- [4-[(2,6-dichlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 84Et), 4-[[6- Preparation of [4-[(2,6-dichlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (compound 84.Na) Example 74 in DMF (5 ml) Potassium carbonate (138 mg) and 2,6-dichlorobenzyl bromide (144 mg) were added to the compound 74Et (214 mg) obtained in 1 above and stirred at room temperature for 3 days. The reaction solution was cooled, and the precipitate was collected by filtration and washed with water to obtain a white solid compound 84Et. To the compound 84Et, 1N sodium hydroxide (1 ml) was added in ethanol (15 ml) and hydrolyzed under reflux for 3 hours. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and dried to obtain white solid compound 84 • Na (177 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 1.84 to 2.04 (4H, m) 4.16 (2H, t, J = 6 Hz) 5.90 (2H, s) 7.18-7.72 (9H, m) 7.88- 8.73 (5H, m) 9.08 (1H, s)

4-[[6- [4-[(2-Fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 85Et), 4-[[6- [ 4-[(2-Fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (compound 85.Na) obtained in Example 74 in DMF (8 ml) To the obtained compound 74Et (171 mg) were added potassium carbonate (111 mg) and 2-fluorobenzyl bromide (91 mg), and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (15 ml), collected by filtration, and washed with water to obtain a white solid compound 85Et. 1N sodium hydroxide (0.8 ml) was added to compound 85Et in ethanol (10 ml) and hydrolyzed under reflux for 2 hours. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and then dried to obtain a white solid compound 85 • Na (151 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 2.4-2.42 (4H, m) 4.16 (2H, t, J = 6 Hz) 5.69 (2H, s) 7.05-7.94 (12H, m) 8.14- 8.30 (2H, m) 8.56 (1H, d, J = 9 Hz) 8.91 (1H, s)
In DMF (15 ml), potassium carbonate (276 mg) and 4-bromo-n-ethyl butyrate (235 mg) were added to compound 49 (422 mg) obtained in Example 49, and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, and n-hexane (30 ml) was added to the residue for crystallization. The precipitate was collected by filtration and washed with water to obtain an ester. The compound obtained by hydrolyzing the ester in the same manner as described above was confirmed to be Compound 85 · Na from the measurement result of 1H-NMR.

4-[[6- [4-[(3-Fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 86Et), 4-[[6- [ 4-[(3-Fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (compound 86 · Na) obtained in Example 74 in DMF (8 ml) To the obtained compound 74Et (171 mg) were added potassium carbonate (111 mg) and 3-fluorobenzyl bromide (91 mg), and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (15 ml), collected by filtration, and washed with water to obtain a white solid compound 86Et. 1N sodium hydroxide (0.8 ml) was added to compound 86Et in ethanol (10 ml) and hydrolyzed under reflux for 2 hours. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and dried to obtain a white solid compound 86 • Na (129 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 2.5-2.41 (4H, m) 4.16 (2H, t, J = 6 Hz) 5.61 (2H, s) 7.00-7.95 (12H, m) 8.16- 8.32 (2H, m) 8.54 (1H, d, J = 9 Hz) 8.90 (1H, s)

4-[[6- [4-[(4-Fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 87Et), 4-[[6- [ 4-[(4-Fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (compound 87 · Na) obtained in Example 74 in DMF (8 ml) To the obtained compound 74Et (171 mg) were added potassium carbonate (111 mg) and 4-fluorobenzyl bromide (91 mg), and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (15 ml), collected by filtration, and washed with water to obtain a white solid compound 87Et. 1N sodium hydroxide (0.8 ml) was added to compound 87Et in ethanol (10 ml) and hydrolyzed under reflux for 2 hours. The hydrolyzed solution was cooled, and the precipitated crystals were collected by filtration and then dried to obtain a white solid compound 87 • Na (98 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 2.4-2.41 (4H, m) 4.16 (2H, t, J = 6 Hz) 5.59 (2H, s) 6.97-7.26 (5H, m) 7.47- 7.96 (7H, m) 8.16-8.31 (2H, m) 8.55 (1H, d, J = 10 Hz) 8.93 (1H, s)

4-[[6- [4-[(2,6-difluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 88Et), 4-[[6 Preparation of-[4-[(2,6-difluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 88 Na) Implementation in DMF (7 ml) To the compound 74Et (300 mg) obtained in Example 74 were added potassium carbonate (193 mg) and 2,6-difluorobenzyl bromide (174 mg), and the mixture was stirred at room temperature for 3 days. DMF (20 ml) was added to the reaction solution and filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (20 ml), collected by filtration, and washed with water to obtain a white solid compound 88Et. 1N sodium hydroxide (0.9 ml) was added to compound 88Et in ethanol (10 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and then dried to obtain a white solid compound 88 • Na (297 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 2.20−2.58 (4H, m) 4.16 (2H, t, J = 6 Hz) 5.74 (2H, s) 6.85-8.29 (13H, m) 8.59 ( 1H, d, J = 9 Hz) 8.98 (1H, s)

4-[[6- [4-[(2,4-Difluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 89Et), 4-[[6 Preparation of [4-[(2,4-difluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 89 Na) Implementation in DMF (10 ml) To the compound 74Et (214 mg) obtained in Example 74 were added potassium carbonate (138 mg) and 2,4-difluorobenzyl bromide (135 mg), and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (10 ml), collected by filtration, and washed with water to obtain a white solid compound 89Et. 1N Sodium hydroxide (0.6 ml) was added to compound 89Et in ethanol (5 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was cooled, and the precipitated crystals were collected by filtration and then dried to obtain a white solid compound 89 · Na (161 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 2.14-2.40 (4H, m) 4.17 (2H, t, J = 6 Hz) 5.65 (2H, s) 6.85-7.95 (11H, m) 8.15- 8.31 (2H, m) 8.56 (1H, d, J = 9 Hz) 8.94 (1H, s)

4-[[6- [4-[(pentafluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 90Et), 4-[[6- [4 Preparation of-[(Pentafluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (compound 90 · Na) Obtained in Example 74 in DMF (10 ml). To compound 74Et (214 mg) were added potassium carbonate (138 mg) and pentafluorobenzyl bromide (170 mg), and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with water to obtain a white solid compound 90Et. 1N sodium hydroxide (0.6 ml) was added to compound 90Et in ethanol (5 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and then dried to obtain a white solid compound 90 • Na (159 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 2.15-2.41 (4H, m) 4.17 (2H, t, J = 6 Hz) 5.75 (2H, s) 7.12-7.26 (3H, m) 7.47- 7.57 (3H, m) 7.75-7.90 (2H, m) 8.15-8.32 (2H, m) 8.55 (1H, d, J = 9 Hz) 8.94 (1H, s)

4-[[6- [4-[(2-Bromophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 91Et), 4-[[6- [ 4-[(2-Bromophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (compound 91 • Na) obtained in Example 74 in DMF (5 ml) To the obtained compound 74Et (214 mg) were added potassium carbonate (138 mg) and 2-bromobenzyl bromide (150 mg), and the mixture was stirred at room temperature for 20 hours. DMF (10 ml) was added to the reaction solution, followed by filtration, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (30 ml), collected by filtration, and washed with water to obtain a white solid compound 91Et. 1N sodium hydroxide (1 ml) was added to compound 91Et in ethanol (15 ml) and hydrolyzed under reflux for 3 hours. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and dried to obtain a white solid compound 91 • Na (208 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 2.03-2.40 (4H, m) 4.16 (2H, t, J = 6 Hz) 5.70 (2H, s) 7.08-7.94 (12H, m) 8.16- 8.31 (2H, m) 8.54 (1H, d, J = 9 Hz) 8.91 (1H, s)

4-[[6- [4-[(4-Bromophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 92Et), 4-[[6- [ 4-[(4-Bromophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (compound 92 · Na) obtained in Example 74 in DMF (8 ml) To the obtained compound 74Et (171 mg) were added potassium carbonate (111 mg) and 4-bromobenzyl bromide (120 mg), and the mixture was stirred at room temperature for 24 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (20 ml) was added to the residue for crystallization. The precipitate was collected by filtration to obtain Compound 92Et. 1N sodium hydroxide (0.8 ml) was added to compound 92Et in ethanol (10 ml) and hydrolyzed under reflux for 1.5 hours. The hydrolyzed solution was cooled, and the precipitated crystals were collected by filtration and dried to obtain Compound 92 · Na (171 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 1.91−2.57 (4H, m) 4.15 (2H, t, J = 6 Hz) 5.67 (2H, s) 7.12-8.60 (15H, m) 8.89 ( 1H, s)

4-[[6- [4-[(2-Fluorophenyl) methoxy] -6- (4-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 93Et), 4- Preparation of [[6- [4-[(2-fluorophenyl) methoxy] -6- (4-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (compound 93 · Na) DMF In (10 ml), potassium carbonate (276 mg) and ethyl 4-bromo-n-butanoate (234 mg) were added to compound 46 (467 mg) obtained in Example 46, and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (10 ml) was added to the residue for crystallization. The precipitate was collected by filtration, washed with water, and dried to give a yellow solid compound 93Et (515 mg).
1N sodium hydroxide (1 ml) was added to compound 93Et (515 mg) in ethanol (10 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was cooled, and the precipitated crystals were collected by filtration and dried to obtain a yellow solid compound 93 • Na (405 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 2.14-2.40 (4H, m) 4.12 (2H, t, J = 6 Hz) 5.57 (2H, s) 7.06-7.87 (9H, m) 8.18- 8.36 (5H, m) 8.77 (1H, s)

4-[[6- [4-[(2-Fluorophenyl) methoxy] -6- (3-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 94Et), 4- Preparation of [[6- [4-[(2-fluorophenyl) methoxy] -6- (3-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 94 · Na) DMF (10 ml), potassium carbonate (276 mg) and ethyl 4-bromo-n-butyrate (234 mg) were added to the compound 47 (467 mg) obtained in Example 47, and the mixture was stirred at room temperature for 19 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and n-hexane (30 ml) was added to the residue for crystallization. The precipitate was collected by filtration, washed with water, and dried to give Compound 94Et (462 mg).
1N sodium hydroxide (1.1 ml) was added to compound 94Et (462 mg) in ethanol (20 ml) and hydrolyzed under reflux for 1.5 hours. About half of the solvent was distilled off from the hydrolyzed solution under reduced pressure, and the remaining solution was cooled. The precipitated crystals were collected by filtration and dried to obtain Compound 94 · Na (320 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 1.88-2.59 (4H, m) 4.10 (2H, t, J = 6 Hz) 5.51 (2H, s) 6.86-7.88 (10H, m) 8.14- 8.53 (3H, m) 8.68-8.80 (2H, m)

4-[[6- [4-[(2-Fluorophenyl) methoxy] -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 95Et), 4- Preparation of [[6- [4-[(2-fluorophenyl) methoxy] -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (compound 95 · Na) DMF In (10 ml), potassium carbonate (276 mg) and ethyl 4-bromo-n-butyrate (234 mg) were added to compound 48 (452 mg) obtained in Example 48, and the mixture was stirred at room temperature for 20 hours. Water (100 ml) was added to the reaction solution for crystallization, and after filtration, it was dried to obtain white solid compound 95Et (340 mg).
1N sodium hydroxide (1 ml) was added to compound 95Et (340 mg) in ethanol (10 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was cooled, and the precipitated crystals were collected by filtration and dried to obtain a white solid compound 95 • Na (315 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 2.05-2.41 (4H, m) 3.87 (3H, s) 4.17 (2H, t, J = 6 Hz) 5.69 (2H, s) 6.97-7.96 ( 11H, m) 8.20 (2H, d, J = 9 Hz) 8.56 (1H, d, J = 8 Hz) 8.93 (1H, s)

4-[[6- [4-[(2-Methylphenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 96Et), 4-[[6- [ 4-[(2-Methylphenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 96 Na) Obtained in Example 74 in DMF (7 ml). To the obtained compound 74Et (300 mg), potassium carbonate (193 mg) and 2-methylbenzyl bromide (155 mg) were added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (20 ml), collected by filtration, and then washed with water to obtain a white solid compound 96Et. 1N sodium hydroxide (0.9 ml) was added to compound 96Et in ethanol (10 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and dried to obtain white solid compound 96 • Na (250 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 2.5-2.46 (7H, m) 4.16 (2H, t, J = 6 Hz) 5.64 (2H, s) 7.12-7.57 (10H, m) 7.75- 7.95 (2H, m) 8.15-8.31 (2H, m) 8.57 (1H, d, J = 9 Hz) 8.93 (1H, s)

4-[[6- [4-[(2-Nitrophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 97Et), 4-[[6- [ 4-[(2-Nitrophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (compound 97 Na) obtained in Example 74 in DMF (10 ml) To the obtained compound 74Et (428 mg), potassium carbonate (276 mg) and 2-nitrobenzyl bromide (259 mg) were added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (20 ml) was added to the residue for crystallization. The precipitate was collected by filtration, washed with water, and then dried to obtain white solid compound 97Et (446 mg).
1N sodium hydroxide (0.9 ml) was added to compound 97Et (446 mg) in ethanol (10 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and dried to obtain white solid compound 97 • Na (387 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 1.95−2.51 (4H, m) 4.13 (2H, t, J = 6 Hz) 5.88 (2H, s) 7.07-8.49 (15H, m) 8.71 ( 1H, s)

4-[[6- [4-[(2-cyanophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 98Et), 4-[[6- [ 4-[(2-Cyanophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (compound 98 · Na) obtained in Example 74 in DMF (10 ml) To the obtained compound 74Et (428 mg), potassium carbonate (276 mg) and 2-cyanobenzyl bromide (235 mg) were added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (20 ml) was added to the residue for crystallization. The precipitate was collected by filtration, washed with water, and dried to give white solid compound 98Et (448 mg).
1N Sodium hydroxide (0.8 ml) was added to Compound 98Et (448 mg) in ethanol (10 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and then dried to obtain a white solid compound 98 • Na (367 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 2.2-2.40 (4H, m) 4.13 (2H, t, J = 7 Hz) 5.72 (2H, s) 7.05-7.94 (12H, m) 8.13- 8.28 (2H, m) 8.49 (1H, d, J = 9 Hz) 8.87 (1H, s)

4-[[6- [4-[(2-methoxyphenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 99Et), 4-[[6- [ Preparation of 4-[(2-methoxyphenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 99 · Na) Obtained in Example 74 in DMF (20 ml). To the obtained compound 74Et (428 mg) were added potassium carbonate (276 mg) and 2-methoxybenzyl chloride (188 mg), and the mixture was stirred at room temperature for 20 hours and further at 80 ° C. for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (20 ml), collected by filtration, and washed with water to give a white solid compound 99Et. 1N sodium hydroxide (1.2 ml) was added to compound 99Et in ethanol (10 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was cooled, and the precipitated crystals were collected by filtration and then dried to obtain a white solid compound 99 • Na (320 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 2.5-2.42 (4H, m) 3.92 (3H, s) 4.16 (2H, t, J = 6 Hz) 5.66 (2H, s) 6.97-7.56 ( 10H, m) 7.75-7.95 (2H, m) 8.15-8.31 (2H, m) 8.56 (1H, d, J = 9 Hz) 8.92 (1H, s)

Preparation of 4-[[6- [4-[[2- (acetyloxy) phenyl] methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 100 Et) DMF (20 ml ), Potassium carbonate (276 mg) and 2-acetoxybenzyl chloride (222 mg) were added to compound 74Et (428 mg) obtained in Example 74, and the mixture was stirred at room temperature for 20 hours and further at 80 ° C. for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Ethanol (10 ml) was added to the residue for crystallization, and after filtration, the residue was washed with water to obtain a crude product. The crude product was recrystallized from ethanol (30 ml) to obtain a white solid compound 100Et (79 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 1.20 (3H, t, J = 7 Hz) 1.97-2.53 (7H, m) 3.92-4.28 (4H, m) 5.67 (2H, s) 7.11- 7.75 (10H, m) 7.88-8.14 (2H, m) 8.29-8.68 (3H, m) 9.01 (1H, s)

4-[[6- [4- (3-Chloropropoxy) -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 101Et), 4-[[6- [4- ( 3-Chloropropoxy) -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid (Compound 101) and its sodium salt (Compound 101 · Na) Obtained in Example 74 in DMF (7 ml). To the obtained compound 74Et (300 mg) were added potassium carbonate (193 mg) and 1,3-bromochloropropane (165 mg), and the mixture was stirred at room temperature for 3 days. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (20 ml), collected by filtration, and then washed with water to obtain a white solid compound 101Et. 1N sodium hydroxide (0.8 ml) was added to compound 101Et in ethanol (10 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was concentrated under reduced pressure, and water (20 ml) and 1N hydrochloric acid (0.8 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 101 (216 mg).
Compound 101 (167 mg), 1N sodium hydroxide (0.35 ml) was dissolved in water (30 ml) by heating and filtered, and then the filtrate was lyophilized to give Compound 101 • Na as a white solid.
1H-NMR (DMSO-d6 / TMS):
δ = 1.94−2.51 (6H, m) 3.88 (2H, t, J = 6 Hz) 4.17 (2H, t, J = 6 Hz) 4.72 (2H, t, J = 6 Hz) 7.17-7.63 (6H, m) 7.87-8.66 (5H, m) 9.02 (1H, s)

5-[[6- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] pentanoic acid ethyl ester (Compound 102Et), 5-[[6- [4-Phenyl-6 Preparation of-(phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] pentanoic acid (Compound 102) and its sodium salt (Compound 102 · Na) Compound 50 obtained in Example 50 in DMF (30 ml) Potassium carbonate (1.02 g) and ethyl 5-bromovalerate (0.93 g) were added to (1.50 g), and the mixture was stirred at room temperature for 20 hours and further at 75 ° C. for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was partitioned with chloroform (150 ml) -water (150 ml). The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain oily compound 102Et. 1N Sodium hydroxide (5.5 ml) was added to Compound 102Et in ethanol (40 ml) and hydrolyzed under reflux for 2 hours. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (100 ml), and then activated carbon (0.1 g) was added and filtered. 1N Hydrochloric acid (5.5 ml) was added to the filtrate for acid precipitation, followed by filtration to obtain a crude product. The crude product was recrystallized from acetone (60 ml) to obtain a white solid compound 102 (1.13 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.67-1.83 (4H, m) 2.34 (2H, t, J = 6 Hz) 4.16 (2H, t, J = 5 Hz) 5.70 (2H, s) 7.16- 7.64 (11H, m) 7.87-8.15 (2H, m) 8.30-8.69 (3H, m) 9.03 (1H, s) 11.41-12.64 (1H, br)
Compound 102 (252 mg), 1N sodium hydroxide (1 ml) was dissolved in water (50 ml) by heating and filtered, and then the filtrate was lyophilized to obtain Compound 102 · Na as a white solid.

5-[[6- (1,4-Dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] pentanoic acid (Compound 103) and its disodium salt (Compound 103 · 2Na) Production In methanol (160 ml), 1N sodium hydroxide (3.2 ml) was added to and dissolved in compound 102 (807 mg) obtained in Example 102, 5% palladium on carbon (400 mg) was added, and hydrogen gas was added. And stirred at room temperature for 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and then water (60 ml) and 1N hydrochloric acid (3.2 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 103 (589 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 1.76-1.91 (4H, m) 2.33 (2H, t, J = 6 Hz) 4.17 (2H, t, J = 5 Hz) 6.91 (1H, s) 7.18− 7.60 (5H, m) 7.87-8.44 (5H, m) 8.13 (1H, s) 12.37 (1H, br s)
Compound 103 (207 mg), 1N sodium hydroxide (1 ml) was dissolved in water (50 ml), filtered, and the filtrate was lyophilized to obtain Compound 103.2Na as a white solid.

5-[[2- [6-[(5-Ethoxy-5-oxopentyl) oxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] pentanoic acid ethyl ester (Compound 104Et), 5- [ Preparation of [2- [6- (4-carboxybutoxy) -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] pentanoic acid (Compound 104) and its disodium salt (Compound 104 · 2Na) DMF (50 ml ), Potassium carbonate (5.53 g) and ethyl 5-bromovalerate (5.02 g) were added to compound 37 (3.14 g) obtained in Example 37, and 20 hours at room temperature and further at 75 ° C. for 20 hours. Stir for hours. Water (700 ml) and sodium carbonate (50 g) were added to the reaction solution for crystallization. The precipitated crystals were collected by filtration and dried to obtain white solid compound 104Et (4.43 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.18 (6H, t, J = 7 Hz) 1.64-2.01 (8H, m) 2.25-2.51 (4H, m) 3.90-4.24 (6H, m) 4.61 (2H, t, J = 6 Hz) 7.15-7.63 (6H, m) 7.86-8.15 (2H, m) 8.28-8.68 (3H, m) 01 (1H, s)
1N sodium hydroxide (22.5 ml) was added to compound 104Et (4.28 g) in ethanol (50 ml) and hydrolyzed under reflux for 2 hours. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (150 ml), and then activated carbon (0.1 g) was added and filtered. 35% hydrochloric acid (2.5 g) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 104 (3.61 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.56−2.05 (8H, m) 2.26−2.51 (4H, m) 4.16 (2H, t, J = 6 Hz) 4.61 (2H, t, J = 5 Hz) 7.17-7.63 (6H, m) 7.86-8.15 (2H, m) 8.30-8.67 (3H, m) 9.01 (1H, s) 12.05 (1H, br s)
Compound 104 (515 mg), 1N sodium hydroxide (2 ml) was dissolved in water (100 ml) and filtered, and then the filtrate was freeze-dried to obtain white solid compound 104 · 2Na.

6-[[6- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 105Et), 6-[[6- [4-Phenyl-6 -(Phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid (Compound 105) and its sodium salt (Compound 105 · Na) Compound 50 obtained in Example 50 in DMF (30 ml) Potassium carbonate (1.02 g) and ethyl 6-bromohexanoate (0.99 g) were added to (1.50 g), and the mixture was stirred at room temperature for 4 hours and further at 75 ° C. for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was partitioned with chloroform (150 ml) -water (150 ml). The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain oily compound 105Et. 1N sodium hydroxide (5 ml) was added to compound 105Et in ethanol (40 ml) and hydrolyzed under reflux for 3 hours. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (100 ml), and then activated carbon (0.1 g) was added and filtered. 1N Hydrochloric acid (5 ml) was added to the filtrate for acid precipitation, followed by filtration to obtain a crude product. The crude product was recrystallized with 77% aqueous acetone (52 ml) to obtain a white solid compound 105 (1.33 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.37-2.40 (8H, m) 4.16 (2H, t, J = 6 Hz) 5.70 (2H, s) 7.17-7.62 (11H, m) 7.89- 8.17 (2H, m) 8.20-8.70 (3H, m) 9.04 (1H, s) 11.98 (1H, br s)
Compound 105 (259 mg), 1N sodium hydroxide (0.5 ml) was dissolved in water (50 ml) by heating and filtered, and the filtrate was freeze-dried to obtain white solid compound 105 · Na.

6-[[6- (1,4-Dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] hexanoic acid (Compound 106) and its disodium salt (Compound 106 · 2Na) Production Compound 105 (882 mg) obtained in Example 105 was dissolved in methanol (170 ml), 5% palladium carbon (400 mg) was added, and the mixture was stirred in a hydrogen stream at 40-45 ° C. for 4 hours. 1N Sodium hydroxide (3.5 ml) was added to the reaction solution, followed by filtration, and the filtrate was concentrated under reduced pressure. Water (60 ml) and 1N hydrochloric acid (3.5 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 106 (553 mg).
1H-NMR (DMSO-d6 / TMS)
δ = 1.60-1.93 (6H, m) 2.28 (2H, t, J = 6 Hz) 4.15 (2H, t, J = 6 JHz) 6.92 (1H, s) 7.19- 7.59 (5H, m) 7.91-8.45 (5H, m) 8.83 (1H, s) 11.61-13.05 (1H, br)
Compound 106 (214 mg), 1N sodium hydroxide (1 ml) was dissolved in water (50 ml) and filtered, and then the filtrate was freeze-dried to obtain white solid compound 106.2Na.

6-[[2- [6-[(6-Ethoxy-6-oxohexyl) oxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] hexanoic acid ethyl ester (Compound 107Et), 6- [ Preparation of [2- [6-[(5-carboxypentyl) oxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] hexanoic acid (Compound 107) and its disodium salt (Compound 107-2Na) In DMF (50 ml), potassium carbonate (5.53 g) and ethyl 6-bromohexanoate (5.35 g) were added to compound 37 (3.14 g) obtained in Example 37, and the mixture was further treated at room temperature for 20 hours and further 75. The mixture was stirred at 0 ° C. for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was partitioned with chloroform (100 ml) -water (100 ml). The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain oily compound 107Et. 1N sodium hydroxide (30 ml) was added to compound 107Et in ethanol (50 ml), and the mixture was hydrolyzed under reflux for 2 hours. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (150 ml), and then activated carbon (0.1 g) was added and filtered. 35% hydrochloric acid (3.2 g) was added to the filtrate for acid precipitation, followed by filtration to obtain a crude product. The crude product was recrystallized from ethanol (150 ml) to obtain a white solid compound 107 (3.85 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.40-2.45 (16H, m) 4.13 (2H, t, J = 6 Hz) 4.59 (2H, t, J = 6 Hz) 7.12-7.63 (6H, m) 7.85-8.13 (2H, m) 8.29-8.65 (3H, m) 8.99 (1H, s) 10.99-12.84 (1H, br)
Compound 107 (543 mg), 1N sodium hydroxide (2 ml) was dissolved in water (100 ml) and filtered, and then the filtrate was lyophilized to obtain Compound 107.2Na as a white solid.

6-[[6- [4-[(2-Fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 108Et), 6-[[6- [ 4-[(2-Fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt (compound 108 Na) obtained in Example 49 in DMF (15 ml) To the obtained compound 49 (422 mg) were added potassium carbonate (276 mg) and ethyl 6-bromohexanoate (268 mg), and the mixture was stirred at room temperature for 18 hours and further at 80-90 ° C. for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (20 ml) was added to the residue for crystallization. The precipitate was collected by filtration and washed with water to give compound 108Et. 1N sodium hydroxide (1.1 ml) was added to compound 108Et in ethanol (20 ml) and hydrolyzed under reflux for 1.5 hours. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and dried to obtain Compound 108 • Na (245 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 1.4-2.33 (8H, m) 4.09 (2H, t, J = 6 Hz) 5.66 (2H, s) 7.10-8.36 (14H, m) 8.53 ( 1H, d, J = 9 Hz) 8.89 (1H, s)

6-[[6- [4-[(2-Fluorophenyl) methoxy] -6- (4-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 109Et), 6- Preparation of [[6- [4-[(2-fluorophenyl) methoxy] -6- (4-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt (Compound 109 · Na) DMF (10 ml), potassium carbonate (276 mg) and ethyl 6-bromohexanoate (286 mg) were added to the compound 46 (467 mg) obtained in Example 46, and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (10 ml) was added to the residue for crystallization. The precipitate was collected by filtration, washed with water, and dried to give a yellow solid compound 109Et (508 mg).
1N sodium hydroxide (1 ml) was added to compound 109Et (508 mg) in ethanol (10 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and then dried to obtain a yellow solid compound 109 • Na (390 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 1.5-2.26 (8H, m) 4.06 (2H, t, J = 6 Hz) 5.57 (2H, s) 7.10-7.85 (9H, m) 8.23- 8.48 (5H, m) 8.76 (1H, s)

6-[[6- [4-[(2-Fluorophenyl) methoxy] -6- (3-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 110Et), 6- Preparation of [[6- [4-[(2-fluorophenyl) methoxy] -6- (3-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt (Compound 110 · Na) DMF (10 ml), potassium carbonate (276 mg) and ethyl 6-bromohexanoate (268 mg) were added to compound 47 (467 mg) obtained in Example 47, and the mixture was stirred at room temperature for 20 hours and further at 80-90 ° C. for 2 hours. did. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and n-hexane (30 ml) was added to the residue for crystallization. The precipitate was collected by filtration, washed with water, and dried to give compound 110Et (556 mg).
1N sodium hydroxide (1.1 ml) was added to compound 110Et (556 mg) in ethanol (10 ml) and hydrolyzed under reflux for 1.5 hours. The hydrolyzed solution was cooled, and the precipitated crystals were collected by filtration and dried to obtain Compound 110 · Na (435 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 1.29-2.26 (8H, m) 4.02 (2H, t, J = 6 Hz) 5.48 (2H, s) 6.90-7.74 (10H, m) 8.08- 8.36 (3H, m) 8.61-8.75 (2H, m)

6-[[6- [4-[(2-Fluorophenyl) methoxy] -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 111Et), 6- Preparation of [[6- [4-[(2-fluorophenyl) methoxy] -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt (compound 111 · Na) DMF (10 ml), potassium carbonate (276 mg) and ethyl 6-bromohexanoate (286 mg) were added to compound 48 (452 mg) obtained in Example 48, and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (10 ml) was added to the residue for crystallization. The precipitate was collected by filtration, washed with water, and dried to give an amber solid compound 111Et (481 mg).
To the compound 111Et (481 mg) was added 1N sodium hydroxide (1 ml) in ethanol (10 ml), and the mixture was hydrolyzed under reflux for 1 hour. The hydrolyzed solution was cooled, and the precipitated crystals were collected by filtration and then dried to obtain a white solid compound 111 · Na (426 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 1.61-2.31 (8H, m) 3.86 (3H, s) 4.12 (2H, t, J = 6Hz) 5.68 (2H, s) 6.96-7.95 ( 11H, m) 8.18 (2H, d, J = 9 Hz) 8.55 (1H, d, J = 8 Hz) 8.91 (1H, s)

7-[[6- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] heptanoic acid ethyl ester (Compound 112Et), 7-[[6- [4-Phenyl-6 -(Phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] heptanoic acid (Compound 112) and its sodium salt (Compound 112 · Na) Compound 50 obtained in Example 50 in DMF (32 ml) Potassium carbonate (1.11 g) and methyl 7-bromoheptanoate (1.14 g) were added to (1.62 g), and the mixture was stirred at room temperature for 22 hours and further at 80 ° C. for 2.5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. After the residue solidified, it was washed with water to obtain Compound 112Et. 1N sodium hydroxide (8.0 ml) was added to compound 112Et in ethanol (50 ml) and hydrolyzed under reflux for 3 hours. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (100 ml) by heating, and then activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (8.0 ml) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 112 (1.55 g).
Compound 112 (266 mg), 1N sodium hydroxide (1 ml) was dissolved in water (150 ml) by heating and then freeze-dried to obtain compound 112 · Na.
1H-NMR (Methanol-d4 / TMS):
δ = 1.27-2.32 (10H, m) 3.96 (2H, t, J = 6 Hz) 5.40 (2H, s) 6.88-8.68 (16H, m) 8.75 ( 1H, s)

7-[[6- (1,4-Dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] heptanoic acid (compound 113) and its disodium salt (compound 113 2Na) Preparation In methanol (300 ml), 1N sodium hydroxide (4.0 ml) was added to and dissolved in compound 112 (905 mg) obtained in Example 112, 5% palladium on carbon (450 mg) was added, and hydrogen gas was added. And stirred at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water (40 ml) and 1N hydrochloric acid (4.0 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 113 (634 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 1.25-2.35 (10H, m) 4.14 (2H, t, J = 6 Hz) 6.91 (1H, s) 7.16-8.42 (10H, m) 8.81 ( 1H, s) 12.31 (2H, br s)
Compound 113 (221 mg), 1N sodium hydroxide (1 ml) was dissolved in water (150 ml) by heating and then freeze-dried to obtain compound 113.2Na.

[3-[[6- [4-[(2-Fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] propyl] propanedioic acid diethyl ester (Compound 114Et), [3- [[6- [4-[(2-Fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] propyl] propanedioic acid (compound 114) and its disodium salt (compound 114 2Na) In DMF (10 ml), potassium carbonate (276 mg) and diethyl (3-chloropropyl) malonate (284 mg) were added to compound 49 (422 mg) obtained in Example 49 and stirred at 80 ° C. for 20 hours. did. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column (toluene-chloroform) to obtain an oily compound 114Et. To the compound 114Et was added 1N sodium hydroxide (2.5 ml) in ethanol (10 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzate was cooled and the precipitate was collected by filtration. The obtained crystals were dissolved in water (50 ml) by heating and filtered, and then the filtrate was freeze-dried to obtain white solid compound 114 · 2Na (171 mg). Compound 114.2Na was acidified with 0.1 N hydrochloric acid to obtain Compound 114 as a white solid.
1H-NMR (DMSO-d6 / TMS):
δ = 1.75-2.15 (4H, m) 3.36 (1H, t, J = 6 Hz) 4.19 (2H, t, J = 6 Hz) 5.75 (2H, s) 7.09− 8.70 (15H, m) 9.04 (1H, s)

[3-[[6- [4-[(2-Fluorophenyl) methoxy] -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] propyl] propanedioic acid diethyl ester (Compound 115Et ), [3-[[6- [4-[(2-Fluorophenyl) methoxy] -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] propyl] propanedioic acid (Compound 115). ) And its disodium salt (compound 115 · 2Na) In DMF (10 ml), compound 48 (452 mg) obtained in Example 48 was added to potassium carbonate (276 mg), diethyl (3-chloropropyl) malonate (473 mg). ) And stirred at 80 ° C. for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column (toluene-chloroform) to obtain an oily compound 115Et. 1N sodium hydroxide (5 ml) was added to compound 115Et in ethanol (10 ml) and hydrolyzed under reflux for 2 hours. The hydrolyzed solution was cooled, and the precipitated crystals were collected by filtration and then dried to obtain white solid compound 115.2Na (439 mg). Compound 115 · 2Na was acidified with 0.1 N hydrochloric acid to obtain Compound 115 as a white solid.
1H-NMR (DMSO-d6 / TMS):
δ = 1.89-1.90 (4H, m) 3.37 (1H, t, J = 6 Hz) 3.87 (3H, s) 4.17 (2H, t, J = 5 Hz) 5.73 ( 2H, s) 7.05-8.70 (14H, m) 9.03 (1H, s)

[5-[[6- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid diethyl ester (Compound 1116Et), [5-[[6- [ Preparation of 4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid (compound 116) and its disodium salt (compound 116 2Na) in DMF (30 ml), To compound 50 (1.50 g) obtained in Example 50 were added potassium carbonate (1.02 g) and diethyl 5-bromopentylmalonate (1.37 g), and the mixture was stirred at room temperature for 20 hours and further at 80 ° C. for 3 hours. Then, potassium carbonate (0.51 g) and diethyl 5-bromopentylmalonate (0.92 g) were added, and the mixture was stirred at the same temperature for 1 hour. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain an oily compound 116Et. 1N sodium hydroxide (18.5 ml) was added to compound 116Et in ethanol (40 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized with 43% aqueous methanol (140 ml) to obtain Compound 116.2Na (1.69 g) as a white solid. Compound 116.2Na was acidified with 0.1 N hydrochloric acid to obtain Compound 116 as a white solid.
1H-NMR (DMSO-d6 / TMS):
δ = 1.2-1-1.97 (8H, m) 3.21 (1H, t, J = 6 Hz) 4.13 (2H, t, J = 6 Hz) 5.70 (2H, s) 7.14− 7.62 (11H, m) 7.80-8.17 (2H, m) 8.31-8.71 (3H, m) 9.02 (1H, s)

[5-[[6- (1,4-Dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid (Compound 117) and its trisodium salt (Compound 117・ Production of 3Na) 1N hydrochloric acid (3 ml) was added to compound 116 · 2Na (931 mg) obtained in Example 116 in methanol (300 ml), dissolved by heating, and then 5% palladium carbon (400 mg) was added. The mixture was stirred in a hydrogen stream at room temperature for 20 hours. To the reaction solution was added 1N sodium hydroxide (3 ml), the mixture was filtered, and the filtrate was concentrated under reduced pressure. Water (100 ml) and 1N hydrochloric acid (3 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration, washed with methanol (100 ml), and then dried to obtain a white solid compound 117 (437 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 1.3-1-1.98 (8H, m) 3.24 (1H, t, J = 6 Hz) 4.15 (2H, t, J = 5 Hz) 6.91 (1H, s) 7.21- 7.59 (5H, m) 7.91-8.44 (5H, m) 8.82 (1H, s) 12.23-13.25 (2H, br)
Compound 117 (243 mg), 1N sodium hydroxide (1.5 ml) were dissolved in water (50 ml), and then lyophilized to obtain Compound 117.3Na as a white solid.

[5-[[2- [6-[[7-Ethoxy-6- (ethoxycarbonyl) -7-oxoheptyl] oxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] pentyl] propane Acid diethyl ester (compound 118 Et), [5-[[2- [6-[(6,6-dicarboxyhexyl) oxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] pentyl] propane Preparation of acid (compound 118) and its tetrasodium salt (compound 118 · 4Na) In DMF (20 ml), compound 37 (943 mg) obtained in Example 37 was added to potassium carbonate (1.66 g) and 5-bromopentylmalon. Diethyl acid (2.23 g) was added, and the mixture was stirred at room temperature for 20 hours and further at 80 ° C. for 1 hour, and then diethyl 5-bromopentylmalonate (0 .56 g) was added and stirred at the same temperature for 1 hour. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain an oily compound 118Et. 1N sodium hydroxide (21 ml) was added to compound 118Et in ethanol (40 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized with 63% aqueous methanol (80 ml) to obtain white solid compound 11.8Na (0.62 g). Compound 18.4Na was acidified with 0.1N hydrochloric acid to obtain white solid compound 118.
1H-NMR (DMSO-d6 / TMS):
δ = 1.51-2.07 (16H, m) 3.24 (2H, t, J = 6Hz) 4.15 (2H, t, J = 6Hz) 4.58 (2H, t, J = 6Hz) 7.17-7.62 (6H, m) 7.86-8.14 (2H, m) 8.31-8.63 (3H, m) 8.99 (1H, s)

Preparation of [[6-phenyl-2- [6- (phenylmethoxy) -2-naphthalenyl] -4-pyrimidinyl] oxy] acetic acid potassium salt (Compound 119 · K) Compound 43 (1. 5 g) was dissolved in DMF (200 ml), potassium carbonate (1.5 g) and methyl bromoacetate (0.8 g) were added, and the mixture was stirred at about 30 ° C. overnight. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure. Water (300 ml) was added to the residue, and the precipitated crystals were collected by filtration to obtain a crude product. The crude product was applied to a silica gel column (chloroform) to obtain a white solid compound 119 · K (1.2 g).
1H-NMR (DMSO-d6 / TMS):
δ = 4.76 (2H, s) 5.19 (2H, s) 7.2-8.95 (17H, m)

[[2- [6-[(2-Methylphenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid ethyl ester (Compound 120Et), [[2- [6-[(2 Preparation of -methylphenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid sodium salt (compound 120 Na) Compound 42Et (300 mg) obtained in Example 42 in DMF (15 ml) ) Were added potassium carbonate (207 mg) and 2-methylbenzylpromide (180 mg), and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (15 ml), collected by filtration, and washed with water to obtain a white solid compound 120Et. 1N sodium hydroxide (1.5 ml) was added to compound 120Et in ethanol (7.5 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and then dried to obtain a white solid compound 120 · Na (225 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 2.41 (3H, s) 4.96 (2H, s) 5.20 (2H, s) 7.17-7.58 (10H, m) 7.77-8.04 (2H, m) 8.18-8.33 (2H, m) 8.62 (1H, d, J = 9 Hz) 8.99 (1H, s)

[[2- [6-[(2-Cyanophenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid ethyl ester (compound 121Et), [[2- [6-[(2 -Cyanophenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid sodium salt (Compound 121 Na) Compound 42Et obtained in Example 42 in DMF (15 ml) (400 mg ) Were added potassium carbonate (276 mg) and 2-cyanobenzyl bromide (255 mg), and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (15 ml), collected by filtration, and washed with water to obtain a white solid compound 121Et. 1N sodium hydroxide (1 ml) was added to compound 121Et in ethanol (15 ml) and hydrolyzed under reflux for 1 hour. After cooling the hydrolyzate, the precipitate was collected by filtration to obtain a crude product. The crude product was recrystallized with 80% aqueous ethanol (10 ml) to obtain a white solid compound 121 · Na (243 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 4.71 (2H, s) 5.44 (2H, s) 7.28-8.65 (15H, m) 9.00 (1H, s)

[[2- [6-[(2-methoxyphenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid ethyl ester (Compound 122Et), [[2- [6-[(2 Preparation of -methoxyphenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid sodium salt (Compound 122 Na) Compound 42Et (300 mg) obtained in Example 42 in DMF (15 ml) ) Were added potassium carbonate (207 mg), 2-methoxybenzyl chloride (153 mg) and potassium iodide (62 mg), and the mixture was stirred at 80 ° C. for 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (15 ml), collected by filtration, and washed with water to give a white solid compound 122Et. 1N Sodium hydroxide (1.5 ml) was added to Compound 122Et in ethanol (7.5 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and then dried to obtain a white solid compound 122 · Na (199 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 3.88 (3H, s) 4.72 (2H, s) 5.23 (2H, s) 7.01-8.65 (15H, m) 8.98 (1H, s)

[[2- [6-[(2-Chlorophenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid ethyl ester (Compound 123Et), [[2- [6-[(2- Chlorophenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid sodium salt (compound 123 · Na) In DMF (15 ml), compound 42Et (300 mg) obtained in Example 42 Potassium carbonate (207 mg) and 2-chlorobenzyl bromide (200 mg) were added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (15 ml), collected by filtration, and washed with water to give a white solid compound 123Et. 1N sodium hydroxide (1.5 ml) was added to compound 123Et in ethanol (7.5 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and then dried to obtain a white solid compound 123 · Na (252 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 4.72 (2H, s) 5.35 (2H, s) 7.23-8.66 (15H, m) 8.99 (1H, s)

[[2- [6-[(2-Fluorophenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid ethyl ester (Compound 124Et), [[2- [6-[(2 -Fluorophenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid sodium salt (Compound 124 Na) Compound 42Et (300 mg) obtained in Example 42 in DMF (15 ml) ) Were added potassium carbonate (207 mg) and 2-fluorobenzyl bromide (184 mg), and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (15 ml), collected by filtration, and then washed with water to obtain a white solid compound 124Et. 1N sodium hydroxide (1.5 ml) was added to compound 124Et in ethanol (7.5 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and then dried to obtain a white solid compound 124 • Na (248 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 4.73 (2H, s) 5.32 (2H, s) 7.14-8.67 (15H, m) 8.99 (1H, s)

[[2- [6-[(2,6-difluorophenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid ethyl ester (compound 125Et), [[2- [6- [ Preparation of (2,6-difluorophenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid sodium salt (compound 125 · Na) Obtained in Example 42 in DMF (15 ml). To compound 42Et (300 mg) were added potassium carbonate (207 mg) and 2,6-difluorobenzyl bromide (202 mg), and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (15 ml), collected by filtration, and washed with water to obtain a white solid compound 125Et. 1N sodium hydroxide (1.5 ml) was added to compound 125Et in ethanol (7.5 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and dried to obtain a white solid compound 125 · Na (275 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 4.70 (2H, s) 5.30 (2H, s) 7.20-8.66 (14H, m) 8.99 (1H, s)

4-[[2- [6-[(2,6-difluorophenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] butanoic acid ethyl ester (Compound 126Et), 4-[[2 Preparation of — [6-[(2,6-difluorophenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] butanoic acid (Compound 126) and its sodium salt (Compound 126 · Na) DMF (10 ml), potassium carbonate (138 mg) and 2,6-difluorobenzyl bromide (135 mg) were added to compound 45Et (214 mg) obtained in Example 45, and the mixture was stirred at room temperature for 2 days. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain an oily compound 126Et. 1N sodium hydroxide (0.6 ml) was added to compound 126Et in ethanol (5 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (20 ml), and then activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (0.6 ml) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 126 (166 mg).
Compound 126 (132 mg), 1N sodium hydroxide (0.25 ml) was dissolved in water (50 ml) by heating and filtered, and then the filtrate was freeze-dried to obtain white solid compound 126 · Na.
1H-NMR (Methanol-d4 / TMS):
δ = 2.2-2.36 (4H, m) 4.64 (2H, t, J = 5 Hz) 5.29 (2H, s) 7.06-7.59 (9H, m) 7.81− 8.04 (2H, m) 8.22-8.34 (2H, m) 8.63 (1H, d, J = 9 Hz) 8.99 (1H, s)

4- [2-[[2- [6-[(2,6-difluorophenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] ethyl] morpholine (Compound 127) and its hydrochloride salt (Compound 127 · HCl) Preparation In DMF (10 ml), potassium carbonate (553 mg) and 2,6-difluorobenzyl bromide (269 mg) were added to compound 52 · HCl (464 mg) obtained in Example 52 at room temperature. Stir for 4 days. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (20 ml) was added to the residue for crystallization. The precipitate was collected by filtration, washed with water, and recrystallized from ethanol (70 ml) to obtain a white solid compound 127 (270 mg).
Compound 127 (111 mg), 1N hydrochloric acid (0.3 ml) were dissolved in methanol (20 ml) and then concentrated under reduced pressure to obtain Compound 127 · HCl as a yellow solid.
1H-NMR (DMSO-d6 / TMS):
δ = 3.23-4.09 (10H, m) 5.09 (2H, t, J = 5 Hz) 5.31 (2H, s) 7.23-7.66 (9H, m) 7.92− 8.20 (2H, m) 8.31-8.40 (2H, m) 8.64 (1H, d, J = 9 Hz) 9.09 (1H, s)

[[2- [6-[(2-Nitrophenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid ethyl ester (Compound 128Et), [[2- [6-[(2 -Nitrophenyl) methoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid sodium salt (compound 128 Na) Compound 42Et (400 mg) obtained in Example 42 in DMF (15 ml) ) Were added potassium carbonate (276 mg) and 2-nitrobenzyl bromide (281 mg), and the mixture was stirred at room temperature for 20 hours. DMF (30 ml) was added to the reaction solution and heated, followed by filtration, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (15 ml), collected by filtration, and washed with water to give a yellow solid compound 128Et.
1N sodium hydroxide (1.5 ml) was added to compound 128Et in ethanol (15 ml) and hydrolyzed under reflux for 1 hour. After cooling the hydrolyzate, the precipitate was collected by filtration to obtain a crude product. The crude product was recrystallized with 60% aqueous ethanol (10 ml) to obtain Compound 128 • Na (178 mg) as a yellow solid.
1H-NMR (DMSO-d6 / TMS):
δ = 4.73 (2H, s) 5.65 (2H, s) 7.21-8.65 (15H, m) 8.99 (1H, s)

4-[[[6- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] methyl] benzoic acid methyl ester (Compound 129Me), 4-[[[[6- [4 -Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] methyl] benzoic acid (Compound 129) and its sodium salt (Compound 129 Na) Example 50 in DMF (30 ml) Potassium carbonate (1.02 g) and methyl 4- (bromomethyl) benzoate (1.02 g) were added to the compound 50 (1.50 g) obtained in 1 above, and the mixture was stirred at room temperature for 20 hours and further at 75 ° C. for 1 hour. The reaction solution was cooled, and the precipitate was collected by filtration. The obtained crystals were washed with water and recrystallized with acetone (200 ml) to obtain a white solid compound 129Me (1.03 g).
1N Sodium hydroxide (6 ml) was added to compound 129Me (995 mg) in ethanol (100 ml) and hydrolyzed under reflux for 20 hours. The hydrolyzed solution was concentrated under reduced pressure, and the residue was washed with water (100 ml) and then dried to obtain a white solid compound 129 • Na (682 mg). Compound 129 · Na was acidified with 0.1N hydrochloric acid to obtain white solid compound 129.
1H-NMR (DMSO-d6 / TMS):
δ = 5.28 (2H, s) 5.69 (2H, s) 7.24-8.71 (20H, m) 9.04 (1H, m)

Preparation of 4- [2-[[6- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] ethyl] morpholine (Compound 130) Example 50 in DMF (20 ml) Potassium carbonate (1.04 g) and 4- (2-chloroethyl) morpholine hydrochloride (558 mg) were added to the compound 50 (1.01 g) obtained in 1 above, and the mixture was stirred at 75 ° C. for 3 hours. Water (200 ml) was added to the reaction solution for crystallization. The precipitated crystals were collected by filtration and dried to obtain white solid compound 130 (1.06 g).
1H-NMR (DMSO-d6 / TMS):
δ = 2.52 (4H, t, J = 5 Hz) 2.79 (2H, t, J = 5 Hz) 3.61 (4H, t, J = 5 Hz) 4.26 (2H, t, J = 5 Hz) 5.69 (2H, s) 7.19-7.54 (11H, m) 7.87-8.14 (2H, m) 8.30-8.69 (3H, m) 9.02 (1H, s)

Preparation of 2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-phenyl-4 (1H) -pyrimidinone hydrochloride (Compound 131 • HCl) Toluene (15 ml) in Example 130 After dissolving the obtained compound 130 (828 mg), ethanol (150 ml) and 5% palladium carbon (400 mg) were added, and the mixture was stirred at 40-45 ° C. for 20 hours in a hydrogen stream. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Acetone (100 ml) and 1N hydrochloric acid (3 drops) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 131 · HCl (540 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 3.01-3.94 (10H, m) 4.52-4.70 (2H, m) 6.94 (1H, s) 7.28-7.55 (5H, m) 7.97- 8.49 (5H, m) 8.86 (1H, s) 10.92-12.43 (1H, s)

4- [2-[[6- [4-[(2-fluorophenyl) methoxy] -6- (4-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] ethyl] morpholine (Compound 132) and Preparation of its hydrochloride (compound 132 · HCl) In DMF (15 ml), compound 46 (701 mg) obtained in Example 46 was added potassium carbonate (829 mg) and 4- (2-chloroethyl) morpholine hydrochloride (335 mg). In addition, the mixture was stirred at 80 ° C. for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Then, n-hexane (15 ml) was added to the residue for crystallization. The precipitated crystals were collected by filtration, washed with water, and dried to give a yellow solid compound 132 (753 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 2.52-2.93 (6H, m) 3.62 (4H, t, J = 4 Hz) 4.29 (2H, t, J = 6 Hz) 5.76 (2H, s) 7.20− 8.68 (14H, m) 9.01 (1H, s)
Compound 132 (145 mg), 1N hydrochloric acid (0.5 ml) were dissolved in methanol (25 ml) and then concentrated under reduced pressure to obtain Compound 132 · HCl as a yellow solid.

Preparation of 6- (4-aminophenyl) -2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -4 (1H) -pyrimidinone dihydrochloride (Compound 133 • 2HCl) Methanol (100 ml ), 1N hydrochloric acid (0.7 ml) was added to and dissolved in the compound 132 (406 mg) obtained in Example 132, 5% palladium carbon (400 mg) was added, and the mixture was added in a hydrogen stream at room temperature for 3 days. Stir. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure. Methanol (20 ml) and 1N hydrochloric acid (1.4 ml) were added to the residue for crystallization. The precipitated crystals were collected by filtration and dried to obtain white solid compound 133.2HCl (196 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 3.27-3.95 (10H, m) 4.58-4.71 (2H, m) 5.45-7.52 (9H, m) 7.91-8.44 (6H, m) 8.85 (1H, s)

4- [2-[[6- [4-[(2-fluorophenyl) methoxy] -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] ethyl] morpholine (Compound 134) and Preparation of its hydrochloride (compound 134 · HCl) In DMF (10 ml), compound 48 (452 mg) obtained in Example 48 was added with potassium carbonate (553 mg) and 4- (2-chloroethyl) morpholine hydrochloride (223 mg). The mixture was further stirred at 80 ° C. for 7 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (10 ml) was added to the residue for crystallization. The precipitated crystals were collected by filtration, washed with water, and dried to give a brown solid compound 134 (433 mg).
Compound 134 (141 mg), 1N hydrochloric acid (1 ml) was dissolved in 63% aqueous acetone (40 ml) and then concentrated under reduced pressure to obtain Compound 134 · HCl as a yellow solid.
1H-NMR (DMSO-d6 / TMS):
δ = 3.22-4.30 (13H, m) 4.51-4.74 (2H, m) 5.74 (2H, s) 7.06-8.72 (14H, m) 9.07 ( 1H, s)

6- (4-Methoxyphenyl) -2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -4 (1H) -pyrimidinone (Compound 135) and its hydrochloride (Compound 135 · HCl) The compound 134 (226 mg) obtained in Example 134 was dissolved by heating in ethanol (200 ml), 5% palladium carbon (200 mg) was added, and the mixture was stirred in a hydrogen stream at room temperature for 3 days. The reaction solution was refluxed and filtered, and then the filtrate was concentrated under reduced pressure. The residue was washed with ethanol (5 ml) and then dried to obtain white solid compound 135 (52.3 mg).
Compound 135 (50 mg), 1N hydrochloric acid (3 ml) were dissolved in methanol (5 ml) and then concentrated under reduced pressure to obtain a green solid compound 135 · HCl.
1H-NMR (DMSO-d6 / TMS):
δ = 3.21-4.01 (9H, m) 4.55-5.35 (6H, m) 6.85 (1H, s) 7.02-8.30 (9H, m) 8.84 ( 1H, s)

4- [2-[[6- [4-[(2-fluorophenyl) methoxy] -6- (3-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] ethyl] morpholine (Compound 136) and Preparation of its hydrochloride (compound 136 · HCl) In DMF (15 ml), compound 47 (701 mg) obtained in Example 47 was charged with potassium carbonate (829 mg) and 4- (2-chloroethyl) morpholine hydrochloride (335 mg). In addition, the mixture was stirred at 80 to 90 ° C. for 8 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (30 ml) was added for crystallization. The precipitate was collected by filtration, washed with water, and dried to give Compound 136 (750 mg).
Compound 136 (286 mg) was dissolved in methanol (50 ml) by adding 1N hydrochloric acid (0.9 ml), and concentrated under reduced pressure to give compound 136 · HCl.
1H-NMR (DMSO-d6 / TMS):
δ = 3.34-4.10 (10H, m) 4.64 (2H, t, J = 5 Hz) 5.76 (2H, s) 7.18-9.06 (15H, m)

Preparation of 6- (3-aminophenyl) -2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -4 (1H) -pyrimidinone dihydrochloride (compound 137.2HCl) Methanol (100 ml ), 1N hydrochloric acid (0.9 ml) was added to and dissolved in the compound 136 (464 mg) obtained in Example 136, 5% palladium carbon (460 mg) was added, and the mixture was stirred in a hydrogen stream at room temperature for 4 days. did. Methanol (30 ml) was added to the reaction solution, refluxed and filtered, and then the solvent was distilled off from the filtrate under reduced pressure of about 80%. The precipitate was collected by filtration, dissolved in methanol (20 ml) by adding 1N hydrochloric acid (1.6 ml), and then cooled. The precipitated crystals were collected by filtration and dried to obtain Compound 137.2HCl (238 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 3.29-4.19 (10H, m) 4.67 (2H, t, J = 4 Hz) 6.94 (1H, s) 7.30-8.54 (9H, m) 8.91 ( 1H, s)

[[2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid ethyl ester (Compound 138Et) and its hydrochloride (Compound 138Et.HCl) , [[2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] acetic acid (Compound 138) and its sodium salt (Compound 138 Na) Preparation In DMF (30 ml), potassium carbonate (1.11 g), 4- (2-chloroethyl) morpholine hydrochloride (558 mg) and potassium iodide (166 mg) were added to the compound 42Et (801 mg) obtained in Example 42. , And stirred at 80 ° C. for 10 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was crystallized by adding n-hexane (30 ml), collected by filtration, and washed with water to obtain a crude product. The crude product was recrystallized from methanol (50 ml) to obtain a white solid compound 138Et (684 mg).
Compound 138Et (103 mg), 1N hydrochloric acid (0.2 ml) were dissolved in methanol (10 ml) and then concentrated under reduced pressure to obtain a yellow solid compound 138Et · HCl.
1H-NMR (DMSO-d6 / TMS):
δ = 1.24 (3H, t, J = 7 Hz) 3.05-4.69 (14H, m) 5.18 (2H, s) 7.28-7.66 (6H, m) 7.92- 8.15 (2H, m) 8.33-8.63 (3H, m) 8.97 (1H, s)
1N sodium hydroxide (1.1 ml) was added to compound 138Et (514 mg) in ethanol (10 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was concentrated under reduced pressure, and water (20 ml) and 1N hydrochloric acid (1.1 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 138 (151 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 2.59 (4H, t, J = 5 Hz) 2.86 (2H, t, J = 6 Hz) 3.46-4.38 (6H, m) 5.10 (2H, s) 7.15- 7.64 (6H, m) 7.87-8.09 (2H, m) 8.31-8.62 (3H, m) 8.98 (1H, s)
Compound 138 (97.1 mg), 1N sodium hydroxide (0.2 ml) was dissolved in water (50 ml) with heating, filtered, and the filtrate was lyophilized to obtain white solid compound 138 · Na. .

4-[[2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] butanoic acid ethyl ester (Compound 139Et), 4-[[2- Preparation of [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] butanoic acid (Compound 139) and its sodium salt (Compound 139 Na) DMF (20 ml ), Potassium carbonate (553 mg), 4- (2-chloroethyl) morpholine hydrochloride (242 mg) and potassium iodide (83 mg) were added to compound 45Et (428 mg) obtained in Example 45, and the mixture was added at 80 ° C. for 7 hours. Stir. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain an oily compound 139Et. 1N Sodium hydroxide (1.5 ml) was added to compound 139Et in ethanol (10 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was concentrated under reduced pressure, and water (20 ml) and 1N hydrochloric acid (1.5 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 139 (203 mg).
Compound 139 (154 mg), 1N sodium hydroxide (0.3 ml) was dissolved in water (50 ml) by heating and filtered, and the filtrate was lyophilized to obtain white solid compound 139 · Na.
1H-NMR (Methanol-d4 / TMS):
δ = 2.18-2.95 (10H, m) 3.74 (4H, t, J = 5 Hz) 4.27 (2H, t, J = 6 Hz) 4.62 (2H, t, J = 6 Hz) 7.12-7.27 (3H, m) 7.48-7.58 (3H, m) 7.75-8.00 (2H, m) 8.17-8.32 (2H, m) 8. 59 (1H, d, J = 9 Hz) 8.95 (1H, s)

4- [2-[[2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] ethyl] morpholine dihydrochloride (Compound 140 / 2HCl) In DMF (10 ml), potassium carbonate (1.04 g) and 4- (chloroethyl) morpholine hydrochloride (670 mg) were added to compound 37 (472 mg) obtained in Example 37 and stirred at 75 ° C. for 5 hours. . Water (200 ml) was added to the reaction solution for crystallization, and the precipitate was collected. The obtained crystals were dissolved in acetone (150 ml), activated carbon (0.1 g) was added, followed by filtration, and 35% hydrochloric acid (0.33 g) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain a yellow solid compound 140-2HCl (557 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 2.93-4.27 (20H, m) 4.60-4.96 (2H, m) 5.02-5.15 (2H, m) 7.23-7.63 (6H, m) 7.92-8.72 (5H, m) 9.09 (1H, s) 11.09-12.64 (2H, br)

Preparation of 4-phenyl-6- (phenylmethoxy) -2- [6-[(4-pyridinyl) methoxy] -2-naphthalenyl] pyrimidine hydrochloride (Compound 141 • HCl) In Example 50 in DMF (15 ml) To the obtained compound 50 (809 mg) were added potassium carbonate (829 mg) and 4- (chloromethyl) pyridine hydrochloride (394 mg), and the mixture was stirred at 85 ° C. for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water (50 ml) was added to the residue for crystallization, and the precipitate was collected by filtration. The obtained crystals were dissolved by heating in acetone (100 ml), and activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (5 ml) was added to the filtrate for acid precipitation. Precipitated crystals were collected by filtration and dried to give an amber solid compound 141.HCl (624 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 5.69 (4H, s) 7.40-8.71 (18H, m) 8.89-9.06 (3H, m)

N, N-dimethyl-3-[[6- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] -1-propanamine (compound 142) and its hydrochloride (compound 142.HCl) In DMF (20 ml), compound 50 (1.01 g) obtained in Example 50 was added to potassium carbonate (1.04 g) and 3- (dimethylamino) propyl chloride hydrochloride (0.47 g). And stirred at 80 ° C. for 23 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with water to obtain Compound 142. Compound 142 was dissolved in acetone (150 ml), and 1N hydrochloric acid (300 ml) was added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 142 · HCl (737 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 2.15−2.47 (2H, m) 2.95 (6H, s) 3.27-3.64 (2H, m) 4.21 (2H, t, J = 6 Hz) 5.57 ( 2H, s) 7.10-8.28 (15 H, m) 8.53 (1 H, d, J = 9 Hz) 8.88 (1 H, s)

Preparation of 2- [6- [3- (dimethylamino) propoxy] -2-naphthalenyl] -6-phenyl-4 (1H) -pyrimidinone hydrochloride (Compound 143.HCl) Obtained in Example 142 in methanol (120 ml). The obtained compound 142 · HCl (500 mg) was dissolved, 5% palladium carbon (250 mg) was added, and the mixture was stirred in a hydrogen stream at room temperature for 3 days. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from methanol (30 ml), washed with acetone (6 ml), and then dried to obtain Compound 143 · HCl (268 mg).
1H-NMR (Methanol-d4-D20 / TMS):
δ = 2.16−2.51 (2H, m) 2.98 (6H, s) 3.29-3.67 (2H, m) 4.24 (2H, t, J = 6 Hz) 6.80 ( 1H, s) 7.15-8.21 (10H, m) 8.48 (1H, s)

2- (4-Hydroxyphenyl) -6- (1,1-dimethylethyl) -4 (1H) -pyrimidinone (compound 144), 4- [4- (1,1-dimethylethyl) -6- (phenylmethoxy) ) -2-Pyrimidinyl] phenol (compound 144Be).
Sodium methoxide (14.3 g) and methyl pivaloyl acetate (11.4 g) were added to 4-amidinophenol hydrochloride (10.4 g) in methanol (105 ml), and the mixture was stirred for 18 hours under reflux. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water (300 ml) and 35% hydrochloric acid were added to the residue for acid precipitation, followed by filtration to obtain a crude product. The crude product was dissolved in diethyl ether (200 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with n-hexane (100 ml) and then dried to obtain Compound 144 (11.0 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.26 (9H, s) 6.11 (1H, s) 6.88 (2H, d, J = 9 Hz) 8.05 (2H, d, J = 9 Hz)
In DMF (100 ml), potassium carbonate (11.9 g) and benzyl bromide (8.83 g) were added to compound 144 (10.5 g), and the mixture was stirred at room temperature for 22 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column (toluene-ethyl acetate) to obtain Compound 144Be (7.61 g).

4- [4- [4- (1,1-dimethylethyl) -6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] butanoic acid ethyl ester (Compound 145Et), 4- [4- [4- (1, Preparation of 1-dimethylethyl) -6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] butanoic acid (Compound 145) and its sodium salt (Compound 145 Na) Obtained in Example 144 in DMF (80 ml) To compound 144Be (2.68 g) were added potassium carbonate (2.21 g) and ethyl 4-bromo-n-butyrate (1.87 g), and the mixture was stirred at room temperature for 21 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. DMF (80 ml), potassium carbonate (2.21 g) and ethyl 4-bromo-n-butyrate (1.87 g) were added to the residue, and the temperature was 90-100 ° C. Reacted for 3 hours. The re-reaction solution was filtered and then concentrated under reduced pressure to obtain Compound 145Et (4.48 g).
1N sodium hydroxide (2.7 ml) in ethanol (20 ml) was added to compound 145Et (1.00 g), and 1N sodium hydroxide (2.7 ml) was further added under reflux for 5 hours. After hydrolysis for 2.5 hours, 1N sodium hydroxide (2.0 ml) was added again and refluxed for 4 hours. The hydrolyzed solution was concentrated under reduced pressure, and water (250 ml) and 1N hydrochloric acid (3.0 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 145 (1.05 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.32 (9H, s) 1.88-2.53 (4H, m) 4.08 (2H, t, J = 6 Hz) 5.54 (2H, s) 6.74 (1H, s) 7.06 (2H, d, J = 9 Hz) 7.30-7.57 (5H, m) 8.37 (2H, d, J = 9 Hz)
Compound 145 (168 mg), 1N sodium hydroxide (0.6 ml) were dissolved in water (150 ml), and then lyophilized to obtain compound 145 · Na.

Preparation of 4- [4- [6- (1,1-dimethylethyl) -1,4-dihydro-4-oxo-2-pyrimidinyl] phenoxy] butanoic acid ethyl ester (Compound 146Et) Example in methanol (400 ml) The compound 145Et (3.0 g) obtained in 145 was dissolved, 5% palladium carbon (1.0 g) was added, and the mixture was stirred at 40-50 ° C. for 5 hours in a hydrogen stream. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with n-hexane (20 ml) and dried to give compound 146Et (1.18 g).
1H-NMR (Chloroform-d / TMS):
δ = 1.5-1.33 (12H, m) 1.99-2.69 (4H, m) 4.00-4.35 (4H, m) 6.36 (1H, s) 7.02 ( 2H, d, J = 9 Hz) 8.23 (2H, d, J = 9 Hz)

4- [4- [4- (1,1-dimethylethyl) -6-[(2-fluorophenyl) methoxy] -2-pyrimidinyl] phenoxy] butanoic acid ethyl ester (Compound 147Et), 4- [4- [ Preparation of 4- (1,1-dimethylethyl) -6-[(2-fluorophenyl) methoxy] -2-pyrimidinyl] phenoxy] butanoic acid (compound 147) and its sodium salt (compound 147 Na) DMF (30 ml ), Potassium carbonate (387 mg) and 2-fluorobenzyl bromide (397 mg) were added to compound 146Et (502 mg) obtained in Example 146, and the mixture was stirred at room temperature for 16 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain Compound 147Et. 1N sodium hydroxide (1.7 ml) in ethanol (20 ml) was added to compound 147Et, and 1N sodium hydroxide (1.7 ml) was further added under reflux for 2.5 hours. Hydrolyzed for hours. The hydrolyzed solution was concentrated under reduced pressure, and the residue was washed with n-hexane (30 ml), and then water (150 ml) and 1N hydrochloric acid (2 ml) were added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 147 (458 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 1.32 (9H, s) 1.87-2.64 (4H, m) 4.09 (2H, t, J = 6 Hz) 5.60 (2H, s) 6.75 (1H, s) 6.99-7.73 (6H, m) 8.38 (2H, d, J = 9 Hz) 11.64-12.63 (1H, br)
Compound 147 (175 mg), 1N sodium hydroxide (0.4 ml) were dissolved in water (250 ml), and then lyophilized to obtain compound 147 · Na.

4- [4- [4- (cyclohexylmethoxy) -6- (1,1-dimethylethyl) -2-pyrimidinyl] phenoxy] butanoic acid ethyl ester (compound 148Et), 4- [4- [4- (cyclohexylmethoxy) ) -6- (1,1-Dimethylethyl) -2-pyrimidinyl] phenoxy] butanoic acid (Compound 148) and its sodium salt (Compound 148 Na) Obtained in Example 146 in DMF (30 ml) To compound 146Et (502 mg) were added potassium carbonate (387 mg) and (bromomethyl) cyclohexane (372 mg), and the mixture was stirred at 100 ° C. for 17 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain Compound 148Et. 1N sodium hydroxide (3.4 ml) was added to compound 148Et in ethanol (20 ml) and hydrolyzed under reflux for 1.3 hours. The hydrolyzed solution was concentrated under reduced pressure, and the residue was washed with n-hexane (30 ml), and then water (150 ml) and 1N hydrochloric acid (2 ml) were added for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain Compound 148 (476 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 0.81-2.51 (24H, m) 3.97-4.31 (4H, m) 6.66 (1H, s) 7.05 (2H, d, J = 9 Hz) 8.34 ( 2H, d, J = 9 Hz) 12.11 (1H, br s)
Compound 148 (170 mg), 1N sodium hydroxide (0.4 ml) were dissolved in water (300 ml), and then lyophilized to obtain compound 148 · Na.

4- [2- [4- [4- (1,1-dimethylethyl) -6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] ethyl] morpholine (Compound 149) and its hydrochloride (Compound 149 · HCl) In DMF (50 ml), the compound 144Be (1.84 g) obtained in Example 144 was added to potassium carbonate (3.04 g), 4- (2-chloroethyl) morpholine hydrochloride (3.04 g), potassium iodide. (0.91 g) was added and stirred at 120-130 ° C. for 2 days. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column (toluene-chloroform) to obtain Compound 149 (1.17 g).
Compound 149 (179 mg) was dissolved in methanol (50 ml) by adding 1N hydrochloric acid (0.4 ml), and concentrated under reduced pressure to give compound 149 • HCl.
1H-NMR (DMSO-d6 / TMS):
δ = 1.33 (9H, s) 3.05-4.12 (10H, m) 4.56 (2H, t, J = 4 Hz) 5.55 (2H, s) 6.77 (1H, s) 7.15 (2H, d, J = 9 Hz) 7.31-7.58 (5H, m) 8.41 (2H, d, J = 9 Hz)

Preparation of 6- (1,1-dimethylethyl) -2- [4- [2- (4-morpholinyl) ethoxy] phenyl] -4 (1H) -pyrimidinone (Compound 150) Example 149 in methanol (300 ml) Toluene (10 ml) was added to and dissolved in compound 149 (1.21 g) obtained in step 5 above, 5% palladium on carbon (0.5 g) was added, and the mixture was stirred in a hydrogen stream at 40-50 ° C. for 10 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The solidified residue was washed successively with n-hexane (30 ml) and acetone (2 ml) and then dried to obtain Compound 150 (645 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 1.27 (9H, s) 2.48 (4H, t, J = 5 Hz) 2.72 (2H, t, J = 6 Hz) 3.59 (4H, t, J = 5 Hz) 4.19 ( 2H, t, J = 6 Hz) 6.15 (1H, s) 7.07 (2H, d, J = 9 Hz) 8.15 (2H, d, J = 9 Hz)

4- [2- [4- [4- (1,1-dimethylethyl) -6-[(2-fluorophenyl) methoxy] -2-pyrimidinyl] phenoxy] ethyl] morpholine (Compound 151) and its hydrochloride ( Preparation of Compound 151 · HCl) Potassium carbonate (221 mg) and 2-fluorobenzyl bromide (227 mg) were added to compound 150 (286 mg) obtained in Example 150 in DMF (15 ml), and the mixture was stirred at room temperature for 17 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Diisopropyl ether (10 ml) was added to the residue, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain Compound 151 (373 mg).
Compound 151 (186 mg) was dissolved in methanol (100 ml) by adding 1N hydrochloric acid (0.4 ml), and concentrated under reduced pressure to give compound 151 · HCl.
1H-NMR (DMSO-d6 / TMS):
δ = 1.33 (9H, s) 3.15-4.01 (10H, m) 4.56 (2H, t, J = 5 Hz) 5.61 (2H, s) 6.78 (1H, s) 7.09-7.63 (6H, m) 8.42 (2H, d, J = 9 Hz)

4- [2- [4- [4- (cyclohexylmethoxy) -6- (1,1-dimethylethyl) -2-pyrimidinyl] phenoxy] ethyl] morpholine (Compound 152) and its hydrochloride (Compound 152 · HCl) In DMF (15 ml), potassium carbonate (221 mg) and (bromomethyl) cyclohexane (212 mg) were added to compound 150 (286 mg) obtained in Example 150, and the mixture was stirred at 90-100 ° C. for 17 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Diisopropyl ether (10 ml) was added to the residue, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give compound 152 (312 mg).
Compound 152 (181 mg) was dissolved in methanol (100 ml) by adding 1N hydrochloric acid (0.4 ml), and concentrated under reduced pressure to give compound 152 · HCl.
1H-NMR (DMSO-d6 / TMS):
δ = 1.07-1.84 (20H, m) 3.07-4.01 (10H, m) 4.28 (2H, d, J = 6 Hz) 4.55 (2H, t, J = 4 Hz) 6.69 (1H, s) 7.14 (2H, d, J = 9 Hz) 8.38 (2H, d, J = 9 Hz)

Preparation of 2- (4-hydroxyphenyl) -6- (trifluoromethyl) -4 (1H) -pyrimidinone (Compound 153) and its disodium salt (Compound 155.3Na) 4-Amidinophenol in methanol (140 ml) Sodium methoxide (9.5 g) and ethyl trifluoroacetoacetate (17.7 g) were added to hydrochloride (13.8 g), and sodium methoxide (9.5 g) was further added under reflux for 17 hours. For 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water (250 ml) and 35% hydrochloric acid (25 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain a crude product. The crude product was washed with diethyl ether (150 ml) and then dried to obtain Compound 153 (16.4 g).
1H-NMR (DMSO-d6 / TMS):
δ = 6.71 (1H, s) 6.91 (2H, d, J = 9 Hz) 8.06 (2H, d, J = 9 Hz) 10.32 (1H, br s) 13.00 (1H, br) s)
Compound 153 (154 mg), 1N sodium hydroxide (0.8 ml) were dissolved in water (200 ml), and then freeze-dried to obtain compound 153.2Na.

Preparation of 4- [4- (phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] phenol (Compound 154) and its sodium salt (Compound 154 Na) Obtained in Example 153 in DMF (160 ml). To the obtained compound 153 (15.4 g) were added potassium carbonate (16.6 g) and benzyl bromide (12.3 g), and the mixture was stirred at room temperature for 3 days. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column (n-hexane-chloroform) to obtain Compound 154 (14.4 g).
1H-NMR (DMSO-d6-D20 / TMS):
δ = 5.61 (2H, s) 6.95 (2H, d, J = 9 Hz) 7.18 (1H, s) 7.32-7.59 (5H, m) 8.26 (2H, d, J = 9Hz)
Compound 154 (173 mg), 1N sodium hydroxide (0.8 ml) were dissolved in water (200 ml), and then lyophilized to obtain compound 154 · Na.

Preparation of 4- [4- [4- (phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] butanoic acid ethyl ester (Compound 155 Et) Obtained in Example 154 in DMF (80 ml). To compound 154 (2.77 g) were added potassium carbonate (2.21 g) and ethyl 4-bromo-n-butyrate (1.87 g), and the mixture was stirred at room temperature for 19 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and n-hexane (100 ml) was added to the residue for crystallization. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 155Et (2.30 g).
1H-NMR (Chloroform-d / TMS):
δ = 1.27 (3H, t, J = 7 Hz) 1.90-2.69 (4H, m) 4.00-4.35 (4H, m) 5.60 (2H, s) 6.91- 7.05 (3H, m) 7.26-7.55 (5H, m) 8.44 (2H, d, J = 9 Hz)

Preparation of 4- [4- [1,4-dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] butanoic acid ethyl ester (Compound 156Et) Obtained in Example 155 in methanol (300 ml). After dissolving the obtained compound 155Et (1.84 g), 5% palladium carbon (0.5 g) was added, and the mixture was stirred at 40-50 ° C. for 2 hours in a hydrogen stream. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain Compound 156Et (1.48 g).
1H-NMR (Chloroform-d / TMS):
δ = 1.27 (3H, t, J = 7 Hz) 2.02-2.66 (4H, m) 4.00-4.36 (4H, m) 6.75 (1H, s) 7.04 ( 2H, d, J = 9 Hz) 8.25 (2H, d, J = 9 Hz)

4- [4- [4- (cyclohexylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] butanoic acid ethyl ester (compound 157Et), 4- [4- [4- (cyclohexylmethoxy) -6 Preparation of-(trifluoromethyl) -2-pyrimidinyl] phenoxy] butanoic acid sodium salt (Compound 157 Na) Compound 156Et obtained in Example 156 (370 mg) in potassium carbonate (276 mg) in DMF (10 ml), (Bromomethyl) cyclohexane (212 mg) was added, (bromomethyl) cyclohexane (53 mg) was further added at room temperature for 16 hours, and the mixture was stirred at 80 to 90 ° C. for 6.5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (30 ml) and water (20 ml) were added to the residue for crystallization. The precipitate was collected by filtration to obtain Compound 157Et. 1N Sodium hydroxide (1.1 ml) was added to compound 157Et in ethanol (10 ml) and hydrolyzed under reflux for 1.5 hours. About half of the solvent of the hydrolyzed solution was distilled off under reduced pressure, and the remaining solution was cooled. The precipitated crystals were collected by filtration and dried to obtain Compound 157 · Na (272 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 0.84−2.53 (15H, m) 4.02-4.57 (4H, m) 6.95-7.10 (3H, m) 8.38 (2H, d, J = 9 Hz)

Preparation of [3- [4- [4- (phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] propyl] propanedioic acid diethyl ester (Compound 158Et) Example 154 in DMF (80 ml) Potassium carbonate (2.21 g) and diethyl (3-chloropropyl) malonate (2.27 g) were added to the compound 154 (2.77 g) obtained in the above, and the mixture was added at room temperature for 17 hours and further at 80-90 ° C. for 8 hours. After stirring, potassium carbonate (1.11 g) was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column (toluene-chloroform), and n-hexane (100 ml) was added to the obtained oily substance for crystallization. The precipitated crystals were collected by filtration and dried to obtain Compound 158Et (1.75 g).
1H-NMR (Chloroform-d / TMS):
δ = 1.16 (6H, t, J = 7 Hz) 1.72-2.21 (4H, m) 3.43 (1H, t, J = 6 Hz) 3.98-4.40 (6H, m) 5.60 (2H, s) 6.82-7.04 (3H, m) 7.26-7.61 (5H, m) 8.43 (2H, d, J = 9 Hz)

Preparation of [3- [4- [1,4-dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] propyl] propanedioic acid diethyl ester (Compound 159 Et) Performed on methanol (200 ml) The compound 158Et (1.37 g) obtained in Example 158 was dissolved, 5% palladium carbon (0.5 g) was added, and the mixture was stirred in a hydrogen stream at 40-50 ° C. for 2 hr. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain Compound 159Et (872 mg).
1H-NMR (Chloroform-d / TMS):
δ = 1.28 (6H, t, J = 7 Hz) 1.86-2.24 (4H, m) 3.44 (1H, t, J = 6 Hz) 4.06-4.45 (6H, m) 6.75 (1H, s) 7.03 (2H, d, J = 9 Hz) 8.23 (2H, d, J = 9 Hz)

[3- [4- [4- (cyclohexylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] propyl] propanedioic acid diethyl ester (Compound 160Et), [3- [4- [4- ( Preparation of (cyclohexylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] propyl] propanedioic acid (compound 160) and its disodium salt (compound 160 · 2Na) Example 159 in DMF (10 ml) To the obtained compound 159Et (411 mg) were added potassium carbonate (249 mg) and (bromomethyl) cyclohexane (248 mg), and the mixture was stirred at room temperature for 18 hours and further at 80-90 ° C. for 6 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and n-hexane (30 ml) was added to the residue for crystallization. The crystals obtained by decanting were washed with water to obtain Compound 160Et. 1N sodium hydroxide (2.2 ml) was added to compound 160Et in ethanol (10 ml) and hydrolyzed under reflux for 1.8 hours. About half of the solvent of the hydrolyzed solution was distilled off under reduced pressure. The precipitated crystals were collected by filtration and dried to give compound 160.2Na (275 mg). Compound 160.2Na was acidified with 1N hydrochloric acid to obtain Compound 160.
1H-NMR (DMSO-d6 / TMS):
δ = 0.84-1.83 (15H, m) 3.35 (1H, t, J = 6 Hz) 4.10 (2H, t, J = 6 Hz) 4.36 (2H, d, J = 6 Hz) 7.09 (2H, d, J = 9 Hz) 7.21 (1H, s) 8.33 (2H, d, J = 9 Hz) 10.84-14.04 (2H, br)

Preparation of 4- [2- [4- [4- (phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] ethyl] morpholine (Compound 161) and its hydrochloride (Compound 161 · HCl) DMF (50 ml), potassium carbonate (2.76 g) and 4- (2-chloroethyl) morpholine hydrochloride (1.12 g) were added to the compound 154 (1.73 g) obtained in Example 154, and 80-90 ° C. Stir for 5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (100 ml) was added for crystallization. The precipitated crystals were collected by filtration, washed with water, and dried to obtain Compound 161 (1.67 g).
Compound 161 (184 mg) was dissolved in methanol (50 ml) by adding 1N hydrochloric acid (0.4 ml), and concentrated under reduced pressure to give compound 161 • HCl.
1H-NMR (DMSO-d6 / TMS):
δ = 3.34-4.05 (10H, m) 4.56 (2H, t, J = 4 Hz) 5.66 (2H, s) 7.12-7.46 (8H, m) 8.42 ( 2H, d, J = 9Hz)

2- [4- [2- (4-morpholinyl) ethoxy] phenyl] -6- (trifluoromethyl) -4 (1H) -pyrimidinone (Compound 162H), 4- [2- [4- [4- (cyclohexyl) Preparation of (methoxy) -6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] ethyl] morpholine (Compound 162) Compound 161 (1.38 g) obtained in Example 161 was dissolved by heating in methanol (300 ml). Thereafter, 5% palladium carbon (1.0 g) was added, and the mixture was stirred in a hydrogen stream at room temperature for 2 days. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain Compound 162H (1.00 g).
In DMF (10 ml), potassium carbonate (249 mg) and bromomethylcyclohexane (248 mg) were added to compound 162H (330 mg), and the mixture was stirred at room temperature for 17 hours and further at 80-90 ° C. for 7 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and n-hexane (30 ml) was added to the residue for crystallization. The crystals obtained by decanting were washed with water and then dried to obtain Compound 162 (18 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 1.06-2.02 (11H, m) 2.50-2.82 (6H, m) 3.61 (4H, t, J = 4 Hz) 4.12-4.45 (4H, m) 7.02-7.25 (3H, m) 8.34 (2H, d, J = 8 Hz)

Preparation of 2- (6-hydroxy-2-naphthalenyl) -6- (trifluoromethyl) -4 (1H) -pyrimidinone (Compound 163) and its disodium salt (Compound 162.3Na) 6 in methanol (700 ml) -Hydroxy-2-naphthalenecarboximido methanesulfonate (25.4 g) was added with sodium methoxide (10.7 g) and stirred at room temperature for 30 minutes, and then ethyl trifluoroacetoacetate (19.9 g) was added. And stirred for 6 hours under reflux. The reaction solution was concentrated under reduced pressure, and water (700 ml) and 35% hydrochloric acid (12 g) were added to the residue for acid precipitation, followed by filtration to obtain a crude product. The crude product was recrystallized from methanol (700 ml) to obtain a yellow solid compound 163 (16.4 g).
1H-NMR (DMSO-d6 / TMS):
δ = 6.83 (1H, s) 7.15-7.26 (2H, m) 7.75-8.22 (3H, m) 8.70 (1H, s) 10.20 (1H, s)
Compound 163 (153 mg), 1N sodium hydroxide (1 ml) was dissolved in water (25 ml), filtered, and lyophilized to obtain a white solid compound 163-1Na.

[[2- (6-hydroxy-2-naphthalenyl) -6- (trifluoromethyl) -4-pyrimidinyl] oxy] acetic acid methyl ester (compound 164Me), [[2- (6-hydroxy-2-naphthalenyl)- 6- (Trifluoromethyl) -4-pyrimidinyl] oxy] acetic acid (Compound 164) and its sodium salt (Compound 164 Na) Compound 163 (4.59 g) obtained in Example 163 in DMF (100 ml) ) Were added potassium carbonate (4.15 g) and methyl bromoacetate (2.75 g), and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water (50 ml) was added to the residue for crystallization, followed by filtration to obtain a crude product. The crude product was applied to a silica gel column (chloroform-methanol), and the obtained solid was recrystallized from toluene (50 ml) to obtain a white solid compound 164Me (1.70 g).
1H-NMR (DMSO-d6 / TMS):
δ = 3.77 (3H, s) 5.25 (2H, s) 7.13-7.24 (2H, m) 7.51 (1H, s) 7.75-8.05 (2H, m) 8.28 (1H, d, J = 9 Hz) 8.78 (1H, s) 10.10 (1H, br s)
1N Sodium hydroxide (9 ml) was added to compound 164Me (1.13 g) in methanol (15 ml) and hydrolyzed at room temperature for 2 hours. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (50 ml), and then activated carbon (0.3 g) was added and filtered. 35% hydrochloric acid (1 g) was added to the filtrate for acid precipitation. The precipitated solid was collected by filtration and dried to obtain white solid compound 164 (0.91 g).
1H-NMR (DMSO-d6 / TMS):
δ = 5.16 (2H, s) 7.12-7.24 (2H, m) 7.47 (1H, s) 7.75-8.05 (2H, m) 8.31 (1H, d, J = 9 Hz) 8.81 (1H, s) 10.11 (1H, br s)
Compound 164 (364 mg), 1N sodium hydroxide (0.9 ml) was dissolved in water (25 ml), filtered, and the filtrate was lyophilized to obtain white solid compound 164 · Na.

Preparation of 6- [4- (phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenol (Compound 165) Compound 163 obtained in Example 163 in DMF (75 ml) (7. 66 g) were added potassium carbonate (6.91 g) and benzyl bromide (5.13 g), and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column (n-hexane-chloroform) to obtain a white solid compound 165 (4.90 g).
1H-NMR (DMSO-d6 / TMS):
δ = 5.72 (2H, s) 7.11-7.75 (8H, m) 7.91-8.10 (2H, m) 8.40 (1H, d, J = 9 Hz) 8.89 ( 1H, s) 10.09 (1H, s)

[[2- [6- (2-methoxy-2-oxoethoxy) -2-naphthalenyl] -6- (trifluoromethyl) -4-pyrimidinyl] oxy] acetic acid methyl ester (Compound 166Me), [[2- [ Preparation of 6- (carboxymethoxy) -2-naphthalenyl] -6- (trifluoromethyl) -4-pyrimidinyl] oxy] acetic acid (compound 166) and its disodium salt (compound 166.2Na) in DMF (100 ml) Compound 163 (3.06 g) obtained in Example 163, potassium carbonate (4.15 g) and methyl bromoacetate (3.82 g) were added, and the mixture was stirred at room temperature for 20 hours. Water (500 ml) was added to the reaction solution for crystallization, followed by filtration to obtain a crude product. The crude product was recrystallized with ethanol (250 ml) to obtain a white solid compound 166Me (3.45 g).
1H-NMR (DMSO-d6 / TMS):
δ = 3.77 (6H, s) 4.98 (2H, s) 5.26 (2H, s) 7.25-7.39 (2H, m) 7.54 (1H, s) 7.86- 8.14 (2H, m) 8.34 (1H, d, J = 9 Hz) 8.83 (1H, s)
1N sodium hydroxide (4 ml) was added to compound 166Me (900 mg) in methanol (20 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (20 ml), and then activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (4 ml) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 166 (0.68 g).
1H-NMR (DMSO-d6 / TMS):
δ = 4.86 (2H, s) 5.17 (2H, s) 7.24-7.37 (2H, m) 7.51 (1H, s) 7.87-8.13 (2H, m) 8.38 (1H, d, J = 8 Hz) 8.88 (1H, s) 12.02-14.07 (1H, br)
Compound 166 (211 mg), 1N sodium hydroxide (0.9 ml) was dissolved in water (25 ml) and filtered, and then the filtrate was freeze-dried to obtain a white solid compound 166.2Na.

[[6- [4- (Phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid ethyl ester (Compound 167Et), [[6- [4- (Phenylmethoxy) Preparation of -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid sodium salt (Compound 167 · Na) Compound 165 (1.98 g) obtained in Example 165 in DMF (40 ml) ) Were added potassium carbonate (1.38 g) and ethyl bromoacetate (1.00 g), and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (20 ml) was added to the residue for crystallization. The precipitated crystals were collected by filtration, washed with water, and dried to give a yellow solid compound 167Et (1.98 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.25 (3H, t, J = 7 Hz) 4.23 (2H, q, J = 7 Hz) 4.97 (2H, s) 5.73 (2H, s) 7.21-7.61 ( 8H, m) 7.87-8.20 (2H, m) 8.48 (1H, d, J = 9 Hz) 8.96 (1H, s)
1N sodium hydroxide (0.55 ml) was added to compound 167Et (241 mg) in ethanol (5 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and then dried to obtain a white solid compound 167 · Na (173 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 4.85 (2H, s) 5.73 (2H, s) 7.38-8.03 (10H, m) 8.48 (1H, d, J = 9 Hz) 8.97 (1H, s)

[[6- [1,4-Dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid ethyl ester (Compound 168Et), [[6- [1,4 Preparation of -dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid (Compound 168) and its sodium salt (Compound 168 · Na) Example in ethanol (1000 ml) The compound 167Et (1.69 g) obtained in 167 was dissolved by heating, 5% palladium carbon (0.6 g) was added, and the mixture was stirred in a hydrogen stream at room temperature for 6 hours. The reaction solution was refluxed and filtered, and then the filtrate was concentrated under reduced pressure. The residue was washed with ethanol (100 ml) and dried to give white solid compound 168Et (1.12 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.24 (3H, t, J = 7 Hz) 4.22 (2H, q, J = 7 Hz) 4.97 (2H, s) 6.86 (1H, s) 7.23-7.41 ( 2H, m) 7.85-8.28 (3H, m) 8.74 (1H, s) 13.32 (1H, br s)
1N sodium hydroxide (12 ml) was added to the compound 166Me (1.35 g) obtained in Example 166 in methanol (30 ml) and hydrolyzed under reflux for 2 hours. After cooling the hydrolyzate, the precipitate was collected by filtration. Water (50 ml) and 35% hydrochloric acid (5 drops) were added to the obtained crystals for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 168 (0.65 g).
1H-NMR (DMSO-d6 / TMS):
δ = 4.83 (2H, s) 5.01 (2H, br s) 7.22-7.33 (3H, m) 7.84-8.16 (2H, m) 8.43 (1H, d , J = 9 Hz) 8.91 (1H, s)
Compound 168 (182 mg) and 0.1N sodium hydroxide (5 ml) were dissolved in water (50 ml) by heating and filtered, and then the filtrate was lyophilized to obtain white solid compound 168 · Na.

[[6- [4-[(2-Fluorophenyl) methoxy] -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid ethyl ester (Compound 169Et), [[6- [4 Preparation of — [(2-fluorophenyl) methoxy] -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid (Compound 169) and its sodium salt (Compound 169 · Na) DMF (15 ml ), Potassium carbonate (415 mg) and 2-fluorobenzyl bromide (340 mg) were added to the compound 168Et (588 mg) obtained in Example 168, and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (20 ml) was added to the residue for crystallization. The precipitate was collected by filtration, washed with water, and dried to give white solid compound 169Et (694 mg).
To the compound 169Et (694 mg), 1N sodium hydroxide (1.5 ml) was added in ethanol (15 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and then dried to obtain a white solid compound 169 · Na (535 mg). Compound 169 · Na was acidified with 0.1 N hydrochloric acid to obtain white solid compound 169.
1H-NMR (DMSO-d6 / TMS):
δ = 4.76 (2H, s) 5.79 (2H, s) 7.19-8.19 (9H, m) 8.44 (1H, d, J = 9 Hz) 8.95 (1H, s)

Preparation of 4-[[6- [4- (Phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 170 Et) Performed in DMF (40 ml) To the compound 165 (1.98 g) obtained in Example 165 were added potassium carbonate (1.38 g) and ethyl 4-bromo-n-butyrate (1.17 g), and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (20 ml) was added to the residue for crystallization. The precipitated crystals were filtered, washed with water, and then dried to obtain a yellow solid compound 170Et (1.93 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.20 (3H, t, J = 7 Hz) 1.88-2.67 (4H, m) 3.93-4.28 (4H, m) 5.72 (2H, s) 7.15- 7.72 (8H, m) 7.87-8.15 (2H, m) 8.46 (1H, d, J = 9 Hz) 8.93 (1H, s)

4-[[6- [1,4-Dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 171 Et), 4-[[6 -Preparation of [1,4-dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid (compound 171) and its disodium salt (compound 171-2Na) The compound 170Et (1.87 g) obtained in Example 170 was heated and dissolved in ethanol (500 ml), 5% palladium carbon (0.7 g) was added, and the mixture was stirred in a hydrogen stream at room temperature for 6 hours. Acetone (1000 ml) was added to the reaction solution, refluxed and filtered, and then the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from ethanol (100 ml) to obtain a white solid compound 171Et (1.37 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.19 (3H, t, J = 7 Hz) 1.88-2.71 (4H, m) 3.92-4.27 (4H, m) 6.85 (1H, s) 7.20- 7.44 (2H, m) 7.85-8.27 (3H, m) 8.73 (1H, s) 13.31 (1H, br s)
1N sodium hydroxide (3.5 ml) was added to the compound 170Et (1.48 g) obtained in Example 170 in ethanol (60 ml) and hydrolyzed under reflux for 2 hours. The hydrolyzed solution was concentrated under reduced pressure, the residue was dissolved in water (100 ml) by heating, activated carbon (0.1 g) was added, and the mixture was filtered. 1N Hydrochloric acid (3.5 m) was added to the filtrate for acid precipitation, and after filtration, recrystallization from 75% aqueous ethanol (30 ml) gave a white solid hydrolyzate (0.90 g).
The hydrolyzate (482 mg) was stirred in a 30% hydrobromic acetic acid solution (10 ml) at 90 ° C. for 1 hour, and then water (100 ml) was added for crystallization. The precipitate was collected by filtration to obtain a crude product. The crude product was recrystallized from ethanol (60 ml) to obtain Compound 171 (110 mg) as a white solid.
1H-NMR (DMSO-d6 / TMS):
δ = 1.92−2.53 (4H, m) 4.17 (2H, t, J = 6 Hz) 6.85 (1H, s) 7.17-7.42 (2H, m) 7.86− 8.27 (3H, m) 8.73 (1H, s) 12.23-13.25 (1H, br)
Compound 171 (98.1 mg), 1N sodium hydroxide (0.5 ml) were dissolved in water (50 ml), filtered, and the filtrate was lyophilized to obtain white solid compound 171-2Na.

4-[[6- [4-[(2-Fluorophenyl) methoxy] -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester (Compound 172Et), 4- [ Preparation of [6- [4-[(2-fluorophenyl) methoxy] -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt (Compound 172 · Na) DMF (15 ml ), Potassium carbonate (415 mg) and 2-fluorobenzyl bromide (340 mg) were added to the compound 171Et (631 mg) obtained in Example 171 and stirred at room temperature for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Then, n-hexane (15 ml) was added to the residue for crystallization. The precipitate was collected by filtration, washed with water, and dried to give white solid compound 172Et (700 mg).
1N Sodium hydroxide (1.5 ml) was added to compound 172Et (700 mg) in ethanol (15 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed liquid was cooled, and the precipitated crystals were collected by filtration and dried to obtain a white solid compound 172 · Na (270 mg).
1H-NMR (Methanol-d4 / TMS):
δ = 2.5-2.40 (4H, m) 4.17 (2H, t, J = 6 Hz) 5.73 (2H, s) 7.06-7.95 (9H, m) 8.45 ( 1H, d, J = 9 Hz) 8.88 (1H, s)

6-[[6- [4- (Phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (Compound 173Be), 6-[[6- [1 , 4-Dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester (compound 173Et), 6-[[6- [1,4-dihydro- 4-Oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid (compound 173) and its disodium salt (compound 173-2Na) Example in DMF (80 ml) Potassium carbonate (2.76 g) and ethyl 6-bromohexanoate (2.68 g) were added to compound 165 (3.96 g) obtained in 165. And stirred at room temperature for 3 days. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. N-Hexane (30 ml) was added to the residue for crystallization. The precipitated crystals were collected by filtration, washed successively with water (300 ml) and methanol (30 ml), and then dried to obtain a white solid compound 173Be (4.23 g).
Compound 173Be (3.66 g) was dissolved by heating in ethanol (700 ml), 5% palladium carbon (1.5 g) was added, and the mixture was stirred in a hydrogen stream at 50 ° C. for 20 hr. Acetone (400 ml) was added to the reaction solution, refluxed and filtered, and then the filtrate was concentrated under reduced pressure. The residue was washed with methanol (50 ml) and then dried to obtain white solid compound 173Et (1.87 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.18 (3H, t, J = 7 Hz) 1.35 to 2.51 (8H, m) 3.89-4.24 (4H, m) 6.84 (1H, s) 7.17- 7.41 (2H, m) 7.84-8.30 (3H, m) 8.73 (1H, s) 13.25 (1H, br s)
1N Sodium hydroxide (4.2 ml) was added to compound 173Be (1.76 g) in ethanol (60 ml), and the mixture was hydrolyzed for 2 hours under reflux. The hydrolyzed solution was concentrated under reduced pressure, the residue was dissolved in water (100 ml) by heating, activated carbon (0.1 g) was added, and the mixture was filtered. 1N Hydrochloric acid (4.2 ml) was added to the filtrate for acid precipitation, and after filtration, recrystallization from 75% aqueous ethanol (20 ml) gave a white solid hydrolyzate (1.23 g).
The hydrolyzate (511 mg) was stirred in a 30% hydrobromic acetic acid solution (10 ml) at 90 ° C. for 1 hour, and then water (50 ml) was added for crystallization. The precipitate was collected by filtration, washed with acetone (30 ml), and then dried to obtain a white solid compound 173 (391 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 1.4-2.38 (8H, m) 4.14 (2H, t, J = 5 Hz) 6.85 (1H, s) 7.17-7.41 (2H, m) 7.85- 8.27 (3H, m) 8.73 (1H, s) 12.02-13.25 (1H, br)
Compound 173 (210 mg), 1N sodium hydroxide (1 ml) was dissolved in water (50 ml) and filtered, and then the filtrate was freeze-dried to obtain white solid compound 173-2Na.

[5-[[6- [1,4-Dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid (compound 174) and its trisodium Preparation of salt (compound 174 · 3Na) In DMF (40 ml), compound 165 (1.98 g) obtained in Example 165 was added to potassium carbonate (1.38 g) and diethyl 5-bromopentylmalonate (2.32 g). Was added and potassium carbonate (0.69 g) and diethyl 5-bromopentylmalonate (0.77 g) were further added and stirred at 80 ° C. for 1 hour. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain an oily ester. 1N sodium hydroxide (25 ml) was added to the ester compound in ethanol (50 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was concentrated under reduced pressure, and the residue was recrystallized with 33% aqueous methanol (90 ml) to obtain a hydrolyzate (1.40 g) as a white solid.
The hydrolyzate (613 mg) was stirred in a 30% hydrobromic acetic acid solution (10 ml) at 90 ° C. for 1 hour, and then water (50 ml) was added for crystallization. The precipitate was collected by filtration, washed with acetone (30 ml), and then dried to obtain a white solid compound 174 (319 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 1.48-2.10 (8H, m) 3.23 (1H, t, J = 6 Hz) 4.14 (2H, t, J = 6 Hz) 6.85 (1H, s) 7.20− 7.50 (2H, m) 7.86-8.26 (3H, m) 8.72 (1H, s) 12.02-13.46 (2H, br)
Compound 174 (239 mg), 1N sodium hydroxide (1.5 ml) was dissolved in water (50 ml), filtered, and the filtrate was lyophilized to obtain white solid compound 174 / 3Na.

4- [2-[[6- [4- (Phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] ethyl] morpholine (Compound 175) and its hydrochloride (Compound 175) Preparation of HCl) Potassium carbonate (2.76 g) and 4- (2-chloroethyl) morpholine hydrochloride (1.12 g) were added to compound 165 (1.98 g) obtained in Example 165 in DMF (40 ml). In addition, the mixture was stirred at 80 ° C. for 7 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (20 ml) was added to the residue for crystallization. The precipitated crystals were collected by filtration, washed with water, and dried to obtain a yellow solid compound 175 (1.97 g).
1H-NMR (DMSO-d6 / TMS):
δ = 2.51 (4H, t, J = 5 Hz) 2.78 (2H, t, J = 6 Hz) 3.61 (4H, t, J = 5 Hz) 4.27 (2H, t, J = 6 Hz) 5.72 (2H, s) 7.19-7.67 (8H, m) 7.87-8.16 (2H, m) 8.47 (1H, d, J = 9 Hz) 8.93 (1H, s)
Compound 175 (204 mg), 1N hydrochloric acid (0.8 ml) were dissolved in methanol (10 ml) and then concentrated under reduced pressure to obtain Compound 175 • HCl as a yellow solid.

2- [6- [2- (4-morpholinyl) ethoxy] -2-naphthalenyl] -6- (trifluoromethyl) -4 (1H) -pyrimidinone (Compound 176) and its hydrochloride (Compound 176 · HCl) Production After dissolving the compound 175 obtained in Example 175 (1.53 g) in ethanol (300 ml) by heating, 5% palladium carbon (0.5 g) was added, and the mixture was stirred in a hydrogen stream at room temperature for 2 hours. . Ethanol (200 ml) was added to the reaction mixture, refluxed and filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with ethanol (10 ml) and then dried to obtain a white solid compound 176 (0.99 g).
1H-NMR (DMSO-d6 / TMS):
δ = 2.53 (4H, t, J = 5 Hz) 2.80 (2H, t, J = 6 Hz) 3.62 (4H, t, J = 5 Hz) 4.27 (2H, t, J = 5 Hz) 6.84 (1H, s) 7.18-7.48 (2H, m) 7.84-8.28 (3H, m) 8.73 (1H, s)
Compound 176 (210 mg), 1N hydrochloric acid (1 ml) were dissolved in methanol (10 ml) and then concentrated under reduced pressure to obtain Compound 176 · HCl as a white solid.

4- [2-[[6- [4-[(2-Fluorophenyl) methoxy] -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] ethyl] morpholine (Compound 177) and its Preparation of hydrochloride (Compound 177 · HCl) Potassium carbonate (276 mg) and 2-fluorobenzyl bromide (227 mg) were added to compound 176 (419 mg) obtained in Example 176 in DMF (10 ml), and the mixture was stirred at room temperature for 5 hours. Stir. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and n-hexane (10 ml) was added to the residue for crystallization. The precipitated crystals were collected by filtration, washed with water, and dried to give white solid compound 177 (416 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 2.52 (4H, t, J = 5 Hz) 2.79 (2H, t, J = 6 Hz) 3.62 (4H, t, J = 5 Hz) 4.27 (2H, t, J = 6 Hz) 5.79 (2H, s) 7.17-8.15 (9H, m) 8.47 (1 H, d, J = 8 Hz) 8.94 (1 H, s)
Compound 177 (211 mg), 1N hydrochloric acid (0.4 ml) were dissolved in methanol (10 ml), and then concentrated under reduced pressure to obtain compound 177 • HCl as a yellow solid.

Preparation of 6- (dimethoxymethyl) -2- [6- (phenylmethoxy) -2-naphthalenyl] -4 (1H) -pyrimidinone (Compound 178) To sodium methoxide (27.2 g) in dehydrated toluene (150 ml). A mixture of methyl dimethoxyacetate (56.3 g) and methyl acetate (37.3 g) was added dropwise at 50-60 ° C., and the mixture was stirred for 3 hours under reflux. The reaction solution was added to a mixture of ice water (150 ml) -acetic acid (50.4 g), and the toluene layer was separated. The toluene layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to obtain a colorless transparent liquid, methyl dimethoxyacetoacetate (22.9 g, bp = 62-65 ° C./2 mmHg) as an intermediate. .
In methanol (400 ml), 6- (phenylmethoxy) -2-naphthalenecarboximidohydrochloride (12.5 g) obtained in Example 43 was added to sodium methoxide (4.75 g) and methyl dimethoxyacetoacetate (14. 1 g) was added, and the mixture was stirred at room temperature for 20 hours and further under reflux for 3 hours. After cooling the reaction solution, the precipitate was collected by filtration to obtain a crude product. Water (30 ml) and 1N hydrochloric acid (5 drops) were added to the crude product for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 178 (12.2 g).
1H-NMR (DMSO-d6 / TMS):
δ = 3.37 (6H, s) 5.20 (1H, s) 5.28 (2H, s) 6.38 (1H, s) 7.24-7.48 (7H, m) 7.83− 8.29 (3H, m) 8.71 (1H, s) 12.23-13.25 (1H, br)

Preparation of 1,6-dihydro-6-oxo-2- [6- (phenylmethoxy) -2-naphthalenyl] -4-pyrimidinecarboxaldehyde (Compound 179) Compound 178 obtained in Example 178 in formic acid (54 ml) (10.9 g) was added, and the mixture was stirred at 60-65 ° C. for 4 hours, and then cooled. The precipitate in the reaction solution was collected by filtration, washed with acetone (20 ml), and then dried to obtain a yellow solid compound 179 (9.31 g).
1H-NMR (DMSO-d6 / TMS):
δ = 5.29 (2H, s) 6.84 (1H, s) 7.31-7.66 (7H, m) 7.87-8.35 (3H, m) 8.77 (1H, s) 9.94 (1H, s) 12.23-13.66 (1H, br)

Preparation of 1,6-dihydro-6-oxo-2- [6- (phenylmethoxy) -2-naphthalenyl] -4-pyrimidinecarboxylic acid (compound 180) and its disodium salt (compound 180 · 2Na) Water (400 ml ), 1N sodium hydroxide (47.2 ml) and potassium permanganate (7.64 g) were added to compound 179 (8.20 g) obtained in Example 179, and the mixture was stirred at 85-90 ° C. for 2 days. . The reaction solution was cooled and filtered, and 1N hydrochloric acid (100 ml) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 180 (3.28 g).
1H-NMR (DMSO-d6 / TMS):
δ = 5.28 (2H, s) 6.87 (1H, s) 7.30-7.48 (7H, m) 7.85-8.35 (3H, m) 8.76 (1H, s) 12.10-14.17 (1H, br)
Compound 180 (37.2 mg) and 0.1 N sodium hydroxide (2 ml) were dissolved in water (20 ml) and filtered, and then the filtrate was lyophilized to obtain Compound 180.2Na as a white solid.

Preparation of 1,6-dihydro-2- (6-hydroxy-2-naphthalenyl) -6-oxo-4-pyrimidinecarboxylic acid (Compound 181) and its sodium salt (Compound 181 Na) Implementation in methanol (150 ml) 1N Sodium hydroxide (5 ml) was added to the compound 180 (931 mg) obtained in Example 180 and dissolved, 5% palladium carbon (1 g) was added, and the mixture was stirred in a hydrogen stream at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Then, water (25 ml) and 1N hydrochloric acid (5 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain yellow solid compound 181 (637 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 6.86 (1H, s) 7.13-7.24 (2H, m) 7.73-8.00 (2H, m) 8.21 (1H, d, J = 9 Hz) 8.72 ( 1H, s) 9.35-11.20 (1H, br) 12.02-14.31 (1H, br)
Compound 181 (28.2 mg) and 0.1N sodium hydroxide (1 ml) were dissolved in water (20 ml), filtered, and the filtrate was lyophilized to obtain Compound 181 • Na as a yellow solid.

6- (2-methoxy-2-oxoethoxy) -2- [6- (2-methoxy-2-oxoethoxy) -2-naphthalenyl] -4-pyrimidinecarboxylic acid 2-methoxy-2-oxoethyl ester (compound 182 Me).
To DMF (20 ml), potassium carbonate (1.66 g) and methyl bromoacetate (960 mg) were added to compound 181 (565 mg) obtained in Example 181 and stirred at room temperature for 20 hours. Ice water (250 ml) was added to the reaction solution for crystallization. The precipitated crystals were collected by filtration and dried to give a brown solid compound 182Me (540 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 3.76 (6H, s) 4.99 (2H, s) 5.07 (2H, s) 5.25 (2H, s) 7.25-7.49 (3H, m) 7.87- 8.11 (2H, m) 8.40 (1 H, d, J = 9 Hz) 8.84 (1 H, s)

Preparation of 6- (2-methoxy-2-oxoethoxy) -2- [6- (phenylmethoxy) -2-naphthalenyl] -4-pyrimidinecarboxylic acid 2-methoxy-2-oxoethyl ester (Compound 183Me) DMF (25 ml ), Potassium carbonate (1.38 g) and methyl bromoacetate (799 mg) were added to the compound 180 (931 mg) obtained in Example 180, and the mixture was stirred at room temperature for 3 hours. Ice water (250 ml) was added to the reaction solution for crystallization. The precipitated crystals were collected by filtration and dried to obtain white solid compound 183Me (1.04 g).
1H-NMR (DMSO-d6 / TMS):
δ = 3.76 (6H, s) 5.07 (2H, s) 5.27 (4H, s) 7.21-7.48 (3H, m) 7.88-8.11 (2H, m) 8.39 (1H, d, J = 10 Hz) 8.83 (1H, s)

Preparation of 6- (carboxymethoxy) -2- [6- (carboxymethoxy) -2-naphthalenyl] -4-pyrimidinecarboxylic acid (compound 184) and its disodium salt (compound 184 · 2Na).
1N sodium hydroxide (4 ml) was added to the compound 182Me (399 mg) obtained in Example 182 in methanol (40 ml) and hydrolyzed at room temperature for 3 hours. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (20 ml), and then activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (4 ml) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain a green solid compound 184 (192 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 4.83 (2H, s) 5.09 (2H, s) 7.21-7.31 (3H, m) 7.83-8.10 (2H, m) 8.45 (1H, d, J = 9 Hz) 8.91 (1H, s)
Compound 184 (79.7 mg) and 0.1 N sodium hydroxide (4 ml) were dissolved in water (20 ml) and filtered, and then the filtrate was lyophilized to obtain white solid compound 188.4Na.

Preparation of 6- (carboxymethoxy) -2- (6-hydroxy-2-naphthalenyl) -4-pyrimidinecarboxylic acid (Compound 185) and its disodium salt (Compound 185-2Na).
The compound 183Me (981 mg) obtained in Example 183 was dissolved by heating in methanol (1000 ml), 5% palladium on carbon (1 g) was added, and the mixture was stirred in a hydrogen stream at room temperature for 2 hours, filtered, and filtrated. Was concentrated under reduced pressure. The residue was washed with water and dried to obtain a debenzylated green solid (492 mg).
To the debenzylated product (341 mg), 1N sodium hydroxide (4 ml) was added in methanol (40 ml) and hydrolyzed at room temperature for 3 hours. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (20 ml), and then activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (4 ml) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain a green solid compound 185 (216 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 5.11 (2H, s) 7.11-7.35 (3H, m) 7.74-8.03 (2H, m) 8.38 (1H, d, J = 8 Hz) 8.86 ( 1H, s)
Compound 185 (68.1 mg) and 0.1N sodium hydroxide (4 ml) were dissolved in water (20 ml) and filtered, and then the filtrate was lyophilized to obtain a white solid compound 185.2Na.

Preparation of 6- (3-furanyl) -2- (6-hydroxy-2-naphthalenyl) -4 (1H) -pyrimidinone (Compound 186) and its disodium salt (Compound 186 · 2Na) in methanol (50 ml), 6 -Hydroxy-2-naphthalenecarboximidamide Methanesulfonate (1.61 g) was added with sodium methoxide (677 mg) and ethyl-β-oxo-3-furanpropionate (1.25 g), and refluxed for 2 days. Stir. The reaction solution was concentrated under reduced pressure, and water (100 ml) and 35% hydrochloric acid (0.6 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration, washed with methanol (30 ml), and then dried to obtain a brown solid compound 186 (0.61 g).
1H-NMR (DMSO-d6 / TMS):
δ = 6.65 (1H, s) 7.15-7.25 (3H, m) 7.74-8.01 (3H, m) 8.27 (1 H, d, J = 9 Hz) 8.51 ( 1H, s) 8.77 (1H, s)
Compound 186 (152 mg), 1N sodium hydroxide (1 ml) was dissolved in water (25 ml) and filtered, and then the filtrate was freeze-dried to obtain white solid compound 188.6Na.

[[6- (3-Furanyl) -2- [6- (2-methoxy-2-oxoethoxy) -2-naphthalenyl] -4-pyrimidinyl] oxy] acetic acid methyl ester (Compound 187Me), [[6- [ 4- (Carboxymethoxy) -6- (3-furanyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid (Compound 187) and its disodium salt (Compound 187 • 2Na) in DMF (5 ml) To compound 186 (304 mg) obtained in Example 186 were added potassium carbonate (415 mg) and methyl bromoacetate (337 mg), and the mixture was stirred at room temperature for 20 hours. Water (50 ml) was added to the reaction solution for crystallization, followed by filtration to obtain a crude product. The crude product was recrystallized from ethanol (60 ml) to obtain a white solid compound 187Me (241 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 3.76 (6H, s) 4.98 (2H, s) 5.18 (2H, s) 7.21-7.38 (4H, m) 7.86-8.11 (3H, m) 8.49 (1H, d, J = 9 Hz) 8.69 (1H, s) 8.93 (1H, s)
1N sodium hydroxide (1.1 ml) was added to compound 187Me (224 mg) in methanol (10 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (25 ml), and then activated carbon (0.1 g) was added and filtered. 1N hydrochloric acid (1.1 ml) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 187 (170 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 4.85 (2H, s) 5.08 (2H, s) 7.27-7.36 (4H, m) 7.85-8.10 (3H, m) 8.51 (1H, d, J = 9 Hz) 8.69 (1H, s) 8.96 (1H, s) 12.23-13.87 (1H, br)
Compound 187 (126 mg), 1N sodium hydroxide (0.6 ml) was dissolved in water (25 ml) and filtered, and then the filtrate was freeze-dried to obtain white solid compound 187.2Na.

Preparation of 1,5,6,7-tetrahydro-2- (6-hydroxy-2-naphthalenyl) -4H-cyclopentapyrimidin-4-one (compound 188) and its disodium salt (compound 188 · 2Na).
6-Hydroxy-2-naphthalenecarboximidamide methanesulfonate (14.1 g) in methanol (200 ml) with sodium methoxide (5.94 g) and 2-oxocyclopentanecarboxylic acid methyl ester (8.53 g) The mixture was further stirred for 2 days under reflux. The reaction mixture was concentrated under reduced pressure, and water (200 ml) and 35% hydrochloric acid (6 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration, washed with methanol (100 ml), and then dried to obtain a brown solid compound 188 (2.23 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.89-2.98 (6H, m) 7.11-7.22 (2H, m) 7.69-7.97 (2H, m) 8.12 (1H, d, J = 9 Hz) 8.63 (1H, s) 9.56-10.58 (1H, br) 11.82-12.97 (1H, br)
Compound 188 (278 mg), 1N sodium hydroxide (2 ml) was dissolved in water (50 ml), filtered, and the filtrate was lyophilized to obtain white solid compound 188.2Na.

[[6- [6,7-dihydro-4- (2-methoxy-2-oxoethoxy) -5H-cyclopentapyrimidin-2-yl] -2-naphthalenyl] oxy] acetic acid methyl ester (compound 189Me), [ [6- [4- (Carboxymethoxy) -6,7-dihydro-5H-cyclopentapyrimidin-2-yl] -2-naphthalenyl] oxy] acetic acid (Compound 189) and its disodium salt (Compound 189.2Na) In DMF (40 ml), potassium carbonate (2.07 g) and methyl bromoacetate (1.68 g) were added to compound 188 (1.39 g) obtained in Example 188, and the mixture was stirred at room temperature for 20 hours. Water (400 ml) was added to the reaction solution for crystallization, followed by filtration to obtain a crude product. The crude product was recrystallized from ethanol (900 ml) to obtain a white solid compound 189Me (1.49 g).
1H-NMR (DMSO-d6 / TMS):
δ = 2.00-2.36 (2H, m) 2.78-3.17 (4H, m) 3.75 (6H, s) 4.96 (2H, s) 5.13 (2H, s) 7.21-7.35 (2H, m) 7.80-8.07 (2H, m) 8.35 (1H, d, J = 8 Hz) 8.79 (1H, s)
1N sodium hydroxide (7.3 ml) was added to compound 189Me (1.39 g) in methanol (33 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzate was concentrated under reduced pressure, and water (70 ml) and 1N hydrochloric acid (7.3 ml) were added to the residue for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain yellow solid compound 189 (1.17 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.99-2.23 (2H, m) 2.78-3.24 (4H, m) 4.84 (2H, s) 5.04 (2H, s) 7.20-7.33 ( 2H, m) 7.80-8.06 (2H, m) 8.40 (1H, d, J = 9 Hz) 8.83 (1H, s)
Compound 189 (197 mg), 1N sodium hydroxide (1 ml) was dissolved in water (50 ml), filtered, and the filtrate was lyophilized to obtain white solid compound 189.2Na.

Preparation of N- (1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl) glycine (compound 190) and its sodium salt (compound 190 · Na) In methanol (60 ml), guanidinoacetic acid (3 g) was added. A 28% sodium methoxide-methanol solution (21.8 g) and methyl acetoacetate (3.6 g) were added, and the mixture was stirred overnight under reflux. After cooling the reaction solution, the precipitate was collected by filtration to obtain a crude product. The crude product was dissolved in water (50 ml), the insoluble material was filtered off, and methanesulfonic acid was added for acid precipitation. The precipitated crystals were filtered, washed with water, and dried to obtain Compound 190 (0.44 g).
1H-NMR (DMSO-d6 / TMS):
δ = 2.15 (3H, s) 4.39 (2H, s) 5.90 (1H, s)
Compound 190 (200 mg) was dissolved in 0.16% aqueous sodium hydroxide solution (25 ml), activated carbon was added and filtered, and then the filtrate was concentrated under reduced pressure to obtain Compound 190 • Na.

N- [4- (2-Ethoxy-2-oxoethoxy) -6-methyl-2-pyrimidinyl] glycine (Compound 191 Et), N- [4- (Carboxymethoxy) -6-methyl-2-pyrimidinyl] glycine ( Preparation of Compound 191) In DMF (30 ml), potassium carbonate (4.0 g) and ethyl bromoacetate (1.31 g) were added to Compound 190 (1.2 g) obtained in Example 190 and stirred overnight at room temperature. . The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column (chloroform-methanol-acetic acid), and then the obtained crystal was recrystallized from ethanol to obtain Compound 191Et (0.63 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.21 (3H, t, J = 7 Hz) 2.18 (3H, s) 4.18 (2H, q, J = 7 Hz) 4.43 (2H, s) 4.65 (2H, s) 6.03 (1H, s)
16% aqueous sodium hydroxide solution (2 ml) was added to compound 191Et (300 mg) in ethanol (8 ml) and hydrolyzed overnight at room temperature. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water (10 ml), and acidified by adding 35% hydrochloric acid. The oily substance was extracted with ether and ethyl acetate, and then the extract was concentrated under reduced pressure to obtain Compound 191 (250 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 2.19 (3H, m) 4.34 (2H, s) 4.64 (2H, s) 6.03 (1H, s)

Preparation of 6-methyl-2- (3-pyridinyl) -4 (1H) -pyrimidinone (Compound 192) 3-Pyridinecarboximidamide hydrochloride (4.73 g) obtained in Example 1 in methanol (50 ml). Were added methyl acetoacetate (5.23 g) and sodium methoxide (4.24 g), and the mixture was stirred under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (150 ml), and then activated carbon (1 g) was added and filtered. 35% hydrochloric acid (3-4 g) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration, washed with ethanol (20 ml), and then dried to obtain a white solid compound 192 (1.76 g).
1H-NMR (DMSO-d6 / TMS):
δ = 2.32 (3H, s) 6.31 (1H, s) 7.45-7.66 (1H, m) 8.46 (1H, d, J = 8 Hz) 8.74 (1H, d, J = 4 Hz) 9.26 (1H, d, J = 2 Hz) 11.81-13.35 (1H, br)

[[6-Methyl-2- (3-pyridinyl) -4-pyrimidinyl] oxy] acetic acid methyl ester (Compound 193Me), [[6-Methyl-2- (3-pyridinyl) -4-pyrimidinyl] oxy] acetic acid ( Compound 193) and sodium salt thereof (Compound 193 · Na) In DMF (30 ml), compound 192 (1.40 g) obtained in Example 192 was mixed with potassium carbonate (2.07 g) and methyl bromoacetate (1. 26 g) was added and stirred for 1 hour under water cooling. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with water to obtain a crude product. The crude product was recrystallized with 67% aqueous methanol (15 ml) to give compound 193Me (1.32 g) as a yellow solid.
1H-NMR (DMSO-d6 / TMS):
δ = 2.51 (3H, s) 3.71 (3H, s) 5.11 (2H, s) 6.94 (1H, s) 7.46-7.66 (1H, m) 8.50- 8.77 (2H, m) 9.43 (1H, s)
1N Sodium hydroxide (14 ml) was added to compound 193Me (907 mg) in methanol (28 ml) and hydrolyzed at room temperature for 1 hour. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (20 ml), and then activated carbon (0.1 g) was added and filtered. 35% hydrochloric acid (1.4 g) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 193 (781 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 2.51 (3H, s) 5.01 (2H, s) 6.90 (1H, s) 7.45-7.66 (1H, m) 8.53-8.77 (2H, m) 9.45 (1H, d, J = 1Hz)
Compound 193 (245 mg), 1N sodium hydroxide (1 ml) was dissolved in water (25 ml) by heating and filtered, and then the filtrate was lyophilized to obtain Compound 193 • Na as a white solid.

Preparation of 6-methyl-2- [4- (trifluoromethyl) phenyl] -4 (1H) -pyrimidinone (Compound 194) 4- (Trifluoromethyl) benzene obtained in Example 2 in methanol (200 ml) Sodium methoxide (3.57 g) was added to carboximide amide hydrochloride (13.48 g), and the mixture was stirred for 15 minutes under water cooling, and then methyl acetoacetate (9.06 g) and sodium methoxide (3.57 g) were added. The mixture was stirred at room temperature for 2 hours and further under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and water (300 ml) and 35% hydrochloric acid (6.5 g) were added to the residue for acid precipitation, followed by filtration to obtain a crude product. The crude product was dissolved by heating in methanol (300 ml), and activated carbon (2 g) was added and filtered. The filtrate was concentrated under reduced pressure, and the residue was washed with methanol (100 ml) and then dried to obtain a white solid compound 194 (10.62 g).
1H-NMR (DMSO-d6 / TMS):
δ = 2.33 (3H, s) 6.34 (1H, s) 7.88 (2H, d, J = 8 Hz) 8.35 (2H, d, J = 8 Hz) 11.82-13.25 ( 1H, br)

[[6-Methyl-2- [4- (trifluoromethyl) phenyl] -4-pyrimidinyl] oxy] acetic acid methyl ester (Compound 195Me), [[6-Methyl-2- [4- (trifluoromethyl) phenyl] ] -4-Pyrimidinyl] oxy] acetic acid (Compound 195) and sodium salt thereof (Compound 195 • Na) In DMF (50 ml), compound 194 (5.08 g) obtained in Example 194 was added to potassium carbonate (5 0.53 g) and methyl bromoacetate (3.67 g) were added, and the mixture was stirred for 2 hours under water cooling. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved by heating in methanol (10 ml), crystallized by adding water (200 ml), and then collected by filtration to obtain a crude product. The crude product was recrystallized with 95% methanol (40 ml) to obtain a white solid compound 195Me (5.05 g).
1H-NMR (DMSO-d6 / TMS):
δ = 2.52 (3H, s) 3.72 (3H, s) 5.11 (2H, s) 6.97 (1H, s) 7.90 (2H, d, J = 8 Hz) 8.50 ( 2H, d, J = 8Hz)
1N sodium hydroxide (10 ml) was added to compound 195Me (1.63 g) in methanol (40 ml) and hydrolyzed at room temperature for 1 hour. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (60 ml), and then activated carbon (0.2 g) was added and filtered. 35% hydrochloric acid (1 g) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 195 (1.38 g).
1H-NMR (DMSO-d6 / TMS):
δ = 2.52 (3H, s) 5.02 (2H, s) 6.93 (1H, s) 7.89 (2H, d, J = 8 Hz) 8.53 (2H, d, J = 8 Hz)
Compound 195 (245 mg), 1N sodium hydroxide (1 ml) was dissolved in water (50 ml) by heating and filtered, and the filtrate was lyophilized to obtain a white solid compound 195 • Na.

6-[[6-Methyl-2- [4- (trifluoromethyl) phenyl] -4-pyrimidinyl] oxy] hexanoic acid ethyl ester (Compound 196Et), 6-[[6-Methyl-2- [4- ( Preparation of (trifluoromethyl) phenyl] -4-pyrimidinyl] oxy] hexanoic acid (compound 196) and its sodium salt (compound 196 Na) Compound 194 obtained in Example 194 (508 mg) in DMF (10 ml) Potassium carbonate (553 mg) and ethyl 6-bromohexanoate (535 mg) were added, and the mixture was stirred at room temperature for 20 hours and further at 80 ° C. for 1 hour. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain an oily compound 196Et. 1N Sodium hydroxide (2.8 ml) was added to compound 196Et in ethanol (20 ml) and hydrolyzed under reflux for 1 hour. The hydrolyzate was concentrated under reduced pressure, and the residue was dissolved in water (50 ml) by heating, and then activated carbon (0.1 g) was added and filtered. 1N Hydrochloric acid (2.8 ml) was added to the filtrate for acid precipitation, followed by decanting to obtain an oily compound 196. 1N sodium hydroxide (1.2 ml) was added to compound 196, dissolved in water (50 ml) with heating, filtered, and the filtrate was lyophilized to give compound 196 • Na (462 mg) as a white solid. .
1H-NMR (Methanol-d4 / TMS):
δ = 1.48-2.20 (8H, m) 2.49 (3H, s) 4.50 (2H, t, J = 8 Hz) 6.65 (1H, s) 7.76 (2H, d, J = 8 Hz) 8.55 (2H, d, J = 8 Hz)

Preparation of 4- [4- (1-cyclohexyl-1H-tetrazol-5-yl) butoxy] -6-methyl-2- [4- (trifluoromethyl) phenyl] pyrimidine (Compound 197) In benzene (150 ml), A benzene solution (50 ml) of 5-chloropentanoic acid chloride (9.89 g) was added dropwise to cyclohexylamine (5.75 g) and stirred at room temperature for 1 hour, and then an aqueous solution (100 ml) of sodium carbonate (6.76 g) was added. In addition, the mixture was stirred at the same temperature for 4 hours. The benzene layer in the reaction solution was collected, washed with water, and concentrated under reduced pressure. The residue was recrystallized from cyclohexane (50 ml) to obtain 5-chloro-N-cyclohexylpentanamide (11.5 g).
To 5-chloro-N-cyclohexylpentanamide (8.71 g), phosphorus pentachloride (10.0 g) in benzene (120 ml) was added, stirred at room temperature for 1 hour, and then sodium azide (5.20 g) was added. The mixture was stirred at the same temperature for 20 hours and further under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, and ice water (200 ml) was added to the residue for hydrolysis, followed by extraction with chloroform (200 ml). The extract was washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in isopropyl alcohol (30 ml) and filtered, and then water (120 ml) was added to the filtrate for crystallization. The precipitated crystals were collected by filtration and dried to obtain 5- (4-chlorobutyl) -1-cyclohexyl-1H-tetrazole (7.03 g) as an intermediate.
In DMF (10 ml), potassium carbonate (553 mg) and 5- (4-chlorobutyl) -1-cyclohexyl-1H-tetrazole (583 mg) were added to the compound 194 (508 mg) obtained in Example 194, and 20% at room temperature. The mixture was further stirred at 80 ° C. for 7 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was partitioned with chloroform (100 ml) -water (100 ml). The chloroform layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain a crude product. The crude product was applied to a silica gel column (n-hexane-chloroform), and the obtained oily substance was recrystallized from cyclohexane (25 ml) to obtain a white solid compound 197 (478 mg).
1H-NMR (DMSO-d6 / TMS):
δ = 1.06-2.11 (14H, m) 2.48 (3H, s) 3.00 (2H, t, J = 5 Hz) 4.38-4.55 (3H, m) 6.80 ( 1H, s) 7.87 (2H, d, J = 8 Hz) 8.57 (2H, d, J = 8 Hz)

Preparation of α-[(1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl) amino] -4-hydroxybenzeneacetic acid (Compound 198) α obtained in Example 30 in methanol (80 ml) Sodium methoxide (3.44 g) and methyl acetoacetate (2.8 g) were added to-[(aminoiminomethyl) amino] -4-hydroxybenzeneacetic acid (4.0 g), and the mixture was stirred under reflux for 2.3 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in water (12 ml), and acidified by adding 35% hydrochloric acid. The precipitated crystals were filtered, washed with water, and dried to obtain Compound 198 (3.33 g).
1H-NMR (DMSO-d6 / TMS):
δ = 1.98 (3H, s) 5.24 (1H, d, J = 9 Hz) 5.43 (1H, s) 6.73 (2H, d, J = 9 Hz) 7.14-7.28 ( 3H, m)

Preparation of 2- (4′-hydroxy [1,1′-biphenyl] -4-yl) -6-methyl-4 (1H) -pyrimidinone (Compound 199) and its disodium salt (Compound 199 · 2Na) Methanol ( 175 ml), sodium methoxide (4.16 g) was added to 4′-hydroxy [1,1′-biphenyl] -4-carboximidamide hydrochloride (8.70 g) obtained in Example 26 at room temperature. After stirring for 30 minutes, methyl acetoacetate (4.88 g) was added and stirred for 4 hours under reflux. Water (350 ml) and 35% hydrochloric acid (4 g) were added to the reaction solution for acid precipitation. The precipitated crystals were collected by filtration, washed with methanol (50 ml), and then dried to obtain a yellow solid compound 199 (9.48 g).
1H-NMR (DMSO-d6 / TMS):
δ = 2.30 (3H, s) 6.20 (1H, s) 6.90 (2H, d, J = 8 Hz) 7.55-7.80 (4H, m)
Compound 199 (139 mg), 1N sodium hydroxide (1 ml) was dissolved in water (25 ml), filtered, and the filtrate was lyophilized to give compound 199.2Na as a yellow solid.

[[2- (4′-hydroxy [1,1′-biphenyl] -4-yl) -6-methyl-4-pyrimidinyl] oxy] acetic acid methyl ester (compound 200Me), [[2- (4′-hydroxy Preparation of [1,1′-biphenyl] -4-yl) -6-methyl-4-pyrimidinyl] oxy] acetic acid (Compound 200) and its sodium salt (Compound 200 • Na) Example 199 in DMF (100 ml) Potassium carbonate (4.15 g) and methyl bromoacetate (2.75 g) were added to the compound 199 (4.17 g) obtained in Step 3, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was partitioned with chloroform (200 ml) -water (200 ml). The chloroform layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain a crude product. The crude product was applied to a silica gel column (n-hexane-chloroform), and the obtained oily substance was dissolved in methanol (20 ml), and then water (200 ml) was added for crystallization. The precipitated crystals were collected by filtration and dried to obtain a white solid compound 200Me (3.11 g).
1H-NMR (DMSO-d6 / TMS):
δ = 2.50 (3H, s) 3.73 (3H, s) 5.08 (2H, s) 6.85-6.96 (3H, m) 7.54-7.80 (4H, m) 8.34 (2H, d, J = 8 Hz) 9.63 (1H, s)
To a compound 200Me (1.75 g) in methanol (25 ml) was added 1N sodium hydroxide (15 ml) and hydrolyzed at room temperature for 3 hours. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (50 ml), and then activated carbon (0.5 g) was added and filtered. 35% hydrochloric acid (1.5 g) was added to the filtrate for acid precipitation. The precipitated crystals were filtered and then dried to obtain a yellow solid compound 200 (1.52 g).
1H-NMR (DMSO-d6 / TMS):
δ = 2.49 (3H, s) 5.00 (2H, s) 6.82-6.96 (3H, m) 7.54-7.79 (4H, m)
Compound 200 (336 mg), 1N sodium hydroxide (0.95 ml) were dissolved in water (30 ml), filtered, and the filtrate was lyophilized to obtain Compound 200 · Na as a white solid.

（製剤処方例 １（錠剤））
本発明化合物 １０．０ｇ
乳糖 ９．０ｇ
ヒドロキシプロピルセルロース ２．０ｇ
結晶セルロース ７．７ｇ
ステアリン酸マグネシウム ０．３ｇ
タルク １．０ｇ
以上を常法により、本発明化合物１００ｍｇを含有する錠剤とする。
（製剤処方例 ２（注射剤））
本発明化合物 １ｍｇ
５％ブドウ糖注射液 ２ｍｌ
以上を常法により注射剤とする。
（製剤処方例 ３（坐剤））
本発明化合物 １０ｍｇ
カカオ脂 適量
以上を常法により坐剤とする。
次に本発明化合物のプラスミン形成促進試験、ｔ−ＰＡ賦活活性試験及びＰＡＩ−１阻害活性試験を示す。
プラスミン形成促進試験：
本発明化合物を注射用水とＤＭＳＯにより１×１０^−３Ｍに調製し、本発明化合物溶液とした。９６穴マイクロプレートを氷上に置き、本発明化合物溶液を２５μＬ（終濃度１．２５×１０^−４Ｍ）、１５０ｍＭ塩化ナトリウムを含む２０ｍＭ燐酸緩衝液（ｐＨ７．４）でそれぞれ調製したヒト組み換えｔ−ＰＡを５０μＬ（終濃度４０００ＩＵ／ｍＬ）、グルタミン酸タイプ−ヒトプラスミノーゲンを２５μＬ（終濃度８．７５μｇ／ｍＬ）及び合成基質Ｓ−２２５１を１００μＬ（終濃度０．５ｍＭ）添加し混合した。コントロールとして本発明化合物溶液の代わりにＤＭＳＯ溶液を２５μＬ（終濃度１．２５％）添加した。３７℃でインキュベートしながらマイクロプレートリーダーで４０５ｎｍの吸光度を２時間測定した。吸光度１．４に達するのに要する時間を算出し、コントロールに対する比からプラスミン形成促進活性を求めた。その結果、本発明化合物が優れたプラスミン形成促進作用を有する事が明らかとなった。結果を表２に示した。

ＰＡＩ−１阻害活性試験及びｔ−ＰＡ賦活活性試験：
本発明化合物を注射用水とＤＭＳＯにより１．８７５×１０^−３Ｍに調製し、さらにこれを注射用水で段階希釈して本発明化合物溶液とした。ＰＡＩ−１及びヒト組み換えｔ−ＰＡ（ｒｔ−ＰＡ）を使用し、下記表３に示すＡ、Ｂ、Ｃ、Ｄの四種類の組み合わせで以下の試験を実施した。

本発明化合物溶液及び注射用水で調製したＰＡＩ−１を室温に於いて９６穴マイクロプレート上で１０分インキュベートした後、トリス塩酸緩衝液で調製したｒｔ−ＰＡを添加・混合し、更に室温で１０分インキュベートした。次に、Ｓ−２２８８を５０μＬ（終濃度０．５ｍＭ）添加・混合し、室温で１０分インキュベートした。その後、３７℃でインキュベートしながらマイクロプレートリーダーで４０５ｎｍの吸光度を測定しＡ、Ｂ、Ｃ、Ｄの吸光度をａ、ｂ、ｃ、ｄとして下記の要領で各活性を求めた。
ｔ−ＰＡ賦活活性：
ａ／ｂを本発明化合物のｔ−ＰＡ賦活活性値とした。
ＰＡＩ−１阻害活性：
先ず、本発明化合物のＰＡＩ−１阻害率を、ａ＝ｃの時１００％、ｃ／ｄ＝ａ／ｂの時０％とした直線関係から求め、得られたＰＡＩ−１阻害率（％）を縦軸に、その時の本発明化合物の終濃度（１．２５×１０^−４Ｍ，１．２５×１０^−５Ｍ）の対数値を横軸に採りＩＣ５０を求めた。その結果、本発明化合物が優れたｔ−ＰＡ賦活活性及びＰＡＩ−１阻害活性を有する事が明らかとなった。結果を表４、表５に示した。

[[2- [4 ′-(2-methoxy-2-oxoethoxy) [1,1′-biphenyl] -4-yl] -6-methyl-4-pyrimidinyl] oxy] acetic acid methyl ester (compound 201Me), Preparation of [[2- [4 ′-(carboxymethoxy) [1,1′-biphenyl] -4-yl] -6-methyl-4-pyrimidinyl] oxy] acetic acid (compound 201) carried out in DMF (30 ml) To compound 199 (1.39 g) obtained in Example 199 were added potassium carbonate (2.07 g) and methyl bromoacetate (1.68 g), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was partitioned with chloroform (150 ml) -water (150 ml). The chloroform layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from toluene (7 ml) to obtain a white solid compound 201Me (1.85 g).
1H-NMR (DMSO-d6 / TMS)
δ = 2.50 (3H, s) 3.72 (6H, s) 4.86 (2H, s) 5.08 (2H, s) 6.85 (1H, s) 7.06 (2H, d, J = 9 Hz) 7.72 (2H, d, J = 9 Hz) 7.77 (2H, d, J = 8 Hz) 8.35 (2H, d, J = 8 Hz)
1N sodium hydroxide (9 ml) was added to compound 201Me (1.27 g) in methanol (30 ml) and hydrolyzed at 60 ° C. for 2 hours. The hydrolyzed solution was concentrated under reduced pressure, and the residue was dissolved in water (50 ml), and then activated carbon (0.5 g) was added and filtered. 35% hydrochloric acid (0.94 g) was added to the filtrate for acid precipitation. The precipitated crystals were collected by filtration and dried to obtain white solid compound 201 (1.08 g).
1H-NMR (DMSO-d6 / TMS):
δ = 2.50 (3H, s) 4.76 (2H, s) 5.01 (2H, s) 6.83 (1H, s) 7.05 (2H, d, J = 9 Hz) 7.69− 7.84 (4H, m) 8.40 (2H, d, J = 8 Hz) 10.99-14.28 (1H, br)
The compounds obtained in the above examples are shown in Table 1. The compound number corresponds to the number assigned in each example.

(Formulation formulation example 1 (tablet))
Present compound 10.0 g
Lactose 9.0g
Hydroxypropylcellulose 2.0g
7.7 g of crystalline cellulose
Magnesium stearate 0.3g
Talc 1.0g
The above is made into a tablet containing 100 mg of the compound of the present invention by a conventional method.
(Formulation example 2 (injection))
1 mg of the present compound
5% glucose injection solution 2ml
The above is made into an injection by a conventional method.
(Formulation formulation example 3 (suppository))
10 mg of the present compound
Appropriate amount of cacao butter Use suppositories in the usual way.
Next, a plasmin formation promotion test, a t-PA activation activity test, and a PAI-1 inhibitory activity test of the compound of the present invention are shown.
Plasmin formation promotion test :
The compound of the present invention was prepared to 1 × 10 ⁻³ M with water for injection and DMSO to obtain a compound solution of the present invention. A 96-well microplate was placed on ice, and 25 μL of the compound solution of the present invention (final concentration: 1.25 × 10 ⁻⁴ M) and human recombinant t-prepared with 20 mM phosphate buffer (pH 7.4) containing 150 mM sodium chloride, respectively. 50 μL of PA (final concentration 4000 IU / mL), 25 μL of glutamic acid type-human plasminogen (final concentration 8.75 μg / mL) and 100 μL of synthetic substrate S-2251 (final concentration 0.5 mM) were added and mixed. As a control, 25 μL of DMSO solution (final concentration 1.25%) was added instead of the compound solution of the present invention. While incubating at 37 ° C., absorbance at 405 nm was measured with a microplate reader for 2 hours. The time required to reach an absorbance of 1.4 was calculated, and the plasmin formation promoting activity was determined from the ratio to the control. As a result, it was revealed that the compound of the present invention has an excellent plasmin formation promoting action. The results are shown in Table 2.

PAI-1 inhibitory activity test and t-PA activation activity test :
The compound of the present invention was prepared to 1.875 × 10 ⁻³ M with water for injection and DMSO, and this was serially diluted with water for injection to obtain a compound solution of the present invention. Using PAI-1 and human recombinant t-PA (rt-PA), the following tests were carried out with four combinations of A, B, C, and D shown in Table 3 below.

After incubating PAI-1 prepared with the compound solution of the present invention and water for injection on a 96-well microplate at room temperature for 10 minutes, rt-PA prepared with Tris-HCl buffer was added and mixed. Incubated for minutes. Next, 50 μL (final concentration 0.5 mM) of S-2288 was added and mixed, and incubated at room temperature for 10 minutes. Thereafter, the absorbance at 405 nm was measured with a microplate reader while incubating at 37 ° C., and the activities of A, B, C and D were determined as a, b, c and d as follows.
t-PA activation activity :
a / b was defined as the t-PA activation activity value of the compound of the present invention.
PAI-1 inhibitory activity :
First, the PAI-1 inhibition rate of the compound of the present invention was determined from a linear relationship with 100% when a = c and 0% when c / d = a / b, and the obtained PAI-1 inhibition rate (%) The IC50 was determined by taking the logarithmic value of the final concentration (1.25 × 10 ⁻⁴ M, 1.25 × 10 ⁻⁵ M) of the compound of the present invention on the vertical axis and the horizontal axis on the vertical axis. As a result, it was revealed that the compound of the present invention has excellent t-PA activation activity and PAI-1 inhibitory activity. The results are shown in Tables 4 and 5.

  The compound of the present invention has an excellent PA activity promoting action and PAI-1 inhibitory activity, and exhibits the promotion of fibrinolysis and thrombolytic action, and is therefore effective for diseases caused by thrombus. In other words, venous thrombosis, myocardial infarction, pulmonary embolism, cerebral infarction, slowly progressing cerebral thrombosis, treatment of thrombosis / embolism associated with vascular surgery and extracorporeal blood circulation, improvement of blood flow disorder, chronic arterial occlusion Thrombus such as thrombolytic agent, antithrombotic agent alone or other thrombolytic agent as a therapeutic agent for all thrombosis / embolism such as improvement of various symptoms, treatment of thrombus / embolism associated with ischemic cerebrovascular disorder It can be used in combination with a symptom treatment agent.

Claims (8)

As an active ingredient, the general formula (1)

[Where:
(1) a is
(I) a1-lower alkylene group -Y-
(Here, the lower alkylene group is a straight-chain or branched group having 1 to 6 carbon atoms.
Means a alkylene group,
(1) a1 is
1. Carboxy group
2. Dicarboxymethyl group
3 . A lower alkoxycarbonyl group (here, a lower alkoxycarbonyl group )
The bonyl group is a straight or branched alkoxy having 1 to 6 carbon atoms.
Means an alkoxycarbonyl group having a group)
Or
4 . Di (lower alkoxycarbonyl) methyl group (where lower alkyl
The alkoxycarbonyl group is a straight chain or branched chain having 1 to 6 carbon atoms.
Means an alkoxycarbonyl group having an alkoxy group)
Means
(2) Y is
1 . -O-arylene group-
(Here, the arylene group is a 1,4-phenylene group, or
(Means 2,6-naphthalenediyl group)
Means)
Means
(2) b is
(I) Hydroxyl group
Or (ii) b1-lower alkylene group -O-
(Here, the lower alkylene group represents the above meaning,
b1 is
1 . Halogen atom
2 . Phenyl group (wherein phenyl group is methyl group, cyano group,
Toxi group, halogen atom, nitro group, carboxy group, carbon number 1
Alkoxy group having 6 to 6 linear or branched alkoxy groups
A phenyl group which may be substituted with a rubonyl group or an acetoxy group;
means)
3 . Cyclohexyl group
4 . 4-morpholinyl group
Or
5 . Pyridinyl group
Means)
Means
(3) c is
(I) a phenyl group (wherein the phenyl group is an amino group, a nitro group, or
(Means a phenyl group that may be substituted with a methoxy group)
Or
(Ii) means trifluoromethyl group]
A pharmaceutical composition for treating thrombosis comprising a compound represented by the formula: or a pharmaceutically acceptable salt compound thereof or a solvate thereof.   The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a thrombolytic agent.   The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is an antithrombotic agent. The pharmaceutical composition according to any one of claims 1 to 3, wherein the compound represented by the formula (1) is a compound selected from the following compound group:
[4- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] acetic acid sodium salt,
[4- (1,4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) phenoxy] acetic acid,
[4- [4-[(2-chlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] phenoxy] acetic acid sodium salt,
4- [4- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] butanoic acid ethyl ester,
4- [4- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] butanoic acid sodium salt,
4- [4- (1,4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) phenoxy] butanoic acid ethyl ester,
4- [4- (1,4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) phenoxy] butanoic acid,
4- [4- [4-[(2-chlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] phenoxy] butanoic acid sodium salt,
4- [4- [4-[(2-fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] phenoxy] butanoic acid sodium salt,
4- [4- [4- (cyclohexylmethoxy) -6-phenyl-2-pyrimidinyl] phenoxy] butanoic acid sodium salt,
6- [4- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] hexanoic acid,
6- [4- (1,4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) phenoxy] hexanoic acid,
[3- [4- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] propyl] propanedioic acid diethyl ester,
[3- [4- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] propyl] propanedioic acid,
[3- [4- [4-[(2-fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] phenoxy] propyl] propanedioic acid,
[3- [4- [4- (cyclohexylmethoxy) -6-phenyl-2-pyrimidinyl] phenoxy] propyl] propanedioic acid,
[[6- (1,4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] acetic acid,
[[6- [1,4-dihydro-6- (4-nitrophenyl) -4-oxo-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid,
[[6- [1,4-dihydro-6- (3-nitrophenyl) -4-oxo-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid,
[[6- [6- (4-aminophenyl) -1,4-dihydro-4-oxo-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid,
[[6- [6- (3-aminophenyl) -1,4-dihydro-4-oxo-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid,
[[6- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid,
[[6- [4-[(2-fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid,
[[6- [4-[(2-fluorophenyl) methoxy] -6- (4-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid sodium salt,
[[6- [4-[(2-fluorophenyl) methoxy] -6- (3-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid sodium salt,
[[6- [4-[(2-fluorophenyl) methoxy] -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid,
[[6- [4- [2- (4-morpholinyl) ethoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid ethyl ester,
[[6- [4- [2- (4-morpholinyl) ethoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid sodium salt,
4-[[6- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester,
4-[[6- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
4-[[6- (1,4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] butanoic acid ethyl ester,
4-[[6- (1,4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] butanoic acid,
4-[[6- [4- [2- (4-morpholinyl) ethoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid,
4-[[6- [4-phenyl-6-[(3-pyridinyl) methoxy] -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid,
4-[[6- [4-phenyl-6-[(4-pyridinyl) methoxy] -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid,
4-[[[2- [6- (3-carboxypropoxy) -2-naphthalenyl] -6-phenyl-4-pyrimidinyl] oxy] methyl] benzoic acid,
4-[[6- [4-[(2-chlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
4-[[6- [4-[(3-chlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
4-[[6- [4-[(4-chlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
4-[[6- [4-[(2,6-dichlorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
4-[[6- [4-[(2-fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
4-[[6- [4-[(3-fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
4-[[6- [4-[(4-fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
4-[[6- [4-[(2,6-difluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
4-[[6- [4-[(2,4-difluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
4-[[6- [4-[(pentafluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
4-[[6- [4-[(2-bromophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
4-[[6- [4-[(4-bromophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
4-[[6- [4-[(2-fluorophenyl) methoxy] -6- (4-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
4-[[6- [4-[(2-fluorophenyl) methoxy] -6- (3-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
4-[[6- [4-[(2-fluorophenyl) methoxy] -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
4-[[6- [4-[(2-methylphenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
4-[[6- [4-[(2-nitrophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
4-[[6- [4-[(2-cyanophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
4-[[6- [4-[(2-methoxyphenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
4-[[6- [4-[[2- (acetyloxy) phenyl] methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester,
4-[[6- [4- (3-chloropropoxy) -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
5-[[6- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] pentanoic acid,
5-[[6- (1,4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] pentanoic acid,
6-[[6- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid,
6-[[6- (1,4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] hexanoic acid,
6-[[6- [4-[(2-fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt,
6-[[6- [4-[(2-fluorophenyl) methoxy] -6- (4-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt,
6-[[6- [4-[(2-fluorophenyl) methoxy] -6- (3-nitrophenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt,
6-[[6- [4-[(2-fluorophenyl) methoxy] -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid sodium salt,
7-[[6- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] heptanoic acid sodium salt,
7-[[6- (1,4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] heptanoic acid,
[3-[[6- [4-[(2-fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] propyl] propanedioic acid,
[3-[[6- [4-[(2-fluorophenyl) methoxy] -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] propyl] propanedioic acid,
[5-[[6- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid,
[5-[[6- (1,4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid,
4- [4- [4- (phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] butanoic acid ethyl ester,
4- [4- [1,4-dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] butanoic acid ethyl ester,
4- [4- [4- (cyclohexylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] butanoic acid sodium salt,
[3- [4- [4- (phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] propyl] propanedioic acid diethyl ester,
[3- [4- [1,4-dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] propyl] propanedioic acid diethyl ester,
[3- [4- [4- (cyclohexylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] propyl] propanedioic acid,
[[6- [4- (phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid ethyl ester,
[[6- [4- (phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid sodium salt,
[[6- [1,4-dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid ethyl ester,
[[6- [1,4-dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid,
[[6- [4-[(2-fluorophenyl) methoxy] -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] acetic acid,
4-[[6- [4- (phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester,
4-[[6- [1,4-dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid ethyl ester,
4-[[6- [1,4-dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid,
4-[[6- [4-[(2-fluorophenyl) methoxy] -6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] butanoic acid sodium salt,
6-[[6- [1,4-dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid ethyl ester,
6-[[6- [1,4-dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] hexanoic acid, and [5-[[6- [1, 4-Dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid.   A compound represented by the above formula (1) according to claim 1 or a compound according to claim 4, or a pharmaceutically acceptable salt compound thereof or a compound for producing a pharmaceutical composition for treating thrombosis Use of the solvate. In the formula (1),
a represents an a1-lower alkylene group -Y- (wherein a1 represents a dicarboxymethyl group or a di (lower alkoxycarbonyl) methyl group (wherein lower alkoxycarbonyl represents the above meaning)). , A lower alkylene group and Y represent the above meanings),
b is a b1-lower alkylene group -O- (where b1 is a phenyl group (where the phenyl group is a methyl group, a cyano group, a methoxy group, a halogen atom, a nitro group, a carboxy group, a carbon number of 1 to 6 represents an alkoxycarbonyl group having a linear or branched alkoxy group, or a phenyl group which may be substituted with an acetoxy group), or a cyclohexyl group, and a lower alkylene group represents the above meaning) And)
c is a phenyl group (wherein the phenyl group means a phenyl group which may be substituted with an amino group, a nitro group or a methoxy group), or a trifluoromethyl group,
Or a pharmaceutically acceptable salt compound or a solvate thereof. The compound according to claim 6, which is selected from the following group of compounds, or a pharmaceutically acceptable salt compound or a solvate thereof:
[3- [4- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] propyl] propanedioic acid diethyl ester,
[3- [4- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] phenoxy] propyl] propanedioic acid,
[3- [4- [4-[(2-fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] phenoxy] propyl] propanedioic acid,
[3- [4- [4- (cyclohexylmethoxy) -6-phenyl-2-pyrimidinyl] phenoxy] propyl] propanedioic acid,
[3-[[6- [4-[(2-fluorophenyl) methoxy] -6-phenyl-2-pyrimidinyl] -2-naphthalenyl] oxy] propyl] propanedioic acid,
[3-[[6- [4-[(2-fluorophenyl) methoxy] -6- (4-methoxyphenyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] propyl] propanedioic acid,
[5-[[6- [4-Phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid,
[5-[[6- (1,4-dihydro-4-oxo-6-phenyl-2-pyrimidinyl) -2-naphthalenyl] oxy] pentyl] propanedioic acid,
[3- [4- [4- (phenylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] propyl] propanedioic acid diethyl ester,
[3- [4- [1,4-dihydro-4-oxo-6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] propyl] propanedioic acid diethyl ester,
[3- [4- [4- (cyclohexylmethoxy) -6- (trifluoromethyl) -2-pyrimidinyl] phenoxy] propyl] propanedioic acid, and [5-[[6- [1,4-dihydro-4 -Oxo-6- (trifluoromethyl) -2-pyrimidinyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid.   A pharmaceutical composition comprising the compound according to claim 6 or 7, or a pharmaceutically acceptable salt compound or solvate thereof as an active ingredient.