JP4137174B2

JP4137174B2 - チロシンキナーゼ阻害作用を有するキナゾリン誘導体

Info

Publication number: JP4137174B2
Application number: JP2007504734A
Authority: JP
Inventors: 昌治粂; 健二松尾; 直樹大森; 正己高山; 愛子大森; 毅遠藤
Original assignee: Shionogi and Co Ltd
Current assignee: Shionogi and Co Ltd
Priority date: 2005-02-23
Filing date: 2006-02-22
Publication date: 2008-08-20
Anticipated expiration: 2026-02-22
Also published as: NO20074311L; EP1854789A4; US20090143414A1; AU2006216266C1; BRPI0606905A2; CA2599328C; RU2007135023A; AU2006216266B2; AU2006216266A2; CA2599328A1; EP1854789A1; TW200640880A; EP1854789B1; CN101163684A; ES2431843T3; CN101163684B; DK1854789T3; KR20070098941A; US8349857B2; AU2006216266A8

Description

本発明は、ＥＧＦ受容体チロシンキナーゼおよびＨＥＲ２チロシンキナーゼの両方を阻害する化合物およびそれらを有効成分として含有する医薬組成物に関する。

チロシンキナーゼは蛋白質中のチロシン残基をリン酸化する酵素であり、細胞の分化・増殖や細胞内情報伝達系において重要な役割を果たすことが知られている。特に、ＨＥＲ２（ＥｒｂＢ２またはＮｅｕとも呼ばれる）およびＥＧＦ受容体等の増殖因子受容体チロシンキナーゼ（以下、受容体チロシンキナーゼ）が癌の形成に深く関与していること、ヒト癌において受容体チロシンキナーゼ活性が亢進していることが知られている（非特許文献１、非特許文献２、および非特許文献３）。さらに、これら受容体チロシンキナーゼは脳、肺、胃、腸、膵臓、頭頚部、食道、膀胱、腎臓、前立腺、卵巣、乳、子宮、甲状腺等における腫瘍で過剰に発現していることが示されている（非特許文献４および特許文献１）。したがって、チロシンキナーゼ阻害剤が、多くの癌種に適応しうる副作用の少ない抗癌剤として有用であると考えられる。チロシンキナーゼ阻害剤としては、特許文献２、特許文献３、特許文献４、特許文献５、特許文献６、特許文献７等に記載の化合物が知られている。
また、ＥＧＦ受容体とＨＥＲ２の共発現によりＥＧＦ受容体単独による癌化がさらに加速されることが知られている（非特許文献５）。さらに、乳癌、口腔癌、肺癌等においてＥＧＦ受容体とＨＥＲ２の共発現があると予後不良になるとの報告がある（非特許文献６）。ＥＧＦ受容体チロシンキナーゼとＨＥＲ２チロシンキナーゼの両方を阻害する薬剤としては、特許文献８等に記載の化合物が知られている。
キナゾリン誘導体の４位にオキシム型置換基を有する抗癌剤が特許文献９および特許文献１０に記載されている。
特開平５−２０８９１１号公報国際公開第９２／２０６４２号パンフレット欧州特許出願公開第９２３０５７０３．８号明細書欧州特許出願公開第０５６６２６６号明細書欧州特許出願公開第０６０２８５１号明細書欧州特許出願公開第０５２０７２２号明細書国際公開第９８／０２４３４号パンフレット国際公開第０２／０６６４４５号パンフレット国際公開第２００４／０６９１４５号パンフレット国際公開第２００４／１０５７６５号パンフレットキャンサーリサーチ（Cancer Res.）1991年、第51巻、p.4430-4435 キャンサーリサーチ（Cancer Res.）1992年、第52巻、p.3636-3641 キャンサーケモセラピーアンドファーマコロジー（Cancer Chemother. Pharmacol.）、1993年、第32巻、p.1-19 エキスパートオピニオンオンインベスティゲーショナルドラッグス（Expert. Opin. Invest. Drugs）1994年、第3巻、第6号、p.577-595 セル（Cell）1987年、第58巻、p.287-292 クリニカルキャンサーリサーチ（Clin. Cancer Res.）1999年、第5巻、p.4164-4174

ＥＧＦ受容体とＨＥＲ２のデュアル阻害剤は単独のキナーゼにのみ作用する化合物と比較して、適応疾患が広く、デュアル阻害の相乗作用によってより強い治療効果が得られる点で優れている。したがって、ＥＧＦ受容体チロシンキナーゼおよびＨＥＲ２チロシンキナーゼの両方を阻害する化合物が求められていた。

そこで、本発明者らは鋭意研究の結果、６位にある種の置換基を有するキナゾリン誘導体が、優れたＥＧＦ受容体およびＨＥＲ２のデュアル阻害作用を有することを見出した。
すなわち、本発明は、
（１）一般式（Ｉ）：

［式中、Ｒ^Ｘは、式：

（式中、Ｒ^１は、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアリール、または置換されていてもよい非芳香族含窒素複素環基；
Ｚは、−Ｏ−、−Ｎ（Ｒ^１０）−、または−Ｏ−もしくは−Ｎ（Ｒ^１１）−を介在してもよいアルキレン；Ｒ^１０およびＲ^１１は、それぞれ独立して、水素原子、アルキル、アシル、アルキルオキシカルボニル、アルケニルオキシカルボニル、またはアラルキルオキシカルボニル；
Ｒ^２は、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいシクロアルキル、置換されていてもよいアリール、または置換されていてもよいヘテロアリール、；
Ｒ^１９は、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいヘテロアリール、または置換されていてもよい非芳香族複素環基；
Ｒ^１８は、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、または置換されていてもよいアルキニル；
Ｗ^１は、置換されていてもよい非芳香族含窒素複素環基または置換されていてもよいヘテロアリール；
Ｒ^１７は、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、または置換されていてもよい非芳香族含窒素複素環基）で表される基；
Ｒ^３およびＲ^４は、それぞれ独立して、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、置換されていてもよいアルケニルオキシ、ハロゲン、ヒドロキシ、メルカプト、または置換されていてもよいアミノ；
Ｘは、−Ｏ−、−Ｓ−、−Ｎ（Ｒ^１２）−、または−Ｏ−、−Ｓ−、もしくは−Ｎ（Ｒ^１３）−を介在してもよいアルキレン；Ｒ^１２およびＲ^１３は、それぞれ独立して、水素原子、アルキル、アシル、アルキルオキシカルボニル、アルケニルオキシカルボニル、またはアラルキルオキシカルボニル；および
Ａは、式：

（式中、Ｒ^５は、水素原子、ハロゲン、置換されていてもよいアルキルオキシ、置換されていてもよいアルケニルオキシ、置換されていてもよいアルキニルオキシ、または式：−Ｙ−Ｒ^８（式中、Yは−Ｏ−、−Ｓ−、−ＳＯ_２−、または−Ｏ−、−Ｓ−、もしくは−Ｎ（Ｒ^９）−を介在してもよいアルキレン；Ｒ^８は置換されていてもよいアリールまたは置換されていてもよいヘテロアリール；Ｒ^９は水素原子、アルキル、アシル、アルキルオキシカルボニル、アルケニルオキシカルボニル、またはアラルキルオキシカルボニル）で表される基；
Ｒ^６およびＲ^７は、それぞれ独立して、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、置換されていてもよいアルケニルオキシ、置換されていてもよいアルキニルオキシ、ハロゲン、ヒドロキシ、メルカプト、シアノ、または置換されていてもよいアミノ；
Ｒ^２０は、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアルキニル、または式：

（式中、Ｒ^５、Ｒ^６、およびＲ^７は、前記と同意義）で表される基；
ＱはＮまたはＣＨ_２）で表される基］
で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物、に関する。

さらに詳しくは、以下の（２）〜（２０）に関する。
（２）Ｒ^Ｘが、式：

（式中、Ｒ^１、Ｒ^２、Ｒ^１８、Ｒ^１９、Ｚ、およびＷ^１は、（１）と同意義）で表される基である、（１）記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（３）Ｒ^１が、置換基群Ａ（置換基群Ａ：ヒドロキシ、ヘテロアリール、カルボキシ、置換されていてもよいアミノ、置換されていてもよい非芳香族含窒素複素環基、置換されていてもよいアミノカルボニル、または置換されていてもよい非芳香族含窒素複素環カルボニル）から選択される置換基で置換されていてもよいアルキル、または置換基群Ｂ（置換基群Ｂ：アルキルオキシカルボニル、置換されていてもよいアミノカルボニル、オキソ、アミノ、カルボキシ、シアノ、シアノアルキル、ヒドロキシアルキル、アルキルカルボニルアミノ、アルキルスルホニルアミノ、およびアミノカルボニルアルキル）から選択される置換基で置換されていてもよい非芳香族含窒素複素環基である、（１）または（２）記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（４）Ｒ^１が、置換基群Ｃ（置換基群Ｃ：アルキル、アルケニル、アルキニル、置換されていてもよいアリール、アラルキル、アルキルオキシ、ヒドロキシアルキル、ヒドロキシアルキルオキシアルキル、ハロアルキル、１または2のアルキルで置換されていてもよいアミノアルキル、アルキルスルホニル、アルキルスルホニルアルキル、ハロゲンもしくはアルキルオキシで置換されていてもよいアルキルカルボニル、アルキルオキシカルボニル、置換されていてもよいシクロアルキル、カルボキシアルキル、置換されていてもよいアミノカルボニルアルキル、置換されていてもよいアミノカルボニルオキシアルキル、アルキルオキシアルキル、アルキルチオアルキル、アルキルカルボニルアミノアルキル、アルキルスルホニルアミノアルキル、アルキルスルホニル（アルキル）アミノアルキル、アルキルオキシカルボニルアルキル、アルキルチオ（ヒドロキシ）アルキル、シクロアルキルアルキル、シアノアルキル、置換されていてもよいアミノアルキルカルボニル、置換されていてもよいヘテロアリール、ヘテロアリールアルキル、ヒドロキシアルキルオキシアルキル、置換されていてもよい非芳香族複素環基、置換されていてもよい非芳香族複素環アルキル）から選択される置換基で置換されていてもよいアミノで置換されたアルキル、置換基群Ｄ（置換基群Ｄ：ハロゲン、アリール、ヒドロキシ、オキソ、置換されていてもよいアミノカルボニル、アルキルオキシカルボニル、置換基群Ｈ（置換基群Ｈ：置換されていてもよいアミノカルボニル、シアノ、アルキルオキシ、アルキルスルホニルアミノ、アミノ、カルボキシ、アルキルオキシカルボニル、およびヒドロキシ）から選択される置換基で置換されていてもよいアルキル、アルキルアミノカルボニル、カルボキシ、シアノ、アルキルスルホニル、アルキルカルボニル、アルケニルカルボニル、アルキルスルホニルアルキルカルボニル、アルキルオキシアルキルカルボニル、アルキルカルボニルアミノ、アミノカルボニルオキシ、非芳香族含窒素複素環基、および非芳香族複素環カルボニル）から選択される置換基で置換されていてもよい非芳香族含窒素複素環基で置換されたアルキル、または置換基群Ｂから選択される置換基で置換されていてもよい非芳香族含窒素複素環基である（１）〜（３）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（５）Ｚが−Ｏ−である、（１）〜（４）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。

（６）Ｒ^１９が、置換基群Ａから選択される置換基で置換されていてもよいアルキル、置換基群Ｉ（置換基群Ｉ：アルキルオキシカルボニル、置換されていてもよいアミノカルボニル、シアノ、シアノアルキル、ヒドロキシアルキル、およびアミノカルボニルアルキル）から選択される置換基で置換されていてもよいアリール、または置換基群Ｉから選択される置換基で置換されていてもよいヘテロアリールである、（１）または（２）記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（７）Ｒ^１９が、置換基群Ｃから選択される置換基で置換されていてもよいアミノで置換されたアルキル、または置換基群Ｄから選択される置換基で置換されていてもよい非芳香族含窒素複素環基で置換されたアルキルである、（１）、（２）、または（６）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（８）Ｗ^１が、置換基群Ｊ（置換基群Ｊ：アルキル、シアノアルキル、ヒドロキシアルキル、アミノカルボニルアルキル、アルキルオキシ、アルキルオキシカルボニル、置換されていてもよいアミノカルボニル、およびシアノ）から選択される置換基で置換されていてもよい非芳香族含窒素複素環基で表される基または置換基群Ｊから選択される置換基で置換されていてもよいヘテロアリールで表される基である、（１）または（２）記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（９）Ｒ^２が、水素原子、ハロゲンで置換されていてもよいＣ１−Ｃ６アルキル、Ｃ２−Ｃ６アルケニル、Ｃ２−Ｃ６アルキニル、ハロゲン、またはフェニルである、（１）〜（８）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１０）Ｒ^２が、Ｃ２−Ｃ４アルキニルである、（１）〜（９）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１１）Ｒ^３およびＲ^４の一方が水素原子、他方が水素原子、置換されていてもよいアルキルオキシまたは置換されていてもよいアルケニルオキシである、（１）〜（１０）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１２）Ｘが、−ＮＨ−である、（１）〜（１１）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。

（１３）Ａが、式：

（式中、Ｒ^５は、水素原子またはハロゲン；Ｒ^６は、ハロゲンまたはアルキニル；およびＲ^７は水素原子）で表される基である、（１）〜（１２）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１４）Ａが、式：

［式中、Ｒ^５は、置換基群Ｅ（置換基群Ｅ：カルボキシ、アルキルオキシカルボニル、シクロアルキル、および置換されていてもよいアミノカルボニル）から選択される置換基で置換されていてもよいアルキルオキシ、置換基群Ｅから選択される置換基で置換されていてもよいアルケニルオキシ、または置換基群Ｅから選択される置換基で置換されていてもよいアルキニルオキシ；Ｒ^６は、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、またはハロゲン；およびＲ^７は水素原子］で表される基である、（１）〜（１２）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。

（１５）Ａが、式：

［式中、Ｒ^５は、式：−Ｙ−Ｒ^８（式中、Yは、−Ｏ−を介在してもよいアルキレン；Ｒ^８は、置換基群Ｆ（置換基群Ｆ：ハロゲン、カルボキシ、アルキル、ハロアルキル、ヒドロキシアルキル、アルキルオキシ、アルキルオキシカルボニル、および置換されていてもよいアミノ）から選択される置換基で置換されていてもよいフェニル、置換基群Ｆから選択される置換基で置換されていてもよいピリジル、置換基群Ｆから選択される置換基で置換されていてもよいフリル、置換基群Ｆから選択される置換基で置換されていてもよいチエニル、置換基群Ｆから選択される置換基で置換されていてもよいチアゾリル、または置換基群Ｆから選択される置換基で置換されていてもよいオキサゾリル）で表される基；Ｒ^６が、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、またはハロゲン；およびＲ^７が水素原子］で表される基である、（１）〜（１２）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１６）Ｒ^Ｘが、式：

（式中、Ｒ^１はアルキル、ヒドロキシアルキル、アルキルカルボニルアミノアルキル、もしくは非芳香族複素環で置換されていてもよいアミノで置換されたアルキル；アルキル、ヒドロキシアルキル、もしくはアルキルカルボニルアミノで置換されていてもよい非芳香族含窒素複素環基で置換されたアルキル；またはヒドロキシアルキルで置換された非芳香族含窒素複素環基、Ｒ²はＣ２〜Ｃ４アルキニル）で表される基；
Ｒ^３およびＲ^４はいずれも水素原子；
Ｘは−ＮＨ−；および
Ａは、式：

［式中、Ｒ^５は、式：−Ｙ−Ｒ^８（式中、Yは、−Ｏ−を介在してもよいＣ１〜Ｃ３アルキレン；Ｒ^８は、ハロゲンで置換されていてもよいフェニルまたはハロゲンで置換されていてもよいピリジル）で表される基；Ｒ^６がハロゲン；およびＲ^７が水素原子］で表される基である、（１）に記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（１７）（１）〜（１６）のいずれかに記載の化合物を有効成分として含有する医薬組成物。
（１８）（１）〜（１６）のいずれかに記載の化合物を有効成分として含有する抗癌剤。
（１９）（１）〜（１６）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする癌の予防および／または治療方法。
（２０）癌の予防および／または治療剤を製造するための（１）〜（１６）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物の使用。

また、本発明は別の態様として以下の発明を包含する。
（Ｉ）一般式（Ｉ）：

［式中、Ｒ^Ｘは、式：

（式中、Ｒ^１は、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、または置換されていてもよい非芳香族含窒素複素環基；
Ｚは、−Ｏ−もしくは−Ｎ（Ｒ^１０）−、または−Ｏ−もしくは−Ｎ（Ｒ^１１）−を介在してもよいアルキレン；Ｒ^１０およびＲ^１１は、それぞれ独立して、水素原子、アルキル、アシル、アルキルオキシカルボニル、アルケニルオキシカルボニル、またはアラルキルオキシカルボニル；
Ｒ^２は、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいアリール、または置換されていてもよいヘテロアリール；
Ｒ^１９は、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいヘテロアリール、または置換されていてもよい非芳香族複素環基；
Ｒ^１８は、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、または置換されていてもよいアルキニル；
Ｗ^１は、置換されていてもよい非芳香族含窒素複素環基または置換されていてもよいヘテロアリール；
Ｒ^１７は、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、または置換されていてもよい非芳香族含窒素複素環基）で表される基；
Ｒ^３およびＲ^４は、それぞれ独立して、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、置換されていてもよいアルケニルオキシ、ハロゲン、ヒドロキシ、メルカプト、または置換されていてもよいアミノ；
Ｘは、−Ｏ−、−Ｓ−、−Ｎ（Ｒ^１２）−、または−Ｏ−、−Ｓ−、もしくは−Ｎ（Ｒ^１３）−を介在してもよいアルキレン；Ｒ^１２およびＲ^１３は、それぞれ独立して、水素原子、アルキル、アシル、アルキルオキシカルボニル、アルケニルオキシカルボニル、またはアラルキルオキシカルボニル；および
Ａは、式：

（式中、Ｒ^５は、水素原子、ハロゲン、置換されていてもよいアルキルオキシ、置換されていてもよいアルケニルオキシ、置換されていてもよいアルキニルオキシ、または式：−Ｙ−Ｒ^８（式中、Yは−Ｏ−、−Ｓ−、または−Ｎ（Ｒ^９）−を介在してもよいアルキレン；Ｒ^８は置換されていてもよいアリールまたは置換されていてもよいヘテロアリール；Ｒ^９は水素原子、アルキル、アシル、アルキルオキシカルボニル、アルケニルオキシカルボニル、またはアラルキルオキシカルボニル）で表される基；
Ｒ^６およびＲ^７は、それぞれ独立して、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、置換されていてもよいアルケニルオキシ、置換されていてもよいアルキニルオキシ、ハロゲン、ヒドロキシ、メルカプト、または置換されていてもよいアミノ；
Ｒ^２０は、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアルキニル、または式：

（式中、Ｒ^５、Ｒ^６、およびＲ^７は、前記と同意義）で表される基）；
ＱはＮまたはＣＨ_２）で表される基］
で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物、に関する。

さらに詳しくは、以下の（ＩＩ）〜（ＸＶ）に関する。
（ＩＩ）Ｒ^Ｘが、式：

（式中、Ｒ^１、Ｒ^２、Ｒ^１８、Ｒ^１９、Ｚ、およびＷ^１は、（Ｉ）と同意義）で表される基である、（Ｉ）記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ＩＩＩ）Ｒ^１が、置換基群Ａ’（置換基群Ａ’：ヒドロキシ、置換されていてもよいアミノ、置換されていてもよい非芳香族含窒素複素環基、置換されていてもよいアミノカルボニル、または置換されていてもよい非芳香族含窒素複素環カルボニル）から選択される置換基で置換されていてもよいアルキル、または置換基群Ｂ’（置換基群Ｂ’：アルキルオキシカルボニル、置換されていてもよいアミノカルボニル、シアノ、シアノアルキル、ヒドロキシアルキル、およびアミノカルボニルアルキル）から選択される置換基で置換されていてもよい非芳香族含窒素複素環基である、（Ｉ）または（ＩＩ）記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ＩＶ）Ｒ^１が、置換基群Ｃ’（置換基群Ｃ’：アルキル、アルキニル、アルキルスルホニルアルキル、ヒドロキシアルキル、ハロゲンで置換されていてもよいアルキルカルボニル、アルキルオキシカルボニル、シクロアルキル、置換されていてもよいアミノカルボニルアルキル、置換されていてもよいアミノカルボニルオキシアルキル、アルキルオキシアルキル、シクロアルキルアルキル、シアノアルキル、および置換されていてもよいアミノアルキルカルボニル）から選択される置換基で置換されていてもよいアミノで置換されたアルキル、または置換基群Ｄ’（置換基群Ｄ’：ヒドロキシ、オキソ、置換されていてもよいアミノカルボニル、アルキルオキシカルボニル、置換基群Ｈ’（置換基群Ｈ’：置換されていてもよいアミノカルボニル、シアノ、アルキルオキシ、およびヒドロキシ）から選択される置換基で置換されていてもよいアルキル、アルキルアミノカルボニル、シアノ、アルキルスルホニル、アルキルカルボニル、アルケニルカルボニル、アルキルスルホニルアルキルカルボニル、アルキルオキシアルキルカルボニル、アルキルカルボニルアミノおよび非芳香族複素環カルボニル）から選択される置換基で置換されていてもよい非芳香族含窒素複素環基で置換されたアルキルである、（Ｉ）〜（ＩＩＩ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。

（Ｖ）Ｒ^１９が、置換基群Ａ’から選択される置換基で置換されていてもよいアルキル、置換基群Ｉ’（置換基群Ｉ’：アルキルオキシカルボニル、置換されていてもよいアミノカルボニル、シアノ、シアノアルキル、ヒドロキシアルキル、およびアミノカルボニルアルキル）から選択される置換基で置換されていてもよいアリール、または置換基群Ｉ’から選択される置換基で置換されていてもよいヘテロアリールである、（Ｉ）または（ＩＩ）記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ＶＩ）Ｒ^１９が、置換基群Ｃ’から選択される置換基で置換されていてもよいアミノで置換されたアルキル、または置換基群Ｄ’から選択される置換基で置換されていてもよい非芳香族含窒素複素環基で置換されたアルキルである、（Ｉ）、（ＩＩ）、または（Ｖ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ＶＩＩ）Ｗ^１が、置換基群Ｊ’（置換基群Ｊ’：アルキル、シアノアルキル、ヒドロキシアルキル、アミノカルボニルアルキル、アルキルオキシ、アルキルオキシカルボニル、置換されていてもよいアミノカルボニル、およびシアノ）から選択される置換基で置換されていてもよい非芳香族含窒素複素環基で表される基または置換基群Ｊ’から選択される置換基で置換されていてもよいヘテロアリールで表される基である、（Ｉ）または（ＩＩ）記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ＶＩＩＩ）Ｒ^２が、水素原子、ハロゲンで置換されていてもよいＣ１−Ｃ６アルキル、Ｃ２−Ｃ６アルケニル、Ｃ２−Ｃ６アルキニル、ハロゲン、またはフェニルである、（Ｉ）〜（ＶＩＩ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ＩＸ）Ｒ^３およびＲ^４の一方が水素原子、他方が水素原子、置換されていてもよいアルキルオキシまたは置換されていてもよいアルケニルオキシである、（Ｉ）〜（ＶＩＩＩ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（Ｘ）Ｘが、−ＮＨ−である、（Ｉ）〜（ＩＸ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。

（ＸＩ）Ａが、式：

（式中、Ｒ^５は、水素原子またはハロゲン；Ｒ^６は、ハロゲンまたはアルキニル；およびＲ^７は水素原子）で表される基である、（Ｉ）〜（ＩＸ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ＸＩＩ）Ａが、式：

［式中、Ｒ^５は、置換基群Ｅ’（置換基群Ｅ’：カルボキシ、アルキルオキシカルボニル、シクロアルキル、および置換されていてもよいアミノカルボニル）から選択される置換基で置換されていてもよいアルキルオキシ、置換基群Ｅ’から選択される置換基で置換されていてもよいアルケニルオキシ、または置換基群Ｅ’から選択される置換基で置換されていてもよいアルキニルオキシ；Ｒ^６は、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、またはハロゲン；およびＲ^７は水素原子］で表される基である、（Ｉ）〜（ＩＸ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。

（ＸＩＩＩ）Ａが、式：

［式中、Ｒ^５は、式：−Ｙ−Ｒ^８（式中、Yは、−Ｏ−を介在してもよいアルキレン；Ｒ^８は、置換基群Ｆ’（置換基群Ｆ’：ハロゲン、カルボキシ、アルキル、ハロアルキル、ヒドロキシアルキル、アルキルオキシ、アルキルオキシカルボニル、および置換されていてもよいアミノ）から選択される置換基で置換されていてもよいフェニル、置換基群Ｆ’から選択される置換基で置換されていてもよいピリジル、置換基群Ｆ’から選択される置換基で置換されていてもよいフリル、置換基群Ｆ’から選択される置換基で置換されていてもよいチエニル、置換基群Ｆ’から選択される置換基で置換されていてもよいチアゾリル、または置換基群Ｆ’から選択される置換基で置換されていてもよいオキサゾリル）で表される基；Ｒ^６が、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、またはハロゲン；およびＲ^７が水素原子］で表される基である、（Ｉ）〜（ＩＸ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ＸＩＶ）（Ｉ）〜（ＸＩＩＩ）のいずれかに記載の化合物を有効成分として含有する医薬組成物。
（ＸＶ）（Ｉ）〜（ＸＩＩＩ）のいずれかに記載の化合物を有効成分として含有する抗癌剤。
（ＸＶＩ）（Ｉ）〜（ＸＩＩＩ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする癌の予防および／または治療方法。
（ＸＶＩＩ）癌の予防および／または治療剤を製造するための（Ｉ）〜（ＸＩＩＩ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物の使用。

本発明のさらなる別の態様として、以下の発明を包含する。
（ｉ）一般式（Ｉ’）：

［式中、Ｒ^１は、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、または置換されていてもよい非芳香族含窒素複素環基；
Ｚは、−Ｏ−もしくは−Ｎ（Ｒ^１０）−、または−Ｏ−もしくは−Ｎ（Ｒ^１１）−を介在してもよいアルキレン；Ｒ^１０およびＲ^１１は、それぞれ独立して、水素原子、アルキル、アシル、アルキルオキシカルボニル、アルケニルオキシカルボニル、またはアラルキルオキシカルボニル；
Ｒ^２は、水素原子、置換されていてもよいアルキル、アルケニル、アルキニル、置換されていてもよいアリール、または置換されていてもよいヘテロアリール；
または、−Ｃ（Ｒ^２）＝Ｎ−Ｚ−Ｒ^１で表される基が、式：

（式中、Ｒ^１７は、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、または置換されていてもよい非芳香族含窒素複素環基）で表される基；
Ｒ^３およびＲ^４は、それぞれ独立して、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、置換されていてもよいアルケニルオキシ、ハロゲン、ヒドロキシ、メルカプト、または置換されていてもよいアミノ；
Ｘは、−Ｏ−、−Ｓ−、もしくは−Ｎ（Ｒ^１２）−、または−Ｏ−、−Ｓ−、もしくは−Ｎ（Ｒ^１３）−を介在してもよいアルキレン；Ｒ^１２およびＲ^１３は、それぞれ独立して、水素原子、アルキル、アシル、アルキルオキシカルボニル、アルケニルオキシカルボニル、またはアラルキルオキシカルボニル；および
Ａは、式：

（式中、Ｒ^５は、水素原子、ハロゲン、置換されていてもよいアルキルオキシ、置換されていてもよいアルケニルオキシ、置換されていてもよいアルキニルオキシ、または式：−Ｙ−Ｒ^８（式中、Yは−Ｏ−、−Ｓ−、または−Ｎ（Ｒ^９）−を介在してもよいアルキレン；Ｒ^８は置換されていてもよいアリールまたは置換されていてもよいヘテロアリール；Ｒ^９は水素原子、アルキル、アシル、アルキルオキシカルボニル、アルケニルオキシカルボニル、またはアラルキルオキシカルボニル）で表される基；
Ｒ^６およびＲ^７は、それぞれ独立して、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、置換されていてもよいアルケニルオキシ、置換されていてもよいアルキニルオキシ、ハロゲン、ヒドロキシ、メルカプト、または置換されていてもよいアミノ）で表される基］
で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ｉｉ）Ｒ^１が、置換基群Ａ’’（置換基群Ａ’’：置換されていてもよいアミノおよび置換されていてもよい非芳香族含窒素複素環基）から選択される置換基で置換されていてもよいアルキル、または置換基群Ｂ’’（置換基群Ｂ’’：アルキルオキシカルボニル、置換されていてもよいアミノカルボニル、およびシアノ）から選択される置換基で置換されていてもよい非芳香族含窒素複素環基である、（ｉ）記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ｉｉｉ）Ｒ^１が、置換基群Ｃ’’（置換基群Ｃ’’：アルキル、アルキルスルホニルアルキル、ハロゲンで置換されていてもよいアルキルカルボニル、アルキルオキシカルボニル、シクロアルキル、置換されていてもよいアミノカルボニルアルキル、置換されていてもよいアミノカルボニルオキシアルキル、アルキルオキシアルキル、および置換されていてもよいアミノアルキルカルボニル）から選択される置換基で置換されていてもよいアミノで置換されたアルキル、または置換基群Ｄ’’（置換基群Ｄ’’：オキソ、置換されていてもよいアミノカルボニル、アルキルオキシカルボニル、シアノもしくはアルキルオキシで置換されていてもよいアルキル、シアノ、アルキルスルホニル、アルキルカルボニル、アルケニルカルボニル、およびアルキルスルホニルアルキルカルボニル）から選択される置換基で置換されていてもよい非芳香族含窒素複素環基で置換されたアルキルである、（ｉ）または（ｉｉ）記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ｉｖ）Ｒ^３およびＲ^４の一方が水素原子、他方が水素原子、置換されていてもよいアルキルオキシまたは置換されていてもよいアルケニルオキシである、（ｉ）〜（ｉｉｉ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ｖ）Ｘが、−ＮＨ−である、（ｉ）〜（ｉｖ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ｖｉ）Ａが、式：

（式中、Ｒ^５は、水素原子またはハロゲン；Ｒ^６は、ハロゲンまたはアルキニル；およびＲ^７は水素原子）で表される基である、（ｉ）〜（ｖ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ｖｉｉ）Ａが、式：

［式中、Ｒ^５は、置換基群Ｅ’’（置換基群Ｅ’’：カルボキシ、アルキルオキシカルボニル、および置換されていてもよいアミノカルボニル）から選択される置換基で置換されていてもよいアルキルオキシ、置換基群Ｅ’’から選択される置換基で置換されていてもよいアルケニルオキシ、または置換基群Ｅ’’から選択される置換基で置換されていてもよいアルキニルオキシ；Ｒ^６は、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、またはハロゲン；およびＲ^７は水素原子］で表される基である、（ｉ）〜（ｖｉ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ｖｉｉｉ）Ａが、式：

［式中、Ｒ^５は、式：−Ｙ−Ｒ^８（式中、Yは、−Ｏ−を介在してもよいアルキレン；Ｒ^８は、置換基群Ｆ’’（置換基群Ｆ’’：ハロゲン、カルボキシ、アルキル、ハロアルキル、ヒドロキシアルキル、アルキルオキシ、アルキルオキシカルボニル、および置換されていてもよいアミノ）から選択される置換基で置換されていてもよいフェニル、置換基群Ｆ’’から選択される置換基で置換されていてもよいピリジル、置換基群Ｆ’’から選択される置換基で置換されていてもよいフリル、置換基群Ｆ’’から選択される置換基で置換されていてもよいチエニル、置換基群Ｆ’’から選択される置換基で置換されていてもよいチアゾリル、または置換基群Ｆ’’から選択される置換基で置換されていてもよいオキサゾリル）で表される基；Ｒ^６が、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、またはハロゲン；およびＲ^７が水素原子］で表される基である、（ｉ）〜（ｖｉｉ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
（ｉｘ）（ｉ）〜（ｖｉｉｉ）のいずれかに記載の化合物を有効成分として含有する医薬組成物。
（ｘ）（ｉ）〜（ｖｉｉｉ）のいずれかに記載の化合物を有効成分として含有する抗癌剤。
（ｘｉ）（ｉ）〜（ｖｉｉｉ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする癌の予防および／または治療方法。
（ｘｉｉ）癌の予防および／または治療剤を製造するための（ｉ）〜（ｖｉｉｉ）のいずれかに記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物の使用。

本明細書中、「ハロゲン」とは、フッ素、塩素、臭素、ヨウ素を意味する。フッ素、塩素、および臭素が好ましい。

本明細書中、単独でもしくは他の用語と組み合わせて用いられる「アルキル」とは、炭素原子数１〜１０の直鎖または分枝鎖の１価の炭化水素基を包含する。例えば、メチル、エチル、ｎ−プロピル、イソプロピル、ｎ−ブチル、イソブチル、ｓｅｃ−ブチル、ｔｅｒｔ−ブチル、ｎ−ペンチル、イソペンチル、ｎｅｏ−ペンチル、ｎ−ヘキシル、イソヘキシル、ｎ−ヘプチル、ｎ−オクチル、ｎ−ノナニル、ｎ−デカニル等が挙げられる。好ましくは、Ｃ１〜Ｃ１０アルキルが挙げられる。さらに好ましくは、Ｃ１〜Ｃ６アルキルが挙げられる。最も好ましくは、Ｃ１〜Ｃ４アルキルが挙げられる。
本明細書中、単独でもしくは他の用語と組み合わせて用いられる「ハロアルキル」なる用語は、前記「ハロゲン」によって１〜８箇所、好ましくは１〜５箇所置換された前記「アルキル」を包含する。例えば、トリフルオロメチル、トリクロロメチル、ジフルオロエチル、トリフルオロエチル、ジクロロエチル、トリクロロエチル等が挙げられる。好ましくは、前記「ハロゲン」によって１〜５箇所置換されたＣ１〜Ｃ６アルキルが挙げられる。特に、前記「ハロゲン」によって１〜３箇所置換されたＣ１〜Ｃ３アルキルが好ましい。最も好ましくは、トリフルオロメチルが挙げられる。
本明細書中、「アルキルスルホニル」としては、メチルスルホニル、エチルスルホニル、プロピルスルホニル等が挙げられる。好ましくは、Ｃ１〜Ｃ６アルキルスルホニルが挙げられる。特に、Ｃ１〜Ｃ３アルキルスルホニルが好ましい。
本明細書中、「アルキルスルホニルアルキル」としては、メチルスルホニルメチル、メチルスルホニルエチル、メチルスルホニルプロピル、メチルスルホニルブチル、メチルスルホニルプロピル等が挙げられる。好ましくは、Ｃ１〜Ｃ６アルキルスルホニルＣ１〜Ｃ６アルキルが挙げられる。特に、Ｃ１〜Ｃ３アルキルスルホニルＣ１〜Ｃ４アルキルが好ましい。
本明細書中、「アルキルオキシ」としては、メチルオキシ、エチルオキシ、ｎ−プロピルオキシ、イソプロピルオキシ、ｎ−ブチルオキシ、イソブチルオキシ、ｓｅｃ−ブチルオキシ、ｔｅｒｔ−ブチルオキシ、ｎ−ペンチルオキシ、ｎ−ヘキシルオキシ、ｎ−ヘプチルオキシ、ｎ−オクチルオキシ、ｎ−ノナニルオキシ、ｎ−デカニルオキシ等が挙げられる。好ましくは、Ｃ１〜Ｃ６アルキルオキシが挙げられる。特に、Ｃ１〜Ｃ３アルキルオキシが好ましい。
本明細書中、「アルキルオキシアルキル」としては、メチルオキシメチル、メチルオキシエチル、メチルオキシプロピル、エチルオキシメチル、エチルオキシエチル、エチルオキシプロピル等が挙げられる。好ましくは、Ｃ１〜Ｃ６アルキルオキシＣ１〜Ｃ６アルキルが挙げられる。特に、Ｃ１〜Ｃ３アルキルオキシＣ１〜Ｃ４アルキルが好ましい。
本明細書中、「アルキルオキシカルボニル」としては、メチルオキシカルボニル、エチルオキシカルボニル、ｎ−プロピルオキシカルボニル、イソプロピルオキシカルボニル、ｎ−ブチルオキシカルボニル、ｔ−ブチルオキシカルボニル、ｎ−ペンチルオキシカルボニル等が挙げられる。好ましくは、Ｃ１〜Ｃ６アルキルオキシカルボニルが挙げられる。特に、Ｃ１〜Ｃ３アルキルオキシカルボニルが好ましい。
本明細書中、「アルキルカルボニル」としては、メチルカルボニル、エチルカルボニル、ｎ−プロピルカルボニル、イソプロピルカルボニル、ｎ−ブチルカルボニル、ｔ−ブチルカルボニル、ｎ−ペンチルカルボニル等が挙げられる。好ましくは、Ｃ１〜Ｃ６アルキルカルボニルが挙げられる。特に、Ｃ１〜Ｃ３アルキルカルボニルが好ましい。
本明細書中、「ハロアルキルオキシ」としては、トリフルオロメチルオキシ、トリクロロメチルオキシ、ジフルオロエチルオキシ、トリフルオロエチルオキシ、ジクロロエチルオキシ、トリクロロエチルオキシ等が挙げられる。好ましくは、ハロＣ１〜Ｃ６アルキルオキシが挙げられる。特に、好ましくは、ハロＣ１〜Ｃ３アルキルオキシが好ましい。最も好ましくは、トリフルオロメチルオキシが挙げられる。
本明細書中、「アミノカルボニルアルキル」としては、アミノカルボニルメチル、アミノカルボニルエチル、アミノカルボニルプロピル、アミノカルボニルブチル等が挙げられる。好ましくは、アミノカルボニルＣ１〜Ｃ６アルキルが挙げられる。特に、アミノカルボニルＣ１〜Ｃ３アルキルが好ましい。
本明細書中、「アミノカルボニルアルキルオキシ」としては、アミノカルボニルメチルオキシ、アミノカルボニルエチルオキシ、アミノカルボニルプロピルオキシ、アミノカルボニルブチルオキシ等が挙げられる。好ましくは、アミノカルボニルＣ１〜Ｃ６アルキルオキシが挙げられる。特に、アミノカルボニルＣ１〜Ｃ３アルキルオキシが好ましい。
本明細書中、「ヒドロキシアルキル」としては、ヒドロキシメチル、ヒドロキシエチル、ヒドロキシプロピル、ヒドロキシブチル等が挙げられる。好ましくは、ヒドロキシＣ１〜Ｃ６アルキルが挙げられる。特に、ヒドロキシＣ１〜Ｃ３アルキルが好ましい。
本明細書中、「アルキルチオ」としては、メチルチオ、エチルチオ、プロピルチオ、ブチルチオ等が挙げられる。好ましくは、Ｃ１〜Ｃ６アルキルチオが挙げられる。特に、Ｃ１〜Ｃ３アルキルチオが好ましい。

本明細書中、単独でもしくは他の用語と組み合わせて用いられる「アルキレン」とは、炭素原子数１〜４の直鎖または分枝鎖の２価の炭化水素基を包含する。例えば、メチレン、エチレン、プロピレン、ブチレン等が挙げられる。好ましくは、Ｃ１〜Ｃ３アルキレンが挙げられる。特に、Ｃ１〜Ｃ２アルキレンが好ましい。
Ｚにおける「−Ｏ−もしくは−Ｎ（Ｒ^１１）−を介在してもよいアルキレン」としては、−ＣＨ_２−Ｏ−、−Ｏ−ＣＨ_２−、−ＣＨ_２−Ｎ（Ｒ^１１）−、−Ｎ（Ｒ^１１）−ＣＨ_２−、−（ＣＨ_２）_２−Ｏ−、−Ｏ−（ＣＨ_２）_２−、−（ＣＨ_２）_２−Ｎ（Ｒ^１１）−、−Ｎ（Ｒ^１１）−（ＣＨ_２）_２−等を包含する。特に、−Ｏ−ＣＨ_２−、−Ｎ（Ｒ^１１）−ＣＨ_２−、−Ｏ−（ＣＨ_２）_２−、−Ｎ（Ｒ^１１）−（ＣＨ_２）_２−等が好ましい。
Ｘにおける「−Ｏ−、−Ｓ−、または−Ｎ（Ｒ^１２）−を介在してもよいアルキレン」としては、−ＣＨ_２−Ｏ−、−Ｏ−ＣＨ_２−、−ＣＨ_２−Ｓ−、−Ｓ−ＣＨ_２−、−ＣＨ_２−Ｎ（Ｒ^１２）−、−Ｎ（Ｒ^１２）−ＣＨ_２−、−（ＣＨ_２）_２−Ｏ−、−Ｏ−（ＣＨ_２）_２−、−（ＣＨ_２）_２−Ｓ−、−Ｓ−（ＣＨ_２）_２−、−（ＣＨ_２）_２−Ｎ（Ｒ^１２）−、−Ｎ（Ｒ^１２）−（ＣＨ_２）_２−等を包含する。
Ｙにおける「−Ｏ−、−Ｓ−、または−Ｎ（Ｒ^９）−を介在してもよいアルキレン」としては、−ＣＨ_２−Ｏ−、−Ｏ−ＣＨ_２−、−ＣＨ_２−Ｓ−、−Ｓ−ＣＨ_２−、−ＣＨ_２−Ｎ（Ｒ^９）−、−Ｎ（Ｒ^９）−ＣＨ_２−、−（ＣＨ_２）_２−Ｏ−、−Ｏ−（ＣＨ_２）_２−、−（ＣＨ_２）_２−Ｓ−、−Ｓ−（ＣＨ_２）_２−、−（ＣＨ_２）_２−Ｎ（Ｒ^９）−、−Ｎ（Ｒ^９）−（ＣＨ_２）_２−、−Ｏ−ＣＨ（ＣＨ_３）−等を包含する。
本明細書中、単独でもしくは他の用語と組み合わせて用いられる「シクロアルキル」とは、炭素原子数が３〜８個であるシクロアルキルを包含する。例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチルが挙げられる。好ましくはＣ５〜Ｃ６シクロアルキルが挙げられる。

本明細書中、「アルケニル」とは、炭素原子数が２〜８個であり、１個もしくは２個以上の二重結合を有する、直鎖または分枝鎖の１価の炭化水素基を包含する。三重結合を鎖内に有していてもよい。例えば、ビニル、アリル、１−プロペニル、２−プロペニル、種々のブテニル異性体等が挙げられる。好ましくは、Ｃ２〜Ｃ６アルケニルが挙げられる。さらに好ましくは、Ｃ２〜Ｃ４アルケニルが挙げられる。
本明細書中、「アルケニルオキシ」としては、ビニルオキシ、アリルオキシ、１−プロペニルオキシ、２−プロペニルオキシ、種々のブテニルオキシが挙げられる。好ましくは、Ｃ２〜Ｃ６アルケニルオキシが挙げられる。特に、Ｃ２〜Ｃ４アルケニルオキシが好ましい。
本明細書中、「アルケニルオキシカルボニル」としては、ビニルオキシカルボニル、アリルオキシカルボニル、１−プロペニルオキシカルボニル、２−プロペニルオキシカルボニル、種々のブテニルオキシカルボニルが挙げられる。好ましくは、Ｃ２〜Ｃ６アルケニルオキシカルボニルが挙げられる。特に、Ｃ２〜Ｃ４アルケニルオキシカルボニルが好ましい。
本明細書中、「アルキニル」とは、炭素原子数が２〜８個であり、１個もしくは２個以上の三重結合を有する、直鎖または分枝鎖の１価の炭化水素基を包含する。例えば、エチニル、１−プロピニル、２−プロピニル、１−ブチニル、２−ブチニル、３−ブチニル、１−ペンチニル、２−ペンチニル、種々のペンチニル異性体等が挙げられる。好ましくは、Ｃ２〜Ｃ６アルキニルが挙げられる。さらに好ましくは、Ｃ２〜Ｃ４アルキニルが挙げられる。
本明細書中、「アルキニルオキシ」としては、エチニルオキシ、プロピニルオキシ、ブチニルオキシ、ペンチニルオキシ等が挙げられる。好ましくは、Ｃ２〜Ｃ６アルキニルオキシが挙げられる。特に、Ｃ２〜Ｃ４アルキニルオキシが好ましい。

本明細書中、単独でもしくは他の用語と組み合わせて用いられる「アリール」とは、単環状もしくは縮合環状芳香族炭化水素を包含する。例えば、フェニル、１−ナフチル、２−ナフチル、アントリル等が挙げられる。フェニル、１−ナフチル、２−ナフチルが好ましい。特にフェニルが好ましい。
本明細書中、「アラルキル」とは、前記「アルキル」に前記「アリ−ル」が１または２以上置換したものを包含し、これらは可能な全ての位置で置換しうる。例えば、ベンジル、フェニルエチル（例えば、２−フェニルエチル等）、フェニルプロピル（例えば、３−フェニルプロピル等）、ナフチルメチル（例えば、１−ナフチルメチル、２−ナフチルメチル等）、アントリルメチル（例えば、９−アントリルメチル等）等が挙げられる。好ましくは、ベンジル、フェニルエチルが挙げられる。
本明細書中、「アラルキルオキシ」としては、ベンジルオキシ、フェニルエチルオキシ（例えば、２−フェニルエチルオキシ等）、フェニルプロピルオキシ（例えば、３−フェニルプロピルオキシ等）、ナフチルメチルオキシ（例えば、１−ナフチルメチル、２−ナフチルメチルオキシ等）、アントリルメチルオキシ（例えば、９−アントリルメチルオキシ等）等が挙げられる。好ましくは、ベンジルオキシ、フェニルエチルオキシが挙げられる。
本明細書中、「アラルキルオキシカルボニル」としては、ベンジルオキシカルボニル、フェニルエチルオキシカルボニル（例えば、２−フェニルエチルオキシカルボニル等）、フェニルプロピルオキシカルボニル（例えば、３−フェニルプロピルオキシカルボニル等）、ナフチルメチルオキシカルボニル（例えば、１−ナフチルメチル、２−ナフチルメチルオキシカルボニル等）、アントリルメチルオキシカルボニル（例えば、９−アントリルメチルオキシカルボニル等）等が挙げられる。好ましくは、ベンジルオキシカルボニル、フェニルエチルオキシカルボニルが挙げられる。

本明細書中、単独でもしくは他の用語と組み合わせて用いられる「非芳香族複素環基」なる用語は、任意に選ばれる、酸素原子、硫黄原子又は窒素原子を環内に１個以上含む非芳香族の５〜７員環またはそれに別の１以上の「非芳香族複素環基」もしくは「ヘテロアリール」が縮合した環から誘導される基を包含する。例えば、ピロリジニル（例えば、１−ピロリジニル、２−ピロリジニル）、ピロリニル（例えば、３−ピロリニル）、イミダゾリジニル（例えば、２−イミダゾリジニル）、イミダゾリニル（例えば、イミダゾリニル）、ピラゾリジニル（例えば、１−ピラゾリジニル、２−ピラゾリジニル）、ピラゾリニル（例えば、ピラゾリニル）、ピペリジル（例えば、ピペリジノ、２−ピペリジル）、ピペラジニル（例えば、１−ピペラジニル、２−ピペラジニル）、インドリニル（例えば、１−インドリニル）、イソインドリニル（例えば、イソインドリニル）、モルホリニル（例えば、モルホリノ、２−モルホリニル、３−モルホリニル）、テトラヒドロフラニル、ジヒドロピラニル、テトラヒドロピラニル、ジオキソラニル、テトラヒドロチエニル、ジヒドロチオピラニル、テトラヒドロチオフラニル、デカヒドロイソキノリル、アゼピニル、オキセピニル、ジヒドロオキセピニル、テトラヒドロオキセピニル、オキセパニル、４，５，６，７−テトラヒドロチエノ［３，２］ピリジル、２−オキサ−５−アザ−ビシクロ［２．２．１］ヘプタ−５−イル、ヘキサヒドロピラジル［２．１−ｂ］［１，３］オキサジン−８−イル等が挙げられる。
Ｒ^１９における「非芳香族複素環基」としては、ピロリジニル（例えば、１−ピロリジニル、２−ピロリジニル）、ピペリジル（例えば、ピペリジノ、２−ピペリジル）、ピペラジニル（例えば、１−ピペラジニル）、モルホリニル（例えば、モルホリノ、３−モルホリニル）、テトラヒドロフラニルが好ましい。
本明細書中、単独でもしくは他の用語と組み合わせて用いられる「非芳香族含窒素複素環基」なる用語は、窒素原子を少なくとも１つ環内に含み、さらに酸素原子および硫黄原子から任意に選ばれる原子を環内に１個以上含んでいてもよい非芳香族の４〜７員環またはそれらが２個以上縮合した環から誘導される基を包含する。例えば、アゼチジニル（例えば、１−アゼチジニル、２−アゼチジニル、３−アゼチジニル）、ピロリジニル（例えば、１−ピロリジニル、２−ピロリジニル、３−ピロリジニル）、ピロリニル（例えば、３−ピロリニル）、イミダゾリジニル（例えば、２−イミダゾリジニル）、イミダゾリニル（例えば、イミダゾリニル）、ピラゾリジニル（例えば、１−ピラゾリジニル、２−ピラゾリジニル）、ピラゾリニル（例えば、ピラゾリニル）、ピペリジル（例えば、ピペリジノ、２−ピペリジル、３−ピペリジル、４−ピペリジル）、ピペラジニル（例えば、１−ピペラジニル、２−ピペラジニル）、インドリニル（例えば、１−インドリニル）、イソインドリニル（例えば、イソインドリニル）、モルホリニル（例えば、モルホリノ、２−モルホリニル、３−モルホリニル）、１，４−チアジニル（例えば、１，４−チアジン−１−イル、１，４−チアジン−２−イル、）、チオモルホリニル（例えば、１−チオモルホリニル、２−チオモルホリニル）、デカヒドロイソキノリル（例えば２−デカヒドロイソキノリル）、アゼピニル（例えば１−アゼピニル）、ジアゼピニル、４，５，６，７−テトラヒドロチエノ［３，２］ピリジル、２−オキサ−５−アザ−ビシクロ［２．２．１］ヘプタ−５−イル、ヘキサヒドロピラジル［２．１−ｂ］［１，３］オキサジン−８−イル等が挙げられる。
Ｒ^１およびＲ^１７における「非芳香族含窒素複素環基」としては、アゼチジニル（例えば、１−アゼチジニル、２−アゼチジニル、３−アゼチジニル）、ピロリジニル（例えば、１−ピロリジニル、２−ピロリジニル、３−ピロリジニル）、ピペリジル（例えば、ピペリジノ、２−ピペリジル、３−ピペリジル、４−ピペリジル）が好ましい。
Ｗ^１における「非芳香族含窒素複素環基」としては、アゼチジニル（例えば、１−アゼチジニル、２−アゼチジニル、３−アゼチジニル）、ピロリジニル（例えば、１−ピロリジニル、２−ピロリジニル、３−ピロリジニル）、ピペリジル（例えば、ピペリジノ、２−ピペリジル、３−ピペリジル、４−ピペリジル）、ピペラジニル（例えば、１−ピペラジニル）、モルホリニル（例えば、モルホリノ、３−モルホリニル）が好ましい。
置換基群Ａにおける「非芳香族含窒素複素環基」としては、ピロリジニル（例えば、１−ピロリジニル、２−ピロリジニル、３−ピロリジニル）、ピペリジル（例えば、ピペリジノ、２−ピペリジル、３−ピペリジル、４−ピペリジル）、ピペラジニル（例えば、１−ピペラジニル、２−ピペラジニル）、モルホリニル（例えば、モルホリノ、２−モルホリニル、３−モルホリニル）、チオモルホリニル（例えば、１−チオモルホリニル、２−チオモルホリニル）、デカヒドロイソキノリル（例えば２−デカヒドロイソキノリル）、アゼピニル（例えば１−アゼピニル）、ジアゼピニル、４，５，６，７−テトラヒドロチエノ［３，２］ピリジル、２−オキサ−５−アザ−ビシクロ［２．２．１］ヘプタ−５−イル、ヘキサヒドロピラジル［２．１−ｂ］［１，３］オキサジン−８−イルが好ましい。

本明細書中、単独でもしくは他の用語と組み合わせて用いられる「ヘテロアリール」とは、任意に選ばれる、酸素原子、硫黄原子又は窒素原子を環内に１個以上含む５〜６員の芳香環基を包含する。これは前記「シクロアルキル」、前記「アリール」、前記「非芳香族複素環基」、もしくは他のヘテロアリールと可能な全ての位置で縮合していてもよい。ヘテロアリールが単環および縮合環のいずれである場合も、すべての可能な位置で結合しうる。例えば、ピロリル（例えば、１−ピロリル、２−ピロリル、３−ピロリル）、フリル（例えば、２−フリル、３−フリル）、チエニル（例えば、２−チエニル、３−チエニル）、イミダゾリル（例えば、２−イミダゾリル、４−イミダゾリル）、ピラゾリル（例えば、１−ピラゾリル、３−ピラゾリル）、イソチアゾリル（例えば、３−イソチアゾリル）、イソオキサゾリル（例えば、３−イソオキサゾリル）、オキサゾリル（例えば、２−オキサゾリル）、チアゾリル（例えば、２−チアゾリル、５−チアゾリル）、ピリジル（例えば、２−ピリジル、３−ピリジル、４−ピリジル）、ピラジニル（例えば、２−ピラジニル）、ピリミジニル（例えば、２−ピリミジニル、４−ピリミジニル）、ピリダジニル（例えば、３−ピリダジニル）、トリアゾリル、テトラゾリル（例えば、１Ｈ−テトラゾリル）、オキサジアゾリル（例えば、１，３，４−オキサジアゾリル）、チアジアゾリル（例えば、１，３，４−チアジアゾリル）、インドリジニル（例えば、２−インドリジニル、６−インドリジニル）、イソインドリル（例えば、２−イソインドリル）、インドリル（例えば、１−インドリル、２−インドリル、３−インドリル）、インダゾリル（例えば、３−インダゾリル）、プリニル（例えば、８−プリニル）、キノリジニル（例えば、２−キノリジニル）、イソキノリル（例えば、３−イソキノリル）、キノリル（例えば、２−キノリル、５−キノリル）、フタラジニル（例えば、１−フタラジニル）、ナフチリジニル（例えば、２−ナフチリジニル）、キノラニル（例えば、２−キノラニル）、キナゾリニル（例えば、２−キナゾリニル）、シンノリニル（例えば、３−シンノリニル）、プテリジニル（例えば、２−プテリジニル）、カルバゾリル（例えば、２−カルバゾリル、４−カルバゾリル）、フェナントリジニル（例えば、２−フェナントリジニル、３−フェナントリジニル）、アクリジニル（例えば、１−アクリジニル、２−アクリジニル）、ジベンゾフラニル（例えば、１−ジベンゾフラニル、２−ジベンゾフラニル）、ベンゾイミダゾリル（例えば、２−ベンゾイミダゾリル）、ベンゾイソオキサゾリル（例えば、３−ベンゾイソオキサゾリル）、ベンゾオキサゾリル（例えば、２−ベンゾオキサゾリル）、ベンゾオキサジアゾリル（例えば、４−ベンゾオキサジアゾリル）、ベンゾイソチアゾリル（例えば、３−ベンゾイソチアゾリル）、ベンゾチアゾリル（例えば、２−ベンゾチアゾリル）、ベンゾフリル（例えば、３−ベンゾフリル）、ベンゾチエニル（例えば、２−ベンゾチエニル）、４，５−ジヒドロナフト［１，２−ｄ］チアゾリル、４Ｈ−クロメノ［４，３−ｄ］チアゾリル、４Ｈ−チオクロメノ［４，３−ｄ］チアゾリル、４，５−ジヒドロチアゾロ［５，４−ｃ］キノリル、８Ｈ−インデノ［１，２−ｄ］チアゾリル、５，６−ジヒドロ−４Ｈ−３−チア−１−アザ−ベンゾ［ｅ］アズレニル等が挙げられる。
Ｒ^２における「ヘテロアリール」としては、ピリジル、フリル、チエニル、チアゾリル、オキサゾリル、チアジアゾリル、オキサジアゾリル、トリアゾリル等が好ましい。さらに好ましくは、ピリジル、フリル、チエニル、チアゾリル等が挙げられる。
Ｒ^８における「ヘテロアリール」としては、ピリジル、フリル、チエニル、チアゾリル、オキサゾリル、チアジアゾリル、オキサジアゾリル、トリアゾリル等が好ましい。さらに好ましくは、ピリジル、フリル、チエニル、チアゾリル等が挙げられる。
Ｒ^１９における「ヘテロアリール」としては、ピリジル、フリル、チエニル等が好ましい。
Ｗ^１における「ヘテロアリール」としては、ピロリル、イミダゾリル、ピラゾリル、トリアゾリル、テトラゾリル等が好ましい。
本明細書中、「ヘテロアリールアルキル」とは、前記「アルキル」の任意の位置に前記「ヘテロアリ−ル」が１または２以上置換したものを包含し、これらは可能な全ての位置で置換しうる。例えば、チエニルメチル（例えば、２−チエニルメチル）、チエニルエチル（例えば、２−（チオフェン−２−イル）エチル）、フリルメチル（例えば、２−フリルメチル）、フリルエチル（例えば２−（フラン−２−イル）エチル）、ピロリルメチル（例えば、２−ピロリルメチル）、ピロリルエチル（例えば、２−（ピロール−２−イル）エチル）、イミダゾリルメチル（例えば、２−イミダゾリルメチル、４−イミダゾリルメチル）、イミダゾリルエチル（例えば、２−（イミダゾール−２−イル）エチル）、ピラゾリルメチル（例えば、３−ピラゾリルメチル）、ピラゾリルエチル（例えば、２−（ピラゾール−３−イル）エチル）、チアゾリルメチル（例えば、２−チアゾリルメチル）、チアゾリルエチル（例えば、２−（チアゾール−２−イル）エチル）、イソチアゾリルメチル（例えば、３−イソチアゾリルメチル）、イソオキサゾリルメチル（例えば、３−イソオキサゾリルメチル）、オキサゾリルメチル（例えば、２−オキサゾリルメチル）、オキサゾリルエチル（例えば、２−（オキサゾール−２−イル）エチル）、ピリジルメチル（例えば、２−ピリジルメチル、３−ピリジルメチル、４−ピリジルメチル）、ピリジルエチル（例えば、２−ピリジルエチル）等が挙げられる。

本明細書中、単独でもしくは他の用語と組み合わせて用いられる「アシル」なる用語は、アルキル部分が前記「アルキル」であるアルキルカルボニル、ハロアルキル部分が前記「ハロアルキル」であるハロアルキルカルボニル、アルケニル部分が前記「アルケニル」であるアルケニルカルボニル、アラルキル部分が前記「アラルキル」であるアラルキルカルボニル、またはアリール部分が前記「アリール」であるアリールカルボニルを包含する。例えば、アセチル、プロピオニル、ブチロイル、トリフルオロメチルカルボニル、ビニルカルボニル、フェニルアセチル、ベンゾイル等が挙げられる。「アルキル」、「アルケニル」、および「アリール」は後述のそれぞれの置換基によって置換されていてもよい。
Ｒ^１０およびＲ^１１における、「アシル」としては、アセチル、ベンゾイル、フェニルアセチル等が好ましい。
Ｒ^１２およびＲ^１３における、「アシル」としては、アセチル、ベンゾイル、フェニルアセチル等が好ましい。
Ｒ^９における、「アシル」としては、アセチル、ベンゾイル、フェニルアセチル等が好ましい。
本明細書中、「アシルオキシ」としては、アセチルオキシ、プロピオニルオキシ、ベンゾイルオキシ等が挙げられる。

本明細書中、単独でもしくは他の用語と組み合わせて用いられる「置換されていてもよいアミノ」なる用語は、置換基群Ａから選択される置換基で選択されていてもよい前記「アルキル」、前記「ハロアルキル」、前記「アルケニル」、前記「アルキニル」、前記「アルキルスルホニル」、前記「アルキルスルホニルアルキル」、前記「アルキルオキシカルボニル」、前記「アミノカルボニルオキシアルキル」、前記「アルキルオキシ」、置換基群Ａから選択される置換基で置換されていてもよい前記「アルキルオキシアルキル」、置換基群Ａから選択される置換基で置換されていてもよい前記「シクロアルキル」、置換基群Ｇから選択される置換基で置換されていてもよい前記「アリール」、前記「アラルキル」、前記「ヘテロアリール」、前記「ヘテロアリールアルキル」、前記「アシル」、置換基群Ｇから選択される置換基で置換されていてもよい前記「アミノカルボニルアルキル」、または置換基群Ｇから選択される置換基で置換されていてもよい前記「アミノアルキルカルボニル」、アルケニルオキシ部分が前記「アルケニルオキシ」である「アルケニルオキシカルボニル」、アラルキルオキシ部分が前記「アラルキルオキシ」である「アラルキルオキシカルボニル」で１または２箇所置換されていてもよいアミノを包含する（置換基群Ｇ：アルキル、アルケニル、およびアラルキル）。例えば、アミノ、メチルアミノ、ジメチルアミノ、エチルメチルアミノ、ジエチルアミノ、エチルメチルアミノ、ジイソプロピルアミノ、ベンジルアミノ、アセチルアミノ、トリフルオロメチルカルボニル、ベンゾイルアミノ、メチルオキシカルボニルアミノ、エチルオキシカルボニルアミノ、ｎ−プロピルオキシカルボニルアミノ、イソプロピルオキシカルボニルアミノ、ｎ−ブチルオキシ、イソブチルオキシカルボニルアミノ、ｓｅｃ−ブチルオキシカルボニルアミノ、ｔｅｒｔ−ブチルオキシカルボニルアミノ、アリルオキシカルボニルアミノ、ベンジルオキシカルボニルアミノ、シクロペンチルアミノ、シクロヘキシルアミノ等が挙げられる。
Ｒ^３およびＲ^４における、「置換されていてもよいアミノ」の置換基としては、アルキル、アシル等が好ましい。
Ｒ^６およびＲ^７における、「置換されていてもよいアミノ」の置換基としては、アルキル等が好ましい。
置換基群Ａにおける、「置換されていてもよいアミノ」および「置換されていてもよいアミノカルボニル」の置換基としては、アルキル、アルケニル、アルキニル、置換基群Ｉから選択される置換基で置換されていてもよいアリール、アラルキル、アルキルオキシ、ヒドロキシアルキル、ヒドロキシアルキルオキシアルキル、ハロアルキル、１または2のアルキルで置換されていてもよいアミノアルキル、アルキルスルホニル、アルキルスルホニルアルキル、ハロゲンもしくはアルキルオキシで置換されていてもよいアルキルカルボニル、アルキルオキシカルボニル、置換基群Ｉから選択される置換基で置換されていてもよいシクロアルキル、カルボキシアルキル、置換基群Ｇから選択される置換基で置換されていてもよいアミノカルボニルアルキル、置換基群Ｇから選択される置換基で置換されていてもよいアミノカルボニルオキシアルキル、アルキルオキシアルキル、アルキルチオアルキル、アルキルカルボニルアミノアルキル、アルキルスルホニルアミノアルキル、アルキルスルホニル（アルキル）アミノアルキル、アルキルオキシカルボニルアルキル、アルキルチオ（ヒドロキシ）アルキル、シクロアルキルアルキル、シアノアルキル、置換基群Ｇから選択される置換基で置換されていてもよいアミノアルキルカルボニル、置換基群Ｇから選択される置換基で置換されていてもよいヘテロアリール、ヘテロアリールアルキル、ヒドロキシアルキルオキシアルキル、置換基群Ｉから選択される置換基で置換されていてもよい非芳香族複素環基、置換基群Ｉから選択される置換基で置換されていてもよい非芳香族複素環アルキル等が好ましい。
本明細書中、「置換されていてもよいアミノカルボニル」における置換基としては、アルキル、アルケニル、アラルキル等が好ましい。特に、アルキルが好ましい。
置換基群Ｂにおける、「置換されていてもよいアミノカルボニル」における置換基としては、アルキル、アルケニル、アラルキル等が好ましい。
置換基群Ｄにおける、「置換されていてもよいアミノカルボニル」における置換基としては、アルキル、アルケニル、アラルキル等が好ましい。
置換基群Ｅにおける、「置換されていてもよいアミノカルボニル」における置換基としては、アルキル、アルケニル、アラルキル等が好ましい。
置換基群Ｈにおける、「置換されていてもよいアミノカルボニル」における置換基としては、アルキル、アルケニル、アラルキル等が好ましい。
本明細書中、「置換されていてもよいアミノカルボニルアルキル」における置換基としては、アルキル、アルケニル、アラルキル等が好ましい。特に、アルキルが好ましい。
置換基群Ｃにおける、「置換されていてもよいアミノカルボニルアルキル」における置換基としては、アルキルアルケニル、アラルキル等が好ましい。
本明細書中、「置換されていてもよいアミノカルボニルオキシアルキル」における置換基としては、アルキル、アルケニル、アラルキル等が好ましい。特に、アルキルが好ましい。
置換基群Ｃにおける、「置換されていてもよいアミノカルボニルオキシアルキル」における置換基としては、アルキル、アルケニル、アラルキル等が好ましい。
本明細書中、「置換されていてもよいアミノアルキルカルボニル」における置換基としては、アルキル、アルケニル、アラルキル等が好ましい。特に、アルキルが好ましい。
置換基群Ｃにおける、「置換されていてもよいアミノアルキルカルボニル」における置換基としては、アルキル、アルケニル、アラルキル等が好ましい。
本明細書中、「置換されていてもよいウレイド」なる用語は、前記「アルキル」、前記「シクロアルキル」、前記「アリール」、前記「アラルキル」、前記「ヘテロアリール」、前記「ヘテロアリールアルキル」、前記「アシル」、シアノアルキル、またはアルキルオキシアルキルで１または２箇所以上置換されていてもよいウレイドを包含する。
本明細書中、「置換されていてもよいグアニジノ」なる用語は、前記「アルキル」、前記「シクロアルキル」、前記「アリール」、前記「アラルキル」、前記「ヘテロアリール」、前記「ヘテロアリールアルキル」、前記「アシル」、シアノ、シアノアルキル、またはアルキルオキシアルキルで１または２箇所以上置換されていてもよいグアニジノを包含する。

本明細書中、「置換されていてもよいアルキル」における置換基としては、置換されていてもよいアミノ、置換されていてもよい非芳香族含窒素複素環基、置換されていてもよい非芳香族含窒素複素環カルボニル、アルキル、アルキルオキシ、シアノ、アルキルスルホニル、シクロアルキル、アルケニル、ヘテロアリール、ヘテロアリールオキシ、ヒドロキシ、メルカプト、アルキルチオ、ハロゲン、ニトロ、カルボキシ、アルキルオキシカルボニル、ヒドロキシアルキル、ハロアルキル、ハロアルキルオキシ、アルキルカルボニルオキシ、カルバモイルオキシ、置換されていてもよいアミノカルボニル、アミノカルボニルアルキルオキシ、アシル、アシルオキシ、アリールオキシ、アラルキル、アラルキルオキシ、置換されていてもよいグアニジノ、アゾ基、置換されていてもよいウレイド等が挙げられる。これらは、全ての可能な位置で１個以上置換しうる。
Ｒ^１、Ｒ^１７およびＲ^１９における「置換されていてもよいアルキル」の置換基としては、置換基群Ａから選択される置換基、アルキルオキシ、シアノ、ハロゲン、ヘテロアリール等が好ましい。特に、置換基群Ｃから選択される置換基で置換されていてもよいアミノ、置換基群Ｄから選択される置換基で置換されていてもよい非芳香族含窒素複素環基が好ましい。
Ｒ^２における「置換されていてもよいアルキル」の置換基としては、置換基群Ａから選択される置換基、アルキルオキシ、アルキルカルボニル、およびハロゲンが好ましい。特に、ヒドロキシ、アルキルオキシ、およびハロゲンが好ましい。
Ｒ^３およびＲ^４における、「置換されていてもよいアルキル」の置換基としては、アルキルオキシ、アルキルオシキカルボニル、アミノカルボニル、シアノ等が好ましい。
Ｒ^６およびＲ^７における、「置換されていてもよいアルキル」の置換基としては、アルキルオキシ、アルキルオシキカルボニル、アミノカルボニル、シアノ、ヒドロキシ等が好ましい。
Ｒ^１８における、「置換されていてもよいアルキル」の置換基としては、ヒドロキシ、アルキルオキシ、ハロゲン、シアノ等が好ましい。
Ｒ^２０における、「置換されていてもよいアルキル」の置換基としては、ヒドロキシ、アルキルオキシ、ハロゲン、シアノ等が好ましい。

本明細書中、「置換されていてもよいアルケニル」および「置換されていてもよいアルキニル」における置換基としては、置換されていてもよいアミノ、置換されていてもよい非芳香族含窒素複素環基、シクロアルキル、ヒドロキシ、アルキルオキシ、メルカプト、アルキルチオ、ハロゲン、ニトロ、シアノ、カルボキシ、アルキルオキシカルボニル、ハロアルキル、ハロアルキルオキシ、置換されていてもよいアミノカルボニル、アシル、アシルオキシ、アリール、アリールオキシ、アラルキル、アラルキルオキシ、アルキルスルホニル、グアニジノ、アゾ基、置換されていてもよいウレイド等が挙げられる。これらは、全ての可能な位置で１個以上置換しうる。
Ｒ^１およびＲ^１７おける「置換されていてもよいアルケニル」の置換基としては、置換基群Ａから選択される置換基が好ましい。特に、置換基群Ｃから選択される置換基で置換されていてもよいアミノ、置換基群Ｄから選択される置換基で置換されていてもよい非芳香族含窒素複素環基が好ましい。
Ｒ^２における、「置換されていてもよいアルケニル」および「置換されていてもよいアルキニル」の置換基としては、置換基群Ａから選択される置換基、シクロアルキル、アルキルオキシ、およびハロゲンが好ましい。特に、ヒドロキシ、シクロアルキル、アルキルオキシ、およびハロゲンが好ましい。
Ｒ^３およびＲ^４における、「置換されていてもよいアルケニル」および「置換されていてもよいアルキニル」の置換基としては、アルキルオキシ、アルキルオキシカルボニル、アミノカルボニル、シアノ等で置換されていてもよいアルキル、アルキルオキシ、アルキルオキシカルボニル、アミノカルボニル、シアノ等で置換されていてもよいアルキルオキシカルボニル、置換されていてもよいアミノカルボニル等が好ましい。
Ｒ^６およびＲ^７における、「置換されていてもよいアルケニル」および「置換されていてもよいアルキニル」の置換基としては、アルキルオキシ、アルキルオキシカルボニル、アミノカルボニル、シアノ等で置換されていてもよいアルキル、アルキルオキシ、アルキルオキシカルボニル、アミノカルボニル、シアノ等で置換されていてもよいアルキルオキシカルボニル、置換されていてもよいアミノカルボニル等が好ましい。
Ｒ^１８における、「置換されていてもよいアルケニル」および「置換されていてもよいアルキニル」の置換基としては、ヒドロキシ、アルキルオキシ、ハロゲン、シアノ等が好ましい。
Ｒ^２０における、「置換されていてもよいアルケニル」および「置換されていてもよいアルキニル」の置換基としては、ヒドロキシ、アルキルオキシ、ハロゲン、シアノ等が好ましい。

本明細書中、「置換されていてもよいシクロアルキル」における置換基としては、アルキルオキシカルボニル、置換基群Ｇから選択される置換基で置換されていてもよいアミノカルボニル、シアノ、置換基群Ｍ（置換基群Ｍ：シアノ、ヒドロキシ、カルボキシ、アミノカルボニル、アルキルオキシカルボニル、およびアルキルオキシ）から選択される置換基で置換されていてもよいアルキル、アルキルスルホニル、アルキルスルホニルアルキルカルボニル、シクロアルキル、ヒドロキシ、アルキルオキシ、メルカプト、アルキルチオ、ハロゲン、ニトロ、カルボキシ、ハロアルキル、ハロアルキルオキシ、アシル、アシルオキシ、アリール、アリールオキシ（例えば、フェニルオキシ）、アラルキル、アラルキルオキシ（例えば、ベンジルオキシ）、非芳香族含窒素複素環基、アルキルカルボニルアミノ、アミノカルボニルオキシ、アミノ、オキソ、グアニジノ、アゾ基、置換されていてもよいウレイド等が挙げられる。
置換基群Ｃにおける、「置換されていてもよいシクロアルキル」の置換基としては、置換基群Ｉで挙げられる置換基が好ましい。
本明細書中、「置換されていてもよいアルキルオキシ」、「置換されていてもよいアルケニルオキシ」、および「置換されていてもよいアルキニルオキシ」における置換基としては、シクロアルキル、アルケニル、ヒドロキシ、アルキルオキシ、メルカプト、アルキルチオ、ハロゲン、ニトロ、シアノ、カルボキシ、アルキルオキシカルボニル、ハロアルキル、ハロアルキルオキシ、置換されていてもよいアミノ、置換されていてもよいアミノカルボニル、アシル、アシルオキシ、置換されていてもよい非芳香族複素環基、アリールオキシ、アラルキルオキシ、アルキルスルホニル、グアニジノ、アゾ基、置換されていてもよいウレイド等が挙げられる。これらは、全ての可能な位置で１個以上置換しうる。好ましくは、ハロゲン等が挙げられる。
Ｒ^３およびＲ^４における、「置換されていてもよいアルキルオキシ」および「置換されていてもよいアルケニルオキシ」の置換基としては、アルキルオキシ、置換されていてもよいアミノ、置換基群Ｄから選択される置換基で置換されていてもよい非芳香族複素環基、シアノ等が好ましい。
Ｒ^５における、「置換されていてもよいアルキルオキシ」、「置換されていてもよいアルケニルオキシ」、および「置換されていてもよいアルキニルオキシ」の置換基としては、置換基群Ｅから選択される置換基が好ましい。
Ｒ^６およびＲ^７における、「置換されていてもよいアルキルオキシ」、「置換されていてもよいアルケニルオキシ」、および「置換されていてもよいアルキニルオキシ」の置換基としては、アルキルオキシ、シアノ、アルキルオキシカルボニル、置換されていてもよいアミノカルボニル等が好ましい。

本明細書中、「置換されていてもよい非芳香族複素環基」における置換基としては、アルキルオキシカルボニル、置換基群Ｇから選択される置換基で置換されていてもよいアミノカルボニル、シアノ、置換基群Ｍ（置換基群Ｍ：シアノ、ヒドロキシ、カルボキシ、アミノカルボニル、アルキルオキシカルボニル、およびアルキルオキシ）から選択される置換基で置換されていてもよいアルキル、アルキルスルホニル、アルキルスルホニルアルキルカルボニル、シクロアルキル、ヒドロキシ、アルキルオキシ、メルカプト、アルキルチオ、ハロゲン、ニトロ、カルボキシ、ハロアルキル、ハロアルキルオキシ、アシル、アシルオキシ、アリール、アリールオキシ（例えば、フェニルオキシ）、アラルキル、アラルキルオキシ（例えば、ベンジルオキシ）、非芳香族含窒素複素環基、アルキルカルボニルアミノ、アミノカルボニルオキシ、アミノ、オキソ、グアニジノ、アゾ基、置換されていてもよいウレイド等が挙げられる。
本明細書中、「置換されていてもよい非芳香族含窒素複素環基」における置換基としては、アルキルオキシカルボニル、置換基群Ｇから選択される置換基で置換されていてもよいアミノカルボニル、シアノ、置換基群Ｍ（置換基群Ｍ：シアノ、ヒドロキシ、カルボキシ、アミノカルボニル、アルキルオキシカルボニル、およびアルキルオキシ）から選択される置換基で置換されていてもよいアルキル、アルキルスルホニル、アルキルスルホニルアルキルカルボニル、シクロアルキル、ヒドロキシ、アルキルオキシ、メルカプト、アルキルチオ、ハロゲン、ニトロ、カルボキシ、ハロアルキル、ハロアルキルオキシ、アシル、アシルオキシ、アリール、アリールオキシ（例えば、フェニルオキシ）、アラルキル、アラルキルオキシ（例えば、ベンジルオキシ）、非芳香族含窒素複素環基、アルキルカルボニルアミノ、アミノカルボニルオキシ、置換されていてもよいアミノ、オキソ、グアニジノ、アゾ基、置換されていてもよいウレイド等が挙げられる。
Ｒ^１およびＲ^１７における「置換されていてもよい非芳香族含窒素複素環基」の置換基としては、アルキル、アルキルオキシカルボニル、置換基群Ｇから選択される置換基で置換されていてもよいアミノカルボニル、シアノ、オキソ、アミノ、カルボキシル、ヒドロキシアルキル、シアノアルキル、アルキルオキシアルキル、アルキルスルホニル、アルキルカルボニル、アルケニルカルボニル、アルキルスルホニルアルキルカルボニル、アルキルカルボニルアミノ、アルキルスルホニルアミノ、カルボキシアルキル、アルキルオキシカルボニルアルキル等が好ましい。特に、置換基群Ｂで挙げられる置換基が好ましい。
Ｗ^１における「置換されていてもよい非芳香族含窒素複素環基」の置換基としては、アルキル、アルキルオキシカルボニル、置換されていてもよいアミノカルボニル、シアノ、ヒドロキシアルキル、シアノアルキル、アルキルオキシアルキル、アルキルスルホニル、アルキルカルボニル、アルケニルカルボニル、アルキルスルホニルアルキルカルボニル等が好ましい。特に、置換基群Ｊで挙げられる置換基が好ましい。
置換基群Ａにおける「置換されていてもよい非芳香族含窒素複素環基」および「置換されていてもよい非芳香族含窒素複素環カルボニル」の置換基としては、置換基群Ｄから選択される置換基が好ましい。

本明細書中、「置換されていてもよいアリール」、「置換されていてもよいフェニル」、「置換されていてもよいヘテロアリール」、「置換されていてもよいピリジル」、「置換されていてもよいフリル」、「置換されていてもよいチエニル」、「置換されていてもよいチアゾリル」、「置換されていてもよいオキサゾリル」、「置換されていてもよい非芳香族複素環基」、「置換されていてもよい非芳香族複素環アルキル」、「置換されていてもよいシクロアルキル」、「置換されていてもよいアラルキル」、および「置換されていてもよいヘテロアリールアルキル」における置換基としては、置換されていてもよいアルキル（置換基としては、ハロゲン、ヒドロキシ、ニトロ、シアノ、カルボキシ、アルキルオキシ、アルキルオキシカルボニル、アシル等）、シクロアルキル、アルケニル、アルキニル、ヒドロキシ、アルキルオキシ、アラルキルオキシ、メルカプト、アルキルチオ、ハロゲン、ニトロ、シアノ、カルボキシ、アルキルオキシカルボニル、アリールオキシカルボニル、ハロアルキル、ハロアルキルオキシ、置換されていてもよいアミノ、置換されていてもよいアミノカルボニル、アシル、アシルオキシ、置換されていてもよいアリール（置換基としては、ハロゲン、ヒドロキシ、ニトロ、シアノ、カルボキシ、アルキルオキシ、アルキルオキシカルボニル、アシル等）、置換されていてもよいヘテロアリ−ル（置換基としては、ハロゲン、ヒドロキシ、ニトロ、シアノ、カルボキシ、アルキルオキシ、アルキルオキシカルボニル、アシル等）、置換されていてもよい非芳香族複素環基（置換基としては、ハロゲン、ヒドロキシ、ニトロ、シアノ、カルボキシ、アルキルオキシ、アルキルオキシカルボニル、アシル等）、置換されていてもよいアラルキル（置換基としては、ハロゲン、ヒドロキシ、ニトロ、シアノ、カルボキシ、アルキルオキシ、アルキルオキシカルボニル、アシル等）、アルキルスルホニル、グアニジノ、アゾ基、−Ｎ＝Ｎ−（置換されていてもよいフェニル）、または置換されていてもよいウレイド等が挙げられる。これらは、全ての可能な位置で１個以上置換しうる。
Ｒ^１における「置換されていてもよいアリール」の置換基としては、置換基群Ｉで挙げられる置換基が好ましい。
Ｒ^２における「置換されていてもよいアリール」および「置換されていてもよいヘテロアリール」の置換基としては、ヒドロキシまたは置換されていてもよいアミノで置換されていてもよいアルキル、置換されていてもよいアミノ、ハロゲン等が好ましい。特に、ヒドロキシまたは置換されていてもよいアミノで置換されていてもよいアルキルが好ましい。
Ｒ^８における「置換されていてもよいアリール」、「置換されていてもよいヘテロアリール」、および「置換されていてもよい非芳香族複素環基」の置換基としては、アルキルオキシカルボニル、置換されていてもよいアミノカルボニル、シアノ、ハロゲン、アルキル、アルキルオキシ、アルキルチオ、ハロアルキル等が好ましい。特に、置換基群Ｆで挙げられる置換基が好ましい。
Ｒ^１９における「置換されていてもよいアリール」および「置換されていてもよいヘテロアリール」の置換基としては、アルキルオキシカルボニル、置換されていてもよいアミノカルボニル、シアノ、シアノアルキル、ヒドロキシアルキル、およびアミノカルボニルアルキル等が好ましい。特に、置換基群Ｉで挙げられる置換基が好ましい。
Ｗ^１における「置換されていてもよいヘテロアリール」の置換基としては、アルキル、ヒドロキシ、アルキルオキシ等が好ましい。特に、置換基群Jで挙げられる置換基が好ましい。
置換基群Ｃにおける「置換されていてもよいアリール」、「置換されていてもよいヘテロアリール」、「置換されていてもよい非芳香族複素環基」、および「置換されていてもよい非芳香族複素環アルキル」の置換基としては、置換基群Ｉで挙げられる置換基が好ましい。

本明細書中、「抗癌剤」および「癌の治療剤」とは、脳腫瘍（例えば神経膠芽細胞種）、泌尿器癌（例えば膀胱癌、腎臓癌）、生殖器癌（例えば前立腺癌、卵巣癌、子宮癌）、リンパ系腫瘍、消化器癌（例えば胃癌、大腸癌）、咽喉癌、肺癌（例えば肺腺癌、小細胞肺癌、非小細胞肺癌）、膵臓癌、乳癌、頭頚部癌、食道癌、甲状腺癌の治療剤を包含する。特に、乳癌、脳腫瘍、膀胱癌、腎臓癌、前立腺癌、卵巣癌、子宮癌、肺癌、膵臓癌、大腸癌、および頭頚部癌の治療剤として好ましく使用される。
本発明は、癌を治療又は予防する必要がある哺乳動物において癌を治療又は予防する方法を包含し、当該方法は、前記哺乳動物に治療有効量の式（Ｉ）の化合物を投与することからなる。治療するのに好ましい癌は、脳腫瘍（例えば神経膠芽細胞種）、泌尿器癌（例えば膀胱癌、腎臓癌）、生殖器癌（例えば前立腺癌、卵巣癌、子宮癌）、リンパ系腫瘍、消化器癌（例えば胃癌）、咽喉癌、肺癌（例えば肺腺癌、小細胞肺癌、非小細胞肺癌）、膵臓癌、乳癌、大腸癌、頭頚部癌、食道癌、甲状腺癌から選択される。より好ましくは、乳癌、脳腫瘍、膀胱癌、腎臓癌、前立腺癌、卵巣癌、子宮癌、肺癌、膵臓癌、大腸癌、および頭頚部癌である。

本発明化合物は、優れたＥＧＦ受容体およびＨＥＲ２の阻害作用を有し、安全性も高い（ＣＹＰ阻害作用が軽減された）ことから、医薬品、とりわけ癌の治療剤として有用である。

本発明化合物（Ｉ）は、以下に記載のＡ法〜Ｅ法のいずれかにより合成することができる。また、キナゾリン誘導体の合成法が、ＷＯ９６／０９２９４号、ＷＯ９８／０２４３４等に記載されているので、これらに従って合成することもできる。化合物が各反応に影響を与える基を有する場合は、適切な保護基で保護し、適切な段階で脱保護することができる。また、各工程の原料、試薬、中間体、および反応生成物が塩を形成し得る場合は、その塩も包含する。

（Ａ法）

（式中、Ｈａｌ^１およびＨａｌ^２はそれぞれ独立してハロゲン；Ｒ^１、Ｒ^５、Ｒ^６、およびＲ^７は前記（１）と同意義）
（第１工程）
ＷＯ９６／０９２９４号等に記載の方法に従って合成できるまたは市販品として入手可能な出発原料（Ｓ．Ｍ．）とＷＯ９８／０２４３４等に記載の方法に従って合成できるまたは市販品として入手できる化合物（ｉｉ）を反応させることにより、化合物（ｉｉｉ）を合成する工程である。
出発原料（Ｓ．Ｍ．）と化合物（ｉｉ）を、テトラヒドロフラン、アセトニトリル等の溶媒中、20℃〜加熱還流下、好ましくは60℃〜加熱還流下で反応させることにより化合物（ｉｉｉ）を得ることができる。
（第２工程）
化合物（ｉｉｉ）をパラジウム触媒の存在下で一酸化炭素を挿入することにより、化合物（ｉｖ）を得る工程である。
化合物（ｉｉｉ）を、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセタミド、Ｎ，Ｎ’−ジメチルイミダゾリジノン、ジメチルスルホキシド等の溶媒中、ギ酸ナトリウム、水素化トリブチルスズ等の水素源、ジクロロビス（トリフェニルホスフィン）パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム、[1,1'-ビス（ジフェニルホスフィノ）フェロセン]ジクロロパラジウム、酢酸パラジウム＋トリフェニルホスフィン等のパラジウム触媒、およびトリエチルアミン、ジ（イソプロピル）エチルアミン等の塩基の存在下、一酸化炭素雰囲気下で、50℃〜150℃、好ましくは70℃〜90℃で反応させることにより化合物（ｉｖ）を得ることができる。
（第３工程）
化合物（ｉｖ）と式：Ｒ^１−Ｏ−ＮＨ_２（式中、Ｒ^１は上記（１）と同意義）で表される化合物を反応させることにより、目的とする化合物（ｖ）を合成する工程である。
出発原料（ｉｖ）と式：Ｒ^１−Ｏ−ＮＨ_２（式中、Ｒ^１は上記（１）と同意義）で表される化合物またはその塩を、テトラヒドロフラン、ジオキサン、メタノール等の溶媒中、またはそれらと水の混合溶媒中、要すれば塩酸、硫酸、ｐ−トルエンスルホン酸、メタンスルホン酸、ギ酸、酢酸、トリフルオロ酢酸等の酸の存在下に、0℃〜加熱還流下、好ましくは20℃〜7 0℃下で反応させることにより化合物（ｖ）を得ることができる。

（Ｂ法）

（Ｒ^１、Ｒ^５、Ｒ^６、およびＲ^７は前記（１）と同意義）
（第１工程）
Ａ法で得られた化合物（ｉｖ）にヒドロキシルアミンを反応させて得られた化合物（ｖ’）と式：Ｒ^１−Ｈａｌ^３（式中、Ｈａｌ^３はハロゲン；Ｒ^１は前記（１）と同意義）で表される化合物を反応させることにより、目的とする化合物（ｖ）を合成する工程である。
化合物（ｖ’）と式：Ｒ^１−Ｈａｌ^３（式中、Ｈａｌ^３はハロゲン；Ｒ^１は前記（１）と同意義）で表される化合物をＮ，Ｎ−ジメチルアセトアミド、Ｎ，Ｎ−ジメチルアセタミド、Ｎ，Ｎ’−ジメチルイミダゾリジノン、ジメチルスルホキシド等の溶媒に溶解し、炭酸カリウム、炭酸ナトリウム等の塩基の存在下、50℃〜150℃、好ましくは60℃〜80℃で反応させることにより、化合物（ｖ）を得ることができる。

（Ｃ法）

（Ｒ^１、Ｒ^５、Ｒ^６、およびＲ^７は前記（１）と同意義）
（第１工程）
Ａ法で得られた化合物（ｉｖ）にヒドロキシルアミンを反応させて得られた化合物（ｖ’）と式：Ｒ^１−ＣＨ＝ＣＨ_２（式中、Ｒ^１は前記（１）と同意義）で表される化合物を反応させることにより、目的とする化合物（ｘｖ）を合成する工程である。
化合物（ｖ’）をクロロホルム、ジクロロメタン、1、2-ジクロロエタン等の溶媒に溶解し、ピリジン、4-ジメチルアミノピリジン等の触媒量の塩基存在下、Ｎ-クロロスクシンイミド，Ｎ-クロロフタルイミド等の塩素系酸化剤と20℃〜100℃、好ましくは50℃〜60℃で反応させた後、続けて、式：Ｒ^１−ＣＨ＝ＣＨ_２（式中、Ｒ^１は前記（１）と同意義）で表される化合物、トリエチルアミン、ジ（イソプロピル）エチルアミン等の塩基を加えて，0℃〜100℃、好ましくは10℃〜30℃で反応させることにより、化合物（ｘｖ）を得ることができる。

（Ｄ法）

（Ｒ^１、Ｒ^２、Ｒ^５、Ｒ^６、およびＲ^７は前記（１）と同意義）
（第１工程）
Ａ法で得られた化合物（ｉｖ）に式：Ｒ^２ＭｇＨａｌ^４またはＲ^２Ｌｉ（式中Ｈａｌ^４はハロゲン；Ｒ^２は前記（１）と同意義）で表される試薬を反応させて、化合物（ｖｉ）を得る工程である。
化合物（ｉｖ）をテトラヒドロフラン、ジエチルエーテル、トルエン、ｎ−ヘキサン等の溶媒中、- 100℃〜50℃、好ましくは-78℃〜10℃で、式：Ｒ^２ＭｇＨａｌ^４またはＲ^２Ｌｉ（式中Ｈａｌ^４はハロゲン；Ｒ^２は前記（１）と同意義）で表される試薬と反応させることにより、化合物（ｖｉ）を得ることができる。
（第２工程）
化合物（ｖｉ）を酸化して、化合物（ｖｉｉ）を合成する工程である。
化合物（ｖｉ）を実験化学講座２３巻、第４版（日本化学会編）等に記載の一般的な2級アルコールの酸化方法で酸化することにより、化合物（ｖｉｉ）を得ることができる。
（第３工程）
Ａ法の第３工程と同様の方法により、化合物（ｖｉｉ）から化合物（ｖｉｉｉ）を得ることができる。

（Ｅ法）

［Ｈａｌ^８はハロゲン；Ｒ^４３は式：Ｒ^４４（Ｒ^４５Ｏ）Ｎ（式中Ｒ^４４、Ｒ^４５は互いに独立してＣ１〜Ｃ３アルキル）で表される基または式：

（式中Ｗ^２は非芳香族含窒素複素環基）で表される基；Ｒ^４６はＣ１〜Ｃ３アルキルまたは式：

（式中Ｌ^１はＣ２〜Ｃ３アルキレン）で表される基；
Ｒ¹、Ｒ²、Ｒ^５、Ｒ^６、およびＲ^７は前記（１）と同意義］
（第１工程）
Ａ法で得られた化合物（ｉｉｉ）を、パラジウム触媒の存在下で一酸化炭素を挿入しながらアルコールまたは式：

（式中Ｌ^１はＣ２〜Ｃ３アルキレン）で表される試薬と反応させることにより、化合物（ｘ）を得る工程である。
化合物（ｉｉｉ）を、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセタミド、Ｎ，Ｎ’−ジメチルイミダゾリジノン、ジメチルスルホキシド等の溶媒中、ジクロロビス（トリフェニルホスフィン）パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、トリス（ジベンジリデンアセトン）ジパラジウム、[1,1'-ビス（ジフェニルホスフィノ）フェロセン]ジクロロパラジウム、酢酸パラジウム＋トリフェニルホスフィン、酢酸パラジウム＋1,3-ビスジフェニルホスフィノプロパン等のパラジウム触媒、およびトリエチルアミン、ジ（イソプロピル）エチルアミン等の塩基の存在下、メタノール、エタノール、ｎ−プロパノール、イソプロパノール等のアルコール、またはＮ−ヒドロキシコハク酸イミド等の試薬と一酸化炭素雰囲気下で、50℃〜150℃、好ましくは70℃〜90℃で反応させることにより化合物（ｘ）を得ることができる。
（第２工程）
化合物（ｘ）を式：Ｒ^４４（Ｒ^４５Ｏ）ＮＨ（式中Ｒ^４４、Ｒ^４５は互いに独立してＣ１〜Ｃ３アルキル）で表される試薬または式：

（式中Ｗ^２は非芳香族含窒素複素環基）で表される試薬と反応させることにより、化合物（ｘｉ）を得る工程である。
化合物（ｘ）と式：Ｒ^４４（Ｒ^４５Ｏ）ＮＨ（式中Ｒ^４４、Ｒ^４５は互いに独立してＣ１〜Ｃ３アルキル）で表される試薬または式：

（式中Ｗ^２は非芳香族含窒素複素環基）で表される試薬をテトラヒドロフラン、Ｎ、Ｎ―ジメチルホルムアミド、クロロホルム、ジクロロメタン等の溶媒中で混合し、-100℃〜50℃、好ましくは-78℃〜20℃で塩化メチルマグネシウム、臭化メチルマグネシウム、塩化イソプロピルマグネシウム、メチルリチウム等の試薬を加え反応させることにより化合物（ｘｉ）を得ることができる。
（第３工程）
化合物（ｘｉ）に式：Ｒ^２Ｍ［式中ＭはＬｉ、Ｎａ、Ｋ、または式：ＭｇＨａｌ^５（式中Ｈａｌ^５はハロゲン）で表される基；Ｒ^２は前記（１）と同意義］で表される試薬を反応させて、化合物（ｖｉｉ）を得る工程である。
化合物（ｘｉ）をテトラヒドロフラン、ジエチルエーテル、トルエン、ｎ−ヘキサン等の溶媒中、-100℃〜50℃、好ましくは-78℃〜2 0℃で、式：Ｒ^２Ｍ［式中ＭはＬｉ、Ｎａ、Ｋ、または式：ＭｇＨａｌ^５（式中Ｈａｌ^５はハロゲン）で表される基；Ｒ^２は前記（１）と同意義］で表される試薬と反応させることにより、化合物（ｖｉｉ）を得ることができる。
（第４工程）
Ａ法の第３工程と同様の方法により、化合物（ｖｉｉ）から化合物（ｖｉｉｉ）を得ることができる。

Ｅ法の第１工程、第２工程の別の方法として、以下に示すＥ’法が挙げられる。
（Ｅ’法）

（Ｈａｌ^８およびＲ^４３は前記と同意義；Ｒ^５、Ｒ^６、およびＲ^７は前記（１）と同意義）
（第１工程）
化合物（ｉｉｉ）を、パラジウム触媒の存在下で一酸化炭素を挿入しながらと式：Ｒ^４３Ｈ（Ｒ^４３は前記と同意義）で表される試薬と反応させることにより、化合物（ｘｉ）を得る工程である。
Ｅ法の第１工程と同様の方法でアルコール等の代わりにＲ^４３Ｈ（Ｒ^４３は前記と同意義）で表される試薬を反応させることにより、化合物（ｉｉｉ）から化合物（ｘｉ）を得ることができる。

Ｅ法のアミド誘導体（xi）を得る別の方法として以下に示すＥ’’法が挙げられる。
（Ｅ’’法）

（Ｈａｌ^６はハロゲン；Ｈａｌ^７はハロゲン；Ｒ^４３およびＲ^４６は前記と同意義；Ｒ^５、Ｒ^６、およびＲ^７は前記（１）と同意義）
（第１工程）
Ｅ法の第１工程と同様の方法により、化合物（ｘｖｉ）から化合物（ｘｉｉ）を得ることができる。

（第２工程）
Ｅ法の第２工程と同様の方法により、化合物（ｘｉｉ）から化合物（ｘｉｉｉ）を得ることができる。

（第３工程）
化合物（ｘｉｉｉ）の水酸基をハロゲンに変換して、化合物（ｘｉｖ）を得る工程である。
化合物（ｘｉｉｉ）をトルエン、テトラヒドロフラン等の溶媒中、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン等の塩基の存在下に、オキシ塩化リン、オキシ臭化リン等のハロゲン化剤と0℃〜20 0℃、好ましくは20℃〜150℃で反応させることにより、化合物（ｘｉｖ）を得ることができる。

（第４工程）
Ａ法の第１工程と同様の方法により、化合物（ｘｉｖ）から化合物（ｘｉ）を得ることができる。

Ａが式：

（式中Ｙ^２は単結合またはＣ１〜Ｃ３アルキレン；Ｒ^６、Ｒ^７、およびＲ^８は前記（１）と同意義）
で表される基である本発明化合物（Ｉ）は下記Ｆ法によっても合成することができる。

（Ｆ法）

（Ｈａｌ⁶およびＨａｌ^７はハロゲン；Ｙ^２は単結合またはＣ１〜Ｃ３アルキレン；Ｐｇは水酸基の適切な保護基；Ｒ^１、Ｒ^２、Ｒ^６、Ｒ^７、およびＲ^８は前記（１）と同意義；Ｒ^４３およびＲ^４６は前記と同意義）
（第１工程）
Ａ法の第１工程と同様の方法により、出発原料（Ｓ．Ｍ．）と化合物（ｉｉ’）から化合物（ｉｉｉ’）を得ることができる。
（第２工程）
化合物（ｉｉｉ’）の水酸基に保護基を結合させて、化合物（ｉｉｉ’’）を合成する工程である。
Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) 等に記載の方法で、適切な保護基を結合させればよい。
（第３工程）
Ｅ法の第１工程と同様の方法により、化合物（ｉｉｉ’’）から化合物（ｘ’）を得ることができる。
（第４工程）
Ｅ法の第２工程と同様の方法により、化合物（ｘ’）から化合物（ｘｉ’）を得ることができる。
（第５工程）
Ｅ法の第３工程と同様の方法により、化合物（ｘｉ’）から化合物（ｖｉｉ’）を得ることができる。
（第６工程）
Ａ法の第３工程と同様の方法により、化合物（ｖｉｉ’）から化合物（ｖｉｉｉ’）を得ることができる。
（第７工程）
化合物（ｖｉｉｉ’）の保護基の脱保護を行い、化合物（ｖｉｉｉ’’）を合成する工程である。
Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) 等に記載の方法で、適切な条件により脱保護を行えばよい。
（第８工程）
化合物（ｖｉｉｉ’’）に式：Ｒ^８−Ｙ^２−Ｈａｌ^８（式中Ｈａｌ^８はハロゲン；Ｙ^２は単結合またはＣ１〜Ｃ３アルキレン；Ｒ^８は前記（１）と同意義）で表される試薬を反応させて、化合物（ｖｉｉｉ’’’）を得る工程である。
化合物（ｖｉｉｉ’’）をＮ、Ｎ−ジメチルホルムアミド、ジメチルスルホキシド、テトラヒドロフラン、ジエチルエーテル、トルエン、ｎ−ヘキサン等の溶媒中、炭酸セシウム、炭酸カリウム、炭酸ナトリウム、炭酸リチウム、炭酸水素カリウム、炭酸水素ナトリウム、水酸化カリウム、水酸化ナトリウム、トリエチルアミン、ピリジン等の塩基の存在下- 2 0℃〜20 0℃、好ましくは0℃〜10 0℃でＲ^８―Ｙ^２―Ｈａｌ^８（式中Ｈａｌ^８はハロゲン；Ｙ^２は単結合またはＣ１〜Ｃ３アルキレン；Ｒ^８は前記（１）と同意義）で表される試薬と反応させることにより、化合物（ｖｉｉｉ’’’）を得ることができる。
Ｆ法におけるＹ^２としてはＣ１〜Ｃ３アルキレンが好ましい。特にメチレンが好ましい。
Ｆ法におけるＲ^８としてはハロゲンで置換されていてもよいフェニルまたはハロゲンで置換されていてもよいピリジルが好ましい。

Ａ法の第3工程で使用する式：Ｒ^１−Ｏ−ＮＨ_２（式中、Ｒ^１は上記（１）と同意義）で表されるアルコキシアミン試薬は、市販品として入手可能であるかJ. Med. Chem., 1999, 42 : 2007-2020、Liebigs Ann. Chem., 1988 : 1149-1153、Organic Letters, 2004, 6 : 4069-4072、Organic Letters, 2005, 7 : 937-939、WO０４／０５４５１４号等に記載の方法に従って合成できるアルコール体を出発原料としてWO０２／０６２１３号等に記載の方法に従って合成できる。

式（Ｉ）で表される化合物において、以下に示す式（Ｉ−Ａ）〜式（Ｉ−Ｐ）で示す化合物が好ましい。
式（Ｉ−Ａ）：

［式中、Ｒ^２１は、置換基群Ｃ（置換基群Ｃ：アルキル、アルケニル、アルキニル、置換されていてもよいアリール、アラルキル、アルキルオキシ、ヒドロキシアルキル、ヒドロキシアルキルオキシアルキル、ハロアルキル、１または2のアルキルで置換されていてもよいアミノアルキル、アルキルスルホニル、アルキルスルホニルアルキル、ハロゲンもしくはアルキルオキシで置換されていてもよいアルキルカルボニル、アルキルオキシカルボニル、置換されていてもよいシクロアルキル、カルボキシアルキル、置換されていてもよいアミノカルボニルアルキル、置換されていてもよいアミノカルボニルオキシアルキル、アルキルオキシアルキル、アルキルチオアルキル、アルキルカルボニルアミノアルキル、アルキルスルホニルアミノアルキル、アルキルスルホニル（アルキル）アミノアルキル、アルキルオキシカルボニルアルキル、アルキルチオ（ヒドロキシ）アルキル、シクロアルキルアルキル、シアノアルキル、置換されていてもよいアミノアルキルカルボニル、置換されていてもよいヘテロアリール、ヘテロアリールアルキル、ヒドロキシアルキルオキシアルキル、置換されていてもよい非芳香族複素環基、置換されていてもよい非芳香族複素環アルキル）から選択される置換基で置換されていてもよいアミノで置換されたアルキル、置換基群Ｄ（置換基群Ｄ：ハロゲン、アリール、ヒドロキシ、オキソ、置換されていてもよいアミノカルボニル、アルキルオキシカルボニル、置換基群Ｈ（置換基群Ｈ：置換されていてもよいアミノカルボニル、シアノ、アルキルオキシ、アルキルスルホニルアミノ、アミノ、カルボキシ、アルキルオキシカルボニル、およびヒドロキシ）から選択される置換基で置換されていてもよいアルキル、アルキルアミノカルボニル、カルボキシ、シアノ、アルキルスルホニル、アルキルカルボニル、アルケニルカルボニル、アルキルスルホニルアルキルカルボニル、アルキルオキシアルキルカルボニル、アルキルカルボニルアミノ、アミノカルボニルオキシ、非芳香族含窒素複素環基、および非芳香族複素環カルボニル）から選択される置換基で置換されていてもよい非芳香族含窒素複素環基（ここで非芳香族含窒素複素環基は、ピロリジニル、ピペリジル、ピペラジニル、モルホリニル、およびチオモルホリニルから選択される）で置換されたアルキル、または置換基群Ｂ（置換基群Ｂ：アルキルオキシカルボニル、置換されていてもよいアミノカルボニル、オキソ、アミノ、カルボキシ、シアノ、シアノアルキル、ヒドロキシアルキル、アルキルカルボニルアミノ、アルキルスルホニルアミノ、およびアミノカルボニルアルキル）から選択される置換基で置換されていてもよい非芳香族含窒素複素環基（ここで非芳香族含窒素複素環基は、アゼチジニル、ピロリジニル、およびピペリジルから選択される）；
Ｒ^２２は、置換基群Ｋ（置換基群Ｋ：アルキルで置換されていてもよいアミノ、ヒドロキシ、アルキルオキシ、およびハロゲン）から選択される置換基で置換されていてもよいアルキル、置換基群Ｋから選択される置換基で置換されていてもよいアルケニル、置換基群Ｋから選択される置換基で置換されていてもよいアルキニル、ヒドロキシ、ハロゲン、フェニル、ピリジル、フリル、チエニル、またはチアゾリル；
Ｒ^２３およびＲ^２４の一方が水素原子、他方が水素原子、アルキルオキシ、アルキルオキシアルキルオキシ、ハロゲン、またはアルキルで置換されていてもよいアミノアルキル；
Ｒ^２７は、水素原子、アルキル、またはアシル；および
Ｒ^２５およびＲ^２６は、それぞれ独立して、水素原子、ハロゲン、アルキニル、ヒドロキシ、アルキルオキシ、アルケニルオキシ、アルキニルオキシ、またはヘテロアリールアルキルオキシ］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
式（Ｉ−Ｂ）：

［式中、Ｒ^２１、Ｒ^２２、Ｒ^２３、Ｒ^２４およびＲ^２７は前記と同意義；
Ｙ^１は、Ｃ１〜Ｃ３アルキレン；
Ｒ^２８は、アルキル、アルキルオキシ、アルキニル、またはハロゲン；および
Ｒ^２９、Ｒ^３０、およびＲ^３１は、それぞれ独立して、水素原子または置換基群Ｆ（置換基群Ｆ：ハロゲン、カルボキシ、アルキル、ハロアルキル、ヒドロキシアルキル、アルキルオキシ、アルキルオキシカルボニル、および置換されていてもよいアミノ）から選択される置換基］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
式（Ｉ−Ｃ）：

［式中、Ｒ^２１、Ｒ^２２、Ｒ^２３、Ｒ^２４、およびＲ^２７は前記と同意義；
Ｒ^３５は、置換基群Ｌ（置換基群Ｌ：ヒドロキシ、アルキルオキシ、ハロゲン、およびシアノ）から選択される置換基で置換されていてもよいアルキル、置換基群Ｌから選択される置換基で置換されていてもよいアルケニル、置換基群Ｌから選択される置換基で置換されていてもよいアルキニル、または式：

（式中、Ｒ^２９、Ｒ^３０、およびＲ^３１は前記と同意義）で表される基；
ＱはＮまたはＣＨ_２］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
式（Ｉ−Ｄ）：

［式中、Ｒ^２１、Ｒ^２２、Ｒ^２３、Ｒ^２４、Ｒ^２５、Ｒ^２６、およびＲ^２７は前記と同意義；および
Ｒ^３６は、置換基群Ｃから選択される置換基で置換されていてもよいアミノカルボニルで置換されたアルキル、または置換基群Ｄから選択される置換基で置換されていてもよい非芳香族複素環カルボニル（ここで非芳香族含窒素複素環は、ピロリジニル、ピペリジル、ピペラジニル、モルホリニル、およびチオモルホリニルから選択される）で置換されたアルキル］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
式（Ｉ−Ｅ）：

［式中、Ｒ^２１、Ｒ^２２、Ｒ^２３、Ｒ^２４、Ｒ^２７、Ｒ^２８、Ｒ^２９、Ｒ^３０、Ｒ^３１、Ｒ^３６、およびＹ^１は前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
式（Ｉ−Ｆ）：

［式中、Ｒ^２２、Ｒ^２３、Ｒ^２４、Ｒ^２７、Ｒ^３６、およびＱは前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
式（Ｉ−Ｇ）：

［式中、Ｒ^２３、Ｒ^２４、Ｒ^２５、Ｒ^２６、およびＲ^２７は前記と同意義；
Ｒ^３２は、置換基群Ｃから選択される置換基で置換されていてもよいアミノで置換されたアルキル、置換基群Ｄから選択される置換基で置換されていてもよい非芳香族含窒素複素環基（ここで非芳香族含窒素複素環基は、ピロリジニル、ピペリジル、ピペラジニル、モルホリニル、およびチオモルホリニルから選択される）で置換されたアルキル、または置換基群Ｂから選択される置換基で置換されていてもよい非芳香族含窒素複素環基（ここで非芳香族含窒素複素環基は、アゼチジニル、ピロリジニル、およびピペリジルから選択される）］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
式（Ｉ−Ｈ）：

［式中、Ｒ^２３、Ｒ^２４、Ｒ^２７、Ｒ^２８、Ｒ^２９、Ｒ^３０、Ｒ^３１、Ｒ^３２、およびＹ^１は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
式（Ｉ−Ｉ）：

［式中、Ｒ^２３、Ｒ^２４、Ｒ^２７、Ｒ^３２、Ｒ^３５、およびＱは前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
式（Ｉ−Ｊ）：

［式中、Ｒ^２２、Ｒ^２３、Ｒ^２４、Ｒ^２５、Ｒ^２６、およびＲ^２７は前記と同意義；
Ｗ^２は、置換基群Ｊから選択される置換基で置換されていてもよいピロリジニル、置換基群Ｊから選択される置換基で置換されていてもよいピペリジル、置換基群Ｊから選択される置換基で置換されていてもよいピペラジニル、置換基群Ｊから選択される置換基で置換されていてもよいモルホリニル、または置換基群Ｊから選択される置換基で置換されていてもよいトリアゾリル］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
式（Ｉ−Ｋ）：

［式中、Ｒ^２２、Ｒ^２３、Ｒ^２４、Ｒ^２７、Ｒ^２８、Ｒ^２９、Ｒ^３０、Ｒ^３１、Ｙ^１、およびW^２は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
式（Ｉ−Ｌ）：

［式中、Ｒ^２２、Ｒ^２３、Ｒ^２４、Ｒ^２７、Ｒ^３５、W^２、およびＱは前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
式（Ｉ−Ｍ）：

［式中、Ｒ^２２、Ｒ^２３、Ｒ^２４、Ｒ^２５、Ｒ^２６、およびＲ^２７は前記と同意義；
Ｒ^３３は、水素原子、置換基群Ｌから選択される置換基で置換されていてもよいＣ１−Ｃ６アルキル、置換基群Ｌから選択される置換基で置換されていてもよいＣ２−Ｃ６置換されていてもよいアルケニル、または置換基群Ｌから選択される置換基で置換されていてもよいＣ２−Ｃ６置換されていてもよいアルキニル；および
Ｒ^３４は、置換基群Ｃから選択される置換基で置換されていてもよいアミノで置換されたアルキル、または置換基群Ｄから選択される置換基で置換されていてもよい非芳香族含窒素複素環基で置換されたアルキル、置換基群Ｆから選択される置換基で置換されていてもよいアリール、置換基群Ｆから選択される置換基で置換されていてもよいヘテロアリール、または置換基群Ｆから選択される置換基で置換されていてもよい非芳香族複素環基］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
式（Ｉ−Ｎ）：

［式中、Ｒ^２２、Ｒ^２３、Ｒ^２４、Ｒ^２７、Ｒ^２８、Ｒ^２９、Ｒ^３０、Ｒ^３１、Ｒ^３３、Ｒ^３４、およびＹ^１は前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
式（Ｉ−Ｏ）：

［式中、Ｒ^２２、Ｒ^２３、Ｒ^２４、Ｒ^２７、Ｒ^３４、Ｒ^３５、およびＱは前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
式（Ｉ−Ｐ）：

［式中、Ｒ^３７は、アルキル、ヒドロキシアルキル、アルキルカルボニルアミノアルキル、もしくは非芳香族複素環で置換されていてもよいアミノで置換されたアルキル、アルキル、ヒドロキシアルキル、もしくはアルキルカルボニルアミノで置換されていてもよい非芳香族含窒素複素環基で置換されたアルキル、またはヒドロキシアルキルで置換された非芳香族含窒素複素環基；
Ｒ^３８はＣ２〜Ｃ４アルキニル；
Ｒ^３９はハロゲン；
Ｒ^４０は、式：−Ｙ^３−Ｒ^４２（式中、Y^３は、−Ｏ−を介在してもよいアルキレン；Ｒ^４２は、ハロゲンで置換されていてもよいフェニルまたはハロゲンで置換されていてもよいピリジル）で表される基；
Ｒ^４１はハロゲン；
Ｙ^１は、前記と同意義］で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
式（Ｉ−Ｑ）：

（式中、Ｒ^４７は式：

で表される基；Ｒ^３７は前記と同意義）で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
式（Ｉ−Ａ）〜式（Ｉ−Ｆ）および式（Ｉ−Ｊ）〜式（Ｉ−Ｏ）で示される化合物におけるＲ^２２としては、メチル、エチル、ｎ−プロピル、イソプロピル、プロピニル、ブチニルまたはフェニルが好ましい。

本明細書中、「溶媒和物」とは、例えば有機溶媒との溶媒和物、水和物等を包含する。水和物を形成する時は、任意の数の水分子を配位していてもよい。
「本発明化合物」という場合には、製薬上許容される塩、またはその水和物も包含される。例えば、アルカリ金属（リチウム、ナトリウム、カリウム等）、アルカリ土類金属（マグネシウム、カルシウム等）、アンモニウム、有機塩基およびアミノ酸との塩、または無機酸（塩酸、臭化水素酸、リン酸、硫酸等）、および有機酸（酢酸、クエン酸、マレイン酸、フマル酸、ベンゼンスルホン酸、ｐ−トルエンスルホン酸等）との塩が挙げられる。これらの塩は、通常行われる方法によって形成させることができる。
また、本発明化合物は特定の異性体に限定するものではなく、全ての可能な異性体やラセミ体を含むものである。
本発明化合物は後述する実験例の記載の通り、優れた細胞増殖阻害作用を示し、「抗癌剤」および「癌の治療剤」として使用しうる。
本発明化合物を、上記の疾患の治療を目的としてヒトに投与する場合は、散剤、顆粒剤、錠剤、カプセル剤、丸剤、液剤等として経口的に、または注射剤、坐剤、経皮吸収剤、吸入剤等として非経口的に投与することができる。また、本化合物の有効量にその剤型に適した賦形剤、結合剤、湿潤剤、崩壊剤、滑沢剤等の医薬用添加剤を必要に応じて混合し、医薬製剤とすることができる。注射剤の場合には、適当な担体と共に滅菌処理を行って製剤とする。
投与量は疾患の状態、投与ルート、患者の年齢、または体重によっても異なるが、成人に経口で投与する場合、通常０．１〜１００mg／kg／日であり、好ましくは１〜２０mg／kg／日である。

以下に実施例および試験例を挙げて本発明をさらに詳しく説明するが、本発明はこれらにより限定されるものではない。
実施例中、以下の略号を使用する。
Ｍｅ：メチル
Ｅｔ：エチル
ｎＰｒ：ｎ−プロピル
ｉＰｒ：イソプロピル
Ｐｈ：フェニル

実施例１

（第１工程） 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-ヨードキナゾリン(III-1)塩酸塩の合成
4-クロロ-6-ヨードキナゾリン(6.0g)と3-クロロ-4-(3-フルオロベンジルオキシ)アニリン(II-1, 5.2g)をテトラヒドロフラン180mlに溶解し、3時間加熱還流した。析出物を濾取し、テトラヒドロフランで洗浄することにより、4-(4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-ヨードキナゾリン塩酸塩(III-1, 10.5g)を黄色固体として得た。
¹H NMR(d₆-DMSO δ): 11.47(1H, brs), 9.25(1H, s), 8.94(1H, s), 8.36(1H, dd, J=1.8Hz, J=8.7Hz), 7.92(1H, d, J=2.7Hz), 7.71(1H, d, J=8.7Hz), 7.66(1H, dd, J=2.7Hz, J=8.7Hz),
7.48(1H, dt, J=6.0Hz, J=7.8Hz), 7.37-7.30(3H, m), 7.19(1H, dt, J=2.7Hz, J=8.7Hz), 5.30(2H, s).

上記第１工程と同様の方法で下記の化合物を合成した。

（第２工程） 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-ホルミルキナゾリン(IV-1)の合成
4-(4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-ヨードキナゾリン塩酸塩(III-1, 5.0g)をジメチルホルムアミド100mlに溶かし、ギ酸ナトリウム1.2 5g、ジクロロビス(トリフェニルホスフィン)パラジウム(324mg)、トリエチルアミン(3.2ml)を加えた。反応液を脱気した後、一酸化炭素雰囲気下、80度で3時間加熱攪拌した。その後、反応液を氷水中に注ぎ、酢酸エチルで抽出した。抽出液を水及び食塩水で洗浄後、硫酸マグネシウムで乾燥した。乾燥した溶液をセライト濾過、濃縮後、酢酸エチル-ヘキサン混液(1：2)で粉末化し、4-(4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-ホルミルキナゾリン(IV-1, 2.86g)を黄色固体として得た。
¹H NMR(d₆-DMSO δ): 10.24(1H, s), 10.13(1H, s), 9.16(1H, s), 8.69(1H, s), 8.27(1H, br d, J=8.7Hz), 8.03(1H, d, J=2.1Hz), 7.90(1H, d, J=9.0Hz), 7.74(1H, dd, J=2.7Hz, J=8.7Hz), 7.48(1H, dt, J=6.0Hz, J=8.4Hz), 7.36-7.30(2H, m), 7.30(1H, d, J=8.7Hz), 7.19(1H, br t, J=8.7Hz), 5.27(2H, s).

上記第２工程と同様の方法で下記の化合物を合成した。

（第３工程） 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(2-(1-ピペリジル)エトキシイミノ)キナゾリン(V-1)の合成
4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-ホルミルキナゾリン(IV-1, 50mg)と2-(1-ピペリジル)エトキシアミン２塩酸塩(36.5mg)をテトラヒドロフラン(2ml)と水(0.1ml)の混液に溶かし、室温で終夜反応した。反応液を酢酸エチルで薄め、飽和炭酸水素ナトリウム水溶液、食塩水で順に洗浄後、硫酸マグネシウム上で乾燥した。濃縮後、アミノカラムを用いたクロマトグラフィー（ヘキサン：酢酸エチル=２：３で溶出）により精製、さらに薄層クロマトグラフィーにより再精製し、4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(2-(1-ピペリジル)エトキシイミノ)キナゾリン(V-1, 13mg)を得た。
¹H NMR(d₆-DMSO, δ ): 9.95(1H, s), 8.63(1H, s), 8.59(1H, s), 8.34(1H, s), 8.10(1H, d, J=9.3Hz), 8.00(1H, d, J=2.4Hz), 7.79(1H, d, J=8.7Hz), 7.72(1H, dd, J=9.0Hz, J=2.1Hz), 7.51-7.44(1H, m), 7.36-7.31(2H, m), 7.28(1H, d, J=9.0Hz), 7.19(1H, br t, J=9.0Hz), 5.26(2H, s), 4.28(2H, t, J=6.0 Hz), 2.63(2H, t, J=6.0Hz), 2.41(4H, t, J=4.8Hz), 1.50(4H, quin, J=5.3Hz), 1.45-1.35(2H, m).

実施例２

（第１工程） 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(2-(N-(t-ブトキシカルボニル)N-エチルアミノ)エチルオキシイミノ)キナゾリン(V-16)の合成
4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-ホルミルキナゾリン(IV-1, 120mg)とN-(t-ブトキシカルボニル)エチルアミノエトキシアミン(110mg)をテトラヒドロフラン(1.5ml)に溶かし、2mol/L塩酸134μlを加えて、室温で4時間反応した。反応終了後、氷冷した飽和炭酸水素ナトリウム水溶液中に注ぎ、酢酸エチルで抽出した。有機層を水及び食塩水で洗浄後、硫酸マグネシウム上で乾燥、濃縮した。得られた残渣をアミノカラムクロマトグラフィー（ヘキサン：酢酸エチル=１：１で溶出）により精製、さらにシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル=１：１で溶出）により再精製し、4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(2-(N-(t-ブトキシカルボニル)-N-エチルアミノ)エチルオキシイミノ)キナゾリン(V-16, 96mg)を黄色粘性油状物質として得た。
¹H NMR(d₆-DMSO, δ): 9.93(1H, s), 8.63(1H, brs), 8.60(1H, s), 8.34(1H, s), 8.12(1H, dd, J=1.2Hz, J=9.0Hz), 8.01(1H, d, J=2.4Hz), 7.79(1H, d, J=8.4Hz), 7.72(1H, dd, J=2.4Hz, J=8.4Hz), 7.48(1H, dt, J=6.0Hz, J=8.1Hz), 7.36-7.30(2H, m), 7.28(1H, d, J=9.0Hz), 7.23-7.14(1H, m), 5.26(2H, s), 4.26(2H, t, J=5.7Hz), 3.50(2H, t, J=6.3Hz), 3.23(2H, q, J=6.9Hz), 1.38(9H, s), 1.12-1.00(3H, m).

上記第１工程と同様の方法で下記の化合物を合成した。

（第２工程） 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(2-(N-エチルアミノ)エチルオキシイミノ)キナゾリン(V-17)の合成
4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(2-(N-(t-ブトキシカルボニル)-N-エチルアミノ)エチルオキシイミノ)キナゾリン(V-16, 54mg)をクロロホルム(1.8ml)に溶かし、トリフルオロ酢酸(1.8ml)を加え、室温で1時間攪拌した。反応終了後、反応液を濃縮し、酢酸エチルで希釈した。飽和炭酸水素ナトリウム水溶液、水、食塩水で順次洗浄後、硫酸マグネシウム上で乾燥した。濃縮後、結晶性残渣をジクロロメタン−ヘキサン（1：4）の混液で洗い、4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(2-(N-エチルアミノ)エチルオキシイミノ)キナゾリン(V-17, 28mg)を白色固体として得た。
¹H NMR(d₆-DMSO, δ ): 9.96(1H, s), 8.65(1H, brs), 8.60(1H, s), 8.35(1H, s), 8.11(1H, d, J=9.0Hz), 8.01(1H, d, J=3.0Hz), 7.80(1H, d, J=9.0Hz), 7.75-7.70(1H, m), 7.52-7.43(1H, m), 7.36-7.31(2H, m), 7.28(1H, d, J=9.3Hz), 7.23-7.14(1H, m), 5.26(2H, s), 4.26(2H, t, J=6.0Hz), 2.93(2H, t, J=6.0Hz), 2.66(2H, q, J=7.2Hz), 1.05(3H, t, J=7.2Hz).

実施例３

（第１工程） 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-(N-シアノメチルピロリジン-2-イル)メトキシイミノ)メチルキナゾリン(V-30)の合成
化合物V-29 40mgおよびヨードアセトニトリル8μLをN,N-ジメチルアセタミド0.4mLに溶かし、炭酸カリウム15mgを加えて、室温で1時間攪拌した。反応後、飽和食塩水溶液を加え、酢酸エチルで抽出した。有機層をプレセップ（登録商標）を通して脱水し、ろ液を濃縮した。濃縮残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル=2：１で溶出）により精製し、4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-(N-シアノメチルピロリジン-2-イル)メトキシイミノ)メチルキナゾリン(V-30)を35mg得た。
¹H NMR(d₆-DMSO, δ ): 9.92(1H, s), 8.62(1H, d, J=1.5Hz), 8.58(1H, s), 8.36(1H, s), 8.09(1H, dd, J=8.7Hz, J=1.5Hz), 7.99(1H, d, J=2.6Hz), 7.78(1H, d, J=8.7Hz), 7.71(1H, dd, J=9.0Hz, J=2.6Hz), 7.49-7.42(1H , m), 7.33-7.25(3H, m), 7.16(1H, dt, J=8.1Hz, J=1.8Hz), 5.24(2H, s), 4.17(2H, d, J=5.7Hz), 3.97(1H, d, J=17Hz), 3.90(1H, d, J=17Hz), 3.00-2.89(2H, m), 2.01-1.89(1H, m), 1.78-1.54(3H, m).

実施例４

（第１工程） 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(2-(4-アクリロイル-1-ピペラジン-1-イル)エトキシイミノ)メチルキナゾリン(V-43)の合成
化合物V-42 40mgおよび塩化アクリロイル6μLをテトラヒドロフラン1.5mLに溶かし、室温で2時間攪拌した。反応後、飽和食塩水溶液を加え、酢酸エチルで抽出した。有機層をCHEM ELUT（商品名）を通して脱水し、ろ液を濃縮した。濃縮残渣を、アミノカラムを用いたクロマトグラフィー(1%メタノール含有酢酸エチルで溶出)により精製し、得られた残渣をヘキサン-酢酸エチル(6：1）にて固体化させ、4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(2-(4-アクリロイル-1-ピペラジン-1-イル)エトキシイミノ)メチルキナゾリン(V-43)を20mg得た。
¹H NMR(d₆-DMSO, δ ): 9.95(1H, s), 8.64(1H, s), 8.59(1H, s), 8.35(1H, s), 8.10(1H, d, J=8.7Hz), 8.00(1H, d, J=2.4Hz), 7.78(1H, d, J=8.7Hz), 7.72(1H, dd, J=9.0Hz, 2.7Hz), 7.44-7.51(1H, m), 7.26-7.35(3H, m), 7.15-7.22(1H, m), 6.79(1H, dd, J=16.5Hz, 10.2Hz), 6.10(1H, dd, J=16.5Hz, 2.4Hz), 6.17(1H, dd, J=10.5Hz, 2.4Hz), 5.26(2H, s), 4.32(2H, t, J=5.7Hz), 3.55(4H, m), 2.72(2H, t, J=5.7Hz), 2.50(4H, m)

実施例５

（第１工程） 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(2-(4-(2-メタンスルホニルエチル)-1-ピペラジン-1-イル)エトキシイミノ)メチルキナゾリン(V-44)の合成
化合物V-42 25mgおよびメチルビニルスルホン4μLをテトラヒドロフラン1mLに溶かし、室温で21時間攪拌した。さらにメチルビニルスルホン4μLを加えた後、室温で29時間攪拌した。反応後、飽和食塩水溶液を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水溶液の順で洗浄後、硫酸マグネシウム上で乾燥した。濃縮残渣をアミノカラムを用いたクロマトグラフィー(酢酸エチルで溶出)により精製し、得られた残渣をヘキサン-酢酸エチル(6：1）にて固体化させ、4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(2-(4-(2-メタンスルホニルエチル)-1-ピペラジン-1-イル)エトキシイミノ)メチルキナゾリン(V-44)を15mg得た。
¹H NMR(d₆-DMSO, δ ): 9.95(1H, s), 8.63(1H, s), 8.59(1H, s), 8.34(1H, s), 8.10(1H, d, J=9.6Hz), 8.00(1H, d, J=2.4Hz), 7.79(1H, d, J=8.4Hz), 7.71(1H, dd, J=8.7Hz, 2.7Hz), 7.44-7.51(1H, m), 7.26-7.34(3H, m), 7.15-7.22(1H, m), 5.26(2H, s), 4.29(2H, t, J=6.0Hz), 3.27(2H, t, J=6.6Hz), 3.02(3H, s), 2.67-2.70(4H, m), 2.46(8H, m)

実施例１〜５と同様の方法で下記の化合物を合成した。

実施例６

（第１工程） 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(4-(N-(2-(メタンスルホニル)エチル)-N-(2,2,2-トリフルオロアセチル)アミノ)ブチルオキシイミノ)キナゾリン(V-14)の合成
4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(ヒドロキシイミノ)キナゾリン(V-2, 84mg)およびN-(4-ブロモブチル)-N-(2-メタンスルホニルエチル)-2,2,2-トリフルオロアセタミド(71mg)をN,N-ジメチルアセタミド(1.5ml)に溶かし、炭酸カリウム(41mg)を加えて、60℃で13時間加熱攪拌した。その後、反応液を0.5Mクエン酸中に注ぎ、酢酸エチルで抽出した。有機層を水、食塩水で洗浄後、硫酸マグネシウム上で乾燥した。粗成績体をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル=１：４で溶出）により精製し、4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(4-(N-(2-(メタンスルホニル)エチル)-2,2,2-トリフルオロアセタミド)ブチルオキシイミノ)キナゾリン(V-14, 41mg)を淡黄色固体として得た。
¹H NMR(d₆-DMSO, δ ): 9.94(1H, s), 8.63(1H, s), 8.59(1H, s), 8.33(1H, s), 8.10(1H, dd, J=8.4Hz, J=1.5Hz), 8.00(1H, d, J=2.4Hz), 7.78(1H, d, J=8.7Hz), 7.71(1H, dd, J=2.3Hz, J=8.7Hz), 7.47(1H, dt, J=6.0Hz, J=8.1Hz), 7.36-7.31(2H, m), 7.28(1H, d, J=9.0Hz), 7.18(1H, dt, J=2.0Hz, J=8.6Hz), 5.26(2H, s), 4.26-4.18(2H, m), 3.79(2H, t, J=7.1Hz), 3.60-3.44(4H, m), 3.05(3H, s), 1.7 8-1.66(4H, m).

（第２工程） 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(4-(2-(メタンスルホニル)エチルアミノ)ブチルオキシイミノ)キナゾリン(V -15 )の合成
4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(4-(N-(2-(メタンスルホニル)エチル)-2,2,2-トリフルオロアセタミド)ブチルオキシイミノ)キナゾリン(V-14, 40mg)をテトラヒドロフランとメタノールの混液（1：1）2.6mlに溶かし、1mol/L水酸化ナトリウム水溶液86μlを加えて、室温で14時間、40℃で1時間攪拌した。反応後、酢酸エチルで抽出し、有機層を脱水し、濾液を濃縮した。濃縮残渣を、アミノカラムを用いたクロマトグラフィー（0〜3%メタノール含有酢酸エチルで溶出）により精製、得られた淡黄色の油状物質をヘキサンと酢酸エチルの混液で粉末化し、4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(4-(2-(メタンスルホニル)エチルアミノ)ブチルオキシイミノ)キナゾリン(V-15, 12mg)を淡黄色固体として得た。
¹H NMR(d₆-DM SO, δ ): 9.95(1H, s), 8.63(1H, s), 8.59(1H, s), 8.33(1H, s), 8.11(1H, d, J=8.7Hz), 8.01(1H, d, J=2.4Hz), 7.79(1H, d, J=8.7Hz), 7.72(1H, br d, J=9.0Hz), 7.51-7.44(1H, m), 7.36-7.31(2H, m), 7.28(1H, d, J=9.0Hz), 7.19(1H, br t, J=9Hz), 5.26(2H, s), 4.20(2H, t, J=6.6Hz), 3.21(2H, t, J=6.9Hz), 2.91(2H, t, J=6.6Hz), 2.56(2H, t, J=6.9Hz), 1.73(2H, quin, J=7Hz), 1.51(2H, quin, J=7Hz).

実施例７

（第１工程） 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-ヒドロキシエタン-1-イル)キナゾリン(VI-1)の合成
4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-ホルミルキナゾリン(IV-1) 620mgをテトラヒドロフラン30mLに溶解後、窒素雰囲気下0℃に冷却し、臭化メチルマグネシウム(0.93M テトラヒドロフラン溶液)を4.9mL滴下した。窒素雰囲気下0℃で1時間反応後、水と酢酸エチルを加え分液操作を行った。有機層を水、飽和食塩水の順で洗浄後、硫酸マグネシウム上で乾燥した。濃縮後、得られた結晶をクロロホルムで洗浄して4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-ヒドロキシエタン-1-イル)キナゾリン(VI-1)330mgを得た。
¹H NMR(d₆-DMSO δ): 9.81(1H, s), 8.55(1H, s), 8.44(1H, s), 8.03(1H, d, J=2.4Hz), 7.86(1H, dd, J=8.7Hz, J=1.2Hz), 7.78-7.73(2H, m), 7.51-7.44(1H, m), 7.35-7.25(3H, m), 7.18(1H, dt, J=8.4Hz, J=2.4Hz), 5.44(1H, d, J=3.9Hz), 5.26(2H, s), 4.93(1H, m), 1.45(3H , d, J=6.6Hz)

（第２工程） 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(エタン-1-オン)キナゾリン(VII-1)の合成
4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-ヒドロキシエタン-1-イル)キナゾリン(VI-1) 360mgをテトラヒドロフラン150mLに溶かし、二酸化マンガン3.7gを加え室温で終夜攪拌した。反応後、無機物をろ去してろ液を濃縮した。得られた結晶をクロロホルムで洗浄して4-(3-クロロ-4- (3-フルオロベンジルオキシ)フェニルアミノ)-6-(エタン-1-オン)キナゾリン(VII-1) 320mgを得た。
¹H NMR(d₆-DMSO δ): 10.18(1H, s), 9.16(1H, d, J=1.5Hz), 8.64(1H, s), 8.31(1H, dd, J=8.4Hz, J=2.4Hz), 7.97(1H, d, J=2.4Hz), 7.83(1H, d, J=8.7Hz), 7.71(1H, dd, J=8.7Hz, J=2.4Hz), 7.51-7.44(1H, m), 7. 35-7.29(3H, m), 7.19(1H, dt, J=8.1Hz, J=2.7Hz), 5.27(2H, s), 2.74(3H, s)

上記第１工程および第２工程と同様の方法で下記の化合物を合成した。

（第３工程） 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-(2-(1-モルホリノ)エトキシイミノ)エチル)キナゾリン( V I II- 1 )の合成
化合物VII-1 100mgと2-(1-モルホリノ)エトキシアミン２塩酸塩78mgをテトラヒドロフランと水の混液6mL(２０：１)に溶かし、室温で終夜反応した。反応液を酢酸エチルで薄め、飽和炭酸水素ナトリウム水溶液で洗浄後、硫酸マグネシウム上で乾燥した。濃縮後、ヘキサンと酢酸エチルの混液(２：１)で固体を洗浄して、4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-(2-(1-モルホリノ)エトキシイミノ)エチル)キナゾリン(VIII-1)を72mg得た。
¹H NMR(d₆-DMSO, δ ): 9.93(1H, s), 8.62(1H, brs), 8.58(1H, s), 8.22(1H, d, J=6.6Hz), 7.96(1H, d, J=1.8Hz), 7.76(1H, d, J=6.6Hz), 7.70(1H, dd, J=6.6Hz, J=1.8Hz), 7.51-7.45(1H, m), 7.35-7.28(3H, m), 7.19(1H, t, J=6.0Hz), 5.27(2H, s), 4.33(2H, t, J=6.0Hz), 3.5 9(4H, t, J=4.5Hz), 2.69(2H, t, J=6.0Hz), 2.47(4H, t, J=4.5Hz), 2.36(3H, s)

参考例１
ケトン誘導体（VII）を得る方法として、実施例７の第１工程、第２工程の他に以下の方法が挙げられる。

（第１工程） 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-キナゾリン-6-カルボン酸メチルエステル(X- 1 )の合成
4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-ヨードキナゾリン塩酸塩(III-1，20g)とジクロロビス(トリフェニルホスフィン)パラジウム1.29gをジメチルホルムアミド200mlおよびメタノール200mlの混合液に溶かし、トリエチルアミン25.7mlを加えた。反応容器内を十分に一酸化炭素ガスで置換した後、一酸化炭素雰囲気下80℃で15時間反応した。反応液をセライトでろ過し、ろ液を攪拌しながら0℃に冷却した。析出物をろ取して冷メタノールで洗浄後乾燥することにより4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-キナゾリン-6-カルボン酸メチルエステル( X-1，13.5g)を無色固体として得た。
¹H NMR(d₆-DMSO，δ): 10.26(1H, s), 9.25(1H, d, J=1.5Hz), 8.65(1H, s), 8.31(1H, dd, J=1.5Hz, J=8.7Hz), 8.02(1H, d, J=2.7Hz), 7.85(1H, d, J=2.7Hz), 7.77(1H, dd, J=2.7Hz, J=8.7Hz), 7.49-7.44(1H, m), 7.35-7.27(3H, m), 7.20-7.16(1H, m), 5.27(2H, s), 3.96(3H, s).

（第２工程） 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-キナゾリン-6-カルボン酸メトキシメチルアミド(X I - 1 )の合成
4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-キナゾリン-6-カルボン酸メチルエステル(X- 1，11.6g)をテトラヒドロフラン(230ml)に溶かし、N、O-ジメチルヒドロキシルアミン塩酸塩(7.8g)を加え、氷冷下２mol/L iPrMgClテトラヒドロフラン溶液(79.8ml)を30分かけて滴下した．滴下終了後20分間、氷冷下で攪拌し、反応終了後に飽和塩化アンモニウム水溶液200mlを加えた．混合液に水100mlを加えた後、酢酸エチルで抽出し、有機層を硫酸ナトリウム上で乾燥した。ろ液を濃縮することにより4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-キナゾリン-6-カルボン酸メトキシメチルアミド(X I - 1，12.7g)を淡黄色固体として得た。
¹H NMR(d₆-DMSO，δ): 10.01(1H, s), 8.79(1H, d, J=1.5Hz), 8.64(1H, s), 8.05(1H, d, J=2.7Hz), 8.00(1H, dd, J=1.5Hz, J=8.7Hz), 7.81(1H, d, J=8.7Hz), 7.76(1H, dd, J=2.7Hz, J=8.7Hz), 7.52-7.44(1H, m), 7.35-7.26(3H, m), 7.22-7.16(1H, m), 5.27(2H, s), 3.57(3H, s), 3.34(3H, s).

（第３工程）4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-オキソ-2-ブチン-1-イル)キナゾリン( VII - 4 )の合成
-78℃に冷却したN,N-ジイソプロピルアミン4.22mlのテトラヒドロフラン(25ml)溶液に1.6mol/L n-BuLiヘキサン溶液18.8mlを滴下した。滴下終了後0℃まで昇温して0℃で20分間攪拌して再び-78℃まで冷却した。2-ブロモ-1-プロペン1.33mlのテトラヒドロフラン(25ml)溶液を加え-78℃で2時間攪拌した。この溶液に4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-キナゾリン-6-カルボン酸メトキシメチルアミド( XI-1，2.33g)のテトラヒドロフラン(50ml)溶液を滴下し、滴下終了後に0℃まで昇温し3時間攪拌した。反応終了後に反応液を氷水中に注ぎ2mol/L 塩酸水溶液で中和後、酢酸エチルで抽出した。有機層を硫酸ナトリウム上で乾燥し、ろ液を濃縮して得られた結晶性残渣を塩化メチレンで洗浄することにより4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-オキソ-2-ブチン-1-イル)キナゾリン (VII-4，1.71g)を黄色固体として得た。

参考例２
参考例１の第３工程の他の方法として、以下に示す方法が挙げられる。

（第３工程）4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-オキソ-2-プロピン-3-シクロプロピル- 1-イル)キナゾリン( VII-7)の合成
-78℃に冷却したエチニルシクロプロパン0.16mlのテトラヒドロフラン(3ml)溶液に1.54mol/L n-BuLiヘキサン溶液1.25mlを滴下した。滴下終了後、-78℃で1時間攪拌した。この溶液に4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-キナゾリン-6-カルボン酸メトキシメチルアミド( XI-1，300mg)のテトラヒドロフラン(3ml)溶液を滴下し、滴下終了後に0℃まで昇温し3時間攪拌した。反応終了後に反応液に水10ml、酢酸エチル10mlを加え、分液操作を行った。水層を酢酸エチル10mlで2回再抽出後、すべての有機層を合わせて硫酸ナトリウム上で乾燥し、ろ液を濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製することにより4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-オキソ-2-プロピン-3-シクロプロピル- 1-イル)キナゾリン( VII-7，265mg)を黄色固体として得た。
¹H NMR(d₆-DMSO，δ ): 10.4(1H, s), 9.21(1H, s), 8.67(1H, s), 8.41(1H, d, J=8.7Hz), 8.01(1H, d, J=2.7Hz), 7.88(1H, d, J=8.7Hz), 7.73(1H, dd, J=8.7Hz, J=3Hz), 7.40-7.52(1H, m), 7.15-7.4(4H, m), 5.28(2H, s), 1.77-1.87(1H, m), 1.05-1.20(3H, m).

参考例３
アミド誘導体（XI）を得る方法として、参考例１の第１工程、第２工程の他に以下の方法が挙げられる。

（第１工程） 4-ヒドロキシキナゾリン-6-カルボン酸メチルエステル(X II - 1 )の合成
4-ヒドロキシ-6-ヨードキナゾリン(250mg)と触媒量の酢酸パラジウム(II)および1,3-ビス(ジフェニルホスフィノ)プロパンをN,N-ジメチルホルムアミド(3.8ml)、メタノール(1.5ml)に溶かし、トリエチルアミン1.5mlを加えた。反応容器内を十分に一酸化炭素ガスで置換した後、一酸化炭素雰囲気下80℃で20時間反応した。反応終了後、10％クエン酸水溶液に注ぎ、酢酸エチルで抽出した。有機層を水で洗浄後、硫酸ナトリウム上で乾燥し、ろ液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチルで溶出）により精製し、4-ヒドロキシキナゾリン-6-カルボン酸メチルエステル(X II - 1， 157mg)を褐色固体として得た。
¹H NMR(d₆-DMSO，δ): 12.48(1H、 s), 8.63(1H, s), 8.26(1H, d, J=8.4Hz), 8.19(1H, s), 7.73(1H, d, J=8.4Hz).

（第２工程） 4-ヒドロキシキナゾリン-6-カルボン酸メトキシメチルアミド(X III - 1 )の合成
4-ヒドロキシキナゾリン-6-カルボン酸メチルエステル(X II - 1，4.0g)をテトラヒドロフラン(120ml)に溶かし、N,O-ジメチルヒドロキシルアミン塩酸塩(5.7g)を加え、氷冷下２mol/L iPrMgClテトラヒドロフラン溶液(59ml)を30分かけて滴下した。滴下終了後30分間、氷冷下で攪拌し、反応終了後に2mol/L塩酸40mlを滴下した。混合液を飽和炭酸水素ナトリウム水溶液で中和後、クロロホルムで抽出し、有機層を食塩水で洗浄後に硫酸ナトリウム上で乾燥した。濃縮後、結晶性残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９：１で溶出）により精製して4-ヒドロキシキナゾリン-6-カルボン酸メトキシメチルアミド(X III - 1，2.9g)を白色固体として得た。
¹H NMR(d₆-DMSO，δ): 12.42(1H、 s), 8.36(1H, s), 8.18(1H, s), 8.02(1H, d, J=8.4Hz), 7.73(1H, d, J=8.4Hz), 3.57(3H, s), 3.32(3H, s).

（第３工程） 4-クロロキナゾリン-6-カルボン酸メトキシメチルアミド(X IV - 1 )の合成
4-ヒドロキシキナゾリン-6-カルボン酸メトキシメチルアミド(X III - 1，2.9g)をトルエン(57ml)に懸濁させ、トリエチルアミン6.8mlおよびオキシ塩化リン3.4mlを加え、130℃で30分間攪拌した。反応終了後に室温まで冷却後、飽和炭酸水素ナトリウム水溶液50mlおよび酢酸エチルを加えた。水層がpH８を示すまで炭酸水素ナトリウムを加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄後に硫酸ナトリウム上で乾燥した。濃縮後、結晶性残渣をジエチルエーテルにより洗浄後、乾燥して4-クロロキシキナゾリン-6-カルボン酸メトキシメチルアミド(X IV - 1，2.3g)を白色固体として得た。
¹H NMR(d₆-DMSO，δ ): 8.75(1H、 s), 8.36(1H, s), 8.11(1H, dd, J=2.0Hz, J=8.4Hz), 7.87(1H, d, J=8.4Hz), 3.56(3H, s), 3.32(3H, s).

（第４工程）4-(3-クロロ-4-(ピリジン-2-イルメトキシ)フェニルアミノ)-キナゾリン-6-カルボン酸メトキシメチルアミド (X I - 2 )の合成
4-クロロナゾリン-6-カルボン酸メトキシメチルアミド(X IV - 1，5.78g)をテトラヒドロフラン(100ml)に溶解させ、3-クロロ-4-(ピリジン-2-イルメトキシ)アニリン5.39gを加え、60℃で1時間攪拌した。析出物を濾取し，テトラヒドロフランで洗浄することにより4-(3-クロロ-4-(ピリジン-2-イルメトキシ)フェニルアミノ)-キナゾリン-6-カルボン酸メトキシメチルアミド(X I - 2，7.87g)を白色固体として得た。濾液を室温で静置して得られた析出物を濾取することにより新たにX I - 2を2.21g得た。
¹H NMR(d₆-DMSO，δ ): 10.02(1H, s), 8.79(1H, s), 8.62-8.59(2H, m), 8.04(1H, s), 8.00-7.98(1H, m), 7.90-7.86(1H, s), 7.80-7.78(1H, m), 7.75-7.73(1H, m), 7.59-7.57(1H,m), 7.37-7.35(1H, m), 7.28-7.26(1H, m), 5.29(2H, s), 3.57(3H, s).

参考例４
参考例３の第４工程の他の方法として、以下に示す方法が挙げられる。
（第４工程）4-(4-ベンゼンスルホニルフェニルアミノ)-キナゾリン-6-カルボン酸メトキシメチルアミド (X I - 3 )の合成
4-クロロナゾリン-6-カルボン酸メトキシメチルアミド(X IV - 1，550mg)、4-ベンゼンスルホニルフェニルアミン611mg、酢酸パラジウム(II) 49mg、Xant phos 190mgおよび炭酸セシウム997mgを1,4-ジオキサン(30ml)に加え、反応容器内を窒素ガスで置換後、100℃で2.5時間攪拌した。反応溶液をセライトろ過して，ろ液に水を加えて酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後に硫酸ナトリウム上で乾燥した。ろ液を濃縮後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝95：5で溶出）により精製して4-(4-ベンゼンスルホニルフェニルアミノ)-キナゾリン-6-カルボン酸メトキシメチルアミド(X I - 3，651mg)を淡黄色固体として得た。
¹H NMR(d₆-DMSO，δ ): 10.66(1H, s), 9.29(1H, s), 8.80(1H, s), 8.48(1H, d, J=7.7Hz), 8.16(2H, d, J=7.7Hz), 7.99-7.94(5H, m), 7.80-7.61 (3H, m), 2.27 (3H, s).

参考例５
アミド誘導体（XI）を得る方法として、参考例１の第１工程、第２工程および参考例３の他にさらに以下の方法が挙げられる。

（第１工程）4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-キナゾリン-6-カルボン酸メトキシメチルアミド(X I - 1 )の合成
4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-ヨードキナゾリン塩酸塩(III-1，500mg)とジクロロビス(トリフェニルホスフィン)パラジウム32mg、N-ヒドロキシスクシンイミド191mgをジメチルホルムアミド10mlに溶かし、トリエチルアミン360μlを加えた。反応容器内を十分に一酸化炭素ガスで置換した後、一酸化炭素雰囲気下80℃で3時間反応した。反応液の五分の一に40％N , O-ジメチルヒドロキシルアミン水溶液0.3mlを加え室温で一夜攪拌した。反応終了後、反応液に水を加えて酢酸エチルで抽出した。有機層を水、飽和食塩水の順で洗浄し、硫酸ナトリウム上で乾燥した。ろ液の濃縮残渣をシリカゲルカラムクロマトグラフィー(酢酸エチルで溶出)により精製することにより4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-キナゾリン-6-カルボン酸メトキシメチルアミド(X I - 1，74mg)を淡黄色固体として得た。

実施例８

（第１工程） 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-((S)-モルホリン-2-イルメトキシイミノ)-2-ブチン-1-イル)キナゾリン二塩酸塩( VIII-32)の合成
4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-オキソ-2-ブチン-1-イル)キナゾリン(VII-4，786mg)と(S)-2-アミノオキシメチル-モルホリン-4-カルボン酸 tert-ブチルエステル614mgの1,4-ジオキサン31ml懸濁液に、2mol/Lメタンスルホン酸水溶液2.21mlを加えて80℃で22時間撹拌した。2mol/Lメタンスルホン酸水溶液1.32mlを追加してさらに5.5時間撹拌した。反応終了後、反応液を氷-炭酸水素ナトリウム水溶液中に注ぎ、酢酸エチルで抽出した。水層を酢酸エチルで再抽出後、すべての有機層を合わせて水洗後、無水硫酸マグネシウム上で乾燥した。ろ液を濃縮後、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝9：1で溶出）で精製することにより黄色油状物を得た。この油状物を酢酸エチル50mlに溶解させてろ過後、撹拌しながら4mol/L塩酸-酢酸エチル溶液0.95mlを加え、室温で1時間撹拌した。析出物をろ取後、酢酸エチル、ヘキサンの順で洗浄した。ろ取物をメタノール-酢酸エチルにより再結晶をすることにより4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-((S)-モルホリン-2-イルメトキシイミノ)-2-ブチン-1-イル)キナゾリン二塩酸塩( VI II-32，839mg)を黄色結晶として得た。
¹H NMR(d₆-DMSO，δ): 11.69(1H, bs), 9.49-9.37(2H, m), 9.05(1H, s), 8.88(1H, s), 8.38(1H, dd, J=1.5Hz, J=8.7Hz), 7.96(1H, d, J=8.7Hz), 7.89(1H, d, J=2.7Hz), 7.64(1H, dd, J=2.4Hz, J=9.0Hz), 7.52-7.45(1H, m), 7.36-7.30(3H, m), 7.23-7.16(1H, m), 5.31(2H, s), 4.36-4.34(1H, m), 4.25-4.22(1H, m), 4.04-3.98(1H, m), 3.84-3.77(1H, m), 3.04-2.85(3H, m), 2.28(3H, s).

実施例９

（第１工程） 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-(2-ヒドロキシエトキシイミノ)-2-ブチン-1-イル)キナゾリン ( VIII-33)の合成
4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-オキソ-2-ブチン-1-イル)キナゾリン( VII-4，10g)を1,4-ジオキサン300mlに溶解させ、1.5当量の2-(アセトキシ)エトキシアミンを加えた後、2mol/Lメタンスルホン酸水溶液28mlを加えて60℃で17時間攪拌した。反応液を飽和炭酸水素ナトリウム水溶液に注ぎ、混合液を酢酸エチルで抽出した。有機層を水洗後、硫酸ナトリウム上で乾燥した。ろ液を濃縮した残渣を含水エタノール-水より再結晶後、ろ取、乾燥することにより4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-(2-ヒドロキシエトキシイミノ)-2-ブチン-1-イル)キナゾリン( VIII-33，7.6g)を無色固体として得た。
¹H NMR(d₆-DMSO，δ): 10.07(1H, s), 8.74(1H, s), 8.58(1H, s), 8.22(1H, d, J=8.8Hz), 7.96(1H, d, J=2.4Hz), 7.80(1H, d, J=8.8Hz), 7.69(1H, dd, J=2.4Hz, J=8.8Hz), 7.50-7.45(1H, m), 7.35-7.24(3H, m), 7.20-7.16(1H, m), 5.27(2H, s), 4.79(1H, t. J=5.6Hz), 4.29(2H, t. J=5.6Hz), 3.75(2H, dd, J=5.2Hz, J=10.4Hz), 2.26(3H, s).

（第２工程） 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-(2-スルホニルオキシエトキシイミノ)-2-ブチン-1-イル)キナゾリン( VIII-34)の合成
4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-(2-ヒドロキシエトキシイミノ)-2-ブチン-1-イル)キナゾリン( VIII-33，7.6g)をテトラヒドロフラン150mlに溶かし、トリエチルアミン4.19mlと塩化メタンスルホニル2.33mlを加え3.5時間攪拌した。反応終了後に反応液を水に注ぎ、飽和炭酸水素ナトリウム水溶液を加えて、酢酸エチルで抽出した。有機層を硫酸ナトリウム上で乾燥し、ろ液を濃縮した。濃縮残渣に酢酸エチルを加え室温で静置すると結晶が析出したのでヘキサンで希釈後、結晶をろ取することによ4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-(2-スルホニルオキシエトキシイミノ)-2-ブチン-1-イル)キナゾリン( VIII-34，7.66g)を淡黄色結晶として得た。
¹H NMR(d₆-DMSO，δ): 10.07(1H, s), 8.77(1H, s), 8.60(1H, s), 8.24(1H, d, J=8.8Hz), 7.97(1H, d, J=2.4Hz), 7.81(1H, d, J=8.8Hz), 7.69(1H, dd, J=2.4Hz, J=8.8Hz), 7.51-7.45(1H, m), 7.35-7.27(3H, m), 7.21-7.17(1H, m), 5.27(2H, s), 4.58(2H, t. J=4.8Hz), 4.54(2H, t. J=4.8Hz), 3.24(3H, s), 2.27(3H, s).

4-(3-クロロ-4-(ピリジン-2-イルメトキシ)フェニルアミノ)-6-(1-(2-スルホニルオキシエトキシイミノ)-2-ブチン-1-イル)キナゾリン( VIII-36)
第１工程および第２工程と同様の方法で合成した。
¹H NMR(d₆-DMSO，δ): 10.09(1H, s), 8.77(1H, s), 8.61(1H, s), 8.59(1H, s), 8.24(1H, d, J=8.1Hz), 7.97(1H, d, J=2.4Hz), 7.89(1H, t, J=7.5Hz), 7.81(1H, d, J=9.0Hz), 7.68(1H, dd, J=2.4Hz, J=9.0Hz), 7.59(1H, d, J=8.1Hz), 7.40-7.35(1H, m), 7.29(1H, d, J=9.0Hz), 5.31(2H, s), 4.57(2H, bs), 4.55(2H, bs), 3.24(3H, s), 2.27(3H, s).

4-(1-(3-フルオロベンジル)-1H-インダゾール-5-イルアミノ)-6-(1-(2-スルホニルオキシエトキシイミノ)-2-ブチン-1-イル)キナゾリン( VIII-37)
第１工程および第２工程と同様の方法で合成した。
¹H NMR(d₆-DMSO，δ): 10.20(1H, s), 8.81(1H, s), 8.53(1H, s), 8.24(1H, d, J=8.7Hz), 8.17(1H, s), 8.13(1H, s), 7.80(1H, d, J=8.7Hz), 7.75(1H, d, J=8.7Hz), 7.67(1H, d, J=9.3Hz), 7.41-7.36(1H, m), 7.14-7.04(3H, m), 5.72(2H, s), 4.58(2H, t. J=5.4Hz), 4.54(2H, t. J=5.4Hz), 3.24(3H, s), 2.26(3H, s).
（第３工程） 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-(2-エチルアミノエトキシイミノ)-2-ブチン-1-イル)キナゾリン( VIII-35)の合成
4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-(2-スルホニルオキシエトキシイミノ)-2-ブチン-1-イル)キナゾリン( VIII-34，100mg)をN,N-ジメチルホルムアミド3mlに溶解し、70％エチルアミン水溶液を160μl加え、60℃で14時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウム上で乾燥し、ろ液の濃縮残渣をアミノカラムを用いたクロマトグラフィー(酢酸エチルで溶出)により精製することにより4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(1-(2-エチルアミノエトキシイミノ)-2-ブチン-1-イル)キナゾリン( VIII-35，53mg)を無色固体として得た。
¹H NMR(d₆-DMSO，δ): 10.08(1H, s), 8.74(1H, s), 8.59(1H, s), 8.21(1H, d, J=8.4Hz), 7.96(1H, s), 7.80(1H, d, J=8.8Hz), 7.69(1H, d, J=8.0Hz), 7.51-7.45(1H, m), 7.35-7.27(3H, m), 7.21-7.16(1H, m), 5.27(2H, s), 4.31(2H, t. J=5.6Hz), 2.89(2H, t, J=6.0Hz), 2.61(2H, q, J=7.2Hz), 2.26(3H, s), 1.02(3H, t, J=7.6Hz).

第３工程のアミノ化では市販品として入手可能であるアミンまたはJ. Syn. Org. Chem., Jpn., 2001, 59 : 779 -789.、Tetrahedron Lett., 1995, 36 : 6373-6374.、Synlett, 1999 : 1301-1303.、Tetrahedron, 2002, 58 : 6267-6276.に記載の方法に従って合成できるアミンまたはその塩を使用できる。

実施例１０

（第１工程） 4-(3-クロロ-4-ヒドロキシフェニルアミノ)-6-ヨードキナゾリン ( III - 4 )の合成
4-クロロ-6-ヨードキナゾリン20.3gおよび3-クロロ-4-ヒドロキシアニリン10gを出発原料として実施例１の第１工程と同様にして4-(3-クロロ-4-ヒドロキシフェニルアミノ)-6-ヨードキナゾリン塩酸塩( III - 4，26.6g)を黄色固体として得た。
¹H NMR(d₆-DMSO，δ): 11.4(1H, s), 10.5(1H, s), 9.21(1H, s), 8.93(1H, s), 8.35(1H, d, J=8.4Hz), 7.79(1H, s), 7.69(1H, d, J=9.0Hz), 7.48(1H, d, J=9.0Hz), 7.10(1H, d, J=8.4Hz).

（第２工程） 4-(3-クロロ-4-トリイソプロピルシリルオキシフェニルアミノ)-6-ヨードキナゾリン ( III - 5 )の合成
4-(3-クロロ-4-ヒドロキシフェニルアミノ)-6-ヨードキナゾリン塩酸塩( III-4，20g)、塩化トリイソプロピルシラン13.3g、イミダゾール12.6gをN,N-ジメチルホルムアミド200mlに溶解させ、室温で4時間撹拌した。反応終了後、飽和炭酸水素ナトリウム水溶液200mlおよび酢酸エチル200mlを加えて分液操作を行った。水層を酢酸エチル200mlで再抽出を2回繰り返した後、すべての有機層を合わせて水、飽和食塩水の順で洗浄し、無水硫酸マグネシウム上で乾燥した。ろ液を濃縮後、残渣をヘキサン-酢酸エチル混合液（２：１）で洗浄することにより4-(3-クロロ-4-トリイソプロピルシリルオキシフェニルアミノ)-6-ヨードキナゾリン ( III-5，25.3g)を無色固体として得た。
¹H NMR(d₆-DMSO，δ ): 9.8(1H, s), 8.96(1H, s), 8.62(1H, s), 8.12(1H, d, J=8.7Hz), 8.02(1H, d, J=2.7Hz), 7.70(1H, dd, J=8.7Hz, J=2.7Hz), 7.56(1H, d, J=8.7Hz), 7.04(1H, d, J=8.7Hz), 1.25-1.40(3H, m), 1.11(18H, d, J=7.2Hz).
（第３工程） 4-(3-クロロ-4-トリイソプロピルシリルオキシフェニルアミノ)-キナゾリン-6-カルボン酸メチルエステル (X-2 )の合成
4-(3-クロロ-4-トリイソプロピルシリルオキシフェニルアミノ)-6-ヨードキナゾリン( I II-5，21.8g)より参考例１の第１工程と同様にして4-(3-クロロ-4-トリイソプロピルシリルオキシフェニルアミノ)-キナゾリン-6-カルボン酸メチルエステル(X- 2，20.4g)を黄色固体として得た。
¹H NMR(d₆-DMSO，δ ): 10.2(1H, s), 9.26(1H, s), 8.66(1H, s), 8.30(1H, d, J=8.7Hz), 8.01(1H, d, J=2.4Hz), 7.84(1H, d, J=8.7Hz), 7.71(1H, dd, J=9Hz, J=2.1Hz), 7.04(1H, d, J=8.7Hz), 3.96(3H, s), 1.29-1.41(3H, m), 1.11(18H, d, J=7.2Hz).
（第４工程） 4-(3-クロロ-4-トリイソプロピルシリルオキシフェニルアミノ)-キナゾリン-6-カルボン酸メトキシメチルアミド (X I - 4 )の合成
4-(3-クロロ-4-トリイソプロピルシリルオキシフェニルアミノ)-キナゾリン-6-カルボン酸メチルエステル(X- 2，10g)より参考例１の第２工程と同様にして4-(3-クロロ-4-トリイソプロピルシリルオキシフェニルアミノ)-キナゾリン-6-カルボン酸メトキシメチルアミド(X I - 4，4.1g)を無色固体として得た。
¹H NMR(d₆-DMSO，δ ): 10.0(1H, s), 8.80(1H, s), 8.65(1H, s), 7.97-8.08(2H, m), 7.81(1H, d, J=8.7Hz), 7.70-7.75(1H, m), 7.04(1H, d, J=9.0Hz), 3.58(3H, s), 3.35(3H, s), 1.29-1.41(3H, m), 1.11(18H, d, J=7.5Hz).
（第５工程） 4-(3-クロロ-4-トリイソプロピルシリルオキシフェニルアミノ)-6-(1-オキソ-2-ブチン-1-イル)キナゾリン( VII - 20 )の合成
4-(3-クロロ-4-トリイソプロピルシリルオキシフェニルアミノ)-キナゾリン-6-カルボン酸メトキシメチルアミド(X I - 4，4.1g)より参考例１の第３工程と同様にして4-(3-クロロ-4-トリイソプロピルシリルオキシフェニルアミノ)-6-(1-オキソ-2-ブチン-1-イル)キナゾリン( VII - 20，1.3g)を黄色油状物として得た。
¹H NMR(d₆-DMSO，δ ): 10.3(1H, s), 9.24(1H, s), 8.67(1H, s), 8.45(1H, d, J=8.7Hz), 7.99(1H, s), 7.88(1H, s, J=8.7Hz), 7.68(1H, d, J=9.0Hz), 7.06(1H, d, J=9.0Hz), 2.28(3H, s), 1.29-1.41(3H, m), 1.11(18H, d, J=6.9Hz).
（第６工程） 4-(3-クロロ-4-トリイソプロピルシリルオキシフェニルアミノ)-6-(1-(2-(N-(tert-ブトキシカルボニル)-N-メチルアミノエトキシイミノ)-2-ブチン-1-イル)キナゾリン( VIII- 201 )の合成
4-(3-クロロ-4-トリイソプロピルシリルオキシフェニルアミノ)-6-(1-オキソ-2-ブチン-1-イル)キナゾリン( VII - 20，1.3g)より実施例２の第２工程と同様にして4-(3-クロロ-4-トリイソプロピルシリルオキシフェニルアミノ)-6-(1-(2-(N-(tert-ブトキシカルボニル)-N-メチルアミノエトキシイミノ)-2-ブチン-1-イル)キナゾリン( VIII- 201，1.1g)を黄色固体として得た。
ESI-MS(m/z): (M+)=666.71, (M+H)=667.73
（第７工程） 4-(3-クロロ-4-ヒドロキシフェニルアミノ)-6-(1-(2-(N-(tert-ブトキシカルボニル)-N-メチルアミノエトキシイミノ)-2-ブチン-1-イル)キナゾリン( VIII- 202 )の合成
4-(3-クロロ-4-トリイソプロピルシリルオキシフェニルアミノ)-6-(1-(2-(N-(tert-ブトキシカルボニル)-N-メチルアミノエトキシイミノ)-2-ブチン-1-イル)キナゾリン( VIII- 201，1.1g)をテトラヒドロフラン20mlに溶解させ、1mol/Lフッ化テトラブチルアンモニウムテトラヒドロフラン溶液を6.7ml加え室温で30分撹拌した。反応終了後、水10mlおよび酢酸エチル10mlを加えて分液操作を行った。水層を酢酸エチル10mlで再抽出を2回繰り返した後、すべての有機層を合わせて水、飽和食塩水の順で洗浄し、無水硫酸マグネシウム上で乾燥した。ろ液を濃縮後、残渣をヘキサン-酢酸エチル混合液（１：１）で洗浄することにより4-(3-クロロ-4-ヒドロキシフェニルアミノ)-6-(1-(2-(N-(tert-ブトキシカルボニル)-N-メチルアミノエトキシイミノ)-2-ブチン-1-イル)キナゾリン ( VIII- 202，0.7g)を黄色固体として得た。
¹H NMR(d₆-DMSO，δ ): 9.96(1H, s), 8.73(1H, s), 8.55(1H, s), 8.21(1H, d, J=8.7Hz), 7.75-7.86(2H, m), 7.50(1H, d, J=7.8Hz), 7.00(1H, d, J=8.7Hz), 4.36(2H, bs), 3.56(2H, bs), 2.86(3H, bs), 2.25(3H, bs), 1.36(9H, s).
（第８工程） 4-(3-クロロ-4-(ピリジン-3-イルメトキシ)フェニルアミノ)-6-(1-(2-(N-(tert-ブトキシカルボニル)-N-メチルアミノエトキシイミノ)-2-ブチン-1-イル)キナゾリン( VIII- 203 )の合成
4-(3-クロロ-4-ヒドロキシフェニルアミノ)-6-(1-(2-(N-(tert-ブトキシカルボニル)-N-メチルアミノエトキシイミノ)-2-ブチン- 1-イル)キナゾリン ( VIII- 202，70mg)、3-ブロモメチルピリジン臭化水素酸塩87mg、炭酸セシウム223mgをN,N-ジメチルホルムアミド-水混合液（１０：１）1.1ｍｌに溶解させ、室温で3時間撹拌させた。反応終了後、水5mlおよび酢酸エチル5mlを加えて分液操作を行った。水層を酢酸エチル5mlで再抽出を2回繰り返した後、すべての有機層を合わせて水、飽和食塩水の順で洗浄し、無水硫酸マグネシウム上で乾燥した。ろ液を濃縮後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１で溶出）で精製することにより4-(3-クロロ-4-(ピリジン-3-イルメトキシ)フェニルアミノ)-6-(1-(2-(N-(tert-ブトキシカルボニル)-N-メチルアミノエトキシイミノ)-2-ブチン-1-イル)キナゾリン ( VIII- 203，70mg)を黄色油状物として得た。
¹H NMR(d₆-DMSO，δ ): 10.0(1H, bs), 8.74(1H, bs), 8.72(1H, bs), 8.60(1H, s), 8.57(1H, d, J=4.4Hz), 8.23(1H, d, J=8.8Hz), 7.97(1H, bs), 7.91(1H, d, J=8.0Hz), 7.80(1H, d, J=8.8Hz), 7.72(1H, d, J=8.8Hz), 7.46(1H, dd, J=7.6Hz, J=4.4Hz), 7.33(1H, d, J=8.8Hz), 5.29(2H, s), 4.37(2H, bs), 3.56(2H, bs), 2.86(3H, bs), 2.25(3H, bs), 1.36(9H, s).
（第９工程） 4-(3-クロロ-4-(ピリジン-3-イルメトキシ)フェニルアミノ)-6-(1-(2-N-メチルアミノエトキシイミノ)-2-ブチン-1-イル)キナゾリン( VIII- 204 )の合成
4-(3-クロロ-4-(ピリジン-3-イルメトキシ)フェニルアミノ)-6-(1-(2-(N-(tert-ブトキシカルボニル)-N-メチルアミノエトキシイミノ)-2-ブチン-1-イル)キナゾリン( VIII- 203，70mg)より実施例２の第２工程と同様にして反応させ、ヘキサン-酢酸エチルから再結晶で精製することにより4-(3-クロロ-4-(ピリジン-3-イルメトキシ)フェニルアミノ)-6-(1-(2-N-メチルアミノエトキシイミノ)-2-ブチン-1-イル)キナゾリン( VIII- 204，7mg)を黄色固体として得た。
10.3(1H, s), 8.84(1H, s), 8.72(1H, s), 8.42-8.65(2H, m), 8.26(1H, d, J=7.6Hz), 7.98(1H, s), 7.91(1H, brs), 7.81(1H, brs), 7.71(1H, brs), 7.47(1H, brs), 7.34(1H, d, J=8.0Hz), 5.30(2H, s), 4.53(2H, brs), 3.38(2H, brs), 2.68(3H, s), 2.26(3H, s).

実施例７〜１０と同様の方法で下記の化合物を合成した。

（式中、＊を付した原子は不斉炭素原子。）

実施例１１

（第１工程） 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(カルボキシメトキシイミノ)-2-ブチン-1-イル)キナゾリン (VIII-38)の合成
4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(メトキシカルボニルメトキシイミノ)-2-ブチン-1-イル)キナゾリン(VIII-43，1.2g)をテトラヒドロフラン12mlとメタノール12mlの混合液に溶解させ、1.5mlの2mol/L水酸化ナトリウム水溶液を加えて室温で1.5時間攪拌した。反応液を酢酸エチル20mlで希釈後、2mol/L塩酸を1.6ml加え、水を加えると目的物が析出した。析出物をろ取後、水、酢酸エチルで洗浄し乾燥することにより4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(カルボキシメトキシイミノ)-2-ブチン-1-イル)キナゾリン(VIII-38，0.9g)を黄色固体として得た。
¹H NMR(d₆-DMSO，δ): 10.18(1H, brs), 8.77(1H, s), 8.60(1H, s), 8.19(1H, dd, J=2.0, 11.6Hz), 7.95(1H, d, J=3.2Hz), 7.80(1H, d, J=11.6Hz), 7.67(1H, dd, J=3.2, 11.6Hz), 7.51-7.44(1H, m), 7.35-7.26(3H, m),7.22-7.15(1H, m), 5.27(2H, s), 4.83(2H, s), 2.27(3H, s).

（第２工程） 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-((2-ジメチルアミノエチルカルバモイル)メトキシイミノ)-2-ブチン-1-イル)キナゾリン (VIII-39)の合成
4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(カルボキシメトキシイミノ)-2-ブチン-1-イル)キナゾリン(VIII-38，70mg)、1-ヒドロキシベンゾトリアゾール24mg、1-エチル3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩27mgをN,N-ジメチルホルムアミド1.4mlに溶かし、室温で5分攪拌後、N,N-ジメチルエチレンジアミン22μlを加え室温で2時間攪拌した。反応終了後に酢酸エチルで希釈し、水と飽和炭酸水素ナトリウム水溶液を加えて、分液操作を行った。有機層を水洗後、硫酸ナトリウム上で乾燥し、ろ液を濃縮した。濃縮残渣に酢酸エチルを加えて固体化させ、固体をろ取、乾燥することにより4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-((2-ジメチルアミノエチルカルバモイル)メトキシイミノ)-2-ブチン- 1-イル)キナゾリン(VIII-39，30mg)を無色結晶として得た。
¹H NMR(d₆-DMSO，δ ): 10.12(1H, s), 8.77(1H, s), 8.59(1H, s), 8.19(1H, dd, J=2.0, 12.0Hz), 8.08(1H, brs), 7.95(1H, d, J=3.2Hz), 7.80(1H, d, J=11.6Hz), 7.70-7.62(2H, m),7.51-7.44(1H, m), 7.34-7.26(3H, m), 7.21-7.15(1H, s), 5.27(2H, s), 4.69(2H, s), 3.22(2H, dd, J=8.4, 16.0Hz) 2.31(1H, t, J=8.4Hz), 2.28(3H, s), 2.11(6H, s).
実施例１１と同様の方法で下記の化合物を合成した。

実施例１２

(第1工程) 4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(ピロリジン-1-イルイミノメチル)キナゾリン(IX-1)の合成
4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-ホルミルキナゾリン(IV-1) 40mgと1-アミノ-ピロリジン塩酸塩 13mgをテトラヒドロフラン1mL、水0.1mLの混液に溶かし、室温で終夜反応した。反応後、飽和炭酸水素ナトリウム水溶液を加え酢酸エチルで抽出した。有機層をプレセップ（登録商標）を通して脱水し、ろ液を濃縮した。濃縮残渣を、アミノカラムを用いたクロマトグラフィー(ヘキサン：酢酸エチル=２：１→１：１で溶出)により精製し、4-(3-クロロ-4-(3-フルオロベンジルオキシ)フェニルアミノ)-6-(ピロリジン-1-イルイミノ) メチルキナゾリン(IX-1)38mgを黄色固体として得た。
¹H NMR(d₆-DMSO, d ): 9.76(1H, s), 8.52(1H, s), 8.40(1H, brs), 8.08(1H, d, J=6.6Hz), 8.06(1H, d, J=1.8Hz), 7.76(1H, dd, J=6.6Hz, J=1.8Hz), 7.69(1H, dd, J=6.6Hz), 7.50-7.45(1H, m), 7.35-7.26(3H, m), 7.19(1H, t, J=6.6Hz), 5.26(2H, s), 3.39(4H, br), 1.94(4H, br)

上記実施例１２と同様の方法で下記の化合物を合成した。

上記実施例と同様の方法によって以下に示す化合物を合成することができる。すなわち、以下の一般式（Ａ）：

で表される化合物において、Ｒ^Ａが以下のａ１〜ａ９０：

（式中、Ｍｅはメチル）から選択される基、
Ｒ^Bが以下のｂ１〜ｂ６：

（式中、Ｍｅはメチル）から選択される基、
Ｒ^Ｃが以下のｃ１〜ｃ３：

から選択される基、
Ｒ^Ｄが以下のｄ１〜ｄ２２：

（式中、Ｍｅはメチル）
から選択される基の組み合わせで表される、以下の化合物を合成することができる。

(a1, b1, c1, d1), (a1, b1, c1, d2), (a1, b1, c1, d3), (a1, b1, c1, d4), (a1, b1, c1, d5), (a1, b1, c1, d6), (a1, b1, c1, d7), (a1, b1, c1, d8), (a1, b1, c1, d9), (a1, b1, c1, d10), (a1, b1, c1, d11), (a1, b1, c1, d12), (a1, b1, c1, d13), (a1, b1, c1, d14), (a1, b1, c1, d15), (a1, b1, c1, d16), (a1, b1, c1, d17), (a1, b1, c1, d18), (a1, b1, c1, d19), (a1, b1, c1, d20), (a1, b1, c1, d 21), (a1, b1, c1, d22), (a1, b1, c2, d1), (a1, b1, c2, d2), (a1, b1, c2, d3), (a1, b1, c2, d4), (a1, b1, c2, d5), (a1, b1, c2, d6), (a1, b1, c2, d7), (a1, b1, c2, d8), (a1, b1, c2, d9), (a1, b1, c2, d10), (a1, b1, c2, d11), (a1, b1, c2, d12), (a1, b1, c2, d13), (a1, b1, c2, d14), (a1, b1, c2, d15), (a1, b1, c2, d16), (a1, b1, c2, d17), (a1, b1, c2, d18), (a1, b1, c2, d19), (a1, b1, c2, d20), (a1, b1, c2, d21), (a1, b1, c2, d22), (a1, b1, c3, d1), (a1, b1, c3, d2), (a1, b1, c3, d3), (a1, b1, c3, d4), (a1, b1 , c3, d5), (a1, b1, c3, d6), (a1, b1, c3, d7), (a1, b1, c3, d8), (a1, b1, c3, d9), (a1, b1, c3, d10), (a1, b1, c3, d11), (a1, b1, c3, d12), (a1, b1, c3, d13), (a1, b1, c3, d14), (a1, b1, c3, d15), (a1, b1, c3, d16), (a1, b1, c3, d17), (a1, b1, c3, d18), (a 1, b1, c3, d19), (a1, b1, c3, d20), (a1, b1, c3, d21), (a1, b1, c3, d22), (a1, b2, c1, d1), (a1, b2, c1, d2), (a1, b2, c1, d3), (a1, b2, c1, d4), (a1, b2, c1, d5), (a1, b2, c1, d6), (a1, b2, c1, d7), (a1, b2, c1, d8), (a1, b2, c1, d9), (a1, b2, c1, d10), ( a1, b2, c1, d11), (a1, b2, c1, d12), (a1, b2, c1, d13), (a1, b2, c1, d14), (a1, b2, c1, d15), (a1, b2, c1, d16), (a1, b2, c1, d17), (a1, b2, c1, d18), (a1, b2, c1, d19), (a1, b2, c1, d20), (a1, b2, c1, d21), (a1, b2, c1, d22), (a1, b2, c2, d1), (a1, b2, c2 , d2), (a1, b2, c2, d3), (a1, b2, c2, d4), (a1, b2, c2, d5), (a1, b2, c2, d6), (a1, b2, c2, d7), (a1, b2, c2, d8), (a1, b2, c2, d9), (a1, b2, c2, d10), (a1, b2, c2, d11), (a1, b2, c2, d12), (a1, b2, c2, d13), (a1, b2, c2, d14), (a1, b2, c2, d15), (a1, b2, c2, d16), (a1, b2, c2, d17), (a1, b2, c2, d18), (a1, b2, c2, d19), (a1, b2, c2, d20), (a1, b2, c2, d21), (a1, b2, c2, d22), (a1, b2, c3, d1), (a1, b2, c3, d2), (a1, b2, c3, d3), (a1, b2, c3, d4), (a1, b2, c3, d5), (a1, b2, c3, d6), (a1, b2, c3, d7), (a1, b 2, c3, d8), (a1, b2, c3, d9), (a1, b2, c3, d10), (a1, b2, c3, d11), (a1, b2, c3, d12), (a1, b2, c3, d13), (a1, b2, c3, d14), (a1, b2, c3, d15), (a1, b2, c3, d16), (a1, b2, c3, d17), (a1, b2, c3, d18), (a1, b2, c3, d19), (a1, b2, c3, d20), (a1, b2, c3, d21) , (a1, b2, c3, d22), (a1, b3, c1, d1), (a1, b3, c1, d2), (a1, b3, c1, d3), (a1, b3, c1, d4), (a1, b3, c1, d5), (a1, b3, c1, d6), (a1, b3, c1, d7), (a1, b3, c1, d8), (a1, b3, c1, d9), (a1, b3, c1, d10), (a1, b3, c1, d11), (a1, b3, c1, d12), (a1, b3, c1, d13 ), (a1, b3, c1, d14), (a1, b3, c1, d15), (a1, b3, c1, d16), (a1, b3, c1, d17), (a1, b3, c1, d18), (a1, b3, c1, d19), (a1, b3, c1, d20), (a1, b3, c1, d21), (a1, b3, c1, d22), (a1, b3, c2, d1), (a1, b3, c2, d2), (a1, b3, c2, d3), (a1, b3, c2, d4), (a1, b3, c 2, d5), (a1, b3, c2, d6), (a1, b3, c2, d7), (a1, b3, c2, d8), (a1, b3, c2, d9), (a1, b3, c2, d10), (a1, b3, c2, d11), (a1, b3, c2, d12), (a1, b3, c2, d13), (a1, b3, c2, d14), (a1, b3, c2, d15), (a1, b3, c2, d16), (a1, b3, c2, d17), (a1, b3, c2, d18), (a1, b3, c2, d19), (a1, b3, c2, d20), (a1, b3, c2, d21), (a1, b3, c2, d22), (a1, b3, c3, d1), (a1, b3, c3, d2), (a1, b3, c3, d3), (a1, b3, c3, d4), (a1, b3, c3, d5), (a1, b3, c3, d6), (a1, b3, c3, d7), (a1, b3, c3, d8), (a1, b3, c3, d9), (a1, b3, c3, d10), (a1, b3, c3, d11), (a1, b3, c3, d12), (a1, b3, c3, d13), (a1, b3, c3, d14), (a1, b3, c3, d15), (a1, b3, c3, d16), (a1, b3, c3, d17), (a1, b3, c3, d18), (a1, b3, c3, d19), (a1, b3, c3, d20), (a1, b3, c3, d21), (a1, b3, c3, d22), (a1, b4, c1, d1), (a1, b4, c1, d 2), (a1, b4, c1, d3), (a1, b4, c1, d4), (a1, b4, c1, d5), (a1, b4, c1, d6), (a1, b4, c1, d7), (a1, b4, c1, d8), (a1, b4, c1, d9), (a1, b4, c1, d10), (a1, b4, c1, d11), (a1, b4, c1, d12), (a1, b4, c1, d13), (a1, b4, c1, d14), (a1, b4, c1, d15), (a1, b4, c1, d16), (a1, b4, c1, d17), (a1, b4, c1, d18), (a1, b4, c1, d19), (a1, b4, c1, d20), (a1, b4, c1, d21), (a1, b4, c1, d22), (a1, b4, c2, d1), (a1, b4, c2, d2), (a1, b4, c2, d3), (a1, b4, c2, d4), (a1, b4, c2, d5), (a1, b4, c2, d6), (a1, b4, c2, d7), (a1, b4, c2, d8), (a1, b4, c2, d9), (a1, b4, c2, d10), (a1, b4, c2, d11), (a1, b4, c2, d12), (a1, b4, c2, d13), (a1, b4, c2, d14), (a1, b4, c2, d15), (a1, b4, c2, d16), (a1, b4, c2, d17), (a1, b4, c2, d18), (a1, b4, c2, d19), (a1, b4, c2, d20), (a1, b4, c2, d21), ( a1, b4, c2, d22), (a1, b4, c3, d1), (a1, b4, c3, d2), (a1, b4, c3, d3), (a1, b4, c3, d4), (a1, b4, c3, d5), (a1, b4, c3, d6), (a1, b4, c3, d7), (a1, b4, c3, d8), (a1, b4, c3, d9), (a1, b4, c3, d10), (a1, b4, c3, d11), (a1, b4, c3, d12), (a1, b4, c3, d13), (a1, b4, c3, d14), (a1, b4, c3, d15), (a1, b4, c3, d16), (a1, b4, c3, d17), (a1, b4, c3, d18), (a1, b4, c3, d19), (a1, b4, c3, d20), (a1, b4, c3, d21), (a1, b4, c3, d22), (a1, b5, c1, d1), (a1, b5, c1, d2), (a1, b5, c1, d3), (a1, b5, c1, d4), (a1, b5, c1, d5), (a1, b5, c1, d6), (a1, b5, c1, d7), (a1, b5, c1, d8), (a1, b5, c1, d9), (a1, b5, c1, d10), (a1, b5, c1, d11), (a1, b5, c1, d12), (a1, b5, c1, d13), (a1, b5, c1, d14), (a1, b5, c1, d15), (a1, b5, c1, d16), (a1, b5, c1, d17), (a1, b5, c1, d18), (a1, b5, c1, d19), (a1, b5, c1, d20), (a1, b5, c1, d21), (a1, b5, c1, d22), (a1, b5, c2, d1), (a1, b5, c2, d2), (a1, b5, c2, d3), (a1, b5, c2, d4), (a1, b5, c2, d5), (a1, b5, c2, d6), (a1, b5, c2, d7), (a1, b5, c2, d8), (a1, b5, c2, d9), (a1, b5, c2, d10), (a1, b5 , c2, d11), (a1, b5, c2, d12), (a1, b5, c2, d13), (a1, b5, c2, d14), (a1, b5, c2, d15), (a1, b5, c2, d16), (a1, b5, c2, d17), (a1, b5, c2, d18), (a1, b5, c2, d19), (a1, b5, c2, d20), (a1, b5, c2, d21), (a1, b5, c2, d22), (a1, b5, c3, d1), (a1, b5, c3, d2), (a1, b5, c3, d3), (a1, b5, c3, d4), (a1, b5, c3, d5), (a1, b5, c3, d6), (a1, b5, c3, d7), (a1, b5, c3, d8), (a1, b5, c3, d9), (a1, b5, c3, d10), (a1, b5, c3, d11), (a1, b5, c3, d12), (a1, b5, c3, d13), (a1, b5, c3, d14), (a1, b5, c3, d15), (a1, b5, c3, d1 6), (a1, b5, c3, d17), (a1, b5, c3, d18), (a1, b5, c3, d19), (a1, b5, c3, d20), (a1, b5, c3, d21), (a1, b5, c3, d22), (a1, b6, c1, d1), (a1, b6, c1, d2), (a1, b6, c1, d3), (a1, b6, c1, d4), (a1, b6, c1, d5), (a1, b6, c1, d6), (a1, b6, c1, d7), (a1, b6, c1, d8), (a1, b6, c1, d9), (a1, b6, c1, d10), (a1, b6, c1, d11), (a1, b6, c1, d12), (a1, b6, c1, d13), (a1, b6, c1, d14), (a1, b6, c1, d15), (a1, b6, c1, d16), (a1, b6, c1, d17), (a1, b6, c1, d18), (a1, b6, c1, d19), (a1, b6, c1, d20), (a1, b6, c1, d21), (a1, b6, c1, d22), (a1, b6, c2, d1), (a1, b6, c2, d2), (a1, b6, c2, d3), (a1, b6, c2, d4), (a1, b6, c2, d5), (a1, b6, c2, d6), (a1, b6, c2, d7), (a1, b6, c2, d8), (a1, b6, c2, d9), (a1, b6, c2, d10), (a1, b6, c2, d11), (a1, b6, c2, d12), (a1, b6, c2, d13), (a1 , b6, c2, d14), (a1, b6, c2, d15), (a1, b6, c2, d16), (a1, b6, c2, d17), (a1, b6, c2, d18), (a1, b6, c2, d19), (a1, b6, c2, d20), (a1, b6, c2, d21), (a1, b6, c2, d22), (a1, b6, c3, d1), (a1, b6, c3, d2), (a1, b6, c3, d3), (a1, b6, c3, d4), (a1, b6, c3, d5) , (a1, b6, c3, d6), (a1, b6, c3, d7), (a1, b6, c3, d8), (a1, b6, c3, d9), (a1, b6, c3, d10), (a1, b6, c3, d11), (a1, b6, c3, d12), (a1, b6, c3, d13), (a1, b6, c3, d14), (a1, b6, c3, d15), (a1, b6, c3, d16), (a1, b6, c3, d17), (a1, b6, c3, d18), (a1, b6, c3 , d19), (a1, b6, c3, d20), (a1, b6, c3, d21), (a1, b6, c3, d22), (a2, b1, c1, d1), (a2, b1, c1, d2), (a2, b1, c1, d3), (a2, b1, c1, d4), (a2, b1, c1, d5), (a2, b1, c1, d6), (a2, b1, c1, d7), (a2, b1, c1, d8), (a2, b1, c1, d9), (a2, b1, c1, d10), (a2, b1, c 1, d11), (a2, b1, c1, d12), (a2, b1, c1, d13), (a2, b1, c1, d14), (a2, b1, c1, d15), (a2, b1, c1, d16), (a2, b1, c1, d17), (a2, b1, c1, d18), (a2, b1, c1, d19), (a2, b1, c1, d20), (a2, b1, c1, d21), (a2, b1, c1, d22), (a2, b1, c2, d1), (a2, b1, c2, d2), (a 2, b1, c2, d3), (a2, b1, c2, d4), (a2, b1, c2, d5), (a2, b1, c2, d6), (a2, b1, c2, d7), (a2, b1, c2, d8), (a2, b1, c2, d9), (a2, b1, c2, d10), (a2, b1, c2, d11), (a2, b1, 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a7, b6, c2, d19), (a7, b6, c2, d20), (a7, b6, c2, d21), (a7, b6, c2, d22), (a7, b6, c3, d1), (a7, b6, c3, d2), (a7, b6, c3, d3), (a7, b6, c3, d4), (a7, b6, c3, d5), (a7, b6, c3, d6), (a7, b6, c3, d7), (a7, b6, c3, d8), (a7, b6, c3, d9), (a7, b6, c3, d10), (a7, b6, c3, d11), (a7, b6, c3, d12), (a7, b6, c3, d13), (a7, b6, c3, d14), (a7, b6, c3, d15), (a7, b6, c3, d16), (a7, b6, c3, d17), (a7, b6, c3, d18), (a7, b6, c3, d19), (a7, b6, c3, d20), (a7, b6, c3, d21), (a7, b6, c3, d22), (a8, b1, c1, d1), (a8, b1, c1, d2), (a8, b1, c1, d3 ), (a8, b1, c1, d4), (a8, b1, c1, d5), (a8, b1, c1, d6), (a8, b1, c1, d7), (a8, b1, c1, d8), (a8, b1, c1, d9), (a8, b1, c1, d10), (a8, b1, c1, d11), (a8, b1, c1, d12), (a8, b1, c1, d13), (a8, b1, c1, d14), (a8, b1, c1, d15), (a8, b1, c1, d16), (a8, b1, c1, d17), (a8, b1, c1, d18), (a8, b1, c1, d19), (a8, b1, c1, d20), (a8, b1, c1, d21), (a8, b1, c1, d22), (a8, b1, c2, d1), (a8, b1, c2, d2), (a8, b1, c2, d3), (a8, b1, c2, d4), (a8, b1, c2, d5), (a8, b1, c2, 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d12), (a18, b5, c1, d13), (a18, b5, c1, d1 4), (a18, b5, c1, d15), (a18, b5, c1, d16), (a18, b5, c1, d17), (a18, b5, c1, d18), (a18, b5, c1, d19), (a18, b5, c1, d20), (a18, b5, c1, d21), (a18, b5, c1, d22), (a18, b5, c2, d1), (a18, b5, c2, d2), (a18, b5, c2, d3), (a18, b5, c2, d4), (a18, b5, c2, d5 ), (a18, b5, c2, d6), (a18, b5, c2, d7), (a18, b5, c2, d8), (a18, b5, c2, d9), (a18, b5, c2, d10), (a18, b5, c2, d11), (a18, b5, c2, d12), (a18, b5, c2, d13), (a18, b5, c2, d14), (a18, b5, c2, d15), (a18, b5, c2, d16), (a18, b5, c2, d17), (a18, b5, c2, d18 ), (a18, b5, c2, d19), (a18, b5, c2, d20), (a18, b5, c2, d21), (a18, b5, c2, d22), (a18, b5, c3, d1), (a18, b5, c3, d2), (a18, b5, c3, d3), (a18, b5, c3, d4), (a18, b5, c3, d5), (a18, b5, c3, d6), (a18, b5, c3, d7), (a18, b5, c3, d8), (a18, b5, c3, d9), (a 18, b5, c3, d10), (a18, b5, c3, d11), (a18, b5, c3, d12), (a18, b5, c3, d13), (a18, b5, c3, d14), (a18, b5, c3, d15), (a18, b5, c3, d16), (a18, b5, c3, d17), (a18, b5, c3, d18), (a18, b5, c3, d19), (a18, b5, c3, d20), (a18, b5, c3, d21), (a18, b5, c3, d22) , (a18, b6, c1, d1), (a18, b6, c1, d2), (a18, b6, c1, d3), (a18, b6, c1, d4), (a18, b6, c1, d5), (a18, b6, c1, d6), (a18, b6, c1, d7), (a18, b6, c1, d8), (a18, b6, c1, d9), (a18, b6, c1, d10), (a18, b6, c1, d11), (a18, b6, c1, d12), (a18, b6, c1, d13), (a1 8, b6, c1, d14), (a18, b6, c1, d15), (a18, b6, c1, d16), (a18, b6, c1, d17), (a18, b6, c1, d18), (a18, b6, c1, d19), (a18, b6, c1, d20), (a18, b6, c1, d21), (a18, b6, c1, d22), (a18, b6, c2, d1), (a18, b6, c2, d2), (a18, b6, c2, d3), (a18, b6, c2, d4), (a1 8, b6, c2, d5), (a18, b6, c2, d6), (a18, b6, c2, d7), (a18, b6, c2, d8), (a18, b6, c2, d9), (a18, b6, c2, d10), (a18, b6, c2, d11), (a18, b6, c2, d12), (a18, b6, c2, d13), (a18, b6, c2, d14), (a18, b6, c2, d15), (a18, b6, c2, d16), (a18, b6, c2, d17), (a18 , b6, c2, d18), (a18, b6, c2, d19), (a18, b6, c2, d20), (a18, b6, c2, d21), (a18, b6, c2, d22), (a18, b6, c3, d1), (a18, b6, c3, d2), (a18, b6, c3, d3), (a18, b6, c3, d4), (a18, b6, c3, d5), (a18, b6, c3, d6), (a18, b6, c3, d7), (a18, b6, c3, d8), (a18, b6 , c3, d9), (a18, b6, c3, d10), (a18, b6, c3, d11), (a18, b6, c3, d12), (a18, b6, c3, d13), (a18, b6, c3, d14), (a18, b6, c3, d15), (a18, b6, c3, d16), (a18, b6, c3, d17), (a18, b6, c3, d18), (a18, b6, c3, d19), (a18, b6, c3, d20), (a18, b6, c3, d21), (a18, b6, c3, d22), (a19, b1, c1, d1), (a19, b1, c1, d2), (a19, b1, c1, d3), (a19, b1, c1, d4), (a19, b1, c1, d5), (a19, b1, c1, d6), (a19, b1, c1, d7), (a19, b1, c1, d8), (a19, b1, c1, d9), (a19, b1, c1, d10), (a19, b1, c1, d11), (a19, b1, c1, d12), (a19, b1, c1, d13), (a19, b1, c1, d14), (a19, b1, c1, d15), (a19, b1, c1, d16), (a19, b1, c1, d17), (a19, b1, c1, d18), (a19, b1, c1, d19), (a19, b1, c1, d20), (a19, b1, c1, d21), (a19, b1, c1, d22), (a19, b1, c2, d1), (a19, b1, c2, d2), (a19, b1, c2, d3), (a19, b1, c2, d4), (a19, b1, c2, d5), (a19, b1, c2, d6), (a19, b1, c2, d7), (a19, b1, c2, d8), (a19, b1, c2, d9), (a19, b1, c2, d10), (a19, b1, c2, d11), (a19, b1, c2, d12), (a19, b1, c2, d13), (a19, b1, c2, d14), (a19, b1, c2, d15), (a19, b1, c2, d16), (a19, b1, c 2, d17), (a19, b1, c2, d18), (a19, b1, c2, d19), (a19, b1, c2, d20), (a19, b1, c2, d21), (a19, b1, c2, d22), (a19, b1, c3, d1), (a19, b1, c3, d2), (a19, b1, c3, d3), (a19, b1, c3, d4), (a19, b1, c3, d5), (a19, b1, c3, d6), (a19, b1, c3, d7), (a19, b1, c3, d8), (a19, b1, c3, d9), (a19, b1, c3, d10), (a19, b1, c3, d11), (a19, b1, c3, d12), (a19, b1, c3, d13), (a19, b1, c3, d14), (a19, b1, c3, d15), (a19, b1, c3, d16), (a19, b1, c3, d17), (a19, b1, c3, d18), (a19, b1, c3, d19), (a19, b1, c3, d20), (a19, b1, c3 , d21), (a19, b1, c3, d22), (a19, b2, c1, d1), (a19, b2, c1, d2), (a19, b2, c1, d3), (a19, b2, c1, d4), (a19, b2, c1, d5), (a19, b2, c1, d6), (a19, b2, c1, d7), (a19, b2, c1, d8), (a19, b2, c1, d9), (a19, b2, c1, d10), (a19, b2, c1, d11), (a19, b2, c1, d12 ), (a19, b2, c1, d13), (a19, b2, c1, d14), (a19, b2, c1, d15), (a19, b2, c1, d16), (a19, b2, c1, d17), (a19, b2, c1, d18), (a19, b2, c1, d19), (a19, b2, c1, d20), (a19, b2, c1, d21), (a19, b2, c1, d22), (a19, b2, c2, d1), (a19, b2, c2, d2), (a19, b2, c2, d 3), (a19, b2, c2, d4), (a19, b2, c2, d5), (a19, b2, c2, d6), (a19, b2, c2, d7), (a19, b2, c2, d8), (a19, b2, c2, d9), (a19, b2, c2, d10), (a19, b2, c2, d11), (a19, b2, c2, d12), (a19, b2, c2, d13), (a19, b2, c2, d14), (a19, b2, c2, d15), (a19, b2, c2, d16) , (a19, b2, c2, d17), (a19, b2, c2, d18), (a19, b2, c2, d19), (a19, b2, c2, d20), (a19, b2, c2, d21), (a19, b2, c2, d22), (a19, b2, c3, d1), (a19, b2, c3, d2), (a19, b2, c3, d3), (a19, b2, c3, d4), (a19, b2, c3, d5), (a19, b2, c3, d6), (a19, b2, c3, d7), ( a19, b2, c3, d8), (a19, b2, c3, d9), (a19, b2, c3, d10), (a19, b2, c3, d11), (a19, b2, c3, d12), (a19, b2, c3, d13), (a19, b2, c3, d14), (a19, b2, c3, d15), (a19, b2, c3, d16), (a19, b2, c3, d17), (a19, b2, c3, d18), (a19, b2, c3, d19), (a19, b2, c3, d20), (a19, b2, c3, d21), (a19, b2, c3, d22), (a19, b3, c1, d1), (a19, b3, c1, d2), (a19, b3, c1, d3), (a19, b3, c1, d4), (a19, b3, c1, d5), (a19, b3, c1, d6), (a19, b3, c1, d7), (a19, b3, c1, d8), (a19, b3, c1, d9), (a19, b3, c1, d10), (a19, b3, c1, d11), (a19 , b3, c1, d12), (a19, b3, c1, d13), (a19, b3, c1, d14), (a19, b3, c1, d15), (a19, b3, c1, d16), (a19, b3, c1, d17), (a19, b3, c1, d18), (a19, b3, c1, d19), (a19, b3, c1, d20), (a19, b3, c1, d21), (a19, b3, c1, d22), (a19, b3, c2, d1), (a19, b3, c2, d2), (a 19, b3, c2, d3), (a19, b3, c2, d4), (a19, b3, c2, d5), (a19, b3, c2, d6), (a19, b3, c2, d7), (a19, b3, c2, d8), (a19, b3, c2, d9), (a19, b3, c2, d10), (a19, b3, c2, d11), (a19, b3, c2, d12), (a19, b3, c2, d13), (a19, b3, c2, d14), (a19, b3, c2, d15), (a19, b3, c2, d16), (a19, b3, c2, d17), (a19, b3, c2, d18), (a19, b3, c2, d19), (a19, b3, c2, d20), (a19, b3, c2, d21), (a19, b3, c2, d22), (a19, b3, c3, d1), (a19, b3, c3, d2), (a19, b3, c3, d3), (a19, b3, c3, d4), (a19, b3, c3, d5), (a19, b3, c3, d6), (a19, b 3, c3, d7), (a19, b3, c3, d8), (a19, b3, c3, d9), (a19, b3, c3, d10), (a19, b3, c3, d11), (a19, b3, c3, d12), (a19, b3, c3, d13), (a19, b3, c3, d14), (a19, b3, c3, d15), (a19, b3, c3, d16), (a19, b3, c3, d17), (a19, b3, c3, d18), (a19, b3, c3, d19), (a19, b3, c3, d20), (a19, b3, c3, d21), (a19, b3, c3, d22), (a19, b4, c1, d1), (a19, b4, c1, d2), (a19, b4, c1, d3), (a19, b4, c1, d4), (a19, b4, c1, d5), (a19, b4, c1, d6), (a19, b4, c1, d7), (a19, b4, c1, d8), (a19, b4, c1, d9), (a19, b4, c1, d10), (a19, b4, c 1, d11), (a19, b4, c1, d12), (a19, b4, c1, d13), (a19, b4, c1, d14), (a19, b4, c1, d15), (a19, b4, c1, d16), (a19, b4, c1, d17), (a19, b4, c1, d18), (a19, b4, c1, d19), (a19, b4, c1, d20), (a19, b4, c1, d21), (a19, b4, c1, d22), (a19, b4, c2, d1), (a19, b4 , c2, d2), (a19, b4, c2, d3), (a19, b4, c2, d4), (a19, b4, c2, d5), (a19, b4, c2, d6), (a19, b4, c2, d7), (a19, b4, c2, d8), (a19, b4, c2, d9), (a19, b4, c2, d10), (a19, b4, c2, d11), (a19, b4, c2, d12), (a19, b4, c2, d13), (a19, b4, c2, d14), (a19, b4, c2 , d15), (a19, b4, c2, d16), (a19, b4, c2, d17), (a19, b4, c2, d18), (a19, b4, c2, d19), (a19, b4, c2, d20), (a19, b4, c2, d21), (a19, b4, c2, d22), (a19, b4, c3, d1), (a19, b4, c3, d2), (a19, b4, c3, d3), (a19, b4, c3, d4), (a19, b4, c3, d5), (a19, b4, c3, d6), (a19, b4, c3, d7), (a19, b4, c3, d8), (a19, b4, c3, d9), (a19, b4, c3, d10), (a19, b4, c3, d11), (a19, b4, c3, d12), (a19, b4, c3, d13), (a19, b4, c3, d14), (a19, b4, c3, d15), (a19, b4, c3, d16), (a19, b4, c3, d17), (a19, b4, c3, d18), (a19, b4, c3, d19), (a19, b4, c3, d20), (a19, b4, c3, d21), (a19, b4, c3, d22), (a19, b5, c1, d1), (a19, b5, c1, d2), (a19, b5, c1, d3), (a19, b5, c1, d4), (a19, b5, c1, d5), (a19, b5, c1, d6), (a19, b5, c1, d7), (a19, b5, c1, d8), (a19, b5, c1, d9), (a19, b5, c1, d10) , (a19, b5, c1, d11), (a19, b5, c1, d12), (a19, b5, c1, d13), (a19, b5, c1, d14), (a19, b5, c1, d15), (a19, b5, c1, d16), (a19, b5, c1, d17), (a19, b5, c1, d18), (a19, b5, c1, d19), (a19, b5, c1, d20), (a19, b5, c1, d21), (a19, b5, c1, d22), (a19, b5, c2, d1), (a19, b5, c2, d2), (a19, b5, c2, d3), (a19, b5, c2, d4), (a19, b5, c2, d5), (a19, b5, c2, d6), (a19, b5, c2, d7), (a19, b5, c2, d8), (a19, b5, c2, d9), (a19, b5, c2, d10), (a19, b5, c2, d11), (a19, b5, c2, d12), (a19, b5, c2, d13), (a19, b5, c2, d14), (a19, b5, c2, d15), (a19, b5, c2, d16), (a19, b5, c2, d17), (a19, b5, c2, d18), (a19, b5, c2, d19), (a19, b5, c2, d20), (a19, b5, c2, d21), (a19, b5, c2, d22), (a19, b5, c3, d1), (a19, b5, c3, d2), (a19, b5, c3, d3), (a19, b5, c3, d4), (a19, b5, c3, d5), (a19, b5, c3, d6), (a19, b5, c3, d7), (a19, b5, c3, d8), (a19, b5, c3, d9), (a19, b5, c3, d10), (a19, b5, c3, d11), (a19, b5, c3, d12), (a19, b5, c3, d13), (a19, b5, c3, d14), (a19, b5, c3, d15), (a19, b5, c3, d16), (a19, b5, c3, d17), (a19, b5, c3, d18), (a19, b5, c3, d19), (a19, b5, c3, d20), (a19, b5, c3, d21), (a19, b5, c3, d22), (a19, b6, c1, d1), (a19, b6, c1, d2), (a19, b6, c1, d3), (a19, b6, c1, d4), (a19, b6, c1, d5), (a19, b6, c1, d6), (a19, b6, c1, d7), (a19, b6, c1, d8), (a19, b6, c1, d9), (a19, b6, c1, d10), (a19, b6, c1, d11), (a19, b6, c1, d12), (a19, b6, c1, d13), (a19, b6, c1, d14), (a19, b6, c1, d15), (a19, b6, c1, d16), (a19, b6, c1, d17), (a19, b6, c1, d18), (a19, b6, c1, d19), (a19, b6, c1, d20)
, (a19, b6, c1, d21), (a19, b6, c1, d22), ( a19, b6, c2, d1), (a19, b6, c2, d2), (a19, b6, c2, d3), (a19, b6, c2, d4), (a19, b6, c2, d5), (a19, b6, c2, d6), (a19, b6, c2, d7), (a19, b6, c2, d8), (a19, b6, c2, d9), (a19, b6, c2, d10), (a19, b6, c2, d11), (a19, b6, c2, d12), (a19, b6, c2, d13), (a19, b6, c2, d14), (a19, b6, c2, d15), (a19, b6, c2, d16), (a19, b6, c2, d17), (a19, b6, c2, d18), (a19, b6, c2, d19), (a19, b6, c2, d20), (a19, b6, c2, d21), (a19, b6, c2, d22), (a19, b6, c3, d1), (a19, b6, c3, d2), (a19, b6, c3, d3), (a19, b6, c3, d4), (a19, b6, c3, d5), (a19, b6, c3, d6), (a19, b6, c3, d7), (a19, b6, c3, d8), (a19, b6, c3, d9), (a19, b6, c3, d10), (a19, b6, c3, d11), (a19, b6, c3, d12), (a19, b6, c3, d13), (a19, b6, c3, d14), (a19, b6, c3, d15), (a19, b6, c3, d16), (a19, b6, c3, d17), (a19, b 6, c3, d18), (a19, b6, c3, d19), (a19, b6, c3, d20), (a19, b6, c3, d21), (a19, b6, c3, d22), (a20, b1, c1, d1), (a20, b1, c1, d2), (a20, b1, c1, d3), (a20, b1, c1, d4), (a20, b1, c1, d5), (a20, b1, c1, d6), (a20, b1, c1, d7), (a20, b1, c1, d8), (a20, b1, c 1, d9), (a20, b1, c1, d10), (a20, b1, c1, d11), (a20, b1, c1, d12), (a20, b1, c1, d13), (a20, b1, c1, d14), (a20, b1, c1, d15), (a20, b1, c1, d16), (a20, b1, c1, d17), (a20, b1, c1, d18), (a20, b1, c1, d19), (a20, b1, c1, d20), (a20, b1, c1, d21), (a20, b1 , c1, d22), (a20, b1, c2, d1), (a20, b1, c2, d2), (a20, b1, c2, d3), (a20, b1, c2, d4), (a20, b1, c2, d5), (a20, b1, c2, d6), (a20, b1, c2, d7), (a20, b1, c2, d8), (a20, b1, c2, d9), (a20, b1, c2, d10), (a20, b1, c2, d11), (a20, b1, c2, d12), (a20, b1, c2, d13), (a20, b1, c2, d14), (a20, b1, c2, d15), (a20, b1, c2, d16), (a20, b1, c2, d17), (a20, b1, c2, d18), (a20, b1, c2, d19), (a20, b1, c2, d20), (a20, b1, c2, d21), (a20, b1, c2, d22), (a20, b1, c3, d1), (a20, b1, c3, d2), (a20, b1, c3, d3), (a20, b1, c3 , d4), (a20, b1, c3, d5), (a20, b1, c3, d6), (a20, b1, c3, d7), (a20, b1, c3, d8), (a20, b1, c3, d9), (a20, b1, c3, d10), (a20, b1, c3, d11), (a20, b1, c3, d12), (a20, b1, c3, d13), (a20, b1, c3, d14), (a20, b1, c3, d15), (a20, b1, c3, d16), (a20, b1, c3, d17), (a20, b1, c3, d18), (a20, b1, c3, d19), (a20, b1, c3, d20), (a20, b1, c3, d21), (a20, b1, c3, d22), (a20, b2, c1, d1), (a20, b2, c1, d2), (a20, b2, c1, d3), (a20, b2, c1, d4), (a20, b2, c1, d5), (a20, b2, c1, d6), (a20, b2, c1, d7), (a20, b2, c1, d8) , (a20, b2, c1, d9), (a20, b2, c1, d10), (a20, b2, c1, d11), (a20, b2, c1, d12), (a20, b2, c1, d13), (a20, b2, c1, d14), (a20, b2, c1, d15), (a20, b2, c1, d16), (a20, b2, c1, d17), (a20, b2, c1, d18), (a20, b2, c1, d19), (a20, b2, c1, d20), (a20, b2, c1, d 21), (a20, b2, c1, d22), (a20, b2, c2, d1), (a20, b2, c2, d2), (a20, b2, c2, d3), (a20, b2, c2, d4), (a20, b2, c2, d5), (a20, b2, c2, d6), (a20, b2, c2, d7), (a20, b2, c2, d8), (a20, b2, c2, d9), (a20, b2, c2, d10), (a20, b2, c2, d11), (a20, b2, c2, d12), (a20, b2, c2, d13), (a20, b2, c2, d14), (a20, b2, c2, d15), (a20, b2, c2, d16), (a20, b2, c2, d17), (a20, b2, c2, d18), (a20, b2, c2, d19), (a20, b2, c2, d20), (a20, b2, c2, d21), (a20, b2, c2, d22), (a20, b2, c3, d1), (a20, b2, c3, d2), (a20, b2, c3, d3), (a20, b2, c3, d4), (a20, b2, c3, d5), (a20, b2, c3, d6), (a20, b2, c3, d7), (a20, b2, c3, d8), (a20, b2, c3, d9), (a20, b2, c3, d10), (a20, b2, c3, d11), (a20, b2, c3, d12), (a20, b2, c3, d13), (a20, b2, c3, d14), (a20, b2, c3, d15), (a20, b2, c3, d16), ( a20, b2, c3, d17), (a20, b2, c3, d18), (a20, b2, c3, d19), (a20, b2, c3, d20), (a20, b2, c3, d21), (a20, b2, c3, d22), (a20, b3, c1, d1), (a20, b3, c1, d2), (a20, b3, c1, d3), (a20, b3, c1, d4), (a20, b3, c1, d5), (a20, b3, c1, d6), (a20, b3, c1, d7), (a20 , b3, c1, d8), (a20, b3, c1, d9), (a20, b3, c1, d10), (a20, b3, c1, d11), (a20, b3, c1, d12), (a20, b3, c1, d13), (a20, b3, c1, d14), (a20, b3, c1, d15), (a20, b3, c1, d16), (a20, b3, c1, d17), (a20, b3, c1, d18), (a20, b3, c1, d19), (a20, b3, c1, d20), (a 20, b3, c1, d21), (a20, b3, c1, d22), (a20, b3, c2, d1), (a20, b3, c2, d2), (a20, b3, c2, d3), (a20, b3, c2, d4), (a20, b3, c2, d5), (a20, b3, c2, d6), (a20, b3, c2, d7), (a20, b3, c2, d8), (a20, b3, c2, d9), (a20, b3, c2, d10), (a20, b3, c2, d11), (a20, b 3, c2, d12), (a20, b3, c2, d13), (a20, b3, c2, d14), (a20, b3, c2, d15), (a20, b3, c2, d16), (a20, b3, c2, d17), (a20, b3, c2, d18), (a20, b3, c2, d19), (a20, b3, c2, d20), (a20, b3, c2, d21), (a20, b3, c2, d22), (a20, b3, c3, d1), (a20, b3, c3, d2), (a20, b3, c3, d3), (a20, b3, c3, d4), (a20, b3, c3, d5), (a20, b3, c3, d6), (a20, b3, c3, d7), (a20, b3, c3, d8), (a20, b3, c3, d9), (a20, b3, c3, d10), (a20, b3, c3, d11), (a20, b3, c3, d12), (a20, b3, c3, d13), (a20, b3, c3, d14), (a20, b3, c3, d15), (a20, b3 , c3, d16), (a20, b3, c3, d17), (a20, b3, c3, d18), (a20, b3, c3, d19), (a20, b3, c3, d20), (a20, b3, c3, d21), (a20, b3, c3, d22), (a20, b4, c1, d1), (a20, b4, c1, d2), (a20, b4, c1, d3), (a20, b4, c1, d4), (a20, b4, c1, d5), (a20, b4, c1, d6), (a20, b4, c1, d7), (a20, b4, c1, d8), (a20, b4, c1, d9), (a20, b4, c1, d10), (a20, b4, c1, d11), (a20, b4, c1, d12), (a20, b4, c1, d13), (a20, b4, c1, d14), (a20, b4, c1, d15), (a20, b4, c1, d16), (a20, b4, c1, d17), (a20, b4, c1, d18), (a20, b4, c1, d19), (a20, b4, c1, d20), (a20, b4, c1, d21), (a20, b4, c1, d22), (a20, b4, c2, d1), (a20, b4, c2, d2), (a20, b4, c2, d3), (a20, b4, c2, d4), (a20, b4, c2, d5), (a20, b4, c2, d6), (a20, b4, c2, d7), (a20, b4, c2, d8), (a20, b4, c2, d9), (a20, b4, c2, d10), (a20, b4, c2, d11), (a20, b4, c2, d12), (a20, b4, c2, d13), (a20, b4, c2, d14), (a20, b4, c2, d15), (a20, b4, c2, d16), (a20, b4, c2, d17), (a20, b4, c2, d18), (a20, b4, c2, d19), (a20, b4, c2, d20), (a20, b4, c2, d21), (a20, b4, c2, d22), (a20, b4, c3, d1), (a20, b4, c 3, d2), (a20, b4, c3, d3), (a20, b4, c3, d4), (a20, b4, c3, d5), (a20, b4, c3, d6), (a20, b4, c3, d7), (a20, b4, c3, d8), (a20, b4, c3, d9), (a20, b4, c3, d10), (a20, b4, c3, d11), (a20, b4, c3, d12), (a20, b4, c3, d13), (a20, b4, c3, d14), (a20, b4, c3, d 15), (a20, b4, c3, d16), (a20, b4, c3, d17), (a20, b4, c3, d18), (a20, b4, c3, d19), (a20, b4, c3, d20), (a20, b4, c3, d21), (a20, b4, c3, d22), (a20, b5, c1, d1), (a20, b5, c1, d2), (a20, b5, c1, d3), (a20, b5, c1, d4), (a20, b5, c1, d5), (a20, b5, c1, d6 ), (a20, b5, c1, d7), (a20, b5, c1, d8), (a20, b5, c1, d9), (a20, b5, c1, d10), (a20, b5, c1, d11), (a20, b5, c1, d12), (a20, b5, c1, d13), (a20, b5, c1, d14), (a20, b5, c1, d15), (a20, b5, c1, d16), (a20, b5, c1, d17), (a20, b5, c1, d18), (a20, b5, c1, d1 9), (a20, b5, c1, d20), (a20, b5, c1, d21), (a20, b5, c1, d22), (a20, b5, c2, d1), (a20, b5, c2, d2), (a20, b5, c2, d3), (a20, b5, c2, d4), (a20, b5, c2, d5), (a20, b5, c2, d6), (a20, b5, c2, d7), (a20, b5, c2, d8), (a20, b5, c2, d9), (a20, b5, c2, d10), ( a20, b5, c2, d11), (a20, b5, c2, d12), (a20, b5, c2, d13), (a20, b5, c2, d14), (a20, b5, c2, d15), (a20, b5, c2, d16), (a20, b5, c2, d17), (a20, b5, c2, d18), (a20, b5, c2, d19), (a20, b5, c2, d20), (a20, b5, c2, d21), (a20, b5, c2, d22), (a20, b5, c3, d1) , (a20, b5, c3, d2), (a20, b5, c3, d3), (a20, b5, c3, d4), (a20, b5, c3, d5), (a20, b5, c3, d6), (a20, b5, c3, d7), (a20, b5, c3, d8), (a20, b5, c3, d9), (a20, b5, c3, d10), (a20, b5, c3, d11), (a20, b5, c3, d12), (a20, b5, c3, d13), (a20, b5, c3, d14), (a 20, b5, c3, d15), (a20, b5, c3, d16), (a20, b5, c3, d17), (a20, b5, c3, d18), (a20, b5, c3, d19), (a20, b5, c3, d20), (a20, b5, c3, d21), (a20, b5, c3, d22), (a20, b6, c1, d1), (a20, b6, c1, d2), (a20, b6, c1, d3), (a20, b6, c1, d4), (a20, b6, c1, d5), (a2 0, b6, c1, d6), (a20, b6, c1, d7), (a20, b6, c1, d8), (a20, b6, c1, d9), (a20, b6, c1, d10), (a20, b6, c1, d11), (a20, b6, c1, d12), (a20, b6, c1, d13), (a20, b6, c1, d14), (a20, b6, c1, d15), (a20, b6, c1, d16), (a20, b6, c1, d17), (a20, b6, c1, d18), (a2 0, b6, c1, d19), (a20, b6, c1, d20), (a20, b6, c1, d21), (a20, b6, c1, d22), (a20, b6, c2, d1), (a20, b6, c2, d2), (a20, b6, c2, d3), (a20, b6, c2, d4), (a20, b6, c2, d5), (a20, b6, c2, d6), (a20, b6, c2, d7), (a20, b6, c2, d8), (a20, b6, c2, d9), (a20, b6 , c2, d10), (a20, b6, c2, d11), (a20, b6, c2, d12), (a20, b6, c2, d13), (a20, b6, c2, d14), (a20, b6, c2, d15), (a20, b6, c2, d16), (a20, b6, c2, d17), (a20, b6, c2, d18), (a20, b6, c2, d19), (a20, b6, c2, d20), (a20, b6, c2, d21), (a20, b6, c2, d22), (a20 , b6, c3, d1), (a20, b6, c3, d2), (a20, b6, c3, d3), (a20, b6, c3, d4), (a20, b6, c3, d5), (a20, b6, c3, d6), (a20, b6, c3, d7), (a20, b6, c3, d8), (a20, b6, c3, d9), (a20, b6, c3, d10), (a20, b6, c3, d11), (a20, b6, c3, d12), (a20, b6, c3, d13), (a20, b6, c3, d14), (a20, b6, c3, d15), (a20, b6, c3, d16), (a20, b6, c3, d17), (a20, b6, c3, d18), (a20, b6, c3, d19), (a20, b6, c3, d20), (a20, b6, c3, d21), (a20, b6, c3, d22), (a21, b1, c1, d1), (a21, b1, c1, d2), (a21, b1, c1, d3), (a21, b1, c1, d4), (a21, b1, c1, d5), (a21, b1, c1, d6), (a21, b1, c1, d7), (a21, b1, c1, d8), (a21, b1, c1, d9), (a21, b1, c1, d10), (a21, b1, c1, d11), (a21, b1, c1, d12), (a21, b1, c1, d13), (a21, b1, c1, d14), (a21, b1, c1, d15), (a21, b1, c1, d16), (a21, b1, c1, d17), (a21, b1, c1, d18), (a21, b1, c1, d19), (a21, b1, c1, d20), (a21, b1, c1, d21), (a21, b1, c1, d22), (a21, b1, c2, d1), (a21, b1, c2, d2), (a21, b1, c2, d3), (a21, b1, c2, d4), (a21, b1, c2, d5), (a21, b1, c2, d6), (a21, b1, c2, d7), (a21, b1, c2, d8), (a21, b1, c2, d9), (a21, b1, c2, d10), (a21, b1, c2, d11), (a21, b1, c2, d12), (a21, b1, c2, d13), (a21, b1, c2, d14), (a21, b1, c2, d15), (a21, b1, c2, d16), (a21, b1, c2, d17), (a21, b1, c2, d18), (a21, b1, c2, d19), (a21, b1, c2, d20), (a21, b1, c2, d21), (a21, b1, c 2, d22), (a21, b1, c3, d1), (a21, b1, c3, d2), (a21, b1, c3, d3), (a21, b1, c3, d4), (a21, b1, c3, d5), (a21, b1, c3, d6), (a21, b1, c3, d7), (a21, b1, c3, d8), (a21, b1, c3, d9), (a21, b1, c3, d10), (a21, b1, c3, d11), (a21, b1, c3, d12), (a21, b1, c3, d1 3), (a21, b1, c3, d14), (a21, b1, c3, d15), (a21, b1, c3, d16), (a21, b1, c3, d17), (a21, b1, c3, d18), (a21, b1, c3, d19), (a21, b1, c3, d20), (a21, b1, c3, d21), (a21, b1, c3, d22), (a21, b2, 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(a24, b1, c2, d14), (a24, b1, c2, d15), (a24, b1, c2, d16), (a24, b1, c2, d17), (a24, b1, c2, d18), (a24, b1, c2, d19), (a24, b1, c2, d20), (a24, b1, c2, d21), (a24, b1, c2, d22), (a24, b1, c3, d1), (a24, b1, c3, d2), (a24, b1, c3, d3), (a24, b1, c3, d4), (a24, b1, c3, d5), (a24, b1, c3, d6), (a24, b1, c3, d7), (a24, b1, c3, d8), (a24, b1, c3, d9), (a24, b1, c3, d10), (a24, b1, c3, d11), (a24, b1, c3, d12), (a24, b1, c3, d13), (a24, b1, c3, d14) , (a24, b1, c3, d15), (a24, b1, c3, d16), (a24, b1, c3, d17), (a24, b1, c3, d18), (a24, b1, c3, d19), (a24, b1, c3, d20), (a24, b1, c3, d21), (a24, b1, c3, d22), (a24, b2, c1, d1), (a24, b2, c1, d2), (a24, b2, c1, d3), (a24, b2, c1, d4), (a24, b2, c1, d5), (a24, b2, c1, d6), (a24, b2, c1, d7), (a24, b2, c1, d8), (a24, b2, c1, d9), (a24, b2, c1, d10), (a24, b2, c1, d11), (a24, b2, c1, d12), (a24, b2, c1, d13), (a24, b2, c1, d14), (a24, b2, c1, d15), (a24, b2, c1, d16), (a24, b2, c1, d17), (a24, b2, c1, d18), (a24, b2, c1, d19), (a24, b2, c1, 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b3, c2, d7), (a25, b3, c2, d8), (a25, b3, c2, d9), (a25, b3, c2, d10), (a25, b3, c2, d11), (a25, b3, c2, d12), (a25, b3, c2, d13), (a25, b3, c2, d14), (a25, b3, c2, d15), (a25, b3, c2, d16), (a25, b3, c2, d17), (a25, b3, c2, d18), (a25, b3, c2, d19), (a25, b3, c2, d20), (a25, b3, c2, d21), (a25, b3, c2, d22), (a25, b3, c3, d1), (a25, b3, c3, d2), (a25, b3, c3, d3), (a25, b3, c3, d4), (a25, b3, c3, d5), (a25, b3, c3, d6), (a25, b3, c3, d7), (a25, b3, c3, d8), (a25, b3, c3, d9), (a25, b3, c3, d10), (a25, b3, c3, d11), (a25, b3, c3, d12), (a25, b3, c3, d13), (a25, b3, c3, d14), (a25, b3, c3, d15), (a25, b3, c3, d16), (a25, b3, c3, d17), (a25, b3, c3, d18), (a25, b3, c3, d19), (a25, b3, c3, d20), (a25, b3, c3, d21), (a25, b3, c3, d22), (a25, b4, c1, d1), (a25, b4, c1, d2), (a25, b4, c1, d3), (a25, b4, c1, d4), (a25, b4, c1, d5), (a25, b4, c1, d6), (a25, b4, c1, d7), (a25, b4, c1, d8), (a25, b4, c1, d9), (a25, b4, c1, d10), (a25, b4, c1, d11), (a25, b4, c1, d12), (a25, b4, c1, d 13), (a25, 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(a25, b4, c3, d21 ), (a25, b4, c3, d22), (a25, b5, c1, d1), (a25, b5, c1, d2), (a25, b5, c1, d3), (a25, b5, c1, d4), (a25, b5, c1, d5), (a25, b5, c1, d6), (a25, b5, c1, d7), (a25, b5, c1, d8), (a25, b5, c1, d9), (a25, b5, c1, d10), (a25, b5, c1, d11), (a25, b5, c1, d12), (a 25, b5, c1, d13), (a25, b5, c1, d14), (a25, b5, c1, d15), (a25, b5, c1, d16), (a25, b5, c1, d17), (a25, b5, c1, d18), (a25, b5, c1, d19), (a25, b5, c1, d20), (a25, b5, c1, d21), (a25, b5, c1, d22), (a25, b5, c2, d1), (a25, b5, c2, d2), (a25, b5, c2, d3), ( a25, b5, c2, d4), (a25, b5, c2, d5), (a25, b5, c2, d6), (a25, b5, c2, d7), (a25, b5, c2, d8), (a25, b5, c2, d9), (a25, b5, c2, d10), (a25, b5, c2, d11), (a25, b5, c2, d12), (a25, b5, c2, d13), (a25, b5, c2, d14), (a25, b5, c2, d15), (a25, b5, c2, d16), (a2 5, b5, c2, d17), (a25, b5, c2, d18), (a25, b5, c2, d19), (a25, b5, c2, d20), (a25, b5, c2, d21), (a25, b5, c2, d22), (a25, b5, c3, d1), (a25, b5, c3, d2), (a25, b5, c3, d3), (a25, b5, c3, d4), (a25, b5, c3, d5), (a25, b5, c3, d6), (a25, b5, c3, d7), (a25, b5, c3, d8), (a25, b5, c3, d9), (a25, b5, c3, d10), (a25, b5, c3, d11), (a25, b5, c3, d12), (a25, b5, c3, d13), (a25, b5, c3, d14), (a25, b5, c3, d15), (a25, b5, c3, d16), (a25, b5, c3, d17), (a25, b5, c3, d18), (a25, b5, c3, d19), (a25, b5, c3, d20), (a25 , b5, c3, d21), (a25, b5, c3, d22), (a25, b6, c1, d1), (a25, b6, c1, d2), (a25, b6, c1, d3), (a25, b6, c1, d4), (a25, b6, c1, d5), (a25, b6, c1, d6), (a25, b6, c1, d7), (a25, b6, c1, d8), (a25, b6, c1, d9), (a25, b6, c1, d10), (a25, b6, c1, d11), (a25, b6, c1, d12), (a25, b6, c1, d13), (a25, b6, c1, d14), (a25, b6, c1, d15), (a25, b6, c1, d16), (a25, b6, c1, d17), (a25, b6, c1, d18), (a25, b6, c1, d19), (a25, b6, c1, d20), (a25, b6, c1, d21), (a25, b6, c1, d22), (a25, b6, c2, d1), (a25, b6, c2, d2), (a25, b 6, c2, d3), (a25, b6, c2, d4), (a25, b6, c2, d5), (a25, b6, c2, d6), (a25, b6, c2, d7), (a25, b6, c2, d8), (a25, b6, c2, d9), (a25, b6, c2, d10), (a25, b6, c2, d11), (a25, b6, c2, d12), (a25, b6, c2, d13), (a25, b6, c2, d14), (a25, b6, c2, d15), (a25, b6, c2, d16), (a25, b6, c2, d17), (a25, b6, c2, d18), (a25, b6, c2, d19), (a25, b6, c2, d20), (a25, b6, c2, d21), (a25, b6, c2, d22), (a25, b6, c3, d1), (a25, b6, c3, d2), (a25, b6, c3, d3), (a25, b6, c3, d4), (a25, b6, c3, d5), (a25, b6, c3, d6), (a25, b6, c3 , d7), (a25, b6, c3, d8), (a25, b6, c3, d9), (a25, b6, c3, d10), (a25, b6, c3, d11), (a25, b6, c3, d12), (a25, b6, c3, d13), (a25, b6, c3, d14), (a25, b6, c3, d15), (a25, b6, c3, d16), (a25, b6, c3, d17), (a25, b6, c3, d18), (a25, b6, c3, d19), (a25, b6, c 3, d20), (a25, b6, c3, d21), (a25, b6, c3, d22), (a26, b1, c1, d1), (a26, b1, c1, d2), (a26, b1, c1, d3), (a26, b1, c1, d4), (a26, b1, c1, d5), (a26, b1, c1, d6), (a26, b1, c1, d7), (a26, b1, c1, d8), (a26, b1, c1, d9), (a26, b1, c1, d10), (a26, b1, c1, d1 1), (a26, b1, c1, d12), (a26, b1, c1, d13), (a26, b1, c1, d14), (a26, b1, c1, d15), (a26, b1, c1, d16), (a26, b1, c1, d17), (a26, b1, c1, d18), (a26, b1, c1, 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d19), (a39, b6, c1, d20), (a39, b6, c1, d21 ), (a39, b6, c1, d22), (a39, b6, c2, d1), (a39, b6, c2, d2), (a39, b6, c2, d3), (a39, b6, c2, d4), (a39, b6, c2, d5), (a39, b6, c2, d6), (a39, b6, c2, d7), (a39, b6, c2, d8), (a39, b6, c2, d9), (a39, b6, c2, d10), (a39, b6, c2, d11), (a39, b6, c2, d12), (a 39, b6, c2, d13), (a39, b6, c2, d14), (a39, b6, c2, d15), (a39, b6, c2, d16), (a39, b6, c2, d17), (a39, b6, c2, d18), (a39, b6, c2, d19), (a39, b6, c2, d20), (a39, b6, c2, d21), (a39, b6, c2, d22), (a39, b6, c3, d1), (a39, b6, c3, d2), (a39, b6, c3, d3), ( a39, b6, c3, d4), (a39, b6, c3, d5), (a39, b6, c3, d6), (a39, b6, c3, d7), (a39, b6, c3, d8), (a39, b6, c3, d9), (a39, b6, c3, d10), (a39, b6, c3, d11), (a39, b6, c3, d12), (a39, b6, c3, d13), (a39, b6, c3, d14), (a39, b6, c3, d15), (a39, b6, c3, d16), (a3 9, b6, c3, d17), (a39, b6, c3, d18), (a39, b6, c3, d19), (a39, b6, c3, d20), (a39, b6, c3, d21), (a39, b6, c3, d22), (a40, b1, c1, d1), (a40, b1, c1, d2), (a40, b1, c1, d3), (a40, b1, 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(a40, b3, c2, d3), (a40, b3, c2, d4), (a40, b3, c2, d5), (a40, b3, c2, d6), (a40, b3, c2, d7), (a40, b3, c2, d8), (a40, b3, c2, d9), (a40, b3, c2, d10), (a4 0, b3, c2, d11), (a40, b3, c2, d12), (a40, b3, c2, d13), (a40, b3, c2, d14), (a40, b3, c2, d15), (a40, b3, c2, d16), (a40, b3, c2, d17), (a40, b3, c2, d18), (a40, b3, c2, d19), (a40, b3, c2, d20), (a40, b3, c2, d21), (a40, b3, c2, d22), (a40, b3, c3, d1), (a40, b3, c3, d2), (a40, b3, c3, d3), (a40, b3, c3, d4), (a40, b3, c3, d5), (a40, b3, c3, d6), (a40, b3, c3, d7), (a40, b3, c3, d8), (a40, b3, c3, d9), (a40, b3, c3, d10), (a40, b3, c3, d11), (a40, b3, c3, d12), (a40, b3, c3, d13), (a40, b3, c3, d14), (a40 , b3, c3, d15), (a40, b3, c3, d16), (a40, b3, c3, d17), (a40, b3, c3, d18), (a40, b3, c3, d19), (a40, b3, c3, d20), (a40, b3, c3, d21), (a40, b3, c3, d22), (a40, b4, c1, d1), (a40, b4, c1, d2), (a40, b4, c1, d3), (a40, b4, c1, d4), (a40, b4, c1, d5), (a40, b4, c1, d6), (a40, b4, c1, d7), (a40, b4, c1, d8), (a40, b4, c1, d9), 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d8), (a4 0, b6, c2, d9), (a40, b6, c2, d10), (a40, b6, c2, d11), (a40, b6, c2, d12), (a40, b6, c2, d13), (a40, b6, c2, d14), (a40, b6, c2, d15), (a40, b6, c2, d16), (a40, b6, c2, d17), (a40, b6, c2, d18), (a40, b6, c2, d19), (a40, b6, c2, d20)
, (a40, b6, c2, d21), (a40, b6, c2, d22), (a40, b6, c3, d1), (a40, b6, c3, d2), (a40, b6, c3, d3), (a40, b6, c3, d4), (a40, b6, c3, d5), (a40, b6, c3, d6), (a40, b6, c3, d7), (a40, b6, c3, d8), (a40, b6, c3, d9), (a40, b6, c3, d10), (a40, b6, c3, d11), (a40, b6, c3, d12), (a40, b6, c3, d13), (a40, b6, c3, d14), (a40, b6, c3, d15), (a40, b6, c3, d16), (a40, b6, c3, d17), (a40, b6, c3, d18), (a40, b6, c3, d19), (a40, b6, c3, d20), (a40, b6, c3, d21), (a40, b6, c3, d22), (a41, b1, c1, d1), (a41, b1, c1, d2), (a41, b1, c1, d3), (a41 , b1, c1, d4), (a41, b1, c1, d5), (a41, b1, c1, d6), (a41, b1, c1, d7), (a41, b1, c1, d8), (a41, b1, c1, d9), (a41, b1, c1, d10), (a41, b1, c1, d11), (a41, b1, c1, d12), (a41, b1, c1, d13), (a41, b1, c1, d14), (a41, b1, c1, d15), (a41, b1, c1, d16), (a41, b1, c1, d17), (a41, b1, c1, d18), (a41, b1, c1, d19), (a41, b1, c1, d20), (a41, b1, c1, d21), (a41, b1, c1, d22), (a41, b1, c2, d1), (a41, b1, c2, d2), (a41, b1, c2, d3), (a41, b1, c2, d4), (a41, b1, c2, d5), (a41, b1, c2, d6), (a41, b1, c2, d7), (a41, b1, c2, d8), (a41, b1, c2, d9), (a41, b1, c2, d10), (a41, b1, c2, d11), (a41, b1, c2, d12), (a41, b1, c2, d13), (a41, b1, c2, d14), (a41, b1, c2, d15), (a41, b1, c2, d16), (a41, b1, c2, d17), (a41, b1, c2, d18), (a41, b1, c2, d19), (a41, b1, c2, d20), (a41, b 1, c2, d21), (a41, b1, c2, d22), (a41, b1, c3, d1), (a41, b1, c3, d2), (a41, b1, c3, d3), (a41, b1, c3, d4), (a41, b1, c3, d5), (a41, b1, c3, d6), (a41, b1, c3, d7), (a41, b1, c3, d8), (a41, b1, c3, d9), (a41, b1, c3, d10), (a41, b1, c3, d11), (a41, b1, c3 , d12), (a41, b1, c3, d13), (a41, b1, c3, d14), (a41, b1, c3, d15), (a41, b1, c3, d16), (a41, b1, c3, d17), (a41, b1, c3, d18), (a41, b1, c3, d19), (a41, b1, c3, d20), (a41, b1, c3, d21), (a41, b1, c3, d22), (a41, b2, c1, d1), (a41, b2, c1, d2), (a41, b2, c1, d3), (a41, b2, c1, d4), (a41, b2, c1, d5), (a41, b2, c1, d6), (a41, b2, c1, d7), (a41, b2, c1, d8), (a41, b2, c1, d9), (a41, b2, c1, d10), (a41, b2, c1, d11), (a41, b2, c1, d12), (a41, b2, c1, d13), (a41, b2, c1, d14), (a41, b2, c1, d15), (a41, b2, c1, d16), (a41, b2, c1, d17), (a41, b2, c1, d18), (a41, b2, c1, d19), (a41, b2, c1, d20), (a41, b2, c1, d21), (a41, b2, c1, d22), (a41, b2, c2, d1), (a41, b2, c2, d2), (a41, b2, c2, d3), (a41, b2, c2, d4), (a41, b2, c2, d5), (a41, b2, c2, d6), (a41, b2, c2, d 7), (a41, b2, c2, d8), (a41, b2, c2, d9), (a41, b2, c2, d10), (a41, b2, c2, d11), (a41, b2, c2, d12), (a41, b2, c2, d13), (a41, b2, c2, d14), (a41, b2, c2, d15), (a41, b2, c2, d16), (a41, b2, c2, d17), (a41, b2, c2, d18), (a41, b2, c2, d19), (a41, b2, c2, d20), (a41, b2, c2, d21), (a41, b2, c2, d22), (a41, b2, c3, d1), (a41, b2, c3, d2), (a41, b2, c3, d3), (a41, b2, c3, d4), (a41, b2, c3, d5), (a41, b2, c3, d6), (a41, b2, c3, d7), (a41, b2, c3, d8), (a41, b2, c3, d9), (a41, b2, c3, d10), (a41, b2, c3, d11), (a41, b2, c3, d12), (a41, b2, c3, d13), (a41, b2, c3, d14), (a41, b2, c3, d15), (a41, b2, c3, d16), (a41, b2, c3, d17), (a41, b2, c3, d18), (a41, b2, c3, d19), (a41, b2, c3, d20), (a41, b2, c3, d21), (a41, b2, c3, d22), (a41, b3, c1, d1), (a41, b3, c1, d2 ), (a41, b3, c1, d3), (a41, b3, c1, d4), (a41, b3, c1, d5), (a41, b3, c1, d6), (a41, b3, c1, d7), (a41, b3, c1, d8), (a41, b3, c1, d9), (a41, b3, c1, d10), (a41, b3, c1, d11), (a41, b3, c1, d12), (a41, b3, c1, d13), (a41, b3, c1, d14), (a41, b3, c1, d15), (a41, b3, c1, d16), (a41, b3, c1, d17), (a41, b3, c1, d18), (a41, b3, c1, d19), (a41, b3, c1, d20), (a41, b3, c1, d21), (a41, b3, c1, d22), (a41, b3, c2, d1), (a41, b3, c2, d2), (a41, b3, c2, d3), (a41, b3, c2, d4), (a41, b3, c2, d5), (a41, b3, c2, d6), (a 41, b3, c2, d7), (a41, b3, c2, d8), (a41, b3, c2, d9), (a41, b3, c2, d10), (a41, b3, c2, d11), (a41, b3, c2, d12), (a41, b3, c2, d13), (a41, b3, c2, d14), (a41, b3, c2, d15), (a41, b3, c2, d16), (a41, b3, c2, d17), (a41, b3, c2, d18), (a41, b3, c2, d19), ( a41, b3, c2, d20), (a41, b3, c2, d21), (a41, b3, c2, d22), (a41, b3, c3, d1), (a41, b3, c3, d2), (a41, b3, c3, d3), (a41, b3, c3, d4), (a41, b3, c3, d5), (a41, b3, c3, d6), (a41, b3, c3, d7), (a41, b3, c3, d8), (a41, b3, c3, d9), (a41, b3, c3, d10), (a41, b3, c3, d11), (a41, b3, c3, d12), (a41, b3, c3, d13), (a41, b3, c3, d14), (a41, b3, c3, d15), (a41, b3, c3, d16), (a41, b3, c3, d17), (a41, b3, c3, d18), (a41, b3, c3, d19), (a41, b3, c3, d20), (a41, b3, c3, d21), (a41, b3, c3, d22), (a41, b4, c1, d1), (a4 1, b4, c1, d2), (a41, b4, c1, d3), (a41, b4, c1, d4), (a41, b4, c1, d5), (a41, b4, c1, d6), (a41, b4, c1, d7), (a41, b4, c1, d8), (a41, b4, c1, d9), (a41, b4, c1, d10), (a41, b4, c1, d11), (a41, b4, c1, d12), (a41, b4, c1, d13), (a41, b4, c1, d14), (a41, b 4, c1, d15), (a41, b4, c1, d16), (a41, b4, c1, d17), (a41, b4, c1, d18), (a41, b4, c1, d19), (a41, b4, c1, d20), (a41, b4, c1, d21), (a41, b4, c1, d22), (a41, b4, c2, d1), (a41, b4, c2, d2), (a41, b4, c2, d3), (a41, b4, c2, d4), (a41, b4, c2, d5), (a41, b4 , c2, d6), (a41, b4, c2, d7), (a41, b4, c2, d8), (a41, b4, c2, d9), (a41, b4, c2, d10), (a41, b4, c2, d11), (a41, b4, c2, d12), (a41, b4, c2, d13), (a41, b4, c2, d14), (a41, b4, c2, d15), (a41, b4, c2, d16), (a41, b4, c2, d17), (a41, b4, c2, d18), (a41, b4 , c2, d19), (a41, b4, c2, d20), (a41, b4, c2, d21), (a41, b4, c2, d22), (a41, b4, c3, d1), (a41, b4, c3, d2), (a41, b4, c3, d3), (a41, b4, c3, d4), (a41, b4, c3, d5), (a41, b4, c3, d6), (a41, b4, c3, d7), (a41, b4, c3, d8), (a41, b4, c3, d9), (a41, b4, c3, d10), (a41, b4, c3, d11), (a41, b4, c3, d12), (a41, b4, c3, d13), (a41, b4, c3, d14), (a41, b4, c3, d15), (a41, b4, c3, d16), (a41, b4, c3, d17), (a41, b4, c3, d18), (a41, b4, c3, d19), (a41, b4, c3, d20), (a41, b4, c3, d21), (a41, b4, c3, d22), (a41, b5, c1, d1), (a41, b5, c1, d2), (a41, b5, c1, d3), (a41, b5, c1, d4), (a41, b5, c1, d5), (a41, b5, c1, d6), (a41, b5, c1, d7), (a41, b5, c1, d8), (a41, b5, c1, d9), (a41, b5, c1, d10), (a41, b5, c1, d11), (a41, b5, c1, d12), (a41, b5, c1, d13), (a41, b5, c1, d14), (a41, b5, c1, d15), (a41, b5, c1, d16), (a41, b5, c1, d17), (a41, b5, c1, d18), (a41, b5, c1, d19), (a41, b5, c1, d20), (a41, b5, c1, d21), (a41, b5, c1, d22), (a41, b5, c2, d1), (a41, b5, c2, d2), (a41, b5, c2, d3), (a41, b5, c2, d4), (a41, b5, c2, d5), (a41, b5, c2, d6), (a41, b5, c2, d7), (a41, b5, c2, d8), (a41, b5, c2, d9), (a41, b5, c2, d10), (a41, b5, c2, d11), (a41, b5, c2, d12), (a41, b5, c2, d13), (a41, b5, c2, d14), (a41, b5, c2, d15), (a41, b5, c2, d16), (a41, b5, c2, d17), (a41, b5, c2, d 18), (a41, b5, c2, d19), (a41, b5, c2, d20), (a41, b5, c2, d21), (a41, b5, c2, d22), (a41, b5, c3, d1), (a41, b5, c3, d2), (a41, b5, c3, d3), (a41, b5, c3, d4), (a41, b5, c3, d5), (a41, b5, c3, d6), (a41, b5, c3, d7), (a41, b5, c3, d8), (a41, b5, c3, d9), (a41, b5, c3, d10), (a41, b5, c3, d11), (a41, b5, c3, d12), (a41, b5, c3, d13), (a41, b5, c3, d14), (a41, b5, c3, d15), (a41, b5, c3, d16), (a41, b5, c3, d17), (a41, b5, c3, d18), (a41, b5, c3, d19), (a41, b5, c3, d20), (a41, b5, c3, d21), (a41, b5, c3, d2 2), (a41, b6, c1, d1), (a41, b6, c1, d2), (a41, b6, c1, d3), (a41, b6, c1, d4), (a41, b6, c1, d5), (a41, b6, c1, d6), (a41, b6, c1, d7), (a41, b6, c1, d8), (a41, b6, c1, d9), (a41, b6, c1, d10), (a41, b6, c1, d11), (a41, b6, c1, d12), (a41, b6, c1, d13), ( a41, b6, c1, d14), (a41, b6, c1, d15), (a41, b6, c1, d16), (a41, b6, c1, d17), (a41, b6, c1, d18), (a41, b6, c1, d19), (a41, b6, c1, d20), (a41, b6, c1, d21), (a41, b6, c1, d22), (a41, b6, c2, d1), (a41, b6, c2, d2), (a41, b6, c2, d3), (a41, b6, c2, d4), ( a41, b6, c2, d5), (a41, b6, c2, d6), (a41, b6, c2, d7), (a41, b6, c2, d8), (a41, b6, c2, d9), (a41, b6, c2, d10), (a41, b6, c2, d11), (a41, b6, c2, d12), (a41, b6, c2, d13), (a41, b6, c2, d14), (a41, b6, c2, d15), (a41, b6, c2, d16), (a41, b6, c2, d17), (a 41, b6, c2, d18), (a41, b6, c2, d19), (a41, b6, c2, d20), (a41, b6, c2, d21), (a41, b6, c2, d22), (a41, b6, c3, d1), (a41, b6, c3, d2), (a41, b6, c3, d3), (a41, b6, c3, d4), (a41, b6, c3, d5), (a41, b6, c3, d6), (a41, b6, c3, d7), (a41, b6, c3, d8), (a41, b6, c3, d9), (a41, b6, c3, d10), (a41, b6, c3, d11), (a41, b6, c3, d12), (a41, b6, c3, d13), (a41, b6, c3, d14), (a41, b6, c3, d15), (a41, b6, c3, d16), (a41, b6, c3, d17), (a41, b6, c3, d18), (a41, b6, c3, d19), (a41, b6, c3, d20), (a41, b6, c3, d21), (a4 1, b6, c3, d22), (a42, b1, c1, d1), (a42, b1, c1, d2), (a42, b1, c1, d3), (a42, b1, c1, d4), (a42, b1, c1, d5), (a42, b1, c1, d6), (a42, b1, c1, d7), (a42, b1, c1, d8), (a42, b1, c1, d9), (a42, b1, c1, d10), (a42, b1, c1, d11), (a42, b1, c1, d12), (a42, b1 , c1, d13), (a42, b1, c1, d14), (a42, b1, c1, d15), (a42, b1, c1, d16), (a42, b1, c1, d17), (a42, b1, c1, d18), (a42, b1, c1, d19), (a42, b1, c1, d20), (a42, b1, c1, d21), (a42, b1, c1, d22), (a42, b1, c2, d1), (a42, b1, c2, d2), (a42, b1, c2, d3), (a42, b 1, c2, d4), (a42, b1, c2, d5), (a42, b1, c2, d6), (a42, b1, c2, d7), (a42, b1, c2, d8), (a42, b1, c2, d9), (a42, b1, c2, d10), (a42, b1, c2, d11), (a42, b1, c2, d12), (a42, b1, c2, d13), (a42, b1, c2, d14), (a42, b1, c2, d15), (a42, b1, c2, 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c3, d1), ( a50, b2, c3, d2), (a50, b2, c3, d3), (a50, b2, c3, d4), (a50, b2, c3, d5), (a50, b2, c3, d6), (a50, b2, c3, d7), (a50, b2, c3, d8), (a50, b2, c3, d9), (a50, b2, c3, d10), (a50, b2, c3, d11), (a50, b2, c3, d12), (a50, b2, c3, d13), (a50, b2, c3, d14), (a50, b2, c3, d15), (a50, b2, c3, d16), (a50, b2, c3, d17), (a50, b2, c3, d18), (a50, b2, c3, d19), (a50, b2, c3, d20), (a50, b2, c3, d21), (a50, b2, c3, d22), (a50, b3, c1, d1), (a50, b3, c1, d2), (a50, b3, c1, d3), (a50, b3, c1, d4), (a50, b3, c1, d5), (a50, b3, c1, d6), (a50, b3, c1, d7), (a50, b3, c1, d8), (a50, b3, c1, d9), (a50, b3, c1, d10), (a50, b3, c1, d11), (a50, b3, c1, d12), (a50, b3, c1, d13), (a50, b3, c1, d14), (a50, b3, c1, d15), (a50, b3, c1, d16), (a50, b3, c1, d17), (a50, b3, c1, d18), (a50, b3, c1, d19), (a50, b3, c1, d20), (a50, b3, c1, d21), (a50, b3, c1, d22), (a50, b3, c2, d1), (a50, b3, c2, d2), (a50, b3, c2, d3), (a50, b3, c2, d4), (a50, b3, c2, d5), (a50, b3, c2, d6), (a50, b3, c2, d7), (a50, b3, c2, d8), (a50, b3, c2, d9), (a50, b3, c 2, d10), (a50, b3, c2, d11), (a50, b3, c2, d12), (a50, b3, c2, d13), (a50, b3, c2, d14), (a50, b3, c2, d15), (a50, b3, c2, d16), (a50, b3, c2, d17), (a50, b3, c2, d18), (a50, b3, c2, d19), (a50, b3, c2, d20), (a50, b3, c2, d21), (a50, b3, c2, d22), (a50, b 3, c3, d1), (a50, b3, c3, d2), (a50, b3, c3, d3), (a50, b3, c3, d4), (a50, b3, c3, d5), (a50, b3, c3, d6), (a50, b3, c3, d7), (a50, b3, c3, d8), (a50, b3, c3, d9), (a50, b3, c3, d10), (a50, b3, c3, d11), (a50, b3, c3, d12), (a50, b3, c3, d13), (a50, b3, c3 , d14), (a50, b3, c3, d15), (a50, b3, c3, d16), (a50, b3, c3, d17), (a50, b3, c3, d18), (a50, b3, c3, d19), (a50, b3, c3, d20), (a50, b3, c3, d21), (a50, b3, c3, d22), (a50, b4, c1, d1), (a50, b4, c1, d2), (a50, b4, c1, d3), (a50, b4, c1, d4), (a50, b4, c1 , d5), (a50, b4, c1, d6), (a50, b4, c1, d7), (a50, b4, c1, d8), (a50, b4, c1, d9), (a50, b4, c1, d10), (a50, b4, c1, d11), (a50, b4, c1, d12), (a50, b4, c1, d13), (a50, b4, c1, d14), (a50, b4, c1, d15), (a50, b4, c1, d16), (a50, b4, c1, d17), (a50, b4, c1, d18), (a50, b4, c1, d19), (a50, b4, c1, d20), (a50, b4, c1, d21), (a50, b4, c1, d22), (a50, b4, c2, d1), (a50, b4, c2, d2), (a50, b4, c2, d3), (a50, b4, c2, d4), (a50, b4, c2, d5), (a50, b4, c2, d6), (a50, b4, c2, d7), (a50, b4, c2, d8), (a50, b4, c2, d9) , (a50, b4, c2, d10), (a50, b4, c2, d11), (a50, b4, c2, d12), (a50, b4, c2, d13), (a50, b4, c2, d14), (a50, b4, c2, d15), (a50, b4, c2, d16), (a50, b4, c2, d17), (a50, b4, c2, d18), (a50, b4, c2, d19), (a50, b4, c2, d20), (a50, b4, c2, d21), (a50, b4, c2, d22), (a50, b4, c3, d1), (a50, b4, c3, d2), (a50, b4, c3, d3), (a50, b4, c3, d4), (a50, b4, c3, d5), (a50, b4, c3, d6), (a50, b4, c3, d7), (a50, b4, c3, d8), (a50, b4, c3, d9), (a50, b4, c3, d10), (a50, b4, c3, d11), (a50, b4, c3, d12), (a50, b4, c3, d13), (a50, b4, c3, d14), (a50, b4, c3, d15), (a50, b4, c3, d16), (a50, b4, c3, d17), (a50, b4, c3, d18), (a50, b4, c3, d19), (a50, b4, c3, d20), (a50, b4, c3, d21), (a50, b4, c3, d22), (a50, b5, c1, d1), (a50, b5, c1, d2), (a50, b5, c1, d3), (a50, b5, c1, d4), (a50, b5, c1, d5), (a50, b5, c1, d6), (a50, b5, c1, d7), (a50, b5, c1, d8), (a50, b5, c1, d9), (a50, b5, c1, d10), (a50, b5, c1, d11), (a50, b5, c1, d12), (a50, b5, c1, d13), (a50, b5, c1, d14), (a50, b5, c1, d15), (a50, b5, c1, d16), (a50, b5, c1, d17), (a50, b5, c1, d18), (a50, b5, c1, d19), (a50, b5, c1, d20), (a50, b5, c1, d21), (a50, b5, c1, d22), (a50, b5, c2, d1), (a50, b5, c2, d2), (a50, b5, c2, d3), (a50, b5, c2, d4), (a50, b5, c2, d5), (a50, b5, c2, d6), (a50, b5, c2, d7), (a50, b5, c2, d8), (a50 , b5, c2, d9), (a50, b5, c2, d10), (a50, b5, c2, d11), (a50, b5, c2, d12), (a50, b5, c2, d13), (a50, b5, c2, d14), (a50, b5, c2, d15), (a50, b5, c2, d16), (a50, b5, c2, d17), (a50, b5, c2, d18), (a50, b5, c2, d19), (a50, b5, c2, d20), (a50, b5, c2, d21), ( a50, b5, c2, d22), (a50, b5, c3, d1), (a50, b5, c3, d2), (a50, b5, c3, d3), (a50, b5, c3, d4), (a50, b5, c3, d5), (a50, b5, c3, d6), (a50, b5, c3, d7), (a50, b5, c3, d8), (a50, b5, c3, d9), (a50, b5, c3, d10), (a50, b5, c3, d11), (a50, b5, c3, d12), (a50, b5, c3, d13), (a50, b5, c3, d14), (a50, b5, c3, d15), (a50, b5, c3, d16), (a50, b5, c3, d17), (a50, b5, c3, d18), (a50, b5, c3, d19), (a50, b5, c3, d20), (a50, b5, c3, d21), (a50, b5, c3, d22), (a50, b6, c1, d1), (a50, b6, c1, d2), (a50, b6, c1, d3), (a50, b6, c1, d4), (a50, b6, c1, d5), (a50, b6, c1, d6), (a50, b6, c1, d7), (a50, b6, c1, d8), (a50, b6, c1, d9), (a50, b6, c1, d10), (a50, b6, c1, d11), (a50, b6, c1, d12), (a50, b6, c1, d13), (a50, b6, c1, d14), (a50, b6, c1, d15), (a50, b6, c1, d16), (a50, b 6, c1, d17), (a50, b6, c1, d18), (a50, b6, c1, d19), (a50, b6, c1, d20), (a50, b6, c1, d21), (a50, b6, c1, d22), (a50, b6, c2, d1), (a50, b6, c2, d2), (a50, b6, c2, d3), (a50, b6, c2, d4), (a50, b6, c2, d5), (a50, b6, c2, d6), (a50, b6, c2, d7), (a50, b6, c2, d8), (a50, b6, c2, d9), (a50, b6, c2, d10), (a50, b6, c2, d11), (a50, b6, c2, d12), (a50, b6, c2, d13), (a50, b6, c2, d14), (a50, b6, c2, d15), (a50, b6, c2, d16), (a50, b6, c2, d17), (a50, b6, c2, d18), (a50, b6, c2, d19), (a50, b6, c2, d20), (a50, b6 , c2, d21), (a50, b6, c2, d22), (a50, b6, c3, d1), (a50, b6, c3, d2), (a50, b6, c3, d3), (a50, b6, c3, d4), (a50, b6, c3, d5), (a50, b6, c3, d6), (a50, b6, c3, d7), (a50, b6, c3, d8), (a50, b6, c3, d9), (a50, b6, c3, d10), (a50, b6, c3, d11), (a50, b6, c3, d12), (a50, b6, c3, d13), (a50, b6, c3, d14), (a50, b6, c3, d15), (a50, b6, c3, d16), (a50, b6, c3, d17), (a50, b6, c3, d18), (a50, b6, c3, d19), (a50, b6, c3, d20), (a50, b6, c3, d21), (a50, b6, c3, d22), (a51, b1, c1, d1), (a51, b1, c1, d2), (a51, b1, c 1, d3), (a51, b1, c1, d4), (a51, b1, c1, d5), (a51, b1, c1, d6), (a51, b1, c1, d7), (a51, b1, c1, d8), (a51, b1, c1, d9), (a51, b1, c1, d10), (a51, b1, c1, d11), (a51, b1, c1, d12), (a51, b1, c1, d13), (a51, b1, c1, d14), (a51, b1, c1, d15), (a51, b1, c1, d16), (a51, b1, c1, d17), (a51, b1, c1, d18), (a51, b1, c1, d19), (a51, b1, c1, d20), (a51, b1, c1, d21), (a51, b1, c1, d22), (a51, b1, c2, d1), (a51, b1, c2, d2), (a51, b1, c2, d3), (a51, b1, c2, d4), (a51, b1, c2, d5), (a51, b1, c2, d6), (a51, b1, c2, d7 ), (a51, b1, c2, d8), (a51, b1, c2, d9), (a51, b1, c2, d10), (a51, b1, c2, d11), (a51, b1, c2, d12), (a51, b1, c2, d13), (a51, b1, c2, d14), (a51, b1, c2, d15), (a51, b1, c2, d16), (a51, b1, c2, d17), (a51, b1, c2, d18), (a51, b1, c2, d19), (a51, b1, c2, d 20), (a51, b1, c2, d21), (a51, b1, c2, d22), (a51, b1, c3, d1), (a51, b1, c3, d2), (a51, b1, c3, d3), (a51, b1, c3, d4), (a51, b1, c3, d5), (a51, b1, c3, d6), (a51, b1, c3, d7), (a51, b1, c3, d8), (a51, b1, c3, d9), (a51, b1, c3, d10), (a51, b1, c3, d11), (a51, b1, c3, d12), (a51, b1, c3, d13), (a51, b1, c3, d14), (a51, b1, c3, d15), (a51, b1, c3, d16), (a51, b1, c3, d17), (a51, b1, c3, d18), (a51, b1, c3, d19), (a51, b1, c3, d20), (a51, b1, c3, d21), (a51, b1, c3, d22), (a51, b2, c1, d1), (a51, b2, c1, d2) , (a51, b2, c1, d3), (a51, b2, c1, d4), (a51, b2, c1, d5), (a51, b2, c1, d6), (a51, b2, c1, d7), (a51, b2, c1, d8), (a51, b2, c1, d9), (a51, b2, c1, d10), (a51, b2, c1, d11), (a51, b2, c1, d12), (a51, b2, c1, d13), (a51, b2, c1, d14), (a51, b2, c1, d15), ( a51, b2, c1, d16), (a51, b2, c1, d17), (a51, b2, c1, d18), (a51, b2, c1, d19), (a51, b2, c1, d20), (a51, b2, c1, d21), (a51, b2, c1, d22), (a51, b2, c2, d1), (a51, b2, c2, d2), (a51, b2, c2, d3), (a51, b2, c2, d4), (a51, b2, c2, d5), (a51, b2, c2, d6), (a5 1, b2, c2, d7), (a51, b2, c2, d8), (a51, b2, c2, d9), (a51, b2, c2, d10), (a51, b2, c2, d11), (a51, b2, c2, d12), (a51, b2, c2, d13), (a51, b2, c2, d14), (a51, b2, c2, d15), (a51, b2, c2, d16), (a51, b2, c2, d17), (a51, b2, c2, d18), (a51, b2, c2, d19), (a 51, b2, c2, d20), (a51, b2, c2, d21), (a51, b2, c2, d22), (a51, b2, c3, d1), (a51, b2, c3, d2), (a51, b2, c3, d3), (a51, b2, c3, d4), (a51, b2, c3, d5), (a51, b2, c3, d6), (a51, b2, c3, d7), (a51, b2, c3, d8), (a51, b2, c3, d9), (a51, b2, c3, d10), (a51, b 2, c3, d11), (a51, b2, c3, d12), (a51, b2, c3, d13), (a51, b2, c3, d14), (a51, b2, c3, d15), (a51, b2, c3, d16), (a51, b2, c3, d17), (a51, b2, c3, d18), (a51, b2, c3, d19), (a51, b2, c3, d20), (a51, b2, c3, d21), (a51, b2, c3, d22), (a51, b3, c1, d1), (a51 , b3, c1, d2), (a51, b3, c1, d3), (a51, b3, c1, d4), (a51, b3, c1, d5), (a51, b3, c1, d6), (a51, b3, c1, d7), (a51, b3, c1, d8), (a51, b3, c1, d9), (a51, b3, c1, d10), (a51, b3, c1, d11), (a51, b3, c1, d12), (a51, b3, c1, d13), (a51, b3, c1, d14), (a51, b3 , c1, d15), (a51, b3, c1, d16), (a51, b3, c1, d17), (a51, b3, c1, d18), (a51, b3, c1, d19), (a51, b3, c1, d20), (a51, b3, c1, d21), (a51, b3, c1, d22), (a51, b3, c2, d1), (a51, b3, c2, d2), (a51, b3, c2, d3), (a51, b3, c2, d4), (a51, b3, c2, d5), (a51, b3, c2, d6), (a51, b3, c2, d7), (a51, b3, c2, d8), (a51, b3, c2, d9), (a51, b3, c2, d10), (a51, b3, c2, d11), (a51, b3, c2, d12), (a51, b3, c2, d13), (a51, b3, c2, d14), (a51, b3, c2, d15), (a51, b3, c2, d16), (a51, b3, c2, d17), (a51, b3, c2, d18), (a51, b3, 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c3, d19), (a59, b3, c3, d20), (a59, b3, c3, d21), (a59, b3, c3, d22), (a59, b4, c1, d1), (a59, b4, c1, d2), (a59, b4, c1, d3), (a59, b4, c1, d4), (a59, b4, c1, d5), (a59, b4, c1, d6), (a59, b4, c1, d7), (a59, b4, c1, d8), (a 59, b4, c1, d9), (a59, b4, c1, d10), (a59, b4, c1, d11), (a59, b4, c1, d12), (a59, b4, c1, d13), (a59, b4, c1, d14), (a59, b4, c1, d15), (a59, b4, c1, d16), (a59, b4, c1, d17), (a59, b4, c1, d18), (a59, b4, c1, d19), (a59, b4, c1, d20), (a59, b4, c1, d21), (a59, b4, c1, d22), (a59, b4, c2, d1), (a59, b4, c2, d2), (a59, b4, c2, d3), (a59, b4, c2, d4), (a59, b4, c2, d5), (a59, b4, c2, d6), (a59, b4, c2, d7), (a59, b4, c2, d8), (a59, b4, c2, d9), (a59, b4, c2, d10), (a59, b4, c2, d11), (a59, b4, c2, d12), (a59 , b4, c2, d13), (a59, b4, c2, d14), (a59, b4, c2, d15), (a59, b4, c2, d16), (a59, b4, c2, d17), (a59, b4, c2, d18), (a59, b4, c2, d19), (a59, b4, c2, d20), (a59, b4, c2, d21), (a59, b4, c2, d22), (a59, b4, c3, d1), (a59, b4, c3, d2), (a59, b4, c3, d3), (a5 9, b4, c3, d4), (a59, b4, c3, d5), (a59, b4, c3, d6), (a59, b4, c3, d7), (a59, b4, c3, d8), (a59, b4, c3, d9), (a59, b4, c3, d10), (a59, b4, c3, d11), (a59, b4, c3, d12), (a59, b4, c3, d13), (a59, b4, c3, d14), (a59, b4, c3, d15), (a59, b4, c3, d16), (a59, b4, c3, d17), (a59, b4, c3, d18), (a59, b4, c3, d19), (a59, b4, c3, d20), (a59, b4, c3, d21), (a59, b4, c3, d22), (a59, b5, c1, d1), (a59, b5, c1, d2), (a59, b5, c1, d3), (a59, b5, c1, d4), (a59, b5, c1, d5), (a59, b5, c1, d6), (a59, b5, c1, d7), (a59, b5 , c1, d8), (a59, b5, c1, d9), (a59, b5, c1, d10), (a59, b5, c1, d11), (a59, b5, c1, d12), (a59, b5, c1, d13), (a59, b5, c1, d14), (a59, b5, c1, d15), (a59, b5, c1, d16), (a59, b5, c1, d17), (a59, b5, c1, d18), (a59, b5, c1, d19), (a59, b5, c1, d20), (a59, b5, c1, d21), (a59, b5, c1, d22), (a59, b5, c2, d1), (a59, b5, c2, d2), (a59, b5, c2, d3), (a59, b5, c2, d4), (a59, b5, c2, d5), (a59, b5, c2, d6), (a59, b5, c2, d7), (a59, b5, c2, d8), (a59, b5, c2, d9), (a59, b5, c2, d10), (a59, b5, 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(a60, b1, c1, d3), (a60, b1, c1, d4), (a60, b1, c1, d5), (a60, b1, c1, d6), ( a60, b1, c1, d7), (a60, b1, c1, d8), (a60, b1, c1, d9), (a60, b1, c1, d10), (a60, b1, c1, d11), (a60, b1, c1, d12), (a60, b1, c1, d13), (a60, b1, c1, d14), (a60, b1, c1, d15), (a60, b1, c1, d16), (a60, b1, c1, d17), (a60, b1, c1, d18), (a60, b1, c1, d19), (a60, b1, c1, d20), (a60, b1, c1, d21), (a60, b1, c1, d22), (a60, b1, c2, d1), (a60, b1, c2, d2), (a60, b1, c2, d3), (a60, b1, c2, d4), (a60, b1, c2, d5), (a60, b1, c2, d6), (a60, b1, c2, d7), (a60, b1, c2, d8), (a60, b1, c2, d9), (a60, b1, c2, d10), (a60, b1, c2, d11), (a60, b1, c2, d12), (a60, b1, c2, d13), (a60, b1, c2, d14), (a60, b1, c2, d15), (a60, b1, c2, d16), (a60, b1, c2, d17), (a60, b1, c2, d18), (a60, b1, c2, d19), (a60, b1, c2, d20), (a60, b1, c2, d21), (a60, b1, c2, d22), (a60, b1, c3, d1), (a 60, b1, c3, d2), (a60, b1, c3, d3), (a60, b1, c3, d4), (a60, b1, c3, d5), (a60, b1, c3, d6), (a60, b1, c3, d7), (a60, b1, c3, d8), (a60, b1, c3, d9), (a60, b1, c3, d10), (a60, b1, c3, d11), (a60, b1, c3, d12), (a60, b1, c3, d13), (a60, b1, c3, d14), (a60, b1, c3, d15), (a60, b1, c3, d16), (a60, b1, c3, d17), (a60, b1, c3, d18), (a60, b1, c3, d19), (a60, b1, c3, d20), (a60, b1, c3, d21), (a60, b1, c3, d22), (a60, b2, c1, d1), (a60, b2, c1, d2), (a60, b2, c1, d3), (a60, b2, c1, d4), (a60, b2, c1, d5), (a60, b 2, c1, d6), (a60, b2, c1, d7), (a60, b2, c1, d8), (a60, b2, c1, d9), (a60, b2, c1, d10), (a60, b2, c1, d11), (a60, b2, c1, d12), (a60, b2, c1, d13), (a60, b2, c1, d14), (a60, b2, c1, d15), (a60, b2, c1, d16), (a60, b2, c1, d17), (a60, b2, c1, d18), (a60, b 2, c1, d19), (a60, b2, c1, d20), (a60, b2, c1, d21), (a60, b2, c1, d22), (a60, b2, c2, d1), (a60, b2, c2, d2), (a60, b2, c2, d3), (a60, b2, c2, d4), (a60, b2, c2, d5), (a60, b2, c2, d6), (a60, b2, c2, d7), (a60, b2, c2, d8), (a60, b2, c2, d9), (a60, b2, c2 , d10), (a60, b2, c2, d11), (a60, b2, c2, d12), (a60, b2, c2, d13), (a60, b2, c2, d14), (a60, b2, c2, d15), (a60, b2, c2, 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d8), (a60, b4, c1, d9), (a60, b4, c1, d10), (a60, b4, c1, d11), (a60, b4, c1, d12), (a60, b4, c1, d13), (a60, b4, c1, d14), (a60, b4, c1, d15), (a60, b4, c1, d16), (a60, b4, c1, d17), ( a60, b4, c1, d18), (a60, b4, c1, d19), (a60, b4, c1, d20), (a60, b4, c1, d21), (a60, b4, c1, d22), (a60, b4, c2, d1), (a60, b4, c2, d2), (a60, b4, c2, d3), (a60, b4, c2, d4), (a60, b4, c2, d5), (a60, b4, c2, d6), (a60, b4, c2, d7), (a60, b4, c2, d8), (a60, b4, c2, d9), (a60, b4, c2, d10), (a60, b4, c2, d11), (a60, b4, c2, d12), (a60, b4, c2, d13), (a60, b4, c2, d14), (a60, b4, c2, d15), (a60, b4, c2, d16), (a60, b4, c2, d17), (a60, b4, c2, d18), (a60, b4, c2, d19), (a60, b4, c2, d20), (a60, b4, c2, d21), (a 60, b4, c2, d22), (a60, b4, c3, d1), (a60, b4, c3, d2), (a60, b4, c3, d3), (a60, b4, c3, d4), (a60, b4, c3, d5), (a60, b4, c3, d6), (a60, b4, c3, d7), (a60, b4, c3, d8), (a60, b4, c3, d9), (a60, b4, c3, d10), (a60, b4, c3, d11), (a60, b4, c3, d12), (a60, b 4, c3, d13), (a60, b4, c3, d14), (a60, b4, 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c1, d4), (a71, b2, c1, d5), (a71, b2, c1, d6), (a71, b2, c1, d7), (a71, b2, c1, d8), (a71, b2, c1, d9), (a71, b2, c1, d10), (a71, b2, c1, d11), (a71, b2, c1, d12), (a71, b2, c1, d13), (a71, b2, c1, d14 ), (a71, b2, c1, d15), (a71, b2, c1, d16)
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d1), (a71, b3, c1, d2), (a71, b3, c1, d3), (a71, b3, c1, d4), (a71, b3, c1, d5), (a71, b3, c1, d6), (a71, b3, c1, d7), (a71, b3, c1, d8), (a71, b3, c1, d9), (a71, b3, c1, d10), (a71, b3, c1, d11), (a71, b3, c1, d12), (a71, b3, c1, d13), (a71 , b3, c1, d14), (a71, b3, c1, d15), (a71, b3, c1, d16), (a71, b3, c1, d17), (a71, b3, c1, d18), (a71, b3, c1, d19), (a71, b3, c1, d20), (a71, b3, c1, d21), (a71, b3, c1, d22), (a71, b3, c2, d1), (a71, b3, c2, d2), (a71, b3, c2, d3), (a71, b3, c2, d4), (a71 , b3, c2, d5), (a71, b3, c2, d6), (a71, b3, c2, d7), (a71, b3, c2, d8), (a71, b3, c2, d9), (a71, b3, c2, d10), (a71, b3, c2, d11), (a71, b3, c2, d12), (a71, b3, c2, d13), (a71, b3, c2, d14), (a71, b3, c2, d15), (a71, b3, c2, d16), (a71, b3, c2, d17), (a71, b3, c2, d18), (a71, b3, c2, d19), (a71, b3, c2, d20), (a71, b3, c2, d21), (a71, b3, c2, d22), (a71, b3, c3, d1), (a71, b3, c3, d2), (a71, b3, c3, d3), (a71, b3, c3, d4), (a71, b3, c3, d5), (a71, b3, c3, d6), (a71, b3, c3, d7), (a71, b3, c3, d8), (a71, b3, c3, d9), (a71, b3, c3, d10), (a71, b3, c3, d11), (a71, b3, c3, d12), (a71, b3, c3, d13), (a71, b3, c3, d14), (a71, b3, c3, d15), (a71, b3, c3, d16), (a71, b3, c3, d17), (a71, b3, c3, d18), (a71, b3, c3, d19), (a71, b3, c3, d20), (a71, b3, c3, d21), (a71, b3, c3, d22), (a71, b4, c1, d1), (a71, b4, c1, d2), (a71, b4, c1, d3), (a71, b4, c1, d4), (a71, b4, c1, d5), (a71, b4, c1, d6), (a71, b4, c1, d7), (a71, b4, c1, d8), (a71, b4, c1, d9), (a71, b4, c1, d10), (a71, b4, c1, d11), (a71, b4, c1, d12), (a71, b4, c 1, d13), (a71, b4, c1, d14), (a71, b4, c1, d15), (a71, b4, c1, d16), (a71, b4, c1, d17), (a71, b4, c1, d18), (a71, b4, c1, d19), (a71, b4, c1, d20), (a71, b4, c1, d21), (a71, b4, c1, d22), (a71, b4, c2, d1), (a71, b4, c2, d2), (a71, b4, c2, d3), (a71, b4, c2, d4), (a71, b4, c2, d5), (a71, b4, c2, d6), (a71, b4, c2, d7), (a71, b4, c2, d8), (a71, b4, c2, d9), (a71, b4, c2, d10), (a71, b4, c2, d11), (a71, b4, c2, d12), (a71, b4, c2, d13), (a71, b4, c2, d14), (a71, b4, c2, 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c1, d7), (a71, b6, c1, d8), (a71, b6, c1, d9), (a71, b6, c1, d10), (a71, b6, c1, d11), (a71, b6, c1, d12), (a71, b6, c1, d13), (a71, b6, c1, d14), (a71, b6, c1, d15), (a71, b6, c1, d16), (a71, b6, c1, d17), (a71, b6, c1, d18), (a71, b6, c1, d19), (a71, b6, c1, d20), (a71, b6, c1, d21), (a71, b6, c1, d22), (a71, b6, c2, d1), (a71, b6, c2, d2), (a7 1, b6, c2, d3), (a71, b6, c2, d4), (a71, b6, c2, d5), (a71, b6, c2, d6), (a71, b6, c2, d7), (a71, b6, c2, d8), (a71, b6, c2, d9), (a71, b6, c2, d10), (a71, b6, c2, d11), (a71, b6, c2, d12), (a71, b6, c2, d13), (a71, b6, c2, d14), (a71, b6, c2, d15), (a71, b6, c2, d16), (a71, b6, c2, d17), (a71, b6, c2, d18), (a71, b6, c2, d19), (a71, b6, c2, d20), (a71, b6, c2, d21), (a71, b6, c2, d22), (a71, b6, c3, d1), (a71, b6, c3, d2), (a71, b6, c3, d3), (a71, b6, c3, d4), (a71, b6, c3, d5), (a71, b6, c3, d6), (a71, b6 , c3, d7), (a71, b6, c3, d8), (a71, b6, c3, d9), (a71, b6, c3, d10), (a71, b6, c3, d11), (a71, b6, c3, d12), (a71, b6, c3, d13), (a71, b6, 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b2, c2, d6), (a72, b2, c2, d7), (a72, b2, c2, d8), (a72, b2, c2, d9), (a72, b2, c2, d10), (a72, b2, c2, d11), (a72, b2, c2, d12), (a72, b2, c2, d13), (a72, b2, c2, d14), (a72, b2, c2, d15), (a72, b2, c2, d16), (a72, b2, c2, d17), (a72, b2, c2, d18), (a72, b2, c2, d19), (a72, b2, c2, d20), (a72, b2, c2, d21), (a72, b2, c2, d22), (a72, b2, c3, d1), (a72, b2, c3, d2), (a72, b2, c3, d3), (a72, b2, c3, d4), (a72, b2, c3, d5), ( a72, b2, c3, d6), (a72, b2, c3, d7), (a72, b2, c3, d8), (a72, b2, c3, d9), (a72, b2, c3, d10), (a72, b2, c3, d11), (a72, b2, c3, d12), (a72, b2, c3, d13), (a72, b2, c3, d14), (a72, b2, c3, d15), (a72, b2, c3, d16), (a72, b2, c3, d17), (a72, b2, c3, d18), ( a72, b2, c3, d19), (a72, b2, c3, d20), (a72, b2, c3, d21), (a72, b2, c3, d22), (a72, b3, c1, d1), (a72, b3, c1, d2), (a72, b3, c1, d3), (a72, b3, c1, d4), (a72, b3, c1, d5), (a72, b3, c1, d6), (a72, b3, c1, d7), (a72, b3, c1, d8), (a72, b3, c1, d9), (a72, b3, c1, d10), (a72, b3, c1, d11), (a72, b3, c1, d12), (a72, 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(a78, b1, c1, d18), (a78, b1, c1, d19), (a78, b1, c1, d20), (a78, b1, c1, d21), (a78, b1, c1, d22), (a78, b1, c2, d1), (a78, b1, c2, d2), (a78, b1, c2, d3), (a78, b1, c2, d 4), (a78, b1, c2, d5), (a78, b1, c2, d6), (a78, b1, c2, d7), (a78, b1, c2, d8), (a78, b1, c2, d9), (a78, b1, c2, d10), (a78, b1, c2, d11), (a78, b1, c2, d12), (a78, b1, c2, d13), (a78, b1, c2, d14), (a78, b1, c2, d15), (a78, b1, c2, d16), (a78, b1, c2, d17 ), (a78, b1, c2, d18), (a78, b1, c2, d19), (a78, b1, c2, d20), (a78, b1, c2, d21), (a78, b1, c2, d22), (a78, b1, c3, d1), (a78, b1, c3, d2), (a78, b1, c3, d3), (a78, b1, c3, d4), (a78, b1, c3, d5), (a78, b1, c3, d6), (a78, b1, c3, d7), (a78, b1, c3, d8), ( a78, b1, c3, d9), (a78, b1, c3, d10), (a78, b1, c3, d11), (a78, b1, c3, d12), (a78, b1, c3, d13), (a78, b1, c3, d14), (a78, b1, c3, d15), (a78, b1, c3, d16), (a78, b1, c3, d17), (a78, b1, c3, d18), (a78, b1, c3, d19), (a78, b1, c3, d20), (a78, b1, c3, d21) , (a78, b1, c3, d22), (a78, b2, c1, d1), (a78, b2, c1, d2), (a78, b2, c1, d3), (a78, b2, c1, d4), (a78, b2, c1, d5), (a78, b2, c1, d6), (a78, b2, c1, d7), (a78, b2, c1, d8), (a78, b2, c1, d9), (a78, b2, c1, d10), (a78, b2, c1, d11), (a78, b2, c1, d12), (a7 8, b2, c1, d13), (a78, b2, c1, d14), (a78, b2, c1, d15), (a78, b2, c1, d16), (a78, b2, c1, d17), (a78, b2, c1, d18), (a78, b2, c1, d19), (a78, b2, c1, d20), (a78, b2, c1, d21), (a78, b2, c1, d22), (a78, b2, c2, d1), (a78, b2, c2, d2), (a78, b2, c2, d3), (a 78, b2, c2, d4), (a78, b2, c2, d5), (a78, b2, c2, d6), (a78, b2, c2, d7), (a78, b2, c2, d8), (a78, b2, c2, d9), (a78, b2, c2, d10), (a78, b2, c2, d11), (a78, b2, c2, d12), (a78, b2, c2, d13), (a78, b2, c2, d14), (a78, b2, c2, d15), (a78, b2, c2, d16), (a78 , b2, c2, d17), (a78, b2, c2, d18), (a78, b2, c2, d19), (a78, b2, c2, d20), (a78, b2, c2, d21), (a78, b2, c2, d22), (a78, b2, c3, d1), (a78, b2, c3, d2), (a78, b2, c3, d3), (a78, b2, c3, d4), (a78, b2, c3, d5), (a78, b2, c3, d6), (a78, b2, c3, d7), (a78, b 2, c3, d8), (a78, b2, c3, 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(a89, b4, c2, d18), (a89, b4, c2, d19), (a89, b4, c2, d20), (a89, b4, c2, d21), (a89, b4, c2, d22), (a89, b4, c3, d1), (a89, b4, c3, d2), (a89, b4, c3, d3), (a89, b4, c3, d4), (a89, b4, c3, d5), (a89, b4, c3, d6), (a89, b4, c3, d7), (a89, b4, c
3, d8), (a89, b4, c3, d9), (a89, b4, c3, d10), (a89, b4, c3, d11), (a89, b4, c3, d12), (a89, b4, c3, d13), (a89, b4, c3, d14), (a89, b4, c3, d15), (a89, b4, c3, d16), (a89, b4, c3, d17), (a89, b4, c3, d18), (a89, b4, c3, d19), (a89, b4, c3, d20), (a89, b4, c3, d21), (a89, b4, c3, d22), (a89, b5, c1, d1), (a89, b5, c1, d2), (a89, b5, c1, d3), (a89, b5, c1, d4), (a89, b5, c1, d5), (a89, b5, c1, d6), (a89, b5, c1, d7), (a89, b5, c1, d8), (a89, b5, c1, d9), (a89, b5, c1, d10), (a89, b5, c1, d11), (a89, b5, c1, d12), (a89, b5, c1, d13), (a89, b5, c1, d14), (a89, b5, c1, d15), (a89, b5, c1, d16), (a89, b5, c1, d17), (a89, b5, c1, d18), (a89, b5, c1, d19), (a89, b5, c1, d20), (a89, b5, c1, d21), (a89, b5, c1, d22), (a89, b5, c2, d1), (a89, b5, c2, d2), (a89, b5, c2, d3), (a89, b5, c2, d4), (a89, b5, c2, d5), (a89, b5, c2, d6), (a89, b5, c2, d7), (a89, b5, c2, d8), (a89, b5, c2, d9), (a89, b5, c2, d 10), (a89, b5, c2, d11), (a89, b5, c2, d12), (a89, b5, c2, d13), (a89, b5, c2, d14), (a89, b5, c2, d15), (a89, b5, c2, d16), (a89, b5, c2, d17), (a89, b5, c2, d18), (a89, b5, c2, d19), (a89, b5, c2, d20), (a89, b5, c2, d21), (a89, b5, c2, d22), (a89, b5, c 3, d1), (a89, b5, c3, d2), (a89, b5, c3, d3), (a89, b5, c3, d4), (a89, b5, c3, d5), (a89, b5, c3, d6), (a89, b5, c3, d7), (a89, b5, c3, d8), (a89, b5, c3, d9), (a89, b5, c3, d10), (a89, b5, c3, d11), (a89, b5, c3, d12), (a89, b5, c3, d13), (a89, b5, c3, d1 4), (a89, b5, c3, d15), (a89, b5, c3, d16), (a89, b5, c3, d17), (a89, b5, c3, d18), (a89, b5, c3, d19), (a89, b5, c3, d20), (a89, b5, c3, d21), (a89, b5, c3, d22), (a89, b6, c1, d1), (a89, b6, c1, d2), (a89, b6, c1, d3), (a89, b6, c1, d4), (a89, b6, c1, d5 ), (a89, b6, c1, d6), (a89, b6, c1, d7), (a89, b6, c1, d8), (a89, b6, c1, d9), (a89, b6, c1, d10), (a89, b6, c1, d11), (a89, b6, c1, d12), (a89, b6, c1, d13), (a89, b6, c1, d14), (a89, b6, c1, d15), (a89, b6, c1, d16), (a89, b6, c1, d17), (a89, b6, c1, d18 ), (a89, b6, c1, d19), (a89, b6, c1, d20), (a89, b6, c1, d21), (a89, b6, c1, d22), (a89, b6, c2, d1), (a89, b6, c2, d2), (a89, b6, c2, d3), (a89, b6, c2, d4), (a89, b6, c2, d5), (a89, b6, c2, d6), (a89, b6, c2, d7), (a89, b6, c2, d8), (a89, b6, c2, d9), (a 89, b6, c2, d10), (a89, b6, c2, d11), (a89, b6, c2, d12), (a89, b6, c2, d13), (a89, b6, c2, d14), (a89, b6, c2, d15), (a89, b6, c2, d16), (a89, b6, c2, d17), (a89, b6, c2, d18), (a89, b6, c2, d19), (a89, b6, c2, d20), (a89, b6, c2, d21), (a89, b6, c2, d22) , (a89, b6, c3, d1), (a89, b6, c3, d2), (a89, b6, c3, d3), (a89, b6, c3, d4), (a89, b6, c3, d5), (a89, b6, c3, d6), (a89, b6, c3, d7), (a89, b6, c3, d8), (a89, b6, c3, d9), (a89, b6, c3, d10), (a89, b6, c3, d11), (a89, b6, c3, d12), (a89, b6, c3, d13), (a8 9, b6, c3, d14), (a89, b6, c3, d15), (a89, b6, c3, d16), (a89, b6, c3, d17), (a89, b6, c3, d18), (a89, b6, c3, d19), (a89, b6, c3, d20), (a89, b6, c3, d21), (a89, b6, c3, d22), (a90, b1, c1, d1), (a90, b1, c1, d2), (a90, b1, c1, d3), (a90, b1, c1, d4), (a9 0, b1, c1, d5), (a90, b1, c1, d6), (a90, b1, c1, d7), (a90, b1, c1, d8), (a90, b1, c1, d9), (a90, b1, c1, d10), (a90, b1, c1, d11), (a90, b1, c1, d12), (a90, b1, c1, d13), (a90, b1, c1, d14), (a90, b1, c1, d15), (a90, b1, c1, d16), (a90, b1, c1, d17), (a90 , b1, c1, d18), (a90, b1, c1, d19), (a90, b1, c1, d20), (a90, b1, c1, d21), (a90, b1, c1, d22), (a90, b1, c2, d1), (a90, b1, c2, d2), (a90, b1, c2, d3), (a90, b1, c2, d4), (a90, b1, c2, d5), (a90, b1, c2, d6), (a90, b1, c2, d7), (a90, b1, c2, d8), (a90, b1 , c2, d9), (a90, b1, c2, d10), (a90, b1, c2, d11), (a90, b1, c2, d12), (a90, b1, c2, d13), (a90, b1, c2, d14), (a90, b1, c2, d15), (a90, b1, c2, d16), (a90, b1, c2, d17), (a90, b1, c2, d18), (a90, b1, c2, d19), (a90, b1, c2, d20), (a90, b1, c2, d21), (a90, b1, c2, d22), (a90, b1, c3, d1), (a90, b1, c3, d2), (a90, b1, c3, d3), (a90, b1, c3, d4), (a90, b1, c3, d5), (a90, b1, c3, d6), (a90, b1, c3, d7), (a90, b1, c3, d8), (a90, b1, c3, d9), (a90, b1, c3, d10), (a90, b1, c3, d11), (a90, b1, c3, d12), (a90, b1, c3, d13), (a90, b1, c3, d14), (a90, b1, c3, d15), (a90, b1, c3, d16), (a90, b1, c3, d17), (a90, b1, c3, d18), (a90, b1, c3, d19), (a90, b1, c3, d20), (a90, b1, c3, d21), (a90, b1, c3, d22), (a90, b2, c1, d1), (a90, b2, c1, d2), (a90, b2, c1, d3), (a90, b2, c1, d4), (a90, b2, c1, d5), (a90, b2, c1, d6), (a90, b2, c1, d7), (a90, b2, c1, d8), (a90, b2, c1, d9), (a90, b2, c1, d10), (a90, b2, c1, d11), (a90, b2, c1, d12), (a90, b2, c1, d13), (a90, b2, c1, d14), (a90, b2, c1, d15), (a90, b2, c1, d16), (a90, b2, c 1, d17), (a90, b2, c1, d18), (a90, b2, c1, d19), (a90, b2, c1, d20), (a90, b2, c1, d21), (a90, b2, c1, d22), (a90, b2, c2, d1), (a90, b2, c2, d2), (a90, b2, c2, d3), (a90, b2, c2, d4), (a90, b2, c2, d5), (a90, b2, c2, d6), (a90, b2, c2, d7), (a90, b2, c2, d8), (a90, b2, c2, d9), (a90, b2, c2, d10), (a90, b2, c2, d11), (a90, b2, c2, d12), (a90, b2, c2, d13), (a90, b2, c2, d14), (a90, b2, c2, d15), (a90, b2, c2, d16), (a90, b2, c2, d17), (a90, b2, c2, d18), (a90, b2, c2, d19), (a90, b2, c2, d20), (a90, b2, c2 , d21), (a90, b2, c2, d22), (a90, b2, c3, d1), (a90, b2, c3, d2), (a90, b2, c3, d3), (a90, b2, c3, d4), (a90, b2, c3, d5), (a90, b2, c3, d6), (a90, b2, c3, d7), (a90, b2, c3, d8), (a90, b2, c3, d9), (a90, b2, c3, d10), (a90, b2, c3, d11), (a90, b2, c3, d12 ), (a90, b2, c3, d13), (a90, b2, c3, d14), (a90, b2, c3, d15), (a90, b2, c3, d16), (a90, b2, c3, d17), (a90, b2, c3, d18), (a90, b2, c3, d19), (a90, b2, c3, d20), (a90, b2, c3, d21), (a90, b2, c3, d22), (a90, b3, c1, d1), (a90, b3, c1, d2), (a90, b3, c1, d 3), (a90, b3, c1, d4), (a90, b3, c1, d5), (a90, b3, c1, d6), (a90, b3, c1, d7), (a90, b3, c1, d8), (a90, b3, c1, d9), (a90, b3, c1, d10), (a90, b3, c1, d11), (a90, b3, c1, d12), (a90, b3, c1, d13), (a90, b3, c1, d14), (a90, b3, c1, d15), (a90, b3, c1, d16) , (a90, b3, c1, d17), (a90, b3, c1, d18), (a90, b3, c1, d19), (a90, b3, c1, d20), (a90, b3, c1, d21), (a90, b3, c1, d22), (a90, b3, c2, d1), (a90, b3, c2, d2), (a90, b3, c2, d3), (a90, b3, c2, d4), (a90, b3, c2, d5), (a90, b3, c2, d6), (a90, b3, c2, d7), ( a90, b3, c2, d8), (a90, b3, c2, d9), (a90, b3, c2, d10), (a90, b3, c2, d11), (a90, b3, c2, d12), (a90, b3, c2, d13), (a90, b3, c2, d14), (a90, b3, c2, d15), (a90, b3, c2, d16), (a90, b3, c2, d17), (a90, b3, c2, d18), (a90, b3, c2, d19), (a90, b3, c2, d20), (a90, b3, c2, d21), (a90, b3, c2, d22), (a90, b3, c3, d1), (a90, b3, c3, d2), (a90, b3, c3, d3), (a90, b3, c3, d4), (a90, b3, c3, d5), (a90, b3, c3, d6), (a90, b3, c3, d7), (a90, b3, c3, d8), (a90, b3, c3, d9), (a90, b3, c3, d10), (a90, b3, c3, d11), (a90 , b3, c3, d12), (a90, b3, c3, d13), (a90, b3, c3, d14), (a90, b3, c3, d15), (a90, b3, c3, d16), (a90, b3, c3, d17), (a90, b3, c3, d18), (a90, b3, c3, d19), (a90, b3, c3, d20), (a90, b3, c3, d21), (a90, b3, c3, d22), (a90, b4, c1, d1), (a90, b4, c1, d2), (a 90, b4, c1, d3), (a90, b4, c1, d4), (a90, b4, c1, d5), (a90, b4, c1, d6), (a90, b4, c1, d7), (a90, b4, c1, d8), (a90, b4, c1, d9), (a90, b4, c1, d10), (a90, b4, c1, d11), (a90, b4, c1, d12), (a90, b4, c1, d13), (a90, b4, c1, d14), (a90, b4, c1, d15), (a90, b4, c1, d16), (a90, b4, c1, d17), (a90, b4, c1, d18), (a90, b4, c1, d19), (a90, b4, c1, d20), (a90, b4, c1, d21), (a90, b4, c1, d22), (a90, b4, c2, d1), (a90, b4, c2, d2), (a90, b4, c2, d3), (a90, b4, c2, d4), (a90, b4, c2, d5), (a90, b4, c2, d6), (a90, b 4, c2, d7), (a90, b4, c2, d8), (a90, b4, c2, d9), (a90, b4, c2, d10), (a90, b4, c2, d11), (a90, b4, c2, d12), (a90, b4, c2, d13), (a90, b4, c2, d14), (a90, b4, c2, d15), (a90, b4, c2, d16), (a90, b4, c2, d17), (a90, b4, c2, d18), (a90, b4, c2, d19), (a90, b4, c2, d20), (a90, b4, c2, d21), (a90, b4, c2, d22), (a90, b4, c3, d1), (a90, b4, c3, d2), (a90, b4, c3, d3), (a90, b4, c3, d4), (a90, b4, c3, d5), (a90, b4, c3, d6), (a90, b4, c3, d7), (a90, b4, c3, d8), (a90, b4, c3, d9), (a90, b4, c3, d10), (a90, b4, c 3, d11), (a90, b4, c3, d12), (a90, b4, c3, d13), (a90, b4, c3, d14), (a90, b4, c3, d15), (a90, b4, c3, d16), (a90, b4, c3, d17), (a90, b4, c3, d18), (a90, b4, c3, d19), (a90, b4, c3, d20), (a90, b4, c3, d21), (a90, b4, c3, d22), (a90, b5, c1, d1), (a90, b5 , c1, d2), (a90, b5, c1, d3), (a90, b5, c1, d4), (a90, b5, c1, d5), (a90, b5, c1, d6), (a90, b5, c1, d7), (a90, b5, c1, d8), (a90, b5, c1, d9), (a90, b5, c1, d10), (a90, b5, c1, d11), (a90, b5, c1, d12), (a90, b5, c1, d13), (a90, b5, c1, d14), (a90, b5, c1 , d15), (a90, b5, c1, d16), (a90, b5, c1, d17), (a90, b5, c1, d18), (a90, b5, c1, d19), (a90, b5, c1, d20), (a90, b5, c1, d21), (a90, b5, c1, d22), (a90, b5, c2, d1), (a90, b5, c2, d2), (a90, b5, c2, d3), (a90, b5, c2, d4), (a90, b5, c2, d5), (a90, b5, c2, d6), (a90, b5, c2, d7), (a90, b5, c2, d8), (a90, b5, c2, d9), (a90, b5, c2, d10), (a90, b5, c2, d11), (a90, b5, c2, d12), (a90, b5, c2, d13), (a90, b5, c2, d14), (a90, b5, c2, d15), (a90, b5, c2, d16), (a90, b5, c2, d17), (a90, b5, c2, d18), (a90, b5, c2, d19), (a90, b5, c2, d20), (a90, b5, c2, d21), (a90, b5, c2, d22), (a90, b5, c3, d1), (a90, b5, c3, d2), (a90, b5, c3, d3), (a90, b5, c3, d4), (a90, b5, c3, d5), (a90, b5, c3, d6), (a90, b5, c3, d7), (a90, b5, c3, d8), (a90, b5, c3, d9), (a90, b5, c3, d10) , (a90, b5, c3, d11), (a90, b5, c3, d12), (a90, b5, c3, d13), (a90, b5, c3, d14), (a90, b5, c3, d15), (a90, b5, c3, d16), (a90, b5, c3, d17), (a90, b5, c3, d18), (a90, b5, c3, d19), (a90, b5, c3, d20), (a90, b5, c3, d21), (a90, b5, c3, d22), (a90, b6, c1, d1), (a90, b6, c1, d2), (a90, b6, c1, d3), (a90, b6, c1, d4), (a90, b6, c1, d5), (a90, b6, c1, d6), (a90, b6, c1, d7), (a90, b6, c1, d8), (a90, b6, c1, d9), (a90, b6, c1, d10), (a90, b6, c1, d11), (a90, b6, c1, d12), (a90, b6, c1, d13), (a90, b6, c1, d14), (a90, b6, c1, d15), (a90, b6, c1, d16), (a90, b6, c1, d17), (a90, b6, c1, d18), (a90, b6, c1, d19), (a90, b6, c1, d20), (a90, b6, c1, d21), (a90, b6, c1, d22), (a90, b6, c2, d1), (a90, b6, c2, d2), (a90, b6, c2, d3), (a90, b6, c2, d4), (a90, b6, c2, d5), (a90, b6, c2, d6), (a90, b6, c2, d7), (a90, b6, c2, d8), (a90, b6, c2, d9), (a90, b6, c2, d10), (a90, b6, c2, d11), (a90, b6, c2, d12), (a90, b6, c2, d13), (a90, b6, c2, d14), (a90, b6, c2, d15), (a90, b6, c2, d16), (a90, b6, c2, d17), (a90, b6, c2, d18), (a90, b6, c2, d19), (a90, b6, c2, d20), (a90, b6, c2, d21), (a90, b6, c2, d22), (a90, b6,
c3, d1), (a90, b6, c3, d2), (a90, b6, c3, d3), (a90, b6, c3, d4), (a90, b6, c3, d5), (a90, b6, c3, d6), (a90, b6, c3, d7), (a90, b6, c3, d8), (a90, b6, c3, d9), (a90, b6, c3, d10), (a90, b6, c3, d11), (a90, b6, c3, d12), (a90, b6, c3, d13), (a90, b6, c3, d14), (a90, b6, c3, d15), (a90, b6, c3, d16), (a90, b6, c3, d17), (a90, b6, c3, d18), (a90, b6, c3, d19), (a90, b6, c3, d20), (a90, b6, c3, d21), (a90, b6, c3, d22)
一般式（Ａ）で表される化合物においては、その光学異性体およびラセミ体も包含する。

試験例１ EGFR及びHER2に対する被験化合物の酵素阻害活性
昆虫細胞発現系から精製されたEGFR、HER2および、ビオチン化基質(グルタミン酸:チロシン=4:1の合成ペプチド)を、ATPが添加された384穴プレートに加え、室温にて酵素反応を行なった。酵素反応終了後に、ユーロピウム標識した抗リン酸化チロシン抗体とアルフィコシアニン標識したストレプトアビジンを添加し、リン酸化チロシン残基を時間分解蛍光法で定量した。
（被験化合物の調製）
被験化合物はDMSOを用いて10mMに調製した。
さらに10%DMSO溶液を用いて1mM溶液を調製し、これを最高濃度ポイントとした。
希釈系列は4倍希釈系列を10段階まで作製した。
（試薬調製）
バッファーの調製：
バッファーは、10mM MgCl₂, 5mM MnCl₂, 0.2mM Na₃VO₄, 0.1%BSAを含むTBSを用いた。
酵素：
EGFR、HER2酵素は、昆虫細胞発現系から精製したものをカルナバイオサイセンス社より購入した。
EGFR酵素溶液は、バッファーを用いて2 50ng/mlに調製した。
HER2キナーゼは、バッファーを用いて1000ng/mlに調製した。
基質溶液：
基質には、ビオチン化poly-Glu-Tyr(4:1, CISbio社製)を用いた。濃度は、上記バッファーを用いて3.125μg/mlとした。
ATP溶液：
EGFR酵素の検討でのATP濃度は、上記バッファーを用いて125μMに調製した。
HER2酵素の検討でのATP濃度は、290μMに調製した。
検出試薬：
検出試薬の調製には、30mM EDTA, 0.8M KF, 0.1% BSAを含むTBSを用いた。
ユーロピウム標識した抗リン酸化チロシン抗体、PT-66K(CISbio社)は195ng/mlにアルフィコシアニン標識したストレプトアビジン、SA-XL(CISbio社)は5μg/mlに調製した。
（アッセイ方法）
アッセイプレートには、384穴プレートを用いた。1ウェルあたり被験化合物を1.1μl、基質溶液4μl、酵素溶液4μl添加した後、ATP溶液2μlを加え酵素反応を開始した。酵素反応は室温にて60分行い、検出試薬を10μl添加して反応を終了した。反応終了の1時間後に時間分解蛍光測定を行なった。
（評価方法）
被験化合物の代わりに10%DMSOを用い、ATP添加時のシグナルを0%阻害(酵素活性100%)、ATP非存在下のシグナルを100%阻害(酵素活性0%)として、被験化合物添加時の阻害活性を算出した。
実施例に記載のEGFR及びHER2に対する阻害活性(IC₅₀値、nM)を以下に示す。

試験例２被験化合物のin vitro細胞増殖抑制試験
ヒト由来がん細胞株として、BT- 474 を用いた。細胞はすべてDulbecco’s Modified Essential Medium (DMEM, ナカライテスク）に10％牛胎児血清（Fetal Bovine Serum, ICN）と50 units/mlペニシリン／50 μg/mlストレプトマイシン溶液（GIBCO）を添加した培地で37℃、5％CO₂インキュベーター内にて培養した。96穴プレート（住友ベークライト）に細胞を3000個／穴ずつ播種し、翌日薬剤を最終濃度3x10^-10−10^-5Mとなるように添加した。3日間培養した後WS T(water-soluble tetrazolium salt)アッセイを行い、IC₅₀値を算出した。
実施例に記載のBT-474に対する増殖阻害活性(IC₅₀値、nM)を以下に示す。

試験例３被験化合物のi n vivo 抗腫瘍評価試験
NCI-N87細胞（ヒト胃癌細胞株）を雌性ヌードマウス(BALB/cA Jcl-nu/nu, 日本クレア)の乳腺部脂肪組織（mammary fat pad ）に5x10⁶細胞／マウスで移植した(day 0)。Day 5に腫瘍の長径と短径をノギスで測定し、群間の腫瘍サイズが均等になるようマウスを群分けした(N=6)。0.5％メチルセルロース(MC)溶液に懸濁した被験化合物(20, 80 mg/kg)をday 5より15日間連日経口投与し、day 20における化合物投与群(T)とcontrol(C; 0.5%MC)群の腫瘍サイズの平均値の比(T/C%)によって抗腫瘍効果を表した。
化合物VIII-11のin vivo抗腫瘍評価の結果を表５４に、化合物VII I-66のin vivo抗腫瘍評価の結果を表５５に示す。

製剤例

製剤例１
以下の成分を含有する顆粒剤を製造する。
成分式（Ｉ）で表わされる化合物 10 mg
乳糖 700 mg
コーンスターチ 274 mg
HPC-L 16 mg
1000 mg
式（Ｉ）で表わされる化合物と乳糖を６０メッシュのふるいに通す。コーンスターチを１２０メッシュのふるいに通す。これらをV型混合機にて混合する。混合末にＨＰＣ−Ｌ（低粘度ヒドロキシプロピルセルロース）水溶液を添加し、練合、造粒（押し出し造粒孔径０．５〜１ｍｍ）したのち、乾燥する。得られた乾燥顆粒を振動ふるい（１２／６０メッシュ）で櫛過し顆粒剤を得る。
製剤例２
以下の成分を含有するカプセル充填用散剤を製造する。
成分式（Ｉ）で表わされる化合物 10 mg
乳糖 79 mg
コーンスターチ 10 mg
ステアリン酸マグネシウム 1 mg
100 mg
式（Ｉ）で表わされる化合物、乳糖を６０メッシュのふるいに通す。コーンスターチは１２０メッシュのふるいに通す。これらとステアリン酸マグネシウムをV型混合機にて混合する。１０倍散１００ｍｇを５号硬ゼラチンカプセルに充填する。
製剤例３
以下の成分を含有するカプセル充填用顆粒剤を製造する。
成分式（Ｉ）で表わされる化合物 15 mg
乳糖 90 mg
コーンスターチ 42 mg
HPC-L 3 mg
150 mg
式（Ｉ）で表わされる化合物、乳糖を６０メッシュのふるいに通す。コーンスターチを１２０メッシュのふるいに通す。これらを混合し、混合末にＨＰＣ−Ｌ溶液を添加して練合、造粒、乾燥する。得られた乾燥顆粒を整粒後、その１５０ｍｇを４号硬ゼラチンカプセルに充填する。
製剤例４
以下の成分を含有する錠剤を製造する。
成分式（Ｉ）で表わされる化合物 10 mg
乳糖 90 mg
微結晶セルロース 30 mg
CMC-Na 15 mg
ステアリン酸マグネシウム 5 mg
150 mg
式（Ｉ）で表わされる化合物、乳糖、微結晶セルロース、ＣＭＣ−Ｎａ（カルボキシメチルセルロースナトリウム塩）を６０メッシュのふるいに通し、混合する。混合末にステアリン酸マグネシウム混合し、製錠用混合末を得る。本混合末を直打し、１５０ｍｇの錠剤を得る。
製剤例５
静脈用製剤は次のように製造する：
式（Ｉ）で表わされる化合物１００ｍｇ
飽和脂肪酸グリセリド１０００ｍｌ
上記成分の溶液は通常、１分間に１ｍｌの速度で患者に静脈内投与される。

本発明化合物は、優れたＥＧＦ受容体およびＨＥＲ２の阻害作用を有し、安全性も高いことから、医薬品、とりわけ癌に対する治療剤として有用である。

Claims

一般式（Ｉ）：

［式中、Ｒ^Ｘは、式：

（式中、Ｒ^１は、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアリール、または置換されていてもよい非芳香族含窒素複素環基；
Ｚは、−Ｏ−、−Ｎ（Ｒ^１０）−、または−Ｏ−もしくは−Ｎ（Ｒ^１１）−を介在してもよいアルキレン；Ｒ^１０およびＲ^１１は、それぞれ独立して、水素原子、アルキル、アシル、アルキルオキシカルボニル、アルケニルオキシカルボニル、またはアラルキルオキシカルボニル；
Ｒ^２は、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいシクロアルキル、置換されていてもよいアリール、または置換されていてもよいヘテロアリール；
Ｒ^１９は、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよいヘテロアリール、または置換されていてもよい非芳香族複素環基；
Ｒ^１８は、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、または置換されていてもよいアルキニル；
Ｗ^１は、置換されていてもよい非芳香族含窒素複素環基または置換されていてもよいヘテロアリール；
Ｒ^１７は、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、または置換されていてもよい非芳香族含窒素複素環基）で表される基；
Ｒ^３およびＲ^４は、それぞれ独立して、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、置換されていてもよいアルケニルオキシ、ハロゲン、ヒドロキシ、メルカプト、または置換されていてもよいアミノ；
Ｘは、−Ｏ−、−Ｓ−、−Ｎ（Ｒ^１２）−、または−Ｏ−、−Ｓ−、もしくは−Ｎ（Ｒ^１３）−を介在してもよいアルキレン；Ｒ^１２およびＲ^１３は、それぞれ独立して、水素原子、アルキル、アシル、アルキルオキシカルボニル、アルケニルオキシカルボニル、またはアラルキルオキシカルボニル；および
Ａは、式：

（式中、Ｒ^５は、水素原子、ハロゲン、置換されていてもよいアルキルオキシ、置換されていてもよいアルケニルオキシ、置換されていてもよいアルキニルオキシ、または式：−Ｙ−Ｒ^８（式中、Yは−Ｏ−、−Ｓ−、−ＳＯ_２−、または−Ｏ−、−Ｓ−、もしくは−Ｎ（Ｒ^９）−を介在してもよいアルキレン；Ｒ^８は置換されていてもよいアリールまたは置換されていてもよいヘテロアリール；Ｒ^９は水素原子、アルキル、アシル、アルキルオキシカルボニル、アルケニルオキシカルボニル、またはアラルキルオキシカルボニル）で表される基；
Ｒ^６およびＲ^７は、それぞれ独立して、水素原子、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、置換されていてもよいアルケニルオキシ、置換されていてもよいアルキニルオキシ、ハロゲン、ヒドロキシ、メルカプト、シアノ、または置換されていてもよいアミノ；
Ｒ^２０は、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアルキニル、または式：

（式中、Ｒ^５、Ｒ^６、およびＲ^７は、前記と同意義）で表される基；
ＱはＮまたはＣＨ_２）で表される基］
で表される化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
Ｒ^Ｘが、式：

（式中、Ｒ^１、Ｒ^２、Ｒ^１８、Ｒ^１９、Ｚ、およびＷ^１は、請求項１と同意義）で表される基である、請求項１記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
Ｒ^１が、置換基群Ａ（置換基群Ａ：ヒドロキシ、ヘテロアリール、カルボキシ、置換されていてもよいアミノ、置換されていてもよい非芳香族含窒素複素環基、置換されていてもよいアミノカルボニル、または置換されていてもよい非芳香族含窒素複素環カルボニル）から選択される置換基で置換されていてもよいアルキル、または置換基群Ｂ（置換基群Ｂ：アルキルオキシカルボニル、置換されていてもよいアミノカルボニル、オキソ、アミノ、カルボキシ、シアノ、シアノアルキル、ヒドロキシアルキル、アルキルカルボニルアミノ、アルキルスルホニルアミノ、およびアミノカルボニルアルキル）から選択される置換基で置換されていてもよい非芳香族含窒素複素環基である、請求項１記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
Ｒ^１が、置換基群Ｃ（置換基群Ｃ：アルキル、アルケニル、アルキニル、置換されていてもよいアリール、アラルキル、アルキルオキシ、ヒドロキシアルキル、ヒドロキシアルキルオキシアルキル、ハロアルキル、１または2のアルキルで置換されていてもよいアミノアルキル、アルキルスルホニル、アルキルスルホニルアルキル、ハロゲンもしくはアルキルオキシで置換されていてもよいアルキルカルボニル、アルキルオキシカルボニル、置換されていてもよいシクロアルキル、カルボキシアルキル、置換されていてもよいアミノカルボニルアルキル、置換されていてもよいアミノカルボニルオキシアルキル、アルキルオキシアルキル、アルキルチオアルキル、アルキルカルボニルアミノアルキル、アルキルスルホニルアミノアルキル、アルキルスルホニル（アルキル）アミノアルキル、アルキルオキシカルボニルアルキル、アルキルチオ（ヒドロキシ）アルキル、シクロアルキルアルキル、シアノアルキル、置換されていてもよいアミノアルキルカルボニル、置換されていてもよいヘテロアリール、ヘテロアリールアルキル、ヒドロキシアルキルオキシアルキル、置換されていてもよい非芳香族複素環基、置換されていてもよい非芳香族複素環アルキル）から選択される置換基で置換されていてもよいアミノで置換されたアルキル、置換基群Ｄ（置換基群Ｄ：ハロゲン、アリール、ヒドロキシ、オキソ、置換されていてもよいアミノカルボニル、アルキルオキシカルボニル、置換基群Ｈ（置換基群Ｈ：置換されていてもよいアミノカルボニル、シアノ、アルキルオキシ、アルキルスルホニルアミノ、アミノ、カルボキシ、アルキルオキシカルボニル、およびヒドロキシ）から選択される置換基で置換されていてもよいアルキル、アルキルアミノカルボニル、カルボキシ、シアノ、アルキルスルホニル、アルキルカルボニル、アルケニルカルボニル、アルキルスルホニルアルキルカルボニル、アルキルオキシアルキルカルボニル、アルキルカルボニルアミノ、アミノカルボニルオキシ、非芳香族含窒素複素環基、および非芳香族複素環カルボニル）から選択される置換基で置換されていてもよい非芳香族含窒素複素環基で置換されたアルキル、または置換基群Ｂ（置換基群Ｂ：アルキルオキシカルボニル、置換されていてもよいアミノカルボニル、オキソ、アミノ、カルボキシ、シアノ、シアノアルキル、ヒドロキシアルキル、アルキルカルボニルアミノ、アルキルスルホニルアミノ、およびアミノカルボニルアルキル）から選択される置換基で置換されていてもよい非芳香族含窒素複素環基である、請求項１記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
Ｒ^１９が、置換基群Ａ（置換基群Ａ：ヒドロキシ、ヘテロアリール、カルボキシ、置換されていてもよいアミノ、置換されていてもよい非芳香族含窒素複素環基、置換されていてもよいアミノカルボニル、または置換されていてもよい非芳香族含窒素複素環カルボニル）から選択される置換基で置換されていてもよいアルキル、置換基群Ｉ（置換基群Ｉ：アルキルオキシカルボニル、置換されていてもよいアミノカルボニル、シアノ、シアノアルキル、ヒドロキシアルキル、およびアミノカルボニルアルキル）から選択される置換基で置換されていてもよいアリール、または置換基群Ｉから選択される置換基で置換されていてもよいヘテロアリールである、請求項１記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
Ｒ^１９が、置換基群Ｃ（置換基群Ｃ：アルキル、アルケニル、アルキニル、置換されていてもよいアリール、アラルキル、アルキルオキシ、ヒドロキシアルキル、ヒドロキシアルキルオキシアルキル、ハロアルキル、１または 2 のアルキルで置換されていてもよいアミノアルキル、アルキルスルホニル、アルキルスルホニルアルキル、ハロゲンもしくはアルキルオキシで置換されていてもよいアルキルカルボニル、アルキルオキシカルボニル、置換されていてもよいシクロアルキル、カルボキシアルキル、置換されていてもよいアミノカルボニルアルキル、置換されていてもよいアミノカルボニルオキシアルキル、アルキルオキシアルキル、アルキルチオアルキル、アルキルカルボニルアミノアルキル、アルキルスルホニルアミノアルキル、アルキルスルホニル（アルキル）アミノアルキル、アルキルオキシカルボニルアルキル、アルキルチオ（ヒドロキシ）アルキル、シクロアルキルアルキル、シアノアルキル、置換されていてもよいアミノアルキルカルボニル、置換されていてもよいヘテロアリール、ヘテロアリールアルキル、ヒドロキシアルキルオキシアルキル、置換されていてもよい非芳香族複素環基、置換されていてもよい非芳香族複素環アルキル）から選択される置換基で置換されていてもよいアミノで置換されたアルキル、または置換基群Ｄ（置換基群Ｄ：ハロゲン、アリール、ヒドロキシ、オキソ、置換されていてもよいアミノカルボニル、アルキルオキシカルボニル、置換基群Ｈ（置換基群Ｈ：置換されていてもよいアミノカルボニル、シアノ、アルキルオキシ、アルキルスルホニルアミノ、アミノ、カルボキシ、アルキルオキシカルボニル、およびヒドロキシ）から選択される置換基で置換されていてもよいアルキル、アルキルアミノカルボニル、カルボキシ、シアノ、アルキルスルホニル、アルキルカルボニル、アルケニルカルボニル、アルキルスルホニルアルキルカルボニル、アルキルオキシアルキルカルボニル、アルキルカルボニルアミノ、アミノカルボニルオキシ、非芳香族含窒素複素環基、および非芳香族複素環カルボニル）から選択される置換基で置換されていてもよい非芳香族含窒素複素環基で置換されたアルキルである、請求項１記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
Ｗ^１が、置換基群Ｊ（置換基群Ｊ：アルキル、シアノアルキル、ヒドロキシアルキル、アミノカルボニルアルキル、アルキルオキシ、アルキルオキシカルボニル、置換されていてもよいアミノカルボニル、およびシアノ）から選択される置換基で置換されていてもよい非芳香族含窒素複素環基で表される基または置換基群Ｊから選択される置換基で置換されていてもよいヘテロアリールで表される基である、請求項１記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
Ｒ^２が、水素原子、ハロゲンで置換されていてもよいＣ１−Ｃ６アルキル、Ｃ２−Ｃ６アルケニル、Ｃ２−Ｃ６アルキニル、ハロゲン、またはフェニルである、請求項１記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
Ｒ^３およびＲ^４の一方が水素原子、他方が水素原子、置換されていてもよいアルキルオキシまたは置換されていてもよいアルケニルオキシである、請求項１記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
Ｘが、−ＮＨ−である、請求項１記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
Ａが、式：

（式中、Ｒ^５は、水素原子またはハロゲン；Ｒ^６は、ハロゲンまたはアルキニル；およびＲ^７は水素原子）で表される基である、請求項１記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
Ａが、式：

［式中、Ｒ^５は、置換基群Ｅ（置換基群Ｅ：カルボキシ、アルキルオキシカルボニル、シクロアルキル、および置換されていてもよいアミノカルボニル）から選択される置換基で置換されていてもよいアルキルオキシ、置換基群Ｅから選択される置換基で置換されていてもよいアルケニルオキシ、または置換基群Ｅから選択される置換基で置換されていてもよいアルキニルオキシ；Ｒ^６は、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、またはハロゲン；およびＲ^７は水素原子］で表される基である、請求項１記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
Ａが、式：

［式中、Ｒ^５は、式：−Ｙ−Ｒ^８（式中、Yは、−Ｏ−を介在してもよいアルキレン；Ｒ^８は、置換基群Ｆ（置換基群Ｆ：ハロゲン、カルボキシ、アルキル、ハロアルキル、ヒドロキシアルキル、アルキルオキシ、アルキルオキシカルボニル、および置換されていてもよいアミノ）から選択される置換基で置換されていてもよいフェニル、置換基群Ｆから選択される置換基で置換されていてもよいピリジル、置換基群Ｆから選択される置換基で置換されていてもよいフリル、置換基群Ｆから選択される置換基で置換されていてもよいチエニル、置換基群Ｆから選択される置換基で置換されていてもよいチアゾリル、または置換基群Ｆから選択される置換基で置換されていてもよいオキサゾリル）で表される基；Ｒ^６が、置換されていてもよいアルキニル、置換されていてもよいアルキルオキシ、またはハロゲン；およびＲ^７が水素原子］で表される基である、請求項１記載の化合物もしくはその製薬上許容される塩またはそれらの溶媒和物。
請求項１記載の化合物を有効成分として含有する医薬組成物。
請求項１記載の化合物を有効成分として含有する抗癌剤。