JP2022508533A - ピラゾール置換縮合環誘導体並びにその製造方法及び応用 - Google Patents
ピラゾール置換縮合環誘導体並びにその製造方法及び応用 Download PDFInfo
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- alkyl
- pyridine
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- cycloalkenyl
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Abstract
Description
[技術分野]
本発明は、薬化学分野に関わるものであり、具体的にピラゾール置換縮合環誘導体並びにその製造方法及び応用に関わるものである。
[背景技術]
RET(Rearranged During Transfection)がん原遺伝子は、1985年にNIH3T3(マウス胚性線維芽細胞株)細胞をヒトリンパ腫DNAとトランスフェクションすることで初めで確認された(Cell、1985、42(2):581-588)。RETがん原遺伝子は染色体10q11.2にあり、そのDNAの全長は60kbで、21個のエクソンが含まれており、1100個のアミノ酸からなるRETタンパク質によってコード化:このRETタンパク質はチロシンキナーゼ受容体であり、システインで構成される細胞外ドメイン1個と、膜貫通ドメイン1個と、およびチロシンキナーゼを触媒することができる細胞内ドメイン1個と、を含む(Mol Cell Endocrinol、 2010, 322(1-2): 2-7)。RETは、細胞増殖、神経伝導、細胞移動、細胞分化に参与し、配位子/複合受容体/RET多タンパク質複合体のシグナルを介して、例に、RAS/RAF/MEK/ERK、PI3K/AKT、STATなどのさまざまな下流経路を活性化させることで、細胞増殖を誘発する(J Clin Oncol, 2012, 30(2): 200-202)。
[発明の内容]
上記課題を改善するため、本発明では、下記式Iに示す化合物、その立体異性体、ラセミ体、互変異性体、同位体マーカー、窒素酸化物、薬学的に許容される塩または溶媒和物を提供:
Eは、Hと、ハロゲンと、CNと、OHと、未置換または任意に1つ、2つまたは複数のReに置換されている以下の基:C1-40アルキル、C2-40アルケニル、C2-40アルキニル、C3-40シクロアルキル、C3-40シクロアルケニル、C3-40シクロアルキニル、C6-20アリール、5-20員複素アリール、3-20員複素環、C1-40アルキルオキシ、C2-40アルケニルオキシ、C2-40アルキニルオキシ、C3-40シクロアルキルオキシ、C3-40シクロアルケニルオキシ、C3-40シクロアルキニルオキシ、C6-20アリールオキシ、5-20員複素アリールオキシ、3-20員複素環基オキシ、と、から選ばれる。
各々のR2は、同じまたは異なり、お互い独立的にHと、未置換または任意にOH、NH2に置換されている以下の基:C1-40アルキル、C2-40アルケニル、C2-40アルキニル、C3-40シクロアルキル、C3-40シクロアルケニル、C3-40シクロアルキニル、C6-20アリール、5-20員複素アリール、3-20員複素環基、-C(O)R4、-S(O)2R6、とから選ばれる。
または、環状基(C3-40シクロアルキル、C3-40シクロアルケニル、C3-40シクロアルキニル、3-20員複素環基などを含むがこれらに限らない)の違う位置が、二つまたはより多くの置換基に置換された場合、上記置換基中の二つも上記環状基と架橋環を形成して良いし、その内、上記架橋環中の橋頭原子以外の橋状原子は1、2、3、4または5個のCH2と、Oと、NHと、から選ばれている二価基を含んでよい。
X1、X2、X3、X4、X5、X6は、同じまたは異なり、お互い独立的にCR1と、-C-AまたはNから選ばれ、その内各々のR1は、同じまたは異なり、お互い独立的にHと、ハロゲンと、CNと、OHと、未置換または任意に1つ、2つまたはより多くのRaに置換されている以下の基:C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-8シクロアルキル、C3-8シクロアルケニル、C3-8シクロアルキニル、C1-6アルキルオキシ、C2-6アルケニルオキシ、C2-6アルキニルオキシ、C3-8シクロアルキルオキシ、C3-8シクロアルケニルオキシ、C3-8シクロアルキニルオキシ、NR2R3、-NHC(O)R2、-C(O)R4、-OCR5、-S(O)2R6、OS(O)2R7と、から選ばれる;Aは、Hと、ハロゲンと、CNと、OHと、未置換または任意に1つ、2つまたはより多くのRbに置換されている以下の基:C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-8シクロアルキル、C3-8シクロアルケニル、C3-8シクロアルキニル、C1-6アルキルオキシ、C2-6アルケニルオキシ、C2-6アルキニルオキシ、C3-8シクロアルキルオキシ、C3-8シクロアルケニルオキシ、C3-8シクロアルキニルオキシ、NR2R3、-C(O)R4、-OCR5、-S(O)2R6、OS(O)2R7と、から選ばれる。
本発明の実施案において、その内、Rgは、ハロゲンと、CNと、OHと、SHと、オキソ(=O)と、NO2と、未置換または任意に一つ、二つまたはより多くのRhに置換されている以下の基:C1-6アルキル、C3-10シクロアルキル、C6-10アリール、5-10員複素アリール、3-10員複素環-、と、から選ばれる。
Eは、Hと、未置換または任意に一つ、二つまたはより多くのReに置換されている以下の基:C1-6アルキル、C1-6アルコキシ、と、から選ばれる;
各々のReは、同じまたは異なり、お互い独立的にOHと、Fと、C1-6アルキルと、から選ばれる;
Gは、未置換または任意にオキソ化された3-10員複素環基から選ばれるが、例として未置換または任意にオキソ化された又はC1-6アルキルに置換されたピペラジン基と、ピペリジニルと、が、挙げられる;または、上記複素環基のメタ位が2つの置換基に置換される場合、上記置換基は上記複素環基と架橋環を形成てよいし、その内、上記架橋環中の橋頭原子以外の橋状原子は、1、2、3、4または5個のCH2から選ばれる二価基を含んでよい。
X6は、-C-AまたはNから選ばれ、Aは、NH2と、メチル基と、エチル基またはプロピル基と、-NH(CH3)2と、OHと、Fと、-NH(O)CH3と、-NHCH3と、メトキシ基と、-NHC2H4-OHと、から選ばれる。
特に説明のない限り、本出願の明細書および特許請求の範囲に記載される基および用語の定義は、それを実例する定義、例示的な定義、好ましい定義、表に記載する定義、実施例中の特定化合物の定義などを含み、お互い任意に組み合わせるまたは結合させることができる。このような組み合わせまたは結合された後の基の定義および化合物の構造は、本出願明細書の記載範囲内とされるべきとする。
本発明者は、驚くことに、本発明で製造された化合物は、RET野生型、突然変異型、融合型を阻害する有意な阻害活性を有することに気づいた。なお、既存の化合物に対してその活性は明らかに改善されていた。他のRET阻害剤と比較して、本発明の代表的な実施例の化合物は、特に優れた医薬品動態学特性を有し、活性成分として使う場合、比較的小さい投与量を患者に投与することができるため、患者の治療費用の削減に繋がる。なお、本出願の化合物は、製造方法が簡単で、量産に適している。
以下、具体的な実施例をもって、本発明の技術案に対してさらに詳しく説明する。以下の実施例は例示的に本発明を説明及び解釈するものにすぎず、本発明の保護範囲を限定するものとして解釈されるべきではないことを理解されたい。本発明の上記内容を基盤に実現された技術は、すべて本発明の保護範囲内とされる。
2-アミノ-4-(6-(4-(2-(5-フルオロピリジン-2-基)アセチル)ピペラジン-1-基)ピリジン-3-基)-6-(1-メチル-1H-ピラゾール-4-基)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS069)
工程B:2-[(アミノオキシ)スルホニル]-1,3,5-トリメチルベンゼン
2-アミノ-6-(1-メチル-1H-ピラゾール-4-イル)-4-(6-(4-(ピリジン-2-イルメチル)ピペリジン-1-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS070)
2-メチル-4-(6-(4-(2-(5-フルオロピリジン-2-イル)アセチル)ピペラジン-1-イル)ピリジン-3-イル)-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS071)
2-メチル-6-(1-メチル-1H-ピラゾール-4-イル)-4-(6-(4-(ピリジン-2-イルメチル)ピペリジン-1-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS072)
2-アミノ-4-(6-(4-((5-フルオロピリジン-3-イル)メチル)ピペラジン-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS014)
工程A:1-(5-ブロモピリジン-2-イル)-4-((5-フルオロピリジン-3-イル)メチル)ピペラジン
2-アミノ-4-(6-(4-((2-フルオロベンジル)ピペラジン-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS015)
4-(5-(2-アミノ-3-シアノ-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-4-イル)ピリジン-2-イル)-1,4-ジエチルピペラジン-1-ホルムアミド(APS016)
2-アミノ-4-(6-(4-((3-フルオロベンジル)ピペラジン-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS019)
[実施例9]
2-アミノ-4-(6-(4-((2,5-ジフルオロベンジル)ピペラジン-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS020)
[実施例10]
2-アミノ-4-(6-(4-((5-クロロピリジン-3-イル)メチル)ピペラジン-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS021)
[実施例11]
2-アミノ-6-(1-メチル-1H-ピラゾール-4-イル)-4-(6-((3-メチルピリジン-2-イル)メチル)ピペラジン-1-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS022)
[実施例12]
2-アミノ-4-(6-(4-((2,6-ジフルオロベンジル)ピペラジン-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS024)
[実施例13]
2-アミノ-6-(1-メチル-1H-ピラゾール-4-イル)-4-(6-((4-メチルピリジン-2-イル)メチル)ピペラジン-1-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS025)
[実施例14]
2-アミノ-4-(6-(4-(3-メトキシベンジル)ピペラジン-1-イル)ピリジン-3-イル)-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS026)
[実施例15]
2-アミノ-4-(6-(4-(2-クロロベンジル)ピペラジン-1-イル)ピリジン-3-イル)-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS027)
[実施例16]
2-アミノ-4-(6-(4-(6-メトキシピリジン-2-イル)メチル)ピペラジン-1-イル)ピリジン-3-イル)-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS030)
[実施例17]
2-アミノ-4-(6-(4-((5-メトキシピリジン-2-イル)メチル)ピペラジン-1-イル)ピリジン-3-イル)-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS033)
[実施例18]
2-アミノ-4-(6-(4-(4-(ジメチルアミノ)ベンジル)ピペラジン-1-イル)ピリジン-3-イル)-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS034)
[実施例19]
2-アミノ-6-(1-メチル-1H-ピラゾール-4-イル)-4-(6-(4-(4-(ピリジン-2-イル)メチル)ピペラジン-1-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS035)
[実施20]
2-アミノ-6-(1-メチル-1H-ピラゾール-4-イル)-4-(6-(6-(ピリジン-2-イルメチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS038)
[実施例21]
2-アミノ-4-(6-(4-((6-(ジメチルアミノ)ピリジン-3-イル)メチル)ピペラジン-1-イル)ピリジン-3-イル)-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS041)
[実施例22]
2-アミノ-4-(6-(4-(2,6-ジフルオロベンゾイル)ピペラジン-1-イル)ピリジン-3-イル)-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS062)
[実施例23]
2-アミノ-6-(1-メチル-1H-ピラゾール-4-イル)-4-(6-(4-(ピラジン-2-イルメチル)ピペラジン-1-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS064)
[実施例24]
2-アミノ-4-(6-(4-((6-メトキシピリジン-3-イル)メチル)ピぺラジン-1-イル)ピリジン-3-イル)-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS068)
[実施例25]
(R)-2-アミノ-6-(1-メチル-1H-ピラゾール-4-イル)-4-(6-(3-メチル-4-(ピリジン-2-イルメチル)ピペラジン-1-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS073)
[実施例26]
2-アミノ-4-(6-(4-ベンジルピペラジン-1-イル)ピリジン-3-イル)-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS074)
[実施例27]
2-アミノ-6-(1-メチル-1H-ピラゾール-4-イル)-4-(6-(4-(ピリジン-3-イルメチル)ピペラジン-1-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS075)
[実施例28]
(R)-2-アミノ-6-(1-メチル-1H-ピラゾール-4-イル)-4-(6-(2-メチル-4-(ピリジン-2-イルメチル)ピペラジン-1-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS076)
[実施例29]
2-アミノ-4-(6-(4-(4-フルオロベンジル)ピペラジン-1-イル)ピリジン-3-イル)-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS077)
[実施例30]
2-アミノ-6-(1-メチル-1H-ピラゾール-4-イル)-4-(6-(4-(ピリジン-4-イルメチル)ピペラジン-1-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS078)
[実施例31]
2-アミノ-4-(6-(4-(3,4-ジフルオロベンジル)ピペラジン-1-イル)ピリジン-3-イル)-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS079)
[実施例32]
2-アミノ-4-(6-(4-(2,6-ジフルオロベンジル)ピペラジン-1-イル)ピリジン-3-イル)-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS024)
[実施例33]
4-(6-(4-((6-メトキシピリジン-3-イル)メチル)ピペラジン-1-イル)ピリジン-3-イル)-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,2,3]トリアゾール[1,5-a]ピリジン-3-ニトリル(APS081)
工程B:4-クロロ-6-(1-メチル-1H-ピラゾール-4-イル)-[1,2,3]トリアゾール[1,5-a]ピリジン-3-ニトリル
[実施例34]
2-(ジメチルアミノ)-4-(6-(4-((6-メトキシピリジン-3-イル)メチル)ピペラジン-1-イル)ピリジン-3-イル)-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS082)
[実施例35]
2-フルオロ-4-(6-(4-((6-メトキシピリジン-3-イル)メチル)ピペラジン-1-イル)ピリジン-3-イル)-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS084)
[実施例36]
2-ヒドロキシル-4-(6-(4-((6-メトキシピリジン-3-イル)メチル)ピペラジン-1-イル)ピリジン-3-イル)-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS083)
[実施例37]
N-(3-シアノ-4-(6-(4-((6-メトキシピリジン-3-イル)メチル)ピペラジン-1-イル)ピリジン-3-イル)-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-2-イル)アセトアミド(APS085)
[実施例38]
2-メチルアミノ-4-(6-(4-((6-メトキシピリジン-3-イル)メチル)ピペラジン-1-イル)ピリジン-3-イル)-6-(1-メチル-1H-ピラゾール-4-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS086)
[実施例39]
2-アミノ-4-(5-(6-((6-メトキシピリジン-3-イル)メチル) -3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピラジン-2-イル)-6-(((S)-モルホリン-2-イル)メトキシ)ピラゾロ[1,5-a]ピリジン-3-ニトリルトリフルオロ酢酸(APS087)
[実施例40]
2-フルオロ-4-(5-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピラジン-2-イル)-6-(((S)-モルホリン-2-イル)メトキシ)ピラゾロ[1,5-a]ピリジン-3-ニトリルトリフルオロ酢酸(APS088)
[実施例41]
2-アミノ-6-(2-ヒドロキシル-2-メチルプロポキシ)-4-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS089)
工程D:6-((6-メトキシピリジン-3-イル)メチル)-3-(5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ピリジン-2-イル)-3,6-ジアザビシクロ[3.1.1]ヘプタン
[実施例42]
2-フルオロ-6-(2-ヒドロキシル-2-メチルプロポキシ)-4-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS090)
[実施例43]
6-(2-ヒドロキシル-2-2メチルプロポキシ)-2-メトキシ-4-(6-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS091)
[実施例44]
2-アミノ-6-エトキシ-4-(5-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピラジン-2-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS092)
[実施例45]
N-(3-シアノ-6-(2-ヒドロキシル-2-メチルプロポキシ)-4-(6-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS093)
[実施例46]
6-(2-ヒドロキシル-2-メチルプロポキシ)-2-((2-2-ヒドロキシルエチル)アミノ)-4-(6-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS094)
[実施例47]
2-アミノ-6-エトキシ-4-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS095)
[実施例48]
6-エトキシ-2-フルオロ-4-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS096)
[実施例49]
2-アミノ-6-(2-メトキシエトキシ)-4-(6-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS097)
[実施例50]
2-フルオロ-6-(2-メトキシエトキシ)-4-(6-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS098)
[実施例51]
2-アミノ-6-エトキシ-4-(6-(6-((6-メトキシピリジン-3-イル)メチル)ピペラジン-1-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS099)
[実施例52]
2-アミノ-6-(2-メトキシエトキシ)-4-(6-(4-((6-メトキシピリジン-3-イル)メチル)ピペラジン-1-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS100)
[実施例53]
6-エトキシ-2-フルオロ-4-(6-(4-((6-メトキシピリジン-3-イル)メチル)ピペラジン-1-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS101)
[実施例54]
2-フルオロ-6-(2-メトキシエトキシ)-4-(6-(4-((6-メトキシピリジン-3-イル)メチル)ピペラジン-1-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS102)
[実施例55]
N-(3-シアノ-6-(2-メトキシエトキシ)-4-(6-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS103)
[実施例56]
2-フルオロ-4-(5-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピラジン-2-イル)-6-(((S)-4-メチルモルホリン-2-イル)メトキシ)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS104)
[実施例57]
2-アミノ-4-(6-(6-((5-クロロ-6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)-6-エトキシピラゾロ[1,5-a]ピリジン-3-ニトリル(APS105)
[実施例58]
2-アミノ-6-(2-ヒドロキシル-2-メチルプロポキシ)-4-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ホルムアミド(APS106)
[実施例59]
2-アミノ-4-(5-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン3-イル)ピラジン-2-イル)-6-(((S)-4-メチルモルホリン-2-イル)メトキシ)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS107)
[実施例60]
2-アミノ-4-(6-(6-((5-クロロ-6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン3-イル)ピリジン-3-イル)-6-(2-メトキシエトキシ)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS108)
[実施例61]
2-アミノ-6-(2-エトキシエトキシ)-4-(6-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ [3.1.1]ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS109)
[実施例62]
2-アミノ-6-(2-メトキシ-2-メチルプロポキシ)-4-(6-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS110)
[実施例63]
2-アミノ-6-エトキシ-4-(6-(6-((5-フルオロピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS111)
[実施例64]
2-アミノ-4-(6-(6-((5-クロロピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)-6-エトキシピラゾロ[1,5-a]ピリジン-3-ニトリル(APS112)
[実施例65]
2-アミノ-6-(2-シクロプロポキシエトキシ)-4-(6-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS113)
[実施例66]
2-アミノ-6-(2,2-ジフルオロエトキシ)-4-(6-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS114)
[実施例67]
2-アミノ-6-(ジフルオロメトキシ)-4-(6-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS115)
[実施例68]
2-アミノ-4-(6-(6-((5-クロロピリジン-2-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)-6-エトキシピラゾロ[1,5-a]ピリジン-3-ニトリル(APS116)
[実施例69]
2-アミノ-4-(6-(6-((5-フルオロピリジン-2-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)-6-エトキシピラゾロ[1,5-a]ピリジン-3-ニトリル(APS117)
[実施例70]
2-アミノ-6-エトキシ-4-(6-(6-((6-メトキシピリジン-2-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS118)
[実施例71]
2-アミノ-6-(2-フルオロエトキシ)-4-(6-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS119)
[実施例72]
2-アミノ-6-(2-イソプロポキシエトキシ)-4-(6-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ[3.1.1]ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ[1,5-a]ピリジン-3-ニトリル(APS120)
トランスフェクション組換え遺伝子(RET)は既に確認されている癌原遺伝子である。これがコードした1回膜貫通型受容体であるチロシンキナーゼは、多くの組織や細胞タイプの発育、成熟、維持に必需的なものである。通常の条件下では、グリア細胞株由来神経栄養因子(GDNF)ファミリーリガンドが、細胞表面のRETと結合することは、細胞内チロシン残基の二量体化と自己リン酸化を引き起こす。これは逆に、下流のRAS-MAPK、PI3K-AKT、およびホスホリパーゼCγ(PLCγ)経路を活性化させるともに、細胞の生存と増殖を増加させる。RETの突然変異を活性化する実例には、C634W、M918T、ゲートキーパー変異、V804LおよびV804Mが含まれる。
DMSOでCEP-32496を、10mMと1mMからそれぞれに3倍段階希釈し、合計10個の濃度を造った。
a)10nl化合物希釈液(5.2で製造)を、測定板(784075、Greiner)の全ての穴に移転する;
b)1000gで、化合物の板を1分間遠心分離する。
穴ごとの比率(665nm/615nm)を算出する。
阻害率%の計算式は下記通り:
阻害率%=[1-(受験化合物蛍光シグナル値-陽性対照蛍光シグナル値)/(陰性対照平均比率-陽性対照平均比率)]*100%
比率:測定された蛍光シグナル値由来である。
陽性対照平均比率は、サンプル板中の陽性対照(200nM AT13148)の平均比率である;
陰性対照平均比率は、サンプル板中の陰性対照(0.1% DMSO)の平均比率である。
GraphPad 6.0にて、阻害率%を、化合物濃度の対数を非線形回帰(用量反応関係―可変勾配)に適合させ、IC50値を算出する。
1、96穴に90μlの細胞混濁液を播種するが、4000細胞/穴とする。培養板を培養箱内で24時間培養(37℃、5% CO2)する。
Claims (10)
- 下記式Iに示す化合物、その立体異性体、ラセミ体、互変異性体、同位体マーカー、窒素酸化物、薬学的に許容される塩または溶媒和物であり、
その内、X1、X2、X3、X4、X5、X6は、同じまたは異なり、お互い独立的にCR1と、-C-AまたはNと、から選ばれるし、その内、各々のR1は同じまたは異なり、お互い独立的にHと、ハロゲンと、CNと、OHと、未置換または任意に1つ、2つ、または複数のRaに置換された以下の基:C1-40アルキルと、C2-40アルケニルと、C2-40アルキニルと、C3-40シクロアルキルと、C3-40シクロアルケニルと、C3-40シクロアルキニルと、C1-40アルキルオキシと、C2-40アルケニルオキシと、C2-40アルキニルオキシと、C3-40シクロアルキルオキシと、C3-40シクロアルケニルオキシと、C3-40シクロアルキニルオキシと、NR2R3と、-NHC(O)R2と、-C(O)R4と、-OCR5と、-S(O)2R6と、OS(O)2R7と、から選ばれ;Aは、Hと、ハロゲンと、CNと、OHと、未置換または任意に1つ、2つまたはより多くのRbに置換されている以下の基:C1-40アルキルと、C2-40アルケニルと、C2-40アルキニルと、C3-40シクロアルキルと、C3-40シクロアルケニルと、C3-40シクロアルキニルと、C1-40アルキルオキシと、C2-40アルケニルオキシと、C2-40アルキニルオキシと、C3-40シクロアルカンオキシと、C3-40シクロアルケニルオキシと、C3-40シクロアルキニルオキシと、NR2R3と、-C(O)R4と、-OCR5と、-S(O)2R6と、-OS(O)2R7と、-NHC(O)R2と、から選ばれ;
Bは、Hと、ハロゲンと、CNと、OHと、未置換または任意に1つ、2つまたはより多くのRcに置換されている以下の基:C1-40アルキルと、C2-40アルケニルと、C2-40アルキニルと、C3-40シクロアルキルと、C3-40シクロアルケニルと、C3-40シクロアルキニルと、C1-40アルキルオキシと、C2-40アルケニルオキシと、C2-40アルキニルオキシと、C3-40シクロアルキルオキシと、C3-40シクロアルケニルオキシと、C3-40シクロアルキニルオキシと、NR2R3と、-C(O)R4と、-NHC(O)R4と、-OCR5と、-S(O)2R6と、OS(O)2R7と、から選ばれ;
Dは、未置換または任意に1つ、2つまたはより多くのRdに置換されているC3-40シクロアルキルと、C3-40シクロアルケニルと、C3-40シクロアルキニルと、C1-40アルキルオキシと、C2-40アルケニルオキシと、C2-40アルキニルオキシと、C6-20アリールと、5-20員複素アリールまたは3-20員複素環基と、から選ばれ;
Eは、Hと、ハロゲンと、CNと、OHと、未置換または任意に1つ、2つまたはより多くのReに置換されている以下の基:C1-40アルキルと、C2-40アルケニルと、C2-40アルキニルと、C3-40シクロアルキルと、C3-40シクロアルケニルと、C3-40シクロアルキニルと、C6-20アリールと、5-20員複素アリールと、3-20員複素環基と、C1-40アルキルオキシと、C2-40アルケニルオキシと、C2-40アルキニルオキシと、C3-40シクロアルキルオキシと、C3-40シクロアルケニルオキシと、C3-40シクロアルキニルオキシと、C6-20アリールオキシと、5-20員複素アリールオキシと、3-20員複素環基オキシと、から選ばれ;
Gは、未置換または任意に1つ、2つまたはより多くのRfに置換されている以下の基:C3-40シクロアルキルと、C3-40シクロアルケニルと、C3-40シクロアルキニルと、C6-20アリールと、5-20員複素アリールと、3-20員複素環基と、C3-40シクロアルキルオキシと、C3-40シクロアルケニルオキシと、C3-40シクロアルキニルオキシと、C6-20アリールオキシと、5-20員複素アリールオキシと、3-20員複素環基オキシと、から選ばれ;
Kは、Hと、ハロゲンと、CNと、OHと、未置換または任意に1つ、2つまたはより多くのRgに置換されている以下の基:C1-40アルキルと、C2-40アルケニルと、C2-40アルキニルと、C3-40シクロアルキルと、C3-40シクロアルケニルと、C3-40シクロアルキニルと、C6-20アリールと、5-20員複素アリールと、3-20員複素環基と、C1-40アルキルオキシと、C2-40アルケニルオキシと、C2-40アルキニルオキシと、C3-40シクロアルキルオキシと、C3-40シクロアルケニルオキシと、C3-40シクロアルキニルオキシと、C6-20アリールオキシと、5-20員複素アリールオキシと、3-20員複素環基オキシと、NR2R3と、-C(O)R4と、-OCR5と、-S(O)2R6と、OS(O)2R7と、から選ばれ;
各々のR2は、同じまたは異なり、お互い独立的にHと、未置換または任意にOHと、NH2とに置換されている以下の基:C1-40アルキルと、C2-40アルケニルと、C2-40アルキニルと、C3-40シクロアルキルと、C3-40シクロアルケニルと、C3-40シクロアルキニルと、C6-20アリールと、5-20員複素アリールと、3-20員複素環基と、-C(O)R4と、-S(O)2R6と、から選ばれ;
各々のR3は、同じまたは異なり、お互い独立的にHと、C1-40アルキルと、C2-40アルケニルと、C2-40アルキニルと、C3-40シクロアルキルと、C3-40シクロアルケニルと、C3-40シクロアルキニルと、C6-20アリールと、5-20員複素アリールと、3-20員複素環基、-C(O)R4と、-S(O)2R6と、から選ばれ;
または、R2及びR3は、接続しているN原子とともに5-20員複素アリールまたは3-20員複素環基を形成し;
各々のR4は、同じまたは異なり、お互い独立的にHと、C1-40アルキルと、C2-40アルケニルと、C2-40アルキニルと、C3-40シクロアルキルと、C3-40シクロアルケニルと、C3-40シクロアルキニルと、C6-20アリールと、5-20員複素アリールと、3-20員複素環基と、C1-40アルキルオキシと、C2-40アルケニルオキシと、C2-40アルキニルオキシと、C3-40シクロアルキルオキシと、C3-40シクロアルケニルオキシと、C3-40シクロアルキニルオキシと、C6-20アリールオキシと、5-20員複素アリールオキシと、3-20員複素環基オキシと、NR2R3と、から選ばれ;
各々のR5は、同じまたは異なり、お互い独立的にHと、C1-40アルキルと、C2-40アルケニルと、C2-40アルキニルと、C3-40シクロアルキルと、C3-40シクロアルケニルと、C3-40シクロアルキニルと、C6-20アリールと、5-20員複素アリールと、3-20員複素環基と、C1-40アルキルカルボニルと、C2-40アルケニルカルボニルと、C2-40アルキニルカルボニルと、C3-40シクロアルキルカルボニルと、C3-40シクロアルケニルカルボニルと、C3-40シクロアルキニルカルボニルと、C6-20アリールカルボニルと、5-20員複素アリールカルボニルと、3-20員複素環基カルボニルと、から選ばれ;
各々のR6は、同じまたは異なり、お互い独立的にHと、C1-40アルキルと、C2-40アルケニルと、C2-40アルキニルと、C3-40シクロアルキルと、C3-40シクロアルケニルと、C3-40シクロアルキニルと、C6-20アリールと、5-20員複素アリールと、3-20員複素環基と、C1-40アルキルオキシと、C2-40アルケニルオキシと、C2-40アルキニルオキシと、C3-40シクロアルキルオキシと、C3-40シクロアルケニルオキシと、C3-40シクロアルキニルオキシと、C6-20アリールオキシと、5-20員複素アリールオキシと、3-20員複素環基オキシと、NR2R3と、から選ばれる。
各々のR7は、同じまたは異なり、お互い独立的にHと、C1-40アルキルと、C2-40アルケニルと、C2-40アルキニルと、C3-40シクロアルキルと、C3-40シクロアルケニルと、C3-40シクロアルキニルと、C6-20アリールと、5-20員複素アリールと、3-20員複素環基と、から選ばれ;
各々のRa、Rb、Rc、Rd、Re、Rf、Rgは、同じまたは異なり、お互い独立的にハロゲンと、CNと、OHと、SHと、オキソ(=O)と、NO2と、未置換または任意に1つ、2つまたはより多くのRhに置換されている以下の基:C1-40アルキルと、C2-40アルケニルと、C2-40アルキニルと、C3-40シクロアルキルと、C3-40シクロアルケニルと、C3-40シクロアルキニルと、C6-20アリールと、5-20員複素アリールと、3-20員複素環基と、C1-40アルキルオキシと、C2-40アルケニルオキシと、C2-40アルキニルオキシと、C3-40シクロアルキルオキシと、C3-40シクロアルケニルオキシと、C3-40シクロアルキニルオキシと、C6-20アリールオキシと、5-20員複素アリールオキシと、3-20員複素環基オキシと、NR2R3と、-C(O)R4と、-OCR5と、-S(O)2R6と、OS(O)2R7と、から選ばれ;
各々のRhは、同じまたは異なり、お互い独立的にハロゲンと、CNと、OHと、SHと、オキソ(=O)と、NO2と、未置換または任意に1つ、2つまたはより多くのRjに置換されている以下の基:C1-40アルキルと、C2-40アルケニルと、C2-40アルキニルと、C3-40シクロアルキルと、C3-40シクロアルケニルと、C3-40シクロアルキニルと、C6-20アリールと、5-20員複素アリールと、3-20員複素環基、C1-40アルキルオキシと、C2-40アルケニルオキシと、C2-40アルキニルオキシと、C3-40シクロアルキルオキシと、C3-40シクロアルケニルオキシと、C3-40シクロアルキニルオキシと、C6-20アリールオキシと、5-20員複素アリールオキシと、3-20員複素環基オキシと、NR2R3と、-C(O)R4と、-OCR5と、-S(O)2R6と、OS(O)2R7と、から選ばれ;または、環状基(C3-40シクロアルキル、C3-40シクロアルケニル、C3-40シクロアルキニル、3-20員複素環基などを含むがこれらに限らない)の違う位置が、二つまたはより多くの置換基に置換された場合、上記置換基中の二つも上記環状基と架橋環を形成して良いし、その内、上記架橋環中の橋頭原子以外の橋状原子は1、2、3、4または5個のCH2と、Oと、NHと、から選ばれているニ価基を含んでよいし;
各々のRjは、同じまたは異なり、お互い独立的にハロゲンと、CNと、OHと、SHと、オキソ(=O)と、NO2と、未置換または任意に1つ、2つまたはより多くのRhに置換されている以下の基:C1-40アルキルと、C2-40アルケニルと、C2-40アルキニルと、C3-40シクロアルキルと、C3-40シクロアルケニルと、C3-40シクロアルキニルと、C6-20アリールと、5-20員複素アリールと、3-20員複素環基と、C1-40アルキルオキシと、C2-40アルケニルオキシと、C2-40アルキニルオキシと、C3-40シクロアルキルオキシと、C3-40シクロアルケニルオキシと、C3-40シクロアルキニルオキシと、C6-20アリールオキシと、5-20員複素アリールオキシと、3-20員複素環基オキシと、NR2R3と、-C(O)R4と、-OCR5と、-S(O)2R6と、OS(O)2R7と、から得られれ;
または、環状基(C3-40シクロアルキル、C3-40シクロアルケニル、C3-40シクロアルキニル、3-20員複素環基などを含むがこれらに限らない)の違う位置が、二つまたはより多くの置換基に置換された場合、上記置換基中の二つも上記環状基と架橋環を形成して良いし、その内、上記架橋環中の橋頭原子以外の橋状原子は1、2、3、4または5個のCH2と、Oと、NHと、から選ばれている二価基を含んでよいし;
または、1つの原子(例えば炭素原子)が2つまたはより多くの置換基に置換される場合、上記置換基中の二つも、それとともに接続されている原子と環状基(C3-40シクロアルキル、C3-40シクロアルケニル、C3-40シクロアルキニル、3-20員複素環基を含むがこれらに限らない)を形成してよい化合物、その立体異性体、ラセミ体、互変異性体、同位体マーカー、窒素酸化物、薬学的に許容される塩または溶媒和物。 - 請求項1または2に記載の化合物において、その内:
X6は、-C-AまたはNから選ばれ、Aは、Hと、未置換または任意に一つ、二つまたはより多くのRbに置換されている以下の基:NH2と、C1-6アルキルと、-NH(C1-6アルキル)2と、OHと、Fと、-NHC(O)C1-6アルキルと、-NHC1-6アルキルと、C1-6アルキルオキシと、-NHC1-6アルキル-OHと、から選ばれ;
各々のRbは、同じまたは異なり、各自独立的にC1-6アルキル基と、C1-6アルコキシ基と、から選ばれ;
Bは、Hと、CNと、-CONH2と、未置換または任意に一つ、二つまたはより多くのRcに置換されているC1-6アルキルと、から選ばれ;
各々のRcは、同じまたは異なり、各自独立的にハロゲンと、C1-6アルキル基と、から選ばれ;
Dは、未置換または任意に一つ、二つまたはより多くのRdに置換されている以下の基:C1-6アルキルオキシまたは5-14員複素アリールから選ばれてよいが、上記Rdは、未置換または任意に一つまたは複数の下記の基に置換されているC1-6アルキルまたは3-10員複素環基:オキソと、ハロゲンと、OHと、-N(C1-6アルキル)2または-S(O)2-C1-6アルキルと、から選ばれ;
Eは、Hと、未置換または任意に一つ、二つまたはより多くのReに置換されている以下の基:C1-6アルキルと、C1-6アルコキシと、から選ばれ;
各々のReは、同じまたは異なり、お互い独立的にOHと、Fと、C1-6アルキルと、から選ばれ;
Gは、未置換または任意にオキソ化された3-10員複素環基から選ばれるし、例として未置換または任意にオキソ化又はC1-6アルキルに置換されたピペラジン基と、ピペリジニルと、が、挙げられる;または、上記複素環基のメタ位が2つの置換基に置換される場合、上記置換基は上記複素環基と架橋環を形成してよいし、その内、上記架橋環中の橋頭原子以外の橋状原子は、1、2、3、4または5個のCH2から選ばれる二価基を含んでよいし、
Kは、未置換または任意に一つ、二つまたはより多くのRgに置換されている以下の基:C1-6アルキルと、-C(O)R4と、から選ばれ、上記Rgは、オキソと、OHと、未置換または任意に一つ、二つまたはより多くのRhに置換されているC1-6アルキルと、C1-6アルコキシと、C3-10シクロアルキルと、C6-14アリールと、5-14員複素アリールと、-SO2-C6-14アリールと、から選ばれ;各々のR4は、同じまたは異なり、お互い独立的にHと、C1-6アルキルと、C2-6アルケニルと、C2-6アルキニルと、C3-10シクロアルキルと、C3-10シクロアルケニルと、C3-10シクロアルキニルと、C6-14アリールと、5-14員複素アリールと、3-10員複素環基と、C1-6アルキルオキシと、C2-6アルケニルオキシと、C2-6アルキニルオキシと、C3-10シクロアルキルオキシと、C3-10シクロアルケニルオキシと、C3-10シクロアルキニルオキシと、C6-14アリールオキシと、5-14員複素アリールオキシと、3-10員複素環基オキシと、-N(C1-6アルキル)2と、から選ばれ;上記Rhは、ハロゲンと、C1-6アルコキシと、NH2と、-N(C1-6アルキル)2と、-NHC6-14アリールと、-NHC1-6アルキルと、から選ばれ;または、K中の原子(例:炭素原子)一つが二つまたはより多くのRgに置換された場合、二つのRgもそれと共に結合している原子と環状基(C3-10シクロアルキル、C3-10シクロアルケニル、C3-10シクロアルキニル、3-10員複素環基などを含むがこれらに限らない)を形成してよい化合物。 - 薬学的組成物であり、治療有効量の請求項1-4の何れの一項に記載の化合物、その立体異性体、ラセミ体、互変異性体、同位体マーカー、窒素酸化物、薬学的に許容される塩または溶媒和物、中の少なくとも一種を含むことを特徴とする薬学的組成物。
- 請求項8に記載の薬学的組成物において、上記薬学的組成物は、さらに、一種又は多種の薬学的に許容される担持体または賦形剤を含むことを特徴とする薬学的組成物。
- 請求項6又は7に記載の薬学的組成物において、上記薬学的組成物は、さらに、一種又は多種の他の治療剤を含むことを特徴とする薬学的組成物。
- 請求項1-4の何れの一項に記載の化合物、その立体異性体、ラセミ体、互変異性体、同位体マーカー、窒素酸化物、薬学的に許容される塩または溶媒和物、中の少なくとも一種の、RETキナーゼが媒介する疾病を治療することに用いる医薬品の製造における用途であり、又は、
RETキナーゼの活性を阻害することに用いる用途であり、又は、
RET関連疾病又は病症を治療することに用いる用途であり、又は、
癌治療及び/又は特定の癌と関係している転移を抑制することに用いる医薬品の製造における用途であり、又は、
過敏性腸症候群(IBS)の治療又はIBSと関係している痛みを治療することに用いる医薬品の製造における用途であり、又は、
癌患者に対して支持的ケアを提供することに用いる医薬品の製造における用途であり、又は、
RETキナーゼの活性を阻害することに用いる医薬品の製造における用途であり、又は、
RET関連疾病または病症を治療することに用いる医薬品の製造における用途を含む用途。 - 請求項9に記載の用途において、上記RETキナーゼが媒介する疾病は、癌、過敏性腸症候群又はそれらと関係している痛み、を含むことを特徴とする用途。
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