JP2012514601A - ピリミド−ジアゼピノンキナーゼ骨格化合物及び疾患を治療する方法 - Google Patents
ピリミド−ジアゼピノンキナーゼ骨格化合物及び疾患を治療する方法 Download PDFInfo
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Abstract
【選択図】 図1
Description
本出願は、2009年1月6日に出願された、米国仮特許出願61/193,901号の優先権を主張する。上記出願の全てが参照により本明細書に取り込まれている。
本発明は、MPS1(TTK)、ERK5(BMK1、MAPK7)、ポロキナーゼ1、2、3、又は4、Ack1、Ack2、Abl、DCAMKL1、ABL1、Abl突然変異体、DCAMKL2、ARK5、BRK、MKNK2、FGFR4、TNK1、PLK1、ULK2、PLK4、PRKD1、PRKD2、PRKD3、ROS1、RPS6KA6、TAOK1、TAOK3、TNK2、Bcr−Abl、GAK、cSrc、TPR−Met、Tie2、MET、FGFR3、Aurora、Axl、Bmx、BTK、c−kit、CHK2、Flt3、MST2、p70S6K、PDGFR、PKB、PKC、Raf、ROCK−H、Rsk1、SGK、TrkA、TrkB及びTrkCを包含する、タンパク質キナーゼを調節することができる、新規なピリミド−ジアゼピノン化合物、並びに多種の疾患、障害及び病気の治療におけるこのような化合物の使用に関する。
Yは、NR5、N、S、SO、SO2、O、CHR5、又はCR5である。
ここで、少なくとも1つのX及びYは、NH、NR4、NR5、N、S、SO、SO2、又はOである。
Aは、単結合又は二重結合である。
Bは、単結合又は二重結合である。
ここでAとBの両方が二重結合である場合はない。
R’はH又はアルキルである。
Lは、存在しないか、或いはS、SO、SO2、又はCOである。
R2は、水素又は置換されていてもよいアルキルである。
R3は、水素、アルキル、アルケニル、アリール、アリールアルキル、ヘテロアリール、複素環、又は炭素環であって、それぞれは置換されていてもよい。
R4は、水素、アルキル、アルケニル、アリール、アリールアルキル、ヘテロアリール、複素環、又は炭素環であって、それぞれは置換されていてもよい。
R5は、水素、アルキル、アルケニル、アリール、アリールアルキル、ヘテロアリール、複素環、又は炭素環であって、それぞれは置換されていてもよい。
或いはR3及びXは、それらが結合している原子と共に、3〜8員の炭素環、アリール、複素環、又はヘテロアリールを形成し、それぞれは置換されていてもよい。
或いはX及びYは、それらが結合している原子と共に、3〜8員の炭素環、アリール、複素環、又はヘテロアリールを形成し、それぞれは置換されていてもよい。そして
R6は、水素又は置換されていてもよいアルキルである。
以下の記載は本発明を記載するために用いられている多種の用語の定義である。これらの定義は、この明細書及び特許請求の範囲を通して用いられる場合に、個々に又は大きなグループの一部としの何れかで、特定の場合において別段に限定されない限り、その用語に適用される。
−F、−Cl、−Br、−I、
−OH、保護されたヒドロキシ、
−NO2、−CN、
−NH2、保護されたアミノ、−NH−C1〜C12アルキル、−NH−C2〜C12アルケニル、−NH−C2〜C12アルキニル、−NH−C3〜C12シクロアルキル、−NH−アリール、−NH−ヘテロアリール、−NH−ヘテロシクロアルキル、ジアルキルアミノ、ジアリールアミノ、ジヘテロアリールアミノ、、
−O−C1〜C12アルキル、−O−C2〜C12アルケニル、−NH−C2〜C12アルキニル、−O−C3〜C12シクロアルキル、−O−アリール、−O−ヘテロアリール、−O−ヘテロシクロアルキル、
−C(O)−C1〜C12アルキル、−C(O)−C2〜C12アルケニル、−NH−C2〜C12アルキニル、−C(O)−C3〜C12シクロアルキル、−C(O)−アリール、−C(O)−ヘテロアリール、−C(O)−ヘテロシクロアルキル、
−CONH2、−CONH−C1〜C12アルキル、−CONH−C2〜C12アルケニル、−NH−C2〜C12アルキニル、−CONH−C3〜C12シクロアルキル、−CONH−アリール、−CONH−ヘテロアリール、−CONH−ヘテロシクロアルキル、
−OCO2−C1〜C12アルキル、−OCO2−C2〜C12アルケニル、−NH−C2〜C12アルキニル、−OCO2−C3〜C12シクロアルキル、−OCO2−アリール、−OCO2−ヘテロアリール、−OCO2−ヘテロシクロアルキル、
−OCONH2、−OCONH−C1〜C12アルキル、−OCONH−C2〜C12アルケニル、−NH−C2〜C12アルキニル、−OCONH−C3〜C12シクロアルキル、−OCONH−アリール、−OCONH−ヘテロアリール、−OCONH−ヘテロシクロアルキル、
−NHC(O)−C1〜C12アルキル、−NHC(O)−C2〜C12アルケニル、−NH−C2〜C12アルキニル、−NHC(O)−C3〜C12シクロアルキル、−NHC(O)−アリール、−NHC(O)−ヘテロアリール、−NHC(O)−ヘテロシクロアルキル、
−NHCO2−C1〜C12アルキル、−NHCO2−C2〜C12アルケニル、−NH−C2〜C12アルキニル、−NHCO2−C3〜C12シクロアルキル、−NHCO2−アリール、−NHCO2−ヘテロアリール、−NHCO2−ヘテロシクロアルキル、
−NHC(O)NH2、−NHC(O)NH−C1〜C12アルキル、−NHC(O)NH−C2〜C12アルケニル、−NH−C2〜C12アルキニル、−NHC(O)NH−C3〜C12シクロアルキル、−NHC(O)NH−アリール、−NHC(O)NH−ヘテロアリール、−NHC(O)NH−ヘテロシクロアルキル、
−NHC(S)NH2、−NHC(S)NH−C1〜C12アルキル、−NHC(S)NH−C2〜C12アルケニル、−NH−C2〜C12アルキニル、−NHC(S)NH−C3〜C12シクロアルキル、−NHC(S)NH−アリール、−NHC(S)NH−ヘテロアリール、−NHC(S)NH−ヘテロシクロアルキル、
−NHC(NH)NH2、−NHC(NH)NH−C1〜C12アルキル、−NHC(NH)NH−C2〜C12アルケニル、−NH−C2〜C12アルキニル、−NHC(NH)NH−C3〜C12シクロアルキル、−NHC(NH)NH−アリール、−NHC(NH)NH−ヘテロアリール、−NHC(NH)NH−ヘテロシクロアルキル、
−NHC(NH)−C1〜C12アルキル、−NHC(NH)−C2〜C12アルケニル、−NH−C2〜C12アルキニル、−NHC(NH)−C3〜C12シクロアルキル、−NHC(NH)−アリール、−NHC(NH)−ヘテロアリール、−NHC(NH)−ヘテロシクロアルキル、
−C(NH)NH−C1〜C12アルキル、−C(NH)NH−C2〜C12アルケニル、−NH−C2〜C12アルキニル、−C(NH)NH−C3〜C12シクロアルキル、−C(NH)NH−アリール、−C(NH)NH−ヘテロアリール、−C(NH)NH−ヘテロシクロアルキル、
−S(O)−C1〜C12アルキル、−S(O)−C2〜C12アルケニル、−NH−C2〜C12アルキニル、−S(O)−C3〜C12シクロアルキル、−S(O)−アリール、−S(O)−ヘテロアリール、−S(O)−ヘテロシクロアルキル、
−SO2NH2、−SO2NH−C1〜C12アルキル、−SO2NH−C2〜C12アルケニル、−NH−C2〜C12アルキニル、−SO2NH−C3〜C12シクロアルキル、−SO2NH−アリール、−SO2NH−ヘテロアリール、−SO2NH−ヘテロシクロアルキル、
−NHSO2−C1〜C12アルキル、−NHSO2−C2〜C12アルケニル、−NH−C2〜C12アルキニル、−NHSO2−C3〜C12シクロアルキル、−NHSO2−アリール、−NHSO2−ヘテロアリール、−NHSO2−ヘテロシクロアルキル、
−CH2NH2、−CH2SO2CH3、−アリール、−アリールアルキル、−ヘテロアリール、−ヘテロアリールアルキル、−ヘテロシクロアルキル、C3〜C12シクロアルキル、ポリアルコキシアルキル、ポリアルコキシ、−メトキシメトキシ、−メトキシエトキシ、
−SH、−S−C1〜C12アルキル、−S−C2〜C12アルケニル、−NH−C2〜C12アルキニル、−S−C3〜C12シクロアルキル、−S−アリール、−S−ヘテロアリール、−S−ヘテロシクロアルキル、又はメチルチオメチル、
を包含する置換基による独立した置換によって、置換されているか又は置換されていない基を示す。
薬学的に許容される塩は当該技術分野において周知である。例えば、S.M. Berge, et al. は J. Pharmaceutical Sciences, 66: 1-19 (1977) で薬学的に許容される塩を詳細に記載している。
これらの塩は、本発明の化合物の最終の単離及び精製の間にその場に(in situ)、或いは別に遊離の塩基性官能基を適切な有機酸と反応させることによって製造できる。
薬学的に許容される非毒性酸付加塩の例は、これに限定されないが、塩酸、臭化水素酸、リン酸、硫酸、過塩素酸などの無機酸、或いは酢酸、マレイン酸、酒石酸、クエン酸、コハク酸又はマロン酸などの有機酸を用いて、或いはイオン交換などの当該技術分野で用いられる別の方法を用いて、形成されたアミノ基の塩である。
その他の薬学的に許容される塩は、これに限定されないが、アジピン酸塩、アルギン酸塩、アスコルビン酸塩、アスパラギン酸塩、ベンゼンスルホン酸塩、安息香酸塩、重硫酸塩、ホウ酸塩、酪酸塩、カンファー酸塩、カンファースルホン酸塩、クエン酸塩、シクロペンタンプロピオン酸塩、ジグルコン酸塩、ドデシル硫酸塩、エタンスルホン酸塩、ギ酸塩、フマル酸塩、グルコヘプトン酸塩、グリセロリン酸塩、グルコン酸塩、ヘミ硫酸塩、ヘプタン酸塩、ヘキサン酸塩、ヨウ化水素酸塩、2−ヒドロキシ−エタンスルホン酸塩、ラクトビオン酸塩、乳酸塩、ラウリン酸塩、ラウリル硫酸塩、リンゴ酸塩、マレイン酸塩、マロン酸塩、メタンスルホン酸塩、2−ナフタレンスルホン酸塩、ニコチン酸塩、硝酸塩、オレイン酸塩、シュウ酸塩、パルミチン酸塩、パモ酸塩、ペクチン酸塩、過硫酸塩、3−フェニルプロピオン酸塩、リン酸塩、ピクリン酸塩、ピバル酸塩、プロピオン酸塩、ステアリン酸塩、コハク酸塩、硫酸塩、酒石酸塩、チオシアン酸塩、p−トルエンスルホン酸塩、ウンデカン酸塩、吉草酸塩等を包含する。
代表的なアルカリ又はアルカリ土類金属塩は、ナトリウム、リチウム、カリウム、カルシウム、マグネシウム等の塩を包含する。
適切な場合には、薬学的に許容される塩は更に、ハライド、ヒドロキシド、カルボン酸塩、硫酸塩、リン酸塩、硝酸塩、1〜6個の炭素原子を有しているアルキル、スルホン酸塩、アリールスルホン酸塩などの対イオンを用いて形成される、非毒性のアンモニウム塩、4級アンモニウム塩、及びアミンカチオンを包含する。
例えば、遊離のアミノ、アミド、ヒドロキシ又はカルボン酸基を有している本発明の化合物をプロドラッグに変換することができる。
プロドラッグは、アミノ酸残基、又は2つ以上の(例えば、2個、3個又は4個の)アミノ酸残基のポリペプチド鎖がアミド又はエステル結合を介して、本発明の化合物の遊離のアミノ、ヒドロキシ又はカルボン酸基に共有結合している、化合物を包含する。
このアミノ酸残基は、これに限定されないが、通常3文字記号で表される20の天然由来アミノ酸を包含し、そして4−ヒドロキシプロリン、ヒドロキシリジン、デモシン、イソデモシン、3−メチルヒスチジン、ノルバリン、ベータ−アラニン、ガンマ−アミノ酪酸、シトルリン、ホモシステイン、オルニチン及びメチオニンスルホンも包含する。
プロドラッグの更なる種類も包含する。例えば、遊離のカルボキシル基をアミド又はアルキルエステルとして誘導体化することができる。遊離のヒドロキシ基を、Advanced Drug Delivery Reviews, 1996, 19, 1 15 に概説されているように、これに限定されないが、ヘミコハク酸エステル、リン酸エステル、ジメチルアミノ酢酸エステル、及びホスホリルオキシメチルオキシカルボニルを包含する基を用いて誘導体化することができる。
ヒドロキシ及びアミノ基のカルバミン酸エステルプロドラッグも、ヒドロキシ基のスルホン酸エステル及び硫酸エステルの炭酸エステルプロドラッグと同様に、包含される。アシル基がアルキルエステルであり、これに限定されないが、エーテル、アミン及びカルボン酸官能基を包含する基で置換されていてもよい場合、或いはアシル基が上記のようなアミノ酸エステルである場合の(アシルオキシ)メチル及び(アシルオキシ)エチルエーテルとしてのヒドロキシ基の誘導体化も包含される。このタイプのプロドラッグは、J. Med. Chem. 1996, 39, 10 に記載されている。遊離のアミンもアミド、スルホンアミド又はホスホンアミドとして誘導体化できる。これらのプロドラッグ部分の全ては、これに限定されないが、エーテル、アミン及びカルボン酸官能基を含有する基を組み込んでいてもよい。
一態様では、本発明は、式Aの化合物又はそれらの薬学的に許容される塩、エステル又はプロドラッグを提供する。
Yは、NR5、N、S、SO、SO2、O、CHR5、又はCR5である。
ここで、X及びYの少なくとも1つは、NH、NR4、NR5、N、S、SO、SO2、又はOである。
Aは、単結合又は二重結合である。
Bは、単結合又は二重結合である。
ここで、A及びBの両方が二重結合である場合はない。
R’はH又はアルキルである。
Lは、存在しないか、S、SO、SO2、又はCOである。
R1は、それぞれがO、S、又はNから選ばれる0、1、2、又は3個のへテロ原子を含有している、H、アルキル、アルケニル、アルキニルであるか、又はR1は、アリール、アリールアルキル、ヘテロアリール、複素環、又は炭素環である。
ここで、R1は置換されていてもよい。
R2は、水素又は置換されていてもよいアルキルである。
R3は、それぞれが置換されていてもよい、水素、アルキル、アルケニル、アリール、アリールアルキル、ヘテロアリール、複素環、又は炭素環である。
R4は、それぞれが置換されていてもよい、水素、アルキル、アルケニル、アリール、アリールアルキル、ヘテロアリール、複素環、又は炭素環である。
R5は、それぞれが置換されていてもよい、水素、アルキル、アルケニル、アリール、アリールアルキル、ヘテロアリール、複素環、又は炭素環である。
或いは、R3及びXは、それらが結合している原子と共に、それぞれが置換されていてもよい、3〜8員の炭素環、複素環、アリール、又はヘテロアリールを形成する。
或いは、X及びYは、それらが結合している原子と共に、それぞれが置換されていてもよい、3〜8員の炭素環、複素環、アリール、又はヘテロアリールを形成する。
R6は、水素又は置換されていてもよいアルキルである。
R2は、水素又は置換されていてもよいアルキルである。
R3は、水素又はメチルである。
R4は、水素又はメチルである。そして、
R6は、水素である。
第2実施態様では、本発明は、式Cの化合物又はそれらの薬学的に許容される塩、エステル又はプロドラッグを提供する。
R2は、水素又はメチルである。
R3は、水素である。
R4は、水素である。そして、
R6は、水素である。
第3実施態様では、本発明は、式Dの化合物又はそれらの薬学的に許容される塩、エステル又はプロドラッグを提供する。
R2は、水素又は置換されていてもよいアルキルである。
R6は、水素又は置換されていてもよいアルキルである。
それぞれのR7は、(それぞれ)独立して、それぞれが置換されていてもよい、アルキル、アルケニル、アリール、アリールアルキル、ヘテロアリール、複素環、炭素環、アルコキシ、NH(アルキル)、NH(アリール)、N(アルキル)(アルキル)又はN(アリール)(アリール);ハロ、ニトロ又はシアノである。
pは、0〜6である。
第4実施態様では、本発明は、式Eの化合物又はそれらの薬学的に許容される塩、エステル又はプロドラッグを提供する。
R2は、水素又は置換されていてもよいアルキルである。
R3は、水素又は置換されていてもよいアルキルである。
R6は、水素又は置換されていてもよいアルキルである。
それぞれのR7は、独立して、それぞれが置換されていてもよい、アルキル、アルケニル、アリール、アリールアルキル、ヘテロアリール、複素環、炭素環、アルコキシ、NH(アルキル)、NH(アリール)、N(アルキル)(アルキル)又はN(アルキル)(アリール);ハロ、ニトロ又はシアノである。
pは、0〜6である。
第5実施態様では、本発明は、式Fの化合物又はそれらの薬学的に許容される塩、エステル又はプロドラッグを提供する。
R2は、水素又は置換されていてもよいアルキルである。
R5は、水素、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ラルキル、又は置換されていてもよい炭素環である。
R6は、水素又は置換されていてもよいアルキルである。
それぞれのR7は、独立して、それぞれが置換されていてもよい、アルキル、アルケニル、アリール、アリールアルキル、ヘテロアリール、複素環、炭素環、アルコキシ、NH(アルキル)、NH(アリール)、N(アルキル)(アルキル)又はN(アルキル)(アリール);ハロ、ニトロ又はシアノである。
pは、0〜4である。
第6実施態様では、本発明は、式F−Iの化合物又はそれらの薬学的に許容される塩、エステル又はプロドラッグを提供する。
R1は、アルキル、アリール、ヘテロアリール、複素環、又は炭素環であり、ここでR1は置換されていてもよい。
R2は、水素又は置換されていてもよいアルキルである。
R6は、水素又は置換されていてもよいアルキルである。
それぞれのR7は、独立して、それぞれが置換されていてもよい、アルキル、アルケニル、アリール、アリールアルキル、ヘテロアリール、複素環、炭素環、アルコキシ、NH(アルキル)、NH(アリール)、N(アルキル)(アルキル)又はN(アルキル)(アリール);ハロ、ニトロ又はシアノである。
pは、0〜4である。
第7実施態様では、本発明は、式Gの化合物又はそれらの薬学的に許容される塩、エステル又はプロドラッグを提供する。
R2は、水素又は置換されていてもよいアルキルである。
R3は、それぞれが置換されていてもよい、水素、アルキル、アルケニル、アリール、アリールアルキル、ヘテロアリール、複素環、又は炭素環である。
R5は、それぞれが置換されていてもよい、水素、アルキル、アルケニル、、アリール、アリールアルキル、ヘテロアリール、複素環、又は炭素環である。
R6は、水素又は置換されていてもよいアルキルである。
別の実施態様では、R5が置換されていてもよいフェニル又は置換されていてもよいシクロペンチルである。
本発明の化合物の合成は下記の実施例に見出せる。
あるいは、本発明の薬学的に許容される塩基付加塩は、化合物の遊離酸形態を薬学的に許容される無機又は有機の塩基と反応させて、製造することができる。
光学異性体を、それらそれぞれの光学活性前駆物質から上記の手順によって、或いはラセミ混合物を分割することによって調製することができる。分割は、分割剤の存在下に、クロマトグラフィーによって又は反復再結晶によって又は当業者に公知のこれらの技術の幾つかの組み合わせによって実施することができる。分割に関する更なる詳細は、 Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981) に見出すことができる。
本発明の化合物は複数の互変異性型で表すこともでき、そのような場合には、本発明は、本明細書に記載されている化合物の全ての互変異性型を明確に包含する(例えば、環系のアルキル化は複数部位のアルキル化をもたらし、本発明はそのような反応産物の全てを明確に包含する)。
本明細書に記載されている化合物がオレフィン二重結合又はその他の幾何学的不斉中心を含有していて、他に特に規定されない場合には、化合物はE及びZの幾何異性体の両方を包含することが意図されている。同様に、全ての互変異性体を包含することが意図されている。
本明細書に現れる何れの炭素−炭素二重結合の配座も便宜的にのみ選択されていて、文脈上そのように記されていない限り、特定の配座を示すことを意図していない;従って、本明細書で任意にトランスと表された炭素−炭素二重結合は、シス、トランス、或いは何れかの比率のその2つの混合物であってよい。このような化合物のこのような異性体の全ては、本発明に明確に包含される。本明細書に記載されている化合物の全ての結晶形態は本発明に明確に包含される。
更に、本明細書で詳述している溶媒、温度、反応時間等は説明のみを目的としていて、反応条件を変えると、所望の本発明の架橋された多環式産生物を生産することができるということを当業者認識するだろう。本明細書に記載されている化合物を合成するのに有用な合成化学変換及び保護基手法(保護及び脱保護)は当該技術分野で公知であって、例えば、R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) 及びこれらの続刊に記載されているようなものを包含する。
別の態様では、本発明は、式Aの化合物、薬学的に許容される塩、エステル又はプロドラッグを対象に投与することを含有してなる、対象における疾患を治療する方法を提供する。
一態様では、本発明は、病気、疾患、又は障害にタンパク質キナーゼが関わっている場合の、病気、疾患、又は障害の重症度を治療又は減少する方法を提供する。
別の態様では、本発明は、酵素活性の阻害が病気の治療に関わっている場合の、キナーゼの疾患、病気又は障害の重症度を治療又は減少する方法を提供する。
その他の態様では、本発明は、タンパク質キナーゼと結合して酵素活性を阻害する化合物を用いて、病気、疾患、又は障害の重症度を治療又は減少する方法を提供する。
その他の態様は、タンパク質キナーゼ阻害剤を用いてキナーゼの酵素活性を阻害することによって、キナーゼの疾患、病気又は障害の重症度を治療又は減少する方法を提供する。
別の実施態様では、当該疾患は増殖性疾患及び神経変性疾患から選ばれる。
用語「癌」は、これに限定されないが、以下の癌を包含する:骨髄腫、リンパ腫、又は胃、腎臓から選ばれる癌、及び/又は以下の癌:頭頸部、口腔咽頭、非小細胞肺癌(NSCLC)、子宮内膜、肝細胞癌、非ホジキンリンパ腫、及び肺。
本明細書に記載されている化合物及び組成物によって阻害され、そしてそれに対して本明細書に記載されている方法が有用である、キナーゼの例は、これに限定されないが、MPS1、ERK5、BMK1、MAPK7、ポロキナーゼ1、2、3、又は4、Ack1、Ack2、Abl、DCAMKL1、ABL1、Abl突然変異体、DCAMKL2、ARK5、BRK、MKNK2、FGFR4、TNK1、PLK1、ULK2、PLK4、PRKD1、PRKD2、PRKD3、ROS1、RPS6KA6、TAOK1、TAOK3、TNK2、Bcr−Abl、GAK、cSrc、TPR−Met、Tie2、MET、FGFR3、Aurora、Axl、Bmx、BTK、c−kit、CHK2、Flt3、MST2、p70S6K、PDGFR、PKB、PKC、Raf、ROCK−H、Rsk1、SGK、TrkA、TrkB及びTrkCキナーゼを包含する。
本明細書で用いられる用語「生体試料」は、これに限定されないが、細胞培養物又はその抽出物;哺乳動物から得られた生検物質又はその抽出物;及び血液、唾液、尿、糞便、精液、涙液又はその他の体液又はその抽出物を包含する、インビトロ又はエクスビボのサンプルを意味する。生体試料におけるタンパク質キナーゼ活性の阻害は、当業者に公知である多種の目的に対して有用である。このような目的の例は、これに限定されないが、輸血、臓器移植、及び生物試料の保管を包含する。
別の態様では、本発明は、式Aの化合物、又はそれらの薬学的に許容されるエステル、塩、又はプロドラッグを、薬学的に許容される担体と共に含有している医薬組成物を提供する。
例えば、経口用組成物は、活性成分をa)希釈剤、例えば、乳糖、ブドウ糖、蔗糖、マンニトール、ソルビトール、セルロース及び/又はグリシン;b)滑沢剤、例えば、シリカ、タルカン、ステアリン酸、そのマグネシウム又はカルシウム塩及び/又はポリエチレングリコール;錠剤にはc)結合剤、例えば、ケイ酸アルミニウム・マグネシウム、澱粉糊、ゼラチン、トラガカント、メチルセルロース、カルボキシメチルセルロース・ナトリウム及び/又はポリビニルピロリドンも;所望によりd)崩壊剤、例えば、澱粉、寒天、アルギン酸又はそのナトリウム塩、又は発泡性混合物;及び/又はe)吸収剤、着色剤、着香剤及び甘味剤と共に含有している、錠剤又はゼラチンカプセルであってよい。
注射用組成物は、水性等張溶液又は懸濁液であってよく、そして坐薬は、脂肪乳剤又は懸濁液から調製できる。組成物は滅菌することができ、そして/又は保存剤、安定化剤、湿潤又は乳化剤、溶解促進剤、浸透圧を調節する塩及び/又は緩衝剤などの補助剤を含有することができる。さらに、これらはその他の治療に役立つ物質も含有することができる。
経皮投与に適している製剤は、本発明の化合物の有効量を担体と共に含有する。担体は、宿主の皮膚を介する浸透を補助する吸収性の薬学的に許容される溶媒を含有できる。
局所投与、例えば皮膚及び目への投与に適している製剤は、当該技術分野で周知である、水溶液、軟膏、クリーム又はゲルが好ましい。このようなものは、可溶化剤、安定化剤、等張化増強剤、緩衝剤及び保存剤を含有できる。
本発明の化合物を他の治療剤と併用して投与する場合、併用投与する化合物の用量は勿論、用いられる併用薬のタイプによって、用いられる特定の薬剤によって、治療される症状等によって変化するだろう。
本明細書で用いられる用語「薬学的に許容される担体」は、非毒性で不活性な、固体、半固体又は液体の、充填剤、希釈剤、封入剤又は何れかのタイプの製剤補助剤を意味する。
本発明の医薬組成物は、ヒト及びその他の動物に、経口で、直腸内に、非経口で、嚢内に、膣内に、腹腔内に、局所に(粉末、軟膏、又は滴下で)、口腔に、又は経口或いは経鼻スプレーとして投与することができる。
眼科用製剤、点耳薬、眼軟膏、粉末及び溶液も本発明の範囲内にあることが意図されている。
本明細書で用いられる用語、本発明の化合物の「治療有効量」は、対象における疾患の症状を減少するために十分な化合物の量を意味する。医学の分野で十分に理解されているように、本発明化合物の治療有効量は何れの薬物療法にも適用可能な妥当な便益/リスクの比にあるだろう。
MS(ESI)m/z:329(M+H)+。
MS(ESI)m/z:267(M+H)+。
MS(ESI)m/z:281(M+H)+。
MS(ESI)m/z:438 (M+H)+。
I−20:1H NMR(400MHz、CDCl3)δ:1.57〜2.01(m、6H)、2.10〜2.30(m、2H)、2.41(t、J=12Hz、2H)、3.10〜3.20(m、3H)、3.34(s、3H)、3.93〜3.97(m、2H)、4.63(t、J=8Hz、2H)、7.73(s、1H)、7.77〜7.80(m、1H)、8.14(s、1H)、8.36(d、J=8Hz、1H)、8.48(d、J=12Hz、1H)、8.60(d、J=8Hz、1H)、9.13(d、J=8Hz、1H)、12.36(bs、1H)。
MS(ESI)m/z:301(M+H)+。
MS(ESI)m/z:239(M+H)+。
MS(ESI)m/z:253(M+H)+。
MS(ESI)m/z:438(M+H)+。
MS(ESI)m/z:337(M+H)+。
MS(ESI)m/z:275(M+H)+。
MS(ESI)m/z:289(M+H)+。
MS(ESI)m/z:337(M+H)+。
MS(ESI)m/z:261(M+H)+。
MS(ESI)m/z:275(M+H)+。
MS(ESI)m/z:460(M+H)+。
MS(ESI)m/z:297(M+H)+。
MS(ESI)m/z:264(M+H)+。
MS(ESI)m/z:278(M+H)+。
MS(ESI)m/z:463(M+H)+。
Hela(又はU2OS)細胞をおおよそ30〜35%の細胞密度でプレートに蒔いた。24時間後に培地*を除去して、2.5mMのチミジンを補完した新鮮な培地を加えて、細胞をG1/S移行期に停止した。チミジン遮断24時間後に、培地を除去し、細胞をPBSで3回洗浄して、330nMのノコダゾール(Noc)を補完した培地と交換した。細胞をノコダゾールと16〜18時間培養して有糸分裂停止を生じさせた。次いで、注意深く培地を除去して、330nMのノコダゾールと所望の濃度の試験化合物(DMSOの最終濃度は0.2%未満で)を補完した培地と交換した。2時間後に、細胞を採取し、RIPA緩衝液中で溶解して、ウェスタンブロッティングでサイクリンB又はリン酸化ヒストン3(Ser10)の濃度を測定した。あるいは、細胞をカバースリップ上で処理し、固定して、リン酸化ヒストン3濃度を免疫蛍光法で測定した。図1を参照されたい。
*Hela/U2OS培地−ダルベッコ変法イーグル培地(DMEM、Sigma)、10%ウシ胎仔血清、1%ペニシリン/ストレプトマイシン
Hela細胞を、ポリリジンをコーティングしたガラスカバースリップ上におおよそ80%の細胞密度で蒔いた。24時間後に培地*を除去して、試験化合物を補完した新鮮な培地を加えた。24時間処理した後、培地を除去して、カバースリップをリン酸緩衝食塩水(PBS、pH7.4)で1回洗浄して、細胞を室温で10分間、以下の固定液を用いて固定した:100mMのK−pipes、pH6.8、10mMのEGTA、1mMのMgCl2、0.2%のトリトンX−100、3%のホルムアルデヒド。0.1%のトリトンX−100を含有しているトリス緩衝食塩溶液(50mMのトリスHCl、pH7.4、150mMのNaCl)(TBST)でカバースリップを3回洗浄した。2%ウシ血清アルブミン(BSA)を用いてサンプルをTBST中に遮断した。次いで、サンプルを、遮断溶液中で、リン酸化特異的抗ヒストン3(ホスホH3)セリン−10抗体(Upstate、1:500〜1:1000)と培養した。細胞を同様に適切な抗体を用いて随意にチューブリン染色することもできる。室温で2時間(又は4℃で1晩)培養した後、サンプルをTBSTで3回洗浄した。次いで、サンプルを遮断溶液中で適切な第2抗体と室温で1〜2時間(又は4℃で1晩)培養した。サンプルをTBSTで3回洗浄した後、TBST中でHoechst 33342染色剤(Invitrogen、1:1000〜1:2000)と室温で15分間培養した。サンプルをTBSTで3回洗浄して、Prolong Gold Antifade Reagent (Invitrogen)を用いてガラススライド上に載せた。図2及び3を参照のこと。
*Hela/U2OS培地−ダルベッコ変法イーグル培地(DMEM、Sigma)、10%ウシ胎仔血清、1%ペニシリン/ストレプトマイシン
LanthaScreen 活性アッセイ
キナーゼ反応を室温で以下の成分を用いて実施した:1Xキナーゼ反応緩衝液、5μg/mL(40nM)のMps1キナーゼ、200nMのAF−647E4Y基質、及び1μMのATP(Km,app<1μM)。1時間後に、TR−FRET希釈緩衝液中のEDTA(20mM)及びEu−PY20 Tb標識化抗体(4nM)の調合物を加えた。反応混合物中のEDTA及びEu−PY20の最終濃度は、それぞれ10mM及び2nMである。LanthaScreen(登録商標)TR−FRETに設定されているプレートリーダーで読み取る前に、反応混合物を室温で30分間培養した。阻害剤の多種の濃度に渡ってキナーゼ反応を行って、図4、5及び6に見られるような用量依存性の曲線を得た。
本願を通して引用されている全ての参照文献(参考文献、登録特許、公開特許出願、及び同時継続特許出願を包含する)の内容は、ここに、参照によりその全てが本明細書に明確に取り込まれている。他に別段定義しない限り、本明細書で用いられている全ての技術及び化学用語は当業者に一般に知られている意味に一致している。
当業者は、本明細書に記載されている本発明の特定の実施態様の様々な均等物を認識できるであろう、或いは通常程度の実験を用いて確認できるだろう。このような均等物は、以下の特許請求の範囲に包含されることが意図されている。
Claims (63)
- 式A:
Yは、NR5、N、S、SO、SO2、O、CHR5、又はCR5であり;
ここで、X及びYの少なくとも1つは、NH、NR4、NR5、N、S、SO、SO2、又はOであり;
Aは、単結合又は二重結合であり;
Bは、単結合又は二重結合であり;
ここで、A及びBの両方が二重結合である場合はなく;
R’は、H又はアルキルであり;
Lは、不存在、S、SO、SO2、又はCOであり;
R1は、それぞれがO、S,又はNから選ばれる0、1、2、又は3個のヘテロ原子を含有している、H、アルキル、アルケニル、アルキニルであるか;又はR1は、アリール、アリールアルキル、ヘテロアリール、複素環、又は炭素環であり;ここで、R1は置換されていてもよい;
R2は、水素又は置換されていてもよいアルキルであり;
R3は、それぞれが置換されていてもよい、水素、アルキル、アルケニル、アリール、アリールアルキル、ヘテロアリール、複素環、又は炭素環であり;
R4は、それぞれが置換されていてもよい、水素、アルキル、アルケニル、アリール、アリールアルキル、ヘテロアリール、複素環、又は炭素環であり;
R5は、それぞれが置換されていてもよい、水素、アルキル、アルケニル、アリール、アリールアルキル、ヘテロアリール、複素環、又は炭素環であり;
或いはR3及びXは、それらが結合している原子と共に、それぞれが置換されていてもよい、3〜8員の炭素環、アリール、複素環又はヘテロアリールを形成し;
或いは、X及びYは、それらが結合している原子と共に、それぞれが置換されていてもよい、3〜8員の炭素環、アリール、複素環又はヘテロアリールを形成し;そして
R6は、水素又は置換されていてもよいアルキルである):
の化合物又はそれらの薬学的に許容される塩、エステル又はプロドラッグ。 - XがCR4又はCHR4であり、そしてYがNR5である、請求項1に記載の化合物。
- R4が、それぞれが置換されていてもよい、水素、アルキル、アリール、ヘテロアリール、複素環、又は炭素環であり、そしてR5が、それぞれが置換されていてもよい、水素、アルキル、アリール、ヘテロアリール、複素環、又は炭素環である、請求項2に記載の化合物。
- X及びYが、それらが結合している原子と共に、それぞれが置換されていてもよい、3〜8員のシクロアルキル、アリール、ヘテロシクロアルキル、又はヘテロアリールを形成する、請求項1に記載の化合物。
- R3及びXが、それらが結合している原子と共に、それぞれが置換されていてもよい、3〜8員のシクロアルキル、アリール、ヘテロシクロアルキル、又はヘテロアリールを形成する、請求項1に記載の化合物。
- XがNであり、そしてYがCR5である、請求項1に記載の化合物。
- R5が、それぞれが置換されていてもよい、アルキル、アリール、ヘテロアリール、複素環、又は炭素環である、請求項6に記載の化合物。
- R1が、それぞれが置換されていてもよい、フェニル又はピリジルである、請求項8に記載の化合物。
- R1が、それぞれがさらに置換されていてもよい、N(RA)(RA)、C(O)NH(RA)、アルコキシ、及び複素環から選ばれる、0〜4個の置換基で置換されている(ここでそれぞれのRAは独立してアルキル及び複素環から選ばれる)、請求項9に記載の化合物。
- R1が、それぞれが置換されていてもよい、フェニル又はピリジルである、請求項12に記載の化合物。
- R1が、それぞれがさらに置換されていてもよい、アルコキシ、又は複素環から選ばれる0〜4個の置換基で置換されている、請求項13に記載の化合物。
- 式D:
ここでR1は、置換されていてもよく;
R2は、水素又は置換されていてもよいアルキルであり;
R6は、水素又は置換されていてもよいアルキルであり;
それぞれのR7は、独立して、それぞれが置換されていてもよい、アルキル、アルケニル、アリール、アリールアルキル、ヘテロアリール、複素環、炭素環、アルコキシ、NH(アルキル)、NH(アリール)N(アルキル)(アルキル)、又はN(アルキル)(アリール);ハロ、ニトロ、又はシアノであり;そして
pは、0〜6である):
の化合物又はそれらの薬学的に許容される塩、エステル又はプロドラッグである、請求項1に記載の化合物。 - R1が、それぞれが置換されていてもよい、メチル、エチル、プロピル、イソプロピル、ブチル、s−ブチル、t−ブチル、ペンチル、ヘキシル、シクロヘキシル、ピペリジニル、ピロリジノ、フェニル、1−ナフチル、2−ナフチル、ピリジル、ピリミジニル、ピラジニル、ピリジジニル、キノリニル、チエニル、チアゾリル、オキサゾリル、イソキサゾリル、ピロリル、フラニル、イソキノリニル、イミダゾリル、又はトリアゾリルである、請求項16に記載の化合物。
- R1が、それぞれが置換されていてもよい、アルキル、フェニル、シクロヘキシル、ピペリジニル、キノリニル、又はピリジルである、請求項17に記載の化合物。
- R1が、それぞれが更に置換されていてもよい、ハロ、ニトロ、シアノ、ヒドロキシル、アミノ、NH(RA)、N(RA)(RA)、CO2H、C(O)RA、C(O)ORA、C(O)NH2、C(O)NH(RA)、C(O)N(RA)(RA)、アルキル、アリール、アリールアルキル、アルコキシ、ヘテロアリール、複素環、及び炭素環から選ばれる0〜4個の置換基で置換されている(ここで、それぞれのRAは、独立して、アルキル、炭素環、アリール、ヘテロアリール、及び複素環から選ばれる)、請求項18に記載の化合物。
- 式E:
ここでR1は、置換されていてもよく;
R2は、水素又は置換されていてもよいアルキルであり;
R3は、水素又は置換されていてもよいアルキルであり;
R6は、水素又は置換されていてもよいアルキルであり;
それぞれのR7は、独立して、それぞれが置換されていてもよい、アルキル、アルケニル、アリール、アリールアルキル、ヘテロアリール、複素環、炭素環、アルコキシ、NH(アルキル)、NH(アリール)、N(アルキル)(アルキル)、又はN(アルキル)(アリール);ハロ、ニトロ、又はシアノであり;そして
pは、0〜6である):
の化合物、又はそれらの薬学的に許容される塩、エステル又はプロドラッグである、請求項1に記載の化合物。 - R1が、それぞれが置換されていてもよい、メチル、エチル、プロピル、イソプロピル、ブチル、s−ブチル、t−ブチル、ペンチル、ヘキシル、シクロヘキシル、ピペリジニル、ピロリジノ、フェニル、1−ナフチル、2−ナフチル、ピリジル、ピリミジニル、ピラジニル、ピリジジニル、キノリニル、チエニル、チアゾリル、オキサゾリル、イソキサゾリル、ピロリル、フラニル、イソキノリニル、イミダゾリル、又はトリアゾリルである、請求項21に記載の化合物。
- R1が、それぞれが置換されていてもよい、フェニル又はピリジルである、請求項22に記載の化合物。
- R1が、それぞれが更に置換されていてもよい、ハロ、ニトロ、シアノ、ヒドロキシル、アミノ、NH(RA)、N(RA)(RA)、CO2H、C(O)RA、C(O)ORA、C(O)NH2、C(O)NH(RA)、C(O)N(RA)(RA)、アルキル、アリール、アリールアルキル、アルコキシ、ヘテロアリール、複素環、及び炭素環から選ばれる0〜4個の置換基で置換されている(ここで、それぞれのRAは、独立して、アルキル、炭素環、アリール、ヘテロアリール、及び複素環から選ばれる)、請求項23に記載の化合物。
- 式F:
ここでR1は、置換されていてもよく;
R2は、水素又は置換されていてもよいアルキルであり;
R5は、水素、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ラルキル、又は置換されていてもよい炭素環であり;そして
R6は、水素又は置換されていてもよいアルキルであり;
それぞれのR7は、独立して、それぞれが置換されていてもよい、アルキル、アルケニル、アリール、アリールアルキル、ヘテロアリール、複素環、炭素環、アルコキシ、NH(アルキル)、NH(アリール)、N(アルキル)(アルキル)、又はN(アルキル)(アリール);ハロ、ニトロ、又はシアノであり;そして
pは、0〜4である):
の化合物、又はそれらの薬学的に許容される塩、エステル又はプロドラッグである、請求項1に記載の化合物。 - R1が、それぞれが置換されていてもよい、メチル、エチル、プロピル、イソプロピル、ブチル、s−ブチル、t−ブチル、ペンチル、ヘキシル、シクロヘキシル、ピペリジニル、ピロリジノ、フェニル、1−ナフチル、2−ナフチル、ピリジル、ピリミジニル、ピラジニル、ピリジジニル、キノリニル、チエニル、チアゾリル、オキサゾリル、イソキサゾリル、ピロリル、フラニル、イソキノリニル、イミダゾリル、又はトリアゾリルである、請求項26に記載の化合物。
- R1が、それぞれが置換されていてもよい、フェニル又はピリジルである、請求項27に記載の化合物。
- R1が、それぞれが更に置換されていてもよい、ハロ、ニトロ、シアノ、ヒドロキシル、アミノ、NH(RA)、N(RA)(RA)、CO2H、C(O)RA、C(O)ORA、C(O)NH2、C(O)NH(RA)、C(O)N(RA)(RA)、アルキル、アリール、アリールアルキル、アルコキシ、ヘテロアリール、複素環、及び炭素環から選ばれる0〜4個の置換基で置換されている(ここで、それぞれのRAは、独立して、アルキル、炭素環、アリール、ヘテロアリール、及び複素環から選ばれる)、請求項28に記載の化合物。
- 式F−I:
R1は、アルキル、アリール、ヘテロアリール、複素環、又は炭素環であり;
ここでR1は、置換されていてもよく;
R2は、水素又は置換されていてもよいアルキルであり;
R6は、水素又は置換されていてもよいアルキルであり;
それぞれのR7は、独立して、それぞれが置換されていてもよい、アルキル、アルケニル、アリール、アリールアルキル、ヘテロアリール、複素環、炭素環、アルコキシ、NH(アルキル)、NH(アリール)、N(アルキル)(アルキル)、又はN(アルキル)(アリール);ハロ、ニトロ、又はシアノであり;そして
pは、0〜4である):
の化合物、又はそれらの薬学的に許容される塩、エステル又はプロドラッグである、請求項1に記載の化合物。 - R1が、それぞれが置換されていてもよい、メチル、エチル、プロピル、イソプロピル、ブチル、s−ブチル、t−ブチル、ペンチル、ヘキシル、シクロヘキシル、ピペリジニル、ピロリジノ、フェニル、1−ナフチル、2−ナフチル、ピリジル、ピリミジニル、ピラジニル、ピリジジニル、キノリニル、チエニル、チアゾリル、オキサゾリル、イソキサゾリル、ピロリル、フラニル、イソキノリニル、イミダゾリル、又はトリアゾリルである、請求項31に記載の化合物。
- R1が、それぞれが置換されていてもよい、フェニル又はピリジルである、請求項32に記載の化合物。
- R1が、それぞれが更に置換されていてもよい、ハロ、ニトロ、シアノ、ヒドロキシル、アミノ、NH(RA)、N(RA)(RA)、CO2H、C(O)RA、C(O)ORA、C(O)NH2、C(O)NH(RA)、C(O)N(RA)(RA)、アルキル、アリール、アリールアルキル、アルコキシ、ヘテロアリール、複素環、及び炭素環から選ばれる0〜4個の置換基で置換されている(ここで、それぞれのRAは、独立して、アルキル、炭素環、アリール、ヘテロアリール、及び複素環から選ばれる)、請求項33に記載の化合物。
- 式G:
ここでR1は、置換されていてもよく;
R2は、水素又は置換されていてもよいアルキルであり;
R3は、それぞれが置換されていてもよい、水素、アルキル、アルケニル、アリール、アリールアルキル、ヘテロアリール、複素環、又は炭素環であり;
R5は、それぞれが置換されていてもよい、水素、アルキル、アルケニル、アリール、アリールアルキル、ヘテロアリール、複素環、又は炭素環であり;そして
R6は、水素又は置換されていてもよいアルキルである):
の化合物、又はそれらの薬学的に許容される塩、エステル又はプロドラッグである、請求項1に記載の化合物。 - R1が、それぞれが置換されていてもよい、メチル、エチル、プロピル、イソプロピル、ブチル、s−ブチル、t−ブチル、ペンチル、ヘキシル、シクロヘキシル、ピペリジニル、ピロリジノ、フェニル、1−ナフチル、2−ナフチル、ピリジル、ピリミジニル、ピラジニル、ピリジジニル、キノリニル、チエニル、チアゾリル、オキサゾリル、イソキサゾリル、ピロリル、フラニル、イソキノリニル、イミダゾリル、又はトリアゾリルである、請求項36に記載の化合物。
- R1が、置換されていてもよいフェニルである、請求項37に記載の化合物。
- R1が、それぞれが更に置換されていてもよい、ハロ、ニトロ、シアノ、ヒドロキシル、アミノ、NH(RA)、N(RA)(RA)、CO2H、C(O)RA、C(O)NH2、C(O)NH(RA)、C(O)N(RA)(RA)、アルキル、アリール、アリールアルキル、アルコキシ、ヘテロアリール、複素環、及び炭素環から選ばれる0〜4個の置換基で置換されている(ここで、それぞれのRAは、独立して、アルキル、炭素環、アリール、ヘテロアリール、及び複素環から選ばれる)、請求項38に記載の化合物。
- R5が、置換されていてもよいフェニル又は置換されていてもよいシクロペンチルである、請求項36に記載の化合物。
- 9−シクロペンチル−2−(5−(4−ヒドロキシピペリジン−1−イル)ピリジン−2−イルアミノ)−5−メチル−8,9−ジヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−6(7H)−オン;
4−(9−シクロペンチル−6−オキソ−6,7,8,9−テトラヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−2−イルアミノ)−3−メトキシ−N−(1−メチルピペリジン−4−イル)ベンズアミド;
4−(9−シクロペンチル−5−メチル−6−オキソ−6,7,8,9−テトラヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−2−イルアミノ)−3−メトキシ−N−(1−メチルピペリジン−4−イル)ベンズアミド;
4−(9−シクロペンチル−5,8−ジメチル−6−オキソ−6,7,8,9−テトラヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−2−イルアミノ)−3−メトキシ−N−(1−メチルピペリジン−4−イル)ベンズアミド;
4−(9−シクロペンチル−5,7−ジメチル−6−オキソ−6,7,8,9−テトラヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−2−イルアミノ)−3−メトキシ−N−(1−メチルピペリジン−4−イル)ベンズアミド;
9−シクロペンチル−2−(4−(4−ヒドロキシピペリジン−1−イル)−2−メトキシフェニルアミノ)−5−メチル−8,9−ジヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−6(7H)−オン;
9−シクロペンチル−2−(4−((2−ヒドロキシエチル)(メチル)アミノ)−2−メトキシフェニルアミノ)−5−メチル−8,9−ジヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−6(7H)−オン;
9−シクロペンチル−2−(4−((3−ヒドロキシプロピル)(メチル)アミノ)−2−メトキシフェニルアミノ)−5−メチル−8,9−ジヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−6(7H)−オン;
9−シクロペンチル−2−(4−(4−ヒドロキシ−4−メチルピペリジン−1−イル)−2−メトキシフェニルアミノ)−5−メチル−8,9−ジヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−6(7H)−オン;
9−シクロペンチル−2−(2−エトキシ−4−(4−ヒドロキシピペリジン−1−イル)フェニルアミノ)−5−メチル−8,9−ジヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−6(7H)−オン;
9−シクロペンチル−2−(4−(4−ヒドロキシピペリジン−1−イル)−2−イソプロポキシフェニルアミノ)−5−メチル−8,9−ジヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−6(7H)−オン;
9−シクロペンチル−2−(4−(4−(2−ヒドロキシエチル)ピペラジン−1−イル)−2−メトキシフェニルアミノ)−5−メチル−8,9−ジヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−6(7H)−オン;
9−シクロペンチル−2−(2−エトキシ−4−(4−ヒドロキシピペリジン−1−イル)フェニルアミノ)−5−エチル−8,9−ジヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−6(7H)−オン;
9−シクロペンチル−5−エチル−2−(4−(4−ヒドロキシピペリジン−1−イル)−2−イソプロポキシフェニルアミノ)−8,9−ジヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−6(7H)−オン;
9−シクロペンチル−5−エチル−2−(5−(4−ヒドロキシピペリジン−1−イル)ピリジン−2−イルアミノ)−8,9−ジヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−6(7H)−オン;
9−シクロペンチル−2−(2−メトキシ−4−(4−(4−メチルピペラジン−1−イル)ピペリジン−1−イル)フェニルアミノ)−5,8−ジメチル−8,9−ジヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−6(7H)−オン;
9−シクロペンチル−2−(2−メトキシ−4−(4−(4−メチルピペラジン−1−イル)ピペリジン−1−イル)フェニルアミノ)−8−メチル−8,9−ジヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−6(7H)−オン;
9−シクロペンチル−2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5,8−ジメチル−8,9−ジヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−6(7H)−オン;
9−シクロペンチル−2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−8−メチル−8,9−ジヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−6(7H)−オン;
10−シクロペンチル−5−メチル−(2−キノリン−6−イルアミノ)−6a、7,8,9,9a,10−ヘキサヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(5H)−オン;
10−シクロペンチル−5−メチル−(2−キノリン−5−イルアミノ)−6a、7,8,9,9a,10−ヘキサヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(5H)−オン;
10−シクロペンチル−2−(2−メトキシ−4−(4−メチルピペラジン−1−カルボニル)フェニルアミノ)−5−メチル−6a、7,8,9,9a,10−ヘキサヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(5H)−オン;
4−(10−シクロペンチル−5−メチル−6−オキソ−5,6,6a、7,8,9,9a,10−オクタヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−2−イルアミノ)−3−メトキシ安息香酸;
4−(10−シクロペンチル−5−メチル−6−オキソ−5,6,6a、7,8,9,9a,10−オクタヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−2−イルアミノ)ベンズアミド;
10−シクロペンチル−2−(4−(4−ヒドロキシピペリジン−1−カルボニル)−2−メトキシフェニルアミノ)−5−メチル−6a、7,8,9,9a,10−ヘキサヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(5H)−オン;
10−シクロペンチル−2−(2−ヒドロキシエチルアミノ)−5−メチル−6a、7,8,9,9a,10−ヘキサヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(5H)−オン;
4−(10−シクロペンチル−5−メチル−6−オキソ−5,6,6a、7,8,9,9a,10−オクタヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−2−イルアミノ)−3−メトキシベンズアミド;
4−(10−シクロペンチル−5−メチル−6−オキソ−5,6,6a、7,8,9,9a,10−オクタヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−2−イルアミノ)−N−(4−ヒドロキシシクロヘキシル)−3−メトキシベンズアミド;
4−(10−シクロペンチル−5−メチル−6−オキソ−5,6,6a、7,8,9,9a,10−オクタヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−2−イルアミノ)−3−メトキシ−N−(1−メチルピペリジン−4−イル)ベンズアミド;
10−シクロペンチル−2−(4−ヒドロキシシクロヘキシルアミノ)−5−メチル−6a、7,8,9,9a,10−ヘキサヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(5H)−オン;
10−シクロペンチル−5−メチル−2−(1−メチルピペリジン−4−イルアミノ)−6a、7,8,9,9a,10−ヘキサヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(5H)−オン;
4−(10−シクロペンチル−5−メチル−6−オキソ−5,6,6a、7,8,9,9a,10−オクタヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−2−イルアミノ)−N−(2−ヒドロキシエチル)−3−メトキシベンズアミド;
10−シクロペンチル−2−(4−(4−ヒドロキシピペリジン−1−イル)−2−メトキシフェニルアミノ)−5−メチル−6a、7,8,9,9a,10−ヘキサヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(5H)−オン;
10−シクロペンチル−2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5−メチル−6a、7,8,9,9a,10−ヘキサヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(5H)−オン;
4−(10−シクロペンチル−5−メチル−6−オキソ−5,6,6a、7,8,9,9a,10−オクタヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−2−イルアミノ)−3−メトキシ−N−メチルベンズアミド;
10−シクロペンチル−2−(2−メトキシ−4−(4−(4−メチルピペラジン−1−イル)ピペリジン−1−イル)フェニルアミノ)−5−メチル−6a、7,8,9,9a,10−ヘキサヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(5H)−オン;
6−(10−シクロペンチル−5−メチル−6−オキソ−5,6,6a、7,8,9,9a,10−オクタヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−2−イルアミノ)−N−メチルニコチンアミド;
1−(4−(10−シクロペンチル−5−メチル−6−オキソ−5,6,6a、7,8,9,9a,10−オクタヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−2−イルアミノ)−3−メトキシフェニル)ピペラジン−4−カルボキサミド;
10−シクロペンチル−2−(2−イソプロポキシ−4−(4−(4−メチルピペラジン−1−イル)ピペリジン−1−カルボニル)フェニルアミノ)−5−メチル−6a、7,8,9,9a,10−ヘキサヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(5H)−オン;
6−(10−シクロペンチル−5−メチル−6−オキソ−5,6,6a、7,8,9,9a,10−オクタヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−2−イルアミノ)−N−(1−メチルピペリジン−4−イル)ニコチンアミド;
2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5−メチル−7a,8,9,10−テトラヒドロ−5H−ピリミド[5,4−b]ピロロ[1,2−d][1,4]ジアゼピン−6(7H)−オン;
2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−7a,8,9,10−テトラヒドロ−5H−ピリミド[5,4−b]ピロロ[1,2−d][1,4]ジアゼピン−6(7H)−オン;
2−(2−メトキシ−4−(4−(4−メチルピペラジン−1−イル)ピペリジン−1−イル)フェニルアミノ)−5−メチル−7a,8,9,10−テトラヒドロ−5H−ピリミド[5,4−b]ピロロ[1,2−d][1,4]ジアゼピン−6(7H)−オン;
2−(5−(4−ヒドロキシピペリジン−1−イル)ピリジン−2−イルアミノ)−5−メチル−7a,8,9,10−テトラヒドロ−5H−ピリミド[5,4−b]ピロロ[1,2−d][1,4]ジアゼピン−6(7H)−オン;
2−(2−エトキシ−4−(4−ヒドロキシピペリジン−1−イル)フェニルアミノ)−5−メチル−7a,8,9,10−テトラヒドロ−5H−ピリミド[5,4−b]ピロロ[1,2−d][1,4]ジアゼピン−6(7H)−オン;
2−(4−(4−ジエチルアミノ)ピペリジン−1−イル)−2−イソプロポキシフェニルアミノ)−5−メチル−7a,8,9,10−テトラヒドロ−5H−ピリミド[5,4−b]ピロロ[1,2−d][1,4]ジアゼピン−6(7H)−オン;
4−(10−シクロペンチル−5−メチル−6−オキソ−5,6,6a、7,8,9,9a,10−オクタヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−2−イルアミノ)−3−メトキシ−N−(1−メチルピペリジン−4−イル)ベンズアミド;
4−(10−シクロペンチル−5−メチル−6−オキソ−5,6,6a、7,8,9,9a,10−オクタヒドロシクロペンタ[e]ピリミド[5,4−b][1,4]ジアゼピン−2−イルアミノ)−3−メトキシベンズアミド;
2−(4−(4−ジメチルアミノ)ピペリジン−1−イル)−2−イソプロポキシフェニルアミノ)−5−メチル−7a,8,9,10−テトラヒドロ−5H−ピリミド[5,4−b]ピロロ[1,2−d][1,4]ジアゼピン−6(7H)−オン;
2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5−メチル−9−フェニル−8,9−ジヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−6(H)−オン;
2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−9−フェニル−8,9−ジヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−6(7H)−オン;
2−(5−(4−ヒドロキシピペリジン−1−イル)ピリジン−2−イルアミノ)−5−メチル−9−フェニル−8,9−ジヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−6(7H)−オン;
2−(4−(4−ヒドロキシピペリジン−1−イル)−2−イソプロポキシフェニルアミノ)−5−メチル−9−フェニル−8,9−ジヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−6(7H)−オン;
2−(2−エトキシ−4−(4−ヒドロキシピペリジン−1−イル)フェニルアミノ)−5−メチル−9−フェニル−8,9−ジヒドロ−5H−ピリミド[4,5−b][1,4]ジアゼピン−6(7H)−オン;
2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5,11−ジメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−11−メチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(4−(4−ヒドロキシピペリジン−1−イル)−2−イソプロポキシフェニルアミノ)−5,11−ジメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(2−メトキシ−4−(4−(4−メチルピペラジン−1−イル)ピペリジン−1−イル)フェニルアミノ)−5,11−ジメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(5−(4−ヒドロキシピペリジン−1−イル)ピリジン−2−イルアミノ)−5,11−ジメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(2−エトキシ−4−(4−ヒドロキシピペリジン−1−イル)フェニルアミノ)−5,11−ジメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(4−(4−ヒドロキシピペリジン−1−イル)−2−メトキシフェニルアミノ)−5,11−ジメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
5−エチル−2−(5−(4−ヒドロキシピペリジン−1−イル)ピリジン−2−イルアミノ)−11−メチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
5−エチル−2−(4−(4−ヒドロキシピペリジン−1−イル)−2−メトキシフェニルアミノ)−11−メチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(2−エトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−11−メチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(2−イソプロポキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−11−メチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
11−エチル−2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5−メチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
11−エチル−2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−4,5,11−トリメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−4,11−ジメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
11−イソプロピル−2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
11−イソプロピル−2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5−メチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
11−シクロペンチル−2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5−メチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
11−シクロペンチル−2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
9−フルオロ−2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5,11−ジメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
9−フルオロ−2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−11−メチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
8−クロロ−2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5,11−ジメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
8−クロロ−2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−11−メチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−8,11−ジメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5,8,11−トリメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5,11−ジメチル−5H−ピリド[3,4−e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−11−メチル−5H−ピリド[3,4−e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
4−(5,11−ジメチル−6−オキソ−6,11−ジヒドロ−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−2−イルアミノ)−3−メトキシ安息香酸メチル;
2−(2−メトキシ−4−(4−メチルピペラジン−1−カルボニル)フェニルアミノ)−5,11−ジメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(2−メトキシ−4−(4−(4−メチルピペラジン−1−イル)ピペリジン−1−イル)フェニルアミノ)−5,11−ジメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(5−(4−ヒドロキシピペリジン)−1−イル)ピリジン−2−イルアミノ)−5,11−ジメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(2−エトキシ−4−(4−ヒドロキシピペリジン−1−イル)フェニルアミノ)−5,11−ジメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(2−メトキシ−4−(4−メチルピペリジン−1−イル)フェニルアミノ)−5−メチル−9−フェニル−5H−ピリミド[5,4−e][1,4]ジアゼピン−6(7H)−オン;
3−メトキシ−4−(5−メチル−6−オキソ−9−フェニル−6,7−ジヒドロ−5H−ピリミド[5,4−e][1,4]ジアゼピン−2−イルアミノ)−N−(1−メチルピペリジン−4−イル)ベンズアミド;
4−(9−シクロペンチル−7−エチル−5−メチル−6−オキソ−6,7−ジヒドロ−5H−ピリミド[5,4−e][1,4]ジアゼピン−2−イルアミノ)−3−ヒドロキシ−N−(1−メチルピペリジン−4−イル)ベンズアミド;
4−(7−エチル−5−メチル−6−オキソ−9−フェニル−6,7−ジヒドロ−5H−ピリミド[5,4−e][1,4]ジアゼピン−2−イルアミノ)−3−メトキシ−N−(1−メチルピペリジン−4−イル)ベンズアミド;
4−(9−シクロペンチル−5−メチル−6−オキソ−6,7−ジヒドロ−5H−ピリミド[5,4−e][1,4]ジアゼピン−2−イルアミノ)−3−メトキシ−N−(1−メチルピペリジン−4−イル)ベンズアミド;
9−クロロ−2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5,11−ジメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
11−ベンジル−2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5−メチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
11−ベンジル−2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
4−(5,11−ジメチル−6−オキソ−6,11−ジヒドロ−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−2−イルアミノ)−3−メトキシ安息香酸;
4−(5,11−ジメチル−6−オキソ−6,11−ジヒドロ−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−2−イルアミノ)−3−メトキシ安息香酸メチル;
3−(5,11−ジメチル−6−オキソ−6,11−ジヒドロ−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−2−イルアミノ)−4−メトキシ安息香酸;
2−(2−メトキシ−4−(4−ピロリジン−1−イル)ピペリジン−1−カルボニル)フェニルアミノ)−5,11−ジメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(2−メトキシ−4−(4−(4−メチルピペラジン−1−イル)ピペリジン−1−カルボニル)フェニルアミノ)−5,11−ジメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(4−(3−ジメチルアミノ)ピロリジン−1−カルボニル)−2−メトキシフェニルアミノ)−5,11−ジメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
4−(5,11−ジメチル−6−オキソ−6,11−ジヒドロ−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−2−イルアミノ)−3−メトキシ−N−(1−メチルピペリジン−4−イル)ベンズアミド;
3−(5,11−ジメチル−6−オキソ−6,11−ジヒドロ−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−2−イルアミノ)−4−メトキシ−N−(1−メチルピペリジン−4−イル)ベンズアミド;
2−(2−メトキシ−5−(4−(4−メチルピペラジン−1−イル)ピペリジン−1−カルボニル)フェニルアミノ)−5,11−ジメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(5−(3−(ジメチルアミノ)ピロリジン−1−カルボニル)−2−メトキシフェニルアミノ)−5,11−ジメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
3−(5,11−ジメチル−6−オキソ−6,11−ジヒドロ−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−2−イルアミノ)−N−(2−(ジメチルアミノ)エチル)−4−メトキシベンズアミド;
2−(4−(4−(2−ヒドロキシエチル)ピペラジン−1−カルボニル)−2−メトキシフェニルアミノ)−5,11−ジメチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5−メチル−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5H−ベンゾ[e]ピリミド[5,4−b][1,4]ジアゼピン−6(11H)−オン;
2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5−メチルベンゾ[f]ピリミド[4,5−b][1,4]チアゼピン−6(5H)−オン;
2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)ベンゾ[f]ピリミド[4,5−b][1,4]チアゼピン−6(5H)−オン;
2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)ベンゾ[f]ピリミド[4,5−b][1,4]オキサゼピン−6(5H)−オン;及び
2−(2−メトキシ−4−(4−メチルピペラジン−1−イル)フェニルアミノ)−5−メチルベンゾ[f]ピリミド[4,5−b][1,4]オキサゼピン−6(5H)−オン:
から選ばれる、請求項1に記載の化合物。 - 請求項1に記載の化合物、又はそれらの薬学的に許容されるエステル、塩又はプロドラッグを、薬学的に許容される担体と共に含有してなる、医薬組成物。
- 請求項1に記載の化合物、薬学的に許容される塩、エステル又はプロドラッグを対象に投与することを含有してなる、対象における疾患を治療する方法。
- 疾患が、MAPキナーゼ、有糸分裂紡錘体キナーゼ、及びポロキナーゼから選ばれるキナーゼに介在される、請求項45に記載の方法。
- 疾患が、MPS1、ERK5、BMK1、MAPK7、ポロキナーゼ1、2、3、又は4、Ack1、Ack2、Abl、DCAMKL1、ABL1、Abl突然変異体、DCAMKL2、ARK5、BRK、MKNK2、FGFR4、TNK1、PLK1、ULK2、PLK4、PRKD1、PRKD2、PRKD3、ROS1、RPS6KA6、TAOK1、TAOK3、TNK2、Bcr−Abl、GAK、cSrc、TPR−Met、Tie2、MET、FGFR3、Aurora、Axl、Bmx、BTK、c−kit、CHK2、Flt3、MST2、p70S6K、PDGFR、PKB、PKC、Raf、ROCK−H、Rsk1、SGK、TrkA、TrkB及びTrkCから選ばれるキナーゼに介在される、請求項45に記載の方法。
- キナーゼが、ERK−5、MPS1、又はBMK−1である、請求項47に記載の方法。
- 疾患が、癌又は増殖性疾患である、請求項47に記載の方法。
- 疾患が、肺、結腸、乳房、前立腺、肝臓、膵臓、脳、腎臓、卵巣、胃、皮膚及び骨の癌;胃、乳房、膵臓癌;神経膠腫、及び肝細胞癌;乳頭状腎細胞癌、頭頸部扁平上皮癌、白血病、リンパ腫、骨髄腫、及び固形腫瘍である、請求項49に記載の方法。
- 疾患が、炎症、関節炎、関節リウマチ、脊椎関節症、痛風性関節炎、変形性関節症、若年性関節炎、及びその他の関節炎疾患、全身性エリテマトーデス(SLE)、皮膚関連疾患、乾癬、皮膚炎、熱傷、皮膚炎、神経炎症、アレルギー、疼痛、神経因性疼痛、発熱、肺疾患、肺の炎症、成人呼吸窮迫症候群、肺サルコイドーシス、喘息、珪肺、慢性炎症性肺疾患、及び慢性閉塞性肺疾患(COPD)、心臓血管疾患、動脈硬化症、心筋梗塞(心筋梗塞後症を包含する)、血栓症、鬱血性心不全、心臓再環流傷害(更に血管臓器損傷などの高血圧及び/又は心不全に関連する合併症も)、再狭窄、心筋症、虚血及び脳出血を含む卒中、再環流傷害、腎臓再環流傷害、卒中及び脳虚血を含む虚血、及び心臓/環血管バイパスに由来する虚血、神経変性疾患、肝疾患及び腎炎、胃腸疾患、炎症性大腸炎、クローン病、胃炎、過敏性腸症候群、潰瘍性大腸炎、潰瘍性疾患、胃潰瘍、ウィルス及び細菌感染症、敗血症、敗血性ショック、グラム陰性菌敗血症、マラリア、髄膜炎、HIV感染症、日和見感染症、感染症又は悪性腫瘍に続発する悪液質、後天性免疫不全症候群(AIDS)に続発する悪液質、ARC(AIDS関連症候群)、肺炎、ヘルペスウィルス、感染に起因する筋肉痛、インフルエンザ、自己免疫疾患、移植片対宿主反応及び同種移植拒絶、骨吸収疾患の治療、骨粗しょう症、多発性硬化症、癌、白血病、リンパ腫、結腸直腸癌、脳の癌、骨の癌、上皮細胞由来新生物(上皮癌)、基底細胞癌、腺癌、消化器癌、口唇癌、口腔癌、食道癌、小腸癌、胃癌、結腸癌、肝臓癌、膀胱癌、膵臓癌、卵巣癌、子宮頸癌、肺癌、乳癌、皮膚癌、扁平上皮細胞及び/又は基底細胞癌、前立腺癌、腎細胞癌、及び体内の上皮細胞に影響を及ぼすその他の公知の癌、慢性骨髄性白血病(CML)、急性骨髄性白血病(AML)及び急性前骨髄球性白血病(APL)、新生物を含む血管形成、転移、中枢神経系疾患、炎症及びアポトーシス成分を有する中枢神経系疾患、アルツハイマー病、パーキンソン病、ホジキン病、筋萎縮性側索硬化症、脊髄損傷、及び末梢神経障害、イヌB−細胞リンパ腫である、請求項47に記載の方法。
- 疾患が、炎症、関節炎、関節リウマチ、脊椎関節症、痛風性関節炎、変形性関節症、若年性関節炎、及びその他の関節炎状態、全身性エリテマトーデス(SLE)、皮膚関連疾患、乾癬、湿疹、皮膚炎、疼痛、肺疾患、肺の炎症、成人呼吸窮迫症候群、肺サルコイドーシス、喘息、慢性炎症性肺疾患、及び慢性閉塞性肺疾患(COPD)、心臓血管疾患、動脈硬化症、心筋梗塞(心筋梗塞後症を包含する)、鬱血性心不全、心臓再環流傷害、炎症性大腸炎、クローン病、胃炎、過敏性腸症候群、白血病、リンパ腫である、請求項51に記載の方法。
- 治療が必要であると確認されている対象に、請求項1に記載の化合物、薬学的に許容される塩、エステル又はプロドラッグを投与することを含有してなる、対象におけるキナーゼが介在する疾患を治療する方法。
- 化合物が、MPS1、ERK5、BMK1、MAPK7、ポロキナーゼ1、2、3、又は4、Ack1、Ack2、Abl、DCAMKL1、ABL1、Abl突然変異体、DCAMKL2、ARK5、BRK、MKNK2、FGFR4、TNK1、PLK1、ULK2、PLK4、PRKD1、PRKD2、PRKD3、ROS1、RPS6KA6、TAOK1、TAOK3、TNK2、Bcr−Abl、GAK、cSrc、TPR−Met、Tie2、MET、FGFR3、Aurora、Axl、Bmx、BTK、c−kit、CHK2、Flt3、MST2、p70S6K、PDGFR、PKB、PKC、Raf、ROCK−H、Rsk1、SGK、TrkA、TrkB又はTrkCの阻害剤である、請求項53に記載の方法。
- 化合物が、ERK5、MPS1、又はBMK1の阻害剤である、請求項54に記載の方法。
- 対象に更なる治療薬を投与する、請求項53に記載の方法。
- 化合物及び更なる治療薬を、同時に又は連続して投与する、請求項56に記載の方法。
- 細胞を、請求項1に記載のキナーゼ阻害性化合物と接触させることを含有してなる、キナーゼ依存性細胞増殖を減少する方法。
- 請求項1に記載の化合物を投与することを含有してなる、そのような治療を必要とすると確認されている対象におけるキナーゼを阻害する方法。
- 対象がヒトである、請求項44〜59の何れか一項に記載の方法。
- キナーゼ阻害剤が約1マイクロモル未満のキナーゼを阻害することについてのKiを有している、請求項59に記載の方法。
- 請求項1に記載の化合物の1つ又はそれ以上から選ばれるキナーゼ活性を阻害できる化合物、及び癌の治療に用いるための使用説明書を含有してなる、キット。
- 式Aの化合物を合成する方法。
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JP6125571B2 (ja) | 2017-05-10 |
US9701683B2 (en) | 2017-07-11 |
EP2379559B1 (en) | 2017-10-25 |
EP3828185A3 (en) | 2021-09-01 |
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EP3255047A2 (en) | 2017-12-13 |
CA2748181A1 (en) | 2010-07-15 |
EP3828185A2 (en) | 2021-06-02 |
WO2010080712A3 (en) | 2010-11-11 |
EP2379559A4 (en) | 2012-05-16 |
JP5908728B2 (ja) | 2016-04-26 |
WO2010080712A2 (en) | 2010-07-15 |
EP3255047B1 (en) | 2021-06-30 |
JP2015205911A (ja) | 2015-11-19 |
US10570154B2 (en) | 2020-02-25 |
US10081639B2 (en) | 2018-09-25 |
CA2748181C (en) | 2019-07-16 |
US20120040961A1 (en) | 2012-02-16 |
US9464091B2 (en) | 2016-10-11 |
EP3255047A3 (en) | 2018-03-14 |
EP2379559A2 (en) | 2011-10-26 |
US20180362545A1 (en) | 2018-12-20 |
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