JP2018168169A - ピリミド−ジアゼピノン化合物および障害の治療方法 - Google Patents
ピリミド−ジアゼピノン化合物および障害の治療方法 Download PDFInfo
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Abstract
Description
本出願は、2013年3月15日に出願された、米国仮特許出願第61/802,075号(この内容は、参照により本明細書に組み込まれる)の恩恵および優先権を主張する。
Aは、単結合または二重結合であり;
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Xは、任意選択の置換基(例えば、ハロゲン、−OH、−NO2、−CN、−NH2、保護アミノ、−NH−C1−C12−アルキル、−NH−C2−C12−アルケニル、−NH−C2−C12−アルケニル、−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、−O−C2−C12−アルケニル、−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、−C(O)−C2−C12−アルケニル、−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、−CONH−C2−C12−アルケニル、−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、−OCO2−C2−C12−アルケニル、−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、−OCONH−C2−C12−アルケニル、−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、−NHC(O)−C2−C12−アルケニル、−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、−NHCO2−C2−C12−アルケニル、−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、−NHC(O)NH−C2−C12−アルケニル、−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、−NHC(S)NH−C2−C12−アルケニル、−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、−NHC(NH)NH−C2−C12−アルケニル、−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、−NHC(NH)−C2−C12−アルケニル、−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、−C(NH)NH−C2−C12−アルケニル、−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、−S(O)−C2−C12−アルケニル、−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、−SO2NH−C2−C12−アルケニル、−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、−NHSO2−C2−C12−アルケニル、−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、−S−C2−C12−アルケニル、−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またはメチルチオメチル)であり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、水素、場合により置換されているアルキル(アラルキルを含む)、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグを提供する。
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Xは、式Iについて定義した任意選択の置換基であり;
Eは、NR2またはCHR2であり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、出現ごとに独立して、水素、場合により置換されているアルキル(アラルキルを含む)、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグを提供する。
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Xは、式Iについて定義した任意選択の置換基であり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、出現ごとに独立して、水素、場合により置換されているアルキル(アラルキルを含む)、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグを提供する。
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、出現ごとに独立して、水素、場合により置換されているアルキル(アラルキルを含む)、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグを提供する。
R2は、水素または場合により置換されているアルキルであり;
R3は、−OHまたは−O−(場合により置換されているアルキル)であり;
R4は、水素または場合により置換されているアルキルであり;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグを提供する。
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Xは、式Iについて定義した任意選択の置換基であり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、出現ごとに独立して、水素、場合により置換されているアルキル、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;または前記チオフェン環の隣接原子上の2個のX部分は、それらが結合している原子と一緒にフェニル環を形成し得;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグを提供する。
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Xは、式Iについて定義した任意選択の置換基であり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、水素、場合により置換されているアルキル、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグを提供する。
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Xは、式Iについて定義した任意選択の置換基であり;
Zは、OまたはSであり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、水素、場合により置換されているアルキル、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグを提供する。
Aは、単結合または二重結合であり;
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Yは、水素、場合により置換されているアルキル、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2およびR2’は、それぞれ独立して、水素、場合により置換されているアルキル、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;
またはYおよびR2’は、それらが結合している原子と一緒に5員環を形成し得;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグを提供する。
以下の記載は本発明を記載するために用いられている様々な用語の定義である。これらの定義は、本明細書および特許請求の範囲を通して用いられる場合に、個々にまたは大きなグループの一部として、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、保護アミノ、−NH−C1−C12アルキル、−NH−C2−C12アルケニル、−NH−C2−C12アルケニル、−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、−O−C2−C12アルケニル、−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、−C(O)−C2−C12アルケニル、−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、−CONH−C2−C12アルケニル、−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、−OCO2−C2−C12アルケニル、−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、−OCONH−C2−C12アルケニル、−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、−NHC(O)−C2−C12アルケニル、−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、−NHCO2−C2−C12アルケニル、−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、−NHC(O)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、−NHC(S)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、−NHC(NH)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、−NHC(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、−C(NH)NH−C2−C12アルケニル、−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、−S(O)−C2−C12アルケニル、−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、−SO2NH−C2−C12アルケニル、−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、−NHSO2−C2−C12アルケニル、−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、−S−C2−C12アルケニル、−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、また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、置換されているかまたは非置換である基を示す。
特定の態様では、本発明は、式I〜IX(または式AもしくはF)の化合物を提供する。
Aは、単結合または二重結合であり;
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Xは、任意選択の置換基(例えば、ハロゲン、−OH、−NO2、−CN、−NH2、保護アミノ、−NH−C1−C12−アルキル、−NH−C2−C12−アルケニル、−NH−C2−C12−アルケニル、−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、−O−C2−C12−アルケニル、−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、−C(O)−C2−C12−アルケニル、−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、−CONH−C2−C12−アルケニル、−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、−OCO2−C2−C12−アルケニル、−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、−OCONH−C2−C12−アルケニル、−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、−NHC(O)−C2−C12−アルケニル、−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、−NHCO2−C2−C12−アルケニル、−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、−NHC(O)NH−C2−C12−アルケニル、−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、−NHC(S)NH−C2−C12−アルケニル、−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、−NHC(NH)NH−C2−C12−アルケニル、−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、−NHC(NH)−C2−C12−アルケニル、−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、−C(NH)NH−C2−C12−アルケニル、−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、−S(O)−C2−C12−アルケニル、−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、−SO2NH−C2−C12−アルケニル、−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、−NHSO2−C2−C12−アルケニル、−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、−S−C2−C12−アルケニル、−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またはメチルチオメチル)であり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、水素、場合により置換されているアルキル(アラルキルを含む)、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグを提供する。
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Xは、式Iについて定義した任意選択の置換基であり;
Eは、NR2またはCHR2であり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、出現ごとに独立して、水素、場合により置換されているアルキル(アラルキルを含む)、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグを提供する。
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Xは、式Iについて定義した任意選択の置換基であり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、出現ごとに独立して、水素、場合により置換されているアルキル(アラルキルを含む)、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグを提供する。
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Xは、式Iについて定義した任意選択の置換基であり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、出現ごとに独立して、水素、場合により置換されているアルキル(アラルキルを含む)、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグを提供する。
Xは、式Iについて定義した任意選択の置換基であり;
R2は、水素または場合により置換されているアルキルであり;
R3は、−OHまたは−O−(場合により置換されているアルキル)であり;
R4は、水素または場合により置換されているアルキルであり;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグを提供する。
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Xは、式Iについて定義した任意選択の置換基であり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、出現ごとに独立して、水素、場合により置換されているアルキル、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;または前記チオフェン環の隣接原子上の2個のX部分は、それらが結合している原子と一緒にフェニル環を形成し得;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグを提供する。
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Xは、式Iについて定義した任意選択の置換基であり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、水素、場合により置換されているアルキル、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグを提供する。
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Xは、式Iについて定義した任意選択の置換基であり;
Zは、OまたはSであり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、水素、場合により置換されているアルキル、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグを提供する。
Aは、単結合または二重結合であり;
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Yは、水素、場合により置換されているアルキル、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2およびR2’は、それぞれ独立して、水素、場合により置換されているアルキル、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;
またはYおよびR2’は、それらが結合している原子と一緒に5員環を形成し得;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグを提供する。
Xは、CHR4、CR4、NH、NR4またはNであり;
Yは、NR5、N、S、SO、SO2、O、CHR5またはCR5であり;ここで、XおよびYの少なくとも一方は、NH、NR4、NR5、N、S、SO、SO2またはOであり;
Aは、単結合または二重結合であり;
Bは、単結合または二重結合であり、ここで、AおよびBの両方が二重結合ではなく;
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、水素または場合により置換されているアルキルであり;
R3は水素であるか、またはそれぞれが場合により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、複素環もしくは炭素環であり;R4は水素であるか、またはそれぞれが場合により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、複素環もしくは炭素環であり;R5は水素であるか、またはそれぞれが場合により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、複素環もしくは炭素環であり;またはR3およびXは、それらが結合している原子と一緒に、それぞれが場合により置換されていてもよい3〜8員炭素環、アリール、複素環またはヘテロアリールを形成し;
またはXおよびYは、それらが結合している原子と一緒に、それぞれが場合により置換されていてもよい3〜8員炭素環、アリール、複素環またはヘテロアリールを形成し;
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしく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、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、水素または場合により置換されているアルキルであり;
R5は、水素、場合により置換されているアルキル、場合により置換されているアラルキルまたは場合により置換されている炭素環であり;ならびに
R6は、水素または場合により置換されているアルキルであり;
各R7は、独立して、それぞれがハロ、ニトロまたはシアノで場合により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)またはN(アルキル)(アリール)であり;pは、0〜4であり;
またはpが2、3もしくは4である場合、出現する2個のR7は結合して、それらが結合している炭素原子と一緒に、(例えば、アリールまたはヘテロアリール環中に5個または6個の原子を有する)アリールまたはヘテロアリール環、例えば縮合フェニル環を形成し得る)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグを提供する。
別の態様では、本発明は、被験体における疾患を治療する方法であって、式I〜IX(または式AもしくはF)の化合物、薬学的に許容され得る塩、エステルまたはプロドラッグを前記被験体に投与することを含む方法を提供する。
別の態様では、本発明は、薬学的に許容され得る担体と共に、式I〜IX(または式AもしくはF)の化合物またはそれらの薬学的に許容され得るエステル、塩もしくはプロドラッグを含む医薬組成物を提供する。
例えば、経皮用のデバイスは、裏打ち材、場合により担体と共に化合物を含有する貯留層、宿主の皮膚へ長期間に渡って制御された所定の速度で化合物を送達する速度制御バリアーを場合により、デバイスを皮膚に固定する手段を含有する包帯の形態にある。マトリックス経皮用製剤を用いることもできる。局所投与、例えば皮膚および目への投与に適切である製剤は、当技術分野で周知である、水溶液、軟膏、クリームまたはゲルが好ましい。このようなものは、可溶化剤、安定化剤、等張化増強剤、緩衝剤および保存剤を含有できる。
実施例1:式IVのチオフェン化合物の合成
エチル2−(シクロペンチルアミノ)ベンゾエート(1.40g、6.0mmol)、4N HClジオキサン溶液(2.25mL、9.0mmol)および2,4−ジクロロ−5−ニトロピリミジン(1.74g、9.0mmol)のジオキサン(40mL)混合物を60℃で90時間加熱した。薄層クロマトグラフィー(TLC)によるモニタリングで反応が完了した後、反応溶液を濃縮し、酢酸エチルおよびヘキサン(1/20、v/v)を用いてシリカゲルカラムクロマトグラフィーによって残留物を精製して、アミノ化生成物12(1.84g、79%)を得た。MS(ESI)m/z391(M+H)+。
スキーム8.4,5,13−トリメチル−2−((1−(ピペリジン−4−イル)−1H−ピラゾール−4−イル)アミノ)−5,13−ジヒドロ−6H−ナフト[2,3−e]ピリミド[5,4−b][1,4]ジアゼピン−6−オン(HTH−01−015)aの合成
Hela(または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、ウエスタンブロッティングでサイクリンBまた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。
*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追加した。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、以下の固定液を使用して固定した:100mMのK−pipes、pH6.8、10mMのEGTA、1mMのMgCl2、0.2%TritonX−100、3%ホルムアルデヒド。0.1%TritonX−100を含有す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)を使用してサンプルを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使用して場合によりチューブリン染色することもできる。室温で2時間(または4℃で一晩)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(または4℃で一晩)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)を使用してガラススライド上に載せた。
*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
キナーゼ反応を室温で以下の成分を使用して実施した:1×キナーゼ反応緩衝液、5μg/mL(40nM)のMps1キナーゼ、200nMのAF−647E4Y基質、および1μMのATP(Km,app<1μM)。1時間後に、TR−FRET希釈緩衝液中のEDTA(20mM)およびEu−PY20 Tb標識抗体(4nM)の調製物を追加した。反応混合物中のEDTAおよびEu−PY20の最終濃度は、それぞれ10mMおよび2nMである。LanthaScreen(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。複数濃度の阻害剤に対してキナーゼ反応を行って、用量依存曲線を得た。
ベンゾ[e]ピリミド−[5,4−b]ジアゼピン−6(11H)−オン骨格のSAR調査は、相対的LRRK2選択的阻害剤24およびERK5選択的阻害剤26の発見につながった(図1)。ラクタム位置(R2)におけるNメチル置換の構造的特徴(4−アミド置換アニリンの2−エトキシ基、N−シクロペンチル置換(X)およびアントラニル酸のアリール環上の置換基(R4=H)の欠如)は、ERK5に対する強力な細胞阻害活性および高い特異性を達成するのに必須であった(図1、赤色で強調)。インドリン−7−カルボン酸基の結合(R6)は、化合物24によって例示される改善されたLRRK2選択性を示した(図1、青色で強調)。2−アニリノ部分の4位におけるアミド官能基の組み込みは、ERK5およびLRRK2の両方に有利である。ERK5およびLRRK2について、2−アニリノ部分のオルト位における置換基(R5)および連結基(X)は、ベンゾ[e]ピリミド−[5,4−b]ジアゼピン−6(11H)−オンのSARを分ける重要な構造的特徴である(図3)。特定のピリミジン誘導体、(4−((5−クロロ−4−(メチルアミノ)ピリミジン−2−イル)アミノ)−3−メトキシフェニル)(モルホリノ)メタノン(HG−10−102−01)および2−アリールメチルオキシ−5−置換基−N−アリールベンズアミド(GSK2578215A)は、強力なLRRK2の阻害剤であり、ERK5を阻害しないと報告されている。
新たなケモタイプのベンゾ[e]ピリミド−[5,4−b]ジアゼピン−6(11H)−オンは、ERK5およびLRRK2キナーゼ阻害剤を開発するための特権的な骨格に相当する。包括的なSAR調査により、ERK5およびLRRK2のためのこの骨格のSARを分ける重要な構造的特徴が同定された。化合物24は、LRRK2−IN−1と同様に強力なLRRK2阻害剤であり、インビトロおよび細胞内の両方において、改善されたLRRK2選択性で作用した。化合物26は、本発明者らがこれまでに開発した最も選択的かつ強力なERK5阻害剤に相当する。顕著な特異性および優れた細胞有効性を考慮すると、26は、ERK5の生物学をさらに調査するための汎用的なツールとして役立ち得る。異種移植腫瘍モデルにおいて優れた選択性、良好な薬物動態パラメータおよび高い有効性を有するベンゾ[e]ピリミド−[5,4−b]ジアゼピン−6(11H)−オンは、ERK5をターゲティングする治療剤を開発するための特権的なテンプレートとして役立ち得る。
HeLa細胞を一晩血清欠乏させ、続いて阻害剤で1時間処理した。次いで、EGF(20ng/mL)で細胞を17分間刺激し、RIPA緩衝液(1×PBS、1%NP40、0.5%デオキシコール酸ナトリウム、0.1%SDS、0.1mg/ml PMSFおよび1mMオルトバナジウム酸ナトリウム)中に回収した。6%ドデシル硫酸ナトリウム(SDS)−ポリアクリルアミドゲル電気泳動(PAGE)によって、全細胞溶解物からのタンパク質を分離し、ニトロセルロース膜に転写し、5%脱脂乳でブロッキングし、抗ERK5抗体でブロッティングした。
Invitrogen(Madison,WI)においてSelectScreen Kinase Profiling Serviceを使用して、インビトロキナーゼアッセイを行った。
試薬および一般方法。組織培養試薬は、Life Technologies製であった。プロテインGセファロースは、Amersham製であった。製造業者のプロトコールにしたがってQiagenまたはInvitrogenのプラスミドMaxiキットを使用して、トランスフェクションに使用するDNA構築物をEscherichia coli DH5αから精製した。Applied Biosystems 自動DNAシーケンサーのDYEnamic ET terminator chemistry(Amersham Biosciences)を使用して、The Sequencing Service,School of Life Sciences,University of Dundee,Scotland,U.K.が実施したDNA配列決定によって、すべてのDNA構築物を確認した。
阻害剤とLRRK2キナーゼドメインとの間の相互作用を解明するための分子ドッキング研究を実施した。最初に、本発明者らは、LRRK2キナーゼドメインの相同性モデル構造を構築した。本発明者らは、ロコキナーゼ(PDBアクセッション番号:4F1T)の結晶構造を使用した。Discovery Studio 3.5 package(http://www.accelrys.com)を使用して、LRRK2およびテンプレートタンパク質の配列アラインメントを作成した。Discovery Studio 3.5 packageのModellerを使用することによってLRRK2の3Dモデル構造を構築し、CHARMM力場を使用することによってさらに微調整した。次に、Maestro build panelを使用して化合物25および26を構築し、Schrodinger suite programのインパクトモジュールMaestroを使用して最小化した。Protein Preparation Wizardを使用してOPLS力場を適用することによって、LRRK2構造を最小化した。グリッド生成のために、結合部位をATP結合部位の重心と定義した。SchrodingerのドッキングプログラムGlideを使用して、LRRK2の活性部位へのリガンドのドッキングを行った。最良のドッキングポーズを最低Glideスコアとして選択した。PyMol package(http://www.pymol.org)を使用して、阻害剤の結合ポケットの分子グラフィックスおよび微調整したドッキングモデルを作成した。
Z’−LYTE(登録商標)Screening Protocolに記載されている方法およびLife Technologiesウェブサイトのアッセイ条件(http://www.invitrogen.comにおいて利用可能)にしたがって、EphA2キナーゼアッセイを実施した。
EphrinA2(100ng/mL)(R&D systems,Cat No.7856−A2−050)でA375細胞を15分間処理し、試験化合物を60分間の処理で細胞培養物に追加した。標準的なウエスタン分析を実施して、EphA2リン酸化(Y594)(Cell Signaling Technology製の抗体、Cat.No.3970)状態をモニタリングした。
本出願を通して引用されているすべての参考文献(参照文献、登録特許、公開特許公報、および同時係属特許出願を包含する)の内容は、その全体が参照により本明細書に明確に組み込まれる。他に別段定義しない限り、本明細書で使用されるすべての技術用語および科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。
当業者であれば、通常の実験のみを使用して、本明細書に記載される本発明の特定の実施形態の多くの均等物を認識するか、または前記均等物を確認することができるであろう。このような均等物は、以下の特許請求の範囲によって包含されるものである。
Claims (68)
- 式I:
Aは、単結合または二重結合であり;
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Xは、任意選択の置換基であり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、水素、場合により置換されているアルキル、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグ。 - R1が、それぞれが場合により置換されていてもよいフェニルまたはピリジルである、請求項1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)、アルコキシおよび複素環(式中、各RAは、アルキルおよび複素環から独立して選択される)から選択される0〜4個の置換基で置換されている、請求項2に記載の化合物。
- R2が、H、メチルまたはエチルである、請求項1に記載の化合物。
- R6がHである、請求項1に記載の化合物。
- XがHである、請求項1に記載の化合物。
- R’がHである、請求項1に記載の化合物。
- Lが存在しない、請求項1に記載の化合物。
- Aが単結合である、請求項1に記載の化合物。
- 式II:
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Xは、式Iについて定義した任意選択の置換基であり;
Eは、NR2またはCHR2であり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、出現ごとに独立して、水素、場合により置換されているアルキル、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグ。 - R1が、それぞれが場合により置換されていてもよいフェニルまたはピリジルである、請求項11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)、アルコキシおよび複素環(式中、各RAは、アルキルおよび複素環から独立して選択される)から選択される0〜4個の置換基で置換されている、請求項12に記載の化合物。
- R2が、H、メチルまたはエチルである、請求項11に記載の化合物。
- R6がHである、請求項11に記載の化合物。
- XがHである、請求項11に記載の化合物。
- R’がHである、請求項11に記載の化合物。
- Lが存在しない、請求項11に記載の化合物。
- EがNR2である、請求項11に記載の化合物。
- 式III:
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Xは、式Iについて定義した任意選択の置換基であり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、出現ごとに独立して、水素、場合により置換されているアルキル、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグ。 - R1が、それぞれが場合により置換されていてもよいフェニルまたはピリジルである、請求項21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)、アルコキシおよび複素環(式中、各RAは、アルキルおよび複素環から独立して選択される)から選択される0〜4個の置換基で置換されている、請求項22に記載の化合物。
- R2が、H、メチルまたはエチルである、請求項21に記載の化合物。
- R6がHである、請求項21に記載の化合物。
- XがHである、請求項21に記載の化合物。
- R’がHである、請求項21に記載の化合物。
- Lが存在しない、請求項21に記載の化合物。
- 式IV:
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Xは、式Iについて定義した任意選択の置換基であり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、出現ごとに独立して、水素、場合により置換されているアルキル、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグ。 - R1が、それぞれが場合により置換されていてもよいフェニルまたはピリジルである、請求項30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)、アルコキシおよび複素環(式中、各RAは、アルキルおよび複素環から独立して選択される)から選択される0〜4個の置換基で置換されている、請求項31に記載の化合物。
- R2が、H、メチルまたはエチルである、請求項30に記載の化合物。
- R6がHである、請求項30に記載の化合物。
- XがHである、請求項30に記載の化合物。
- R’がHである、請求項30に記載の化合物。
- Lが存在しない、請求項30に記載の化合物。
- R2が、H、メチルまたはエチルである、請求項39に記載の化合物。
- R6がHである、請求項39に記載の化合物。
- R3が、−OCH3または−OCH2CH3である、請求項39に記載の化合物。
- R4が、メチルまたはエチルである、請求項39に記載の化合物。
- 薬学的に許容され得る担体と共に、請求項1〜43のいずれか一項に記載の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグを含む、医薬組成物。
- 被験体における疾患を治療する方法であって、請求項1〜43のいずれか一項に記載の化合物、薬学的に許容され得る塩、エステルまたはプロドラッグを前記被験体に投与することを含む、方法。
- 前記疾患が、MAPキナーゼ、有糸分裂紡錘体キナーゼおよびポロキナーゼから選択されるキナーゼによって媒介される、請求項45に記載の方法。
- 前記疾患が、MPS1、ERK5、LRKK2、EphA2、BMK1、MAPK7、ポロキナーゼ1、2、3、または4、Ack1、Ack2、Abl、DCAMKL1、ABL1、Abl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およびTrkCから選択されるキナーゼによって媒介される、請求項45に記載の方法。
- 前記キナーゼが、ERK−5、LRKK2またはEphA2である、請求項47に記載の方法。
- 前記疾患が、癌または増殖性疾患である、請求項47に記載の方法。
- 前記疾患が、肺、結腸、乳房、前立腺、肝臓、膵臓、脳、腎臓、卵巣、胃、皮膚、および骨の癌、胃腸、乳房、膵臓の癌、神経膠腫、および肝細胞癌、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、および固形腫瘍である、請求項49に記載の方法。
- 前記疾患が、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、および他の関節炎疾患、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、およ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、心臓再環流傷害ならびに高血圧および/または心不全に関連する合併症、例えば血管臓器損傷、再狭窄、心筋症、虚血および脳出血を含む卒中、再環流傷害、腎臓再環流傷害、卒中および脳虚血を含む虚血、および心臓/環血管バイパスに由来する虚血、神経変性疾患、肝疾患および腎炎、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、ウイルスおよび細菌感染症、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、感染症また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、AIDS、ARC(AIDS関連症候群)、肺炎、ヘルペスウイルス、感染に起因する筋肉痛、インフルエンザ、自己免疫疾患、移植片対宿主反応および同種移植拒絶、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、扁平上皮細胞および/または基底細胞癌、前立腺癌、腎細胞癌、および体内の上皮細胞に影響を及ぼす他の公知の癌、慢性骨髄性白血病(CML)、急性骨髄性白血病(AML)およ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、炎症または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、および末梢神経障害、イヌB−細胞リンパ腫である、請求項47に記載の方法。
- 前記疾患が、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、および他の関節炎状態、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、およ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。
- 被験体におけるキナーゼ媒介性障害を治療する方法であって、それを必要とすると判定された前記被験体に、請求項1〜43のいずれか一項に記載の化合物、薬学的に許容され得る塩、エステルまたはプロドラッグを投与することを含む、方法。
- 前記化合物が、MPS1、ERK5、LRKK2、EphA2、BMK1、MAPK7、ポロキナーゼ1、2、3、または4、Ack1、Ack2、Abl、DCAMKL1、ABL1、Abl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またはTrkCの阻害剤である、請求項53に記載の方法。
- 前記化合物が、ERK−5、LRKK2またはEphA2の阻害剤である、請求項54に記載の方法。
- さらなる治療剤を前記被験体に投与する、請求項53に記載の方法。
- 前記化合物および前記さらなる治療剤を同時投与または逐次投与する、請求項56に記載の方法。
- キナーゼ依存性細胞成長を減少させるための方法であって、細胞を、請求項1〜43のいずれか一項に記載のキナーゼ阻害剤化合物と接触させることを含む、方法。
- このような治療を必要とすると判定された被験体におけるキナーゼを阻害する方法であって、請求項1〜43のいずれか一項に記載の化合物を投与することを含む、方法。
- 前記被験体がヒトである、請求項44〜59のいずれか一項に記載の方法。
- 前記キナーゼ阻害剤が、キナーゼの阻害について約1マイクロモル未満のKiを有する、請求項59に記載の方法。
- キットであって、請求項1〜43のいずれか一項に記載の1つ以上の化合物から選択される、キナーゼ活性を阻害することができる化合物と、癌治療の使用説明書とを含む、キット。
- 式I〜IXの化合物を合成する方法。
- 表6の化合物。
- 式VI:
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Xは、式Iについて定義した任意選択の置換基であり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、出現ごとに独立して、水素、場合により置換されているアルキル、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;または前記チオフェン環の隣接原子上の2個のX部分は、それらが結合している原子と一緒にフェニル環を形成し得;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグ。 - 式VII:
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Xは、式Iについて定義した任意選択の置換基であり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、水素、場合により置換されているアルキル、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグ。 - 式VIII:
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Xは、式Iについて定義した任意選択の置換基であり;
Zは、OまたはSであり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2は、水素、場合により置換されているアルキル、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグ。 - 式IX:
Aは、単結合または二重結合であり;
R’は、Hまたはアルキルであり;
Lは存在しないか、またはS、SO、SO2もしくはCOであり;
Yは、水素、場合により置換されているアルキル、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;
R1はHであるか、またはO、SもしくはNから選択される0個、1個、2個もしくは3個のヘテロ原子をそれぞれが含有するアルキル、アルケニル、アルキニルであり;またはR1は、アリール、アリールアルキル、ヘテロアリール、複素環または炭素環であり;ここで、R1は、場合により置換されていてもよく;
R2およびR2’は、それぞれ独立して、水素、場合により置換されているアルキル、場合により置換されているシクロアルキルおよび場合により置換されているヘテロシクリルであり;
またはYおよびR2’は、それらが結合している原子と一緒に5員環を形成し得;ならびに
R6は、水素または場合により置換されているアルキルである)の化合物またはその薬学的に許容され得る塩、エステルもしくはプロドラッグ。
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JP6553772B2 (ja) | 2019-07-31 |
JP6553589B2 (ja) | 2019-07-31 |
EP3738964A1 (en) | 2020-11-18 |
EP2970317A4 (en) | 2016-11-02 |
US9676792B2 (en) | 2017-06-13 |
JP2016515537A (ja) | 2016-05-30 |
US20170283422A1 (en) | 2017-10-05 |
EP2970317A2 (en) | 2016-01-20 |
US20200071340A1 (en) | 2020-03-05 |
EP3670515A1 (en) | 2020-06-24 |
EP3670515B1 (en) | 2024-03-06 |
CA2902599C (en) | 2023-03-21 |
US10787461B2 (en) | 2020-09-29 |
JP2019206534A (ja) | 2019-12-05 |
CA2902599A1 (en) | 2014-09-18 |
WO2014145909A2 (en) | 2014-09-18 |
US20190084998A1 (en) | 2019-03-21 |
US10457692B2 (en) | 2019-10-29 |
EP3388436A1 (en) | 2018-10-17 |
US10189861B2 (en) | 2019-01-29 |
US20160024115A1 (en) | 2016-01-28 |
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