JP6262383B2 - C−jun−n−末端キナーゼ(jnk)の阻害剤 - Google Patents
C−jun−n−末端キナーゼ(jnk)の阻害剤 Download PDFInfo
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- JP6262383B2 JP6262383B2 JP2017042266A JP2017042266A JP6262383B2 JP 6262383 B2 JP6262383 B2 JP 6262383B2 JP 2017042266 A JP2017042266 A JP 2017042266A JP 2017042266 A JP2017042266 A JP 2017042266A JP 6262383 B2 JP6262383 B2 JP 6262383B2
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Description
本発明は、2011年11月17日に出願された米国仮特許出願U.S.S.N. 61/561,078に対する35 U.S.C.§119(e)に基づく優先権を主張し、当該出願は、本明細書において参考として援用される。
本発明は、国立衛生学研究所により付与された助成金番号1RC2HG005693、5 RCD HG005693-02、RC2 CA148164-02および1 U54 HG 006907-01に基づく米国政府の支援によりなされた。米国政府は、本発明において一定の権利を有する。
哺乳動物細胞において、MAPK(マイトジェン活性化タンパク質キナーゼ)シグナル伝達系は、少なくとも、各々の経路における「末端」MAPKキナーゼ;MAP4K、MAP3K、MAP2K、ならびにERK1/2、JNK1/2/3、p38alpha/betaおよびERK5にちなんで名づけられるMAPKsのコアにより定義される、4つの区別し得るシグナル伝達モジュールからなる(Changら、2001年;Johnsonら、2002年;Pearsonら、2001年;およびRamanら、2007年)。JNK(c-Jun NH2−末端キナーゼ)は、細胞が、サイトカイン、浸透圧ストレス、低酸素およびUV光などのストレス状態に曝された後で高く活性化され、成長因子またはマイトジェンへの暴露によって低く活性化される(Derijardら、1994年;およびPulvererら、1991年)。3つの区別し得る遺伝子Jnk1、Jnk2およびJnk3が存在し、これらは、選択的にスプライシングされて、優勢なアイソフォームを有する約10種のタンパク質を生じる;JNK1およびJNK2は、ユビキタスに発現し、JNK3は、主に神経系において発現する(Derijardら、1994年;Kallunkiら、1994年;Slussら、1994年;およびMohitら、1995年)。JNKは、MAP2K:MKK4およびMKK7による活性化T−ループ残基Thr183/Tyr185におけるリン酸化により活性化され、MKP1およびMKP5を含むMAPキナーゼホスファターゼにより不活化される。JNK経路を通してのシグナル伝達は、JNKによりリン酸化されるc-Jun、TF2およびElk1などの転写因子に加えて、MAP3K、MAP2KおよびMAPKsを含むシグナル伝達複合体を組み立てる、JIPなどの「足場」タンパク質への結合を通して組織化される。JNKは炎症シグナル応答における中心節を含むので、癌、炎症および神経変性疾患を含む多くの疾患状態においてJNKシグナル伝達の高活性化が非常に一般的な知見であることは、驚くにはあたらない。JNKシグナル伝達の阻害剤が有望な治療戦略を提供し得ることを示唆する、大量の遺伝子的および薬理学的エビデンスが生み出されている。JNK3ノックアウトマウスは、パーキンソン病およびアルツハイマー病の動物モデルにおいて、神経変性の寛解を示す(Kyriakisら、2001年;Zhangら、2005年;およびHunotら、2004年)。JNK1は、インスリンセンシング経路における重要な分子でありインスリンシグナル伝達を下方調節するIRS-1をリン酸化し、JNK1ノックアウトマウスは、食餌により誘導される肥満に対して耐性である(Aguirreら、2000年および2002年;Hirosumiら、2002年;ならびにSabioら、2010年)。JNK2は、しばしばJNK1と協調して、関節リウマチ(Hanら、2002年)および喘息(Wong, W.S.、2005年;Pelaiaら、2005年;Bleaseら、2003年;Chialdaら、2005年)などの自己免疫性障害の病理学に関連付けられてきた。最近の研究は、JNK2が、多様な疾患およびアテローム性動脈硬化症においてもまた重要な役割を果たし得ることを示唆する(Ostoら、2008年)。しかし、今日まで、直接的なJNK阻害剤は、ヒトにおける使用のためには承認されていない。
マイトジェン活性化c-Jun-N-末端キナーゼ(JNK1、JNK2およびJNK3などのJNK)は、細胞外刺激を伝達して、協調された細胞応答中に組み込む、シグナル伝達モジュールにおける重要な酵素である。JNK-IN-7などの不可逆的JNK阻害剤は、JNK中の保存システイン残基と共有結合を形成することが発見された。JNK-IN-8などの幾つかの不可逆的JNK阻害剤は、細胞において、直接的なJNKの基質であるc-Junのリン酸化を保存システイン残基の共有結合的修飾に依存する様式において阻害する、選択的JNK阻害剤である。広範な生化学的な細胞および経路に基づくプロファイリングを用いて、これらの化合物のJNKの選択性を確立し、JNKに媒介される生物学的現象の多目的薬理学的プローブとしてのそれらの応用性を示唆した。
の化合物、ならびにその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体およびプロドラッグを提供し、ここで、環A、環B、X、L1、L2、RA、RC、RD、RE、m、nおよびpは、本明細書において定義されるとおりである。
特定の官能基および化学用語を、以下により詳細に記載する。化学元素は、元素の周期表(CASバージョン、Handbook of Chemistry and Physic、第75版、内表紙)に従って同定され、特定の官能基は、それにおいて一般的に定義される。さらに、有機化学の一般原則ならびに特定の官能部分および反応性は、以下において記載される:Thomas Sorrell、Organic Chemistry、University Science Books、Sausalito(1999年);SmithおよびMarch、March’s Advanced Organic Chemistry、第5版、John Wiley & Sons, Inc.、New York(2001年);Larock、Comprehensive Organic Transformations、VCH Publishers, Inc.、New York(1989年);ならびにCarruthers、Some Modern Methods of Organic Synthesis、第3版、Cambridge University Press、Cambridge(1987年)。
は、C3炭化水素鎖である。値の範囲が用いられる場合(例えばC1−6炭化水素鎖)、範囲の意味は、本明細書において記載されるとおりである。炭化水素鎖は、飽和していてもよい(例えば−(CH2)4−)。炭化水素鎖はまた、不飽和であってもよく、炭化水素鎖のいずれにおいて1または2以上のC=Cおよび/またはC≡C結合を含んでもよい。例えば、−CH=CH−(CH2)2−、−CH2−C≡C−CH2−および−C≡C−CH=CH−は全て、未置換の不飽和炭化水素鎖の例である。ある態様において、炭化水素鎖は、未置換である(例えば、−(CH2)4−)。ある態様において、炭化水素鎖は、置換されている(例えば、−CH(C2H5)−および−CF2−)。炭化水素鎖上の任意の2つの置換基は、連結されて、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリールまたは任意に置換されたヘテロアリール環を形成してもよい。例えば、
は全て、炭化水素鎖の例である。対照的に、ある態様において、
は、本明細書において記載される炭化水素鎖の範囲内ではない。
あるいは、炭素原子上の2つのジェミナルな水素は、基=O、=S、=NN(Rbb)2、=NNRbbC(=O)Raa、=NNRbbC(=O)ORaa、=NNRbbS(=O)2Raa、=NRbbまたは=NORccで置き換えられ;
Raaの各々の場合は、独立して、C1−10アルキル、C1−10ペルハロアルキル、C2−10アルケニル、C2−10アルキニル、C3−10カルボシクリル、3〜14員のヘテロシクリル、C6−14アリール、および5〜14員のヘテロアリールから選択されるか、または2つのRaa基は、連結されて、3〜14員のヘテロシクリルまたは5〜14員のヘテロアリール環を形成し、ここで、各々のアルキル、アルケニル、アルキニル、カルボシクリル、ヘテロシクリル、アリールおよびヘテロアリールは、独立して、0、1、2、3、4または5つのRdd基で置換され;
Rbbの各々の場合は、独立して、水素、−OH、−ORaa、−N(Rcc)2、−CN、−C(=O)Raa、−C(=O)N(Rcc)2、−CO2Raa、−SO2Raa、−C(=NRcc)ORaa、−C(=NRcc)N(Rcc)2、−SO2N(Rcc)2、−SO2Rcc、−SO2ORcc、−SORaa、−C(=S)N(Rcc)2、−C(=O)SRcc、−C(=S)SRcc、−P(=O)2Raa、−P(=O)(Raa)2、−P(=O)2N(Rcc)2、−P(=O)(NRcc)2、C1−10アルキル、C1−10ペルハロアルキル、C2−10アルケニル、C2−10アルキニル、C3−10カルボシクリル、3〜14員のヘテロシクリル、C6−14アリール、および5〜14員のヘテロアリールから選択されるか、または2つのRbb基は、連結されて、3〜14員のヘテロシクリルまたは5〜14員のヘテロアリール環を形成し、ここで、各々のアルキル、アルケニル、アルキニル、カルボシクリル、ヘテロシクリル、アリールおよびヘテロアリールは、独立して、0、1、2、3、4または5つのRdd基で置換され;
Rccの各々の場合は、独立して、水素、C1−10アルキル、C1−10ペルハロアルキル、C2−10アルケニル、C2−10アルキニル、C3−10カルボシクリル、3〜14員のヘテロシクリル、C6−14アリール、および5〜14員のヘテロアリールから選択されるか、または2つのRcc基は、連結されて、3〜14員のヘテロシクリルまたは5〜14員のヘテロアリール環を形成し、ここで、各々のアルキル、アルケニル、アルキニル、カルボシクリル、ヘテロシクリル、アリールおよびヘテロアリールは、独立して、0、1、2、3、4または5つのRdd基で置換され;
Rddの各々の場合は、独立して、ハロゲン、−CN、−NO2、−N3、−SO2H、−SO3H、−OH、−ORee、−ON(Rff)2、−N(Rff)2、−N(Rff)3 +X−、−N(ORee)Rff、−SH、−SRee、−SSRee、−C(=O)Ree、−CO2H、−CO2Ree、−OC(=O)Ree、−OCO2Ree、−C(=O)N(Rff)2、−OC(=O)N(Rff)2、−NRffC(=O)Ree、−NRffCO2Ree、−NRffC(=O)N(Rff)2、−C(=NRff)ORee、−OC(=NRff)Ree、−OC(=NRff)ORee、−C(=NRff)N(Rff)2、−OC(=NRff)N(Rff)2、−NRffC(=NRff)N(Rff)2,−NRffSO2Ree、−SO2N(Rff)2、−SO2Ree、−SO2ORee、−OSO2Ree、−S(=O)Ree、−Si(Ree)3、−OSi(Ree)3、−C(=S)N(Rff)2、−C(=O)SRee、−C(=S)SRee、−SC(=S)SRee、−P(=O)2Ree、−P(=O)(Ree)2、−OP(=O)(Ree)2、−OP(=O)(ORee)2、C1−6アルキル、C1−6ペルハロアルキル、C2−6アルケニル、C2−6アルキニル、C3−10カルボシクリル、3〜10員のヘテロシクリル、C6−10アリール、5〜10員のヘテロアリールから選択され、ここで、各々のアルキル、アルケニル、アルキニル、カルボシクリル、ヘテロシクリル、アリールおよびヘテロアリールは、独立して、で置換される0、1、2、3、4または5つのRgg基、または2つのジェミナルなRdd置換基は、連結して、=Oまたは=Sを形成してもよく;
Reeの各々の場合は、独立して、C1−6アルキル、C1−6ペルハロアルキル、C2−6アルケニル、C2−6アルキニル、C3−10カルボシクリル、C6−10アリール、3〜10員のヘテロシクリル、および3〜10員のヘテロアリールから選択され、ここで、各々のアルキル、アルケニル、アルキニル、カルボシクリル、ヘテロシクリル、アリールおよびヘテロアリールは、独立して、0、1、2、3、4または5つのRgg基で置換され;
Rffの各々の場合は、独立して、水素、C1−6アルキル、C1−6ペルハロアルキル、C2−6アルケニル、C2−6アルキニル、C3−10カルボシクリル、3〜10員のヘテロシクリル、C6−10アリールおよび5〜10員のヘテロアリールから選択されるか、または2つのRff基は、連結されて、3〜14員のヘテロシクリルまたは5〜14員のヘテロアリール環を形成し、ここで、各々のアルキル、アルケニル、アルキニル、カルボシクリル、ヘテロシクリル、アリールおよびヘテロアリールは、独立して、0、1、2、3、4または5つのRgg基で置換され;ならびに、
Rggの各々の場合は、独立して、ハロゲン、−CN、−NO2、−N3、−SO2H、−SO3H、−OH、−OC1−6アルキル、−ON(C1−6アルキル)2、−N(C1−6アルキル)2、−N(C1−6アルキル)3 +X−、−NH(C1−6アルキル)2 +X−、−NH2(C1−6アルキル)+X−、−NH3 +X−、−N(OC1−6アルキル)(C1−6アルキル)、−N(OH)(C1−6アルキル)、−NH(OH)、−SH、−SC1−6アルキル、−SS(C1−6アルキル)、−C(=O)(C1−6アルキル)、−CO2H、−CO2(C1−6アルキル)、−OC(=O)(C1−6アルキル)、−OCO2(C1−6アルキル)、−C(=O)NH2、−C(=O)N(C1−6アルキル)2、−OC(=O)NH(C1−6アルキル)、−NHC(=O)(C1−6アルキル)、−N(C1−6アルキル)C(=O)(C1−6アルキル)、−NHCO2(C1−6アルキル)、−NHC(=O)N(C1−6アルキル)2、−NHC(=O)NH(C1−6アルキル)、−NHC(=O)NH2、−C(=NH)O(C1−6アルキル)、−OC(=NH)(C1−6アルキル)、−OC(=NH)OC1−6アルキル、−C(=NH)N(C1−6アルキル)2、−C(=NH)NH(C1−6アルキル)、−C(=NH)NH2、−OC(=NH)N(C1−6アルキル)2、−OC(NH)NH(C1−6アルキル)、−OC(NH)NH2、−NHC(NH)N(C1−6アルキル)2、−NHC(=NH)NH2、−NHSO2(C1−6アルキル)、−SO2N(C1−6アルキル)2、−SO2NH(C1−6アルキル)、−SO2NH2、−SO2C1−6アルキル、−SO2OC1−6アルキル、−OSO2C1−6アルキル、−SOC1−6アルキル、−Si(C1−6アルキル)3、−OSi(C1−6アルキル)3、−C(=S)N(C1−6アルキル)2、C(=S)NH(C1−6アルキル)、C(=S)NH2、−C(=O)S(C1−6アルキル)、−C(=S)SC1−6アルキル、−SC(=S)SC1−6アルキル、−P(=O)2(C1−6アルキル)、−P(=O)(C1−6アルキル)2、−OP(=O)(C1−6アルキル)2、−OP(=O)(OC1−6アルキル)2、C1−6アルキル、C1−6ペルハロアルキル、C2−6アルケニル、C2−6アルキニル、C3−10カルボシクリル、C6−10アリール、3〜10員のヘテロシクリル、5〜10員のヘテロアリールであるか;または2つのジェミナルなRgg置換基は、連結して=Oまたは=Sを形成してもよく;ここで、X−は対イオンである。
以下の定義は、本願を通して用いられるより一般的な用語である。
互変異性体形態は、目的の化合物の最適な化学反応性および生物学的活性の達成のために適切であり得る。
本発明は、対象の疾患の予防および処置のための、キナーゼを阻害する化合物、およびその医薬組成物を提供する。ある態様において、化合物は、c-Jun-N-末端キナーゼ(JNK)を阻害する。ある態様において、化合物は、JNKを不可逆的に阻害する。本発明はさらに、本明細書において記載される化合物を、例えばJNKの活性の阻害を研究するための生物学的プローブとして、および例えばJNKの活性に関連する疾患の予防および処置における治療薬として用いる方法を提供する。ある態様において、疾患として、限定されないが、増殖性疾患(例えば、癌および良性新生物)、神経変性疾患、代謝障害、炎症性疾患および心血管疾患が挙げられる。
本発明の一側面において、提供されるのは、式(I):
の化合物、ならびにその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体、プロドラッグおよび組成物であって;
式中:
環Aは、炭素環式環、ヘテロ環式環、ヘテロアリール環またはアリール環であり;
RAの各々の場合は、独立して、水素、ハロゲン、任意に置換されたアシル、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリール、任意に置換されたヘテロアリール、−ORA1、−N(RA1)2および−SRA1からなる群より選択され、ここで、RA1の各々の存在は、独立して、水素、アシル、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリール、任意に置換されたヘテロアリール、窒素原子に結合している場合は窒素保護基、酸素原子に結合している場合は酸素保護基、硫黄原子に結合している場合は硫黄保護基からなる群より選択されるか、または2つのRA1基は、連結されて、任意に置換されたヘテロ環式環を形成し;
mは、0、1、2、3または4であり;
環Bは、式:
の基であり;
RB1は、水素、ハロゲン、任意に置換されたアシル、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリール、任意に置換されたヘテロアリール、−ORB1a、−N(RB1a)2および−SRB1aからなる群より選択され、ここで、RB1aの各々の存在は、独立して、水素、アシル、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリール、任意に置換されたヘテロアリール、窒素原子に結合している場合は窒素保護基、酸素原子に結合している場合は酸素保護基、硫黄原子に結合している場合は硫黄保護基からなる群より選択されるか、または2つのRB1a基は、連結されて、任意に置換されたヘテロ環式環を形成し;
WBは、NまたはCRB2であって、ここで、RB2は、水素、ハロゲン、任意に置換されたアシル、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリール、任意に置換されたヘテロアリール、−ORB2a、−N(RB2a)2および−SRB2aからなる群より選択され、ここで、RB2aの各々の存在は、独立して、水素、アシル、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリール、任意に置換されたヘテロアリール、窒素原子に結合している場合は窒素保護基、酸素原子に結合している場合は酸素保護基、硫黄原子に結合している場合は硫黄保護基からなる群より選択されるか、または2つのRB2a基は、連結されて、任意に置換されたヘテロ環式環を形成し;
任意にここで、RB1およびRB2は、連結されて、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたヘテロアリールまたは任意に置換されたアリール環を形成し;
L1は、環Aを環Bに直接結合させる結合であるか、または、L1は、=C(RL1a)−、−O−、−S−、−NRL1b−、−NRL1bC(=O)−、−C(=O)NRL1b−、−SC(=O)−、−C(=O)S−、−OC(=O)−、−C(=O)O−、−NRL1bC(=S)−、−C(=S)NRL1b−、トランス−CH=CH−、シス−CH=CH−、−S(=O)2O−、−OS(=O)2−、−S(=O)2NRL1b−、−NRL1bS(=O)2−、または任意に置換されたC1−4炭化水素鎖であって、任意にここで、炭化水素鎖の1個のメチレン単位は、=C(RL1a)−、−O−、−S−、−NRL1b−、−NRL1bC(=O)−、−C(=O)NRL1b−、−SC(=O)−、−C(=O)S−、−OC(=O)−、−C(=O)O−、−NRL1bC(=S)−、−C(=S)NRL1b−、トランス−CH=CH−、シス−CH=CH−、−S(=O)2O−、−OS(=O)2−、−S(=O)2NRL1b−または−NRL1bS(=O)2−で置き換えられ、ここで、RL1aは、水素、ハロゲン、任意に置換されたアシル、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリール、任意に置換されたヘテロアリール、−CNまたは−NO2であり、RL1bは、水素、C1−6アルキルまたは窒素保護基であり;
は、単結合または二重結合を表わし;
Xは、任意に置換されたC1−4炭化水素鎖であって、任意にここで、前記炭化水素鎖の1または2以上の炭素単位は、−O−、−S−または−NRX−で置き換えられ、ここでRXは、水素、C1−6アルキルまたは窒素保護基であり;
L2は、結合、−O−、−S−、−NRL2a−、−NRL2aC(=O)−、−C(=O)NRL2a−、−SC(=O)−、−C(=O)S−、−OC(=O)−、−C(=O)O−、−NRL2aC(=S)−、−C(=S)NRL2a−、トランス−CRL2b=CRL2b−、シス−CRL2b=CRL2b−、−C≡C−、−OC(RL2b)2−、−C(RL2b)2O−、−NRL2aC(RL2b)2−、−C(RL2b)2NRL2a−、−SC(RL2b)2−、−C(RL2b)2S−、−S(=O)2O−、−OS(=O)2−、−S(=O)2NRL2a−、−NRL2aS(=O)2−、または任意に置換されたC1−4炭化水素鎖であり、任意にここで、前記炭化水素鎖の1または2以上の炭素単位は、−O−、−S−、−NRL2a−、−NRL2aC(=O)−、−C(=O)NRL2a−、−SC(=O)−、−C(=O)S−、−OC(=O)−、−C(=O)O−、−NRL2aC(=S)−、−C(=S)NRL2a−、トランス−CRL2b=CRL2b−、シス−CRL2b=CRL2b−、−C≡C−、−S(=O)2O−、−OS(=O)2−、−S(=O)2NRL2a−または−NRL2aS(=O)2−で置き換えられ、ここで、RL2aは、水素、C1−6アルキルまたは窒素保護基であり、およびここで、RL2bの各々の存在は、独立して、水素、ハロゲン、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリールおよび任意に置換されたヘテロアリールからなる群より選択されるか、または2つのRL2b基は、連結されて、任意に置換された炭素環式環もしくは任意に置換されたヘテロ環式環を形成し;
RCの各々の場合は、独立して、水素、ハロゲン、任意に置換されたアシル、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリール、任意に置換されたヘテロアリール、−ORC1、−N(RC1)2および−SRC1からなる群より選択され、ここで、RC1の各々の存在は、独立して、水素、アシル、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリール、任意に置換されたヘテロアリール、窒素原子に結合している場合は窒素保護基、酸素原子に結合している場合は酸素保護基、硫黄原子に結合している場合は硫黄保護基からなる群より選択されるか、または2つのRC1基は、連結されて、任意に置換されたヘテロ環式環を形成し;
nは、0、1、2、3または4であり;
RDの各々の場合は、独立して、水素、ハロゲン、任意に置換されたアシル、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリール、任意に置換されたヘテロアリール、−ORD1、−N(RD1)2および−SRD1からなる群より選択され、ここで、RD1の各々の存在は、独立して、水素、アシル、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリール、任意に置換されたヘテロアリール、窒素原子に結合している場合は窒素保護基、酸素原子に結合している場合は酸素保護基、硫黄原子に結合している場合は硫黄保護基からなる群より選択されるか、または2つのRD1基は、連結されて、任意に置換されたヘテロ環式環を形成し;
pは、0、1、2、3または4であり;
REは、式:
の基であって、
式中:
L3は、結合、−O−、−S−、−NRL3a−、−NRL3aC(=O)−、−C(=O)NRL3a−、−SC(=O)−、−C(=O)S−、−OC(=O)−、−C(=O)O−、−NRL3aC(=S)−、−C(=S)NRL3a−、トランス−CRL3b=CRL3b−、シス−CRL3b=CRL3b−、−C≡C−、−OC(RL3b)2−、−C(RL3b)2O−、−NRL3aC(RL3b)2−、−C(RL3b)2NRL3a−、−SC(RL3b)2−、−C(RL3b)2S−、−S(=O)2O−、−OS(=O)2−、−S(=O)2NRL3a−、−NRL3aS(=O)2−、または任意に置換されたC1−4炭化水素鎖であって、任意にここで、前記炭化水素鎖の1または2以上の炭素単位は、−O−、−S−、−NRL3a−、−NRL3aC(=O)−、−C(=O)NRL3a−、−SC(=O)−、−C(=O)S−、−OC(=O)−、−C(=O)O−、−NRL3aC(=S)−、−C(=S)NRL3a−、トランス−CRL3b=CRL3b−、シス−CRL3b=CRL3b−、−C≡C−、−S(=O)2O−、−OS(=O)2−、−S(=O)2NRL3a−または−NRL3aS(=O)2−で置き換えられ、ここで、RL3aは、水素、C1−6アルキルまたは窒素保護基であり、およびここで、RL3bの各々の存在は、独立して、水素、ハロゲン、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリールおよび任意に置換されたヘテロアリールからなる群より選択されるか、または2つのRL3b基は、連結されて、任意に置換された炭素環式環もしくは任意に置換されたヘテロ環式環を形成し;
L4は、結合、または任意に置換されたC1−4炭化水素鎖であり;
RE1は、水素、ハロゲン、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリール、任意に置換されたヘテロアリール、−CH2ORE1a、−CH2N(RE1a)2、−CH2SRE1a,−ORE1a、−N(RE1a)2および−SRE1aからなる群より選択され、ここで、RE1aの各々の存在は、独立して、水素、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリールおよび任意に置換されたヘテロアリールからなる群より選択されるか、または2つのRE1a基は、連結されて、任意に置換されたヘテロ環式環を形成し;
RE2は、水素、ハロゲン、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリール、任意に置換されたヘテロアリール、−CH2ORE2a、−CH2N(RE2a)2、−CH2SRE2a、−ORE2a、−N(RE2a)2および−SRE2aからなる群より選択され、ここで、RE2aの各々の存在は、独立して、水素、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリールおよび任意に置換されたヘテロアリールからなる群より選択されるか、または2つのRE2a基は、連結されて、任意に置換されたヘテロ環式環を形成し;
RE3は、水素、ハロゲン、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリール、任意に置換されたヘテロアリール、−CH2ORE3a、−CH2N(RE3a)2、−CH2SRE3a、−ORE3a、−N(RE3a)2および−SRE3aからなる群より選択され、ここで、RE3aの各々の存在は、独立して、水素、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリールおよび任意に置換されたヘテロアリールからなる群より選択されるか、または2つのRE3a基は、連結されて、任意に置換されたヘテロ環式環を形成し;
任意にここで、RE1およびRE3またはRE2およびRE3またはRE1およびRE2は、連結されて、任意に置換された炭素環式環もしくは任意に置換されたヘテロ環式環を形成し;
RE4は、脱離基であり;
Yは、O、SまたはNRE5であって、ここで、RE5は、水素、C1−6アルキルまたは窒素保護基であり;
aは、1または2であり;ならびに
zは、0、1、2、3、4、5または6である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
ある態様において、環Aは、
である。
である。
である。
式中:
RB3は、水素、ハロゲン、任意に置換されたアシル、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリール、任意に置換されたヘテロアリール、−ORB3a、−N(RB3a)2および−SRB3aからなる群より選択され、ここで、RB3aの各々の存在は、独立して、水素、アシル、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたアルキニル、任意に置換されたカルボシクリル、任意に置換されたヘテロシクリル、任意に置換されたアリール、任意に置換されたヘテロアリール、窒素原子に結合している場合は窒素保護基、酸素原子に結合している場合は酸素保護基、硫黄原子に結合している場合は硫黄保護基からなる群より選択されるか、または2つのRB3a基は、連結されて、任意に置換されたヘテロ環式環を形成し;ならびに
qは、0、1、2または3である。
ある態様において、RB3は、Hである。ある態様において、RB3は、ハロゲンである。ある態様において、RB3はFである。ある態様において、RB3はClである。ある態様において、RB3はBrである。ある態様において、RB3はI(ヨウ素)である。ある態様において、RB3は、アシルである。ある態様において、RB3は、アセチルである。ある態様において、RB3は、置換されたアルキルである。ある態様において、RB3は、未置換のアルキルである。ある態様において、RB3は、C1−6アルキルである。ある態様において、RB3は、メチルである。ある態様において、RB3は、エチルである。ある態様において、RB3は、プロピルである。ある態様において、RB3は、ブチルである。ある態様において、RB3は、置換されたアルケニルである。ある態様において、RB3は、未置換のアルケニルである。ある態様において、RB3は、置換されたアルキニルである。ある態様において、RB3は、未置換のアルキニルである。ある態様において、RB3は、置換されたカルボシクリルである。ある態様において、RB3は、未置換のカルボシクリルである。ある態様において、RB3は、置換されたヘテロシクリルである。ある態様において、RB3は、未置換のヘテロシクリルである。ある態様において、RB3は、置換されたアリールである。ある態様において、RB3は、未置換のアリールである。ある態様において、RB3は、置換されたフェニルである。ある態様において、RB3は、未置換のフェニルである。ある態様において、RB3は、置換されたヘテロアリールである。ある態様において、RB3は、未置換のヘテロアリールである。ある態様において、RB3は、置換されたピリジルである。ある態様において、RB3は、未置換のピリジルである。ある態様において、RB3は、−ORB3aである。ある態様において、RB3は、−N(RB3a)2である。ある態様において、RB3は、−SRB3aである。
L1と環Aとの間の
は、単結合である。ある態様において、式(I)に関して、
は、二重結合である。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。
のもの、またはその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体もしくはプロドラッグである。化合物THZ-2-071-1、ZG-9、ZG-10、ZG-6およびTHZ-2-102-1は、JNKに対して顕著な活性を有さない場合もあるが、これらの化合物は、他のキナーゼを阻害することにおいて有用であり得る。
本発明は、本発明の化合物、例えば式(I)の化合物、ならびに、本明細書において記載されるようなその薬学的に受容可能な塩、溶媒和物、水和物、多形、共結晶、互変異性体、立体異性体、同位体標識された誘導体およびプロドラッグ、ならびに任意に薬学的に受容可能な賦形剤当業者を含む、医薬組成物を提供する。ある態様において、本発明の化合物またはその薬学的に受容可能な塩は、医薬組成物中で有効量において提供される。ある態様において、有効量とは治療有効量である。ある態様において、有効量とは予防有効量である。
本発明は、多様な疾患、例えば、神経変性疾患、代謝障害、炎症性疾患、心血管疾患、および増殖性疾患(例えば、癌および良性新生物)の予防および処置のための方法を提供する。
本明細書において記載される本発明がより完全に理解され得るために、以下の例を記載する。本願において記載される合成例および生物学的例は、本明細書において記載される化合物、医薬組成物および方法を説明するために提供され、決してそれらの範囲を限定するものとして解釈されるべきではない。
一般的合成方法
本明細書において提供される化合物は、容易に入手可能な出発材料から、以下の一般的方法および手順を用いて調製することができる。例えば、以下のスキーム1を参照。典型的なまたは好ましいプロセスの条件(すなわち、反応温度、時間、反応物のモル比、溶媒、圧力など)が示される場合、他のプロセスの条件もまた、他に記述されない限りにおいて、用いることができることが、理解されるであろう。最適な反応条件は、用いられる特定の反応物または溶媒により変化し得るが、かかる条件は、当業者により慣用的な最適化の手順により決定され得る。
スキーム1.本発明の化合物の例示的な合成
試薬および条件:(1)Pd2(dba)3、X−Phos、K2CO3、t−BuOH、90℃;(2)TFA、CH2Cl2;(3)ピリジン、90℃;(4)SnCl2;(5)塩化アクリロイルまたは4−ブロモブト−2−エノイル塩化物、NHMe2または塩化プロピオニル。
t−ブタノール中の4−置換−2−クロロピリミドの溶液に、t−ブチル−4−アミノフェニルカルバメートまたはt−ブチル−3−アミノフェニルカルバメート(1.0当量)、K2CO3(1.0当量)、X-Phos(0.1当量)およびPd2(dba)3を添加した。90℃で6時間の加熱の後で、反応混合物を、クロロホルムと2−プロパノールとの混合物(4:1)で希釈した。有機相を、水で洗浄し(3×)、MgSO4上で乾燥させ、減圧下で濾過および濃縮した。生じた粗生成物を、さらなる精製なしで次のステップに用いた。
CH2Cl2中の上の粗生成物の撹拌溶液に、室温において、TFAを添加した。反応混合物を、2時間撹拌し、減圧下において濃縮した。生じた粗生成物を、CH2Cl2/メタノール(10/1)を用いるフラッシュカラムクロマトグラフィーにより精製し、表題の化合物を得た。
BOC脱保護ステップから得た遊離のアミンを、ピリジン中で溶解し、塩化ニトロベンゾイル(1.2当量)をこの溶液に添加した。2時間の90℃における撹拌の後で、反応混合物を濃縮し、生じた粗生成物を、さらなる精製なしで次のステップのために用いた。
アニリンと塩化ニトロベンゾイルとの反応から得られたニトロ化合物を、エチル酢酸/メタノール(5:1)中で懸濁し、SnCl2(2.5当量)で処理した。2〜5時間の80℃における撹拌の後で、反応混合物を室温まで冷却し、飽和水性NaHCO3中に注いだ。混合物を10分間撹拌し、水相を次いでクロロホルムおよび2−プロパノール(4:1)で抽出した。組み合わせた有機相を、水および鹹水で洗浄し、MgSO4上で乾燥させ、減圧下においてセライトのパッドを通して濾過して濃縮した。生じた粗生成物を、CH2Cl2/メタノール(10/1)を用いるフラッシュカラムクロマトグラフィーにより精製し、表題の化合物を得た。
還元のステップにおいて得られたアニリンのDMF溶液に、N,N-ジイソプロピルエチルアミン(1.2当量)を添加した。反応混合物を−60℃まで冷却し、次いで、CH2Cl2中の4−クロロ−ブト−2−エノイル塩化物(5.0当量)で処理した。反応混合物を10分間−60℃で撹拌し、次いで、THF中のジメチルアミンの溶液で処置した。反応混合物を、次いで室温まで加温し、1時間撹拌し、減圧下で濃縮した。生じた粗生成物を、調製HPLCにより精製して、表題の化合物を得た。
完全なタンパク質の分析
各々の分析について、約100pmolのJNKタンパク質+/−阻害剤(JNK-IN-7)を、セルフパック逆相カラム(1/32’’O.D.×500μmI.D.、5cmのPOROS 10R2樹脂)上に注入した。脱塩後、HPLC勾配(4分間に0〜100%のB、A=水中0.2Mの酢酸、B=アセトニトリル中0.2Mの酢酸、および流速=10μL/分)を用いて、QTRAP質量分析器(AB Sciex, Toronto, Canada)またはLTQ Orbitrap質量分析器(ThermoFisher Scientific, San Jose, CA)中に、タンパク質を溶離させた。QTRAPは、Q1 MSモードにおいて、2000amu/秒における単位分解スキャニングにおいて、行った。質量中心モードにおいて、イオン検出のために電子倍増管を用いて、LTQ OrbitrapMSスペクトルを得た。MagTran 1.03b2ソフトウェアを用いて、質量スペクトルをデコンボリュートした。
JNK-IN-7処理されたJNK(25μg、約620pmol)を、アンモニウム重炭酸バッファー(pH8.0)で希釈し、次いで、30分間56℃において、10mMのDTTで還元した。5分間の冷却の後で、22.5mMのヨードアセタミドで30分間室温において暗所においてタンパク質をアルキル化し、1.5μgのトリプシンで37℃において一晩消化した。朝になって、1μgのGlu−Cを添加し、溶液をさらに、37℃で8時間インキュベートした。消化されたペプチド(約2pmol)を、セルフパックプレカラム(4cmのPOROS10R2)上に注入し、質量分析器(LTQ OrbitrapVelos, ThermoFisher Scientific)中に溶離させた。ペプチドを、CAD(電子倍増管検出、相対的衝突エネルギー35%、q=0.25)ならびにHCD(イメージ電流検出、m/z400=7500における分解能、および相対的衝突エネルギー=35%)により、MS2に供した。
それぞれGFP-c-Jun 1-79およびGFP-ATF2 19-106を安定に発現するLanthaScreenTM c-Jun (1-79) HeLa細胞株(Life Technologies, Carlsbad, CA)を用いて、c-Junのリン酸化についての細胞ベースのキナーゼアッセイを行った。テルビウム標識されたホスホ−c-Jun特異的抗体とGFPとの間の時間分解FRET(TR-FRET)を測定することにより、リン酸化を決定した。白色の組織培養処理された384ウェルプレート中で、1ウェルあたり32μLアッセイ培地(Opti-MEM(登録商標):0.5%のチャコール/デキストラン処理されたFBS、100U/mlのペニシリンおよび100μg/mlのストレプトマイシン、0.1mMの非必須アミノ酸、1mMピルビン酸ナトリウム、25mMのHepes(pH7.3)を添加され、フェノールレッドを欠くもの)中で10,000細胞の密度において、細胞を播種した。一晩のインキュベーションの後で、細胞を、90分間、4μLのアッセイバッファー中で希釈した化合物(示した濃度において)で前処理し、その後、30分間、4μLのアッセイバッファー中の5ng/mlのTNF−αで刺激した(最終アッセイ容積は40μlであった)。培地を、次いで、吸入により取り除き、20μlの溶解バッファー(20mMのTris-HCl(pH7.6)、5mMのEDTA、1%のNonidet P-40代用品、5mMのNaF、150mMのNaClおよび1:100のプロテアーゼとホスファターゼ阻害剤との混合物(それぞれSIGMA P8340およびP2850))を添加することにより細胞を溶解した。溶解バッファーは、2nMのテルビウム標識された抗c-Jun(pSer73)検出抗体(Life Technologies)を含んだ。アッセイを60分間室温において平衡化させた後で、BMG Pherastar蛍光プレートリーダー(BMG Labtech, Cary, NC)において、以下のパラメーターを用いて、TR-FRETの発光比を決定した:340nmにおける励起;520nmおよび490nmにおける発光;100μsのラグタイム;200μsの積分時間;ならびに発光比=Em520/Em490。全てのデータを、Graphpad Prism 4を用いて分析およびプロットした。
細胞を、7500細胞/ウェルで、96ウェルの顕微鏡プレート(Corning)に、推奨される培地中で24時間にわたって播種し、次いで、血清を欠く培地中で16時間飢餓させた。細胞を、JNK阻害剤の10倍のストック溶液で180分間、対照化合物MK2206、PD0325901、SB239063、KIN040およびKIN208の10倍のストック溶液で10分間前処理し、IGF-1、IL-6、TNF−α(全てPeproTech)の10倍のストック溶液、またはアニソマイシンで60分間処理した。細胞を、2%のパラホルムアルデヒドで10分間室温で固定し、PBS-Tで洗浄した(リン酸緩衝化食塩水、0.1%のTween 20)。細胞をメタノールで10分間浸透化し、PBS-Tで洗浄し、Odysseyブロッキングバッファー(LI-COR Biosciences)中で1時間室温においてブロッキングした。細胞を、Odysseyブロッキングバッファー中で1:400に希釈したErk1/2(pT202/pY204)、Akt(pS473)、c-Jun(pS73)、pP38(T180/Y182)およびpSTAT3(Y705)(Cell Signaling Technology)、pRSK1(S380)およびpMSK1(S376)(Epitomics)ならびにNF-κB(Santa Cruz Biotechnology)に対して特異的な抗体と共に、一晩4℃でインキュベートした。細胞をPBS-T中で3回洗浄し、Odysseyブロッキングバッファー中で1:2000に希釈したAlexa Fluor 647(Invitrogen)標識ウサギ特異的二次抗体と共にインキュベートした。細胞をPBS-T中で1回、PBS中で1回洗浄し、250ng/mlのHoechst 33342(Invitrogen)および1:1000のWhole Cell Stain(青色;Thermo Scientific)溶液中でインキュベートした。細胞をPBS中で2回洗浄し、imageWoRxハイスループット顕微鏡(Applied Precision)においてイメージングした。データをDataPflexを用いてプロットした。
A375細胞(ATCC(登録商標)CRL-1619TM)を、示した時間量にわたり、1μMの化合物で前処理した。培地を取り除き、PBSで3回洗浄した。細胞ペレットを、1mLの溶解バッファー(1%のNP-40、1%のCHAPS、25mMのTris、150mMのNaCl、ホスファターゼ阻害剤カクテル(Roche 04906845001)およびプロテアーゼ阻害剤カクテル(Roche 11836170001))で再懸濁した。30分間4℃でエンド・トゥ・エンドで回転させた。ライセートを、Eppendorf中での14000rpmにおける15分間の遠心分離により清澄化した。清澄化したライセートを、キナーゼバッファー(0.1%のNP-40、20mMのHEPES、150mMのNaCl、ホスファターゼ阻害剤カクテルおよびプロテアーゼ阻害剤カクテル)中へ、Bio-Rad 10DGカラムを用いて、ゲル濾過した。ゲル濾過されたライセートの合計のタンパク質濃度は、5〜15mg/mlであるべきである。細胞ライセートを、ActivX(登録商標)からのプローブにより、5μMで1時間標識した。試料をDTTで還元し、システインをヨードアセタミドでブロッキングし、ゲル濾過して過剰な試薬を取り除き、バッファーを交換した。1容積の2×結合バッファー(2%のTriton-100、1%のNP-40、2mMのEDTA、および2×PBS)ならびに50μLのストレプトアビジンビーズスラリーを添加し、エンド・トゥ・エンドで2時間回転させ、7000rpmで2分間遠心分離した。1×結合バッファーで3回、PBSで3回洗浄した。30μLの1×サンプルバッファーをビーズに添加し、試料を95℃で10分間加熱した。試料をSDS-PAGEゲルに110Vでロードした。トランスファーの後で、メンブレンをJNK抗体(Cell signaling 9258)でイムノブロットした
溶解バッファーは、50mMのTris/HCl(pH7.5)、1mMのEGTA、1mMのEDTA、1%(w/v)の1mMのバナジン酸ナトリウム、10mMのβ−グリセロリン酸ナトリウム、50mMのNaF、5mMのリン酸ナトリウム、0.27Mのスクロース、1mMのベンズアミジンおよび2mMのフェニルメタンスルホニルフロリド(PMSF)を含有し、これに1%(v/v)のTriton X-100を添加した。キナーゼアッセイバッファーは、50mMのTris/HCl(pH7.5)および0.1mMのEGTAを含有した。
インターロイキン受容体1を安定して発現するHEK-293細胞(HEK293-IL1R)を、10%のFBS、2mMのグルタミンおよび1×抗真菌剤/抗菌剤溶液を添加したダルベッコ改変イーグル培地(DMEM)中で培養した。細胞を、18時間血清を欠乏させ、その後、DMSOまたは異なる阻害剤と共にインキュベートし、2μMのアニソマイシン(Sigma)で1時間刺激して、ライセートを、10分間、16000gおよび4℃で遠心分離することにより清澄化した。
パンJNKアイソフォーム((#9252)、ホスホ−パンJNKアイソフォーム(Thr183/Tyr185)、(#4668)、全p38(#9212)またはホスホ−p38 MAPK(Thr180/Tyr182)、(それぞれ4631)、全c-Jun(#9165)、ホスホ−c-Jun(Ser63)(#9261)、およびホスホ−MSK1(Ser376)(#9591)に対するウサギモノクローナル抗体は、Cell Signalling technologyからのものであった。
細胞ライセート(30μg)を、SDSポリアクリルアミドゲル(10%)またはNovexの4〜12%勾配のゲル上での電気泳動により分離し、ニトロセルロースメンブレンに電気ブロットした。メンブレンを、50mMのTris/HCl(pH7.5)、0.15MのNaClおよび0.1%の(v/v)のTween(TBSTバッファー)中の5%のスキムミルク(w/v)でブロッキングした。一次抗体を、TBST中5%のスキムミルク中で希釈して、1μg/mlの濃度において用い、一晩4℃でインキュベートした。セイヨウワサビペルオキシダーゼ共役二次抗体(Pierce)および高感度化学発光試薬(自家製)を用いて、免疫複合体の検出を行った。
野生型JNK2または変異体JNK2[Cys116Ser]を、0.1mMのATPおよび10mMの塩化マグネシウムを含有するキナーゼアッセイバッファー中に2μMのJNK2、200nMのMKK4、200nMのMKK7を含有する反応混合物中で活性化させた。30分間30℃でのインキュベーションの後で、反応混合物を、アリコートにおいてスナップ凍結した。0.1mMの[γ−32P]ATP(約500〜1000cpm/pmol)、10mMの塩化マグネシウムおよび基質として2μMのATF2(残基19〜96)を含有するキナーゼバッファー中に200nMの活性化された野生型JNKまたは変異体JNK2[Cys116Ser]を含有する、合計50μlの反応容積において、JNK2の活性を評価した。20mMのEDTAを添加することにより、反応を停止させた。40μlの反応混合物を、P81ホスホセルロース紙に塗付し、これを、50mMのリン酸中で洗浄し、p81紙に結合したリン酸化ATF2ペプチドをCerenkovカウントにより定量した。
JNKファミリーのキナーゼは、ストレスにより活性化されるMAPKシグナル伝達経路における中心点を構成し、癌、炎症性疾患および神経疾患を処置するための将来的な潜在的標的を提供し得る。9Lアナログを例外として(図1;Crockerら、2011年)、動物モデルにおいてJNKの薬理学的阻害を達成することは、好適な薬物動態学的特徴を有する強力かつ選択的な阻害剤の欠失により大幅に妨害されてきた。これらの限定要因に取り組むために、保存的システイン残基を共有的に修飾する不可逆的JNK阻害剤が開発される。このアプローチの主要な利点は、持続的な標的阻害は、阻害剤に対する標的の一次的な暴露のみを達成することができ、これは、薬理学的特徴を達成する必要性を軽減し、これは、in vivoでの持続的な薬物レベルを可能にする(Singhら、2010年)。さらなる利点は、強力な阻害は、共有的修飾に完全に依存し、したがって、反応性システイン残基の変異は、化合物に対して非感受性なJNKのバージョンを生み出すことである。JNKのこれらの変異形態は、したがって、任意の観察される阻害剤により誘導される表現型のJNK依存性を確立するために用いることができ、これは、特異性についての強力な制御を提供する。
表5は、CおよびD環の向きを変更することがJNKの活性に対して有する劇的な効果を示す。例えば、本発明の「パラ−メタ」化合物、すなわち、フェニル環C上にパラNH基を、フェニル環D上にメタNH(C=O)基を含む化合物は、反対の構造的立体配置を有する化合物、すなわち、フェニル環C上にメタ−NH置換基を含み、フェニル環D上にパラNH(C=O)基を含む「メタ−パラ」の化合物よりも、驚異的に活性が高い。
JNK3の結晶構造中へのJNK-IN-7の分子ドッキングは、キナーゼ−ヒンジセグメントに連結すると予測されるフェニルアミノピリミジンファルマコアを反応性アクリルアミド部分に連結するために役立つであろう適切なリンカーエレメントの、構造により導かれる設計のための、理論的基礎を提供した。本発明の本発明者らにより、強力な酵素によるおよび細胞でのJNKの阻害の最も重要な特徴は、このリンカーセグメントが、JNK-IN-7およびJNK-IN-8により例示されるように、ジアニリン部分の1,4−配置および末端アミノ安息香酸部分の1,3−配置を含むことであることが発見された。JNK-IN-7とJNK3との間の2.97Åの共構造は、分子モデルを完全に実証し、JNK3の残基Cys154との共有結合形成を示した。広範な生化学的なおよび細胞による選択性のプロファイリングにより、IRAK1、MPSK1、NEK9、PIP3K3C、PIP4K2CおよびPIP5K3を含むJNK-IN-7についての幾つかのさらなるキナーゼ標的を同定することが可能となった。興味深いことに、これらのさらなる標的の殆どは、効率的な阻害を達成するために、アクリルアミドの弾頭を必要とすると考えられる。なぜならば、それらは非アクリルアミド含有阻害剤であるJNK-IN-6によっては標的とされないからである。IRAK1を例外として、これらのキナーゼは、JNK3のCys154と類似の位置に位置する反応性システインを含有しないと考えられる。このことは、JNK-IN-7が、これらのキナーゼを認識するために異なる立体配置を用い得、それにより代替的なシステイン残基にアクセスすることを示唆する。代替的に、JNK-IN-7は、反応性リジン残基と共有的アダクトを形成することができ、例えば、天然生成物阻害剤であるワートマニンは、異なる求電子性部分ではあるが、Pi3KのLys833とMichael付加反応を経験する。JNK-IN-7が、実際に、高い濃度(1〜10μM)においてではあるが、細胞におけるpellinoのIRAK-1依存的なE3リガーゼ活性を阻害することができることが検証されており、この標的のより強力な細胞での阻害を達成することができるとすれば、細胞ベースのアッセイにより導かれるさらなる最適化が必要とされるであろう(Gohら、2011年)。本発明の本発明者らは、JNK-IN-7のキナーゼ感受性をさらに増強するための、2つの方法を発見した。第1は、イマニチブの「フラッグ」メチル基に類似するオルト−メチル基、またはALK阻害剤であるTAE684(Galkinら、2007年)およびpolo−キナーゼ阻害剤であるBI-2356(Kotheら、2007年)のオルト−メトキシ基を導入することである。この改変は、JNK-IN-8により例示され、JNK-IN-7の結晶構造は、このメチル基が、JNK3のAsp150とAla151との間のヒンジセグメントに沿った小さな溝の中に落ち着く可能性があることを予測する。第2は、JNK-IN-12により例示されるように、ピリジン部分を、幾何学的により複雑な、JNKのATP部位に結合するための有利なファルマコアとして先に同定された、ベンゾチアゾール−2−イルアセトニトリル部分で置き換えることである(Gaillardら、2005年)。「ゲートキーパー」メチオニンの近傍において結合することが予測される阻害剤のこの部分において存在する官能基は、阻害剤についての重要な選択性決定要因を提供する。例えば、嵩張る2−フェニルピラゾロ[1,5−a]ピリジン基を有するJNK-IN-11は、生化学的アッセイと細胞におけるアッセイとの両方において、劇的に拡大された阻害プロフィールを示す。
上記は、本発明のある非限定的な態様の記載である。当業者は、以下の請求の範囲において定義するような本発明の精神または範囲から解離することなく、この記載に対する多様な変更および改変を行ってもよいことを理解するであろう。
請求の範囲において、「a」、「an」および「the」などの冠詞は、それと反対であることが示されるかまたは文脈から他に明らかでない限りにおいて、1または1より多くを意味し得る。群の1または2以上のメンバーの間に「or」を含む請求の範囲および説明は、それと反対であることが示されるかまたは文脈から他に明らかでない限りにおいて、当該群のメンバーのうちの1、1より多く、または全てが、所与の生成物またはプロセスにおいて存在するか、それにおいて使用されるかまたは他にそれに関連する場合、満たされるとみなされる。本発明は、群のうちの正確に1のメンバーが所与の生成物またはプロセスにおいて存在するか、それにおいて使用されるかまたは他にそれに関連する態様を含む。本発明は、群のうちの1より多くのメンバーが所与の生成物またはプロセスにおいて存在するか、それにおいて使用されるかまたは他にそれに関連する態様を含む。
Claims (8)
- 式:
- 式:
- 請求項1または2に記載の化合物、またはその薬学的に受容可能な塩;および薬学的に受容可能な賦形剤を含む、医薬組成物。
- 請求項1または2に記載の化合物、またはその薬学的に受容可能な塩を含む、対象において増殖性疾患を処置することにおける使用のための医薬組成物。
- 増殖性疾患が癌である、請求項4に記載の使用のための医薬組成物。
- 増殖性疾患が黒色腫である、請求項4に記載の使用のための医薬組成物。
- 増殖性疾患が肺癌である、請求項4に記載の使用のための医薬組成物。
- 請求項1または2に記載の化合物、またはその薬学的に受容可能な塩を含む、対象において神経変性疾患、脳卒中、パーキンソン病、アルツハイマー病、炎症性疾患、関節リウマチ、代謝障害、または糖尿病を処置することにおける使用のための医薬組成物。
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JP6106685B2 (ja) | 2017-04-05 |
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