JP2013530192A - キナーゼ誘発疾患の処置に有用なビピリジル誘導体 - Google Patents
キナーゼ誘発疾患の処置に有用なビピリジル誘導体 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract
Description
ATPを結合し、そのエネルギーを利用して構造を変化させ、基質をリン酸化し、シグナル伝達カスケードを開始するタンパク質は、多くのクラス、例えばキナーゼ、ホスファターゼ、シャペロンまたはイソメラーゼから知られている。特定のツールおよび技術で、ATP結合タンパク質を富化させることができる。
WO 2004/014891は、GABA受容体のためのリガンドとしてのピリダジン誘導体を扱う。当該国際出願は、ビピリジル誘導体を開示しない。
WO 2004/084824は、ナトリウムチャネルブロッカーとしてのビアリール置換6員環複素環を記載する。当該国際出願は、ビピリジル誘導体を開示しない。
WO 2006/071960は、チロシンキナーゼ阻害剤としての抗増殖化合物を対象とする。当該国際出願は、ビピリジル誘導体を開示しない。
US 2007/191371は、ペルオキシソーム増殖因子活性化受容体PPARモジュレーターとしての置換複素環式化合物を記載する。当該米国出願は、ビピリジル誘導体を開示しない。
WO 2008/008059は、抗癌剤としてのヘテロ原子含有化合物に関する。当該国際出願は、ビピリジル誘導体を開示しない。
WO 2009/011850は、例えば関節リウマチ、喘息、敗血症、乾癬、炎症性腸疾患、クローン病、多発性硬化症、疼痛および癌を処置するのに有用な、新規なトリス(ヘテロ)アリール置換スルホンアミド、アミドまたは硫化物誘導体を対象とする。当該国際出願は、ビピリジル誘導体を開示しない。
本出願におけるいかなる参考文献の引用も、当該参考文献が本出願に対する関連する従来技術である旨承認するわけではない。
本発明は、新規なビピリジル誘導体を提供する目的を有する。
W1、W2、W3は、互いに独立してNまたはCR3を示し、
R1は、5、6、7、8、9もしくは10個のC原子を有する単環式アリールまたは5、6、7、8、9、10、11、12、13もしくは14個のC原子および1、2、3、4もしくは5個のN、Oおよび/もしくはS原子を有する単環式ヘテロアリールを示し、その各々は、互いに独立してY、Hal、CN、CF3、OYからなる群から選択された少なくとも1つの置換基によって置換され得、
R3は、H、NYYまたはNY−COYを示し、
R4は、Hal、A、−(CYY)n−OY、−(CYY)n−NYY、(CYY)n−Het3、(CYY)n−O−Het3、SY、NO2、CF3、CN、COOY、−CO−NYY、−NY−COA、−NY−SO2A、−SO2−NYY、S(O)mA、−CO−Het3、−O(CYY)n−NYY、−O(CYY)n−Het3、−NH−COOA、−NH−CO−NYY、−NH−COO−(CYY)n−NYY、−NH−COO−(CYY)n−Het3、−NH−CO−NH−(CYY)n−NYY、−NH−CO−NH(CYY)n−Het3、−OCO−NH−(CYY)n−NYY、−OCO−NH−(CYY)n−Het3、CHO、COA、=S、=NY、=Oを示し、
Aは、1、2、3、4、5、6、7、8、9または10個のC原子を有する非分枝状または分枝状アルキルを示し、ここで1、2、3、4、5、6または7個のH原子は、互いに独立してHalによって置き換えられ得、かつ/またはここで、1つもしくは2つのCH2基は、互いに独立してO、S、SO、SO2、−CY=CY−基および/もしくは−C≡C−基によって置き換えられ得、
Arは、5、6、7、8、9、または10個のC原子を有する飽和の、不飽和の、または芳香族の単環式または二環式炭素環を示し、
Het2は、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19または20個のC原子ならびに1、2、3、4または5個のN、Oおよび/またはS原子を有する単環式、二環式または三環式ヘテロアリールを示し、
mは、0、1または2を示し、
nは、0、1、2、3または4を示す、
で表される化合物、ならびにその生理学的に許容し得る塩、溶媒和物、互変異性体および立体異性体、ならびにすべての比率でのそれらの混合物を提供することにより解決された。
W1、W2、W3は、CR3を示し、
または
W1、W2は、CR3を示し、および
W3は、Nを示す、
式(I)による化合物、ならびに、その生理学的に許容し得る塩、溶媒和物、互変異性体および立体異性体、ならびに比率でのそれらの混合物を提供する。
R1は、5、6、7、8、9または10個のC原子を有する単環式アリール、好ましくはフェニルを示し、それは、独立してY、Hal、CN、CF3またはOYからなる群から選択された少なくとも1つの置換基によって置換され得る、
式(I)で表されるおよび上記態様による化合物、ならびに、その生理学的に許容し得る塩、溶媒和物、互変異性体および立体異性体、ならびにすべての比率でのそれらの混合物を提供する。
R2は、Ar、Het2またはNY−Het2を示し、好ましくはHet2を示し、それは、互いに独立してR4によって置換され得る、
式(I)および上記態様による化合物、ならびに、その生理学的に許容し得る塩、溶媒和物、互変異性体および立体異性体、ならびに比率でのそれらの混合物を提供する。
R4は、A、CF3、Hal、−(CYY)n−OY、−(CYY)n−NYY、(CYY)n−Het3を示し、好ましくは−(CYY)n−OY、−(CYY)n−NYY、(CYY)n−Het3を示す、
式(I)および上記態様による化合物、ならびに、その生理学的に許容し得る塩、溶媒和物、互変異性体および立体異性体、ならびにすべての比率でのそれらの混合物を提供する。
Het3は、4または5個のC原子ならびに1または2個のNおよび/またはO原子を有する飽和の単環式複素環を示し、それは、独立してHal、A、−(CYY)n−OY、−(CYY)n−NYY、SY、NO2、CN、CF3、COOY、−CO−NYY、−NY−COA、−NY−SO2A、−SO2−NYY、S(O)mA、−NH−COOA、−NH−CO−NYY、CHO、COA、=S、=NY、=Oの群から選択された少なくとも1つの置換基によって置換され得る、
式(I)および上記態様による化合物、ならびに、その生理学的に許容し得る塩、溶媒和物、互変異性体および立体異性体、ならびにすべての比率でのそれらの混合物を提供する。
すべての上記の一般的にまたは明示的に開示した化合物ならびに本明細書中に開示する式(I)および化合物1〜45の好ましい部分集合/態様を、以下で(本)発明の化合物と称する。。
本発明の上記の化合物の説明のために示した用語は、常に、明細書または特許請求の範囲において他に示さない限り以下の意味を有する:
「置換された」の用語は、対応するラジカル、基または部分が1つまたは2つ以上の置換基を有することを意味する。ラジカルが複数の置換基を有し、様々な置換基の選択を特定する場合には、置換基は、互いに独立して選択され、同一である必要はない。
「アルキルカルボニル」の用語は、本発明の目的に対し、「アルキル−C(O)−」基を指し、式中アルキルは、本明細書中で定義した通りである。
「アルコキシアルキル」の用語は、本発明の目的のために「アルキル−O−アルキル−」基を指し、式中アルキルは、本明細書中で定義した通りである。
「ヒドロキシル」または「ヒドロキシ」の用語は、OH基を意味する。
可能な場合には、本発明の化合物は、互変異性体、例えばケト−エノール互変異性体の形態であり得る。
(i) Wermuth CG et al., 第31章:671-696, The Practice of Medicinal Chemistry, Academic Press 1996;
(ii) Bundgaard H, Design of Prodrugs, Elsevier 1985;および
(iii) Bundgaard H, 第5章:131-191, A Textbook of Drug Design and Development, Harwood Academic Publishers 1991。
前記参考文献は、参照によって本明細書中に組み込まれる。
本発明の化合物のいずれからも代謝によってin vivoで変換されたいかなる生物学的に活性な化合物も、本発明の範囲および精神内の代謝物質である。
「溶媒和物」の用語によって、水和物、アルコラートまたは結晶の他の溶媒和物を意味する。
(a)式(II)
R5は、HalまたはB(OH)2を示し、ならびに
R1およびHalは、上に定義した意味を有する、
で表される化合物を、
式(III)
R6は、Hal、ボロン酸またはボロン酸のエステルを示し、ならびに
R2、W1、W2、W3およびHalは、上に定義した意味を有する、
で表される化合物と反応させて、
R1、R2、W1、W2およびW3は、上に定義した意味を有する、
で表される化合物を得、
ならびに任意に上に定義した残基R1および/またはR2を他の残基R1および/またはR2に、例えば保護基を切断し、かつ/またはアルキル基を導入することによって変換すること、
あるいは
R7は、Hal、ボロン酸またはボロン酸のエステルを示し、ならびに
R2、W1、W2、W3およびHalは、上に定義した意味を有する、
で表される化合物を、
式(V)
R8−R1 (V)
式中、
R8は、HalまたはB(OH)2を示し、ならびに
R1およびHalは、上に定義した意味を有する、
で表される化合物と反応させて、
R1、R2、W1、W2およびW3は、上に定義した意味を有する、
で表される化合物を得、
ならびに任意に上に定義した残基R1および/またはR2を他の残基R1および/またはR2に、例えば保護基を切断し、かつ/またはアルキル基を導入することによって変換すること、
あるいは
R9は、HalまたはB(OH)2を示し、ならびに
R1、W1、W2、W3およびHalは、上に定義した意味を有する、
で表される化合物を、
式(VII)
R10−R2 (VII)
式中、
R10は、Hal、ボロン酸またはボロン酸のエステルを示し、ならびに
R2およびHalは、上に定義した意味を有する、
で表される化合物と反応させて、
R1、R2、W1、W2およびW3は、上に定義した意味を有する、
で表される化合物を得、
ならびに任意に上に定義した残基R1および/またはR2を他の残基R1および/またはR2に、例えば保護基を切断し、かつ/またはアルキル基を導入することによって変換すること、
ならびに任意に
(d)式(I)で表される化合物の塩基または酸をその塩に変換すること。
本発明の化合物の生理学的に許容し得る塩をまた、酸または塩基との記載した反応によって得られた本発明の化合物を単離および/または処理することにより得ることができる。
反応時間は、一般的にそれぞれの化合物の反応性およびそれぞれの反応条件に依存して数分〜数日の範囲内にある。好適な反応時間は、当該分野において知られている方法、例えば反応モニタリングによって容易に決定可能である。上記で示した反応温度に基づいて、好適な反応時間は、一般的に10分〜48時間の範囲内にある。
好ましい態様において、当該少なくとも1種の薬理学的に活性な物質は、本明細書中に記載した物質である。
好ましい態様において、当該少なくとも1種の薬理学的に活性な物質は、本明細書中に記載した物質である。
好ましい態様において、医薬組成物は、生理学的に許容し得る賦形剤、補助剤、アジュバント、希釈剤、担体および/または本発明の化合物以外の追加の医薬活性物質からなる群から選択された少なくとも1種の追加の化合物を含む。
カプセル:活性成分(単数)/(複数)および補助剤を混合して、流動可能な粉末を得、任意に粉末を顆粒化し、粉末を充填し/開放したカプセル中に顆粒化し、カプセルの最上部を覆う。
半固体(軟膏、ゲル、クリーム):活性成分(単数)/(複数)を水性または脂肪性担体に溶解/分散させ;その後水性/脂肪性相を補足的な脂肪性/水性相と混合し、均質化する(クリームのみ)。
エアゾール:活性成分(単数)/(複数)を推進剤に分散/溶解させ、前記混合物を噴霧器中に詰める。
カラム:Chromolith SpeedROD RP-18e、50×4.6mm2
勾配:A:B=96:4〜0:100
流量:2.4ml/分
溶離剤A:水+0.05%ギ酸
溶離剤B:アセトニトリル+0.04%ギ酸
波長:220nm
質量分析法(MS):ESI(エレクトロスプレーイオン化)(M+H)+
AcOH 酢酸、anh 無水、atm 気圧(単数または複数)、BOC tert−ブトキシカルボニル、CDI 1’−カルボニルジイミダゾール、conc 濃、d 日(単数または複数)、dec 分解、DIAD アゾジカルボン酸ジイソプロピル、DMAC NN−ジメチルアセトアミド、DMPU 1,3−ジメチル−3,4,5,6−テトラヒドロ−2(IH)−ピリミジノン、DMF NN−ジメチルホルムアミド、DMSO ジメチルスルホキシド、DPPA ジフェニルホスホリルアジド1、EDCI 1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド、EtOAc 酢酸エチル、EtOH エタノール(100%)、Et2O ジエチルエーテル、Et3N トリエチルアミン、h 時間(単数または複数)、MeOH メタノール、pet.エーテル 石油エーテル(沸点範囲30〜60℃)、PPh3 トリフェニルホスフィン、temp. 温度、THF テトラヒドロフラン、TFA トリフルオロAcOH、Tf トリフルオロメタンスルホニル。
I.本発明の選択された化合物の合成
以下の化合物を合成し、特徴づけした。しかしながら、これらの化合物を様々に製造し、特徴づけすることは、当業者についての知識内にある。
例1 − 2−(5−クロロ−2−フルオロ−フェニル)−ピリジン−4−ボロン酸の合成
例3 − 2’−(5−クロロ−2−フルオロ−フェニル)−5−(1−ピペリジン−4−イル−1H−ピラゾール−4−イル)−[3,4’]ビピリジニルおよび2’−(5−クロロ−2−フルオロ−フェニル)−5−[1−(1−メチル−ピペリジン−4−イル)−1H−ピラゾール−4−イル]−[3,4’]ビピリジニルの合成
2’−(2−フルオロ−5−トリフルオロメチル−フェニル)−5−[1−(1−メチル−ピペリジン−4−イル)−1H−ピラゾール−4−イル]−[3,4’]ビピリジニル;HPLC/MS:1.76分、[M+H] 482。
2’−(2−フルオロ−フェニル)−5−(1−ピペリジン−4−イル−1H−ピラゾール−4−イル)−[3,4’]ビピリジニル;HPLC/MS:1.54分、[M+H] 400。
HPLC−MS:2.05分、[M+H] 385。
HPLC−MS:2.24分、[M+H] 445。
HPLC−MS:1.74分、[M+H] 361。
HPLC−MS:2.02分、[M+H] 395
HPLC−MS:1.88分、[M+H] 379
HPLC−MS:2.11分、[M+H] 429
HPLC−MS:1.80分、[M+H] 375
(3−{4−[2’−(5−クロロ−2−フルオロ−フェニル)−[3,4’]ビピリジニル−5−イル]−ピラゾール−1−イル}−プロピル)−ジメチル−アミン
HPLC−MS:1.63分、[M+H] 436
HPLC−MS:1.46分、[M+H] 402
HPLC−MS:1.54分、[M+H] 420
HPLC−MS:1.56分、[M+H] 412
HPLC−MS:1.54分、[M+H] 426
HPLC−MS:1.63分、[M+H] 226。
HPLC−MS:1.23分、[M+H] 366。
HPLC−MS:1.49分、[M+H] 457。
HPLC−MS:1.50分、[M+H] 444。
HPLC−MS[M+H] 318。
HPLC−MS:1.50分、[M+H] 444。
HPLC−MS[M+H] 286。
HPLC−MS[M+H] 446。
HPLC−MS[M+H] 362。
HPLC−MS:2.19分、[M+H] 317。
250mgの5−ブロモ−2−トリフルオロメチル−1H−ピロロ[2,3−b]ピリジンを、窒素および360mgのKOAcの下で2mlのジオキサンに溶解し、328mgのビス(ピナコラト)ジボロン、15mgの1,1’−ビス(ジフェニルホスフィノ)フェロセンおよび23mgの(1,1’−ビス(ジフェニルホスフィノ)フェロセン)−パラジウム(II)クロリド、ジクロロメタン付加物を、加えた。混合物を、マイクロ波の下で140℃で1h30撹拌した。
生成物をジクロロメタンで抽出し、無水Na2SO4で乾燥し、濾過し、真空下で濃縮して、黒色−赤色油を得る。
HPLC−MS:2.24分、[M+H] 375。
200mgの2’−クロロ−5−(2−トリフルオロメチル−1H−ピロロ[2,3−b]ピリジン−5−イル)−[3,4’]ビピリジニルおよび149mgの2−フルオロ−フェニルボロン酸を、窒素下でDMFに溶解し、112mgのNaHCO3および1.5mlの水を加えた。混合物を80℃で加熱した。次に、7.5mgのビス(トリフェニルホスフィン)−パラジウム(II)−クロリドを加え、混合物を80℃で一晩撹拌した。
HPLC−MS:2.43分、[M+H] 435。
(2’−クロロ−[3,4’]ビピリジニル−5−イル)−(2−エトキシ−ピリジン−4−イル)−アミンおよび2−フルオロ−フェニルボロン酸および2’−(2−フルオロ−フェニル)−5−(2−トリフルオロメチル−1H−ピロロ[2,3−b]ピリジン−5−イル)−[3,4’]ビピリジニルの合成において記載した方法、ステップ2(上記を参照)を使用して、表題化合物(2−エトキシ−ピリジン−4−イル)−[2’−(2−フルオロ−フェニル)−[3,4’]ビピリジニル−5−イル]−アミンを得た。
HPLC−MS:1.57分、[M+H] 387。
HPLC−MS:1.93分、[M+H] 373。
HPLC−MS:1.67分、[M+H] 416。
例14:TGF−ベータ受容体Iキナーゼ阻害剤を試験するための細胞アッセイ
例として、阻害剤がTGF−ベータ媒介成長阻害を排除する能力を試験した。肺上皮細胞株Mv1Luの細胞を、規定の細胞密度で96ウェルマイクロタイタープレート中に蒔き、標準的条件下で一晩培養した。翌日、培地を、0.5%のFCSおよび1ng/mlのTGF−ベータを含む培地で交換し、試験物質を、規定の濃度で、一般的に5倍ステップを有する希釈系列の様式で加えた。溶媒DMSOの濃度は、0.5%で一定であった。さらに2日後、細胞のクリスタルバイオレット染色を行った。クリスタルバイオレットの固定した細胞からの抽出の後、吸収を、分光光度法的に550nmで測定した。それを、存在する接着細胞およびしたがって培養中の細胞増殖の定量的評価基準として使用することができた。
このアッセイを使用して、Smad2(Ser465/467)およびSmad3(Ser423/425)のTGF−ベータ誘発リン酸化に対する化合物の阻害効力を決定した。Mv1−Lu細胞(ミンクアメリカミンクからの肺上皮細胞株;ATCC番号:CCL−64)を、10%ウシ胎仔血清(Pan Biotech)を補足したDMEM(Invitrogen)中に、規定の細胞密度で24ウェルまたは96ウェルプレート中に播種した(24ウェルプレート:ウェルあたり1.5×105個の細胞;96ウェルプレート:ウェルあたり4×104個の細胞)。細胞培養物を、37℃および10%CO2でDMEM中でインキュベートした。翌日、培地を交換し、細胞を16〜20時間血清欠乏とした。翌日、連続希釈の化合物をウェルに加え、1.5時間プレインキュベートし、その後組換えTGF−ベータ1リガンド(最終濃度5ng/ml;R&D systems)を加えた。
キナーゼアッセイを、384ウェルフラッシュプレート(flashplate)アッセイとして行った。31.2nMのGST−ALK5、439nMのGST−SMAD2および3mMのATP(0.3μCiの33P−ATP/ウェルを有する)を、35μlの全容積(20mMのHEPES、10mMのMgCl2、5mMのMnCl2、1mMのDTT、0.1%のBSA、pH7.4)において、試験物質なしで、または試験物質(5〜10濃度)と共に、30℃で45分間インキュベートした。反応を、25μlの200mM EDTA溶液を使用して停止し、30分後に室温で吸引により濾過し、ウェルを、100μlの0.9%のNaCl溶液で3回洗浄した。放射能を、TopCountで測定した。IC50値を、RS1を使用して計算した。結果を表2に示す。
Claims (15)
- 式(I)
W1、W2、W3は、互いに独立してNまたはCR3を示し、
R1は、5、6、7、8、9もしくは10個のC原子を有する単環式アリールまたは5、6、7、8、9、10、11、12、13もしくは14個のC原子および1、2、3、4もしくは5個のN、Oおよび/もしくはS原子を有する単環式ヘテロアリールを示し、その各々は、互いに独立してY、Hal、CN、CF3、OYからなる群から選択される少なくとも1つの置換基によって置換され得、
R2は、Ar、Het1、Het2、NY−Het1またはNY−Het2を示し、好ましくはAr、Het1またはHet2を示し、その各々は、互いに独立してR4によって置換され得、
R3は、H、NYYまたはNY−COYを示し、
R4は、Hal、A、−(CYY)n−OY、−(CYY)n−NYY、(CYY)n−Het3、(CYY)n−O−Het3、SY、NO2、CF3、CN、COOY、−CO−NYY、−NY−COA、−NY−SO2A、−SO2−NYY、S(O)mA、−CO−Het3、−O(CYY)n−NYY、−O(CYY)n−Het3、−NH−COOA、−NH−CO−NYY、−NH−COO−(CYY)n−NYY、−NH−COO−(CYY)n−Het3、−NH−CO−NH−(CYY)n−NYY、−NH−CO−NH(CYY)n−Het3、−OCO−NH−(CYY)n−NYY、−OCO−NH−(CYY)n−Het3、CHO、COA、=S、=NY、=Oを示し、
Yは、HまたはAを示し、
Aは、1、2、3、4、5、6、7、8、9または10個のC原子を有する非分枝状または分枝状アルキルを示し、ここで1、2、3、4、5、6または7個のH原子は、互いに独立してHalによって置き換えられ得、かつ/またはここで、1つもしくは2つのCH2基は、互いに独立してO、S、SO、SO2、−CY=CY−基および/もしくは−C≡C−基によって置き換えられ得、
Arは、5、6、7、8、9または10個のC原子を有する飽和の、不飽和の、または芳香族の単環式または二環式炭素環を示し、
Het1は、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19または20個のC原子ならびに1、2、3、4または5個のN、Oおよび/またはS原子を有する飽和の、または不飽和の単環式、二環式または三環式複素環を示し、
Het2は、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19または20個のC原子ならびに1、2、3、4または5個のN、Oおよび/またはS原子を有する単環式、二環式または三環式ヘテロアリールを示し、
Het3は、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19または20個のC原子ならびに1、2、3、4または5個のN、Oおよび/またはS原子を有する飽和の、または不飽和の単環式、二環式または三環式複素環を示し、それは、互いに独立してHal、A、−(CYY)n−OY、−(CYY)n−NYY、SY、NO2、CN、CF3、COOY、−CO−NYY、−NY−COA、−NY−SO2A、−SO2−NYY、S(O)mA、−NH−COOA、−NH−CO−NYY、CHO、COA、=S、=NY、=Oの群から選択される少なくとも1つの置換基によって置換され得、
Halは、F、Cl、BrまたはIを示し、
mは、0、1または2を示し、
nは、0、1、2、3または4を示す、
で表される化合物、あるいはその生理学的に許容し得る塩、溶媒和物、互変異性体または立体異性体、あるいはすべての比率でのそれらの混合物。 - W1、W2、W3がCR3を示す、
または
W1、W2がCR3を示し、および
W3がNを示す、
請求項1に記載の化合物、あるいはその生理学的に許容し得る塩、溶媒和物、互変異性体または立体異性体、あるいはすべての比率でのそれらの混合物。 - R1が、5、6、7、8、9または10個のC原子を有する単環式アリール、好ましくはフェニルを示し、それが、独立してY、Hal、CN、CF3またはOYからなる群から選択される少なくとも1つの置換基によって置換され得る、
請求項1または2に記載の化合物、あるいはその生理学的に許容し得る塩、溶媒和物、互変異性体または立体異性体、あるいはすべての比率でのそれらの混合物。 - R2がAr、Het2またはNY−Het2を示し、それが互いに独立してR4によって置換され得る、
請求項1〜3のいずれか一項に記載の化合物、あるいはその生理学的に許容し得る塩、溶媒和物、互変異性体または立体異性体、あるいはすべての比率でのそれらの混合物。 - R4がA、CF3、Hal、−(CYY)n−OY、−(CYY)n−NYY、(CYY)n−Het3を示す、
請求項1〜4のいずれか一項に記載の化合物、あるいはその生理学的に許容し得る塩、溶媒和物、互変異性体または立体異性体、あるいはすべての比率でのそれらの混合物。 - Het3が、4または5個のC原子ならびに1または2個のNおよび/またはO原子を有し、独立してHal、A、−(CYY)n−OY、−(CYY)n−NYY、SY、NO2、CN、CF3、COOY、−CO−NYY、−NY−COA、−NY−SO2A、−SO2−NYY、S(O)mA、−NH−COOA、−NH−CO−NYY、CHO、COA、=S、=NY、=Oの群から選択される少なくとも1つの置換基によって置換され得る飽和の単環式複素環を示す、
請求項1〜5のいずれか一項に記載の化合物、あるいはその生理学的に許容し得る塩、溶媒和物、互変異性体または立体異性体、あるいはすべての比率でのそれらの混合物。 - 以下のもの:
- 式(I)で表される化合物の製造方法であって、以下のステップ:
(a)式(II)
R5は、HalまたはB(OH)2を示し、ならびに
R1およびHalは、上に定義される意味を有する、
で表される化合物を、
式(III)
R6は、Hal、ボロン酸またはボロン酸のエステルを示し、ならびに
R2、W1、W2、W3およびHalは、上に定義される意味を有する、
で表される化合物と反応させて、
式(I)
R1、R2、W1、W2およびW3は、上に定義される意味を有する、
で表される化合物を得、
ならびに任意に上に定義される残基R1および/またはR2を他の残基R1および/またはR2に、例えば保護基を切断し、かつ/またはアルキル基を導入することによって変換すること、
あるいは
(b)式(IV)
R7は、Hal、ボロン酸またはボロン酸のエステルを示し、ならびに
R2、W1、W2、W3およびHalは、上に定義される意味を有する、
で表される化合物を、
式(V)
R8−R1 (V)
式中、
R8は、HalまたはB(OH)2を示し、ならびに
R1およびHalは、上に定義した意味を有する、
で表される化合物と反応させて、
式(I)
R1、R2、W1、W2およびW3は、上に定義される意味を有する、
で表される化合物を得、
ならびに任意に上に定義される残基R1および/またはR2を他の残基R1および/またはR2に、例えば保護基を切断し、かつ/またはアルキル基を導入することによって変換すること、
あるいは
(c)式(VI)
R9は、HalまたはB(OH)2を示し、ならびに
R1、W1、W2、W3およびHalは、上に定義される意味を有する、
で表される化合物を、
式(VII)
R10−R2 (VII)
式中、
R10は、Hal、ボロン酸またはボロン酸のエステルを示し、ならびに
R2およびHalは、上に定義される意味を有する、
で表される化合物と反応させて、
式(I)
R1、R2、W1、W2およびW3は、上に定義される意味を有する、
で表される化合物を得、
ならびに任意に上に定義される残基R1および/またはR2を他の残基R1および/またはR2に、例えば保護基を切断し、かつ/またはアルキル基を導入することによって変換すること、
ならびに任意に
(d)式(I)で表される化合物の塩基または酸をその塩に変換すること
を含む、前記方法。 - ATP消費タンパク質、好ましくはTGF−ベータ受容体キナーゼ、RON、TAK1、PKD1、MINK1、SAPK2−アルファ、SAPK2−ベータおよび/またはCHK2を阻害するための、請求項1〜7のいずれか一項に記載の化合物の使用。
- 少なくとも1種の請求項1〜7のいずれか一項に記載の化合物を含む、医薬。
- 「癌、腫瘍、悪性腫瘍、良性腫瘍、固形腫瘍、肉腫、癌腫、過剰増殖障害、カルチノイド、ユーイング肉腫、カポジ肉腫、脳腫瘍、脳および/または神経系および/または髄膜から発生する腫瘍、神経膠腫、神経膠芽腫、神経芽細胞腫、胃癌、腎臓癌、腎細胞癌腫、前立腺癌、前立腺癌腫、結合組織腫瘍、軟部組織肉腫、膵臓腫瘍、肝臓腫瘍、頭部腫瘍、頸部腫瘍、喉頭癌、食道癌、甲状腺癌、骨肉腫、網膜芽細胞腫、胸腺腫、精巣癌、肺癌、肺腺癌、小細胞肺癌、気管支癌、乳癌、乳房癌、腸癌、直腸結腸腫瘍、結腸癌、直腸癌、婦人科の腫瘍、卵巣の腫瘍/卵巣腫瘍、子宮癌、子宮頸部癌、子宮頸癌、子宮体部癌、コーパス癌、子宮内膜癌、膀胱癌、尿生殖路癌、膀胱癌、皮膚癌、上皮性腫瘍、扁平上皮癌腫、基底細胞腫、棘細胞癌、黒色腫、眼球内黒色腫、白血病、単球白血病、慢性白血病、慢性骨髄性白血病、慢性リンパ性白血病、急性白血病、急性骨髄性白血病、急性リンパ性白血病、リンパ腫、眼疾患、脈絡膜新生血管、糖尿病性網膜症、炎症性疾患、関節炎、神経変性、移植片拒絶、転移成長、線維症、再狭窄、HIV感染症、アテローム性動脈硬化症、炎症および創傷治癒の障害、血管新生、心血管系、骨、CNSおよび/またはPNS」からなる群から選択される生理学的および/または病態生理学的状態の処置および/または予防において使用するための、少なくとも1種の請求項1〜7のいずれか一項に記載の化合物を含む、医薬。
- そのような医薬において、少なくとも1種の追加の薬理学的に活性な物質を含む、請求項10または11に記載の医薬。
- 医薬を、少なくとも1種の追加の薬理学的に活性な物質での処置前および/または処置中および/または処置後に適用する、請求項10または11に記載の医薬。
- 請求項1〜7のいずれか一項に記載の治療的に有効な量の少なくとも1種の化合物を含み、任意にさらに生理学的に許容し得る賦形剤、補助剤、アジュバント、希釈剤、担体および/または請求項1〜7のいずれか一項に記載の化合物以外の追加の薬学的に活性な物質からなる群から選択される少なくとも1種の追加の化合物を含む、医薬組成物。
- 請求項1〜7のいずれか一項に記載の少なくとも1種の化合物の治療的に有効な量ならびに/または請求項14に記載の少なくとも1種の医薬組成物および請求項1〜7のいずれか一項に記載の化合物以外の少なくとも1種のさらなる薬理学的に活性な物質の治療的に有効な量を含む、キット。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2020510078A (ja) * | 2017-03-15 | 2020-04-02 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | Hpk1の阻害剤としてのアザインドール |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ587051A (en) | 2008-01-04 | 2012-12-21 | Intellikine Llc | Isoquinolinone derivatives, compositions and methods of inhibiting phosphatidyl inositol-3 kinase (pi3 kinase) |
US8193182B2 (en) | 2008-01-04 | 2012-06-05 | Intellikine, Inc. | Substituted isoquinolin-1(2H)-ones, and methods of use thereof |
CN103648499B (zh) | 2011-01-10 | 2017-02-15 | 无限药品股份有限公司 | 用于制备异喹啉酮的方法及异喹啉酮的固体形式 |
US8828998B2 (en) | 2012-06-25 | 2014-09-09 | Infinity Pharmaceuticals, Inc. | Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors |
EA201590693A1 (ru) * | 2012-10-05 | 2015-08-31 | Ригель Фармасьютикалс, Инк. | Ингибиторы gdf-8 |
GB201312800D0 (en) | 2013-07-17 | 2013-08-28 | Heptares Therapeutics Ltd | mGlu5 modulators |
EP3094326A4 (en) | 2014-01-14 | 2017-07-26 | Millennium Pharmaceuticals, Inc. | Heteroaryls and uses thereof |
WO2015108861A1 (en) | 2014-01-14 | 2015-07-23 | Millennium Pharmaceuticals, Inc. | Heteroaryls and uses thereof |
WO2015160975A2 (en) | 2014-04-16 | 2015-10-22 | Infinity Pharmaceuticals, Inc. | Combination therapies |
CN104004762B (zh) * | 2014-05-20 | 2016-03-30 | 南京医科大学附属南京儿童医院 | Tgf-r反义序列及其在制备抗气道炎症反应药物中的应用 |
US9981944B2 (en) * | 2015-02-20 | 2018-05-29 | Rigel Pharmaceuticals, Inc | GDF-8 inhibitors |
WO2017223422A1 (en) | 2016-06-24 | 2017-12-28 | Infinity Pharmaceuticals, Inc. | Combination therapies |
CA3128468A1 (en) | 2017-10-05 | 2019-04-11 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce dux4 and downstream gene expression for the treatment of fshd |
US10342786B2 (en) | 2017-10-05 | 2019-07-09 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
IL277071B1 (en) | 2018-03-08 | 2024-03-01 | Incyte Corp | Aminopyrizine diol compounds as PI3K–y inhibitors |
US11046658B2 (en) | 2018-07-02 | 2021-06-29 | Incyte Corporation | Aminopyrazine derivatives as PI3K-γ inhibitors |
US20230090552A1 (en) | 2020-01-08 | 2023-03-23 | Synthis Therapeutics, Inc. | Alk5 inhibitor conjugates and uses thereof |
JP2024511841A (ja) * | 2021-03-29 | 2024-03-15 | アービュタス バイオファーマ コーポレイション | 置換された1-アリール-1’-ヘテロアリール化合物、置換された1,1’-ビヘテロアリール化合物、及びこれらを使用する方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004013135A1 (en) * | 2002-07-31 | 2004-02-12 | Smithkline Beecham Corporation | 2-phenylpyridin-4-yl derivatives as alk5 inhibitors |
WO2004014891A1 (en) * | 2002-08-13 | 2004-02-19 | Merck Sharp & Dohme Limited | Pyridazine derivatives as ligands for gaba receptors |
WO2009087212A2 (en) * | 2008-01-11 | 2009-07-16 | Novartis Ag | Pyridine derivatives |
WO2009087224A1 (en) * | 2008-01-11 | 2009-07-16 | Novartis Ag | Pyrimidines as kinase inhibitors |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9904387D0 (en) | 1999-02-25 | 1999-04-21 | Pharmacia & Upjohn Spa | Antitumour synergistic composition |
WO2000061186A1 (en) | 1999-04-08 | 2000-10-19 | Arch Development Corporation | Use of anti-vegf antibody to enhance radiation in cancer therapy |
CN101468965A (zh) | 2003-03-24 | 2009-07-01 | 默克公司 | 联芳基取代的6元杂环钠通道阻滞剂 |
US20050014753A1 (en) | 2003-04-04 | 2005-01-20 | Irm Llc | Novel compounds and compositions as protein kinase inhibitors |
US7504401B2 (en) | 2003-08-29 | 2009-03-17 | Locus Pharmaceuticals, Inc. | Anti-cancer agents and uses thereof |
KR101328273B1 (ko) | 2004-12-28 | 2013-11-14 | 키넥스 파마슈티컬즈, 엘엘씨 | 세포 증식 질환의 치료를 위한 조성물 및 방법 |
SI1959955T1 (sl) | 2005-12-05 | 2011-02-28 | Pfizer Prod Inc | Postopek zdravljenja abnormalne celične rasti |
US20070191371A1 (en) | 2006-02-14 | 2007-08-16 | Kalypsys, Inc. | Heterocyclic modulators of ppar |
US20080280891A1 (en) | 2006-06-27 | 2008-11-13 | Locus Pharmaceuticals, Inc. | Anti-cancer agents and uses thereof |
CN101595084B (zh) | 2006-06-29 | 2013-01-02 | 金克斯医药品有限公司 | 用于调整激酶级联的二芳基组合物和方法 |
PT2041071E (pt) | 2006-06-29 | 2014-09-23 | Kinex Pharmaceuticals Llc | Composições de biarilo e processos para a regulação de uma cascata de cinases |
WO2008008059A1 (en) | 2006-07-12 | 2008-01-17 | Locus Pharmaceuticals, Inc. | Anti-cancer agents ans uses thereof |
US8217177B2 (en) | 2006-07-14 | 2012-07-10 | Amgen Inc. | Fused heterocyclic derivatives and methods of use |
JP4751856B2 (ja) | 2007-07-03 | 2011-08-17 | 本田技研工業株式会社 | 車体側部構造 |
US20090069288A1 (en) | 2007-07-16 | 2009-03-12 | Breinlinger Eric C | Novel therapeutic compounds |
WO2009024825A1 (en) | 2007-08-21 | 2009-02-26 | Astrazeneca Ab | 2-pyrazinylbenzimidazole derivatives as receptor tyrosine kinase inhibitors |
-
2011
- 2011-06-07 BR BR112012033658A patent/BR112012033658A2/pt not_active IP Right Cessation
- 2011-06-07 EA EA201300080A patent/EA201300080A1/ru unknown
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004013135A1 (en) * | 2002-07-31 | 2004-02-12 | Smithkline Beecham Corporation | 2-phenylpyridin-4-yl derivatives as alk5 inhibitors |
WO2004014891A1 (en) * | 2002-08-13 | 2004-02-19 | Merck Sharp & Dohme Limited | Pyridazine derivatives as ligands for gaba receptors |
WO2009087212A2 (en) * | 2008-01-11 | 2009-07-16 | Novartis Ag | Pyridine derivatives |
WO2009087224A1 (en) * | 2008-01-11 | 2009-07-16 | Novartis Ag | Pyrimidines as kinase inhibitors |
Non-Patent Citations (1)
Title |
---|
JPN6015021860; J. Med. Chem. 49, 2006, 2210-2221 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2020510078A (ja) * | 2017-03-15 | 2020-04-02 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | Hpk1の阻害剤としてのアザインドール |
JP7132937B2 (ja) | 2017-03-15 | 2022-09-07 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | Hpk1の阻害剤としてのアザインドール |
US11944606B2 (en) | 2017-03-15 | 2024-04-02 | Genentech, Inc. | Azaindoles as inhibitors of HPK1 |
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