JP6189434B2 - ピリミジンピラゾリル誘導体 - Google Patents
ピリミジンピラゾリル誘導体 Download PDFInfo
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- JP6189434B2 JP6189434B2 JP2015520844A JP2015520844A JP6189434B2 JP 6189434 B2 JP6189434 B2 JP 6189434B2 JP 2015520844 A JP2015520844 A JP 2015520844A JP 2015520844 A JP2015520844 A JP 2015520844A JP 6189434 B2 JP6189434 B2 JP 6189434B2
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- Prior art keywords
- pyrazol
- mmol
- phenyl
- methyl
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Classifications
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Description
キナーゼは、タンパク質、脂質、糖類、ヌクレオシドおよび他の細胞内代謝物のリン酸化を触媒し、真核細胞の生理機能の全ての面においてキーとなる役割を果たす。特に、タンパク質キナーゼおよび脂質キナーゼは、成長因子、サイトカインまたはケモカイン等の細胞外のメディエーターまたは刺激に応答して、細胞の活性化、成長、分化および生存を制御するシグナリング事象に関与する。一般に、タンパク質キナーゼは、チロシン残基を優先的にリン酸化する群と、セリンおよび/またはトレオニン残基をリン酸化する群との2つに分類される。
本発明の一側面に従い、式(I)で表される化合物が提供される。
本発明の他の側面に従い、IRAKに関連した障害の処置および/または予防に好適な式(I)で表される化合物が提供される。
本発明の他の側面に従い、哺乳動物、特にヒトの病態におけるIRAKの活性または機能を調整、特に阻害することが可能な化合物が提供される。
好ましくは、キットは、
(a)有効量の、式(I)で表される化合物および/またはその薬学的に使用可能な誘導体、溶媒和物、互変異性体、塩、水和物および立体異性体ならびにあらゆる比率でのそれらの混合物、ならびに、
(b)有効量のさらなる医薬活性成分
の別個のパックからなる。
一態様において、本発明は、式(I)
R1が、存在しないか、または、AもしくはQ−Hetを示し、
Zが、基:
Xが、O、SもしくはNを示し、
Yが、CもしくはNを示し、
Tが、CもしくはNを示す、
を示すか、または、
Zが、ピリジン基もしくはピリダジン基を示し、
Rbが、存在しないか、または、AおよびCOHetから選択される基の1つを示し、
R2が、H、Het、Q−Het、Cyc、AまたはOAを示し、
R3が、Hか、またはC1〜C6のアルキルを示し、ここで1個のH原子が、OH、O−C1〜C6のアルキルおよびHalから選択される基で交換されていてもよく、
Cyc1が、3〜7個の原子を有するシクロアルキルを示す、
で表される化合物、および、その薬学的に許容し得る誘導体、溶媒和物、互変異性体、塩、水和物および立体異性体、ならびに、そのあらゆる比率での混合物を提供する。
を示してもよい。
Zは、式(I)および関連する式において、好ましくは、ピリダジン、ピラゾールおよび4−ピリジンから選択される基を示す。
から選択される。
代わりに、式(I)および関連する式における基R2は、好ましくは、以下の基から選択される:
代わりに、Rbは、COHetまたは直鎖もしくは分岐のC1〜C6のアルキル基、ここで1個のH原子が、NR3またはOR3から選択される基で交換されていてもよく、1個のCH2基が、基COで交換されていてもよい、から選択される基を示してもよい。
代わりに、式(I)および関連する式におけるHetは、基Aで任意に単置換されていてもよい、窒素および酸素から選択される1〜2個のヘテロ原子を含有する4〜9員のスピロのまたは架橋された二環を示す。
Cyc1は、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルまたはシクロヘプチルである。
で表される化合物も含む。
さらなる態様において、最も好ましい化合物は、例121、233、234、278、250、251、260、262、285、286および287のようなアミドならびにスピロ−アミドである。
「C1〜C6のアルキル」または「C1〜C6のアルキル基」は、1〜6個の炭素原子を有する直鎖または分岐のアルキル鎖を示す。
「C1〜C6のアルキル」または「C1〜C3のアルキル」はまた、ハロ−アルキルも含んでもよい。ハロ−アルキルは、1〜10個のハロゲン原子、好ましくは1〜3個のハロゲン原子を含有する。ハロ−アルキルは、例えば基−CF3、−CHF2または−CH2F等を含有する。
さらに、Aは、好ましくは、CH2OCH3、OCH2CH2OCH3、CH2OH、CH2NH2、NHCH2CH2OH、CH2CH2OH、CH2NHCH2またはNHCH2CH3を示す。
Halは、好ましくはClまたはFを示す。
R3は、好ましくはHまたはCH3を示す。
Qは、好ましくは存在しないか、または、好ましくは、NR3COCH2、CH2CONR3、COCH(CH3)、CH(CH3)CO、COCH2CH2、CH2CH2CO、CH2、CH2CH2、CH2CO、COCH2、CH(OH)CH2、CH2CH(OH)、CO−C(CH3)2もしくは(CH3)2C−COを示す。
本明細書全体にわたって、脱離基という用語は、好ましくはCl、Br、I、あるいは、例えば活性化されたエステル、イミダゾリド、1〜6個の炭素原子を有するアルキルスルホニルオキシ(好ましくはメチルスルホニルオキシもしくはトリフルオロメチルスルホニルオキシ)または6〜10個の炭素原子を有するアリールスルホニルオキシ(好ましくはフェニル−もしくはp−トリルスルホニルオキシ)等の、反応性の高く修飾されたOH基を示す。
活性化されたエステルは、有利には、例えばHOBtまたはNヒドロキシスクシンイミドの添加等を通じてin situで形成される。
さらなる置換に関係なく、Hetは、例えば、2−もしくは3−フリル、2−もしくは3−チエニル、1−、2−もしくは3−ピロリル、1−、2、4−もしくは5−イミダゾリル、1−、3−、4−もしくは5−ピラゾリル、2−、4−もしくは5−オキサゾリル、3−、4−もしくは5−イソオキサゾリル、2−、4−もしくは5−チアゾリル、3−、4−もしくは5−イソチアゾリル、2−、3−もしくは4−ピリジル、2−、4−、5−もしくは6−ピリミジニル、さらに好ましくは、1,2,3−トリアゾール−1−、−4−もしくは−5−イル、1,2,4−トリアゾール−1−、−3−もしくは5−イル、1−もしくは5−テトラゾリル、1,2,3−オキサジアゾール−4−もしくは−5−イル、1,2,4−オキサジアゾール−3−もしくは−5−イル、1,3,4−チアジアゾール−2−もしくは−5−イル、1,2,4−チアジアゾール−3−もしくは−5−イル、1,2,3−チアジアゾール−4−もしくは−5−イル、3−もしくは4−ピリダジニル、ピラジニル、1−、2−、3−、4−、5−、6−もしくは7−インドリル、4−もしくは5−イソインドリル、インダゾリル、1−、2−、4−もしくは5−ベンズイミダゾリル、1−、3−、4−、5−、6−もしくは7−ベンゾピラゾリル、2−、4−、5−、6−もしくは7−ベンズオキサゾリル、3−、4−、5−、6−もしくは7−ベンズイソオキサゾリル、2−、4−、5−、6−もしくは7−ベンゾチアゾリル、2−、4−、5−、6−もしくは7−ベンズイソチアゾリル、4−、5−、6−もしくは7−ベンズ−2,1,3−オキサジアゾリル、2−、3−、4−、5−、6−、7−もしくは8−キノリル、1−、3−、4−、5−、6−、7−もしくは8−イソキノリル、3−、4−、5−、6−、7−もしくは8−シンノリニル、2−、4−、5−、6−、7−もしくは8−キナゾリニル、5−もしくは6−キノキサリニル、2−、3−、5−、6−、7−もしくは8−2H−ベンゾ−1,4−オキサジニル、さらに好ましくは、1,3−ベンゾジオキソール−5−イル、1,4−ベンゾジオキサン−6−イル、2,1,3−ベンゾチアジアゾール−4−、−5−イルもしくは2,1,3−ベンズオキサジアゾール−5−イル、アザビシクロ[3.2.1]オクチルまたはジベンゾフラニルを示す。
さらなる置換に関係なく、Hetはまた、よって、例えば、2,3−ジヒドロ−2−、−3−、−4−もしくは−5−フリル、2,5−ジヒドロ−2−、−3−、−4−もしくは5−フリル、テトラヒドロ−2−もしくは−3−フリル、1,3−ジオキサン−4−イル、テトラヒドロ−2−もしくは−3−チエニル、2,3−ジヒドロ−1−、−2−、−3−、−4−もしくは−5−ピロリル、2,5−ジヒドロ−1−、−2−、−3−、−4−もしくは−5−ピロリル、1−、2−もしくは3−ピロリジニル、テトラヒドロ−1−、−2−もしくは−4−イミダゾリル、2,3−ジヒドロ−1−、−2−、−3−、−4−もしくは−5−ピラゾリル、テトラヒドロ−1−、−3−もしくは−4−ピラゾリル、1,4−ジヒドロ−1−、−2−、−3−もしくは−4−ピリジル、1,2,3,4−テトラヒドロ−1−、−2−、−3−、−4−、−5−もしくは−6−ピリジル、1−、2−、3−もしくは4−ピペリジニル、2−、3−もしくは4−モルホリニル、テトラヒドロ−2−、−3−もしくは−4−ピラニル、1,4−ジオキサニル、1,3−ジオキサン−2−、−4−もしくは−5−イル、ヘキサヒドロ−1−、−3−もしくは−4−ピリダジニル、ヘキサヒドロ−1−、−2−、−4−もしくは−5−ピリミジニル、1−、2−もしくは3−ピペラジニル、1,2,3,4−テトラヒドロ−1−、−2−、−3−、−4−、−5−、−6−、−7−もしくは−8−キノリル、1,2,3,4−テトラヒドロ−1−,−2−,−3−、−4−、−5−、−6−、−7−もしくは−8−イソキノリル、2−、3−、5−、6−、7−もしくは8− 3,4−ジヒドロ−2H−ベンゾ−1,4−オキサジニル、さらに好ましくは、2,3−メチレンジオキシフェニル、3,4−メチレンジオキシフェニル、2,3−エチレンジオキシフェニル、3,4−エチレンジオキシフェニル、3,4−(ジフルオロメチレンジオキシ)フェニル、2,3−ジヒドロベンゾフラン−5−もしくは6−イル、2,3−(2−オキソメチレンジオキシ)フェニルまたは3,4−ジヒドロ−2H−1,5−ベンゾジオキセピン−6−もしくは−7−イルもまた、さらに好ましくは、2,3−ジヒドロベンゾフラニル、2,3−ジヒドロ−2−オキソフラニル、3,4−ジヒドロ−2−オキソ−1H−キナゾリニル、2,3−ジヒドロベンズオキサゾリル、2−オキソ−2,3−ジヒドロベンズオキサゾリル、2,3−ジヒドロベンズイミダゾリル、1,3−ジヒドロインドール、2−オキソ−1,3−ジヒドロインドールまたは2−オキソ−2,3−ジヒドロベンズイミダゾリルも示す。
Zは、極めて特に好ましくは、1−メチル−1H−ピラゾール−4−イルまたは6−メチル−ピリダジン−4−イルを示し、
Het1
Het2は、好ましくは、ピペリジニルまたはピロリジニルを示す。
R2は、好ましくは、H、Het、Q−Het、CycまたはAを示す。
R1が、存在せず、
Zが、イソオキサゾリル、イミダゾリル、チアゾリル、オキサゾリル、ピリダジニル、トリアゾリル、ピリジル、ピラゾリルまたはフリルを示し、これらの各々は、非置換であるか、あるいは、A、Hal、N(R3)2、CH2COHet2および/もしくはベンジルで単置換または二置換されており、
Rbが、存在しないか、または、CONH2、COOH、CONHA、COHet1もしくはCH2OHを示し、
R2が、H、Het、Q−Het、Cyc、A、OA、CH2COOH、NHA、NA2、CH2CONH2、CH2CONHA、CH(A)CONHAもしくはNR3SO2Aを示すか、
または、OAで任意に単置換または二置換されたフェニルを示し、
Ar1が、Halで任意に置換されていてもよいフェニルを示し、
R3が、HまたはC1〜C6のアルキルを示し、ここで、1個のH原子が、OH、O−C1〜C6のアルキルおよびHalから選択される基で交換されていてもよく、
Het2が、ピペリジニルまたはピロリジニルを示し、
nが、0、1、2または3を示す、
で表される化合物、ならびに、その薬学的に許容し得る誘導体、溶媒和物、互変異性体、塩、水和物および立体異性体、ならびに、あらゆる比率でのそれらの混合物に関する。
以下の略語は、下記で使用される略語を指す:
Ac(アセチル)、BINAP(2,2’−ビス(ジスフェニルホスフィノ)−1,1’−ビナフタレン)、dba(ジベンジリデンアセトン)、Bu(ブチル)、tBu(tert−ブチル)、DCE(ジクロロエタン)、DCM(ジクロロメタン)、DIEA(ジ−イソプロピルエチルアミン)、DMA(ジメチルアセトアミド)、DMSO(ジメチルスルホキシド)、DMF(N,N−ジメチルホルムアミド)、Dppf(1,1’−ビス(ジフェニルホスフィンフェロセン))、EtOAc(酢酸エチル)、EtOH(エタノール)、g(グラム)、cHex(シクロヘキサン)、HATU(N−[(ジメチルアミノ)(3H−[1,2,3]トリアゾロ[4,5−b]ピリジン−3−イルオキシ)メチレン]−N−メチルメタンaminiumヘキサフルオロホスファート)、HPLC(高速液体クロマトグラフィ)、hr(時間)、LDA(リチウムジイソプロピルアミン)、LiHMDS(リチウムビス(トリメチルシリル)アミド)、MHz(メガヘルツ)、MeOH(メタノール)、min(分間)、mL(ミリリットル)、mmol(ミリモル)、mM(ミリモラー)、mp(融点)、MS(質量分析)、MW(マイクロ波)、NMR(核磁気共鳴)、O/N(終夜)、PBS(リン酸緩衝食塩水)、PPh3(トリフェニルホスフィン)、RT(室温)、TEA(トリエチルアミン)、TFA(トリフルオロ酢酸)、THF(テトラヒドロフラン)、TLC(薄層クロマトグラフィ)、oTol(オルト−トリル)、UV(紫外線)。
使用される条件にもよるが、反応時間は、一般に、数分間と14日間との間である。反応温度は、約−30℃と約140℃との間であり、通常、−10℃と90℃との間、特に約0℃と70℃との間である。
式(I)および関連する式はまた、例えば1:1、1:2、1:3、1:4、1:5、1:10、1:100または1:1000等の比率における例えば2種のジアステレオマーの混合物等、式Iで表される化合物の混合物も包含する。
医薬製剤は、投薬単位あたり所定量の活性成分を含む投薬単位の形態で投与され得る。かかる単位は、処置される疾患状態、投与の方法ならびに患者の年齢、体重および状態に応じて、本発明に従う化合物の、例えば0.5mg〜1g、好ましくは1mg〜700mg、特に好ましくは5mg〜100mgを含み得るか、あるいは、医薬製剤は、投薬単位あたり所定量の活性成分を含む投薬単位の形態で投与され得る。好ましい投薬単位製剤は、先に示されているように、1日用量もしくは部分用量(part-dose)を、または、活性成分をその対応する割合で含むものである。さらに、このタイプの医薬製剤は、医薬分野において一般に知られている方法を使用して調製され得る。
膣内投与に適応される医薬製剤は、膣坐薬、タンポン、クリーム、ゲル、ペースト、泡またはスプレーの製剤として投与され得る。
以下、本発明はいくつかの例を介して説明されるが、本発明の範囲を限定するものとして見なされるとは解釈されない。
下記例において提供されたHPLCデータは、次のようにして得られた。
条件A:Column Waters XbridgeTM C8 50 mm x 4.6 mm、2mL/minの流れで;8min勾配 H2O:CH3CN:TFAが100:0:0.1%から0:100:0.05%まで。
全条件においてUV検出(maxplot)。
下記例において提供されたMSデータは、次のようにして得られた:質量スペクトル:LC/MS Waters ZMD (ESI)。
下記例において提供されたNMRデータは、次のようにして得られた:1H−NMR:Bruker DPX-300MHz または Bruker AV-400 MHz。
自動分取(autopreparative)LC/MS精製を、別段の報告がない限り、Sunfire Prep C18 OBD column 19x100 mm 5μmを備えたWatersからの質量指向性(mass directed)の自動精製Fractionlynxを用いて実施した。全てのHPLC精製を、ACN/H2OまたはACN/H2O/HCOOH(0.1%)の勾配を用いて実施した。
マイクロ波化学を、単一モードのマイクロ波反応器であるBiotageからのEmrysTM Optimiser または InitiatorTM Sixtyにより実施した。
本発明の化合物は、プログラムAutonomにおいて使用される規格に従って命名された。
ステップ1:tert−ブチル4−{4−[2−(3−アミノフェニル)ピリミジン−5−イル]−1H−ピラゾール−1−イル}ピペリジン−1−カルボキシラートの形成
ステップ1:tert−ブチル4−[4−(2−アミノピリミジン−5−イル)−1H−ピラゾール−1−イル]ピペリジン−1−カルボキシラートの形成
ステップ1:tert−ブチル−trans−3−フルオロ−4−ヒドロキシピペリジン−1−カルボキシラートの形成
ステップ1:3−[5−(1H−ピラゾール−4−イル)−ピリミジン−2−イル]−フェニルアミンの形成
ステップ1:tert−ブチル4−{4−[2−(3−アミノフェニル)ピリミジン−5−イル]−1H−ピラゾール−1−イル}ピペリジン−1−カルボキシラートの形成
ステップ1:トルエン−4−スルホン酸1,4−ジオキサ−スピロ[4.5]デカ−8−イルエステルの形成
第1の溶出化合物:無色のり(234mg、18%)。Cis−4−(4−ヨード−ピラゾール−1−イル)−シクロヘキサノール。HPLC(条件A):Rt2.69min(純度99.7%)。MS (ESI+): 293.1.
第2の溶出化合物:白色粉末(730mg、55%)。Trans−4−(4−ヨード−ピラゾール−1−イル)−シクロヘキサノール。HPLC(条件A):Rt2.65min(純度100%)。MS (ESI+): 293.1.
ステップ1:N’−(2−オキソ−1−アザ−スピロ[4.5]デカ−8−イル)−ヒドラジンカルボン酸tert−ブチルエステルの形成
キラル分取HPLC((Chiralpak IC 250 x 4.6 mm);EtOH/DEA)による分離によって、2つの純粋な異性体が得られた(任意に帰せた)。
第1の溶出異性体(174mg、Rt=4.68min):中間体23
ステップ1:4−(N’−tert−ブトキシカルボニル−ヒドラジノ)−3,3−ジフルオロ−ピペリジン−1−カルボン酸tert−ブチルエステルの形成
ステップ1:メチル1,4−ジオキサスピロ[4.5]デカ−8−イリデンアセタートの形成
ステップ6で得られた混合物を、分取HPLC(Chiralpak AD-H、ヘキサン:IPA:DEA80:20:0.1)によって分離した。
第1の溶出化合物:中間体30、Rt=19.32min
DMF(10mL)中8−(4−ブロモ−1H−ピラゾール−1−イル)−2−アザスピロ[4.5]デカン−3−オン(ステップ5で得られた中間体30および31の混合物;4g、13.4mmol)の溶液へ、水素化ナトリウム(60%)(0.8g、0.0116mol)を、続くヨウ化メチル(2.2mL、14.8mmol)を、0℃で加えた。反応混合物を放置してRTまでゆっくり温め、1h撹拌した。反応混合物を水でクエンチし、酢酸エチルで抽出した。合わせた有機相を水(50mL)およびブライン(50mL)で洗浄し、硫酸ナトリウム上で乾燥させ、濾過し濃縮した。シリカ上のフラッシュクロマトグラフィ(Pet.エーテル:酢酸エチル)による精製によって、表題の化合物(2つの異性体の混合物)が灰白色固体(1.8g、43%)として得られた。1H NMR (400MHz, DMSO-d6) δ 8.04-8.03 (m, 1H), 7.51-7.50 (m, 1H), 4.16-4.10 (m, 1H), 3.24 (s, 1H), 3.09 (s, 1H), 2.70-2.69 (m, 3H), 2.21 (s, 1H), 2.09 (s, 1H), 1.90-1.86 (m, 6H), 1.79-1.54 (m, 2H).
ステップ1で得られた混合物を、分取HPLC(Zorbax RX-SIL、ヘキサン:EtOH:DEA;90:10:0.1)で分離した。
第1の溶出化合物:中間体32;Rt=12.87min
ステップ1:メチル−6−(2−tert−ブトキシカルボニルヒドラジノ)−cis−7a−ヒドロキシ−1,3,4,5,6,7−ヘキサヒドロイソベンゾフラン−3a−カルボキシラートの形成
少量の異性体:50mg;HPLC(条件A):Rt3.72min(純度93.8%)
主要な異性体:0.5g。1H NMR (400MHz; DMSO): δ 7.47 (s, 2H), 4.48-4.44 (m, 1H), 4.22-4.20 (d, J = 11.08 Hz, 1H), 3.99-3.93 (m, 2H), 3.70-3.68 (d, J = 8.32 Hz, 1H), 3.54-3.51 (d, J = 10.0Hz, 2H), 2.28-2.10 (m, 4H), 2.02-1.95 (m, 1H), 1.64-1.59 (m, 1H). HPLC(条件A):Rt2.95min(純度99.9%)。MS (ESI+): 319.0. 化合物に対し実施されたNOE実験によって示されたCis−cis異性体は例に記載した。
第1の溶出鏡像異性体:中間体35;200mg;Rt=15.6min(Chiralcel OD-H、250x4.6 mm;5uM;溶離液:ヘキサン:IPA:TFA、90:10:0.1)。
第2の溶出鏡像異性体:中間体36;200mg;Rt=16.78min(Chiralcel OD-H、250x4.6 mm;5uM;溶離液:ヘキサン:IPA:TFA、90:10:0.1)。
ステップ1:4−(N’−tert−ブトキシカルボニル−ヒドラジノ)−3−フルオロ−ピペリジン−1−カルボン酸tert−ブチルエステルの形成
ステップ1:tert−ブチル4−(4−{2−[3−(1−メチル−1H−ピラゾール−4−イル)フェニル]ピリミジン−5−イル}−1H−ピラゾール−1−イル)ピペリジン−1−カルボキシラートの形成
ステップ1:4−{4−[2−(3−ピリジン−3−イル−フェニル)−ピリミジン−5−イル]−ピラゾール−1−イル}−ピペリジン−1−カルボン酸tert−ブチルエステルの形成
ステップ1:tert−ブチル4−(4−{2−[3−(3−フリル)フェニル]ピリミジン−5−イル}−1H−ピラゾール−1−イル)ピペリジン−1−カルボキシラートの形成
ステップ1:tert−ブチル4−{4−[2−(3−イソオキサゾール−4−イルフェニル)ピリミジン−5−イル]−1H−ピラゾール−1−イル}ピペリジン−1−カルボキシラートの形成
ステップ1:tert−ブチル4−(4−{2−[3−(1,3−ジメチル−1H−ピラゾール−4−イル)フェニル]ピリミジン−5−イル}−1H−ピラゾール−1−イル)ピペリジン−1−カルボキシラートの形成
ステップ1:tert−ブチル4−(4−{2−[3−(1,5−ジメチル−1H−ピラゾール−4−イル)フェニル]ピリミジン−5−イル}−1H−ピラゾール−1−イル)ピペリジン−1−カルボキシラートの形成
ステップ1:tert−ブチル4−{4−[2−(3−{1−[2−フルオロ−1−(フルオロメチル)エチル]−1H−ピラゾール−4−イル}フェニル)ピリミジン−5−イル]−1H−ピラゾール−1−イル}ピペリジン−1−カルボキシラートの形成
ステップ1:tert−ブチル4−[4−(2−{3−[1−(2−オキソ−2−ピロリジン−1−イルエチル)−1H−ピラゾール−4−イル]フェニル}ピリミジン−5−イル)−1H−ピラゾール−1−イル]ピペリジン−1−カルボキシラートの形成
ステップ1:tert−ブチル4−(4−{2−[3−(1H−ピラゾール−4−イル)フェニル]ピリミジン−5−イル}−1H−ピラゾール−1−イル)ピペリジン−1−カルボキシラートの形成
ステップ1:tert−ブチル4−(4−{2−[3−(1−プロピル−1H−ピラゾール−4−イル)フェニル]ピリミジン−5−イル}−1H−ピラゾール−1−イル)ピペリジン−1−カルボキシラートの形成
ステップ1:tert−ブチル4−(4−{2−[3−(1−イソプロピル−1H−ピラゾール−4−イル)フェニル]ピリミジン−5−イル}−1H−ピラゾール−1−イル)ピペリジン−1−カルボキシラートの形成
ステップ1:tert−ブチル4−(4−{2−[3−(1−ベンジル−1H−ピラゾール−4−イル)フェニル]ピリミジン−5−イル}−1H−ピラゾール−1−イル)ピペリジン−1−カルボキシラートの形成
ステップ1:5−[1−(2−{[tert−ブチル(ジメチル)シリル]オキシ}エチル)−1H−ピラゾール−4−イル]−2−[3−(1−メチル−1H−ピラゾール−4−イル)フェニル]ピリミジンの形成
ステップ1:tert−ブチル3−(4−{2−[3−(1−メチル−1H−ピラゾール−4−イル)フェニル]ピリミジン−5−イル}−1H−ピラゾール−1−イル)アゼチジンe−1−カルボキシラートの形成
ステップ1:4−(4−{2−[3−(1−メチル−1H−ピラゾール−4−イル)−フェニル]−ピリミジン−5−イル}−ピラゾール−1−イルメチル)−ピペリジン−1−カルボン酸tert−ブチルエステルの形成
ステップ1:Trans−3−フルオロ−4−(4−{2−[3−(1−メチル−1H−ピラゾール−4−イル)−フェニル]−ピリミジン−5−イル}−ピラゾール−1−イル)−ピペリジン−1−カルボン酸tert−ブチルエステルの形成
ステップ1:4−{4−[2−(3−ピリジン−4−イル−フェニル)−ピリミジン−5−イル]−ピラゾール−1−イル}−ピペリジン−1−カルボン酸tert−ブチルエステルの形成
ステップ1:1−ピロリジン−1−イル−2−(4−{2−[3−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−フェニル]−ピリミジン−5−イル}−ピラゾール−1−イル)−エタノンの形成
反応混合物溶液は、次のステップにおいて、そのまま使用した。
ステップ1:2−(4−{2−[3−(1−メチル−1H−ピラゾール−4−イル)−フェニル]−ピリミジン−5−イル}−ピラゾール−1−イルメチル)−モルホリン−4−カルボン酸tert−ブチルエステルの形成
ステップ1:{2−[4−(3−{5−[1−(2−オキソ−2−ピロリジン−1−イル−エチル)−1H−ピラゾール−4−イル]−ピリミジン−2−イル}−フェニル)−ピラゾール−1−イル]−エチル}−カルバミン酸tert−ブチルエステルの形成
ステップ1:4−(4−{2−[3−(1−メチル−1H−ピラゾール−4−イル)−フェニル]−ピリミジン−5−イル}−ピラゾール−1−イル)−シクロヘキサンカルボン酸エチルエステルの形成
ステップ1:3−(4−{2−[3−(1−メチル−1H−ピラゾール−4−イル)−フェニル]−ピリミジン−5−イル}−ピラゾール−1−イルメチル)−ピロリジン−1−カルボン酸tert−ブチルエステルの形成
ステップ1:3−(4−{2−[3−(1−メチル−1H−ピラゾール−4−イル)−フェニル]−ピリミジン−5−イル}−ピラゾール−1−イルメチル)−アゼチジンe−1−カルボン酸tert−ブチルエステルの形成
ステップ1:(S)−2−(4−{2−[3−(1−メチル−1H−ピラゾール−4−イル)−フェニル]−ピリミジン−5−イル}−ピラゾール−1−イルメチル)−ピロリジン−1−カルボン酸tert−ブチルエステルの形成
ステップ1:(R)−2−(4−{2−[3−(1−メチル−1H−ピラゾール−4−イル)−フェニル]−ピリミジン−5−イル}−ピラゾール−1−イルメチル)−ピロリジン−1−カルボン酸tert−ブチルエステルの形成
ステップ1:4−(4−{2−[3−(1−トリメチルシラニルメチル−1H−[1,2,3]トリアゾール−4−イル)−フェニル]−ピリミジン−5−イル}−ピラゾール−1−イル)−ピペリジン−1−カルボン酸tert−ブチルエステルの形成
他の例は、先に記載したとおりの類似の手順に従うか、または当業者に周知の手順に従い合成された。
IRAK1酵素アッセイ
IRAK1は、ヒト精製組換え酵素(His−TEV−IRAK1(194−712))である。
このアッセイにおいて、IRAK−1は、ATPを加水分解し、自己リン酸化する。
IRAK−1阻害の測定は、ストレプトアビジンがコーティングされた384ウェルのFlashPlate(PerkinElmer #SMP410A)で実施する。
IRAK4は、ヒト精製組換え酵素(His−TEV−IRAK1(194−712)である。
IRAK4はATPを加水分解し、セリン/トレオニンの包括的なペプチド性基質(STK:CisBio International based in Bagnols/Ceze FR からの61ST1BLC)を自己リン酸化およびリン酸化する。
結果を以下の表に示す:
製剤1−錠剤
式(I)で表される化合物を、乾燥粉末として、乾燥ゼラチンバインダーとともに、おおよそ1:2の重量比率で混合する。少量のステアリン酸マグネシウムを、潤滑剤として加える。混合物は、打錠機において、240〜270mgの錠剤へ形成される(錠剤あたり、80〜90mgの本発明に従う活性化合物)。
式(I)で表される化合物を、乾燥粉末として、デンプン希釈剤とともに、おおよそ1:1の重量比率で混合する。混合物は、250mgのカプセル中へ満たされる(カプセルあたり、125mgの本発明に従う活性化合物)。
式(I)で表される化合物(1250mg)、スクロース(1.75g)およびキサンタンガム(4mg)をブレンドし、No.10メッシュU.S.篩に通過させ、その後、予め調製した水中の微結晶性セルロースおよびナトリウムカルボキシメチルセルロース(11:89、50mg)の溶液と混合した。安息香酸ナトリウム(10mg)、香味料および顔料を水で希釈し、撹拌しながら加える。その後、十分量の水を加え、総容量を5mLとする。
式(I)で表される化合物を、乾燥粉末として、乾燥ゼラチンバインダーとともに、おおよそ1:2の重量比率で混合する。少量のステアリン酸マグネシウムを潤滑剤として加える。混合物は、打錠機において、450〜900mgの錠剤へ形成される(150〜300mgの本発明に従う活性化合物)。
式(I)で表される化合物を、おおよそ5mg/mLの濃度まで、注入可能な水性媒体の緩衝滅菌食塩水に溶解する。
Claims (15)
- 式(I)
R1が、存在しないか、または、AもしくはQ−Hetを示し、
Zが、基:
Xが、O、SもしくはNを示し、
Yが、CもしくはNを示し、
Tが、CもしくはNを示す、
を示すか、または、
Zが、ピリジン基もしくはピリダジン基を示し、
Raが、存在しないか、または、OR3、CF3、HalもしくはNO2を示し、
Rbが、存在しないか、または、AおよびCOHetから選択される基の1つを示し、
R2が、H、Het、Q−Het、Cyc、AまたはOAを示し、
Hetが、N、OおよびSから独立して選択される1〜3個のヘテロ原子または基CO、SOもしくはSO2を含有し、飽和か、不飽和か、または芳香族である、4〜9員の単環か、あるいは、融合されたか、スピロか、もしくは、架橋された二環を示し、ここで1個または2個のH原子が、A、OA、COA、CN、Hal、NO2、OR3、SOAおよび/またはSO2Aで交換されていてもよく、
Cycが、基であるSO、SO2もしくはCOを任意に含有し得、CO(NR3)2、COHet、OR3、Het1、A、CH2Het1、NH2、NHCOA、OCH2Cyc1、SO2Aおよび/または−SA(=NH)(=O)から選択される基で1回もしくは2回任意に置換され得る、4〜8個の飽和炭素環を示し、
Qが、1〜6個の炭素原子を有する、直鎖もしくは分岐のアルキレンを示すか、ここで1〜5個のH原子が、OR3、HalおよびN(R3)2から独立して選択される基で交換されていてもよく、ここで1個もしくは2個のCH2基が、CO、SO、SO2およびNR3から独立して選択される基で交換されていてもよく、または、Qが、飽和か、不飽和か、もしくは芳香族であり、N、OおよびSから独立して選択される1〜3個のヘテロ原子を含有する、4〜8員の2価のヘテロ環を示し、
Aが、1〜10個の炭素原子を有する、直鎖または分岐のアルキルを示し、ここで1〜7個のH原子が、−OR3、Hal、NHSO2A、SO2A、SOAおよびN(R3)2から独立して選択される基で交換されていてもよく、ここで1個、2個もしくは3個の非近接の−CH2−基が、−CO−、NR3および/または−O−から独立して選択される基で交換されていてもよく、
Halが、F、Cl、BrまたはIを示し、
R3が、HまたはC1〜C6のアルキルを示し、ここで1個のH原子が、OH、O−C1〜C6のアルキルおよびHalから選択される基で交換されていてもよく、
Het1が、1〜3個のN原子および/またはO原子を含有し、任意にAで単置換されていてもよい、5員もしくは6員の飽和の単環のヘテロ環を示し、
Cyc1が、3〜7個の原子を有するシクロアルキルを示す、
で表される化合物、または、その溶媒和物、互変異性体、塩、水和物もしくは立体異性体、あるいは、そのあらゆる比率での混合物。 - Zが、以下の基:
- 基であるZ−R1が、以下の基:
- R2が、以下の基:
- Rbが、以下の基:
- 化合物が、以下の群
- 医薬としての使用のための、請求項1〜6のいずれか一項に記載の式(I)で表される化合物、または、その溶媒和物、互変異性体、塩、水和物もしくは立体異性体、あるいは、あらゆる比率でのそれらの混合物。
- 炎症性疾患、自己免疫疾患、がんもしくは多発性硬化症および関連した疾患の処置または予防における使用のための、請求項1に記載の化合物。
- 自己免疫疾患が、喘息、リウマチ性関節炎、急性散在性脳脊髄炎(ADEM)、アジソン病、円形脱毛症、強直性脊椎炎、抗リン脂質抗体症候群(APS)、自己免疫性溶血性貧血、自己免疫性肝炎、自己免疫性内耳疾患、水疱性類天疱瘡、ベーチェット病、セリアック病、抗トランスグルタミナーゼ、シャガス病、慢性閉塞性肺疾患、クローン病、皮膚筋炎、1型糖尿病、子宮内膜症、グッドパスチャー症候群、グレーブス病、ギラン・バレー症候群(GBS)、橋本病、化膿性汗腺炎、川崎病、IgA腎症、特発性血小板減少性紫斑病、間質性膀胱炎、紅斑性狼瘡、混合性結合組織病、限局性強皮症、多発性硬化症(MS)、重症筋無力症、ナルコレプシー、神経性筋強直症、尋常性天疱瘡、悪性貧血、乾癬、乾癬性関節炎、多発性筋炎、原発性胆汁性肝硬変、リウマチ性関節炎、統合失調症、強皮症、シェーグレン症候群、全身硬直症候群、全身性硬化症、側頭動脈炎、潰瘍性大腸炎、血管炎、白斑、ウェゲナー肉芽腫症からなる群から選択される、請求項8に記載の化合物。
- 疾患が、リウマチ性関節炎、ループス腎炎および全身性紅斑性狼瘡から選択される、請求項8に記載の化合物。
- IRAKの過剰発現に関連した疾患の予防および/または処置のための、請求項1に記載の式(I)で表される化合物。
- (a)有効量の、請求項1〜6のいずれか一項に記載の式(I)で表される化合物および/またはその溶媒和物、互変異性体、塩、水和物および立体異性体ならびにあらゆる比率でのそれらの混合物、ならびに、
(b)有効量のさらなる医薬活性成分
の別個のパックからなるキット。 - 請求項1〜6のいずれか一項に記載の式(I)で表される化合物の少なくとも1つを含有する、医薬組成物。
- 炎症性疾患もしくは免疫障害の処置において使用されるさらなる医薬か、または免疫調節剤の少なくとも1つを追加して含有する、請求項13に記載の医薬組成物。
- 式(II)
で表される化合物を、式(III)
で表される化合物と反応させるステップを含む、請求項1〜6のいずれか一項に記載の式(I)で表される化合物を製造するための方法。
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WO2021127283A2 (en) | 2019-12-17 | 2021-06-24 | Kymera Therapeutics, Inc. | Irak degraders and uses thereof |
CN110950839B (zh) * | 2019-12-17 | 2023-04-14 | 蚌埠中实化学技术有限公司 | 4-(4-卤代-1h-吡唑-1-基)哌啶-1-羧酸叔丁酯的制备方法 |
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