JP2013536863A - ピリジノン/ピラジノン、その作製方法、および使用方法 - Google Patents
ピリジノン/ピラジノン、その作製方法、および使用方法 Download PDFInfo
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- JP2013536863A JP2013536863A JP2013527279A JP2013527279A JP2013536863A JP 2013536863 A JP2013536863 A JP 2013536863A JP 2013527279 A JP2013527279 A JP 2013527279A JP 2013527279 A JP2013527279 A JP 2013527279A JP 2013536863 A JP2013536863 A JP 2013536863A
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Abstract
Description
米国特許施行規則(37CFR)第1.53条(b)で、下で出願された本出願は、2010年9月1日に出願された米国仮特許出願第61/379,044号の利益を米国特許法(35USC)第119条(e)で、下で主張するものであり、全体が参照により援用される。
本明細書において使用される「アルキル」という用語は、1〜12個の炭素原子(C1〜C12)を有する飽和した直鎖状または分枝鎖状の一価炭化水素基を意味し、ここで、アルキル基は、後述される1つ以上の置換基で適宜選択的に置換されてもよい。別の実施形態におけるアルキル基は、1〜8個の炭素原子(C1〜C8)、または1〜6個の炭素原子(C1〜C6)を有する。アルキル基の例としては、以下に限定されるものではないが、メチル(Me、−CH3)、エチル(Et、−CH2CH3)、1−プロピル(n−Pr、n−プロピル、−CH2CH2CH3)、2−プロピル(i−Pr、i−プロピル、−CH(CH3)2)、1−ブチル(n−Bu、n−ブチル、−CH2CH2CH2CH3)、2−メチル−1−プロピル(i−Bu、i−ブチル、−CH2CH(CH3)2)、2−ブチル(s−Bu、s−ブチル、−CH(CH3)CH2CH3)、2−メチル−2−プロピル(t−Bu、t−ブチル、−C(CH3)3)、1−ペンチル(n−ペンチル、−CH2CH2CH2CH2CH3)、2−ペンチル(−CH(CH3)CH2CH2CH3)、3−ペンチル(−CH(CH2CH3)2)、2−メチル−2−ブチル(−C(CH3)2CH2CH3)、3−メチル−2−ブチル(−CH(CH3)CH(CH3)2)、3−メチル−1−ブチル(−CH2CH2CH(CH3)2)、2−メチル−1−ブチル(−CH2CH(CH3)CH2CH3)、1−ヘキシル(−CH2CH2CH2CH2CH2CH3)、2−ヘキシル(−CH(CH3)CH2CH2CH2CH3)、3−ヘキシル(−CH(CH2CH3)(CH2CH2CH3))、2−メチル−2−ペンチル(−C(CH3)2CH2CH2CH3)、3−メチル−2−ペンチル(−CH(CH3)CH(CH3)CH2CH3)、4−メチル−2−ペンチル(−CH(CH3)CH2CH(CH3)2)、3−メチル−3−ペンチル(−C(CH3)(CH2CH3)2)、2−メチル−3−ペンチル(−CH(CH2CH3)CH(CH3)2)、2,3−ジメチル−2−ブチル(−C(CH3)2CH(CH3)2)、3,3−ジメチル−2−ブチル(−CH(CH3)C(CH3)3)、1−ヘプチル、1−オクチルなどが挙げられる。
本発明は、Btkキナーゼによって調節される疾患、病態および/または障害の治療に潜在的に有用な、式Ia〜bfを含む式Iのピリドンおよびピラジノン化合物、およびその医薬製剤を提供する。
式中のR1は、
R4は、OH、CN、NRbRc、ピペリジニル、C1〜C6アルキルまたはC1〜C4ハロアルキルで適宜選択的に置換されるC3〜C6シクロアルキル、及び、OHまたはOC1〜C4アルキルで適宜選択的に置換されるC1〜C6アルキルから選択される。
R2は、H、CH3またはCF3であり;
環Bは、フェニル、少なくとも1個の窒素環原子を有する5〜6員のヘテロアリール、及び、少なくとも1個の窒素環原子を有する8〜11員のヘテロシクリルから選択され;
R3は、独立して、H、−Ra、−ORb、−SRb、−NRbRc、ハロ、シアノ、ニトロ、−CORb、−CO2Rb、−CONRbRc、−OCORb、−OCO2Ra、−OCONRbRc、−NRcCORb、−NRcCO2Ra、−NRcCONRbRc、−CO2Rb、−CONRbRc、−NRcCORb、−SORa、−SO2Ra、−SO2NRbRc、および−NRcSO2Raから選択されるか;または2つの隣接するR3基が、適宜選択的に一緒になって、O、SまたはNから選択される0〜2個のヘテロ原子を有する5〜6員環を形成すると共に環Bと融合する。
上記Raは、C1〜C6アルキル、シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリールである。ここで、Raの各メンバーが、1〜3個のR11基で適宜選択的に置換され;
Rbは、H、C1〜C6アルキル、シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリールであり、ここで、Hを除くRbの各メンバーは、1〜3個のR11基で適宜選択的に置換されてもよい。
Rcは、Hまたは1個若しくは3個のR11基で適宜選択的に置換されるC1〜C4アルキルであり;またはRbおよびRc、およびそれらが結合される窒素が、適宜選択的に置換されるヘテロシクロアルキル基を形成し;
各R11は、独立して、C1〜C4アルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、アリール−C1〜C4アルキル−、ヘテロアリール−C1〜C4アルキル−、シクロアルキル−C1〜C4アルキル−、ヘテロシクロアルキル−C1〜C4アルキル−、C1〜C4ハロアルキル−、−OC1〜C4アルキル、−O−ヘテロシクロアルキル、−OC1〜C4アルキルフェニル、−C1〜C4アルキル−OH、−OC1〜C4ハロアルキル、ハロ、−OH、−NH2、−C1〜C4アルキル−NH2、−NH(C1〜C4アルキル)、−N(C1〜C4アルキル)(C1〜C4アルキル)、−N(C1〜C4アルキル)(C1〜C4アルキルフェニル)、−NH(C1〜C4アルキルフェニル)、シアノ、ニトロ、オキソ、−CO2H、−C(O)OC1〜C4アルキル、−CON(C1〜C4アルキル)(C1〜C4アルキル)、−CONH(C1〜C4アルキル)、−CONH2、−NHC(O)(C1〜C4アルキル)、−NHC(O)(フェニル)、−N(C1〜C4アルキル)C(O)(C1〜C4アルキル)、−N(C1〜C4アルキル)C(O)(フェニル)、−C(O)C1〜C4アルキル、−C(O)C1〜C4フェニル、−C(O)C1〜C4ハロアルキル、−OC(O)C1〜C4アルキル、−SO2(C1〜C4アルキル)、−SO2(フェニル)、−SO2(C1〜C4ハロアルキル)、−SO2NH2、−SO2NH(C1〜C4アルキル)、−SO2NH(フェニル)、−NHSO2(C1〜C4アルキル)、−NHSO2(フェニル)、および−NHSO2(C1〜C4ハロアルキル)から選択される。
R5は、HまたはFであり;
R6は、H、CH3、F、Cl、CN、OCH3、OH、またはOH、OCH3もしくは1つ以上のハロ基で置換されるメチルであり;
R7は、H、CH3、F、Cl、CNまたはOCH3であり;
R8は、H、CH3、CF3、F、Cl、CNまたはOCH3であり;
Vは、CHまたはNであり;
各R9は、独立して、C1〜C3アルキルであり;
各R10は、独立して、HまたはCH3である。
酵素活性(または他の生物活性)を有する阻害剤としての式I化合物の相対的効力は、各化合物が所定の程度まで活性を阻害する濃度を測定し、次に結果を比較することによって確定することができる。典型的には、好ましい測定値は、生化学的アッセイにおいて活性の50%を阻害する濃度、すなわち、50%の抑制濃度または「IC50」である。当該技術分野における公知の従来技術を用いて、IC50値の測定を行うことができる。一般に、試験する様々な濃度範囲の阻害剤の存在下で、与えられた酵素の活性を測定することによって、IC50を測定することができる。次に、酵素活性の実験により得られた値が、使用される阻害剤の濃度に対してプロットされる。(阻害剤が全く存在しない場合の活性と比較して)50%の酵素活性を示す阻害剤の濃度が、IC50値とみなされる。同様に、他の抑制濃度は、活性の適切な測定によって規定することができる。例えば、ある設定においては、90%の抑制濃度、すなわち、IC90などを確定するのが望ましいことがある。
本発明の化合物は、治療される病態に適した任意の経路によって投与すればよい。好適な経路としては、経口、非経口(皮下、筋肉内、静脈内、動脈内、皮内、髄腔内および硬膜外を含む)、経皮、直腸、経鼻、局所(口腔および舌下を含む)、膣内、腹腔内、肺内および鼻腔内が挙げられる。局所的な免疫抑制療法では、化合物は、移植の前に、移植片に阻害剤を浸み込ませるか、または別の方法で移植片を阻害剤と接触させることを含む病巣内投与によって投与してもよい。好ましい経路は、例えば受容者の病態によって変わり得ることが理解されよう。化合物が経口投与される場合、薬学的に許容できる担体または賦形剤とともに、丸薬、カプセル剤、錠剤などとして製剤化してもよい。化合物が非経口投与される場合、以下に詳述するように、薬学的に許容できる非経口媒体とともに、および注射剤型の単位剤形で製剤化してもよい。
本発明の式I化合物は、免疫障害、心血管疾患、ウイルス感染、炎症、がん、代謝/内分泌障害または神経障害などの、Btkキナーゼに関連する異常な細胞増殖、機能または挙動から生じる疾患若しくは障害に罹患したヒト若しくは動物患者を治療するのに有用である。したがって、これらの疾患または障害は、上に定義される本発明の化合物を患者に投与することを含む方法によって治療することができる。がんに罹患したヒトまたは動物患者も、上に定義される本発明の化合物を患者に投与することを含む方法によって治療され得る。それによって、患者の病態は、好転または改善され得る。
ヒトを含む哺乳動物の治療処置に本発明の化合物を使用するために、本発明の化合物は、通常、医薬組成物としての標準的な薬務にしたがって製剤化される。本発明のこの態様によれば、薬学的に許容できる希釈剤または担体と共に、本発明の化合物を含む医薬組成物が提供される。
式I化合物は、単独で用いられるかあるいは炎症または過剰増殖性疾患(例えば、がん)などの、本明細書に記載された疾患または障害の治療のための、他の治療剤と併用されてもよい。特定の実施形態における式I化合物は、医薬的複合製剤中で、または併用療法としての投与計画中に、抗炎症性または抗過剰増殖性を有するかあるいは炎症、免疫応答障害、または過剰増殖性疾患(例えば、がん)を治療するのに有用な第2の治療用化合物と組み合わされる。第2の治療剤は、NSAID抗炎症剤であってもよい。第2の治療剤は、化学療法剤であってもよい。医薬的複合製剤または投与計画の第2の化合物は、好ましくは、互いに悪影響を与えないように式I化合物を補完する活性を有する。このような化合物は、意図した目的に有効な量で組み合わされて存在させることが好ましい。一実施形態において、本発明の組成物は、式Iの化合物、あるいはその立体異性体、互変異性体、溶媒和物、代謝産物、または薬学的に許容できる塩またはプロドラッグを、NSAIDなどの治療剤と組み合わせて含む。
本明細書に記載された式Iの生体内代謝産物も本発明の範囲内に含まれる。このような産物は、例えば、投与される化合物の酸化、還元、加水分解、アミド化、脱アミド化、エステル化、脱エステル化、酵素的切断などから得られる。したがって、本発明は、本発明の化合物を、その代謝産物を得るのに十分な期間にわたって哺乳動物と接触させることを含む方法によって生成される化合物を含む、式Iの化合物の代謝産物を含む。
本発明の別の実施形態においては、上述される疾患および障害の治療に有用な材料を含有する、製品、または「キット」が提供される。一実施形態におけるキットは、式Iの化合物、あるいはその立体異性体、互変異性体、溶媒和物、代謝産物、または薬学的に許容できる塩もしくはプロドラッグを含む容器を含む。キットは、容器上にまたは容器に付属するラベルまたは添付文書をさらに含むことができる。「添付文書」という用語は、治療製品の商品包装に通例含まれる説明書を指すのに使用され、このような治療製品の使用に関する、指示、使用法、用量、投与、禁忌および/または注意事項についての情報を含む。好適な容器としては、例えば、ボトル、バイアル、注射器、ブリスターパックなどが挙げられる。容器は、ガラスまたはプラスチックなどの様々な材料で形成されてもよい。容器は、病態を治療するのに有効な式I化合物またはその製剤を保持することができ、滅菌したアクセスポート(access port)を有し得る(例えば、容器は、皮下注射針によって突き刺し可能な栓を有する静脈注射用の溶液バッグまたはバイアルであってもよい。)。組成物中の少なくとも1種の活性剤が式Iの化合物である。ラベルまたは添付文書には、組成物が、がんなどの選択される病態を治療するのに使用されることが示される。さらに、ラベルまたは添付文書には、治療対象の患者が、過剰増殖性疾患、神経変性、心臓肥大、疼痛、片頭痛または神経外傷性の疾患もしくはイベントなどの障害を有する患者であることが示されてもよい。一実施形態においては、ラベルまたは添付文書に、式Iの化合物を含む組成物が、異常な細胞増殖から生じる障害を治療するのに使用され得ることが示される。ラベルまたは添付文書には、この組成物が、他の障害を治療するのに使用され得ることが示されてもよい。その代わりに、またはそれに加えて、製品は、注射用静菌水(BWFI)、リン酸緩衝生理食塩水、リンゲル液およびデキストロース溶液などの薬学的に許容できる緩衝剤を含む、第2の容器をさらに含むことができる。製品は、他の緩衝剤、希釈剤、フィルタ、針、および注射器を含む、商業上および使用者の観点から望ましい他の材料をさらに含むことができる。
式Iの化合物は、特に、本明細書に含まれる説明を考慮して、化学の技術分野で周知の方法、およびそれぞれ参照することにより明示的に援用される、Comprehensive Heterocyclic Chemistry II,Editors Katritzky and Rees,Elsevier,1997、例えばVolume 3;Liebigs Annalen der Chemie,(9):1910−16,(1985);Helvetica Chimica Acta,41:1052−60,(1958);Arzneimittel−Forschung,40(12):1328−31,(1990)に記載される他の複素環についての方法と同様の方法を含む合成経路によって合成することができる。出発材料は、一般に、Aldrich Chemicals(Milwaukee,WI)などの商業的供給源から入手可能であるか、または当業者に周知の方法を用いて容易に調製することができる(例えば、Louis F.Fieser and Mary Fieser,Reagents for Organic Synthesis,v.1−23,Wiley,N.Y.(1967−2006 ed.)、またはBeilsteins Handbuch der organischen Chemie,4,Aufl.ed.Springer−Verlag,Berlinに一般に記載される方法によって調製される(補足:Beilsteinのオンラインデータベースによっても入手可能なものを含む。)。
実施例101a 4−tert−ブチル−2−メチル安息香酸 101a
酸101i(97mg、0.16ミリモル)、ジイソプロピルエチルアミン(0.08mL、0.48ミリモル)が入ったDMF(5mL)を入れた25mLの丸底フラスコに、(ベンゾトリアゾール−1−イルオキシ)トリス(ジメチルアミノ)ホスホニウムヘキサフルオロホスフェート(84mg、0.19ミリモル)を加えた。反応物を室温で2時間撹拌した後、H2O(5mL)およびEtOAc(10mL)を加えた。有機相をHCl水溶液(1M、2×5mL)、H2O(5mL)、Na2CO3水溶液(1M、5mL)、塩水(5mL)で抽出し、Na2SO4を用いて乾燥し、濃縮した。残渣を、(勾配、0%〜100%の60:35:5のCH2Cl2:Et2O:MeOH/CH2Cl2)を用いてクロマトグラフィーにかけたところ、45mg(48%)で、101が得られた。
MH+(m/z):591.5。 1H NMR(300MHz、CDCl3)δ m;8.44(s,1H)、8.39(m,1H)、7.88(s,1H)、7.82(s,1H)、7.39〜7.49(m,5H)、7.31〜7.35(,2H)、7.07(d,J=7.5Hz,1H)、6.81(s,1H)、6.58(d,J=7.5Hz,1H)、3.69(broad s,6H)、3.62(s,3H)、3.07(m,1H)、2.21(s,3H)、1.35(s,3H)、1.33(s,3H);MS(ESI+)m/z (M+H)590.58。
実施例102a メチル3−メチルチオフェン−2−カルボキシレート 102a
磁気撹拌器を備えた10mLの一口丸底フラスコに窒素をパージし、102l(270mg、0.39ミリモル)、メタノール(6mL)、および、HClの4Mジオキサン溶液(6mL)を入れ、混合物を2時間撹拌した。この後、酢酸エチル(60mL)および水(60mL)を加えた。10%の炭酸カリウム水溶液を用いてpHを6.5に調整した。水層を分離し、酢酸エチル(2×75mL)で抽出した。一緒にした有機層を、塩水(60mL)で洗浄し、硫酸ナトリウム上で乾燥した。乾燥剤をろ過によって除去した。ろ液を減圧下で濃縮して残渣を得、それをカラムクロマトグラフィーによって精製したところ、36%の収率(83mg)で、102がオフホワイトの固体として得られた:融点164〜166℃;1H NMR(500MHz、DMSO−d6)δ 9.17(s,1H)、7.90(d,2H,J=5.1Hz)、7.41(t,2H,J=8.0Hz)、7.33(t,1H,J=7.5Hz)、7.22(d,3H,J=9.5Hz)、7.14(s,1H)、4.77(s,2H)、4.29(s,1H)、3.56(s,3H)、3.38(m,1H)、3.24(m,1H)、2.97〜2.86(m,3H)、2.84(s,3H)、2.23(s,3H)、1.42(9H);MS(ESI+)m/z 597.2(M+H)。
実施例103a 4−tert−ブチル−N,N−ジエチル−2−ホルミルベンズアミド 103a
還流冷却器、磁気撹拌器および窒素導入口を備えた25mLの三つ口丸底フラスコに、103f(444mg、0.99ミリモル)、103l(258mg、0.76ミリモル)、炭酸ナトリウム(242mg、2.29ミリモル)、DMF(5mL)、水(2.5mL)および1,4−ジオキサン(8mL)を入れた。得られた懸濁液に窒素を通して30分間バブリングした後、テトラキス(トリフェニルホスフィン)パラジウム(0)(89mg、0.076ミリモル)を加え、反応混合物を14時間還流状態で加熱した。この後、混合物を室温に冷まし、酢酸エチル(100mL)および水(30mL)で希釈した。有機層を分離し、水層を酢酸エチル(3×25mL)で抽出した。一緒にした有機層を硫酸ナトリウム上で乾燥し、濃縮した。残渣をカラムクロマトグラフィー(シリカ、0%〜10%のメタノール/塩化メチレン)によって精製したところ、50%の収率(210mg)で、103がオフホワイトの固体として得られた:146〜147℃;1H NMR(500MHz、DMSO−d6)δ 8.11(s,1H)、7.98(d,1H,J=2.3Hz)、7.72(m,2H)、7.61(m,1H)、7.48(m,1H)、7.41(m,1H)、7.35(m,1H)、7.23(d,1H,J=2.2Hz)、5.87(s,1H)、4.93(s,2H)、4.88(t,1H,J=5.1Hz)、4.34(d,2H,J=5.0Hz)、3.91(t,2H,J=4.9Hz)、3.57(s,3H)、3.48(s,2H)、2.77(t,2H,J=5.1Hz)、2.34(s,3H)、1.37(s,9H);MS(ESI+)m/z 553.2(M+H)。
実施例104a 3−(4−ニトロフェニル)−5,6−ジヒドロピラジン−2(1H)−オン 104a
磁気撹拌器を備えた5mLの反応管に、104d(65mg、0.166ミリモル)、102g(68mg、0.166ミリモル)、炭酸ナトリウム(53mg、0.498ミリモル)、ジオキサン(1.0mL)および水(0.2mL)を入れた。この混合物を、窒素を用いて30分間脱気した。テトラキス(トリフェニルホスフィン)パラジウム(19mg、0.017ミリモル)を加え、管を密閉した。110℃(浴温度)で16時間加熱した後、反応混合物を室温に冷まし、濃縮して残渣を得た。得られた残渣を、シリカゲルを用いたフラッシュクロマトグラフィーによって精製した。この材料を、分取HPLCを用いてさらに精製したところ、13%の収率(12.5mg)で、104が黄色の固体として得られた:融点174〜176℃ dec;1H NMR(500MHz、DMSO−d6)δ 9.19(s,1H)、7.91(d,2H,J=8.5Hz)、7.82(d,1H,J=4.5Hz)、7.43(t,2H,J=8.0Hz)、7.34(t,1H,J=7.8Hz)、7.22(s,1H)、7.19(d,2H,J=8.5Hz)、7.14(s,1H)、4.78(s,2H)、3.55(s,3H)、3.52(s,1H)、3.40(td,1H,J=11.0,3.5Hz)、3.13(m,1H)、2.90(dd,1H,J=6.0,3.0Hz)、2.47(m,1H)、2.24(s,3H)、2.05(s,3H)、1.42(s,9H);MS(ESI+)m/z 597.7(M+H)。
実施例105a 5−ブロモ−3−(1,5−ジメチル−1H−ピラゾール−3−イルアミノ)−1−メチルピリジン−2(1H)−オン 105a
磁気撹拌器および還流冷却器を備えた100mLの三つ口丸底フラスコに、103f(556mg、1.20ミリモル)、105a(300mg、1.00ミリモル)、炭酸ナトリウム(424mg、4.00ミリモル)、水(4mL)および1,4−ジオキサン(20mL)を入れた。得られた溶液に窒素を通して20分間バブリングした後、テトラキス(トリフェニルホスフィン)−パラジウム(0)(115mg、0.100ミリモル)を加え、反応混合物を100℃で4時間加熱した。この後、反応混合物を室温に冷まし、ろ過し、ろ過ケーキを、メタノールと塩化メチレンとの1:10の混合液(30mL)で洗浄した。ろ液を減圧下で濃縮したところ、褐色の残渣が得られた。磁気撹拌器および還流冷却器を備えた別の100mLの一口丸底フラスコに、上で得られた残渣、THF(5mL)、エタノール(5mL)、水(5mL)および水酸化リチウム(86.4mg、3.60ミリモル)を入れた。混合物を50℃で2時間撹拌した。この後、反応混合物を減圧下で濃縮した。得られた残渣を、フラッシュクロマトグラフィーによって精製したところ、35%(190mg)の収率で、105が白色の固体として得られた:融点225〜227℃;1H NMR(500MHz、DMSO−d6)δ 7.94(s,2H)、7.72(d,1H,J=7.5Hz)、7.71(s,1H)、7.61(d,1H,J=7.5Hz)、7.48(t,1H,J=7.5Hz)、7.42(d,1H,J=7.5Hz)、7.36(d,1H,J=7.5Hz)、7.22(s,1H)、5.88(s,1H)、4.89(s,2H)、4.88(t,1H,J=4.5Hz)、4.35(d,2H,J=4.5Hz)、3.57(s,3H)、3.56(s,3H)、2.17(s,3H)、1.36(s,9H);MS(ESI+)m/z 512.3(M+H)。
実施例106a 5−ブロモ−3−(1−エチル−1H−ピラゾール−3−イルアミノ)−1−メチルピリジン−2(1H)−オン 106a
105についての記載と同様の一般的な手順にしたがって、103f(556mg、1.20ミリモル)と、106a(300mg、1.00ミリモル)との反応により、20%(101mg)の収率で、106を白色の固体として得た:融点175〜177℃;1H NMR(500MHz、DMSO−d6)δ 8.07(s,1H)、8.01(d,1H,J=2.0Hz)、7.73(d,1H,J=7.5Hz)、7.71(s,1H)、7.62(dd,1H,J=8.0,1.0Hz)、7.52(d,1H,J=2.5Hz)、7.49(t,1H,J=7.5Hz)、7.42(dd,1H,J=7.5,1.0Hz)、7.36(dd,1H,J=7.5,1.0Hz)、7.25(d,1H,J=2.0Hz)、6.06(d,1H,J=2.0Hz)、4.94(s,2H)、4.89(t,1H,J=5.0Hz)、4.35(d,2H,J=5.0Hz)、3.98(q,2H,J=7.5Hz)、3.58(s,3H)、1.37(s,9H)、1.31(t,3H,J=7.5Hz);MS(ESI+)m/z 512.3(M+H)。
実施例107a 5−ブロモ−1−メチル−3−(ピリミジン−4−イルアミノ)ピリジン−2(1H)−オン 107a
実施例105と同じ一般的な手順を用いて、107a(250mg、0.889ミリモル)と103f(495mg、1.07ミリモル)との反応により、38%の収率(166mg)で、107が非晶質のオフホワイトの固体として得られた:融点216〜218℃;1H NMR(500MHz、DMSO−d6)δ 9.18(s,1H)、8.72(d,J=2.0Hz,1H)、8.65(s,1H)、8.30(d,J=5.5Hz,1H)、7.73(d,J=8.5Hz,2H)、7.62(dd,J=8.0,1.5Hz,1H)、7.54(d,J=2.0Hz,1H)、7.51(t,J=7.5Hz,1H)、7.46(dd,J=7.5,1.0Hz,1H)、7.40(dd,J=7.5,1.5Hz,1H)、7.32(dd,J=6.0,1.0Hz,1H)、4.95(s,2H)、4.92(t,J=4.5Hz,1H)、4.34(d,J=5.0Hz,2H)、3.61(s,3H)、1.37(s,9H);MS(ESI+)m/z 496.2(M+H)。
実施例108a 5−ブロモ−1−メチル−3−(4−モルホリノフェニルアミノ)ピラジン−2(1H)−オン108a
実施例105と同じ一般的な手順を用いて、108a(296mg、0.810ミリモル)と103f(413mg、0.891ミリモル)との反応により、47%の収率(205mg)で、108を非晶質の黄色の固体として得た:融点225〜227℃;1H NMR(500MHz、DMSO−d6)δ 9.08(s,1H)、7.83(d,J=9.0Hz,2H)、7.73(d,J=8.5Hz,2H)、7.62(dd,J=8.0,1.5Hz,1H)、7.58(dd,J=8.0,1.5Hz,1H)、7.50(t,J=7.5Hz,1H)、7.42(dd,J=8.0,1.0Hz,1H)、7.34(s,1H)、6.89(d,J=9.0Hz,2H)、4.92(s,2H)、4.83(t,J=5.0Hz,1H)、4.43(d,J=5.0Hz,2H)、3.72(t,J=5.5Hz,4H)、3.54(s,3H)、3.03(t,J=5.5Hz,4H)、1.37(s,9H);MS(ESI+)m/z 580.3(M+H)。
実施例109a 1−シクロプロピル−4−ニトロ−1H−ピラゾール 109a
実施例105と同じ一般的な手順を用いて、109c(310mg、1.00ミリモル)と103f(536mg、1.20ミリモル)との反応により、35%の収率(184mg)で、109をオフホワイトの固体として得た:融点218〜219℃;1H NMR(500MHz、DMSO−d6)δ 9.58(s,1H)、8.20(s,1H)、7.73(m,3H)、7.61(m,2H)、7.51(t,1H,J=7.9Hz)、7.43(m,1H)、7.31(s,1H)、4.95(s,2H)、4.90(t,1H,J=5.0Hz)、4.48(d,2H,J=5.0Hz)、3.64(m,1H)、3.52(s,3H)、1.37(s,9H)、0.93(m,4H);MS(ESI+)m/z 525.2(M+H)。
実施例110a 5−ブロモ−3−(3−シクロプロピル−1H−ピラゾール−5−イルアミノ)−1−メチルピリジン−2(1H)−オン 110a
実施例105と同じ一般的な手順を用いて、110a(260mg、0.841ミリモル)と103f(429mg、0.926ミリモル)との反応により、33%の収率(144mg)で、110をオフホワイトの固体として得た:融点178〜180℃;1H NMR(500MHz、DMSO−d6)δ 11.76(d,1H,J=2.0Hz)、7.98(d,1H,J=2.0Hz)、7.92(s,1H)、7.71(m,2H)、7.61(dd,1H,J=7.9,1.6Hz)、7.48(m,1H)、7.42(dd,1H,J=7.6,1.1Hz)、7.35(dd,1H,J=7.6,1.1Hz)、7.23(d,1H,J=2.1Hz)、5.79(d,1H,J=2.2Hz)、4.93(s,2H)、4.90(t,1H,J=4.9Hz)、4.35(d,2H,J=4.6Hz)、3.57(s,3H)、1.81(m,1H)、1.37(s,9H)、0.89(m,2H)、0.64(m,2H);MS(ESI+)m/z 524.2(M+H)。
実施例111a 1−エチル−4−ニトロ−1H−ピラゾール 111a
実施例105と同じ一般的な手順を用いて、111c(253mg、0.85ミリモル)と103f(473mg、1.02ミリモル)との反応により、48%の収率(210mg)で、111をオフホワイトの固体として得た:融点138〜140℃;1H NMR(500MHz、DMSO−d6)δ 9.57(s,1H)、8.17(s,1H)、7.72(m,3H)、7.61(m,2H)、7.51(t,1H,J=7.6Hz)、7.43(m,1H)、7.31(s,1H)、4.94(s,2H)、4.88(t,1H,J=5.0Hz)、4.49(d,2H,J=5.0Hz)、4.06(q,2H,J=7.1Hz)、3.52(s,3H)、1.37(s,9H)、1.33(t,3H,J=7.2Hz);MS(ESI+)m/z 513.2(M+H)。
実施例112a 5−ブロモ−1−メチル−3−(ピリジン−3−イルアミノ)ピラジン−2(1H)−オン 112a
磁気撹拌器および還流冷却器を備えた100mLの一口丸底フラスコに窒素をパージし、103f(298mg、0.643ミリモル)、112a(150mg、0.536ミリモル)、炭酸ナトリウム(170mg、1.61ミリモル)、1,4−ジオキサン(5mL)および水(1mL)を入れた。この混合物を、窒素を用いて30分間脱気した。テトラキス(トリフェニルホスフィン)パラジウム(62mg、0.054ミリモル)を加えた。100℃で3時間加熱した後、反応混合物を室温に冷まし、水(40mL)と塩化メチレン(100mL)とに分液した。層を分離し、水相を塩化メチレン(2×50mL)で抽出した。有機抽出物を一緒にして、硫酸ナトリウム上で乾燥し、ろ過し、減圧下で濃縮した。得られた残渣をメタノール(5mL)に溶解した混合物に、炭酸カリウム(500mg、3.62ミリモル)を加えた。室温で2時間撹拌した後、反応混合物を水(20mL)と塩化メチレン(20mL)とに分液した。層を分離し、水相を塩化メチレン(2×20mL)で抽出した。有機抽出物を一緒にして硫酸ナトリウム上で乾燥し、ろ過し、減圧下で濃縮した。得られた残渣を、フラッシュクロマトグラフィーによって精製したところ、27%の収率(70mg)で、112がオフホワイトの固体として得られた:融点149〜150℃;1H NMR(500MHz、DMSO−d6)δ 9.54(s,1H)、9.14(d,1H,J=2.0Hz)、8.44(m,1H)、8.18(dd,1H,J=5.0,1.5Hz)、7.73〜7.71(m,2H)、7.63〜7.59(m,2H)、7.52(t,1H,J=8.0Hz)、7.48(s,1H)、7.44(dd,1H,J=8.0,1.5Hz)、7.30(dd,1H,J=7.5,4.5Hz)、4.93(s,2H)、4.88(t,1H,J=5.0Hz)、4.44(d,2H,J=5.0Hz)、3.56(s,3H)、1.37(s,9H);MS(ESI+)m/z 496.2(M+H)。
実施例113a 5−ブロモ−1−メチル−3−(ピリジン−2−イルアミノ)ピリジン−2(1H)−オン 113a
105の調製についての記載と同様の一般的な手順を用いて、103f(298mg、0.643ミリモル)と113a(150mg、0.536ミリモル)との反応により、34%の収率(90mg)で、113を白色の固体として得た:融点138〜139℃;1H NMR(500MHz、DMSO−d6)δ 8.68(d,1H,J=2.0Hz)、8.58(s,1H)、8.17(m,1H)、7.73〜7.71(m,2H)、7.62〜7.56(m,2H)、7.50(t,1H,J=7.5Hz)、7.44(d,1H,J=7.5Hz)、7.39〜7.37(m,2H)、7.28(d,1H,J=7.5Hz)、6.78(dd,1H,J=6.5,5.0Hz)、4.94(s,2H)、4.89(t,1H,J=4.5Hz)、4.34(d,2H,J=4.5Hz)、3.60(s,3H)、1.65(s,9H);MS(ESI+)m/z 495.2(M+H)。
実施例114a 1−ブロモ−2−(ブロモメチル)−3−ニトロベンゼン 114a
磁気撹拌器および還流冷却器を備えた100mLの一口丸底フラスコに窒素をパージし、114i(264mg、0.563ミリモル)、103 l(190mg、0.563ミリモル)、炭酸ナトリウム(179mg、1.69ミリモル)、1,4−ジオキサン(5mL)および水(1mL)を入れた。この混合物を、窒素を用いて30分間脱気した。テトラキス(トリフェニルホスフィン)パラジウム(65mg、0.056ミリモル)を加えた。3時間還流状態で加熱した後、反応混合物を室温に冷まし、水(40mL)と塩化メチレン(100mL)とに分液した。層を分離し、水相を塩化メチレン(2×50mL)で抽出した。有機抽出物を一緒にして硫酸ナトリウム上で乾燥し、ろ過し、減圧下で濃縮した。得られた残渣をメタノール(5mL)に溶解させた混合物に、炭酸カリウム(500mg、3.62ミリモル)を加えた。室温で2時間撹拌した後、反応混合物を水(20mL)と塩化メチレン(20mL)とに分液した。層を分離し、水相を塩化メチレン(2×20mL)で抽出した。有機抽出物を一緒にして、硫酸ナトリウム上で乾燥し、ろ過し、減圧下で濃縮した。得られた残渣を、フラッシュクロマトグラフィーによって精製したところ、18%の収率(57mg)で、114がオフホワイトの固体として得られた:融点164〜165℃;1H NMR(500MHz、DMSO−d6)δ 8.10(s,1H)、7.97(d,1H,J=2.5Hz)、7.46(t,1H,J=8.0Hz)、7.39(dd,1H,J=8.0,1.5Hz)、7.34(dd,1H,J=8.0,1.5Hz)、7.22(d,1H,J=2.5Hz)、7.15(s,1H)、5.87(s,1H)、4.89(t,1H,J=4.5Hz)、4.84(s,2H)、4.34(d,2H,J=4.5Hz)、3.91(t,2H,J=5.0Hz)、3.57(s,3H)、3.48(s,2H)、2.77(t,2H,J=5.0Hz)、2.36(s,3H)、1.42(s,9H);MS(APCI+)m/z 559.4(M+H)。
実施例115a 5−ブロモ−3−(1−シクロプロピル−1H−ピラゾール−3−イルアミノ)−1−メチルピリジン−2(1H)−オン 115a
還流冷却器、磁気撹拌器および窒素導入口を備えた50mLの三つ口丸底フラスコに、115a(263mg、0.850ミリモル)、103f(473mg、1.02ミリモル)、炭酸ナトリウム(270mg、2.55ミリモル)、DMF(5mL)、水(2.5mL)および1,4−ジオキサン(8mL)を入れた。得られた懸濁液に窒素を通して30分間バブリングした後、テトラキス(トリフェニルホスフィン)パラジウム(0)(98mg、0.085ミリモル)を加え、反応混合物を14時間還流状態で加熱した。この後、混合物を室温に冷まし、酢酸エチル(150mL)および水(30mL)で希釈した。有機層を分離し、水層を酢酸エチル(3×150mL)で抽出した。一緒にした有機層を硫酸ナトリウム上で乾燥し、減圧下で濃縮した。残渣を、THF(8mL)と、メタノール(4mL)と、水(4mL)との混合液に溶解させた。得られた溶液に、水酸化リチウム一水和物(420mg、10.0ミリモル)を加えた。混合物を室温で4時間撹拌してから、真空中で濃縮した。残渣を酢酸エチル(150mL)と水(30mL)とに分液した。有機層を分離し、水層を、メタノールの20%塩化メチレン(v/v)溶液(3×150mL)で抽出した。一緒にした有機層を硫酸ナトリウム上で乾燥し、減圧下で濃縮した。残渣をカラムクロマトグラフィー(シリカ、0%〜10%のメタノール/塩化メチレン)によって精製したところ、39%の収率(175mg)で、115がオフホワイトの固体として得られた:融点173〜175℃;1H NMR(500MHz、DMSO−d6)δ 8.10(s,1H)、8.08(d,1H,J=2.5Hz)、7.71(m,2H)、7.61(dd,1H,J=7.9,1.5Hz)、7.55(d,1H,J=2.5Hz)、7.50(m,1H)、7.43(dd,1H,J=7.9,1.5Hz)、7.38(dd,1H,J=8.0,1.5Hz)、7.25(d,1H,J=2.1Hz)、6.06(d,1H,J=2.4Hz)、4.94(s,2H)、4.89(t,1H,J=4.5Hz)、4.35(d,2H,J=4.5Hz)、3.58(s,3H)、3.54(m,1H)、1.37(s,9H)、0.96(m,2H)、0.87(m,2H);MS(ESI+)m/z 524.2(M+H)。
実施例116a 1−メチル−3−(ピリミジン−4−イルアミノ)−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ピリジン−2(1H)−オン 116a
1H NMR(300MHz、CDCl3)δ 7.39(d,1H,J=5.0Hz)、7.11(d,1H,J=5.1Hz)、4.85(s,2H)、3.83(s,3H)。
還流冷却器、磁気撹拌器および窒素導入口を備えた50mLの三つ口丸底フラスコに、116h(124mg、0.300ミリモル)、116a(100mg、0.300ミリモル)、炭酸ナトリウム(95mg、0.900ミリモル)、DMF(2.5mL)、水(1.2mL)および1,4−ジオキサン(4mL)を入れた。得られた懸濁液に窒素を通して30分間バブリングした後、テトラキス(トリフェニルホスフィン)パラジウム(0)(35mg、0.003ミリモル)を加え、反応混合物を14時間還流状態で加熱した。この後、混合物を室温に冷まし、メタノール(2mL)、水(2mL)および水酸化リチウム一水和物(42mg、1.00ミリモル)を加えた。混合物を室温で4時間撹拌してから、真空中で濃縮した。残渣を酢酸エチル(150mL)と水(30mL)とに分液した。有機層を分離し、水層を、メタノールの20%(v/v)塩化メチレン溶液(3×150mL)で抽出した。一緒にした有機層を硫酸ナトリウム上で乾燥し、減圧下で濃縮した。残渣をカラムクロマトグラフィー(シリカ、0%〜10%のメタノール/塩化メチレン)によって精製したところ、22%の収率(32mg)で、116がオフホワイトの固体として得られた:融点140〜141℃;1H NMR(500MHz、DMSO−d6)δ 9.17(s,1H)、8.70(d,1H,J=1.1Hz)、8.64(s,1H)、8.29(d,1H,J=5.8Hz)、7.52(d,1H,J=2.5Hz)、7.48(m,1H)、7.43(m,1H)、7.38(m,1H)、7.31(dd,1H,J=5.9,1.1Hz)、7.04(s,1H)、4.91(t,1H,J=5.0Hz)、4.83(s,2H)、4.34(d,2H,J=5.0Hz)、3.60(s,3H)、2.29(m,1H)、1.12(m,2H)、0.82(m,2H);MS(ESI+)m/z 486.2(M+H)。
実施例117a tert−ブチル3−(6−クロロピリジン−3−イル)アゼチジン−1−カルボキシレート 117a
磁気撹拌器を備えた100mLの一口丸底フラスコに、117e(495mg、0.761ミリモル)、塩化メチレン(3mL)およびトリフルオロ酢酸(3mL)を入れ、混合物を室温で3時間撹拌した。この後、反応混合物を濃縮し、得られた残渣を10%の炭酸カリウム水溶液(10mL)と塩化メチレン(20mL)とに分液した。層を分離し、水相を塩化メチレン(20mL)で抽出した。有機抽出物を一緒にして、硫酸ナトリウム上で乾燥し、ろ過し、溶媒を減圧下で除去した。得られた残渣をカラムクロマトグラフィーによって精製したところ、25%の収率(104mg)で、117が白色の固体として得られた:融点185〜186℃;1H NMR(500MHz、DMSO−d6)δ 8.66(s,1H)、8.54(s,1H)、8.10(s,1H)、7.71(d,2H,J=8.5Hz)、7.66(d,1H,J=8.5Hz)、7.61(d,1H,J=8.0Hz)、7.49(t,1H,J=8.0Hz)、7.44(d,1H,J=6.5Hz)、7.37(m,2H)、7.28(d,1H,J=8.5Hz)、4.94(s,2H)、4.88(t,1H,J=4.5Hz)、4.34(d,2H,J=4.5Hz)、3.71(m,3H)、3.59(s,3H)、3.54(m,2H)、1.33(s,9H);MS(ESI+)m/z 550.2(M+H)。
実施例118 5−tert−ブチル−2−(2−(ヒドロキシメチル)−3−(1−メチル−5−(5−(1−メチルアゼチジン−3−イル)ピリジン−2−イルアミノ)−6−オキソ−1,6−ジヒドロピリジン−3−イル)フェニル)イソインドリン−1−オン 118
磁気撹拌器を備えた150mLの一口丸底フラスコに、窒素をパージし、117(72mg、0.130ミリモル)、ホルムアルデヒド(5mg、0.170ミリモル)の37%水溶液、および無水メタノール(5mL)を入れた。無水メタノール(2.5mL)にシアノ水素化ホウ素ナトリウム(25mg、0.400ミリモル)および無水塩化亜鉛(27mg、0.200ミリモル)が入った懸濁液を加え、反応物を室温で5時間撹拌した。この後、反応混合物を濃縮し、10%の炭酸カリウム水溶液(5mL)を加えた。得られた懸濁液をろ過し、ろ過ケーキを水(2mL)で洗浄した。ろ過ケーキを、カラムクロマトグラフィーによって精製したところ、64%の収率(56mg)で、118が白色の固体として得られた:融点201〜202℃;1H NMR(500MHz、DMSO−d6)δ 8.66(s,1H)、8.54(s,1H)、8.11(s,1H)、7.72(d,2H,J=8.5Hz)、7.64(m,2H)、7.49(t,1H,J=8.0Hz)、7.44(d,1H,J=6.5Hz)、7.37(m,2H)、7.27(d,1H,J=8.5Hz)、4.94(s,2H)、4.88(t,1H,J=4.5Hz)、4.34(d,2H,J=4.5Hz)、3.59(s,3H)、3.54(t,2H,J=7.0Hz)、3.45(m,1H)、3.01(t,2H,J=6.5Hz)、2.24(s,3H)、1.36(s,9H);MS(ESI+)m/z 564.3(M+H)。
実施例119a 1−(2−(tert−ブチルジメチルシリルオキシ)エチル)−3−ニトロ−1H−ピラゾール 119a
114の調製についての記載と同様の一般的な手順を用いて、119c(200mg、0.469ミリモル)と103f(261mg、0.563ミリモル)との反応により、34%の収率(83mg)で、119をオフホワイトの固体として得た:融点198〜199℃;1H NMR(500MHz、DMSO−d6)δ 8.07(s,1H)、8.00(d,1H,J=2.5Hz)、7.73〜7.71(m,2H)、7.61(dd,1H,J=8.0,1.5Hz)、7.50〜7.47(m,2H)、7.42(dd,1H,J=8.0,1.5Hz)、7.37(dd,1H,J=8.0,1.5Hz)、7.24(d,1H,J=2.5Hz)、6.06(d,1H,J=2.5Hz)、4.94(s,2H)、4.89(t,1H,J=5.0Hz)、4.78(t,1H,J=5.0Hz)、4.35(d,2H,J=9.5Hz)、3.99(t,2H,J=5.5Hz)、3.67(q,2H,J=5.5Hz)、3.58(s,3H)、1.37(s,9H);MS(ESI+)m/z 528.3(M+H)。
実施例120a 1−(6−ニトロピリジン−3−イル)アゼチジン−3−オール 120a
磁気撹拌器および還流冷却器を備えた100mLの一口丸底フラスコに窒素をパージし、120c(215mg、0.613ミリモル)、103f(340mg、0.735ミリモル)、炭酸ナトリウム(195mg、1.84ミリモル)、1,4−ジオキサン(8mL)および水(2mL)を入れた。この混合物を、窒素を用いて30分間脱気した。テトラキス(トリフェニルホスフィン)パラジウム(71mg、0.061ミリモル)を加えた。100℃で3時間加熱した後、反応混合物を室温に冷まし、水(40mL)と塩化メチレン(100mL)とに分液した。層を分離し、水相を塩化メチレン(2×50mL)で抽出した。有機抽出物を一緒にして、硫酸ナトリウム上で乾燥し、ろ過し、減圧下で濃縮した。得られた残渣をメタノール(5mL)に溶解させ、炭酸カリウム(500mg、3.62ミリモル)を加えた。室温で2時間撹拌した後、反応混合物を水(20mL)と塩化メチレン(20mL)とに分液した。層を分離し、水相を塩化メチレン(2×20mL)で抽出した。有機抽出物を一緒にして、硫酸ナトリウム上で乾燥し、ろ過し、減圧下で濃縮した。得られた残渣を、フラッシュクロマトグラフィーによって精製したところ、21%の収率(72mg)で、120がオフホワイトの固体として得られた:>250℃;1H NMR(500MHz、DMSO−d6)δ 8.48(s,1H)、8.25(d,1H,J=2.0Hz)、7.73〜7.71(m,2H)、7.62(d,1H,J=8.5Hz)、7.51〜7.42(m,3H)、7.36(d,1H,J=7.5Hz)、7.28(d,1H,J=2.0Hz)、7.17(d,1H,J=9.0Hz)、6.87(dd,1H,J=9.0,3.0Hz)、5.56(d,1H,J=6.5Hz)、4.94(s,2H)、4.88(t,1H,J=5.0Hz)、4.54(m,1H)、4.33(d,2H,J=5.0Hz)、4.02(t,2H,J=7.0Hz)、3.58(s,3H)、3.43(t,2H,J=7.0Hz)、1.36(s,9H);MS(ESI+)m/z 566.3(M+H)。
実施例121a tert−ブチル4−(6−ニトロピリジン−3−イル)−3−オキソピペラジン−1−カルボキシレート 121a
磁気撹拌器および還流冷却器を備えた100mLの三つ口丸底フラスコに、121c(477mg、1.00ミリモル)、103f(463mg、1.00ミリモル)、炭酸ナトリウム(424mg、4.00ミリモル)、水(4mL)および1,4−ジオキサン(20mL)を入れた。得られた懸濁液に窒素を通して20分間バブリングした後、テトラキス(トリフェニルホスフィン)−パラジウム(0)(115mg、0.100ミリモル)を加え、反応混合物を100℃で4時間加熱した。この後、反応混合物を室温に冷ましてからろ過し、ろ過ケーキを、メタノールと塩化メチレンとの1:10の混合物(30mL)で洗浄した。ろ液を減圧下で濃縮したところ、褐色の残渣が得られた。
実施例122a 5−ブロモ−1−メチル−3−ニトロピリジン−2(1H)−オン 122a
磁気撹拌器、窒素導入口および還流冷却器を備えた100mLの三つ口丸底フラスコに、122d(550mg、1.19ミリモル)、122e(255mg、1.19ミリモル)、炭酸セシウム(860mg、2.64ミリモル)および1,4−ジオキサン(20mL)を入れた。得られた混合物に窒素を通して20分間バブリングした後、キサントホス(59.0mg、0.102ミリモル)およびトリス(ジベンジリデンアセトン)ジパラジウム(0)(55.0mg、0.06ミリモル)を加え、反応混合物を5時間還流状態で加熱した。この後、反応物を室温に冷まし、ろ過し、減圧下で濃縮したところ、褐色の残渣が得られた。磁気撹拌器および還流冷却器を備えた別の100mLの一口丸底フラスコに、上で得られた残渣、THF(10mL)、エタノール(10mL)、水(10mL)および水酸化リチウム(115mg、4.80ミリモル)を入れた。混合物を50℃で2時間撹拌した。この後、反応混合物を減圧下で濃縮した。得られた残渣を、フラッシュクロマトグラフィーによって精製したところ、23%(165mg)の収率で、122が白色の固体として得られた:融点171〜172℃;1H NMR(500MHz、DMSO−d6)δ 8.66(d,1H,J=2.0Hz)、8.57(s,1H)、7.72(d,1H,J=8.5Hz)、7.71(s,1H)、7.61(d,1H,J=8.0,1.5Hz)、7.54(d,1H,J=9.5Hz)、7.50(t,1H,J=8.0Hz)、7.45(dd,1H,J=8.0,1.5Hz)、7.38〜7.36(m,2H)、7.30(d,1H,J=9.5Hz)、4.94(s,2H)、4.84(t,1H,J=5.0Hz)、4.34(d,2H,J=5.0Hz)、3.60(s,3H)、3.41(t,4H、J=5.0Hz)、2.39(t,4H、J=5.0Hz)、2.20(s,3H)、1.36(s,9H);MS(ESI+)m/z 594.3(M+H)。
実施例123a メチル2−シアノ−4−フルオロベンゾエート 123a
1H NMR(500MHz、CDCl3)δ 8.18(dd,1H,J=9.0,5.5Hz)、7.50(dd,1H,J=8.0,2.5Hz)、7.38(m,1H)、4.01(s,3H)。
103の調製についての記載と同様の一般的な手順を用いて、123e(450mg、1.00ミリモル)と103 l(260mg、0.800ミリモル)との反応と、その後の加水分解により、24%の収率(130mg)で、123を白色の固体として得た:融点148〜150℃;1H NMR(500MHz、DMSO−d6)δ 8.09(s,1H)、7.98(d,1H,J=2.0Hz)、7.56(d,1H,J=8.0Hz)、7.47(t,1H,J=8.0Hz)、7.39(dd,1H,J=8.0,1.5Hz)、7.33(dd,1H,J=8.0,1.5Hz)、7.24(d,1H,J=2.0Hz)、6.88〜6.85(m,2H)、5.88(s,1H)、4.89(t,1H,J=5.0Hz)、4.85(s,2H)、4.31(d,2H,J=5.0Hz)、3.91(t,2H,J=5.5Hz)、3.59(s,3H)、3.48(s,2H)、3.04(s,6H)、2.77(t,2H,J=5.5Hz)、2.34(s,3H);MS(ESI+)m/z 540.3(M+H)。
実施例124 5−(ジメチルアミノ)−2−(2−(ヒドロキシメチル)−3−(1−メチル−6−オキソ−5−(ピリミジン−4−イルアミノ)−1,6−ジヒドロピリジン−3−イル)フェニル)イソインドリン−1−オン 124
104の調製についての記載と同様の一般的な手順を用いて、123e(400mg、0.890ミリモル)と107a(207mg、0.740ミリモル)との反応と、その後の加水分解により、28%の収率(120mg)で、124を白色の固体として得た:融点206〜208℃;1H NMR(500MHz、DMSO−d6)δ 9.17(s,1H)、8.73(d,1H,J=2.0Hz)、8.65(s,1H)、8.30(d,1H,J=6.0Hz)、7.57(d,1H,J=8.5Hz)、7.55(d,1H,J=2.5Hz)、7.49(t,1H,J=2.5Hz)、7.43(dd,1H,J=8.0,1.5Hz)、7.37(dd,1H,J=8.0,1.5Hz)、7.31(dd,1H,J=6.0,1.5Hz)、6.88〜6.85(m,2H)、4.94(t,1H,J=4.5Hz)、4.86(s,2H)、4.32(d,2H,J=4.5Hz)、3.61(s,3H)、3.04(s,6H);MS(ESI+)m/z 483.2(M+H)。
実施例125a メチル4−(ブロモメチル)−2−tert−ブチルチアゾール−5−カルボキシレート 125a
101fの調製についての記載と同様の一般的な手順を用いて、125aと4,4,4’,4’,5,5,5’,5’−オクタメチル−2,2’−ビ(1,3,2−ジオキサボロラン)との反応により、125bを得た。
塩化メチレン(40mL)中に2−tert−ブチル−5−((2−((tert−ブチルジメチルシリルオキシ)メチル)−3−(1−メチル−6−オキソ−5−(ピリミジン−4−イルアミノ)−1,6−ジヒドロピリジン−3−イル)フェニルアミノ)−メチル)チアゾール−4−カルボン酸(125e)(500mg、0.78ミリモル)が入った溶液に、N,N−ジイソプロピルエチルアミン(503mg、3.9ミリモル)およびN,N,N’,N’−テトラメチル−O−(7−アザベンゾトリアゾール−1−イル)ウロニウムヘキサフルオロホスフェート(900mg、2.37ミリモル)を加えた。混合物を25℃で2時間撹拌した。溶離剤としてPE:EA(1:3〜1:6)を用いたフラッシュカラムで精製したところ、125が、白色の固体(32mg、10%)として得られた。LCMS:(M+H)+ 503。1H NMR(500MHz、MeOD)ppm 8.84(d,J=2Hz,1H)、8.66(s,1H)、8.29(d,J=5.5Hz,1H)、7.49〜7.56(m,4H)、7.09(d,J=5.5Hz,2H)、5.04(s,2H)、4.57(s,2H)、3.73(s,3H)、1.54(s,9H)。
実施例126a tert−ブチル5−アミノ−3−シクロプロピル−1H−ピラゾール−1−カルボキシレート 126a
LCMS:(M−Boc)+ 124。
1H NMR(500MHz、DMSO)δ 11.85(s,1H)、8.23(s,1H)、8.02(d,J=2.5,1H)、7.35(d,J=2.5,1H)、5.77(d,J=2,1H)、3.46(s,3H)、1.83(m,1H)、0.90(m,2H)、0.64(m,2H)
LCMS:(M+H)+ 677。
実施例125の手順にしたがい、125dから出発して、126が、白色の固体(30mg、5%、3ステップ)として得られた。LCMS:(M+H)+ 531。1H NMR(500MHz、MeOD)ppm 7.75(d,J=1.5Hz,1H)、7.51(m,3H)、7.21(s,1H)、5.80(s,1H)、5.03(d,J=10Hz,2H)、4.54(s,1H)、4.57(s,2H)、3.70(s,3H)、1.88(m,1H)、1.55(s,3H)、0.97(d,J=7.5Hz,2H)、0.73(m,2H)。
式Iの化合物を試験するのに使用され得る標準的な生化学的Btkキナーゼアッセイのために一般化した手順は以下の通りである。1×細胞シグナル伝達キナーゼ緩衝剤(25mMのトリス−HCl、pH7.5、5mMのβ−グリセロリン酸塩、2mMのジチオスレイトール、0.1mMのNa3VO4、10mMのMgCl2)、0.5μMのPromega PTKビオチン化ペプチド基質2、および0.01%のBSAを含有する、マスターミックス(master mix)マイナスBtk酵素を調製する。1×細胞シグナル伝達キナーゼ緩衝剤、0.5μMのPTKビオチン化ペプチド基質2、0.01%のBSA、および100ng/ウェル(0.06mU/ウェル)で、Btk酵素を含有する、マスターミックスプラスBtk酵素を調製する。Btk酵素を以下のとおりに調製する:C末端にV5および6x Hisタグを有する完全長ヒト野生型Btk(受託番号NM−000061)を、このエピトープタグの付いたBtkを有するバキュロウイルスを作製するために、pFastBacベクター中にサブクローニングした。バキュロウイルスの作製を、その公表されたプロトコル“Bac−to−Bac Baculovirus Expression Systems”(Cat.Nos.10359−016および10608−016)に詳述されるInvitrogenの説明書に基づいて行う。3代継代ウイルスを用いてSf9細胞を感染させて、組み換えBtkタンパク質を過剰発現させる。次に、Btkタンパク質を、Ni−NTAカラムを用いて、均質になるまで精製する。最終的なタンパク質調製物の純度は、高感度Sypro−Ruby染色に基づいて95%を超える。200μMのATPの溶液を、水中で調製し、1NのNaOHを用いてpH7.4に調整する。1.25μLの量の化合物を含む5%DMSOを、96ウェルのハーフエリアCostarポリスチレンプレートに移す。化合物を単独で、11点用量反応曲線(出発濃度が10μM;1:2の希釈)を用いて試験する。18.75μLの量のマスターミックスマイナス酵素(陰性対照として)およびマスターミックスプラス酵素を、96ウェルのハーフエリアcostarポリスチレンプレート中の適切なウェルに移す。5μLの200μMのATPを、最終的なATP濃度が40μMになるように96ウェルのハーフエリアCostarポリスチレンプレート中のその混合物に加える。反応物を、室温で1時間インキュベートする。30mMのEDTA、20nMのSA−APC、および1nMのPT66 Abを含有するPerkin Elmer 1×検出緩衝剤を用いて、反応を停止させる。励起フィルタ330nm、発光フィルタ665nm、および第2の発光フィルタ615nmを用いたPerkin Elmer Envisionによって、時間分解蛍光を用いてプレートを読み取る。次に、IC50値を計算する。あるいは、Lanthascreenアッセイを用いて、そのリン酸化ペプチド産物の定量化によってBtk活性を評価することができる。ペプチド産物におけるフルオレセインと検出抗体におけるテルビウムとの間で起こるFRET(蛍光共鳴エネルギー移動)は、ペプチドのリン酸化を抑えるBtkの阻害剤の添加により減少する。25μLの最終的な反応体積で、Btk(h)(0.1ng/25μl反応)を、50mMのHepes pH 7.5、10mMのMgCl2、2mMのMnCl2、2mMのDTT、0.2mMのNaVO4、0.01%のBSA、および0.4μMのフルオレセインポリ−GATを用いてインキュベートする。ATPを25μM(ATPのKm)まで加えることによって反応を開始させる。室温で60分間のインキュベーションした後、60mMのEDTA中の最終濃度が2nMとなるように、室温で30分間かけてTb−PY20検出抗体を加えることによって反応を停止させる。340nMの励起、ならびに495nmおよび520nmにおける発光を用いたPerkin Elmer Envisionで検出を測定する。典型的なBtk阻害のIC50値は表1および2に示した。
式Iの化合物を試験するのに使用され得る標準的な細胞Btkキナーゼアッセイのために、別に一般化した手順は以下のとおりである。ラモス細胞を、試験化合物の存在下で0.5×107細胞/mlの密度で、37℃で1時間インキュベートする。次に、37℃で5分間、10μg/mlの抗ヒトIgM F(ab)2を用いてインキュベートすることによって細胞を刺激する。細胞をペレット化し、溶解させ、透明化された溶解物においてタンパク質アッセイを行う。各試料の等しい量のタンパク質について、SDS−PAGEを行い、そして、Btk自己リン酸化を評価するために抗ホスホBtk(Tyr223)抗体(Cell Signaling Technology #3531;Epitomics,cat.#2207−1)またはホスホBtk(Tyr551)抗体(BD Transduction Labs #558034)で、いずれかを用いるか、あるいは各溶解物中のBtkの総量を制御するために抗Btk抗体(BD Transduction Labs #611116)を用いて、ウェスタンブロッティングを行う。
式Iの化合物を試験するのに使用され得る標準的な細胞B細胞増殖アッセイのために一般化した手順は以下のとおりである。B細胞単離キット(Miltenyi Biotech、Cat # 130−090−862)を用いて、8〜16週齢のBalb/cマウスの脾臓からB細胞を精製する。試験化合物を、0.25%のDMSOに希釈し、100μlの最終体積中10μg/mlの抗マウスIgM抗体(Southern Biotechnology Associates Cat # 1022−01)を加える前に、2.5×105個の精製されたマウス脾臓B細胞とともに30分間インキュベートする。24時間のインキュベーションの後、1μCiの3H−チミジンを加え、SPA[3H]チミジン取り込みアッセイ系(Amersham Biosciences # RPNQ 0130)で、製造業者のプロトコルを用いて採取する前に、プレートを更に36時間インキュベートする。SPAビーズによる蛍光を、マイクロベータ(microbeta)カウンタ(Wallace Triplex 1450,Perkin Elmer)でカウントする。
式Iの化合物を試験するのに使用され得る標準的なT細胞増殖アッセイのために一般化した手順は以下のとおりである。Pan T細胞単離キット(Miltenyi Biotech、Cat # 130−090−861)を用いて、8〜16週齢のBalb/cマウスの脾臓からT細胞を精製する。試験化合物を、0.25%のDMSOに希釈し、それぞれ、10μg/mlの抗CD3(BD # 553057)および抗CD28(BD # 553294)抗体が37℃で90分間予め塗布された透明平底プレート中で、100μlの最終体積中の、2.5×105個の精製されたマウス脾臓T細胞と共にインキュベートする。24時間のインキュベーションの後、1μCiの3H−チミジンを加え、SPA[3H]チミジン取り込みアッセイ系(Amersham Biosciences # RPNQ 0130)で、製造業者のプロトコルを用いて採取する前に、プレートをさらに36時間インキュベートする。SPAビーズによる蛍光を、マイクロベータカウンタ(Wallace Triplex 1450,Perkin Elmer)でカウントする。
式Iの化合物を試験するのに使用され得るB細胞活性の阻害のための標準的なアッセイのために一般化した手順は以下のとおりである。赤血球溶解(BD Pharmingen #555899)によって、8〜16週齢のBalb/cマウスの脾臓から全マウス脾細胞を精製する。試験化合物を、0.5%のDMSOに希釈し、透明平底プレート(Falcon 353072)中で、200μlの最終体積中の、1.25×106個の脾細胞と共に、37℃で60分間インキュベートする。次に、15μg/mlのIgM(Jackson ImmunoResearch 115−006−020)を加えることによって細胞を刺激し、37℃、CO25%で24時間インキュベートする。24時間のインキュベーションの後、細胞を円錐底透明96ウェルプレートに移し、1200×g×5分間での遠心分離によってペレット化する。細胞を、CD16/CD32(BD Pharmingen #553142)によって予めブロック(preblock)した後、CD19−FITC(BD Pharmingen #553785)、CD86−PE(BD Pharmingen #553692)、および7AAD(BD Pharmingen #51−68981E)を用いてそれに三重染色を行う。細胞をBD FACSCaliburで分類し、CD19+/7AAD−集団においてゲーティングする。ゲーティングされた集団におけるCD86表面発現のレベルを、試験化合物濃度に対して測定する。典型的な結果を表3に示した。
以下は、生存細胞の数を測定するためにXTT読み取りを用いた標準的なB−ALL(急性リンパ芽球性白血病)細胞生存試験のための手順である。このアッセイを用いて、培養液中でのB−ALL細胞の生存を阻害する能力について、式Iの化合物を試験することができる。使用され得る1つのヒトB細胞急性リンパ芽球性白血病細胞株はSUP−B15、すなわちATCCから入手可能なヒトPre−B細胞ALL細胞株である。
ヒト血液を、以下の条件に合う健常な被験者から得る:1週間の休薬、非喫煙者。血液(8種の化合物を試験するために約20ml)を、ヘパリンナトリウム(sodium heparin)を含むVacutainer(登録商標)(Becton,Dickinson and Co.)管中に静脈穿刺によって採取する。
Claims (28)
- 下記式Iで表される構造式を有する化合物から選択される化合物、およびその立体異性体、互変異性体、または薬学的に許容できる塩;
但し、式中のR1は下記
から選択され、式中、波線は結合部位を示し;
R4は、OH、CN、NRbRc、ピペリジニル、C1〜C6アルキルまたはC1〜C4ハロアルキルで適宜選択的に置換されるC3〜C6シクロアルキル、およびOHまたはOC1〜C4アルキルに適宜選択的に置換されるC1〜C6アルキルから選択され;
R2は、H、CH3またはCF3であり;
環Bは、フェニル、少なくとも1個の窒素環原子を有する5〜6員ヘテロアリール、および少なくとも1個の窒素環原子を有する8〜11員ヘテロシクリルから選択され;
R3は、独立して、H、−Ra、−ORb、−SRb、−NRbRc、ハロ、シアノ、ニトロ、−CORb、−CO2Rb、−CONRbRc、−OCORb、−OCO2Ra、−OCONRbRc、−NRcCORb、−NRcCO2Ra、−NRcCONRbRc、−CO2Rb、−CONRbRc、−NRcCORb、−SORa、−SO2Ra、−SO2NRbRc、および−NRcSO2Raから選択されるか;または2つの隣接するR3基が、適宜選択的に一緒になって、O、SまたはNから選択される0〜2個のヘテロ原子を有する5〜6員環を形成し、ここで、前記5〜6員環は環Bと融合し;
Raは、C1〜C6アルキル、シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリールであり、ここで、Raの各メンバーは、1個〜3個のR11基で適宜選択的に置換され;
Rbは、H、C1〜C6アルキル、シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリールであり、ここで、Hを除くRbの各メンバーが、1〜3個のR11基で適宜選択的に置換され;
Rcは、Hまたは1個若しくは3個のR11基で適宜選択的に置換されるC1〜C4アルキルであり;またはRbおよびRc、およびそれらが結合される窒素が、適宜選択的に置換されるヘテロシクロアルキル基を形成し;
各R11は、独立して、C1〜C4アルキル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、アリール−C1〜C4アルキル−、ヘテロアリール−C1〜C4アルキル−、シクロアルキル−C1〜C4アルキル−、ヘテロシクロアルキル−C1〜C4アルキル−、C1〜C4ハロアルキル−、−OC1〜C4アルキル、−O−ヘテロシクロアルキル、−OC1〜C4アルキルフェニル、−C1〜C4アルキル−OH、−OC1〜C4ハロアルキル、ハロ、−OH、−NH2、−C1〜C4アルキル−NH2、−NH(C1〜C4アルキル)、−N(C1〜C4アルキル)(C1〜C4アルキル)、−N(C1〜C4アルキル)(C1〜C4アルキルフェニル)、−NH(C1〜C4アルキルフェニル)、シアノ、ニトロ、オキソ、−CO2H、−C(O)OC1〜C4アルキル、−CON(C1〜C4アルキル)(C1〜C4アルキル)、−CONH(C1〜C4アルキル)、−CONH2、−NHC(O)(C1〜C4アルキル)、−NHC(O)(フェニル)、−N(C1〜C4アルキル)C(O)(C1〜C4アルキル)、−N(C1〜C4アルキル)C(O)(フェニル)、−C(O)C1〜C4アルキル、−C(O)C1〜C4フェニル、−C(O)C1〜C4ハロアルキル、−OC(O)C1〜C4アルキル、−SO2(C1〜C4アルキル)、−SO2(フェニル)、−SO2(C1〜C4ハロアルキル)、−SO2NH2、−SO2NH(C1〜C4アルキル)、−SO2NH(フェニル)、−NHSO2(C1〜C4アルキル)、−NHSO2(フェニル)、および−NHSO2(C1〜C4ハロアルキル)から選択され;
R5は、HまたはFであり;
R6は、H、CH3、F、Cl、CN、OCH3、OH、またはOH、OCH3もしくは1個以上のハロ基で置換されるメチルであり;
R7は、H、CH3、F、Cl、CNまたはOCH3であり;
R8は、H、CH3、CF3、F、Cl、CNまたはOCH3であり;
Vは、CHまたはNであり;
各R9は、独立して、C1〜C3アルキルであり;
各R10は、独立して、HまたはCH3である。 - 前記R2が、HまたはCH3である、請求項1に記載された化合物。
- 前記R3が、H、−Ra、−NRbRcまたは−C(O)Rbである、請求項1に記載された化合物。
- 前記R3が、F、OH、CH3、またはCOCH3で適宜選択的に置換される、シクロプロピル、アゼチジニル、モルホリニル、ピペリジニル、オキソピペリジニル、ピペラジニル、およびオキソピペラジニルから選択される、請求項1に記載された化合物。
- 前記R4が、H、t−ブチル、N−ピロリジニル、N−ピペリジニル、N−アゼパニル、2−ヒドロキシ−2−メチルプロピル、プロパ−1−エン−2−イル、−N(CH3)Et、i−プロピル、シクロペンチル、シクロヘキシル、3−メチルブタン−2−イル、−N(CH3)(i−Pr)、または−NH(シクロプロピル)である、請求項1に記載された化合物。
- 前記R5が、HまたはFである、請求項1に記載された化合物。
- 前記R6が、H、CH3、F、またはCH2OHである、請求項1に記載された化合物。
- 前記R7が、HまたはFである、請求項1に記載された化合物。
- 前記環Bが、ピラゾロ[1,5−a]ピラジン−2−イル、ピラゾール−3−イル、ピリミジン−4−イル、またはピリジン−2−イルの環である、請求項1に記載された化合物。
- 前記式Iで表される化合物が表1から選択される、請求項1に記載された化合物。
- 前記式Iで表される化合物が表2から選択される、請求項1に記載された化合物。
- 請求項1〜16のいずれか一項に記載された化合物と、薬学的に許容できる担体、滑剤、希釈剤、または賦形剤とを含む医薬組成物。
- 第2の治療剤をさらに含む、請求項17に記載された医薬組成物。
- 請求項1〜16のいずれか一項に記載された化合物を薬学的に許容できる担体と組み合わせることを含む、医薬組成物を製造するための方法。
- 免疫障害、がん、心血管疾患、ウイルス感染、関節炎、炎症、代謝/内分泌機能障害および神経障害から選択される、ブルトン型チロシンキナーゼによって媒介される疾患または障害に罹患した患者に、治療的に有効な量の請求項1〜16のいずれか一項に記載された化合物を投与することを含む、疾患または障害を治療する方法。
- 前記疾患または障害が免疫障害である、請求項20に記載された方法。
- 前記疾患または障害が、全身性および局所炎症、関節炎、免疫抑制に関連する炎症、臓器移植拒絶反応、アレルギー、潰瘍性大腸炎、クローン病、皮膚炎、喘息、全身性エリテマトーデス、シェーグレン症候群、多発性硬化症、強皮症/全身性硬化症、特発性血小板減少性紫斑病(ITP)、抗好中球細胞質抗体(ANCA)脈管炎、慢性閉塞性肺疾患(COPD)、乾癬である、請求項21に記載された方法。
- 前記疾患または障害が関節リウマチである、請求項22に記載された方法。
- 前記疾患または障害が、乳癌、卵巣癌、頸癌、前立腺癌、精巣癌、泌尿生殖器癌、食道癌、喉頭癌、膠芽細胞腫、神経芽細胞腫、胃癌、皮膚癌、角化棘細胞腫、肺癌、類表皮癌、大細胞癌、非小細胞肺癌(NSCLC)、小細胞癌、肺腺癌、骨癌、結腸癌、腺腫、膵臓癌、腺癌、甲状腺癌、濾胞腺癌、未分化癌、乳頭癌、精上皮腫、黒色腫、肉腫、膀胱癌、肝臓癌および胆道癌、腎臓癌、膵癌、骨髄疾患、リンパ腫、毛様細胞腫、口腔癌、上咽頭癌、咽頭癌、口唇癌、舌癌、口腔癌、小腸癌、結腸直腸癌、大腸癌、直腸癌、脳および中枢神経系の癌、ホジキン病、白血病、気管支癌、甲状腺癌、肝臓および肝内胆管の癌、肝細胞癌、胃癌、神経膠腫/膠芽細胞腫、子宮内膜癌、黒色腫、腎臓および腎盂の癌、膀胱癌、子宮体癌、子宮頸癌、多発性骨髄腫、急性骨髄性白血病、慢性骨髄性白血病、リンパ性白血病、骨髄性白血病、口腔および咽頭の癌、非ホジキンリンパ腫、黒色腫、および絨毛結腸腺腫から選択されるがんである、請求項20に記載された方法。
- 抗炎症剤、抗関節炎剤、免疫調節剤、化学療法剤、神経栄養因子、心血管疾患を治療するための薬剤、肝疾患を治療するための薬剤、抗ウイルス剤、血液疾患を治療するための薬剤、糖尿病を治療するための薬剤、および免疫不全疾患を治療するための薬剤から選択されるさらなる治療剤を投与することからなる、請求項20に記載された方法。
- ブルトン型チロシンキナーゼによって媒介される病態を治療するためのキットであって:
a)請求項1〜16のいずれか一項に記載された化合物からなる第1の医薬組成物と、
b)使用説明書と
からなるキット。 - 免疫障害、がん、心血管疾患、ウイルス感染、炎症、代謝/内分泌機能障害および神経障害から選択され、且つブルトン型チロシンキナーゼによって媒介される疾患または障害を治療するための薬剤として使用する、請求項1〜16のいずれか一項に記載された化合物。
- 免疫障害、がん、心血管疾患、関節炎、ウイルス感染、炎症、代謝/内分泌機能障害および神経障害の治療のためのブルトン型チロシンキナーゼを調節する薬剤の製造における、請求項1〜16のいずれか一項に記載された化合物の使用。
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KR101837223B1 (ko) | 2018-03-09 |
BR112013007506A2 (pt) | 2016-07-12 |
US9249123B2 (en) | 2016-02-02 |
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