JP5073655B2 - キナーゼ阻害物質として有用なピロロトリアジンおよびそれを用いるキナーゼ関連疾患の治療方法 - Google Patents
キナーゼ阻害物質として有用なピロロトリアジンおよびそれを用いるキナーゼ関連疾患の治療方法 Download PDFInfo
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Description
R1はH、-NR6C(=O)R7、-OR7、または-C(=O)NR7R8;
Q2はアリール、置換アリール、ヘテロアリール、または置換ヘテロアリール;
R2はH、アルキル、置換アルキル、ヒドロキシ (-OH)、アルコキシ、ハロゲン、ハロアルキル、ハロアルコキシ、オキソ、アリールオキシ、アリールアルキル、アリールアルキルオキシ、アルカノイル、置換アルカノイル、アルカノイルオキシ、アミノ、アミノアルキル、置換アミノアルキル、アルキルアミノ、置換アルキルアミノ、ヒドロキシアルキル、二置換アミノ、アミド、置換アミド、カルバメート、置換カルバメート、ウレイド、シアノ、スルホンアミド、置換スルホンアミド、アルキルスルホン、ヘテロシクロアルキル、置換ヘテロシクロアルキル、シクロアルキル、置換シクロアルキル、シクロアルケニル、置換シクロアルケニル、シクロアルキルアルキル、シクロアルキルアルコキシ、ニトロ、チオ、チオアルキル、アルキルチオ、アルキルスルホニル、アルキルスルフィニル、カルボキシ、アルコキシカルボニル、アルキルカルボニルオキシ、カルバモイル、-NR6(C=O)R9、アルケニル、置換アルケニル、アルキニル、置換アルキニル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、ヘテロアリールオキシ、アリールヘテロアリール、アリールアルコキシカルボニル、ヘテロアリールアルキル、ヘテロアリールアルコキシ、アリールオキシアルキル、アリールオキシアリール、ヘテロサイクル、置換ヘテロサイクル、アルキルカルボニル、ヘテロアルキル、置換ヘテロアルキル、ヘテロアルケニル、置換ヘテロアルケニル、ヘテロアルキニル、置換ヘテロアルキニル、アリールアミノ、アリールアルキルアミノ、アルカノイルアミノ、アリールアミノ、アリールアルカノイルアミノ、アリールチオ、アリールアルキルチオ、アリールスルホニル、アリールアルキルスルホニル、アルキルスルホニル、アリールカルボニルアミノ、またはアルキルアミノカルボニル;
R3、R4およびR5はH、アルキル、置換アルキル、ヒドロキシ、アルコキシ、ハロゲン、ハロアルキル、ハロアルコキシ、アルカノイル、置換アルカノイル、アミノ、アミノアルキル、置換アミノアルキル、アルキルアミノ、置換アルキルアミノ、アミド、置換アミド、カルバメート、ウレイド、シアノ、スルホンアミド、置換スルホンアミド、アルキルスルホン、シクロアルキル、置換シクロアルキル、ニトロ、チオ、チオアルキル、アルキルチオ、二置換アミノ、アルキルスルホニル、アルキルスルフィニル、カルボキシ、アルコキシカルボニル、アルキルカルボニルオキシ、カルバモイル、-NR6(C=O)R9、アルケニル、置換アルケニル、アルキニル、置換アルキニルおよびアルキルカルボニルから独立して選択され、
R6はH、低級アルキル、または置換された低級アルキル;
R7およびR8はH、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、ヘテロシクロアルキル、置換ヘテロシクロアルキル、ヘテロアルキル、置換ヘテロアルキル、ヘテロアルケニル、置換ヘテロアルケニル、ヘテロアルキニル、または置換ヘテロアルキニルから独立して選択され;および
R9はH、アルキル、置換アルキル、アルコキシ、アミノアルキル、置換アミノアルキル、アルキルアミノ、置換アルキルアミノ、アリール、または置換アリールである]
で表される化合物またはその医薬上許容される塩が本明細書に提供される。
、チアゾリル、ピリジル [すなわち、
a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Acamedic Press, 1985);
b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter 5、"Design and Application of Prodrugs," by H. Bundgaard, p. 113-191 (1991); および
c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992).
で表される化合物またはその医薬上許容される塩は本明細書に開示される。
本明細書の実施例に記載された化合物を含めた式(I)の少なくとも1つの化合物を、後記の少なくとも1つのアッセイ方法においてテストし、少なくとも1つのオーロラキナーゼA、Bおよび/またはCの阻害物質としての活性を示した。
ヒト細胞におけるオーロラキナーゼの機能を阻害する化合物の能力を決定するために、セリン10に対するヒストンH3(HH3)のリン酸化状態を分析した。HH3は、Ser-10 およびSer-28を含めた少なくとも2つのセリン残基に対してリン酸化されたクロマチン蛋白質である。動原体性HH3上のSer-10は、細胞周期のG2相において、有糸分裂までにリン酸化される。Ser-10は全染色体にわたりリン酸化される。HH3上のこのサイトでのリン酸化は、クロマチン凝縮の開始を調節し、オローラキナーゼを必要とするようである。
適当な細胞分裂の調節におけるオローラキナーゼの役割を広範囲に試験した。モデル生物および哺乳動物細胞におけるこれらのキナーゼの遺伝子破壊は、オローラキナーゼ機能の喪失と関連した特定の表現型を示した。特に、細胞質分裂での失敗に起因する倍数体細胞の出現を含めた有系分裂の欠陥は、オローラ・キナーゼ活性を欠失する細胞における顕著で測定可能な表現型である。さらに、これらの倍数体細胞は、細胞分裂での引き続いての試みに際してアポトーシスを受ける。これらのよく特徴付けられた表現型に基づいて、機能的アッセイを、オローラ・キナーゼ阻害剤で処理した細胞中で倍数性およびアポトーシスを同時に測定するために開発した。
式(I)に記載の化合物で処置した細胞に対する長期の効果を決定するために、細胞傷害性アッセイを用いて、72時間の式(I)化合物の曝露後の全体的な細胞生存率を測定した。細胞傷害性アッセイは、死滅細胞ではなく生存細胞における着色された生成物に代謝変換される可溶性のテトラゾリウム塩、MTS(Promega Corporation; Madison, WI)を用いる。
式(I)の少なくとも1つの化合物は、約0.01〜約100μMのIC50値により少なくとも1つの前記に参照されたアッセイにおいて活性を示した。1つの具体例において、式(I)の少なくとも1つの化合物は、約0.1μM未満のIC50値により少なくとも1つの前記に参照されたアッセイにおいて活性を示した。もう一つの具体例において、式(I)の少なくとも1つの化合物は、約0.5μM未満のIC50値により少なくとも1つの前記に参照されたアッセイにおいて活性を示した。
さらに、本発明は以下の実施例において定義される。実施例は、例示にだけ与えられると理解されるべきである。前記および実施例から、当業者は、本発明の本質的な特徴を確認し、その精神および範囲から逸脱することなく、本発明を種々の使用および条件に適用するように種々の変更および修飾を行うことができる。結果的に、本発明は、以下に記載される例示的な実施例により限定されず、むしろ本明細書に添付された特許請求の範囲により定義される。
実施例1〜4において、分析的逆相HPLCの保持時間を、各実施例において同定したカラムタイプおよび長さ、流量、および直線勾配溶出を用いて得た。本明細書に特記しない限りは、全ての勾配は、100%溶媒A(MeOH: 水: TFA=1:9:0.01)および0%溶媒Bで開始し、100%溶媒B(MeOH: 水: TFA=1:9:0.01)および0%溶媒Aで終了した。UV検出を220nmで行った。
N-[4-({4-[(5-メチル-1H-ピラゾール-3-イル)アミノ]ピロロ[2,1-f][1,2,4]トリアジン-2-イル}スルファニル)フェニル]シクロプロパンカルボキシアミド
乾燥DCM (0.8 mL)中の塩化シクロプロパンカルボニル (9.1 uL, 0.1 mmol)の溶液をバイアル中の乾燥ピリジン中の1D (33.7 mg, 0.1 mmol)の溶液に添加した。バイアルを密閉し、週末にわたり撹拌させた。分取用HPLCを用いて、TFA塩として13mgの1E(27%収率)を単離した。1H NMR (MeOH-d4): 0.84 (m, 2H), 0.91 (m, 2H), 1.72 (m, 1H), 2.12 (s, 3H), 5.80 (m, 1H), 6.63 (m, 1H), 7.02 (m, 1H), 7.56 (m, 1H), 7.58 (m, 4H); MS: 406 (M+H)+; および RP HPLC保持時間: 3.23 min (Phenomenex-Luna S10: 4.6 x 50 mm カラム, 4 min 勾配, 4 mL/min).
N-(3-シクロプロピル-1H-ピラゾール-5-イル)-2-{[3-(メチルオキシ)フェニル]スルファニル}ピロロ[2,1-f][1,2,4]トリアジン-4-アミン
N2雰囲気下、乾燥DMF (0.1 mL)中の2A (28 mg, 0.1 mmol)、3-メトキシベンゼンチオール (61 uL, 5当量)およびK2CO3 (28 mg, 2当量)の混合物を120℃にて加熱した。6時間後、混合物を室温に冷却し、Phenomenex strata-X-Cカチオンカートリッジに適用した。引き続いて、カートリッジを、MeOHで洗浄し、粗製の生成物をMeOH中のNH3の2N溶液で溶出した。粗製の生成物を分取用HPLCにより精製して、17mgの2B(44%収率)を生成した。1H NMR (MeOH-d4): 0.61 (m, 2H), 0.92 (m, 2H), 1.80 (m, 1H), 3.81 (s, 3H), 5.8 (br.s, 1H), 6.63 (m, 1H), 6.94 (m, 1H), 7.01 (br.s, 1H), 7.21 (br.s, 1H), 7.37 (br.s, 1H), 7.49 (s, 1H), 7.75 (s, 1H); MS: 379 (M+H)+; および RP HPLC保持時間: 1.88 min (Phenomenex-Luna S10: 4.6 x 50 mm カラム, 3 min 勾配, 4 mL/min).
N-[4-({4-[(3-シクロプロピル-1H-ピラゾール-5-イル)アミノ]ピロロ[2,1-f][1,2,4]トリアジン-2-イル}スルファニル)フェニル]アセトアミド
3-({4-[(3-シクロプロピル-1H-ピラゾール-5-イル)アミノ]ピロロ[2,1-f][1,2,4]トリアジン-2-イル}スルファニル)-N-メチルベンズアミド
メチルアミン (0.28 mL, 1.4当量, THF中の2.0 M溶液)に続いて、EDC (58 mg, 1.5当量)をN2雰囲気下の室温の乾燥DCM (0.5 mL)中の4A (78 mg, 0.2 mmol)の懸濁液に添加した。一晩撹拌した後、分取用HPLCを用いて、34mgの4B(43%収率)を得た。1H NMR (MeOH-d4): 0.57 (m, 2H), 0.92 (m, 2H), 1.77 (m, 1H), 2.92 (s, 3H), 5.74 (br.s, 1H), 6.62 (br., 1H), 6.94 (br.s, 1H), 7.48 (br.s, 1H), 7.56 (m, 1H), 7.79 (m, 1H), 7.95 (m, 1H), 8.12 (s, 1H); MS: 406 (M+H)+; および RP HPLC保持時間: 1.63 min (Phenomenex-Luna S10: 4.6 x 50 mm カラム, 3 min 勾配, 4 mL/min).
N-(5-メチル-1H-ピラゾール-3-イル)-2-(フェニルスルファニル)ピロロ[2,1-f][1,2,4]トリアジン-4-アミン
N-(4-((4-((5-メチル-1H-ピラゾール-3-イル)アミノ)ピロロ[2,1-f][1,2,4]トリアジン-2-イル)スルファニル)フェニル)ベンズアミド
6A (184 mg, 2当量)を室温の5 mL DMF中のK2CO3 (255 mg, 2.3当量)の懸濁液に添加した。10分後、1C(100mg、1当量)を1mL DMF溶液として添加した。反応物を110℃にて一晩撹拌した結果、LCMSによって示された生成物を形成した。次いで、反応物をEtOAcを用いて抽出し、合わせた有機相を水およびブラインで洗浄した。有機相をMgSO4で乾燥させ、次いで濃縮した。粗製の混合物をEtOAcでトリチュレートして、6Bを得た。MS: 442 [M+H]+; 1H NMR (DMSO-d6): 12.05 (s, 1H), 10.85 (s,1H), 10.64(s, 1H), 8.00 (br. m, 5H), 7.45 (br. m, 6H), 7.23 (br. s, 1H), 6.59 (br. s, 1H) , 5.8 (br. s, 1H) 2.2 (s, 1H).
Claims (6)
- R 1 が-NR 6 C(=O)R 7 である請求項1記載の化合物。
- R 1 が-NR 6 C(=O)R 7 である請求項4記載の化合物。
- (i) N-[4-({4-[(5-メチル-1H-ピラゾール-3-イル)アミノ]ピロロ[2,1-f][1,2,4]トリアジン-2-イル}スルファニル)フェニル]シクロプロパンカルボキシアミド;
N-(3-シクロプロピル-1H-ピラゾール-5-イル)-2-{[3-(メチルオキシ)フェニル]スルファニル}ピロロ[2,1-f][1,2,4]トリアジン-4-アミン;
N-[4-({4-[(3-シクロプロピル-1H-ピラゾール-5-イル)アミノ]ピロロ[2,1-f][1,2,4]トリアジン-2-イル}スルファニル)フェニル]アセトアミド;
3-({4-[(3-シクロプロピル-1H-ピラゾール-5-イル)アミノ]ピロロ[2,1-f][1,2,4]トリアジン-2-イル}スルファニル)-N-メチルベンズアミド;
N-(5-メチル-1H-ピラゾール-3-イル)-2-(フェニルスルファニル)ピロロ[2,1-f][1,2,4]トリアジン-4-アミン;および
N-(4-((4-((5-メチル-1H-ピラゾール-3-イル)アミノ)ピロロ[2,1-f][1,2,4]トリアジン-2-イル)スルファニル)フェニル)ベンズアミド;ならびに
(ii) その医薬上許容される塩
から選択される請求項1記載の化合物。
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US69621505P | 2005-07-01 | 2005-07-01 | |
US60/696,215 | 2005-07-01 | ||
PCT/US2006/025768 WO2007005708A1 (en) | 2005-07-01 | 2006-06-29 | Pyrrolotriazine compounds useful as kinase inhibitors and methods of treating kinase-associated conditions therewith |
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JP2008519651A Expired - Fee Related JP5073655B2 (ja) | 2005-07-01 | 2006-06-29 | キナーゼ阻害物質として有用なピロロトリアジンおよびそれを用いるキナーゼ関連疾患の治療方法 |
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EP (1) | EP1899348A1 (ja) |
JP (1) | JP5073655B2 (ja) |
CN (1) | CN101233136A (ja) |
AU (1) | AU2006265784B2 (ja) |
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Families Citing this family (21)
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DE602005023333D1 (de) * | 2004-10-15 | 2010-10-14 | Takeda Pharmaceutical | Kinaseinhibitoren |
US7442700B2 (en) * | 2005-07-01 | 2008-10-28 | Bristol-Myers Squibb Company | Pyrrolotriazine compounds useful as kinase inhibitors and methods of treating kinase-associated conditions therewith |
US7232901B2 (en) * | 2005-07-01 | 2007-06-19 | Bristol-Myers Squibb Company | Intermediates useful in preparing certain pyrrolotriazine compounds and process for making such intermediates |
BRPI0616630B8 (pt) * | 2005-09-30 | 2021-05-25 | Miikana Therapeutics Inc | compostos de pirazol substituídos |
JP2010529193A (ja) * | 2007-06-11 | 2010-08-26 | ミイカナ セラピューティクス インコーポレイテッド | 置換ピラゾール化合物 |
US8445676B2 (en) * | 2008-10-08 | 2013-05-21 | Bristol-Myers Squibb Company | Pyrrolotriazine kinase inhibitors |
WO2011088045A1 (en) | 2010-01-12 | 2011-07-21 | Ambit Biosciences Corporation | Aurora kinase compounds and methods of their use |
US8791257B2 (en) | 2010-03-31 | 2014-07-29 | Bristol-Myers Squibb Company | Substituted pyrrolotriazines as protein kinase inhibitors |
CA3052927C (en) * | 2010-08-18 | 2023-01-03 | Scott D. Boden | Compounds and compositions for ossification and methods related thereto |
CN104876935B (zh) * | 2015-05-18 | 2017-04-19 | 南方医科大学 | 2‑氨基吡咯并[1,2‑f][1,2,4]三嗪类化合物、合成方法及应用 |
CN111018860B (zh) * | 2018-10-10 | 2022-06-10 | 中国药科大学 | 吡咯并三嗪类化合物及其应用 |
US11066404B2 (en) | 2018-10-11 | 2021-07-20 | Incyte Corporation | Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors |
WO2020168197A1 (en) | 2019-02-15 | 2020-08-20 | Incyte Corporation | Pyrrolo[2,3-d]pyrimidinone compounds as cdk2 inhibitors |
US11472791B2 (en) | 2019-03-05 | 2022-10-18 | Incyte Corporation | Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors |
WO2020205560A1 (en) | 2019-03-29 | 2020-10-08 | Incyte Corporation | Sulfonylamide compounds as cdk2 inhibitors |
US11440914B2 (en) | 2019-05-01 | 2022-09-13 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
US11447494B2 (en) | 2019-05-01 | 2022-09-20 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
CR20220066A (es) | 2019-08-14 | 2022-11-28 | Incyte Corp | Compuestos de imidazolil pirimidinilamina como inhibidores de cdk2 |
WO2021072232A1 (en) | 2019-10-11 | 2021-04-15 | Incyte Corporation | Bicyclic amines as cdk2 inhibitors |
US11981671B2 (en) | 2021-06-21 | 2024-05-14 | Incyte Corporation | Bicyclic pyrazolyl amines as CDK2 inhibitors |
US11976073B2 (en) | 2021-12-10 | 2024-05-07 | Incyte Corporation | Bicyclic amines as CDK2 inhibitors |
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US6982265B1 (en) * | 1999-05-21 | 2006-01-03 | Bristol Myers Squibb Company | Pyrrolotriazine inhibitors of kinases |
JP2001302667A (ja) | 2000-04-28 | 2001-10-31 | Bayer Ag | イミダゾピリミジン誘導体およびトリアゾロピリミジン誘導体 |
EP2289894A3 (en) * | 2002-04-23 | 2011-07-20 | Bristol-Myers Squibb Company | Pyrrolo-triazine compounds useful as kinase inhibitors |
TWI329112B (en) * | 2002-07-19 | 2010-08-21 | Bristol Myers Squibb Co | Novel inhibitors of kinases |
DE602005023333D1 (de) * | 2004-10-15 | 2010-10-14 | Takeda Pharmaceutical | Kinaseinhibitoren |
US7442700B2 (en) * | 2005-07-01 | 2008-10-28 | Bristol-Myers Squibb Company | Pyrrolotriazine compounds useful as kinase inhibitors and methods of treating kinase-associated conditions therewith |
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CA2613895A1 (en) | 2007-01-11 |
AU2006265784B2 (en) | 2012-03-01 |
US20100137319A1 (en) | 2010-06-03 |
CN101233136A (zh) | 2008-07-30 |
US20070004731A1 (en) | 2007-01-04 |
JP2008544991A (ja) | 2008-12-11 |
WO2007005708A1 (en) | 2007-01-11 |
US20090062288A1 (en) | 2009-03-05 |
EP1899348A1 (en) | 2008-03-19 |
AU2006265784A1 (en) | 2007-01-11 |
US7442700B2 (en) | 2008-10-28 |
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