JP2010528021A - キナーゼのインヒビターとして有用なチアゾールおよびピラゾール - Google Patents
キナーゼのインヒビターとして有用なチアゾールおよびピラゾール Download PDFInfo
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- JP2010528021A JP2010528021A JP2010509424A JP2010509424A JP2010528021A JP 2010528021 A JP2010528021 A JP 2010528021A JP 2010509424 A JP2010509424 A JP 2010509424A JP 2010509424 A JP2010509424 A JP 2010509424A JP 2010528021 A JP2010528021 A JP 2010528021A
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- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229940001814 uvadex Drugs 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 229960000653 valrubicin Drugs 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 208000009540 villous adenoma Diseases 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
- 229940061261 zolinza Drugs 0.000 description 1
- 229940002005 zometa Drugs 0.000 description 1
- 229940088909 zyloprim Drugs 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本発明は、Auroraプロテインキナーゼのインヒビターとして有用な化合物に関する。本発明はまた、本発明の化合物を含む薬学的に受容可能な組成物、上記化合物および組成物を、種々の障害の処置において使用するための方法、ならびに上記化合物を調製するためのプロセスに関する。
上記Auroraプロテインは、細胞周期の有糸分裂相を通過する進行に必須である、3つの関連するセリン/スレオニンキナーゼ(Aurora−A、Aurora−BおよびAurora−Cといわれる)のファミリーである。具体的には、Aurora−Aは、セントロメア成熟および分離、有糸分裂紡錘糸の形成ならびに染色体の忠実な分離において重要な役割を果たす。Aurora−Bは、中期板上の染色体のアラインメントの調節、紡錘糸組み立てチェックポイントおよび細胞質分裂の正確な完了において重要な役割を果たす、染色体パッセンジャータンパク質である。
本発明は、Auroraプロテインキナーゼのインヒビターとして有用な化合物およびその薬学的に受容可能な組成物を提供する。これら化合物は、式I:
本発明の一実施形態は、式Iの化合物:
X1は、NもしくはCHであり;
X2は、NもしくはCHであり;
X3は、NもしくはCRXであり;
ただし、X3がCRXである場合、X1およびX2のうちの一方のみがNであり;そしてただしX1、X2およびX3のうちの少なくとも一方はNであり;
Htは、チアゾールもしくはピラゾールであり、ここで各環は、必要に応じてかつ独立して、R2およびR2’で置換されており;
Qは、−O−、−NR’−、−S−、−C(=O)−、もしくは−C(R’)2−であり;
RXは、HもしくはFであり;
RYは、−Z−R10であり;
R1は、T−(環D)であり;
環Dは、5〜7員の単環式アリールもしくはヘテロアリール環であり、ここで該ヘテロアリールは、O、N、もしくはSから選択される1〜4個の環ヘテロ原子を有し;環Dは、必要に応じて、環D’と縮合され得;
環D’は、窒素、酸素、もしくは硫黄から選択される0〜4個の環ヘテロ原子を含む、5〜8員の芳香族の、部分飽和の、もしくは完全不飽和の環であり;
環Dおよび環D’は、各々独立してかつ必要に応じて、オキソもしくは−W−R5の0〜4個の存在で置換されており;
各Tは、独立して、C1−4アルキリデン鎖であるか、もしくは存在せず;
R2は、H、C1−3アルキル、もしくはシクロプロピルであり;
R2’はHであり;
各ZおよびWは、独立して、存在しないか、もしくはC1−10アルキリデン鎖であり、ここで該アルキリデン鎖の最大6個までのメチレン単位は、必要に応じて、Vによって置換されており;
各Vは、−O−、−C(=O)−、−S(O)−、−S(O)2−、−S−、もしくは−N(R4)−から選択され;
各R5は、独立して、−R、−ハロ、−OR、−C(=O)R、−CO2R、−COCOR、COCH2COR、−NO2、−CN、−S(O)R、−S(O)2R、−SR、−N(R4)2、−CON(R7)2、−SO2N(R7)2、−OC(=O)R、−N(R7)COR、−N(R7)CO2(C1−6脂肪族)、−N(R4)N(R4)2、−C=NN(R4)2、−C=N−OR、−N(R7)CON(R7)2、−N(R7)SO2N(R7)2、−N(R4)SO2R−もしくは−OC(=O)N(R7)2であり;
各Rは、H、C1−6脂肪族基、C6−10アリール環、5〜10個の環原子を有するヘテロアリール環、もしくは4〜10個の環原子を有するヘテロシクリル環であり;ここで上記ヘテロアリール環もしくはヘテロシクリル環は、窒素、酸素、もしくは硫黄から選択される1〜4個の環ヘテロ原子を有し;Rは、必要に応じて、0〜6個のR9で置換されており;
各R4は、−R7、−COR7、−CO2R7、−CON(R7)2、もしくは−SO2R7であり;
各R7は、独立して、H、または必要に応じて、1〜6個のハロもしくは−O(C1−6アルキル)で置換されているC1−6脂肪族であるか;あるいは同じ窒素原子上の2個のR7は、上記窒素と一緒になって、必要に応じて、窒素、酸素、もしくは硫黄から選択される1〜4個のヘテロ原子を含む、置換された4〜8員のヘテロシクリルもしくはヘテロアリール環を形成し;
各R9は、−R’、−ハロ、−OR’、−C(=O)R’、−CO2R’、−COCOR’、COCH2COR’、−NO2、−CN、−S(O)R’、−S(O)2R’、−SR’、−N(R’)2、−CON(R’)2、−SO2N(R’)2、−OC(=O)R’、−N(R’)COR’、−N(R’)CO2(C1−6脂肪族)、−N(R’)N(R’)2、−N(R’)CON(R’)2、−N(R’)SO2N(R’)2、−N(R’)SO2R’、−OC(=O)N(R’)2、=NN(R’)2、=N−OR’、もしくは=Oであり;
各R10は、O、N、もしくはSから選択される1個のヘテロ原子を含む5〜6員の複素環式環であり;各R10は、必要に応じて、0〜6個のJの存在で置換されており;
各Jは、独立して、R、−ハロ、−OR、オキソ、−C(=O)R、−CO2R、−COCOR、−COCH2COR、−NO2、−CN、−S(O)R、−S(O)2R、−SR、−N(R4)2、−CON(R7)2、−SO2N(R7)2、−OC(=O)R、−N(R7)COR、−N(R7)CO2(C1−6脂肪族)、−N(R4)N(R4)2、=NN(R4)2、=N−OR、−N(R7)CON(R7)2、−N(R7)SO2N(R7)2、−N(R4)SO2R、−OC(=O)N(R7)2、もしくは−OP(=O)(OR”)2であるか;または
同じ原子上もしくは異なる原子上の2個のJ基は、それらが結合される原子と一緒になって、O、N、もしくはSから選択される0〜2個のヘテロ原子を有する3〜8員の飽和の、部分飽和の、もしくは不飽和の環を形成し;ここで上記2個のJ基によって形成される環上の1〜4個の水素原子は、必要に応じて、JRで置換されているか;または上記環上の2個の水素原子は、必要に応じて、オキソもしくはスピロ結合したC3−4シクロアルキルで置換されており;ここで上記C3−4アルキルは、必要に応じて、1〜3個のフッ素で置換されており;
各JRは、FもしくはR7’であり;
各R7’は、独立して、C1−6脂肪族;−O(C1−6脂肪族);またはO、N、もしくはSから選択される1〜4個のヘテロ原子を含む5〜6員のヘテロアリールであり;各R7’は、必要に応じて、0〜3個のJ7で置換されており;
J7は、独立して、NH2、NH(C1−4脂肪族)、N(C1−4脂肪族)2、ハロゲン、C1−4脂肪族、OH、O(C1−4脂肪族)、NO2、CN、CO2H、CO2(C1−4脂肪族)、O(ハロC1−4脂肪族)、もしくはハロC1−4脂肪族であり;
各R’は、独立して、HもしくはC1−6脂肪族基であるか;または2個のR’は、それらが結合される原子と一緒になって、3〜6員のカルボシクリルまたはO、N、もしくはSから選択される0〜1個のヘテロ原子を含む3〜6員のヘテロシクリルを形成し;そして
各R”は、独立して、HもしくはC1−2アルキルである。
RYは、
Zは存在せず;
RYは、
RYは、
nは1であり;
Jは、F、−N(R4)2、CN、−OR、オキソ(=O)、または必要に応じてOHもしくはOCH3の1個の存在で置換されているC2−6アルキルであり;そしてR1は、−NHC(O)(C1−6脂肪族)の1個の存在で置換ンされており、ここで上記C1−6脂肪族は、0〜6個のハロで置換されている、
化合物を提供する。
RYは、
HPLCは、液体高速クロマトグラフィーである。
LCMSは、液体クロマトグラフィー質量分析法である。
1H NMRは、核磁気共鳴法である。
いくつかの実施形態において、上記さらなる治療剤は、カンプトテシン(MEKインヒビター:U0126)、KSP(キネシン紡錘糸タンパク質)インヒビター、アドリアマイシン、インターフェロン、および白金誘導体(例えば、シスプラチン)から選択される。
Myleran)(登録商標));カルステロン(メトサーブ(登録商標));カペシタビン(ゼローダ(登録商標));カルボプラチン(パラプラチン(登録商標));カルムスチン(BCNU(登録商標)、BiCNU(登録商標));カルムスチン(グリアデル(登録商標));カルムスチンとポリフェプロサン(Polifeprosan)20インプラント(グリアデルウェハ(登録商標));セレコキシブ(セレブレックス(登録商標));セツキシマブ(エルビタックス(登録商標));クロラムブシル(ロイケラン(Leukeran)(登録商標));シスプラチン(プラチノール(登録商標));クラドリビン(ロイスタチン(登録商標)、2−CdA(登録商標));クロファラビン(クロラール(登録商標));シクロホスファミド(シトキサン(登録商標)、ネオサール(登録商標));シクロホスファミド(シトキサン注射(登録商標));シクロホスファミド(シトキサン錠剤(登録商標));シタラビン(シトサール−U(登録商標));シタラビンリポソーム(DepoCyt(登録商標));ダカルバジン(DTIC−Dome(登録商標));ダクチノマイシン、アクチノマイシンD(コスメゲン(登録商標));ダルベポエチンα(アラネスプ(登録商標));ダウノルビシンリポソーム(ダウノゾーム(DanuoXome)(登録商標));ダウノルビシン、ダウノマイシン(ダウノルビシン(登録商標));ダウノルビシン、ダウノマイシン(セルビジン(Cerubidine)(登録商標));ダニロイキンジフチトックス(Denileukin diftitox)(オンタック(登録商標));デクスラゾキサン(Zinecard(登録商標));ドセタキセル(タキソテール(登録商標));ドキソルビシン(アドリアマイシン PFS(登録商標));ドキソルビシン(アドリアマイシン(登録商標),ルベックス(登録商標));ドキソルビシン(アドリアマイシン PFS注射(登録商標));ドキソルビシンリポソーム(ドキシル(登録商標));プロピオン酸ドロモスタノロン(ドロモスタノロン(登録商標));プロピオン酸ドロモスタノロン(マステロン注射(登録商標));Elliott’s B Solution(Elliott’s B Solution(登録商標));エピルビシン(エレンス(Ellence)(登録商標));エポエチンα(エポゲン(epogen)(登録商標));エルロチニブ(タルセバ(登録商標));エストラムスチン(Emcyt(登録商標));リン酸エトポシド(エトポホス(登録商標));エトポシド、VP−16(ベプシド(Vepesid)(登録商標));エキセメスタン(アロマシン(登録商標));フィルグラスチム(ニューポジェン(Neupogen)(登録商標));フロクスウリジン(動脈内)(FUDR(登録商標));フルダラビン(フルダラ(登録商標));フルオロウラシル、5−FU(アドルシル(Adrucil)(登録商標));フルベストラント(ファスロデックス(登録商標));ゲフィチニブ(イレッサ(登録商標));ゲムシタビン(ジェムザール(登録商標));ゲムツズマブオゾガマイシン(マイロターグ(登録商標));酢酸ゴセレリン(ゾラデックスインプラント(登録商標));酢酸ゴセレリン(ゾラデックス(登録商標));酢酸ヒストレリン(ヒストレリンインプラント(登録商標));ヒドロキシウレア(ヒドレア(登録商標));イブリツモマブチウキセタン(ゼバリン(登録商標));イダルビシン(イダマイシン(登録商標));イホスファミド(IFEX(登録商標));イマチニブメシレート(グリベック(登録商標));インターフェロンα2a(ロフェロンA(登録商標));インターフェロンα−2b(イントロンA(登録商標));イリノテカン(カンプトサール(登録商標));レナリドミド(レブリミド(登録商標));レトロゾール(フェマーラ(登録商標));ロイコボリン(ウェルコボリン(登録商標)、ロイコボリン(登録商標));酢酸ロイプロリド(エリガード(登録商標));レバミソール(エルガミゾール(登録商標));ロムスチン、CCNU(CeeBU(登録商標));メクロレタミン、ナイトロジェンマスタード(マスタージェン(登録商標));酢酸メゲストロール(メゲース(登録商標));メルファラン、L−PAM(アルケラン(登録商標));メルカプトプリン、6−MP(プリントール(登録商標));メスナ(メスネックス(登録商標));メスナ(メスネックス錠剤(登録商標));メトトレキサート(メトトレキサート(登録商標));メトキサレン(ウバデックス(Uvadex)(登録商標));マイトマイシンC(ムタマイシン(Mutamycin)(登録商標));ミトータン(リソドレン(Lysodren)(登録商標));ミトキサントロン(ノバントロン(登録商標));フェンプロピオン酸ナンドロロン(デュラボリン−50(登録商標));ネララビン(アラノン(登録商標));ノフェツモマブ(ベルルマ(Verluma)(登録商標));オプレルベキン(ニューメガ(Neumega)(登録商標));オキサリプラチン(エロキサチン(登録商標));パクリタキセル(パキセン(Paxene)(登録商標));パクリタキセル(タキソール(登録商標));パクリタキセルタンパク質結合粒子(アブラキサン(登録商標));パリフェルミン(ケピバンス(登録商標));パミドネート(アレディア(登録商標));ペガデマーゼ(アダジェン(Adagen)(ウシペガデマーゼ)(登録商標));ペガスパルガーゼ(オンカスパール(Oncaspar)(登録商標));ペグフィルグラスチム(ニューラスタ(登録商標));ペメトレキセド・二ナトリウム(アリムタ(登録商標));ペントスタチン(Nipent(登録商標));ピポブロマン(バーサイト(Vercyte)(登録商標));プリカマイシン、ミトラマイシン(ミトラシン(登録商標));ポルフィマーナトリウム(フォトフリン(登録商標));プロカルバジン(マチュラン(Matulane)(登録商標));キナクリン(アタブリン(登録商標));ラスブリカーゼ(エリテック(登録商標));リツキシマブ(リツキサン(登録商標));サルグラモスチム(ロイキン(登録商標));サルグラモスチム(プロカイン(登録商標));ソラフェニブ(ネクサバール(登録商標));ストレプトゾシン(ザノサール(登録商標));スニチニブマレエート(スーテント(Sutent)(登録商標));タルク(スクレロゾール(Sclerosol)(登録商標));タモキシフェン(ノルバデックス(登録商標));テモゾロミド(テモダール(登録商標));テニポシド、VM−26(ブモン(Vumon)(登録商標));テストラクトン(テスラック(登録商標));チオグアニン、6−TG(チオグアニン(登録商標));チオテパ(チオプレックス(登録商標));トポテカン(ハイカムチン(登録商標));トレミフェン(フェアストン(登録商標));トシツモマブ(ベキサール(登録商標));トシツモマブ/I−131トシツモマブ(ベキサール(登録商標));トラスツズマブ(ハーセプチン(登録商標));トレチノイン、ATRA(ベサノイド(登録商標))ウラシルマスタード(ウラシルマスタードカプセル剤(登録商標));バルルビシン(バルスター(登録商標));ビンブラスチン(ベルバン(登録商標));ビンクリスチン(オンコビン(登録商標));ビノレルビン(ナベルビン(登録商標));ゾレドロネート(ゾメタ(登録商標))およびボリノスタット(ゾリンザ(登録商標))。
カラム:ACE C8カラム,4.6×150mm
勾配:0〜100% アセトニトリル+メタノール 60:40(20mM トリスホスフェート)
流速:1.5mL/分
検出:225nm。
エタノール(50mL)中の(S)−(+)−3−フルオロピロリジン塩酸塩(2.0g,15.9mmol)およびDiPEA(6.1mL,35mmol)の混合物に、2,4,6−トリクロロピリジン(2.9g,15.9mmol)を添加した。上記混合物を1時間還流し、次いで、乾燥するまでエバポレートした。上記残渣を、ISCO(EtOAc/ヘプタン;TLC:SiO2,EtOAc/ヘプタン=1:4,Rf=0.5(2−置換されたピリジン),Rf=0.2(4−置換されたピリジン)によって精製して、0.70g(19%)の所望の生成物を得た。
1H−NMR(300MHz,CDCl3): δ 6.37(s,2H);5.51−5.48(m,1/2H);5.33−5.31(m,1/2H);3.64−3.59(m,1H);3.53−3.47(m,3H);2.51−2.39(m,1H);2.39−2.08(m,1H)ppm。
ジオキサン中の、(S)−2,6−ジクロロ−4−(3−フルオロピロリジン−1−イル)ピリジン(1.73g,7.36mmol)、2−アミノ−5−メチルチアゾール(0.92g,8.1mmol)、Pd2dba3(0.34g,0.37mmol)、xantphos(0.32g,0.55mmol)、およびNa2CO3(1.1g,10.3mmol)の混合物に窒素を曝気した。上記混合物を、電子レンジで180℃になるまで1時間にわたって加熱した。HPLC分析によって、完全な変換が示され、上記混合物を、セライトに対して濾過した。上記セライトをジオキサンですすいだ後、その合わせた濾液を乾燥するまでエバポレートした。その残渣を、カラムクロマトグラフィー(SiO2(100mL),EtOAc/ヘプタン=1:9−1:0)によって精製した。Rf=0.5〜0.8を有する画分(TLC,SiO2,EtOAc)をプールし、乾燥するまでエバポレートして、58〜71%の純度(HPLC,Rf=8.578分)を有する1.4gの所望の生成物を得た。
1H−NMR(300MHz,CDCl3): δ 7.00(s,1H);6.11(s,1H);5.99(s,1H);5.47−5.44(m,1/2H);5.29−5.27(m,1/2H);3.61−3.47(m,4H);2.52−2.40(m,1H);2.38(s,3H);2.28−2.04(m,1H)ppm。
1−メチル−2−ピロリジノン(NMP,10mL)中の、(S)−6−クロロ−4−(3−フルオロピロリジン−1−イル)−N−(5−メチルチアゾール−2−イル)ピリジン−2−アミン(0.5g,1.6mmol)、N−(4−メルカプトフェニル)シクロプロパンカルボキサミド(330mg,1.7mmol)、炭酸カリウム(500mg,3.6mmol)、およびテトラキス(トリフェニルホスフィン)パラジウム(0)(120mg,0.1mmol)の混合物に、15分間窒素を曝気した。その混合物を、電子レンジで180℃になるまで1時間加熱した。HPLCによって完全な変換が示された。上記混合物を、セライトに対して濾過した。上記セライトをメタノールですすいだ。その合わせた濾液を減圧下でエバポレートして、メタノールを除去した。水(25mL)をその残渣に攪拌しながら添加した。攪拌を30分間継続し、形成された固体を濾過によって集め、水で洗浄した。上記固体をメタノール中に溶解させることによって、それをシリカ上にコーティングした。上記シリカを、カラムに詰め、次いで、それを、CH2Cl2/4〜6% 2−プロパノールで溶出した。生成物含有画分(TLC(SiO2,CH2Cl2/8% 2−プロパノール) Rf=0.65)をプールし、乾燥するまでエバポレートして、66〜72% 純度(HPLC)を有する200mgの生成物を得た。この物質を、分取用HPLCによって精製した。エバポレートおよび凍結乾燥した後に、99+% 純度(HPLC,Rf=8.598分)を有する41mg(5.5%)の(S)−N−(4−(4−(3−フルオロピロリジン−1−イル)−6−(5−メチルチアゾール−2−イルアミノ)ピリジン−2−イルチオ)フェニル)シクロプロパンカルボキサミドを得た。
1H−NMR(300MHz,DMSO−d6): δ 10.49(s,1H);10.39(s,1H);7.70(d,J=8.6Hz,2H);7.48(d,J=8.6Hz,2H);6.86(s,1H);5.89(d,J=1.8Hz,1H);5.85(d,J=1.8Hz,1H);5.50−5.32(m,1H);3.51−3.20(m,4H);2.26−2.08(m,2H);2.14(s,3H);1.91−1.78(m,1H);0.82−0.80(m,4H)ppm。
(S)−N−(4−(4−(3−フルオロピロリジン−1−イル)−6−(3−メチル−1H−ピラゾール−5−イルアミノ)ピリジン−2−イルチオ)フェニル)シクロプロパンカルボキサミド(化合物2)
ジオキサン(10mL)中の(S)−2,6−ジクロロ−4−(3−フルオロピロリジン−1−イル)ピリジン(600mg,2.6mmol)、tert−ブチル3−アミノ−5−メチル−1H−ピラゾール−1−カルボキシレート(510mg,2.6mmol)、Pd2dba3(119mg)、xantphos(150mg)、および炭酸ナトリウム(382mg,3.6mmol)の混合物に、窒素を曝気した。上記混合物を、電子レンジ中で、140℃まで45分にわたって加熱し、次いで、170℃まで15分にわたって加熱した。セライトに対して濾過し、ジオキサンですすいだ後、上記溶媒を減圧下で除去した。その残渣を、カラムクロマトグラフィー(SiO2(75mL),CH2Cl2/2.5〜7% 2−プロパノール; TLC:CH2Cl2/5% 2−プロパノール,Rf=0.3)によって精製して、230mgの所望の生成物を乳白色固体(HPLC:Rf=7.341分)として得た。
NMP(5mL)中の、(S)−6−クロロ−4−(3−フルオロピロリジン−1−イル)−N−(3−メチル−1H−ピラゾール−5−イル)ピリジン−2−アミン(230mg,0.87mmol)、N−(4−メルカプトフェニル)−シクロプロパンカルボキサミド(194mg,0.94mmol)、テトラキス(トリフェニルホスフィン)−パラジウム(0)(90mg)、およびK2CO3(237mg,1.7mmol)の混合物に、窒素を15分間曝気した後、上記混合物を、190℃まで1時間にわたって加熱した。上記混合物を水(100mL)中に注ぎ、30分間の撹拌後、上記固体を濾過によって集め、水で(2回)洗浄した。上記固体を乾燥させ、カラムクロマトグラフィー(SiO2,CH2Cl2/2〜10% 2−プロパノール)によって精製した。Rf=0.1(TLC:SiO2,CH2Cl2/5% 2−プロパノール)を有する画分をプールし、乾燥するまでエバポレートして、純度80%(HPLC,Rf=8.08分)を有する300mgを得た。この物質を、分取用HPLCによって精製して、エバポレーションおよび凍結乾燥した後に、純度97+%(HPLC,Rf=8.092分)を有する45mgの(S)−N−(4−(4−(3−フルオロピロリジン−1−イル)−6−(3−メチル−1H−ピラゾール−5−イルアミノ)ピリジン−2−イルチオ)フェニル)シクロプロパンカルボキサミドを得た。
1H−NMR(300MHz,DMSO−d6):δ11.54(s,1H);10.39(s,1H);8.69(s,1H);7.70(d,J=8.5Hz,2H);7.46(d,J=8.6Hz,2H);6.17(s,1H);5.66−5.60(m,2H);5.48−5.30(m,1H);3.48−3.16(m,4H);2.25−2.15(m,2H);2.06(s,3H);1.84−1.77(m,2H);0.85−80(m,2H)ppm。
化合物を、標準的な結合酵素アッセイ(Foxら,Protein Sci.,(1998)7,2249)を使用して、Aurora−2を阻害するそれらの活性についてスクリーニングした。アッセイを、100mM Hepes(pH7.5)、10mM MgCl2、1mM DTT、25mM NaCl、2.5mM ホスホエノールピルビン酸、300μM NADH、 30μg/ml ピルビン酸キナーゼおよび10μg/ml 乳酸デヒドロゲナーゼの混合物中で実施した。このアッセイにおける最終基質濃度は、400μM ATP(Sigma Chemicals)および570μM ペプチド(Kemptide,American Peptide,Sunnyvale,CA)であった。アッセイを30℃で40nM Aurora−2の存在下で行った。
25mM HEPES(pH7.5)、10mM MgCl2、0.1% BSAおよび10% グリセロールからなるアッセイ緩衝溶液を調製した。22nM Aurora−B溶液(これはまた、1.7mM DTTおよび1.5mM Kemptide(LRRASLG)を含む)を、アッセイ緩衝液中に調製した。22μLの上記Aurora−B溶液に、96ウェルプレートにおいて、DMSO中の2μlの化合物ストック溶液を添加し、その混合物を25℃で10分間平衡化させた。その酵素反応を、最終アッセイ濃度800μMになるまでアッセイ緩衝液中に調製した16μl ストック[γ−33P]−ATP溶液(約20nCi/μL)を添加することによって開始した。その反応を、16μL 500mM リン酸を添加することによって3時間後に停止させ、上記ペプチド基質への33P組み込みのレベルを、以下の方法によって決定した。
化合物を、ECACCから得たColo205細胞を使用し、そして以下に示すアッセイを使用して、それらの細胞増殖を阻害する能力およびそれらの細胞生存に対する効果についてスクリーニングした。
Claims (72)
- 式Iの化合物:
X1は、NもしくはCHであり;
X2は、NもしくはCHであり;
X3は、NもしくはCRXであり;
ただし、X3がCRXである場合、X1およびX2のうちの一方のみがNであり;そしてただしX1、X2およびX3のうちの少なくとも1つはNであり;
Htは、チアゾールもしくはピラゾールであり、ここで各環は、必要に応じてかつ独立して、R2およびR2’で置換され;
Qは、−O−、−NR’−、−S−、−C(=O)−、もしくは−C(R’)2−であり;
RXは、HもしくはFであり;
RYは、−Z−R10であり;
R1は、T−(環D)であり;
環Dは、5〜7員の単環式アリールもしくはヘテロアリール環であり、ここで該ヘテロアリールは、O、N、もしくはSから選択される1〜4個の環ヘテロ原子を有し;環Dは、必要に応じて、環D’と縮合され得;
環D’は、窒素、酸素、もしくは硫黄から選択される0〜4個の環ヘテロ原子を含む、5〜8員の芳香族の、部分飽和の、もしくは完全不飽和の環であり;
環Dおよび環D’は、各々独立してかつ必要に応じて、オキソもしくは−W−R5の0〜4個の存在で置換され;
各Tは、独立して、C1−4アルキリデン鎖であるかもしくは存在せず;
R2は、H、C1−3アルキル、もしくはシクロプロピルであり;
R2’はHであり;
各ZおよびWは、独立して、存在しないかもしくはC1−10アルキリデン鎖であり、ここで該アルキリデン鎖の最大6個までのメチレン単位は、必要に応じて、Vによって置換され;
各Vは、−O−、−C(=O)−、−S(O)−、−S(O)2−、−S−、もしくは−N(R4)−から選択され;
各R5は、独立して、−R、−ハロ、−OR、−C(=O)R、−CO2R、−COCOR、COCH2COR、−NO2、−CN、−S(O)R、−S(O)2R、−SR、−N(R4)2、−CON(R7)2、−SO2N(R7)2、−OC(=O)R、−N(R7)COR、−N(R7)CO2(C1−6脂肪族)、−N(R4)N(R4)2、−C=NN(R4)2、−C=N−OR、−N(R7)CON(R7)2、−N(R7)SO2N(R7)2、−N(R4)SO2R、もしくは−OC(=O)N(R7)2であり;
各Rは、H、C1−6脂肪族基、C6−10アリール環、5〜10個の環原子を有するヘテロアリール環、もしくは4〜10個の環原子を有するヘテロシクリル環であり;ここで該ヘテロアリール環もしくはヘテロシクリル環は、窒素、酸素、もしくは硫黄から選択される1〜4個の環ヘテロ原子を有し;Rは、必要に応じて、0〜6個のR9で置換されており;
各R4は、−R7、−COR7、−CO2R7、−CON(R7)2、もしくは−SO2R7であり;
各R7は、独立して、Hもしくは1〜6個のハロもしくは−O(C1−6アルキル)で必要に応じて置換されたC1−6脂肪族であるか;または同じ窒素上の2つのR7が該窒素と一緒になって、 必要に応じて置換された、窒素、酸素、もしくは硫黄から選択される1〜4個のヘテロ原子を含む4〜8員のヘテロシクリル環もしくはヘテロアリール環を形成し;
各R9は、−R’、−ハロ、−OR’、−C(=O)R’、−CO2R’、−COCOR’、COCH2COR’、−NO2、−CN、−S(O)R’、−S(O)2R’、−SR’、−N(R’)2、−CON(R’)2、−SO2N(R’)2、−OC(=O)R’、−N(R’)COR’、−N(R’)CO2(C1−6脂肪族)、−N(R’)N(R’)2、−N(R’)CON(R’)2、−N(R’)SO2N(R’)2、−N(R’)SO2R’、−OC(=O)N(R’)2、=NN(R’)2、=N−OR’、もしくは=Oであり;
各R10は、O、N、もしくはSから選択される1個のヘテロ原子を含む5〜6員の複素環式環であり;各R10は、必要に応じて、0〜6個のJの存在で置換されており;
各Jは、独立して、R、−ハロ、−OR、オキソ、−C(=O)R、−CO2R、−COCOR、−COCH2COR、−NO2、−CN、−S(O)R、−S(O)2R、−SR、−N(R4)2、−CON(R7)2、−SO2N(R7)2、−OC(=O)R、−N(R7)COR、−N(R7)CO2(C1−6脂肪族)、−N(R4)N(R4)2、=NN(R4)2、=N−OR、−N(R7)CON(R7)2、−N(R7)SO2N(R7)2、−N(R4)SO2R、−OC(=O)N(R7)2、もしくは−OP(=O)(OR”)2であるか;または
同じ原子上もしくは異なる原子上の2個のJ基が、それらが結合される原子と一緒になって、O、N、もしくはSから選択される0〜2個のヘテロ原子を有する、3〜8員の飽和の、部分飽和の、もしくは不飽和の環を形成し;ここで該2個のJ基によって形成される該環上の1〜4個の水素原子は、必要に応じて、JRで置換されるか;または該環上の2つの水素原子は、必要に応じて、オキソもしくはスピロ結合C3−4シクロアルキルで置換され;ここで該C3−4アルキルは、必要に応じて、1〜3個のフッ素で置換され;
各JRは、FもしくはR7’であり;
各R7’は、独立して、C1−6脂肪族;−O(C1−6脂肪族);もしくはO、N、もしくはSから選択される1〜4個のヘテロ原子を含む5〜6員のヘテロアリールであり;各R7’は、必要に応じて、0〜3個のJ7で置換され;
J7は、独立して、NH2、NH(C1−4脂肪族)、N(C1−4脂肪族)2、ハロゲン、C1−4脂肪族、OH、O(C1−4脂肪族)、NO2、CN、CO2H、CO2(C1−4脂肪族)、O(ハロC1−4脂肪族)、もしくはハロC1−4脂肪族であり;
各R’は、独立して、HもしくはC1−6脂肪族基であるか;または2個のR’は、それらが結合される原子と一緒になって、3〜6員のカルボシクリル、またはO、N、もしくはSから選択される0〜1個のヘテロ原子を含む3〜6員のヘテロシクリルを形成し;そして
各R”は、独立して、HもしくはC1−2アルキルである、
化合物。 - X3はCRXである、請求項1に記載の化合物。
- X3はNである、請求項1に記載の化合物。
- X1はNである、請求項2もしくは3に記載の化合物。
- X1はCHである、請求項2または3に記載の化合物。
- X2はNである、請求項2〜5のいずれか1項に記載の化合物。
- X2はCHである、請求項2〜5のいずれか1項に記載の化合物。
- 式I−bの化合物から選択される、請求項8に記載の化合物。
- Qは−S−である、請求項1〜10のいずれか1項に記載の化合物。
- Qは−O−である、請求項1〜10のいずれか1項に記載の化合物。
- R2は、HもしくはC1−3アルキルである、請求項1〜12のいずれか1項に記載の化合物。
- 環Dは、5〜6員の単環式アリールもしくはヘテロアリール環であり;そして環Dは、環D’と縮合されている、請求項1〜13のいずれか1項に記載の化合物。
- 環D−D’は、8〜12員の二環式アリールまたは窒素、酸素、もしくは硫黄から選択される1〜5個のヘテロ原子を含むヘテロアリールである、請求項1〜13のいずれか1項に記載の化合物。
- 環D−D’は6:6環系である、請求項16に記載の化合物。
- 環D−D’はキノリンである、請求項17に記載の化合物。
- 環D−D’は、6:5環系である、請求項16に記載の化合物。
- 前記6:5環系は、2個の窒素原子を含む、請求項19に記載の化合物。
- 環D−D’は、ベンズイミダゾール、インダゾール、もしくはイミダゾピリジン環である、請求項20に記載の化合物。
- 環D−D’は、ベンズイミダゾールである、請求項21に記載の化合物。
- 環Dは、5〜6員の単環式アリールもしくはヘテロアリール環であり;Dは、D’と縮合されていない、請求項1〜13のいずれか1項に記載の化合物。
- 環Dは、6員の単環式アリールもしくはヘテロアリール環である、請求項23に記載の化合物。
- 環Dはフェニルもしくはピリジルである、請求項24に記載の化合物。
- 環Dはフェニルである、請求項25に記載の化合物。
- 環Dはフェニルであり、該フェニルは、独立して、−ハロおよび−N(R7)CO2(C1−6脂肪族)から選択される1個もしくは2個の置換基で置換されている、請求項25に記載の化合物。
- 環Dはフェニルであり、該フェニルは、独立して、−Fおよび−NHCO2(C1−3脂肪族)で置換されている、請求項25に記載の化合物。
- 環Dはフェニルであり、該フェニルは、独立して、−Fおよび−NHCO2(シクロプロピル)で置換されている、請求項25に記載の化合物。
- RYは、−Z−R10である、請求項1〜29のいずれか1項に記載の化合物。
- Zは存在しない、請求項30に記載の化合物。
- Zは、C1−6アルキリデン鎖であり、ここでZの1〜2個のメチレン単位は、必要に応じて、O、−N(R4)−、もしくはSで置換されている、請求項30に記載の化合物。
- R10は、1個の窒素原子を含む5〜6員の複素環式環である、請求項30〜32のいずれか1項に記載の化合物。
- R10はピロリジンである、請求項33に記載の化合物。
- R10はピペリジンである、請求項33に記載の化合物。
- 各Jは、独立して、C1−6アルキル、F、−N(R4)2、CN、もしくは−ORであり、ここで各−N(R4)2基のうちの少なくとも1個のR4は、Hではないか;または2個のJ基が、これらが結合される原子と一緒になって、NもしくはOから選択される1〜2個のヘテロ原子を含む4〜7員のヘテロシクリル環を形成し;ここで該環は、必要に応じて、0〜3個のJRで置換されている、請求項36に記載の化合物。
- Rは、H、C1−4アルキルもしくはC3−6シクロアルキルであり;ここで該C1−4アルキルもしくはC3−6シクロアルキルは、必要に応じて、1〜3個のフッ素原子で置換されている、請求項37に記載の化合物。
- R4は、H、C1−5アルキル、もしくはC3−6シクロアルキルであり;ここで各−N(R4)2基のうちの少なくとも1個のR4は、Hではないか;または2個のR4は、それらが結合される窒素原子と一緒になって、O、N、もしくはSから選択される1〜2個のヘテロ原子を含む3〜6員の単環式環を形成し;ここで該単環式環は、必要に応じて、0〜3個のJRで置換されている、請求項37に記載の化合物。
- JRは、ハロ、C1−3アルキル、もしくは−O(C1−3アルキル)である、請求項1〜39のいずれか1項に記載の化合物。
- Jは、F、−N(R4)2、CN、−OR、オキソ(=O)、または必要に応じて、OHもしくはOCH3の1個の存在で置換されたC2−6アルキルであり;ここで各−N(R4)2基のうちの少なくとも1個のR4は、Hではない、請求項41に記載の化合物。
- JはFである、請求項42に記載の化合物。
- nは1である、請求項36〜43のいずれか1項に記載の化合物。
- nは2である、請求項36〜43のいずれか1項に記載の化合物。
- 前記2個のJ基は、それらが結合される原子と一緒になって、NもしくはOから選択される1〜2個のヘテロ原子を含む4〜7員のスピロ環式ヘテロシクリル環を形成し;ここで該環は、必要に応じて、0〜3個のJRで置換されている、請求項47に記載の化合物。
- 前記2個のJ基は、それらが結合される原子と一緒になって、NもしくはOから選択される1個のヘテロ原子を含む5員のスピロ環式ヘテロシクリル環を形成し;ここで該環は、必要に応じて、0〜3個のJRで置換されている、請求項48に記載の化合物。
- 前記2個のJ基は、それらが結合される原子と一緒になって、1個のNヘテロ原子を含む5員のスピロ環式ヘテロシクリル環を形成し;ここで該環は、必要に応じて、0〜3個のJRで置換されている、請求項49に記載の化合物。
- 前記2個のJ基は、それらが結合される原子と一緒になって、1個のNヘテロ原子を含む5員のスピロ環式ヘテロシクリル環を形成し;ここで該環は、必要に応じて、1個のJRで置換されている、請求項50に記載の化合物。
- JRは、ハロ、C1−3アルキル、もしくは−O(C1−3アルキル)である、請求項46〜51のいずれか1項に記載の化合物。
- JRはCH3である、請求項54に記載の化合物。
- 前記増殖性障害は癌である、請求項62に記載の方法。
- 前記増殖性障害は、黒色腫、骨髄腫、白血病、リンパ腫、神経芽細胞腫、または結腸癌、乳癌、胃癌、卵巣癌、子宮頸癌、肺癌、中枢神経系(CNS)癌、腎癌、前立腺癌、膀胱癌、膵臓癌、脳の癌(神経膠腫)、頭頸部癌、腎臓癌、肝臓癌、黒色腫、肉腫、もしくは甲状腺癌から選択される癌、から選択される、請求項62に記載の方法。
- 別の治療剤を逐次的投与する工程または同時に投与する工程をさらに包含する、請求項63に記載の方法。
- 前記治療剤は、タキサン、bcr−ablのインヒビター、EGFRのインヒビター、DNA損傷剤、および代謝拮抗産物から選択される、請求項65に記載の方法。
- 前記治療剤は、パクリタキセル、グリベック、ダサチニブ、ニロチニブ、タルセバ、イレッサ、シスプラチン、オキサリプラチン、カルボプラチン、アントラサイクリン、AraCおよび5−FUから選択される、請求項65に記載の方法。
- 前記治療剤は、カンプトテシン、ドキソルビシン、イダルビシン、シスプラチン、タキソール、タキソテール、ビンクリスチン、タルセバ、MEKインヒビター、U0126、KSPインヒビター、ボリノスタット、グリベック、ダサチニブ、およびニロチニブから選択される、請求項65に記載の方法。
- 前記治療剤は、ダサチニブもしくはニロチニブである、請求項65に記載の方法。
- 前記治療剤はダサチニブである、請求項65に記載の方法。
- 前記治療剤はニロチニブである、請求項65に記載の方法。
- 以下:
(S)−N−(4−(4−(3−フルオロピロリジン−1−イル)−6−(5−メチルチアゾール−2−イルアミノ)ピリジン−2−イルチオ)フェニル)シクロプロパンカルボキサミド;および
(S)−N−(4−(4−(3−フルオロピロリジン−1−イル)−6−(3−メチル−1H−ピラゾール−5−イルアミノ)ピリジン−2−イルチオ)フェニル)シクロプロパンカルボキサミド.
から選択される、請求項1に記載の化合物。
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Also Published As
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EP2164842A2 (en) | 2010-03-24 |
WO2008147626A3 (en) | 2009-03-19 |
US20110060013A1 (en) | 2011-03-10 |
JP2014141529A (ja) | 2014-08-07 |
MX2009012719A (es) | 2010-02-04 |
CA2687966A1 (en) | 2008-12-04 |
WO2008147626A2 (en) | 2008-12-04 |
CN101687852A (zh) | 2010-03-31 |
AU2008257044A1 (en) | 2008-12-04 |
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