JP2017506267A - 癌及び増殖性疾患の治療のための抗有糸分裂性アミド - Google Patents
癌及び増殖性疾患の治療のための抗有糸分裂性アミド Download PDFInfo
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 229960002431 trimipramine Drugs 0.000 description 1
- ZSCDBOWYZJWBIY-UHFFFAOYSA-N trimipramine Chemical compound C1CC2=CC=CC=C2N(CC(CN(C)C)C)C2=CC=CC=C21 ZSCDBOWYZJWBIY-UHFFFAOYSA-N 0.000 description 1
- SYHDSBBKRLVLFF-UHFFFAOYSA-N triparanol Chemical class C1=CC(OCCN(CC)CC)=CC=C1C(O)(C=1C=CC(C)=CC=1)CC1=CC=C(Cl)C=C1 SYHDSBBKRLVLFF-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
- 208000021331 vascular occlusion disease Diseases 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 1
- 229960004982 vinblastine sulfate Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 1
- 229960002110 vincristine sulfate Drugs 0.000 description 1
- 229960005212 vindesine sulfate Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- 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
- C07D401/02—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 two hetero rings
- C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
Description
で表される化合物、塩、プロドラッグ、及び溶媒和物が開示される。本化合物は、癌並びに増殖性疾患及び障害の治療及び予防に使用することができる。
で表される化合物である。
で表される化合物である。
本開示は、癌を直接治療するため、又は他の癌治療の効力を改善するための有効な抗増殖剤、抗有糸分裂剤に対するニーズに取り組む。本開示は、癌等の増殖性疾患の治療又は予防に有用な化合物及び医薬組成物に関する。
(1) X1がNであり、X2がCHであり、またArが非置換フェニルであり、さらにR8、R9及びR11のそれぞれが水素である場合、R5及びR6がいずれもCl又はOCH3である場合はない;
(2) X1及びX2がいずれもCHであり、さらにArが非置換フェニルである場合、R5、R6、R8、R9及びR11の少なくとも1つは水素ではない;
(3) X1がCHであり、X2がC-Clであり、Arが非置換フェニルであり、さらにR11がCl又はO-イソプロピルである場合、R5、R6、R8及びR9の少なくとも1つは水素ではない;
(4) ArがN-(5-(3-(ピリジン-3-イル)-5-(トリフルオロメチル)-1H-ピラゾール-1-イル)であり、X1がCHである場合、R5、R6、R7、R8、R9及びR11のそれぞれは水素ではない;
(5) ArがN-(5-(3-(ピリジン-3-イル)-5-(トリフルオロメチル)-1H-ピラゾール-1-イル)であり、X1及びX2がCHであり、さらにR5、R6、R8及びR9のそれぞれがHである場合、R11は、-OCH2CF3、2-(ピロリジン-1-イル)エトキシ、2-モルホリノエトキシ、又はシアノではない;
を適用することが可能であり、あるいは上記の(4)及び(5)の代わりに、Arが1H-ピラゾロ-1-イルである場合、Arがピリジン-3-イル及びトリフルオロメチルで置換されることはなく;
あるいは上記の(1)〜(5)の全ての代わりに、以下の化合物の1つ以上を除外し得る。
(1) X1がNであり、X2がCHであり、さらにR1、R2、R3、R4、R8、R9及びR11のそれぞれが水素である場合、R5及びR6がいずれもCl又はOCH3である場合はない;
(2) X1及びX2がいずれもCHである場合、R1、R2、R3、R4、R5、R6、R8、R9及びR11の少なくとも1つは水素ではない;
(3) X1がCHであり、X2がC-Clであり、さらにR11がCl又はO-イソプロピルである場合、R1、R2、R3、R4、R5、R6、R8及びR9の少なくとも1つは水素ではない;
を適用し、あるいは上記の(1)〜(3)の代わりに、本化合物のいずれか1つ以上は、上記式Iの潜在的な例外として特定される。
(1) B及びD1がNであり、D2がC-3-ピリジルであり、D3がCHであり、またD4がC(CF3)であり、X1がCHであり、さらにR5、R6、R8、R9、R11のそれぞれがHである場合、X2はNではない;並びに
(2) B及びD1がNであり、D2がC-3-ピリジルであり、D3がCHであり、またD4がC(CF3)であり、X1及びX2がCHであり、さらにR2、R3、R6、R7のそれぞれがHである場合、R5は、OCH2CF3、2-(ピロリジン-1-イル)エトキシ、2-モルホリノエトオキシ、又はシアノではない;
を適用し、あるいは上記の(1)及び(2)の代わりに、B及びD1がNである場合、D2及びD4はC-ピリジン-3-イル又はC-トリフルオロメチルではあり得ず、
あるいは上記の(1)及び(2)の代わりに、本化合物のいずれか1つ以上は、上記式Iについて上記に特定される。
本明細書に記載される化合物、又は製薬上許容されるその付加塩もしくは水和物は、様々な経路又は投与様式を用いて患者に送達することができる。適切な投与経路としては、限定するものではないが、例えば、吸入投与、経皮投与、経口投与、直腸投与、経粘膜投与、腸内投与及び非経口投与(例えば筋肉内注射、皮下注射及び静脈内注射)等が挙げられる。
上記の化合物との使用に適した医薬組成物としては、活性成分が治療上有効量(その意図される目的を達成するために有効な量)で含まれる組成物が挙げられる。当然、特定の適用に有効な実際量は、治療される状態に応じて決定される。例えば、細胞増殖を阻害する方法において投与する場合、このような組成物は、この結果を得るのに有効な活性成分量を含む。異常な細胞増殖を特徴とする疾患に罹患している患者に投与する場合、このような組成物は、治療対象の患者の既存の症状の発達を予防するか又は既存の症状を軽減するため、あるいは治療対象の患者の生存時間を延長するために有効な活性成分量を含む。癌の治療における使用のため、治療上有効量は、腫瘍の成長を阻止するか又は退行させる化合物の量をさらに包含する。有効量の決定は、十分に当業者の能力の範囲内である。
表Iにおいて、式I〜IIIの化合物がリストされ、1H-NMRデータにより同定される。NDは、1H-NMRデータが同定されなかったことを示す。表Iにリストされる化合物は、表IIにおいてさらに特性決定される。表Iにおける化合物のそれぞれを調製する方法は、表IIにおいても同定される。表IIのモノマー合成列におけるNAは、化合物51、52、53、54、55、56、58、60、65及び68を除き、出発物質として使用したモノマーが市販されていたことを示す。化合物 51、52、53、54、55、56、58、60、65及び68の調製方法は、実施例中の他の箇所に記載される。
ステップ1/2:2-クロロ-1-メチルピリジニウムヨージド(679mg、2.66mmol、2.0当量)とDIPEA(344mg、463μL、2.66mmol、2.0当量)を、5-[3-(シクロプロピルオキシ)フェニル]ピリジン-2-アミン(300mg、1.33mmol、1.0当量)と6-({2-[(tert-ブトキシカルボニル)アミノ]エチル}アミノ)ピリジン-3-カルボン酸(373mg、1.33mmol、1.0当量)のTHF(30mL)中撹拌溶液に加えた。反応混合物を室温で16時間撹拌した。次いで、反応混合物を減圧下で濃縮し、得られた粗生成物を、石油エーテル中30%酢酸エチルで溶出する(100〜200メッシュのシリカゲル上の)フラッシュクロマトグラフィーにより精製した。その後、精製した物質をジオキサン(4N、50ml)中HCl溶液に溶解し、室温で1時間撹拌した。次いで、反応混合物を減圧下で濃縮して残留物を得て、これをペンタンでの粉砕により精製し、2-[(2-アミノエチル)アミノ]-N-[5-(3-シクロプロピルオキシフェニル)ピリジン-2-イル]ピリミジン-5-カルボキサミド(58)(10mg;2.8%)を生じた。
チューブリン重合アッセイはブタ神経チューブリンを使用し、測定は、重合が起こる際の蛍光レポーターの微小管への組み込みによる蛍光増強に基づく。このアッセイは、微小管形成の三相(核形成相、伸長相及び平衡相)を示す重合曲線を生成する。試験した化合物のIC50値は、観測重合曲線から生成することができる。
細胞をトリプシン処理し、計数し、25mL培地中1ウェル当たり1000細胞で384ウェル組織培養プレートに再播種した。細胞を、37℃で5%CO2雰囲気中24時間インキュベートした。最初にDMSOに溶解しさらに培地中で希釈した実験化合物をウェルに加え、72時間インキュベートした。ATPlite 1ステップ発光検出アッセイシステム(Perkin Elmer社)を使用して、細胞生存率を、アッセイキットの指示書に記載されるとおりに測定した。選択された化合物を用いた結果は、表IVに示される。
Claims (40)
- 式I:
Arは、ハロゲン、置換又は非置換C1-8アルキル、置換又は非置換C3-6シクロアルキル、置換又は非置換C2-8アルケニル、置換又は非置換C2-8アルキニル、-CN、-NO2、-C(O)RA、-CO2RA、-C(O)NRARB、-ORA、-OC(O)RA、-OC(O)NRARB、-NRCC(O)RA、-NRCC(O)NRARB、-NRARB、-NRCCO2RA、-NRCS(O)2RA、-SRA、-S(O)RA、-S(O)2RA、-S(O)2NRARB、置換又は非置換C6-10アリール、置換又は非置換5〜10員ヘテロアリール、及び置換又は非置換3〜10員ヘテロシクリルから選択される0〜5個の置換基をそれぞれ有する置換されていてもよいフェニル又は置換されていてもよい5員ヘテロアリール環であり;但し、Arがフェニルである場合、少なくとも1つのオルト置換は-Hであり;
X1は、N及びCR7から選択され;
X2は、N及びCR10から選択され;
R5、R6、R7、R10及びR11のそれぞれは、-H、ハロゲン、置換又は非置換C1-8アルキル、置換又は非置換C2-8アルケニル、置換又は非置換C2-8アルキニル、-CN、-NO2、-C(O)RA、-CO2RA、-C(O)NRARB、-ORA、-OC(O)RA、-OC(O)NRARB、-NRCC(O)RA、-NRCC(O)NRARB、-NRARB、-NRCCO2RA、-NRCS(O)2RA、-SRA、-S(O)RA、-S(O)2RA、-S(O)2NRARB、置換又は非置換C6-10アリール、置換又は非置換5〜10員ヘテロアリール、及び置換又は非置換3〜10員ヘテロシクリルから独立して選択され;
R8及びR9のそれぞれは、H、ハロゲン、-ORA、-NH2、-NO2、-O(CO)RA、-O(CO)NRARB、-SH、及びSRAから独立して選択され;
RA、RB及びRCのそれぞれは、存在する場合、-H、ハロゲン、置換又は非置換C1-8アルキル、置換又は非置換C3-6シクロアルキル、置換又は非置換C2-8アルケニル、置換又は非置換C2-8アルキニル、-CN、=O、-NO2、-OR'、-OC(O)R'、-CO2R'、-C(O)R'、-C(O)NR'R''、-OC(O)NR'R''、-NR'''C(O)R'、-NR'''C(O)NR'R''、-NR'R''、-NR'''CO2R'、-SR'、-S(O)R'、-S(O)2R'、-S(O)2NR'R''、-NR'S(O)2R''、置換又は非置換C6-10アリール、置換又は非置換5〜10員ヘテロアリール、及び置換又は非置換3〜10員ヘテロシクリルから独立して選択され;
R'、R''及びR'''は、それぞれ独立して、-H、非置換C1-4アルキル、置換又は非置換C3-6シクロアルキルであり、あるいはR'とR''は、それらが置換する原子と一緒になって、置換又は非置換5、6、又は7員環を形成し;
但し、X1がNであり、X2がCHであり、またArが非置換フェニルであり、さらにR8、R9及びR11のそれぞれが水素である場合、R5及びR6はいずれもがCl又はOCH3ではあり得ず;
但し、X1及びX2がいずれもCHであり、さらにArが非置換フェニルである場合、R5、R6、R8、R9及びR11の少なくとも1つは水素ではなく;
但し、X1がCHであり、X2がC-Clであり、Arが非置換フェニルであり、さらにR11がCl又はO-イソプロピルである場合、R5、R6、R8及びR9の少なくとも1つは水素ではなく;
但し、Arが1H-ピラゾロ-1-イルである場合、Arはピリジン-3-イル及びトリフルオロメチルで置換されない)
で表される化合物又は塩。 - 式II:
X1は、N及びCR7から選択され;
X2は、N及びCR10から選択され;
R1、R2、R3及びR4のそれぞれは、-H、ハロゲン、置換又は非置換C1-8アルキル、置換又は非置換C3-6シクロアルキル、置換又は非置換C2-8アルケニル、置換又は非置換C2-8アルキニル、-CN、-NO2、-C(O)RA、-CO2RA、-C(O)NRARB、-ORA、-OC(O)RA、-OC(O)NRARB、-NRCC(O)RA、-NRCC(O)NRARB、-NRARB、-NRCCO2RA、-NRCS(O)2RA、-SRA、-S(O)RA、-S(O)2RA、-S(O)2NRARB、置換又は非置換C6-10アリール、置換又は非置換5〜10員ヘテロアリール、及び置換又は非置換3〜10員ヘテロシクリルから独立して選択され;
R5、R6、R7、R10及びR11のそれぞれは、-H、ハロゲン、置換又は非置換C1-8アルキル、置換又は非置換C2-8アルケニル、置換又は非置換C2-8アルキニル、-CN、-NO2、-C(O)RA、-CO2RA、-C(O)NRARB、-ORA、-OC(O)RA、-OC(O)NRARB、-NRCC(O)RA、-NRCC(O)NRARB、-NRARB、-NRCCO2RA、-NRCS(O)2RA、-SRA、-S(O)RA、-S(O)2RA、-S(O)2NRARB、置換又は非置換C6-10アリール、置換又は非置換5〜10員ヘテロアリール、及び置換又は非置換3〜10員ヘテロシクリルから独立して選択され;
R8及びR9のそれぞれは、-H、ハロゲン、-ORA、-NH2、-NO2、-O(CO)RA、-O(CO)NRARB、-SH、及びSRAから独立して選択され;
RA、RB及びRCのそれぞれは、存在する場合、-H、ハロゲン、置換又は非置換C1-8アルキル、置換又は非置換C3-6シクロアルキル、置換又は非置換C2-8アルケニル、置換又は非置換C2-8アルキニル、-CN、=O、-NO2、-OR'、-OC(O)R'、-CO2R'、-C(O)R'、-C(O)NR'R''、-OC(O)NR'R''、-NR'''C(O)R'、-NR'''C(O)NR'R''、-NR'R''、-NR'''CO2R'、-SR'、-S(O)R'、-S(O)2R'、-S(O)2NR'R''、-NR'S(O)2R''、置換又は非置換C6-10アリール、置換又は非置換5〜10員ヘテロアリール及び置換又は非置換3〜10員ヘテロシクリルから独立して選択され;
R'、R''及びR'''は、それぞれ独立して、水素、非置換C1-4アルキル、及び置換又は非置換C3-6シクロアルキルであり、あるいはR'とR''は、それらが置換する原子と一緒になって、置換又は非置換5、6、又は7員環を形成し;
但し、X1がNであり、X2がCHであり、さらにR1、R2、R3、R4、R8、R9及びR11のそれぞれが水素である場合、R5及びR6はいずれもがCl又はOCH3ではあり得ず;
但し、X1及びX2がいずれもCHである場合、R1、R2、R3、R4、R5、R6、R8、R9及びR11の少なくとも1つは水素ではなく;
但し、X1がCHであり、X2がC-Clであり、さらにR11がCl又はO-イソプロピルである場合、R1、R2、R3、R4、R5、R6、R8及びR9の少なくとも1つは水素ではない)
で表される化合物又は塩。 - R1、R2、R3及びR4のそれぞれが、-H、ハロゲン、置換又は非置換C1-8アルキル、置換又は非置換C3-6シクロアルキル、-C(O)NRARB、-ORA、-NRARB、置換又は非置換5〜10員ヘテロアリール、及び置換又は非置換3〜10員ヘテロシクリルから独立して選択される、請求項1及び2のいずれか1項に記載の化合物又は塩。
- R1、R2、R3及びR4のそれぞれが-Hである、請求項2及び3のいずれか1項に記載の化合物又は塩。
- R1、R2、R3及びR4の少なくとも1つが、ハロゲン、置換又は非置換C1-8アルキル、置換又は非置換C3-6シクロアルキル、-C(O)NRARB、-ORA、-NRARB、-S(O)2RA、置換又は非置換5〜10員ヘテロアリール、あるいは置換又は非置換3〜10員ヘテロシクリルである、請求項2に記載の化合物又は塩。
- R1が、-H、クロロ、トリフルオロメチル、シクロプロピル、-(C=O)NHCH3、-OCH3、-O-シクロプロピル、-NH-シクロプロピル、1-メチル-ピペラジン-1-イル、4-メチルピペラジン-1-イル)エトキシル、フェニル、オキセタン-3-イル、シクロブチル、tert-ブチル、-S(O)2-シクロプロピル、ピペラジン-1-イル、ピロリジン-3-イル-アミノ、及びOHから選択され;
R2が、-H、クロロ、及び-OCH3から選択され;
R3が、-H、クロロ、シクロプロピル、-(C=O)NHCH3、-OCH3、-O-シクロプロピル、-NH-シクロプロピル、-S(O)2-シクロプロピル、1-メチル-ピペラジン-1-イル、4-メチルピペラジン-1-イル)エトキシル、フェニル、オキセタン-3-イル、シクロブチル、tert-ブチル、-S(O)2-シクロプロピル、ピペラジン-1-イル、ピロリジン-3-イル-アミノ、及び-OHから選択され;
R4が、-H、クロロ、トリフルオロメチル、及び-OCH3から選択され;
ここでR1、R2、R3及びR4の少なくとも1つは-Hではない、
請求項2及び5のいずれか1項に記載の化合物又は塩。 - R1及びR3の少なくとも一方が、-S(O)2-シクロプロピル及び1-メチル-ピペラジン-1-イルから選択される、請求項2、5及び6のいずれか1項に記載の化合物又は塩。
- R1及びR3の一方が、-S(O)2-シクロプロピル及び1-メチル-ピペラジン-1-イルから選択され、R1及びR3の他方が、-H、-Cl、-S(O)2-シクロプロピル、-NH-シクロプロピル、及びシクロプロピルから選択される、請求項2、5、6及び7のいずれか1項に記載の化合物又は塩。
- R1及びR3の少なくとも一方が-S(O)2-シクロプロピルである、請求項2及び5〜8のいずれか1項に記載の化合物又は塩。
- R1が-S(O)2-シクロプロピルであり、且つR3が-Hである、請求項2、5及び6〜9のいずれか1項に記載の化合物又は塩。
- R1及びR3の少なくとも一方が1-メチル-ピペラジン-1-イルである、請求項2、5、6及び7のいずれか1項に記載の化合物又は塩。
- R1及びR3の少なくとも一方がピペラジン-1-イルである、請求項2、5及び6のいずれか1項に記載の化合物又は塩。
- R1及びR3の少なくとも一方が-O-シクロプロピルであり、R1及びR3の他方が-Hである、請求項2、5及び6のいずれか1項に記載の化合物又は塩。
- R1及びR3のそれぞれが、シクロプロピル、-O-シクロプロピル、-NH-シクロプロピル、-S(O)2-シクロプロピル、1-メチル-ピペラジン-1-イル、ピペラジン-1-イル、及びオキセタン-3-イルから選択される、請求項2、5及び6のいずれか1項に記載の化合物又は塩。
- 式III:
X1は、N及びCR7から選択され;
X2は、N及びCR10から選択され;
D1、D2、D3、及びD4のそれぞれは、CR1、CR2、CR3、CR4、N、O、及びSから選択され;
Bは、C及びNから選択され;
R1、R2、R3及びR4のそれぞれは、-H、ハロゲン、置換又は非置換C1-8アルキル、置換又は非置換C3-6シクロアルキル、置換又は非置換C2-8アルケニル、置換又は非置換C2-8アルキニル、-CN、-NO2、-C(O)RA、-CO2RA、-C(O)NRARB、-ORA、-OC(O)RA、-OC(O)NRARB、-NRCC(O)RA、-NRCC(O)NRARB、-NRARB、-NRCCO2RA、-NRCS(O)2RA、-SRA、-S(O)RA、-S(O)2RA、-S(O)2NRARB、置換又は非置換C6-10アリール、置換又は非置換5〜10員ヘテロアリール、及び置換又は非置換3〜10員ヘテロシクリルから独立して選択され;
R5、R6、R7、R10及びR11のそれぞれは、-H、ハロゲン、置換又は非置換C1-8アルキル、置換又は非置換C2-8アルケニル、置換又は非置換C2-8アルキニル、-CN、-NO2、-C(O)RA、-CO2RA、-C(O)NRARB、-ORA、-OC(O)RA、-OC(O)NRARB、-NRCC(O)RA、-NRCC(O)NRARB、-NRARB、-NRCCO2RA、-NRCS(O)2RA、-SRA、-S(O)RA、-S(O)2RA、-S(O)2NRARB、置換又は非置換C6-10アリール、置換又は非置換5〜10員ヘテロアリール、及び置換又は非置換3〜10員ヘテロシクリルから独立して選択され;
R8及びR9のそれぞれは、-H、ハロゲン、-ORA、-NH2、-NO2、-O(CO)RA、-O(CO)NRARB、-SH、及び-SRAから独立して選択され;
RA、RB及びRCのそれぞれは、存在する場合、-H、ハロゲン、置換又は非置換C1-8アルキル、置換又は非置換C3-6シクロアルキル、置換又は非置換C2-8アルケニル、置換又は非置換C2-8アルキニル、-CN、=O、-NO2、-OR'、-OC(O)R'、-CO2R'、-C(O)R'、-C(O)NR'R''、-OC(O)NR'R''、-NR'''C(O)R'、-NR'''C(O)NR'R''、-NR'R''、-NR'''CO2R'、-SR'、-S(O)R'、-S(O)2R'、-S(O)2NR'R''、-NR'S(O)2R''、置換又は非置換C6-10アリール、置換又は非置換5〜10員ヘテロアリール及び置換又は非置換3〜10員ヘテロシクリルから独立して選択され;
R'、R''及びR'''は、-H、非置換C1-4アルキル、及び置換又は非置換C3-6シクロアルキルからそれぞれ独立して選択され、あるいはR'とR''は、それらが置換する原子と一緒になって、置換又は非置換5、6、又は7員環を形成し;
但し、B及びD1がNである場合、D2及びD4がC-ピリジン-3-イル又はC-トリフルオロメチルである場合はない)
で表される化合物又は塩。 - BがCである、請求項15に記載の化合物又は塩。
- D1、D2、及びD4のそれぞれがCHであり、さらにD3がSである、請求項15及び16のいずれか1項に記載の化合物又は塩。
- D2、D3、及びD4のそれぞれがCHであり、さらにD1がSである、請求項15及び16のいずれか1項に記載の化合物又は塩。
- D1、D3、及びD4のそれぞれがCHであり、さらにD2がOである、請求項15及び16のいずれか1項に記載の化合物又は塩。
- D1、D2、及びD3のそれぞれがCHであり、さらにD4がOである、請求項15及び16のいずれか1項に記載の化合物又は塩。
- X1がC-Hである、請求項1〜20のいずれか1項に記載の化合物又は塩。
- X1がC-Fである、請求項1〜20のいずれか1項に記載の化合物又は塩。
- X2がC-Hである、請求項1〜22のいずれか1項に記載の化合物又は塩。
- X2がNである、請求項1〜22のいずれか1項に記載の化合物又は塩。
- R5及びR6がいずれも-Hである、請求項1〜24のいずれか1項に記載の化合物又は塩。
- R5が-CH3であり、且つR6が-Hである、請求項1〜24のいずれか1項に記載の化合物又は塩。
- R8及びR9のそれぞれが、-H及びハロゲンから独立して選択される、請求項1〜26のいずれか1項に記載の化合物又は塩。
- R8及びR9が-Hである、請求項1〜26のいずれか1項に記載の化合物又は塩。
- R8がフルオロであり、且つR9が-Hである、請求項1〜26のいずれか1項に記載の化合物又は塩。
- R11が、-H、置換又は非置換C1-8アルキル、及び-NRARBから選択される、請求項1〜29のいずれか1項に記載の化合物又は塩。
- R11が、-H、-CH3、及び-NH2から選択される、請求項1〜30のいずれか1項に記載の化合物又は塩。
- R11が-Hである、請求項1〜31のいずれか1項に記載の化合物又は塩。
- R11が-CH3である、請求項1〜31のいずれか1項に記載の化合物又は塩。
- R11が-NH2である、請求項1〜31のいずれか1項に記載の化合物又は塩。
- X1がNであり、且つR7が存在しない、請求項1〜20及び22〜31のいずれか1項に記載の化合物又は塩。
- 請求項1〜35のいずれか1項に記載の化合物及び製薬上許容される担体又は賦形剤を含む医薬組成物。
- 請求項1〜35のいずれか1項に記載の化合物又は請求項36に記載の医薬組成物を患者に投与することを含む、それを必要とする患者において増殖性疾患を治療する方法。
- 増殖性疾患が癌であり、副腎癌、肛門癌、再生不良性貧血、胆管癌、膀胱癌、骨癌、脳癌、乳癌、頸部癌、中枢神経系癌、結腸癌、子宮内膜癌、食道癌、ユーイング腫瘍、眼癌、胆嚢癌、消化管カルチノイド、消化管間質腫瘍、カポジ肉腫、腎癌、喉頭癌、白血病、肝臓癌、肺癌、リンパ腫、悪性中皮腫、多発性骨髄腫、骨髄異形成症候群、鼻腔及び副鼻腔癌、鼻咽頭癌、神経芽細胞腫、口腔及び中咽頭癌、骨肉腫、卵巣癌、膵臓癌、陰茎癌、下垂体癌、前立腺癌、直腸癌、網膜芽細胞腫、横紋筋肉腫、唾液腺癌、肉腫、皮膚癌、小腸癌、胃癌、精巣癌、胸腺腫瘍、甲状腺癌、子宮肉腫、膣癌、及びウィルムス腫瘍から選択される、請求項37に記載の方法。
- 増殖性疾患が胃癌である、請求項37に記載の方法。
- 増殖性疾患が、キャッスルマン病、妊娠性絨毛性疾患、及びホジキン病から選択される、請求項37に記載の方法。
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WO2015127284A2 (en) | 2015-08-27 |
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US20200397758A1 (en) | 2020-12-24 |
RU2016135555A (ru) | 2018-03-28 |
BR112016019161B1 (pt) | 2022-12-20 |
US20220008395A1 (en) | 2022-01-13 |
ES2893374T3 (es) | 2022-02-08 |
KR20160116009A (ko) | 2016-10-06 |
IL247293B (en) | 2021-01-31 |
US11129813B2 (en) | 2021-09-28 |
KR102420508B1 (ko) | 2022-07-13 |
SG11201606869TA (en) | 2016-09-29 |
EP3107909B1 (en) | 2021-07-14 |
CA2940237A1 (en) | 2015-08-27 |
RU2713179C2 (ru) | 2020-02-04 |
CA2940237C (en) | 2023-03-07 |
SG10202000590SA (en) | 2020-03-30 |
JP6506313B2 (ja) | 2019-04-24 |
MX2016010877A (es) | 2017-05-04 |
CN114634483A (zh) | 2022-06-17 |
US10016398B2 (en) | 2018-07-10 |
EP3107909A2 (en) | 2016-12-28 |
AU2015218775A1 (en) | 2016-08-25 |
US10772872B2 (en) | 2020-09-15 |
BR112016019161A2 (ja) | 2017-08-15 |
US20180325871A1 (en) | 2018-11-15 |
US20170172984A1 (en) | 2017-06-22 |
CN106068263A (zh) | 2016-11-02 |
WO2015127284A3 (en) | 2015-10-15 |
IL247293A0 (en) | 2016-09-29 |
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