CN104822677A - 氟烷基-1,4-苯并二氮杂*酮化合物 - Google Patents
氟烷基-1,4-苯并二氮杂*酮化合物 Download PDFInfo
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- CN104822677A CN104822677A CN201380060053.6A CN201380060053A CN104822677A CN 104822677 A CN104822677 A CN 104822677A CN 201380060053 A CN201380060053 A CN 201380060053A CN 104822677 A CN104822677 A CN 104822677A
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- Prior art keywords
- phenyl
- oxo
- dihydro
- trifluoropropyl
- succinamide
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
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- 150000004654 triazenes Chemical class 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
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- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
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- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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Abstract
本发明公开了式(I)化合物,其中R2为苯基、氟苯基、氯苯基、三氟苯基、甲基异噁唑基或吡啶基;R3为H、-CH3、-CH2(环丙基)、吡啶基、氯吡啶基或甲氧基吡啶基;Ra、Rb、y和z如本文中所定义本发明还公开了使用这些化合物抑制Notch受体的方法,及包含这些化合物的药物组合物。这些化合物可用于治疗、预防各种医疗领域中的疾病或病症(例如癌症)或减缓其进展。
Description
发明内容
一般而言,本发明涉及用作Notch抑制剂的苯并二氮杂酮化合物。本发明进一步涉及包含至少一种本发明的可用于治疗与Notch路径相关的病状(例如癌症及其他增殖性疾病)的化合物的药物组合物。
现有技术
Notch信号传导参与各种细胞过程,如细胞命运特化、分化、增殖、凋亡及血管生成。(Bray,Nature Reviews Molecular Cell Biology,7:678-689(2006);Fortini,Developmental Cell,16:633-647(2009))。Notch蛋白为单程异源二聚体跨膜分子。Notch家族包括4种受体NOTCH 1至4,其在结合至来自DSL家族(δ-样1、3、4和Jagged 1及2)的配体时变活化。
NOTCH的活化及成熟需要一系列加工步骤,包括由γ分泌酶(即含有早老素1或早老素2、纳卡斯特罗因(nicastrin)、APH1及PEN2的多蛋白蛋白复合物)介导的蛋白水解切割步骤。在切割NOTCH后,自膜释放NOTCH细胞内结构域(NICD)。所释放的NICD易位至核,在该核中其与CSL家族成员(RBPSUH、“无毛基因抑制因子(suppressor of hairless)”及LAG1)协作起转录活化子的作用。NOTCH靶基因包括HES家族成员,例如HES-1。HES-1起到基因的转录抑制子的作用,例如HERP1(亦称为HEY2)、HERP2(亦称为HEY1)及HATH1(亦称为ATOH1)。
Notch路径的异常活化有助于肿瘤生成。Notch信号传导的活化参与各种实体肿瘤(包括卵巢癌、胰腺癌以及乳癌)及血液肿瘤(例如白血病、淋巴瘤及多发性骨髓瘤)的发病机制。Notch抑制的作用及其治疗各种实体及血液肿瘤的效用阐述于Miele,L.等,Current Cancer Drug Targets,6:313-323(2006);Bolos,V.等,Endocrine Reviews,28:339-363(2007);Shih,I-M.等,CancerResearch,67:1879-1882(2007);Yamaguchi,N.等,Cancer Research,68:1881-1888(2008);Miele,L.,Expert Review Anticancer Therapy,8:1197-1201(2008);Purow,B.,Current Pharmaceutical Biotechnology,10:154-160(2009);Nefedova,Y.等,Drug Resistance Updates,11:210-218(2008);Dufraine,J.等,Oncogene,27:5132-5137(2008);及Jun,H.T.等,Drug Development Research,69:319-328(2008)中。
仍需要可用作Notch抑制剂且具有足够代谢稳定性以提供有效的药物暴露水平的化合物。此外,仍需要用作Notch抑制剂的可向患者经口或经静脉内给药的化合物。
美国专利第7,053,084B1号公开用于治疗神经病症如阿兹海默氏病(Alzheimer's Disease)的琥珀酰基氨基苯并二氮杂化合物。该参考文献公开这些琥珀酰基氨基苯并二氮杂化合物抑制γ分泌酶活性及与类淀粉蛋白的神经沉积物形成相关的类淀粉前体蛋白加工。
申请人已发现具有作为Notch抑制剂的活性且具有足够代谢稳定性以在静脉内或经口给药时提供有效含量的药物暴露的强效化合物。提供这些化合物用作具有对其可成药性甚为重要的期望稳定性、生物可用度、治疗指数及毒性值的医药。
发明内容
本发明藉由提供用作Notch信号传导路径的选择性抑制剂的氟烷基-1,4苯并二氮杂酮化合物来满足前述需求。
本发明亦提供包含药学上可接受的载体;及至少一种式(I)化合物的药物组合物。
本发明亦提供治疗与Notch受体的活性相关的疾病或病症的方法,该方法包含向哺乳动物患者给药至少一种式(I)化合物。
本发明亦提供用于制造式(I)化合物的方法及中间体。
本发明亦提供用于疗法的式(I)化合物。
本发明亦提供式(I)化合物用于制造治疗癌症的药物的用途。
式(I)化合物及包含这些化合物的组合物为Notch抑制剂,可用于治疗、预防或治愈各种Notch受体相关病状。包含这些化合物的药物组合物可用于治疗、预防各种医疗领域中的疾病或病症(如癌症)或减缓其进展。
随着本公开内容的继续将以展开形式阐述本发明的这些及其他特征。
发明详述
本发明的第一方面提供至少一种式(I)化合物或其至少一种前药:
其中:
R2为苯基、氟苯基、氯苯基、三氟苯基、甲基异噁唑基或吡啶基;
R3为H、-CH3、-CH2(环丙基)、吡啶基、氯吡啶基或甲氧基吡啶基;
各Ra独立地为F、Cl、-CH3、-OCH3、-CN和/或-O(环丙基);
或者两个Ra与它们连接的碳原子一起形成间二氧杂环戊烯(dioxole)环;
各Rb独立地为F、Cl、-CHF2和/或-CF3;
y为零、1或2;和
z为零、1或2.
一个实施方案提供至少一种式(I)化合物,其中R2为苯基、氟苯基、氯苯基或三氟苯基;且R3、Ra、Rb、y和z在第一方面中定义。在该实施方案中包括其中R3为H或-CH3的化合物。在该实施方案中还包括其中R3为-CH2(环丙基)的化合物。进一步地,在该实施方案中包括其中R3为吡啶基、氯吡啶基或甲氧基吡啶基的化合物。
一个实施方案提供至少一种式(I)化合物,其中R2为甲基异噁唑基;其R3、Ra、Rb、y和z在第一方面中定义。在该实施方案中包括其中R3为H或-CH3的化合物。在该实施方案中还包括其中R3为-CH2(环丙基)的化合物。进一步地,在该实施方案中包括其中R3为吡啶基、氯吡啶基或甲氧基吡啶基的化合物。
一个实施方案提供至少一种式(I)化合物,其中R2为吡啶基;且R3、Ra、Rb、y和z在第一方面中定义。在该实施方案中包括其中R3为H或-CH3的化合物。在该实施方案中还包括其中R3为-CH2(环丙基)的化合物。进一步地,在该实施方案中包括其中R3为吡啶基、氯吡啶基或甲氧基吡啶基的化合物。
一个实施方案提供至少一种式(I)化合物,其中R2为苯基且R3、Ra、Rb、y和z在第一方面中定义。在该实施方案中包括其中R3为H或-CH3。
一个实施方案提供至少一种具有以下结构的式(I)化合物:
其中R3、Ra、Rb、y和z在第一方面中定义。在该实施方案中包括其中R3为H或-CH3的化合物。
一个实施方案提供至少一种具有以下结构的式(I)化合物:
其中R3、Ra、Rb、y和z在第一方面中定义。在该实施方案中包括其中R3为H或-CH3的化合物。
一个实施方案提供至少一种具有以下结构的式(I)化合物:
其中R3、Ra、Rb、y和z在第一方面中定义。在该实施方案中包括其中R3为H或-CH3的化合物。
一个实施方案提供至少一种具有以下结构的式(I)化合物:
其中R3、Ra、Rb、y和z在第一方面中定义。在该实施方案中包括其中R3为H或-CH3的化合物。
一个实施方案提供至少一种具有以下结构的式(I)化合物:
其中R3、Ra、Rb、y和z在第一方面中定义。在该实施方案中包括其中R3为H或-CH3的化合物。
一个实施方案提供至少一种具有以下结构的式(I)化合物:
其中R2、R3、Ra、Rb和z在第一方面中定义。在该实施方案中包括其中R3为H或-CH3的化合物。
一个实施方案提供至少一种具有以下结构的式(I)化合物:
其中R2、R3、Rb和z在第一方面中定义。在该实施方案中包括其中R3为H或-CH3的化合物。
一个实施方案提供至少一种式(I)化合物,其中R3为H;且R2、Ra、Rb、y和z在第一方面中定义。在该实施方案中包括其中R3为氘(D)或氚(T)的化合物。
一个实施方案提供至少一种式(I)化合物,其中R3为-CH3;且R2、Ra、Rb、y和z在第一方面中定义。R3包括其中一个或多个氢原子被氘(D)和/或氚(T)同位素置换的甲基。在该实施方案的一个实例中,R3为-CD3。
一个实施方案提供选自以下的式(I)化合物:(2R,3R)-N-((3S)-1-甲基-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(1);(2R,3R)-3-(4-氟苯基)-N-((3S)-1-甲基-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-2-(3,3,3-三氟丙基)琥珀酰胺(2);(2R,3R)-N-((3S)-1-甲基-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-(2,3,4-三氟苯基)-2-(3,3,3-三氟丙基)琥珀酰胺(3);(2R,3R)-N-((3S)-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(4);(2R,3R)-N1-((S)-5-(3-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(5);(2R,3R)-N1-((S)-1-甲基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酰胺(6);(2R,3R)-N1-((S)-1-(环丙基甲基)-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(7);(2R,3R)-N1-((S)-1-(环丙基甲基)-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(4-氟苯基)-2-(3,3,3-三氟丙基)琥珀酰胺(8);(2R,3R)-3-(3-甲基异噁唑-4-基)-N1-((S)-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-2-(3,3,3-三氟丙基)琥珀酰胺(9);(2R,3R)-N1-((S)-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(吡啶-3-基)-2-(3,3,3-三氟丙基)琥珀酰胺(10);(2R,3R)-3-(3-甲基-4-异噁唑基)-N-((3S)-2-氧代-5-苯基-1-(2-吡啶基)-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-2-(3,3,3-三氟丙基)琥珀酰胺(11);(2R,3R)-N-((3S)-2-氧代-5-苯基-1-(2-吡啶基)-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(12);(2R,3R)-3-(3-甲基-4-异噁唑基)-N-((7S)-6-氧代-9-苯基-6,7-二氢-5H-[1,3]二氧杂环戊并[4,5-h][1,4]苯并二氮杂-7-基)-2-(3,3,3-三氟丙基)琥珀酰胺(13);(2R,3R)-N-((3S)-1-(5-甲氧基-2-吡啶基)-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-(3-甲基-4-异噁唑基)-2-(3,3,3-三氟丙基)琥珀酰胺(14);(2R,3R)-N-((3S)-1-(5-甲氧基-2-吡啶基)-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(15);(2R,3R)-N-((3S)-1-(6-甲氧基-2-吡啶基)-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(16);(2R,3R)-N1-((S)-9-氯-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酰胺(17);(2R,3R)-N1-((S)-9-氟-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酰胺(18);(2R,3R)-N1-((S)-9-氟-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(19);(2R,3R)-N1-((S)-9-甲氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酰胺(20);(2R,3R)-N1-((S)-9-甲氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3苯基-2-(3,3,3-三氟丙基)琥珀酰胺(21);(2R,3R)-N-((3S)-1-(5-氯-2-吡啶基)-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(22);(2R,3R)-N-((3S)-1-(5-氯-2-吡啶基)-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-(3-甲基-4-异噁唑基)-2-(3,3,3-三氟丙基)琥珀酰胺(23);(2R,3R)-N1-((S)-9-氯-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(24);(2R,3R)-N1-((S)-7-氰基-9-甲氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(25);(2R,3R)-N1-((S)-9-环丙氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(26);(2R,3R)-N1-((S)-5-(4-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(27);(2R,3R)-N1-((S)-9-甲基-2-氧代-5-(3-(三氟甲基)苯基)-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酰胺(28);(2R,3R)-N1-((S)-9-甲基-2-氧代-5-(3-(三氟甲基)苯基)-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(29);(2R,3R)-N1-((S)-9-甲基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(30);(2R,3R)-N1-((S)-5-(3-氯苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(31);(2R,3R)-N1-((S)-5-(3-氯苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酰胺(32);(2R,3R)-N1-((S)-5-(4-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酰胺(33);(2R,3R)-N1-((S)-5-(3-(二氟甲基)苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(34);(2R,3R)-N1-((S)-9-环丙氧基-5-(3-氟苯基)-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(35);和(2R,3R)-3-(4-氯苯基)-N1-((S)-9-甲氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-2-(3,3,3-三氟丙基)琥珀酰胺(36)。
一个实施方案提供至少一种式(I)化合物,其具有至少45分钟的代谢半衰期,如于本文中所阐述的人类代谢稳定性半衰期分析中所测量。
一个实施方案提供至少一种式(I)化合物,其具有至少60分钟的代谢半衰期,如于本文中所阐述的人类代谢稳定性半衰期分析中所测量。
本发明可以其他具体形式体现,此不背离其精神或本质属性。本发明涵盖本文所提及的本发明方面和/或实施方案的所有组合。应理解,本发明的任一及所有实施方案可结合任一或多个其他实施方案来阐述其他实施方案。亦应理解,这些实施方案的每一个别元素意欲与来自任一实施方案的任一及所有其他元素组合来阐述其他实施方案。
定义
在阅读以下详细阐述时,本领域技术人员可更容易地理解本发明的特征及优势。应了解,本发明的出于清晰的原因于上下文中在单独实施方案的情形下阐述的某些特征亦可组合以形成单一实施方案。相反地,本发明的出于简洁的原因在单一实施方案的情形下所阐述的各种特征亦可组合以形成其子组合。本文中识别为实例性或优选的实施方案意欲为阐释性的,且并非限制性的。
除非本文中另有明确说明,否则所提及的单数形式亦可包括复数。例如,“一(a及an)”可为指一个、一或多个。
除非另有指示,否则假设具有未满足原子价的任何杂原子具有足以满足这些原子价的氢原子。
本文中所阐释的定义优先于以引用的方式并入本文中的任一专利、专利申请案和/或专利申请公开案中所阐释的定义。
下文列示用于描述本发明的各术语的定义。当在本说明书通篇中个别地或作为较大基团的一部分使用这些术语(除非在具体情况下另外限制这些术语)时,这些定义适用于这些术语。
在本说明书通篇中,本领域技术人员可选择基团及其取代基以提供稳定部分及化合物。
本文所用的术语“烷基”为指含有(例如)1个至12个碳原子、1个至6个碳原子及1个至4个碳原子的具支链及直链饱和脂肪族烃基团。烷基的实例包括(但不限于)甲基(Me)、乙基(Et)、丙基(例如正丙基及异丙基)、丁基(例如正丁基、异丁基、仲丁基及叔丁基)及戊基(例如正戊基、异戊基、新戊基)、正己基、2-甲基戊基、2-乙基丁基、3-甲基戊基及4-甲基戊基。当数字在符号“C”后面以下标形式出现时,该下标更具体地定义特定基团可含有的碳原子的数量。例如、“C1-6烷基”表示具有1个至6个碳原子的直链及具支链烷基。
本文所用的短语“药学上可接受”为指那些化合物、材料、组合物和/或剂型在合理医学判断范围内适于与人类及动物组织接触使用且无过度毒性、刺激性、过敏反应或其他问题或并发症,与合理益处/风险比率相应。
式(I)化合物可以非晶形固体或结晶固体的形式提供。可采用冻干来提供呈固体形式的式(I)化合物。
应进一步了解,式(I)化合物的溶剂合物(例如水合物)亦属于本发明的范围内。术语“溶剂合物”意指式(I)化合物与一种或多种溶剂分子(有机或无机)的物理缔合。此物理缔合包括氢键合。在某些情况下,溶剂合物将能够分离,例如当将一或多个溶剂分子并入结晶固体的晶格中时。“溶剂合物”涵盖溶液相及可分离溶剂合物二者。实例性溶剂合物包括水合物、醇合物、甲醇合物、异丙醇合物、乙腈溶剂合物及乙酸乙酯溶剂合物。溶剂化方法为领域内已知。
任一可在活体内转化以提供生物活性剂(即式I化合物)的化合物为属于本发明的范围及精神内的前药。
各种形式的前药为领域内所熟知且为阐述于以下文献中:
a)Wermuth,C.G.等,The Practice of Medicinal Chemistry,第31章,Academic Press(1996);
b)Bundgaard,H.编,Design of Prodrugs,Elsevier(1985);
c)Bundgaard,H.,第5章,“Design and Application of Prodrugs”,Krogsgaard-Larsen,P.等编,A Textbook of Drug Design and Developmen,第113页第191页,Harwood Academic Publishers(1991);及
d)Testa,B.等,Hydrolysis in Drug and Prodrug Metabolism,Wiley-VCH(2003)。
另外,在制备式(I)化合物后可对其实施分离及纯化,以获得含有等于或大于99重量%的量的式(I)化合物(“基本上纯”)的组合物,然后如本文中所阐述对其进行使用或配制。这些“基本上纯的”式(I)化合物亦作为本发明的一部分涵盖于本文中。
“稳定化合物”及“稳定结构”意欲指示足够稳固以经受自反应混合物分离至有用纯度并配制成有效治疗剂的化合物。本发明意欲体现稳定化合物。
“治疗有效量”意欲包括仅本发明化合物单独的量、或要求保护的化合物的组合的量,或本发明化合物与可有效用作NOTCH受体的抑制剂或可有效治疗或预防增殖性疾病(如癌症)的其他活性成份的组合的量。
本文所用“治疗(treating或treatment)”涵盖哺乳动物(特定而言人类)中的疾病状态的治疗,且包括:(a)在哺乳动物中、特定而言在该哺乳动物易患该疾病状态但尚未诊断为患有该疾病状态时预防该疾病状态发生;(b)抑制该疾病状态,即遏制其发展;和/或(c)缓解该疾病状态,即使该疾病状态消退。
本发明化合物意欲包括在本发明化合物中出现的原子的所有同位素。同位素包括那些具有相同原子序数但具有不同质量数的原子。根据一般实例且不加以限制,氢的同位素包括氘(D)及氚(T)。碳的同位素包括13C及14C。本发明的经同位素标记的化合物通常可藉由本领域技术人员已知的常规技术来制备,或可藉由与本文中所阐述方法类似的方法使用适当的经同位素标记试剂代替原本采用的未经标记试剂来制备。
式(I)化合物可藉由适于预治疗的病状的任何方式给药,此可取决于对位点特异性治疗的需求或预递送的式(I)化合物的量。
本发明中亦涵盖一类药物组合物,其包含至少一种式(I)化合物;及一种或多种无毒、药学上可接受的载体和/或稀释剂和/或佐剂(本文中统称为“载体”材料)及(若期望)其他活性成份。式(I)化合物可藉由任何适宜途径给药,优选以适于此一途径的药物组合物形式且以对期望治疗有效的剂量给药。本发明的化合物及组合物可(例如)经口、经粘膜或胃肠外(parentally)(包括经血管内、经静脉内、经腹膜内、经皮下、经肌内及经胸骨内)以含常规药学上可接受的载体、佐剂及媒剂的剂量单位配制物给药。例如,该药物载体可含有甘露醇或乳糖与微晶纤维素的混合物。该混合物可含有其他组份,例如润滑剂(例如硬脂酸镁)及崩解剂(例如交联聚维酮(crospovidone))。可将该载体混合物填充至明胶胶囊中或压制为片剂。该药物组合物可以例如经口剂型或输注形式给药。
对于经口给药,药物组合物可呈(例如)片剂、胶囊、液体胶囊、悬浮液或液体形式。药物组合物优选制成含有特定量的活性成份的剂量单位形式。例如,药物组合物可以包含在约1mg至2000mg、优选约1mg至500mg且更优选约5mg至150mg的范围内的量的活性成份的片剂或胶囊形式提供。适于人类或其他哺乳动物的日剂量可视患者的病状及其他因素而宽泛地变化,但可使用常规方法确定。
本文中所涵盖的任一药物组合物可(例如)经由任何可接受且适宜的经口制剂经口递送。实例性经口制剂包括(但不限于,例如)片剂(tablets)、含片(troches)、锭剂(lozenges)、水性及油性悬浮液、可分散粉末或颗粒、乳液、硬胶囊及软胶囊、糖浆及酏剂。意欲用于经口给药的药物组合物可根据领域内已知用于制造意欲用于经口给药的药物组合物的任何方法制备。为提供医药上可口的制剂,本发明的药物组合物可含有至少一种选自甜味剂、矫味剂、着色剂、缓和剂(demulcents)、抗氧化剂及防腐剂的药剂。
片剂可藉由(例如)将至少一种式(I)化合物与至少一种适于制造片剂的无毒且药学上可接受的赋形剂混合来制备。实例性赋形剂包括(但不限于,例如)惰性稀释剂,例如碳酸钙、碳酸钠、乳糖、磷酸钙及磷酸钠;造粒剂及崩解剂,例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉及海藻酸;粘合剂,例如淀粉、明胶、聚乙烯吡咯烷酮及阿拉伯胶(acacia);及润滑剂,例如硬脂酸镁、硬脂酸及滑石粉。另外,片剂可未经涂覆,或藉由已知技术涂覆,以遮蔽味道令人不快的药物的坏味道,或延迟活性成份在胃肠道中的崩解及吸收,从而使活性成份的效应持续较长时期。实例性水溶性遮味材料包括(但不限于)羟丙基-甲基纤维素及羟丙基-纤维素。实例性延时材料包括(但不限于)乙基纤维素及乙酸丁酸纤维素。
硬明胶胶囊可藉由(例如)将至少一种式(I)化合物与至少一种惰性固体稀释剂(例如碳酸钙;磷酸钙;及高岭土(kaolin))混合来制备。
软明胶胶囊可藉由(例如)将至少一种式(I)化合物与至少一种水溶性载体(例如聚乙二醇);及至少一种油性介质(例如花生油、液体石蜡及橄榄油)混合来制备。
水性悬浮液可藉由(例如)将至少一种式(I)化合物与至少一种适于制造水性悬浮液的赋形剂混合来制备。适于制造水性悬浮液的实例性赋形剂包括(但不限于,例如)悬浮剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基-纤维素、海藻酸钠、海藻酸、聚乙烯吡咯烷酮、黄蓍胶及阿拉伯胶;分散或润湿剂,例如天然存在的磷脂、例如卵磷脂;环氧烷与脂肪酸的缩合产物,例如聚氧乙烯硬脂酸酯;环氧乙烷与长链脂肪族醇的缩合产物,例如十七烷乙烯-氧基鲸蜡醇;环氧乙烷与衍生自脂肪酸及己糖醇的偏酯的缩合产物,例如聚氧乙烯山梨糖醇单油酸酯;及环氧乙烷与衍生自脂肪酸及己糖醇脱水物的偏酯的缩合产物,例如聚乙烯脱水山梨醇单油酸酯。水性悬浮液亦可含有至少一种防腐剂,例如对羟基苯甲酸乙酯及对羟基苯甲酸正丙酯;至少一种着色剂;至少一种矫味剂;和/或至少一种甜味剂,包括(但不限于,例如)蔗糖、糖精及阿司巴甜(aspartame)。
油性悬浮液可藉由(例如)将至少一种式(I)化合物悬浮于植物油(例如花生油;橄榄油;芝麻油;及椰子油)中;或矿物油(例如液体石蜡)中来制备。油性悬浮液亦可含有至少一种增稠剂,例如蜂蜡;硬石蜡;及鲸蜡醇。为提供可口油性悬浮液,可将至少一种上文已述甜味剂和/或至少一种矫味剂添加至油性悬浮液中。油性悬浮液可进一步含有至少一种防腐剂,包括(但不限于,例如)抗氧化剂例如丁基化羟基苯甲醚及α-生育酚。
可分散粉末及颗粒可藉由(例如)将至少一种式(I)化合物与至少一种分散剂和/或润湿剂;至少一种悬浮剂;和/或至少一种防腐剂混合来制备。适宜分散剂、润湿剂及悬浮剂为如上文已阐述。实例性防腐剂包括(但不限于,例如)抗氧化剂,例如抗坏血酸。另外,可分散粉末及颗粒亦可含有至少一种赋形剂,包括(但不限于,例如)甜味剂;矫味剂;及着色剂。
至少一种式(I)化合物的乳液可(例如)制备成水包油型乳液。包含式(I)化合物的乳液的油相可自已知成份以已知方式构成。油相可由(但不限于,例如)植物油(例如橄榄油及花生油);矿物油(例如液体石蜡);及其混合物提供。尽管该相可仅包含乳化剂,但其可包含至少一种乳化剂与脂肪或油或者与脂肪及油二者的混合物。适宜乳化剂包括(但不限于,例如)天然存在的磷脂,例如大豆卵磷脂;衍生自脂肪酸及己糖醇脱水物的酯或偏酯,例如脱水山梨醇单油酸酯;及偏酯与环氧乙烷的缩合产物,例如聚氧乙烯脱水山梨醇单油酸酯。优选地,包括亲水性乳化剂以及用作稳定剂的亲脂性乳化剂。亦优选包括油与脂肪二者。乳化剂在具有或不具有稳定剂的情况下一起构成所谓的乳化蜡,且该蜡与油及脂肪一起构成所谓的乳化软膏基质,该乳化软膏基质形成乳膏配制物的油性分散相。乳液亦可含有甜味剂、矫味剂、防腐剂和/或抗氧化剂。适用于本发明配制物的乳化剂及乳液稳定剂包括吐温60(Tween60)、斯盘80(Span 80)、鲸蜡硬脂醇、肉豆蔻醇、甘油单硬脂酸酯、月桂基硫酸钠、甘油二硬脂酸酯,单独或与蜡或领域内熟知的其他材料一起。
式(I)化合物亦可(例如)经静脉内、经皮下和/或经肌内经由任何药学上可接受且适宜的可注射形式递送。实例性可注射形式包括(但不限于,例如)包含可接受的媒剂及溶剂(例如水、林格式溶液(Ringer's solution)及等渗氯化钠溶液)的灭菌水溶液;灭菌水包油型微乳液;及水性或油性悬浮液。
用于胃肠外给药的配制物可呈水性或非水性等渗灭菌注射溶液或悬浮液的形式。这些溶液及悬浮液可自灭菌粉末或颗粒使用一种或多种所提及用于经口给药配制物中的载体或稀释剂或藉由使用其他适宜分散剂或润湿剂及悬浮剂来制备。这些化合物可溶于水、聚乙二醇、丙二醇、乙醇、玉米油、棉籽油、花生油、芝麻油、苯甲醇、氯化钠、黄蓍胶和/或各种缓冲剂中。佐剂及给药模式在医药技术中为众所周知。活性成份亦可藉由以与适宜载体(包括盐水、右旋糖或水)或与环糊精(即,)的组合物形式注射、共溶剂溶解(即,丙二醇)或胶束(micellar)溶解(即,吐温80)来给药。
灭菌可注射制剂亦可为存于无毒胃肠外可接受的稀释剂或溶剂中的灭菌可注射溶液或悬浮液,例如呈存于1,3-丁二醇中的溶液形式。可采用的可接受媒剂及溶剂包括水、林格氏溶液及等渗氯化钠溶液。另外,通常采用灭菌不挥发性油(fixed oils)作为溶剂或悬浮介质。出于此目的,可采用任一温和不挥发性油,包括合成单甘油酯或二甘油酯。另外,脂肪酸如油酸可用于制备可注射剂。
灭菌可注射的水包油型微乳液可藉由(例如)以下方式来制备:1)将至少一种式(I)化合物溶解于油相(例如大豆油与卵磷脂的混合物)中;2)将含式(I)油相与水及甘油混合物组合;及3)加工该组合以形成微乳液。
灭菌水性或油性悬浮液可依照领域内已知方法来制备。例如,灭菌水溶液或悬浮液可利用无毒的胃肠外可接受的稀释剂或溶剂(例如1,3-丁二醇)来制备;且灭菌油性悬浮液可利用灭菌无毒的可接受的溶剂或悬浮介质(例如灭菌不挥发性油,例如合成单甘油酯或二甘油酯;及脂肪酸(例如油酸))来制备。
可用于本发明药物组合物中的药学上可接受的载体、佐剂及媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、自乳化药物递送系统(SEDDS,例如d-α-生育酚聚乙二醇1000琥珀酸酯)、药物剂型中所用的表面活性剂(例如吐温、聚乙氧基化蓖麻油如表面活性剂(BASF)或其他类似聚合递送基质)、血清蛋白(例如人血清白蛋白)、缓冲物质(例如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(例如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶质二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素基物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段共聚物、聚乙二醇及羊毛脂。环糊精(α-、β-及γ-环糊精)或经化学修饰的衍生物(例如羟基烷基环糊精包括2-及3-羟丙基-环糊精或其他溶解衍生物)亦可有利地用于增强本文中所述式的化合物的递送。
本发明的药物上活性化合物可依照常规药学方法加工以产生向患者(包括人及其他哺乳动物)给药的药剂。药物组合物可经受常规医药操作(例如灭菌),和/或可含有常规佐剂,例如防腐剂、稳定剂、润湿剂、乳化剂、缓冲液等。片剂及丸剂可另外制备有肠溶包衣。这些组合物亦可包含佐剂,例如润湿剂、甜味剂、矫味剂及香化剂。
所给药化合物的量及利用本发明的化合物和/或组合物治疗疾病状况的剂量方案取决于各种因素,包括受试者的年龄、重量、性别及医学状况、疾病类型、疾病的严重性、给药的途径及频率及所采用的特定化合物。因此,该剂量方案可在宽范围内改变,但可使用标准方法常规地确定。约0.001mg/kg体重至100mg/kg体重、优选约0.005-约50mg/kg体重且最优选约0.01mg/kg体重-10mg/kg体重的日剂量可为适当的。日剂量可每天以1次至4次剂量来给药。
出于治疗目的,本发明的活性化合物通常与一种或多种适于所指示给药途径的佐剂组合。若经口给药,则化合物可与乳糖、蔗糖、淀粉粉末、烷酸的纤维素酯、纤维素烷基酯、滑石粉、硬脂酸、硬脂酸镁、氧化镁、磷酸及硫酸的钠盐及钙盐、明胶、阿拉伯胶、海藻酸钠、聚乙烯基吡咯烷酮和/或聚乙烯醇混合,且然后压锭或囊封以方便给药。这些胶囊或片剂可含有受控释放配制物,其可以活性化合物存于羟丙基甲基纤维素中的分散液提供。
本发明的药物组合物包含式(I)化合物和任选的选自任何药学上可接受的载体、佐剂及媒剂的其他药剂。本发明的替代组合物包含本文中所述的式(I)化合物及药学上可接受的载体、佐剂或媒剂。
效用
式(I)化合物可用于治疗癌症,例如依赖于Notch活化的癌症。Notch活化参与各种实体肿瘤(包括卵巢癌、胰腺癌以及乳癌)及血液肿瘤(例如白血病、淋巴瘤及多发性骨髓瘤)的发病机制。
在一实施方案中,提供用于治疗癌症的方法,其包含向有需要的哺乳动物给药式(I)化合物。此实施方案的方法可用于治疗各种癌症,包括(但不限于)膀胱癌、乳癌、结肠直肠癌、胃癌、头颈癌、肾癌、肝癌、肺癌包括非小细胞肺癌(NSCLC)、卵巢癌、胰腺癌、胆囊癌、前列腺癌、甲状腺癌、骨肉瘤、横纹肌肉瘤、恶性纤维组织细胞瘤(MFH)、纤维肉瘤、神经胶质母细胞瘤/星形细胞瘤、神经胚细胞瘤、黑色素瘤、T细胞急性淋巴胚细胞白血病(T-ALL)及间皮瘤。例如,此实施方案的方法为用于治疗乳癌、结肠癌或胰腺癌。优选地,哺乳动物为人类。例如,在本实施方案的方法中可给药用于治疗癌症的治疗有效量。
在一实施方案中,提供用于治疗癌症的方法,其包含向有需要的哺乳动物给药一种或多种式(I)化合物,其中该癌症为结肠直肠癌。优选地,哺乳动物为人类。例如,在本实施方案的方法中可给药用于治疗癌症的治疗有效量。本实施方案中的给药途径包括胃肠外给药和经口给药。
在一实施方案中,提供用于治疗癌症的方法,其包含向有需要的哺乳动物给药一种或多种式(I)化合物,其中该癌症为三阴性乳腺癌。优选地,哺乳动物为人类。例如,在本实施方案的方法中可给药用于治疗癌症的治疗有效量。本实施方案中的给药途径包括胃肠外给药和经口给药。
在一实施方案中,提供用于治疗癌症的方法,其包含向有需要的哺乳动物给药一种或多种式(I)化合物,其中该癌症为非小细胞肺癌。优选地,哺乳动物为人类。例如,在本实施方案的方法中可给药用于治疗癌症的治疗有效量。本实施方案中的给药途径包括胃肠外给药和经口给药。
在一实施方案中,提供用于治疗癌症的方法,其包含向有需要的哺乳动物给药一种或多种式(I)化合物,其中该癌症为胰腺癌。优选地,哺乳动物为人类。例如,在本实施方案的方法中可给药用于治疗癌症的治疗有效量。本实施方案中的给药途径包括胃肠外给药和经口给药。
在一实施方案中,提供用于治疗癌症的方法,其包含向有需要的哺乳动物给药一种或多种式(I)化合物,其中该癌症为卵巢癌。优选地,哺乳动物为人类。例如,在本实施方案的方法中可给药用于治疗癌症的治疗有效量。本实施方案中的给药途径包括胃肠外给药和经口给药。
在一实施方案中,提供用于治疗癌症的方法,其包含向有需要的哺乳动物给药一种或多种式(I)化合物,其中该癌症为黑素瘤。优选地,哺乳动物为人类。例如,在本实施方案的方法中可给药用于治疗癌症的治疗有效量。本实施方案中的给药途径包括胃肠外给药和经口给药。
在一实施方案中,提供一种或多种式(I)化合物用于制造用以治疗癌症的药品的用途。优选地,在本发明实施方案中,经受治疗的癌症包括膀胱癌、乳癌、结肠直肠癌、胃癌、头颈癌、肾癌、肝癌、肺癌包括非小细胞肺癌(NSCLC)、卵巢癌、胰腺癌、胆囊癌、前列腺癌、甲状腺癌、骨肉瘤、横纹肌肉瘤、恶性纤维组织细胞瘤(MFH)、纤维肉瘤、神经胶质母细胞瘤/星形细胞瘤、神经胚细胞瘤、黑色素瘤、T细胞急性淋巴胚细胞白血病(T-ALL)及间皮瘤中的一种或多种。本发明实施方案的适宜药品包括用于胃肠外给药的药品(例如溶液及悬浮液)及用于经口给药的药品(例如片剂、胶囊、溶液及悬浮液)。
一实施方案提供一种或多种用于治疗癌症的疗法中的式(I)化合物。在本发明实施方案中,经受治疗的癌症包括膀胱癌、乳癌、结肠直肠癌、胃癌、头颈癌、肾癌、肝癌、肺癌包括非小细胞肺癌(NSCLC)、卵巢癌、胰腺癌、胆囊癌、前列腺癌、甲状腺癌、骨肉瘤、横纹肌肉瘤、恶性纤维组织细胞瘤(MFH)、纤维肉瘤、神经胶质母细胞瘤/星形细胞瘤、神经胚细胞瘤、黑色素瘤、T细胞急性淋巴胚细胞白血病(T-ALL)及间皮瘤中的一种或多种。
在一实施方案中,提供治疗哺乳动物的癌症的方法,其中该癌症依赖于Notch活化,该方法包含向患者给药一种或多种式(I)化合物。此实施方案的方法可用于治疗各种癌症,包括(但不限于)膀胱癌、乳癌、结肠直肠癌、胃癌、头颈癌、肾癌、肝癌、肺癌包括非小细胞肺癌(NSCLC)、卵巢癌、胰腺癌、胆囊癌、前列腺癌、甲状腺癌、骨肉瘤、横纹肌肉瘤、恶性纤维组织细胞瘤(MFH)、纤维肉瘤、神经胶质母细胞瘤/星形细胞瘤、神经胚细胞瘤、黑色素瘤、T细胞急性淋巴胚细胞白血病(T-ALL)及间皮瘤。优选地,此实施方案的方法为用于治疗乳癌、结肠癌或胰腺癌。优选地,哺乳动物为人类。例如,在本发明实施方案的方法中可给药用于治疗癌症的治疗有效量。适宜给药途径包括胃肠外给药及经口给药。
在治疗癌症中,化学治疗剂和/或其他治疗(例如辐射疗法)的组合经常为有利的。相较于主要治疗剂,第二(或第三)药剂可具有相同或不同作用机制。例如,可采用药物组合,其中所给药的两种或更多种药物以不同方式或在细胞周期的不同阶段作用,和/或其中该两种或更多种药物具有不重迭毒性或副效应,和/或其中所组合的药物在治疗患者所表现的特定疾病状态中各具有已证明的效力。
在一实施方案中,提供治疗癌症的方法,其包含向有需要的哺乳动物给药一种或多种式(I)化合物;及给药一种或多种其他抗癌剂。
短语“其他抗癌剂”为指选自以下中的一种或多种的药物:烷基化剂(包括氮芥、烷基磺酸盐、亚硝基脲、乙烯亚胺衍生物及三氮烯);抗血管生成剂(包括基质金属蛋白酶抑制剂);抗代谢物质(包括腺苷去胺酶抑制剂、叶酸拮抗剂、嘌呤类似物及嘧啶类似物);抗生素或抗体(包括单株抗体、CTLA-4抗体、蒽环抗生素);芳香酶抑制剂;细胞周期反应修饰剂;酶;法呢基-蛋白转移酶抑制剂(farnesyl-protein transferase inhibitor);激素剂及抗激素剂及类固醇(包括合成类似物、糖皮质激素、雌激素/抗雌激素[例如SERM]、雄激素/抗雄激素、黄体素、黄体酮受体激动剂及促黄体激素释放[LHRH]激动剂及拮抗剂);胰岛素样生长因子(IGF)/胰岛素样生长因子受体(IGFR)系统调节剂(包括IGFR1抑制剂);整合素信号传导抑制剂;激酶抑制剂(包括多激酶抑制剂和/或Src激酶或Src/abl的抑制剂、周期素依赖性激酶[CDK]抑制剂、panHer、Her-1及Her-2抗体、VEGF抑制剂(包括抗VEGF抗体)、EGFR抑制剂、有丝分裂促进剂活化蛋白[MAP]抑制剂、MET抑制剂、MEK抑制剂、极光(Aurora)激酶抑制剂、PDGF抑制剂及其他酪胺酸激酶抑制剂或丝胺酸/苏胺酸激酶抑制剂);微管破坏剂,例如海鞘素或其类似物及衍生物;微管稳定剂,例如紫杉烷(taxane)及天然存在的埃博霉素(epothilone)及其合成及半合成类似物;微管结合去稳定剂(包括长春花生物碱);拓扑异构酶抑制剂;异戊二烯基蛋白转移酶抑制剂;铂配位错合物;信号转导抑制剂;及用作抗癌症及细胞毒性剂的其他作用剂,例如生物反应修饰剂、生长因子及免疫调节剂。
因此,本发明的化合物可与用于治疗癌症或其他增殖性疾病的其他抗癌症治疗组合给药。本发明在本文中进一步包含一种或多种式(I)化合物用于制备用以治疗癌症的药品的用途,和/或其包含将本文中的式(I)化合物与关于该化合物与用于治疗癌症的其他抗癌症或细胞毒性剂及治疗组合使用的说明书包装在一起。本发明进一步包含至少一种式(I)化合物和一种或多种其他药剂呈套组形式的组合,例如其中将其包装在一起或置于单独包装中以套组形式一起销售,或其中其为经包装以配制在一起。
在一实施方案中,提供治疗癌症的方法,其包含向有需要的哺乳动物给药一种或多种式(I)化合物;给药达沙替尼(dasatinib);和任选的一种或多种其他抗癌剂。
在一实施方案中,提供治疗癌症的方法,其包含向有需要的哺乳动物给药一种或多种式(I)化合物;给药紫杉醇;和任选的一种或多种其他抗癌剂。
在一实施方案中,提供治疗癌症的方法,其包含向有需要的哺乳动物给药一种或多种式(I)化合物;给药他莫昔芬(tamoxifen);和任选的一种或多种其他抗癌剂。
在一实施方案中,提供治疗癌症的方法,其包含向有需要的哺乳动物给药一种或多种式(I)化合物;给药糖皮质激素;和任选的一种或多种其他抗癌剂。适宜糖皮质激素的实例为地塞米松(dexamethasone)。
在一实施方案中,提供治疗癌症的方法,其包含向有需要的哺乳动物给药一种或多种式(I)化合物;给药卡铂(carboplatin);及任选的一种或多种其他抗癌剂。
本发明的化合物可与针对在解决与上述病状相关的副效应中的特定用途所选择的其他治疗剂一起配制或共给药。例如,本发明的化合物可与恶心、过敏及胃刺激的药剂(例如止吐剂及H1及H2抗组胺剂)一起配制。
在一实施方案中,提供药物组合物,其包含一种或多种式(I)化合物;一种或多种选自激酶抑制剂(小分子、多肽及抗体)、免疫阻抑剂、抗癌剂、抗病毒剂、抗炎剂、抗真菌剂、抗生素或抗血管超增殖化合物的其他药剂;及任何药学上可接受的载体、佐剂或媒剂。
当与本发明的化合物组合采用时,可以(例如)那些于Physicians'DeskReference(PDR)中所指示或本领域技术人员以其他方式确定的量使用以上其他治疗剂。在本发明的方法中,这些其他治疗剂可在给药本发明化合物之前、与其同时或在其之后给药。
然而,针对任何特定受试者的具体剂量值及剂量频率可有所变化,且通常取决于各种因素,包括(但不限于,例如)呈所给药形式的具体式(I)化合物的生物可用度、具体式(I)化合物的代谢稳定性及作用长度、受试者的物种、体重、总体健康、性别、饮食、给药的模式及时间、排泄速率、药物组合及特定病状的严重性。例如,约0.001mg/kg体重至100mg/kg体重、优选约0.005mg/kg体重-约50mg/kg体重且最优选约0.01mg/kg体重-10mg/kg体重的日剂量可为适当的。。日剂量可每天以1次至4次剂量来给药。
可连续地(即,每日)或间歇地给药。本文所用的术语“间歇”或“间歇地”意指以规则或不规则间隔停止及开始。例如,间歇给药包括每周给药1天至6天;以周期形式给药(例如,每天给药并连续持续2周至8周、接着为长达1周不给药的停药期(rest period));或隔天(on alternate days)给药。
在一实施方案中,向有需要的患者连续给药一种或多种式(I)化合物,每天给药一或多次。例如,向有需要的患者给药治疗有效量的式(I)化合物,每天给药一或多次并连续持续数天。
在一实施方案中,向有需要的患者间歇地给药一种或多种式(I)化合物,每天给药一或多次。例如,向有需要的患者给药治疗有效量的式(I)化合物,根据间歇时间表每天给药一或多次。
在一实施方案中,向有需要的患者给药一种或多种式(I)化合物,每天给药一或多次并连续持续数天、接着不给药一或多天。优选地,给药治疗有效量的式(I)化合物。具有药物假期的连续给药实例为如下的周期:7天治疗、接着7天不治疗;14天治疗、接着7天不治疗;及7天治疗、接着14天不治疗。可根据需要,多次重复治疗/不治疗的周期来治疗患者。
在一实施方案中,根据间歇给药时间表向有需要的患者给药一种或多种式(I)化合物。间歇给药时间表为重复时间表,其包括向患者给药式(I)化合物的各天及不向患者给药式(I)化合物的各天。间歇给药时间表的实例为:每周给药4天并连续持续3周,接着1周不给药,并以4周间隔重复;每周给药5天并连续持续2周,接着1周不给药,并以3周间隔重复;及,每周给药4天并持续1周,接着2周不给药,并以3周间隔重复。优选地,给药治疗有效量的式(I)化合物。
在一实施方案中,于某日给药将至少一种式(I)化合物,接着停药6天,并根据每周时间表重复。
在一实施方案中,于某日给药至少一种式(I)化合物,接着停药6天,并根据每周时间表重复并持续1周至4周,然后接着停药1周。例如,于某日给药式(I)化合物,接着停药6天,并持续3周,且然后接着停药1周。此4周周期可重复一或多次。
在一实施方案中,连续两天给药至少一种式(I)化合物,接着停药5天,并根据每周时间表重复。
在一实施方案中,连续3天给药至少一种式(I)化合物,接着停药4天,并根据每周时间表重复。
在一实施方案中,于某日给药至少一种式(I)化合物,接着停药10天至13天。
在一实施方案中,每天一次(QD)给药至少一种式(I)化合物。此实施方案包括每天一次经口给药。
在一实施方案中,每天两次(BID)给药至少一种式(I)化合物。此实施方案包括每天两次经口给药。
在一实施方案中,隔天给药至少一种式(I)化合物:1天给药,接着1天停药。此2天周期可重复一或多次。
制备方法
本发明的化合物可以有机合成领域的技术人员熟知的多种方式来制备。本发明的化合物可使用下文所阐述方法以及合成有机化学领域内已知的合成方法或其变化形式来合成,如那些本领域技术人员所了解。优选方法包括(但不限于)下文所阐述的那些。本文所引用的所有参考文献通过提述全文并入本文中。
可使用此部分中所阐述的反应及技术来制备本发明的化合物。各反应为在适于所用试剂及材料且适于所实施转变的溶剂中进行。而且,在下蚊所阐述合成方法的说明中,应理解,所有提出的反应条件(包括溶剂、反应氛围、反应温度、实验持续时间及处理程序的选择)均为选择为用于彼反应的标准条件,其应由本领域技术人员容易地识别。有机合成领域的技术人员应理解,分子的不同部分上存在的官能团必须与所提出的试剂及反应相容。本领域技术人员应容易地明了对与反应条件相容的取代基的这些限制,且然后必须使用替代方法。有时此需要进行判断以修改合成步骤的顺序或选择一种特定方法方案而非另一种,以获得本发明的期望化合物。亦应认识到,在计划此领域中的任一合成途径时的另一主要考虑因素为慎重选择用于保护本发明中所阐述的化合物中存在的反应官能团的保护基团。向训练有素的从业者阐述多种替代选择的权威解释为Greene等(Protective Groups in Organic Synthesis,第三版,Wiley and Sons(1999))。
式(I)化合物可参照以下方案中所阐释的方法来制备。如本文中所显示,终产物为具有与式(I)相同的结构式的化合物。应理解,任何式(I)化合物可藉由这些方案藉由试剂的适宜选择利用适当取代来产生。本领域技术人员可容易地选择溶剂、温度、压力及其他反应条件。起始材料为市售或容易由本领域技术人员制备。化合物的成份为如此处或说明书中的其他部分所定义。
式(I)化合物的合成可使用方案1至4中所总结的方法进行。
方案1
步骤1:苯并二氮杂酮(4)的制备例可以本领域技术人员已知的多种方法完成。例如,将适当的2-氨基苯甲酮(1)(例如,来自Walsh,D.A.,Synthesis,677(1980);以及其中引用的文献)可以偶联至受保护的甘氨酸衍生物(2)(PG=保护基,例如PG=CBz,参见Katritzky,A.R.,J.Org.Chem.,55:2206-2214(1990)),以试剂如胺处理并环化得到(3),根据在文献(例如Sherrill,R.G.等,J.Org.Chem.,60:730(1995);或本领域技术人员已知的其他途径)概述的方法。所得外消旋的混合物可以通过标准方法分离,如制备型手性色谱。此外,如果R3=H,(3)可在溶剂如DMF中以试剂如MeI和碱如K2CO3处理以制备R3=Me的(3)。
步骤2:化合物(3)的脱保护可以本领域技术人员已知的多种方式完成。例如,如果PG=CBz,(3)可以试剂如HBr在溶剂如AcOH中处理。如果(3)为外消旋的,然后(3)可以其本身使用,或分离对映异构体,并各自后续使用。
方案2
步骤1:方案2的第一步骤涉及以羧酸(6)在碳二亚胺如DCC、碱如TEA和催化剂如DMAP的存在下在溶剂如DCM中处理化合物(5)提供化合物(7)。
步骤2:化合物(7)至化合物(8)的转化可通过以试剂如氰基硼氢化钠在酸如HCl的存在下于可以为惰性的大气压条件例如在N2下进行处理来完成。
步骤3:化合物(8)至化合物(9)的转化可以经由携带合适离去基团(LG)的化合物(9)继续。例如,以碱如2,6-二甲基吡啶和试剂如三氟甲磺酸酐在溶剂如DCM于适当的温度如-78℃处理化合物(8)提供化合物(9)的三氟甲磺酸酯。化合物(9)现在可以经历交叉偶联反应条件提供化合物(10)。例如,以适当取代的偶联配偶体例如硼酸在催化剂如四(三苯基膦)钯(0)、碱如磷酸钾在溶剂如二噁烷在可以为惰性的大气压条件下例如在N2下处理化合物(9)提供化合物(10)。
步骤4:化合物(10)至化合物(11)的转化可以经由本领域技术人员已知的标准方法来完成。例如,在氢气气氛下在催化剂如Pd/C的存在下在溶剂如甲醇中处理化合物(10)得到化合物(11)。
步骤5:化合物(12)可以通过化合物(11)与化合物(4)的偶联来得到。例如,转化可以使用试剂如AlMe3在溶剂如DCM在惰性气氛如N2下来完成。在此情况中,所得到的的非对映异构体的混合物可以作为混合物使用或者可以通过适当的方法如手性色谱分离。
步骤6:化合物(12)使用氧化剂如琼斯试剂(Jones reagent)在溶剂如丙酮中进行氧化得到化合物(13)。如果化合物为非对映异构体混合物,然后其可以作为混合物使用或者使用适当方法如手性色谱来分离。
步骤7:化合物(13)至化合物(14)的转化可以经由本领域技术人员已知的标准方法来完成。例如,化合物(13)与合适胺源如氯化铵、碳二亚胺如EDC、HOBT和碱如TEA在溶剂如DMF中偶联提供化合物(14)。如有必要,非对映异构体混合物可以使用合适的分离技术如手性色谱来分离。
方案3
步骤1:方案3的第一步骤通过以试剂如硝酸钠在酸如H2SO4和如水中处理化合物(15)提供化合物(16)。
步骤2:化合物(16)的酸基团以保护基保护得到化合物(17),本领域技术人员已知的策略。例如,反应使用醇如苄基醇在溶剂如甲苯和酸如H2SO4中进行提供化合物(17)。
步骤3:携带合适离去基团的化合物(18)可通过以碱如2,6-二甲基吡啶和试剂如三氟甲磺酸酐在溶剂如DCM中于合适的温度处理化合物(17)而制备。
步骤4:化合物(19)可以本领域技术人员已知的多种方式转化成化合物(21)。例如,处理酰氯(19)(从相应的羧酸与试剂如草酰氯在溶剂如DCM中制备,或者市售获得)可以噁唑烷酮(20)在标准条件下处理得到化合物(21)(Evans,D.A.等,J.Am.Chem.Soc.,112:4011(1990))。
步骤5:化合物(22)的制备可以通过以碱如LiHMDS在溶剂如THF在合适的温度如-78℃处理化合物(21),接着添加的化合物(18)在溶剂如THF中的溶液来完成。
步骤6:化合物(22)的保护基团可以经由本领域技术人员已知的多种方法除去。例如,苄基可以使其经历使用钯催化剂如Pearlman's催化剂的氢化条件在溶剂如甲醇中除去提供化合物(23)。
步骤7:化合物(4)可以与化合物(23)在偶联试剂如TBTU和碱如TEA在溶剂如DMF中进行偶联提供化合物(24)。非对映异构体可以合适的方法如手性色谱进行分离。
步骤8:化合物(24)的水解可以过氧化氢和氢氧化锂在合适的温度使用各溶剂的混合物如THF/水对其尽心刚处理得到化合物(25)。
步骤9:化合物(25)至化合物(26)的转化可以经由本领域技术人员已知的标准方法完成。例如,化合物(25)与合适的胺源如氯化铵、碳二亚胺如EDC、HOBT和碱如TEA在溶剂如DMF中进行偶联提供化合物(26)。如有必要,非对映异构体混合物可以使用合适的分离技术如手性色谱来分离。
方案4
步骤1:适当保护的酸(27)可以具有合适离去基团的化合物(18)如三氟甲磺酸酯在碱如KHMDS的存在下进行烷基化得到化合物(28),为主要非对映异构体。化合物(28)可以作为非对映异构体混合物使用或者可以使用合适的分离技术如手性制备型色谱进行分离得到纯的非对映异构体化合物。
步骤2:化合物(28)的保护基可以经由本领域技术人员已知的多种方法除去。例如,苄基可以使其经历使用钯催化剂的氢化条件在溶剂如甲醇中除去提供化合物(29)。
步骤3:苯并二氮杂酮(30)可以偶联至化合物(29)(为醇的非对映异构体或非对映异构体混合物)在偶联剂如TBTU和碱如TEA的存在下在溶剂如DMF提供化合物(31),为非对映异构体纯的化合物或者为非对映异构体的混合物,如果合适的话。该混合物可以其本身用于后续步骤,或者如有需要,可以使用合适的分离技术如手性制备型色谱进行纯化提供非对映异构体纯的化合物。
步骤4:于合适的温度如25℃在溶剂如DCM中以酸如TFA处理化合物(31)提供化合物(32),为非对映异构体纯的化合物或非对映异构体的混合物。该混合物可以其本身用于后续步骤,或者如有需要,可以使用合适的分离技术如手性制备型色谱进行纯化提供非对映异构体纯的化合物。
步骤5:化合物(32)至化合物(33)的转化可以化合物(32)与合适胺源如胺、碳二亚胺如EDC和HOBT在溶剂如THF中的偶联来完成。如有必要,非对映异构体混合物可以使用合适的技术如手性制备型色谱分离。
实施例
在以下实例中对本发明进一步加以定义。应理解,这些实例仅以阐释性方式给出。根据上文论述及实例,本领域技术人员可确定本发明的基本特性,且可在不背离其精神及范围的情况下作出各种变化及修改,以使本发明适用于各种用途及条件。因此,本发明并不限于下文所述的阐释性实例,而是由所附的权利要求书加以限定。
缩写
ACN 乙腈
AcOH 乙酸
AlMe3 三甲基铝
Boc 叔丁基氧基羰基
CBz 苄基氧基羰基
DBU 1,8-二氮杂双环[5.4.0]十一-7-烯
DCC 1,3-二环己基碳二亚胺
DCM 二氯甲烷
DEA 二乙基胺
DMAP 二甲基氨基吡啶
DME 二甲醚
DMF 二甲基甲酰胺
DMSO 二甲基亚砜
EDC 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐
Et2O 二乙醚
EtOAc 乙酸乙酯
Et2AlCl 二乙基氯化铝
Et3N 三乙胺
H2SO4 硫酸
HCl 氢氯酸
HOBT 羟基苯并三唑
HPLC 高效液相色谱
hr 小时
IPA 异丙醇
iPrOH 异丙醇
KHMDS 双(三甲基甲硅烷基)氨基钾
LCMS 液相色谱-质谱法
LDA 二异丙基氨基锂
LiHMDS 双(三甲基甲硅烷基)氨基锂
Me 甲基
MeOH 甲醇
min 分钟
MTBE 甲基叔丁基醚
N2 氮气
NaHMDS 双(三甲基甲硅烷基)氨基钠
n-BuLi 正丁基锂
Pd/C 钯/碳
Pd(Ph3P)4 四(三苯基膦)钯(0)
Ph 苯基
RT 保留时间
sat 饱和
TBTU O-(1H-苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓四氟硼酸盐
TEA 三乙胺
TFA 三氟乙酸
THF 四氢呋喃
TMSCl 氯三甲基硅烷
实施例1
(2R,3R)-N-((3S)-1-甲基-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺
制备例1A:4-羟基-3-(3,3,3-三氟丙酰基)呋喃-2(5H)-酮
向呋喃-2,4(3H,5H)-二酮(16.46g,164mmol)在DCM(650mL)中的冷(0℃)的搅拌溶液添加TEA(23.0mL,165mmol)、DMAP(6.04g,49.4mmol)、3,3,3-三氟丙酸(16.0mL,181mmol)和DCC(40.70g,197mmol),产生黄色均匀溶液。于0℃搅拌溶液,并且然后随着浴升温温热至室温,同时搅拌过夜。悬浮液经过滤并且固体以DCM洗涤。深红色滤液经减压浓缩。剩余物在EtOAc和1M HCl(400mL)之间分配。有机相以盐水洗涤,干燥(Na2SO4),过滤并减压浓缩得到琥珀色固体。将其溶解于最小量的CH3CN中,向其中添加DCM以形成沉淀。悬浮液在冻干机中静置过夜。对其进行超声处理然后冷却并过滤,固体以冷DCM洗涤并且然后干燥以提供制备例1A(31.62g,91%),为乳状固体:1H NMR(400MHz,DMSO-d6)δppm 13.07(1H,br.s.),4.29(2H,s),3.80(2H,q,J=11.67Hz)。
制备例1B:4-羟基-3-(3,3,3-三氟丙基)呋喃-2(5H)-酮
三颈烧瓶配备以氮气入口、隔膜和出口(具有通过K2CO3水溶液捕集器的流)。向该烧瓶中添加制备例1A(13g,61.9mmol)(在THF(40mL)和2MHCl(40mL,80mmol)中)。向悬浮液中添加氰基硼氢化钠(3.89g,61.9mmol)(每30min分份,5x)。反应混合物于室温搅拌过夜。添加1N HCl(50mL)和更多的氰基硼氢化钠(2.4g,每20min分份)。再搅拌反应混合物30min。反应混合物以EtOAc稀释并且有机相经分离并减压浓缩得到黄色固体。将固体悬浮至水中,并搅拌10min,然后通过过滤收集并以水漂洗。固体经干燥得到制备例1B(11g,90%),为浅黄色固体:HPLC:RT=1.418min(YMC S-5ODS-A 4.6x 50mm,以10-90%MeOH水溶液洗脱4分钟,含0.2%H3PO4,4mL/min,在220nm监控);1H NMR(400MHz,DMSO-d6)δppm 2.29-2.40(m,4H),4.60(s,2H),12.16(s,1H)。
制备例1C:三氟甲磺酸5-氧代-4-(3,3,3-三氟丙基)-2,5-二氢呋喃-3-基酯
向制备例1B(8.1g,41.3mmol)在DCM(300mL)中的冷(-78℃)的搅拌悬浮液中添加2,6-二甲基吡啶(7.22mL,62.0mmol)产生均匀溶液。经10min添加三氟甲磺酸酐(8.02mL,47.5mmol)并于-78℃搅拌反应混合物30min。将反应混合物倒入1N HCl和盐水的1:1混合物中。分离有机相并且水相以DCM萃取。合并的有机物以盐水洗涤,干燥(Na2SO4),过滤并减压浓缩。粗物质通过快速色谱纯化(Teledyne ISCO,80g柱,60mL/min,A:己烷,B:EtOAc.0-50%,在25min内)。浓缩合适的级分提供制备例1C(12.5g,91%),为浅黄色液体,其在-20℃储存后固化:HPLC:RT=2.806min(YMC S-5ODS-A 4.6x 50mm,以10-90%MeOH水溶液洗脱4分钟,含0.2%H3PO4,4mL/min,在220nm监控);MS(ES):m/z=329[M+H]+;1H NMR(400MHz,CDCl3)δppm4.96(2H,s.),2.6(2H,m),2.46(2H,m)。
制备例1D:4-苯基-3-(3,3,3-三氟丙基)呋喃-2(5H)-酮
将氮气鼓泡通过制备例1C(4g,12.19mmol)在二噁烷(130mL)中的溶液20min。向脱气的溶液添加苯基硼酸(2.67g,21.94mmol)、磷酸钾(5.17g,24.38mmol)和四(三苯基膦)钯(0)(0.704g,0.609mmol)。反应混合物于80℃在氮气气氛下搅拌12h。反应通过LCMS判断完成。反应混合物经过滤。滤液经浓缩得到粗物质,其通过快速色谱纯化(Teledyne ISCO,220g柱,150mL/min 0-0%B,5min,然后0-50%EtOAc/己烷,在25min内)。得到制备例1D(3.2g,95%),为浅黄色固体:HPLC:RT=2.713min(YMC S-5ODS-A4.6x 50mm,以10-90%MeOH水溶液洗脱4分钟,含0.2%H3PO4,4mL/min,在220nm监控);MS(ES):m/z=257[M+H]+;1H NMR(400MHz,CDCl3)δ2.40-2.52(m,2H)2.75-2.84(m,2H)5.05(s,2H)7.37(dd,J=4.89,1.63Hz,2H)7.39(s,1H)7.50(d,J=2.01Hz,3H)7.51(d,J=2.01Hz,2H)。
制备例1E:(3R,4R)-4-苯基-3-(3,3,3-三氟丙基)二氢呋喃-2(3H)-酮
将氮气鼓泡通过制备例1D(3.1g,12.10mmol)在无水MeOH(100mL)中的溶液20min。向该脱气溶液中添加10%Pd/C(2g,12.10mmol))。反映容器以真空排空并填充以氢气。此过程重复两次并且反应混合物在氢气气氛下于室温搅拌15h。反应混合物以真空排空,并填充以氮气然后过滤。滤液经浓缩得到外消旋的制备例1E(2.8g,85%),为白色固体:HPLC:RT=2.650min(YMC S-5ODS-A 4.6x 50mm以10-90%MeOH水溶液洗脱4分钟,含0.2%H3PO4,4mL/min,在220nm监控);1H NMR(400MHz,CDCl3)δ1.30-1.41(m,1H)1.64-1.74(m,J=14.18,9.85,7.72,6.15Hz,1H)2.06-2.17(m,J=15.47,10.20,9.85,5.65Hz,1H)2.23-2.35(m,1H)2.89(q,J=7.78Hz,1H)3.71(ddd,J=8.16,6.15,1.76Hz,1H)4.51(dd,J=9.41,1.88Hz,1H)4.57-4.67(m,1H)7.12-7.21(m,2H)7.28-7.39(m,3H)。
制备例1F:(3S)-3-氨基-1-甲基-5-苯基-1,3-二氢-2H-1,4-苯并二氮杂-2-酮
外消旋的3-氨基-1-甲基-5-苯基-1,3-二氢-2H-1,4-苯并二氮杂-2-酮(Rittle,K.E.等,Tetrahedron Letters,28(5):521-522(1987))根据文献方法制备。各对映异构体在手性-SFC条件下使用下列方法分离:AS-H5x25;移动相:30%MeOH+0.1%DEA in CO2;流速:280mL/min;压强:100bar;温度:35℃。
得到S-对映异构体(制备例1F):HPLC:RT=1.75min(30%MeOH+0.1%DEA in CO2on手性AS-H 4.6x250mm,3mL/min,35℃,100bar,230nm,10μl注射);1H NMR(400MHz,CDCl3)δ7.58-7.63(2H,m),7.55(1H,ddd,J=8.50,7.11,1.76Hz),7.40-7.47(1H,m),7.34-7.40(3H,m),7.31(1H,dd,J=7.81,1.51Hz),7.14-7.22(1H,m),4.46(1H,s),3.44(3H,s),3.42(2H,s);[α]D=-155°(c=1.9,MeOH)(Lit.Rittle,K.E.等,Tetrahedron Letters,28(5):521-522(1987)[α]D=-236°)。
还得到R-对映异构体:HPLC:RT=1.71min;[α]D=+165°(c=2.1,MeOH)(Lit[α]D=+227°)。
制备例1G:(2R)-5,5,5-三氟-2-((1R)-2-羟基-1-苯基乙基)-N-((3S)-1-甲基-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)戊酰胺,和
(2S)-5,5,5-三氟-2-((1S)-2-羟基-1-苯基乙基)-N-((3S)-1-甲基-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)戊酰胺
向制备例1E(2g,7.36mmol)和制备例1F(2.93g,11.04mmol)在DCM(80mL)中的溶液于室温添加MeOH(0.209mL,5.15mmol),接着添加2M AlMe3(在甲苯(14.72mL,29.4mmol)中)。溶液的颜色变成蓝色,然后变成灰色并冒泡。反应混合物然后于40℃在氮气下加热1h 15min。反应混合物冷却至室温并以DCM稀释,并且然后将反应混合物缓慢添加至20%Na/K酒石酸盐水溶液中。30min后分离有机相,以盐水洗涤,干燥(Na2SO4),过滤并减压浓缩。粗物质通过快速色谱纯化(Teledyne ISCO,120g柱,85mL/min 0-60%EtOAc-DCM,在30min内)。得到制备例1G(2g,51%),为非对映异构体制备例1G-1和制备例1G-2(1.7:1)的混合物:HPLC:RT=3.096和3.051min(YMCS-5ODS-A 4.6x 50mm,以10-90%MeOH水溶液洗脱4分钟,含0.2%H3PO4,4mL/min,在220nm监控);MS(ES):m/z=524[M+H]+;1H NMR(400MHz,CDCl3)δ1.82(m,1H)1.95(m,1H)2.2(m,2H)2.96(m,1H)3.22(m,1H)3.45(d,3H)3.97(m,1H)4.13(m,1H)5.43(m,1H)7.21-7.62(m,15H)。
制备例1H:(2R,3R)-6,6,6-三氟-3-(((3S)-1-甲基-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)氨基甲酰基)-2-苯基己酸,和
(2S,3S)-6,6,6-三氟-3-(((3S)-1-甲基-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)氨基甲酰基)-2-苯基己酸
向制备例1G(2g,3.8mmol)在丙酮(20mL)中的冷(0℃)的搅拌溶液添加1.35M琼斯试剂(CrO3+H2SO4+H2O)(5.66mL,7.64mmol)。反应混合物于0℃搅拌10min,然后于室温搅拌1h 45min。反应通过LCMS判断完成。反应混合物以EtOAc和1%NaHSO3稀释。有机相以盐水洗涤、干燥(MgSO4),过滤并减压浓缩。粗物质通过快速色谱纯化(Teledyne ISCO,120g柱,85mL/min,0-100%EtOAc/CH2Cl230min)提供制备例1H(1.7g,81%),为无色固体,其为非对映异构体制备例1H-1和制备例1H-2的混合物(1.65:1):HPLC:RT=3.078(YMC S-5ODS-A 4.6x 50mm以10-90%MeOH水溶液洗脱4分钟,含0.2%H3PO4,4mL/min,在220nm监控);MS(ES):m/z=538[M+H]+;1HNMR(400MHz,CDCl3)δ2.0(m,2H)2.3(m,2H)3.3(m,1H)3.4(s,3H)3.9(m,1H)5.24(d,1H)7.16-7.55(m,15H)。
实施例1
向中间体1H(1.17g,2.0mmol)在DMF(30mL)中的溶液添加EDCI(1.819g,9.49mmol)、HOBt(1.453g,9.49mmol)、NH4Cl(1.690g,31.6mmol)和Hunig碱(8.29mL,47.4mmol)。反应混合物于室温搅拌16h。添加水并搅拌10min。形成沉淀并过滤以收集固体。该固体然后以CH2Cl2溶解并以盐水洗涤。有机相以MgSO4干燥,过滤并浓缩并且粗物质通过快速色谱纯化(Teledyne ISCO,120g柱,85mL/min,0-100%EtOAc/己烷)提供实施例1(1.1g,),为无色固体,其为非对映异构体的混合物(1.8:1)。
非对映异构体混合物在Thar制备型SFC上分离:柱:OD-H(5x25cm,5μm);BPR压强:100bars;温度:35℃;流速:280mL/min;移动相:CO2/MeOH(87/13);检测器波长:225nm。实施例1:HPLC:RT=8.21min(30%MeOH+0.1%DEA,在CO2中,在上AS-H 4.6x250mm,3mL/min,35℃,100bar,230nm,10μl inj);MS(ES):m/z=537[M+H]+;1H NMR(400MHz,CDCl3)δ1.9(m,2H)2.16(m,2H)3.2(m,1H)3.6(m 3H)5.21(d,1H)5.35(bs,1H)5.52(bs 1H)7.12-7.52(m,15H)。
实施例2
(2R,3R)-3-(4-氟苯基)-N-((3S)-1-甲基-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-2-(3,3,3-三氟丙基)琥珀酰胺
实施例2根据实施例1显示的一般程序制备。HPLC:RT=24.5min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=30min,波长=220和254nm);MS(ES):m/z=555.3[M+H+];1H NMR(400MHz,氯仿-d)δ7.57(td,J=7.8,1.5Hz,1H),7.53-7.29(m,11H),7.25-7.17(m,1H),7.13-7.03(m,2H),5.59(br.s.,1H),5.49(br.s.,1H),5.27(d,J=8.0Hz,1H),3.66(d,J=9.8Hz,1H),3.42(s,3H),3.32-3.19(m,1H),2.24(dd,J=16.6,10.5Hz,2H),2.04-1.91(m,2H)。
实施例3
(2R,3R)-N-((3S)-1-甲基-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-(2,3,4-三氟苯基)-2-(3,3,3-三氟丙基)琥珀酰胺
实施例3根据实施例1显示的一般程序制备。HPLC:RT=25.49min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=30min,波长=220和254nm);MS(ES):m/z=591.4[M+H+];1H NMR(400MHz,氯仿-d)δ7.65-7.54(m,2H),7.52-7.43(m,2H),7.43-7.29(m,6H),7.25-7.18(m,1H),7.06(d,J=9.3Hz,1H),5.72(br.s.,1H),5.57(br.s.,1H),5.29(d,J=8.0Hz,1H),4.08(d,J=10.3Hz,1H),3.43(s,3H),3.41-3.29(m,1H),2.36-2.17(m,2H),2.07-1.91(m,2H)。
实施例4
(2R,3R)-N-((3S)-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺
制备例4A:(3S)-3-氨基-5-苯基-1,3-二氢-2H-1,4-苯并二氮杂-2-酮
外消旋的(3S)-3-氨基-5-苯基-1,3-二氢-2H-1,4-苯并二氮杂-2-酮(J.Med.Chem.,49:2311-2319(2006),化合物#5)根据文献方法制备。对映异构体在Berger SFC MGIII柱上分离:Lux 25x3cm,5cm;移动相:30%MeOH+0.1%DEA,在CO2中;流速:150mL/min;温度:40℃;检测器波长:250nM。得到S-对映异构体,为白色固体:1H NMR(400MHz,DMSO-d6)δ10.67(1H,br.s.),7.58(1H,td,J=7.65,1.76Hz),7.37-7.53(5H,m),7.23-7.30(2H,m),7.14-7.22(1H,m),4.23(1H,s),2.60(2H,br.s.);HPLC:RT=3.0625min(30%MeOH+0.1%DEA in CO2on OD-H柱,3mL/min,35℃,96bar,230nm,10μl注射);[α]D=-208.3°(5.05mg/mL,MeOH)。还得到R-对映异构体,为灰白色固体:R–对映异构体:HPLC:RT=3.970min;[α]D=182.1°(2.01mg/mL,MeOH)。
制备例4B:(2R)-5,5,5-三氟-2-羟基戊酸
经由滴液漏斗经60min向(2R)-2-氨基-5,5,5-三氟戊酸(4.09g,23.90mmol)(U.S公开号2009/0111858A1)和H2SO4(2.8mL,52.5mmol)在水(95mL)中的冷(0℃)的搅拌溶液中滴加亚硝酸钠(9.89g,143mmol)在水(30mL)中的溶液。
反应混合物缓慢地温热至室温并搅拌过夜。反应混合物以Et2O稀释,分离水相并以Et2O(3x)萃取。合并的有机物经干燥(Na2SO4),过滤并减压浓缩提供制备例4B(4.1551g,>99%),为琥珀色有状物。1H NMR(400MHz,CDCl3)δ4.33(1H,dd,J=8.03,4.27Hz),2.09-2.42(3H,m),1.88-2.02(1H,m)。
制备例4C:(2R)-5,5,5-三氟-2-羟基戊酸苄基酯
向制备例4B(4.1551g,24.14mmol)、苄基醇(3.2mL,30.8mmol)在苯(40mL)中的搅拌溶液添加H2SO4(0.28mL,5.25mmol)。将反应混合物加热至50℃保持10h。反应混合物冷却至室温,在冰/水浴中冷却并且然后添加0.5MNaOH(32mL,16.00mmol)。搅拌混合物数分钟,并以Et2O萃取,以盐水洗涤,干燥(Na2SO4),过滤并减压浓缩。剩余物通过快速色谱纯化(TeledyneISCO CombiFlash Rf,0%至100%溶剂CH2Cl2/EtOAc,SiO2120g).浓缩合适的级分提供制备例4C(3.88g,61%),为无色油状物:1H NMR(400MHz,CDCl3)δ7.33-7.44(5H,m),5.25(2H,s),4.28(1H,dt,J=8.09,4.11Hz),2.85(1H,d,J=4.77Hz),2.07-2.34(3H,m),1.84-1.96(1H,m)。
制备例4D:(2R)-5,5,5-三氟-2-{[(三氟甲基)磺酰基]氧基}戊酸苄基酯
向2,6-二甲基吡啶(2.352mL,20.19mmol)在CH2Cl2(30mL)中的冷(-25℃)的搅拌溶液经2分钟缓慢添加三氟甲磺酸酐(3.18mL,18.85mmol)。
反应混合物于-25℃搅拌并且颜色变成浅黄色/橙色。10min后,经5min滴加制备例4C(3.53g,13.46mmol)并于-25℃搅拌30分钟。反应混合物温热至室温并浓缩至小体积。剩余物以庚烷稀释并直接装载至硅胶柱(220g)上,以20%CH2Cl2/庚烷至50%CH2Cl2/庚烷的梯度洗脱。浓缩合适的级分提供制备例4D(3.476g,66%):1H NMR(400MHz,CDCl3)δ7.33-7.45(5H,m),5.29(2H,d,J=5.50Hz),5.21(1H,t,J=5.50Hz),2.04-2.37(4H,m)。
制备例4E:(4R)-4-苄基-3-(苯基乙酰基)-1,3-噁唑烷-2-酮
经由注射器经10min向(4R)-4-苄基-1,3-噁唑烷-2-酮(4.17g,23.53mmol)在THF(100mL)中的冷(-78℃)的搅拌溶液中在氮气气氛下滴加n-BuLi(9.5mL,23.75mmol)。搅拌10min后,经由套管经10min添加2-苯基乙酰基氯(3.2mL,24.20mmol)在THF(20mL)中的溶液。完成添加后,将反应混合物置于冰-水浴中并于0℃搅拌1hr。然后从浴移出。向反应混合物添加饱和NH4Cl水溶液并以EtOAc(2x)萃取。合并的有机物以盐水洗涤,干燥(Na2SO4),过滤并减压浓缩。剩余物通过快速色谱纯化(Teledyne ISCO CombiFlash Rf,0%至100%溶剂己烷/EtOAc,SiO2120g)。浓缩合适的级分提供制备例4E(6.19g,89%),无色粘稠油状物:1H NMR(400MHz,CDCl3)δ7.32-7.39(4H,m),7.21-7.32(4H,m),7.10-7.17(2H,m),4.67(1H,dddd,J=10.29,6.34,3.45,3.26Hz),4.30(2H,q,J=15.56Hz),4.15-4.22(2H,m),3.26(1H,dd,J=13.30,3.26Hz),2.76(1H,dd)。
制备例4F:(2R)-2-((1R)-2-((4R)-4-苄基-2-氧代-1,3-噁唑烷-3-基)-2-氧代-1-苯基乙基)-5,5,5-三氟戊酸苄基酯
经5min向制备例4E(1g,3.39mmol)在THF(10mL)中的冷(-78℃)的搅拌溶液中滴加LiHMDS(1M in THF)(4.06mL,4.06mmol)。反应混合物于-78℃搅拌1.5hr,并且然后置入-45℃浴中。经1min向反应混合物添加制备例4D(1.602g,4.06mmol)(在THF(5mL)中)并于-45℃搅拌2hr。接下来,将反应混合物从-45℃浴除去并温热至室温。反应通过HPLC判断完成。向反应混合物添加饱和NH4Cl水溶液并以EtOAc萃取,以盐水洗涤,干燥(Na2SO4),过滤并减压浓缩。剩余物通过快速色谱纯化(Teledyne ISCO,5%至40%溶剂A/B=己烷/EtOAc,SiO2120g)。浓缩合适的级分提供制备例4F(1.429g,78%):HPLC:RT=3.790min(SpeedROD 4.6x 50mm(4min grad),以10-90%MeOH水溶液洗脱4分钟,含0.1%TFA,4mL/min,在220nm监控);MS(ES):m/z=540[M+H]+;1H NMR(500MHz,CDCl3)δ7.31-7.39(4H,m),7.24-7.31(7H,m),7.22(2H,d,J=7.15Hz),6.99-7.05(2H,m),5.38(1H,d,J=11.00Hz),4.76-4.88(2H,m),4.58(1H,dddd,J=10.10,7.35,2.89,2.75Hz),4.08-4.12(1H,m),4.02(1H,t,J=8.25Hz),3.45(1H,td,J=10.45,3.30Hz),3.34(1H,dd,J=13.20,3.30Hz),2.76(1H,dd,J=13.20,9.90Hz),1.97-2.20(3H,m),1.83-1.94(1H,m)。
制备例4G:(2R)-2-((1R)-2-((4R)-4-苄基-2-氧代-1,3-噁唑烷-3-基)-2-氧代-1-苯基乙基)-5,5,5-三氟戊酸
制备例4F(1.42g,2.63mmol)和Pearlman's催化剂(0.111g,0.790mmol)在MeOH(20mL)中的搅拌悬浮液于氢气气氛下搅拌45min。反应通过HPLC判断完成。反应混合物经0.45μm膜滤器过滤并以MeOH漂洗。滤液经浓缩并高真空干燥提供制备例4G(1.182g,100%),为灰白色固体:HPLC:RT=3.138min(SpeedROD 4.6x 50mm(4min grad),以10-90%MeOH水溶液洗脱4分钟,含0.1%TFA,4mL/min,在220nm监控);MS(ES):m/z=450[M+H]+;1H NMR(500MHz,CDCl3)δ7.32-7.41(4H,m),7.27-7.31(4H,m),7.23(2H,d,J=7.70Hz),5.37(1H,d,J=10.45Hz),4.59(1H,t,J=8.25Hz),4.12(1H,d,J=8.25Hz),4.04(1H,t,J=8.25Hz),3.32-3.43(2H,m),2.79(1H,dd,J=13.20,9.90Hz),2.18(2H,dq,J=18.35,9.10Hz),1.97-2.08(1H,m),1.85-1.96(1H,m)。
制备例4H:(2R)-2-((1R)-2-((4R)-4-苄基-2-氧代-1,3-噁唑烷-3-基)-2-氧代-1-苯基乙基)-5,5,5-三氟-N-((3S)-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)戊酰胺
向制备例4A(408mg,1.624mmol)和制备例4G(730mg,1.624mmol)在DMF(10mL)中的搅拌溶液中添加O-苯并三唑-1-基-N,N,N′,N′-四-甲基脲鎓四氟硼酸盐(573mg,1.786mmol)和二异丙基乙基胺(0.60mL,3.41mmol)。反应混合物搅拌过夜。反应通过LCMS判断完成。反应混合物以水(56mL)和饱和NaHCO3(7mL)稀释,室温搅拌30min,然后沉淀通过过滤收集并以水(3x 10mL)漂洗,经真空干燥。得到制备例4H(1.080g,97%):HPLC:RT=3.171min(ODS 4.6x 50mm(4min grad),以10-90%MeOH水溶液洗脱4分钟,含0.%TFA,4mL/min,在220nm监控);MS(ES):m/z=600[M+H]+;1H NMR(400MHz,CDCl3)δ8.03(1H,s),7.95(1H,s),7.42-7.58(4H,m),7.23-7.43(13H,m),7.15-7.22(1H,m),7.10(1H,d,J=8.03Hz),6.87(1H,d,J=8.03Hz),5.44(1H,d,J=10.79Hz),5.27(1H,d,J=8.03Hz),4.58-4.70(1H,m),4.00-4.17(2H,m),3.30-3.48(2H,m),2.27-2.44(2H,m),2.06-2.23(1H,m),1.85-2.00(1H,m)。
制备例4I:(2R,3R)-6,6,6-三氟-3-(((3S)-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)氨基甲酰基)-2-苯基己酸
过氧化氢(0.404mL,3.95mmol)和氢氧化锂(31.6mg,1.318mmol)吸收在水(1.50mL)中并于室温搅拌直到溶液为均匀和澄清的。将该混合物添加至制备例4H(300mg,0.439mmol)在THF(5mL)中的溶液并搅拌30min。反应混合物以pH 4磷酸盐缓冲液(20mL)和1%NaHSO3溶液(10mL)(pH~4)稀释并以EtOAc(2x80mL)萃取。合并的有机物以盐水洗涤,干燥(Na2SO4),过滤并减压浓缩。剩余物通过快速色谱纯化(Teledyne ISCO,25%至100%溶剂A/B=己烷/EtOAc,SiO240g,DCM液体装载)。浓缩合适的级分提供制备例4I(129.6mg,56%)。
实施例4
实施例4由制备例4I(92.6mg,0.177mmol)通过实施例1显示的一般方法制备。得到实施例4(54.7mg,58%),为白色固体:HPLC:RT=2.447min(ODS 4.6x 50mm(4min grad),以10-90%MeOH水溶液洗脱4分钟,含0.%TFA,4mL/min,在220nm监控);MS(ES):m/z=523[M+H]+;1H NMR(500MHz,DMSO-d6)δ10.78(1H,s),9.27(1H,d,J=7.70Hz),7.70(1H,br.s.),7.55-7.65(1H,m),7.51(1H,t,J=7.15Hz),7.44(2H,t,J=7.42Hz),7.36(4H,dd,J=19.25,7.15Hz),7.13-7.30(6H,m),6.93(1H,br.s.),4.89(1H,d,J=7.15Hz),3.70(1H,d,J=11.00Hz),3.43(1H,td,J=10.86,3.02Hz),2.58-2.77(1H,m),2.25-2.41(1H,m),1.74-1.87(1H,m),1.55-1.74(1H,m)。
实施例4
实施例4由中间体4A(36.3mg,0.144mmol)和中间体S-1(50.0mg,0.144mmol)根据实施例5所显示的一般程序制备。得到实施例4(24.0mg,29.3%)。HPLC:RT=8.62min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=523.3[M+H+];1HNMR(400MHz,DMSO-d6)δ10.77(s,1H),9.25(d,J=7.5Hz,1H),7.69(br.s.,1H),7.60(ddd,J=8.3,6.2,2.5Hz,1H),7.54-7.49(m,1H),7.44(t,J=7.4Hz,2H),7.40-7.32(m,4H),7.29-7.17(m,6H),6.92(br.s.,1H),4.89(d,J=7.7Hz,1H),3.70(d,J=11.2Hz,1H),3.50-3.39(m,1H),2.75-2.62(m,1H),2.34(d,J=11.9Hz,1H),1.86-1.74(m,1H),1.73-1.61(m,1H)。
苯并二氮杂中间体的合成
中间体B-1:外消旋的3-氨基-5-(3-氟苯基)-9-甲基-1H-苯并[e][1,4]二氮杂-2(3H)-酮
中间体B-1A:2-氨基-N-甲氧基-N,3-二甲基苯甲酰胺
在1L圆底烧瓶中添加在CH2Cl2(500mL)中的2-氨基-3-甲基苯甲酸(11.2g,74.1mmol)、N,O-二甲基羟胺盐酸盐(14.45g,148mmol)得到淡棕色悬浮液。反应混合物以Et3N(35mL)处理得到浅棕/红色溶液。溶液以HOBT(11.35g,74.1mmol)和EDC(14.20g,74.1mmol)处理并于室温搅拌24小时。混合物然后以10%LiCl水溶液(以1N HCl酸化)洗涤。有机层连续以10%LiCl水溶液和NaHCO3水溶液依次洗涤。有机层以木炭脱色,过滤并滤液经MgSO4干燥。混合物经过滤并浓缩得到13.22g(92%产率)的2-氨基-N-甲氧基-N,3-二甲基苯甲酰胺,为油状物。MS(ES):m/z=195.1[M+H+];HPLC:RT=1.118min.(H2O/MeOH,含TFA,ODS S54.6x 50mm,梯度=4min,波长=220nm);1H NMR(500MHz,氯仿-d)δ7.22(dd,J=7.8,0.8Hz,1H),7.12-7.06(m,1H),6.63(t,J=7.5Hz,1H),4.63(br.s.,2H),3.61(s,3H),3.34(s,3H),2.17(s,3H)。其不经进一步纯化用于后续反应。
中间体B-1B:(2-氨基-3-甲基苯基)(3-氟苯基)甲酮
在500mL圆底烧瓶中1-氟-3-碘苯(13.61mL,116mmol)在THF(120mL)的溶液中于-78℃浴中冷却。经10min滴加BuLi(2.5M在己烷(46.3mL,116mmol)得到略浑浊的黄色溶液。于-78℃搅拌溶液30分钟并且然后以2-氨基-N-甲氧基-N,3-二甲基苯甲酰胺(6.43g,33.1mmol)在THF(30mL)中的溶液。1.5小时后,将反应混合物添加至冰和1N HCl(149mL,149mmol)中的混合物并且反应烧瓶以THF(5ml)漂洗并且与混合物水溶液合并。所得混合物以10%LiCl水溶液稀释并且pH以1N NaOH调节至4.00。混合物以Et2O萃取,以盐水洗涤,经MgSO4干燥,过滤并浓缩。所得剩余物在硅胶柱(220g ISCO)上纯化以从10%EtOAc/己烷至30%EtOAc/己烷的梯度洗脱。产物经收集并浓缩得到(2-氨基-3-甲基苯基)(3-氟苯基)甲酮(7.11g,94%产率),为油状物。MS(ES):m/z=230.1[M+H+];HPLC:RT=2.820min纯度=99%.(H2O/MeOH,含TFA,ODS S54.6x 50mm,梯度=4min,波长=220nm);
中间体B-1C:(5-(3-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)氨基甲酸苄基酯
在1L圆底烧瓶中,2-(1H-苯并[d][1,2,3]三唑-1-基)-2-((苯氧基羰基)氨基)乙酸(19.37g,62.0mmol)在THF(135mL)中的溶液在冰/水浴中冷却并以草酰氯(5.43mL,62.0mmol)和4滴DMF处理(冒泡)。搅拌反应混合物4小时(直到HPLC分析显示完全转化成酰氯)。然后添加(2-氨基-3-甲基苯基)(3-氟苯基)甲酮(7.11g,31.0mmol)在THF(35mL)中的溶液(以5mL THF漂洗)且所得溶液从冰/水浴除去并于室温搅拌1.5小时。混合物然后以氨(7M,在MeOH中)(19.94mL,140mmol)处理(轻微放热,立即形成白色沉淀并且混合物在冰/水浴中冷却)。15min后,再添加另一份氨(7M,在MeOH中)(19.94mL,140mmol)并且所得混合物从冰/水浴除去并在N2下密封并于室温搅拌过夜。反应混合物经浓缩至~1/2体积并且所得混合物以AcOH(63mL)稀释并于室温室温搅拌4小时(直到HPLC分析显示完全转化。反应混合物经浓缩并且剩余物以500mL水稀释并得到橙色粘稠沉淀。添加己烷和Et2O并于室温搅拌1小时以形成橙色固体。Et2O在氮气流中除去并且倾析水层。橙色粘稠剩余物以40mL iPrOH研磨并于室温搅拌得到白色沉淀。固体经过滤并以iPrOH洗涤,在氮气流下在烧结玻璃漏斗上干燥得到(5-(3-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)氨基甲酸苄基酯(5.4g,41.7%产率)。MS(ES):m/z=418.3[M+H+];HPLC:RT=3.075min纯度=99%。(H2O/MeOH,含TFA,ODS S54.6x 50mm,梯度=4min,波长=220nm)。
中间体B-1
(5-(3-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)氨基甲酸苄基酯(470mg,1.126mmol)在乙酸(5mL)中的悬浮液以HBr(33%在乙酸中)(1.853mL,11.26mmol)处理并室温搅拌1.5小时。反应混合物以乙醚稀释并且所得沉淀于室温搅拌1小时并且然后过滤得到中间体B-1(370mg,90%产率),为黄棕色/橙色固体。MS(ES):m/z=284.0[M+H+].HPLC:RT=1.75min(H2O/MeOH,含0.1%TFA,Luna C183μm,4.6x30mm,梯度=3.5min,波长=220)。
中间体B-2:(S)-3-氨基-5-(3-氟苯基)-9-甲基-1H-苯并[e][1,4]二氮杂-2(3H)-酮
中间体B-2A:(S)-(5-(3-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)氨基甲酸苄基酯
外消旋的(5-(3-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)氨基甲酸苄基酯(5.9g,14.3mmol)在手性SFC条件下拆分。BergerSFC MGIII,柱:IC 25x 3cm ID,5μm,移动相:45/55CO2/MeOH;流速:160mL/min;检测器波长:220nM。收集所需的立体异构体,为洗脱顺序中的第二峰。蒸发溶剂后,得到(S)-(5-(3-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)氨基甲酸苄基酯(2.73g,46%产率),为白色固体。HPLC:RT=3.075min纯度=99%。(H2O/MeOH,含TFA,ODS S54.6x 50mm,梯度=4min,波长=220nm).手性HPLC RT:8.661min(AD,60%(EtOH/MeOH)/庚烷)>99%ee.(在所期望的AD手性柱上为第一峰,其为在IC SFC上的第二峰)。
中间体B-2
在100mL圆底烧瓶中,(S)-(5-(3-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)氨基甲酸苄基酯(2.729g,6.54mmol)在乙酸(12mL)中的溶液以HBr(33%在HOAc中)(10.76mL,65.4mmol)处理并于室温搅拌1小时。
溶液以Et2O稀释得到黄色沉淀。黄色固体经过滤并以Et2O在氮气下漂洗。将固体转移至100mL圆底烧瓶并添加水(形成白色沉淀)并且缓慢地以饱和NaHCO3碱化。所得粘稠沉淀以EtOAc萃取(不是很好地溶解于EtOAc中,需要大量体积)。有机层以水洗涤并且然后经MgSO4干燥。所得物质经过滤,浓缩,并真空干燥得到中间体B-2(1.68g,91%产率),为白色泡沫状固体。MS(ES):m/z=284.2[M+H+];HPLC:RT=1.72min纯度=99%.(H2O/MeOH,含TFA,ODS S54.6x 50mm,梯度=4min,波长=220nm)。
中间体B-3:3-氨基-5-(4-氟苯基)-9-甲基-1H-苯并[e][1,4]二氮杂-2(3H)-酮
中间体B-3根据用于合成中间体B-1的方法合成,得到3-氨基-5-(4-氟苯基)-9-甲基-1H-苯并[e][1,4]二氮杂-2(3H)-酮,氢溴酸盐,为黄棕色固体:MS(ES):m/z=284.0[M+H+].HPLC:RT=0.65min(H2O/CH3CN,含0.05%TFA,BEH C181.7μm,2.1x50mm,梯度(2%-98%)=1min,波长=220。
中间体B-4:3-氨基-9-甲基-5-(3-(三氟甲基)苯基)-1H-苯并[e][1,4]二氮杂-2(3H)-酮
中间体B-4根据用于合成中间体B-1的方法合成得到3-氨基-9-甲基-5-(3-(三氟甲基)苯基)-1H-苯并[e][1,4]二氮杂-2(3H)-酮,氢溴酸盐,为浅黄色固体:MS(ES):m/z=334.0[M+H+]。HPLC:RT=0.73min(H2O/CH3CN,含0.05%TFA,BEH C181.7μm,2.1x50mm,梯度(2%-98%)=1min,波长=220。
中间体B-5:3-氨基-5-(3-氯苯基)-9-甲基-1H-苯并[e][1,4]二氮杂-2(3H)-酮
中间体B-5根据用于合成中间体B-1的方法合成得到3-氨基-5-(3-氯苯基)-9-甲基-1H-苯并[e][1,4]二氮杂-2(3H)-酮,氢溴酸盐为浅黄色固体:MS(ES):m/z=300.3[M+H+]。HPLC:RT=1.91min(H2O/MeOH with0.1%TFA,Luna C183μm,4.6x30mm,梯度=3.5min,波长=220)。
中间体B-6:氨基-5-(3-(二氟甲基)苯基)-9-甲基-1H-苯并[e][1,4]二氮杂-2(3H)-酮
中间体B-6根据用于合成中间体B-1的方法合成得到3-氨基-5-(3-(二氟甲基)苯基)-9-甲基-1H-苯并[e][1,4]二氮杂-2(3H)-酮,氢溴酸盐为浅黄色固体:MS(ES):m/z=316.1[M+H+]。HPLC:RT=0.70min(H2O/CH3CN,含0.05%TFA,BEH C181.7μm,2.1x50mm,梯度(2%-98%)=1min,波长=220。
中间体B-7:3-氨基-9-环丙氧基-5-(3-氟苯基)-1H-苯并[e][1,4]二氮杂-2(3H)-酮
中间体B-7A:2-硝基-3-(乙烯基氧基)苯甲酸甲基酯
乙酸铜(II)(11.98g,65.9mmol)和二氯甲烷(80mL)的混合物于室温搅拌10分钟,然后添加2,4,6-三乙烯基-1,3,5,2,4,6-三氧杂三硼烷化合物和吡啶(1:1)(10.63g,44.2mmol,0.67当量)、3-羟基-2-硝基苯甲酸甲基酯(U.S.公开号2012/0035194A1[0202])(13g,65.9mmol)、吡啶(26.7mL,330mmol)和分子筛(1g)。所得深蓝色混合物于室温搅拌5天,其中反应混合物对空气开放。反应混合物经垫过滤,以一些二氯甲烷洗涤。滤液以3M乙酸铵水溶液(2x)、水、盐水洗涤,并且然后干燥,过滤并真空浓缩。粗产物混合物经由纯化(0%至20%的EtOAc/DCM,在15分钟内,120g柱)得到2-硝基-3-(乙烯基氧基)苯甲酸甲基酯(7.42g,33.2mmol,50.4%产率)。HPLC:RT=2.487min(H2O/MeOH,含TFA,SunFire C183.5μm,2.1x 30mm,梯度=4min,波长=220nm);MS(ES):m/z=246[M+Na]+;1H NMR(400MHz,氯仿-d)δ7.77(dd,J=7.8,1.2Hz,1H),7.55(t,J=8.1Hz,1H),7.38(dd,J=8.4,1.3Hz,1H),6.61(dd,J=13.6,5.9Hz,1H),4.95(dd,J=13.6,2.4Hz,1H),4.69(dd,J=5.9,2.4Hz,1H),3.93(s,3H),1.56(s,1H),0.03(s,1H)。
中间体B-7B:3-环丙氧基-2-硝基苯甲酸甲基酯
在500mL三颈烧瓶中,在氮气气氛下经由滴液漏斗将2,2,2-三氯乙酸(16.30g,100mmol)在二氯甲烷(100mL)中的溶液缓慢添加至二乙基锌的-10℃溶液(1M己烷,100mL,100mmol)。搅拌反应混合物10min。接下来,通过注射器滴加二碘甲烷(8mL,100mmol)并且反应溶液搅拌10min。经由滴液漏斗缓慢地添加2-硝基-3-(乙烯基氧基)苯甲酸甲基酯(7.42g,33.2mmol)在二氯甲烷(20mL)中的溶液。将溶液温热至室温过夜。反应混合物冷却至0℃并以1M HCl淬灭。将反应溶液转移至分液漏斗中,并且水层以二氯甲烷(3x)萃取。合并的萃取物以饱和碳酸氢钠、水和盐水洗涤,经无水硫酸钠干燥,过滤并浓缩。粗产物混合物通过ISCO纯化(0%的EtOAc/庚烷,在15分钟内,220g柱)提供3-环丙氧基-2-硝基苯甲酸甲基酯(4.7g,19.81mmol,60.0%产率)。HPLC:RT=2.66min(H2O/MeOH,含TFA,SunFire C183.5μm,2.1x 30mm,梯度=4min,波长=220nm);MS(ES):m/z=260[M+Na]+;1H NMR(400MHz,氯仿-d)δ7.68-7.57(m,2H),7.57-7.41(m,1H),4.03-3.82(m,4H),0.94-0.78(m,4H)。
中间体B-7C:3-环丙氧基-2-硝基苯甲酸
3-环丙氧基-2-硝基苯甲酸甲基酯(4.7g,19.81mmol)在THF(30mL)和MeOH(30mL)中的溶液以氢氧化锂(2.88g,120mmol)在水(15mL,833mmol)中的溶液处理。混合物于室温搅拌2小时。在减压下除去有机溶剂。所得浆料水溶液以水稀释,以1M HCl酸化并以乙酸乙酯(3x)萃取。将各萃取物合并并以盐水洗涤,经无水硫酸钠干燥,过滤并浓缩提供3-环丙氧基-2-硝基苯甲酸(4.35g,19.8mmol,98%产率),为黄色固体。HPLC:RT=2.186min(H2O/MeOH,含TFA,SunFire C183.5μm,2.1x 30mm,梯度=4min,波长=220nm);
MS(ES):m/z=246[M+Na]+;1H NMR(400MHz,氯仿-d)δ7.76(dd,J=7.7,1.8Hz,1H),7.68-7.46(m,2H),4.02(tt,J=6.0,2.9Hz,1H),1.00-0.52(m,4H)。
中间体B-7D:2-氨基-3-环丙氧基苯甲酸
50mL圆底烧瓶装有3-环丙氧基-2-硝基苯甲酸(205mg,0.919mmol)、10%Pd/C(25mg,0.919mmol)和甲醇(6mL)。烧瓶以氮气真空冲洗(3x),接着以氢气球真空冲洗(3x)。所得悬浮液在氢气球下于室温搅拌过夜。溶液经过滤,以甲醇洗涤,且滤液经浓缩提供淡红色油状物。粗物质与甲苯(2x)共沸并真空干燥提供粗的2-氨基-3-环丙氧基苯甲酸(175mg,0.906mmol,99%产率),为淡红色固体。产物不经进一步纯化而用于后续反应中。HPLC:RT=2.31min(H2O/MeOH,含TFA,SunFire C183.5μm,2.1x 30mm,梯度=4min,波长=220nm);MS(ES):m/z=194.12[M+H]+。
中间体B-7E:2-氨基-3-环丙氧基-N-甲氧基-N-甲基苯甲酰胺
在烧瓶中于室温添加2-氨基-3-环丙氧基苯甲酸(6.61g,34.2mmol)N,O-二甲基羟胺盐酸盐(10.01g,103mmol),N-乙基-N″-(3-二甲基氨基丙基)碳二亚胺盐酸盐(7.87g,41.1mmol)和1-羟基苯并三唑水合物(6.29g,41.1mmol)于50ml的DMF中。向溶液中添加三乙胺(19.07mL,137mmol)。反应溶液在60℃搅拌过夜并且然后冷却至室温.反应混合物在水和乙酸乙酯之间分配并转移至分液漏斗并以10%LiCl、水和盐水洗涤。有机相经无水硫酸钠干燥,过滤并浓缩提供深色油状物。粗产物混合物经由ISCO(0%-50%ofEtOAC/DCM,在15分钟内,120g柱)纯化得到2-氨基-3-环丙氧基-N-甲氧基-N-甲基苯甲酰胺(5.2g,22.01mmol,64.3%产率)。HPLC:RT=1.975min(H2O/MeOH,含TFA,SunFire C183.5μm,2.1x 30mm,梯度=4min,波长=220nm);MS(ES):m/z=237.12[M+H]+;1H NMR(400MHz,氯仿-d)δ7.17(dd,J=8.0,1.2Hz,1H),7.02(dd,J=7.9,1.3Hz,1H),6.67(t,J=7.9Hz,1H),4.78(br.s.,2H),3.88-3.73(m,1H),3.69-3.56(m,3H),3.36(s,3H),0.92-0.72(m,4H))。
中间体B-7F:(2-氨基-3-环丙氧基苯基)(3-氟苯基)甲酮
在干冰/丙酮浴中于氮气下将1-氟-3-碘苯(1.009mL,8.59mmol)在四氢呋喃(100mL)中的溶液冷却至-78℃。然后经由注射器经15分钟n-BuLi的溶液(1.8M,在己烷中,5.37mL,8.59mmol)并搅拌60分钟得到深黄色悬浮液。然后2-氨基-3-环丙氧基-N-甲氧基-N-甲基苯甲酰胺(0.58g,2.455mmol)在10mL的THF中的溶液添加经由注射器并于-78℃搅拌反应混合物40分钟。0分钟后,将混合物倒入冰和1N HCl的混合物并且萃取进入乙酸乙酯中,得到浅黄色溶液。有机层以水和盐水洗涤并浓缩得到深黄色残余物。粗产物混合物经由ISCO纯化(0%-100%的EtOAC/庚烷,在15分钟内,40g柱)得到(2-氨基-3-环丙氧基苯基)(3-氟苯基)甲酮(0.46g,1.696mmol,69.1%产率)。HPLC:RT=3.481min(H2O/MeOH,含TFA,SunFire C183.5μm,2.1x 30mm,梯度=4min,波长=220nm);MS(ES):m/z=272.16[M+H]+;1H NMR(400MHz,氯仿-d)δ7.48-7.40(m,2H),7.36(ddd,J=9.3,1.9,1.1Hz,1H),7.27-7.18(m,2H),7.08(dd,J=8.3,1.2Hz,1H),6.58(t,J=8.0Hz,1H),6.39(br.s.,2H),3.83(t,J=4.5Hz,1H),0.86(d,J=4.4Hz,4H)。
中间体B-7
中间体B-7从进行合成(2-氨基-3-环丙氧基苯基)(3-氟苯基)甲酮根据用于合成中间体B-1的方法得到3-氨基-9-环丙氧基-5-(3-氟苯基)-1H-苯并[e][1,4]二氮杂-2(3H)-酮。HPLC:RT=2.25min(H2O/MeOH,含TFA,SunFire C183.5μm,2.1x 30mm,梯度=4min,波长=254nm);MS(ES):m/z=326.15[M+H]+;1H NMR(400MHz,甲醇-d4)δ7.66-7.57(m,1H),7.55-7.30(m,3H),7.30-7.17(m,2H),7.05-6.81(m,1H),4.10-3.88(m,1H),0.90(dt,J=9.9,2.8Hz,4H)。
中间体B-8:3-氨基-9-环丙氧基-5-苯基-1H-苯并[e][1,4]二氮杂-2(3H)-酮
中间体B-8从2-氨基-3-环丙氧基-N-甲氧基-N-甲基苯甲酰胺根据合成中间体B-7描述的方法进行合成得到3-氨基-9-环丙氧基-5-苯基-1H-苯并[e][1,4]二氮杂-2(3H)-酮。HPLC:RT=2.18min(H2O/MeOH,含TFA,SunFire C183.5μm,2.1x 30mm,梯度=4min,波长=254nm);MS(ES):m/z=308.14[M+H]+;1HNMR(400MHz,甲醇-d4)δ7.68-7.37(m,11H),7.23(t,J=8.0Hz,2H),6.90(dd,J=7.9,1.3Hz,2H),4.44(s,2H),4.06-3.88(m,2H),1.02-0.72(m,4H)。
中间体B-9:(S)-3-氨基-9-甲基-5-苯基-1H-苯并[e][1,4]二氮杂-2(3H)-酮
中间体B-9A:(S)-(9-甲基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)氨基甲酸苄基酯
2-(1H-苯并[d][1,2,3]三唑1-基)-2-(((苄基氧基)羰基)氨基)乙酸(17.30g,53.0mmol)在THF(128ml)中的悬浮液并冷却至0℃。添加草酰氯(4.64ml,53.0mmol),接着添加50μL DMF。于0℃搅拌反应混合物2h。添加(2-氨基-3-甲基苯基)(苯基)甲酮(5.09g,24.09mmol)和N-甲基吗啉(7.95ml,72.3mmol)的溶液,并且反应混合物逐渐温热至室温。2.5h后,添加氨(7M,在MeOH中)(21.29ml,149mmol)并且搅拌反应混合物过夜。所得混合物以EtOAc(250mL)稀释,并且然后以H2O(250mL)、1M NaOH(250mL)和盐水(250mL)洗涤。有机层经浓缩并且然后悬浮于乙酸(48.2ml)中。添加乙酸铵(9.29g,120mmol)。2.5小时后,将H2O添加沉淀产物中,产生粘稠固体。固体通过过滤收集并悬浮于最小量的MeOH并冷却至0℃。所得白色固体通过过滤收集,以冷的MeOH洗涤并且然后以二乙醚洗涤。所得物质经真空干燥。对映异构体的混合物使用SFC分离得到所需化合物:(S)-(9-甲基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)氨基甲酸苄基酯(1.6g,16.63%)。HPLC RT=2.773min(SpeedROD,5.0μm,4.6mm x 50mm,10-90%甲醇水溶液,含0.1%TFA,4min梯度,在220nm监控)。[M+H+]=400.4.1H NMR(400MHz,DMSO-d6)δ8.35(d,J=8.6Hz,1H),7.56-7.37(m,11H),7.23-7.17(m,1H),7.16-7.12(m,1H),5.12-4.99(m,3H),2.42(s,3H)。
中间体B-9
(S)-(9-甲基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)氨基甲酸苄基酯(1.6g,4.01mmol)在33%HBr(在HOAc(6.59ml,40.1mmol)中)的溶液于室温搅拌2h。添加乙醚(100mL)并且将所得黄色悬浮液冷却至0℃保持1h。所得固体通过过滤收集并以乙醚漂洗。该吸湿固体然后溶解于MeOH中,浓缩至干燥并经真空干燥。固体(HBr盐)以己烷经研磨并超声处理(含少量EtOAc以除去剩余的HOAc),该固体通过过滤收集,并真空干燥得到所需产物。HPLC RT=1.378min(SpeedROD,5.0μm,4.6mm x 50mm,10-90%甲醇水溶液,含0.1%TFA,4min梯度,在220nm监控).[M+H+]=266.4.1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.99(br.s.,3H),7.64-7.45(m,6H),7.28-7.22(m,1H),7.20-7.15(m,1H),5.05(d,J=4.6Hz,1H),2.43(s,3H)。
中间体B-10:(S)-3-氨基-9-甲氧基-5-苯基-1H-苯并[e][1,4]二氮杂-2(3H)-酮
中间体B-10A:8-甲氧基-2-甲基-4H-苯并[d][1,3]噁嗪-4-酮
在100mL圆底烧瓶中加入2-氨基-3-甲氧基苯甲酸(10.1g,60.4mmol)和乙酸酐(50ml,530mmol)得到悬浮液。将混合物加热至140℃,伴随搅拌180min。将反应混合物冷却至室温并浓缩提供8-甲氧基-2-甲基-4H-苯并[d][1,3]噁嗪-4-酮(11.51g,100%)。1H NMR(400MHz,DMSO-d6)δ7.59(dd,J=6.9,2.3Hz,1H),7.52-7.42(m,2H),3.89(s,3H),2.39(s,3H);HPLC:RT=0.795min(H2O/MeOH,含TFA,SunFire C182.5μm,2.1x30mm,梯度=2min,波长=220);MS(ES):m/z=292[M+H]+。
中间体B-10B:(2-氨基-3-甲氧基苯基)(苯基)甲酮
含8-甲氧基-2-甲基-4H-苯并[d][1,3]噁嗪-4-酮(1g,5.23mmol)(在二乙醚(20mL)、甲苯(10mL)和THF(10mL)中)的100mL圆底烧瓶冷却至0℃。以一份添加苯基溴化镁(1.9mL,5.75mmol,3M,在Et2O中)。将反应混合物温热至室温并搅拌过夜。反应混合物冷却至0℃并添加30g碎冰和25ml 6N HCl。反应混合物缓慢地温热至室温。反应混合物在乙酸乙酯(100mL)和盐水(50mL)之间分配。分离水相并以乙酸乙酯(1x100mL)萃取。合并的有机层经干燥(MgSO4),过滤并浓缩。剩余物通过硅胶色谱法纯化提供882mg无色固体。该物质溶解于AcOH(10mL)并以浓HCl(6mL,72.0mmol)处理,然后加热至100℃,伴随搅拌过夜。反应混合物经冷却至室温,浓缩并经真空干燥。剩余物以乙酸乙酯稀释(100mL),pH以饱和NaHCO3调节至pH 10,并且然后分离各相。水相以乙酸乙酯萃取(2x50mL),合并的有机相经干燥(MgSO4),过滤并浓缩。剩余物通过硅胶色谱纯化(EtOAc/己烷)提供(2-氨基-3-甲氧基苯基)(苯基)甲酮(370mg,31%):1H NMR(400MHz,DMSO-d6)δ9.43(br.s.,2H),7.70-7.63(m,1H),7.33-7.22(m,5H),7.10-7.03(m,1H),6.91(dd,J=6.7,2.1Hz,1H),3.87(s,3H):HPLC:RT=1.888min(H2O/MeOH,含TFA,SunFire C182.5μm,2.1x30mm,梯度=2min,波长=220);MS(ES):m/z=228[M+H]+。
中间体B-10
中间体B-10从(2-氨基-3-甲氧基苯基)(苯基)甲酮进行合成根据中间体B-1描述的方法得到外消旋的3-氨基-9-甲氧基-5-苯基-1H-苯并[e][1,4]二氮杂-2(3H)-酮,其通过手性SFC拆分(仪器:Berger SFC MGII,柱:AS 25x 3cm,5μm;柱温度:45℃;移动相:CO2/MeOH-0.1DEA(67/33);流速:85mL/min;在220nm检测.)得到中间体B-10:(S)-3-氨基-9-甲氧基-5-苯基-1H-苯并[e][1,4]二氮杂-2(3H)-酮.MS(ES):m/z=282.1[M+H]+.HPLC:RT=3.21min(Luna C184.6x30mm3μm H2O/MeOH/TFA,梯度=5min,波长=220nm)。
中间体B-11:(S)-3-氨基-9-氟-5-苯基-1H-苯并[e][1,4]二氮杂-2(3H)-酮
中间体B-11从(2-氨基-3-氟苯基)(苯基)甲酮根据用于合成中间体B-10的方法进行合成,在手性SFC后(仪器:Berger SFC MGII,柱:AS 25x 3cm,5μm;柱温度:45℃;移动相:CO2/MeOH-0.1DEA(67/33);流速:85mL/min;在220nm检测.)得到中间体B-11:(S)-3-氨基-9-氟-5-苯基-1H-苯并[e][1,4]二氮杂-2(3H)-酮.MS(ES):m/z=270[M+H]+。HPLC:RT=1.29min(H2O/MeOH,含TFA,ODS S5,4.6x50mm,梯度=4min,波长=220nm)。
中间体B-12:3-氨基-9-氯-5-苯基-1H-苯并[e][1,4]二氮杂-2(3H)-酮
中间体B-12从(2-氨基-3-氯苯基)(苯基)甲酮根据用于合成中间体B-1的方法进行合成得到3-氨基-9-氯-5-苯基-1H-苯并[e][1,4]二氮杂-2(3H)-酮:MS(ES):m/z=286[M+H+].HPLC:RT=0.63min(H2O/CH3CN,含0.05%TFA,BEH C181.7μm,2.1x50mm,梯度(2%-98%)=1min,波长=220。
中间体B-13:3-氨基-9-氟-5-(间甲苯基)-1H-苯并[e][1,4]二氮杂-2(3H)-酮
中间体B-13从(2-氨基-3-氯苯基)(间甲苯基)甲酮根据用于合成中间体B-1的方法进行合成得到3-氨基-9-氟-5-(间甲苯基)-1H-苯并[e][1,4]二氮杂-2(3H)-酮:MS(ES):m/z=284[M+H+]。HPLC:RT=0.61min H2O/MeOH,含TFA,BEH C181.7μm,2.1x50mm,梯度=2min,波长=220nm.1HNMR(400MHz,甲醇-d4)δ7.48-7.38(m,2H),7.36-7.27(m,3H),7.26-7.19(m,1H),7.12(d,J=7.9Hz,1H),4.45(s,1H),2.37(s,3H)。
中间体B-14:(S)-7-氨基-9-苯基-5H-[1,3]二氧杂环戊并[4′,5′:4,5]苯并[1,2-e][1,4]二氮杂-6(7H)-酮
中间体B-14从(6-氨基苯并[d][1,3]二氧杂环戊烯-5-基)(苯基)-甲酮根据用于合成中间体B-2的方法进行合成得到(S)-7-氨基-9-苯基-5H-[1,3]二氧杂环戊并[4′,5′:4,5]苯并[1,2-e][1,4]二氮杂-6(7H)-酮:MS(ES):m/z=296[M+H+]。HPLC:RT=1.24min(H2O/CH3CN,含TFA,SunFire C183.5μm,2.1x30mm,梯度=2min,波长=220nm)。
中间体B-15:(S)-3-氨基-5-苯基-1-(吡啶-2-基)-1H-苯并[e][1,4]二氮杂-2(3H)-酮
中间体B-15A:2-氧代-5-苯基-1-(吡啶-2-基)-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基氨基甲酸苄基酯
向2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基氨基甲酸苄基酯(1.20g,3.11mmol,根据J.Med.Chem.,49:2311-2319(2006)、化合物#4a制备)、2-碘吡啶(1.00g,4.88mmol)、碘化亚铜(0.15g,0.788mmol)和Cs2CO3(3.05g,9.36mmol)的搅拌混合物合并在二噁烷(25mL)中。在氮气下向该混合物中添加(+/-)-反式-1,2-二氨基环己烷(0.19mL,1.58mmol)。反应混合物然后加热至120℃并温和地回流10min。然后在氮气下冷却至室温。该混合物以100mL的EtOAc、40mL的pH 4磷酸盐缓冲液和40mL的饱和NaHCO3溶液稀释。不溶性物质通过的2’垫过滤除去,并以EtOAc(2x 30mL)漂洗。分离水相并以160mL的EtOAc萃取。合并的EtOAc萃取物以饱和NaHCO3溶液(1x 30mL)和盐水(1x 20mL)洗涤,然后干燥(MgSO4),过滤并真空浓缩。剩余物通过硅胶色谱纯化(己烷/EtOAc)得到2-氧代-5-苯基-1-(吡啶-2-基)-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基氨基甲酸苄基酯(0.88g,61%):1H NMR(400MHz,DMSO-d6)δ8.61(1H,d,J=8.14Hz),8.47(1H,dd,J=4.73,1.21Hz),7.94-8.03(1H,m),7.64(2H,d,J=7.92Hz),7.47-7.60(4H,m),7.27-7.44(9H,m),6.97(1H,d,J=8.14Hz),5.39(1H,d,J=8.36Hz),5.10(2H,s);HPLC:RT=2.930min(ODS 4.6x 50mm(4mingrad),以10-90%MeOH水溶液洗脱4分钟,含0.%TFA,4mL/min,在220nm监控);MS(ES):m/z=463.3[M+H]+。
中间体B-15
合并2-氧代-5-苯基-1-(吡啶-2-基)-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基氨基甲酸苄基酯(5.24g,11.33mmol)和33%HBr/HOAc(50mL,11.33mmol)并于室温搅拌2h。反应混合物以300mL乙醚稀释。所得沉淀通过过滤收集,以乙醚漂洗(2x 50mL),并且然后经真空干燥。固体溶解于100mL的水中并通过添加固体NaHCO3而变成碱性。混合物以EtOAc(2x 200mL)萃取,并且合并的有机萃取物以水(1x 40mL)和盐水(1x 50mL)洗涤,然后干燥(MgSO4),过滤并真空浓缩得到粗的外消旋的胺。制备型SFC色谱(BergerSFC MGII,AD-H 250x 30mm ID,5μm,78/22CO2/MeOH with 0.1%DEA,85mL/min)得到中间体B-15(1.576g,42.4%),为无色固体。1H NMR(400MHz,DMSO-d6)δ8.47(1H,dd,J=4.73,1.65Hz),7.98(1H,td,J=7.70,1.98Hz),7.62(3H,dd,J=14.75,7.48Hz),7.45-7.57(5H,m),7.26-7.43(3H,m),6.92(1H,d,J=8.14Hz),4.57(1H,br.s.),2.67(1H,br.s.);手性HPLC:RT=5.160min(Berger SFC,AD-H 250x 4.6mm ID,5μm,75/25CO2/MeOH,含0.1%DEA,2.0mL/min);HPLC:RT=1.290min(ODS 4.6x 50mm(4min grad),以10-90%MeOH水溶液洗脱4分钟,含0.%TFA,4mL/min,在220nm监控);MS(ES):m/z=329.0[M+H]+。
中间体B-16:(S)-3-氨基-5-苯基-1-(5-氯吡啶-2-基)-1H-苯并[e][1,4]二氮杂-2(3H)-酮
中间体B-16由2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基氨基甲酸苄基酯和5-氯-2-碘吡啶根据中间体B-15描述的过程制备。RT=2.430min(H2O/CH3OH,含TFA,ODS S54.6x 50mm,梯度=3min,波长=220和254nm);MS(ES):m/z=363.12[M+H+]。
中间体B-17:(S)-3-氨基-1-(5-甲氧基吡啶-2-基)-5-苯基-1H-苯并[e][1,4]二氮杂-2(3H)-酮
中间体B-17根据中间体B-15显示的过程制备,在制备型SFC色谱(BergerSFC MGII,手性AS-H 25x 3cm ID,5μm,83/17CO2/MeOH w/0.1%DEA)后得到中间体B-17(0.51g,43.6%),为无色固体:1H NMR(400MHz,DMSO-d6)δ8.17(d,J=2.9Hz,1H),7.65-7.60(m,2H),7.58-7.45(m,6H),7.37-7.25(m,2H),6.92(d,J=7.7Hz,1H),4.54(s,1H),3.86(s,3H),2.62(s,2H);手性HPLC:RT=3.889min(Berger SFC,AS-H 250x 4.6mm ID,5μm,75/25CO2/MeOH,含0.1%DEA,2.0mL/min);HPLC:RT=2.16min(ODS 4.6x 50mm(4min grad),以10-90%MeOH水溶液洗脱4分钟,含0.%TFA,4mL/min,在220nm监控);MS(ES):m/z=359.2[M+H]+。
中间体B-18:(S)-3-氨基-1-(6-甲氧基吡啶-2-基)-5-苯基-1H-苯并[e][1,4]二氮杂-2(3H)-酮
中间体B-18根据中间体B-15显示的过程很制备。在制备型SFC色谱(仪器:Berger SFC MGII,柱:AS-H 25x 3cm,5μm;移动相:CO2/MeOH-0.1DEA(83/17);流速:85mL/min;在220nm检测.)之后,得到中间体B-18,为无色固体:手性HPLC:RT=3.44min(Berger SFC,AS-H 250x 4.6mm ID,5μm,75/25CO2/MeOH,含0.1%DEA,2.0mL/min);HPLC:RT=2.07min(ODS 4.6x 50mm(4min grad),以10-90%MeOH水溶液洗脱4分钟,含0.%TFA,4mL/min,在220nm监控);MS(ES):m/z=359.2[M+H]+。
中间体B-19:3-氨基-9-甲氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-7-甲腈
中间体B-19A:(7-溴-9-甲氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)氨基甲酸叔丁基酯
于室温向3-氨基-7-溴-9-甲氧基-5-苯基-1H-苯并[e][1,4]二氮杂-2(3H)-酮(200mg,0.555mmol)在二噁烷(5mL)中的悬浮液添加一缩二碳酸二叔丁基酯(0.140mL,0.611mmol),接着添加三乙胺(0.085mL,0.611mmol)。悬浮液搅拌过夜过夜,并且然后反应混合物经浓缩。粗物质通过硅胶色谱纯化(己烷/EtOAc)得到(7-溴-9-甲氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)氨基甲酸叔丁基酯:(240mg,0.516mmol,93%产率):HPLC RT=4.301min(H2O/MeOH,含H3PO4,SunFire C18,5.0μm,4.6mm x 50mm,4min梯度,在220nm监控).[M+H+]=461;1H NMR(400MHz,DMSO-d6)δ10.15(1H,s),7.76(1H,d,J=8.58Hz),7.40-7.57(7H,m),6.97(1H,d,J=1.76Hz),5.01(1H,d,J=8.58Hz),3.95(3H,s),1.41(10H,s)。
中间体B-19B:7-氰基-9-甲氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基氨基甲酸叔丁基酯
(7-溴-9-甲氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)氨基甲酸叔丁基酯(0.050g,0.109mmol)、氰化锌(0.013g,0.109mmol)和Pd(Ph3P)4(0.013g,10.86μmol)溶解于DMA(0.543ml)中并加热至90℃。1h后,反应以饱和NaHCO3淬灭。反应混合物以EtOAc萃取三次。合并的有机层经MgSO4干燥并蒸发。剩余物通过硅胶色谱纯化(己烷/EtOAc)得到7-氰基-9-甲氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基氨基甲酸叔丁基酯(41mg,93%):HPLC RT=1.948min(H2O/MeOH,含TFA,SunFireC18,5.0μm,2.1mm x 30mm,4min梯度,在220nm监控)。[M+H+]=407。
中间体B-19
7-氰基-9-甲氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基氨基甲酸叔丁基酯(0.441g,1.086mmol)溶解于DCM(4ml)和TFA(1ml,12.98mmol)中并于室温搅拌1.5h。添加TFA(1ml,12.98mmol),并且反应混合物搅拌过夜。反应混合物经浓缩,然后溶解于EtOAc中并以饱和NaHCO3洗涤。水层再萃取两次,然后有机层经Na2SO4干燥并蒸发。剩余物经硅胶色谱(DCM/MeOH)纯化。含产物的各级分经蒸发,然后该物质以EtOAc研磨得到3-氨基-9-甲氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-7-甲腈(中间体B-19)。1H NMR(400MHz,氯仿-d)δ7.54-7.45(m,3H),7.42-7.37(m,2H),7.26(d,J=1.8Hz,1H),7.22(d,J=1.5Hz,1H),4.46(s,1H),4.01(s,3H),2.45(br.s.,2H)。
中间体S-1:(R)-2-((R)-2-(叔丁氧基)-2-氧代-1-苯基乙基)-5,5,5-三氟戊酸
中间体S-1A:2-苯基乙酸叔丁基酯
2-苯基乙酸(12g,88mmol)在tBuOAc(250mL)中的溶液于1L圆底烧瓶中以过氯酸,70%再蒸馏(0.212mL,3.53mmol)处理并于室温搅拌20小时。将溶液缓慢地换衣至饱和NaHCO3水溶液和Et2O的搅拌混合物中,这导致冒泡。分离所得各层并且有机层以饱和NaHCO3水溶液洗涤,经MgSO4干燥,过滤并浓缩得到2-苯基乙酸叔丁基酯(11.6g,68%产率)。1H NMR(500MHz,氯仿-d)δ7.34-7.29(m,2H),7.28-7.22(m,3H),3.52(s,2H),1.44(s,9H)。
中间体S-1B:(2R,3R)-3-苯基-2-(3,3,3-三氟丙基)琥珀酸1-苄基酯4-叔丁基酯
2-苯基乙酸叔丁基酯(8.5g,44.2mmol)在THF(400mL)中的溶液于1L圆底烧瓶中于-78℃浴冷却并经由套管以KHMDS 0.5M在甲苯中的溶液(97mL,48.6mmol)处理10分钟。10分钟后,混合物从浴移出并置于室温水浴中并搅拌15分钟并且然后再次于-78℃浴冷却。15分钟后,制备例4D(R)-5,5,5-三氟-2-(((三氟甲基)磺酰基)氧基)戊酸苄基酯(19.18g,48.6mmol)在THF(50mL)中的溶液添加于100mL圆底烧瓶中经10min经由套管(具有20mL THF漂洗液)添加。反应混合物变浑浊。反应混合物于-78℃搅拌1小时并且然后以饱和NH4Cl水溶液淬灭。混合物从-78℃浴移出,以10%LiCl水溶液稀释并以Et2O萃取。有机层经MgSO4干燥,过滤并浓缩。所得棕色残余物溶解于100mL CH2Cl2中并以木炭和MgSO4处理。混合物经过滤得到几乎无色的溶液。CH2Cl2溶液经浓缩并以己烷稀释并于-20℃冻干机中冷却。所得固体经过滤并以冷己烷(含5%MTBE)漂洗并在烧结玻璃过滤漏斗上在氮气流中干燥得到8.16g。固体以40mL己烷和4mL MTBE研磨,于室温搅拌白色悬浮液1小时并且然后于-20℃冷却3小时,然后过滤所述白色固体并以冷溶剂(10:1己烷:MTBE)洗涤得到(2R,3R)-3-苯基-2-(3,3,3-三氟丙基)琥珀酸1-苄基酯4-叔丁基酯(7.16g,37%产率),为白色固体。1H NMR(500MHz,氯仿-d)δ7.32-7.23(m,8H),7.05-6.97(m,2H),4.89-4.76(m,2H),3.69(d,J=11.4Hz,1H),3.23(ddd,J=11.2,9.9,3.9Hz,1H),2.19-2.04(m,2H),2.03-1.88(m,2H),1.40(s,9H)。
中间体S-1
在250mL圆底烧瓶中,(2R,3R)-3-苯基-2-(3,3,3-三氟丙基)琥珀酸1-苄基酯4-叔丁基酯(7.16g,16.40mmol)和Pd/C,10%(1.746g,1.640mmol)在乙酸乙酯(35mL)和MeOH(35mL)中的悬浮液使用氢气填充的气球氢化,同时于室温搅拌。当反应完成(接着HPLC)时,悬浮液通过0.45μm膜过滤并以MeOH和EtOAc漂洗。滤液经浓缩并真空干燥得到中间体S-1(5.65g,99%产率)。MS(m-1)=345.1H NMR(500MHz,DMSO-d6)δ7.37-7.26(m,5H),3.67(d,J=10.5Hz,1H),3.04(td,J=10.3,3.7Hz,1H),2.38-2.20(m,2H),1.88-1.70(m,2H),1.37(s,9H)。
中间体S-2:(R)-2-((R)-2-叔丁氧基-1-(3-甲基异噁唑-4-基)-2-氧代乙基)-5,5,5-三氟戊酸
中间体S-2A:(2R,3R)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酸1-苄基酯4-叔丁基酯
在250mL圆底烧瓶中,2-(3-甲基异噁唑-4-基)乙酸叔丁基酯(1.75g,8.87mmol)在THF(56mL)和甲苯(27mL)中的溶液于-78℃浴中冷却并以1MKHMDS(11.09mL,11.09mmol)在THF中的溶液处理(经注射器经2分钟滴加)。于-78℃搅拌15分钟后,反应混合物置于室温水浴中保持15分钟并且然后再次置于-78℃浴中保持另一15分钟,然经2分钟将制备例4D(R)-5,5,5-三氟-2-(三氟甲基磺酰基氧基)戊酸苄基酯(4.55g,11.53mmol)在6mL THF和3mL甲苯中的溶液添加至反应。反应混合物于-78℃浴搅拌2小时,然后以饱和NH4Cl水溶液淬灭并且然后温热至室温。混合物以盐水稀释并以EtOAc萃取。有机层经MgSO4干燥、过滤并浓缩。剩余物在硅胶柱(330g ISCO)上纯化以0-30%EtOAc/CH2Cl2的梯度洗脱,并且收集含产物的试管,经浓缩得到(2R,3R)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酸1-苄基酯4-叔丁基酯(2.394g,61%产率),含约30%的(2R,3S)异构体。
中间体S-2
在200mL圆底烧瓶中,(2R,3R)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酸1-苄基酯4-叔丁基酯(2.4g,5.44mmol)在MeOH(体积:50mL)中的无色溶液以Pearlman's催化剂(0.076g,0.544mmol)处理并使用氢气填充的气球于室温氢化1小时直到反应完成(通过HPLC监控)。混合物通过以MeOH漂洗的0.45μm膜过滤反应。滤液经浓缩得到2.03g的粗固体。固体在PrepHPLC[C18Luna 30x100,以从10%B至100%B的梯度洗脱(15min)]上纯化得到99%纯的中间体S-2(896mg,46%产率),为白色固体。MS(ES):m/z=352[M+H+],m/z=350[M-H-].1H NMR(500MHz,氯仿-d)δ8.40(s,1H),3.62(d,J=10.0Hz,1H),3.08(td,J=10.0,3.6Hz,1H),2.34(s,3H),2.33-2.14(m,2H),2.03-1.89(m,2H),1.46(s,9H)。
中间体S-3:(R)-2-((R)-2-叔氧基-2-氧代-1-(吡啶-3-基)乙基)-5,5,5-三氟戊酸
中间体S-3从2-(吡啶-3-基)乙酸叔丁基酯(100mg,0.517mmol)和(R)-5,5,5-三氟-2-(三氟甲基磺酰基氧基)戊酸苄基酯(245mg,0.621mmol)合成,使用中间体S-2描述的方法得到中间体S-3(60mg,0.173mmol),为白色固体,含约30%的(R,S)异构体。MS(ES):m/z=483.3[M+H+]。
中间体S-4:(R)-2-((R)-2-(叔丁氧基)-1-(4-氯苯基)-2-氧代乙基)-5,5,5-三氟戊酸
中间体S-4从2-(4-氯苯基)乙酸叔丁基酯(20mg,0.088mmol)和(2R,3R)-3-(4-氯苯基)-2-(3,3,3-三氟丙基)琥珀酸1-苄基酯4-叔丁基酯(37mg,0.079mmol,89%产率)合成,使用合成中间体S-1描述的方法得到中间体S-4(30mg,88%),为白色固体,含约30%的(R,S)异构体。MS(ES):m/z=379.4[M-H-]。
实施例5
(2R,3R)-N1-((S)-5-(3-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺
中间体5A:(2R,3R)-6,6,6-三氟-3-((5-(3-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)氨基甲酰基)-2-苯基己酸叔丁基酯
在20ml闪烁小瓶中添加在DMF(2mL)中的中间体B-1(100mg,0.275mmol)、中间体S-1(95mg,0.275mmol)和TBTU(176mg,0.549mmol)。混合物以TEA(0.115mL,0.824mmol)处理并室温搅拌2小时。混合物以水稀释并且固体悬浮液萃取进入乙酸乙酯中,以水洗涤并浓缩得到(2R,3R)-6,6,6-三氟-3-((5-(3-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)氨基甲酰基)-2-苯基己酸叔丁基酯,为浅棕褐色固体。MS(ES):m/z=612.1[M+H+]。
中间体5B:(2R,3R)-6,6,6-三氟-3-((5-(3-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)氨基甲酰基)-2-苯基己酸
(2R,3R)-6,6,6-三氟-3-((5-(3-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)氨基甲酰基)-2-苯基己酸叔丁基酯(168mg,0.275mmol)在二氯甲烷(2mL)中的溶液以TFA(2mL)处理并且于室温静置3小时。该混合物以DCM稀释并蒸发至干燥。剩余物溶解于DCM中并以水洗涤且浓缩得到(2R,3R)-6,6,6-三氟-3-((5-(3-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)氨基甲酰基)-2-苯基己酸,为浅黄灰白色固体。MS(ES):m/z=556.1[M+H+]。
实施例5
(2R,3R)-6,6,6-三氟-3-((5-(3-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)氨基甲酰基)-2-苯基己酸(153mg,0.275mmol)在四氢呋喃(2mL)中的溶液以EDC(106mg,0.551mmol)和HOBT(84mg,0.551mmol)处理并于室温搅拌。然后添加氨(2M,在异丙醇(1.377mL,2.75mmol)中)且所得悬浮液于室温搅拌过夜。以水稀释并萃取进入乙酸乙酯中,以水洗涤并浓缩。粗产物在ISCO Companion上使用40g硅胶柱并以EtOAc/己烷梯度(20-100%)洗脱而色谱纯化得到55mg白色固体。通过制备型SFC色谱(仪器:Berger SFC MGII,柱:手性IC 25x 3cm,5μm;移动相:85/15CO2/MeOH流速:85mL/min;在220nm检测.)分离非对映异构体得到实施例5(14mg,9%产率),为白色固体。HPLC:RT=8.844min(H2O/CH3CN,含TFA,SunFire C183.5μm,3.0x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=555.1[M+H+];1H NMR(400MHz,氯仿-d)δ7.99(s,1H),7.50-7.43(m,2H),7.42-7.34(m,5H),7.32-7.26(m,1H),7.17-7.01(m,5H),5.59-5.45(m,2H),5.27(d,J=8.1Hz,1H),3.66(d,J=9.7Hz,1H),3.35(td,J=9.8,4.2Hz,1H),2.39(s,3H),2.29-2.17(m,2H),2.07-1.90(m,2H)。
实施例6
(2R,3R)-N1-((S)-1-甲基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酰胺
实施例6由中间体1F(100mg,0.2mmol)和中间体S-2(53mg,0.2mmol)根据实施例5所显示的一般程序制备。在制备型色谱(Column-IC(250x4.6)mm 5μm,移动相A:0.2%二乙胺-己烷(60%),移动相B:乙醇(40%),220和250nm Flow-1ml/Min,Run-25min)之后,得到实施例6(100mg,66%)。HPLC:RT=9.32min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=542[M+H+];1H NMR(400MHz,CDCl3)δ8.72(s,1H),7.57-7.61(t,1H)),7.51-7.56(t,3H),7.48-7.50(d,1H),7.34-7.50(m,4H),7.21-7.25(d,1H),5.73(bs,1H),5.53(bs,1H),5.33-5.35(d,1H),3.55-3.57(d,1H),3.44(s,3H),3.13-3.17(m,1H),2.32(s,3H),2.13-2.31(m,2H),1.70-2.05(m,1H),1.10-1.60(m,1H)。
实施例7
(2R,3R)-N1-((S)-1-(环丙基甲基)-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺
在5mL顶部旋盖小瓶中,添加在DMF(1mL)中的实施例4(2R,3R)-N1-((S,Z)-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(20mg,0.038mmol)和氟化钾40%/氧化铝(60mg,0.413mmol)得到悬浮液。添加(溴甲基)环丙烷(4.08μL,0.042mmol)并且混合物在氢气下于室温搅拌72小时。反应混合物溶解在1ml的1:1DMF/AcOH中并且通过制备型HPLC(Luna ODS 5μm 21.2x100mm,其以10min梯度从100%ACN/水0.1%TFA至100%洗脱)纯化得到实施例7(14mg,61%)。HPLC:RT=10.33min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=577[M+H+];1H NMR(400MHz,氯仿-d)δ7.58-7.51(m,1H),7.50-7.33(m,13H),7.26-7.16(m,1H),5.49(br.s.,1H),5.34(br.s.,1H),5.29(d,J=7.9Hz,1H),4.24(dd,J=14.3,7.3Hz,1H),3.67(d,J=9.5Hz,1H),3.51(dd,J=14.2,6.9Hz,1H),3.27(td,J=9.4,4.3Hz,1H),2.35-2.11(m,2H),2.04-1.83(m,2H),0.86(t,J=7.7Hz,1H),0.36-0.29(m,1H),0.28-0.19(m,1H),0.10-0.02(m,2H)。
实施例8
(2R,3R)-N1-((S)-1-(环丙基甲基)-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(4-氟苯基)-2-(3,3,3-三氟丙基)琥珀酰胺
实施例8由(2R,3R)-3-(4-氟苯基)-N1-((S,Z)-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-2-(3,3,3-三氟丙基)琥珀酰胺(10mg,0.019mmol)和(溴甲基)环丙烷(10mg,0.074mmol)使用如实施例7所示的方法制备,得到实施例8(7.2mg,65%)。HPLC:RT=10.529min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=595[M+H+];1H NMR(400MHz,氯仿-d)δ7.60-7.50(m,1H),7.50-7.34(m,10H),7.32-7.28(m,1H),7.24-7.18(m,1H),7.14-7.04(m,2H),5.56(d,J=12.5Hz,2H),5.28(d,J=8.1Hz,1H),4.23(dd,J=14.2,7.4Hz,1H),3.65(d,J=9.9Hz,1H),3.49(dd,J=14.2,6.9Hz,1H),3.26-3.14(m,1H),2.29-2.15(m,2H),2.00-1.89(m,1H),0.89-0.77(m,1H),0.36-0.27(m,1H),0.26-0.19(m,1H),0.04(d,J=4.0Hz,2H)。
实施例9
(2R,3R)-3-(3-甲基异噁唑-4-基)-N1-((S)-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-2-(3,3,3-三氟丙基)琥珀酰胺
实施例9由中间体4A(75mg,0.3mmol)和中间体S-2(120mg,0.3mmol)根据实施例5所显示的一般程序制备。在通过制备型色谱(Column-C18(250x4.6)5μm)移动相A:0.5%TFA/水移动相B:ACN波长=220nm和254nm);梯度=35min.)分离非对映异构体,得到实施例9(130mg,6%)。HPLC:RT=8.52min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=528[M+H+];1H NMR(400MHz,CDCl3)δ10.9(s,1H),9.39-9.41(d,1H),8.68(s,1H),7.83(s,1H),7.61-7.65(m,1H),7.41-7.54(m,5H),7.18-7.30(m,4H),5.02-5.04(d,1H),3.54-3.57(d,1H),3.19-3.25(m,1H),2.64-2.67(m,1H),2.30-2.33(m,1H),2.17(s,3H),1.69-1.77(m,2H)。
实施例10
(2R,3R)-N1-((S)-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(吡啶-3-基)-2-(3,3,3-三氟丙基)琥珀酰胺
实施例10由中间体4A(47.7mg,0.190mmol)和中间体S-3(60.0mg,0.173mmol)根据实施例5所显示的一般程序制备。得到实施例10(12.5mg,16%)。HPLC:RT=5.708min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=524.2[M+H+];1H NMR(400MHz,甲醇-d4)δ8.56(d,J=1.8Hz,1H),8.51-8.42(m,1H),8.06-7.95(m,1H),7.66-7.54(m,1H),7.52-7.46(m,1H),7.46-7.32(m,5H),7.30-7.15(m,3H),4.99(s,1H),3.78(d,J=11.2Hz,1H),3.47-3.41(m,1H),2.67-2.46(m,1H),2.44-2.27(m,1H),2.01-1.84(m,2H)。
实施例11
(2R,3R)-3-(3-甲基-4-异噁唑基)-N-((3S)-2-氧代-5-苯基-1-(2-吡啶基)-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-2-(3,3,3-三氟丙基)琥珀酰胺
实施例11由中间体B-15(134mg,0.40mmol)和中间体S-2(130.0mg,0.37mmol)根据实施例5所显示的一般程序制备。在通过制备型手性色谱(IC 250x 4.6mm ID,5μm,65/35H2O/CH3CN,含TFA)分离非对映异构体之后,得到实施例11(130mg,53%)。HPLC:RT=8.66min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=605[M+H+];1H NMR(400MHz,DMSO-d6)δ9.51(d,J=7.5Hz,1H),8.71(s,1H),8.50-8.44(m,1H),7.99(td,J=7.8,2.0Hz,1H),7.84(br.s.,1H),7.62-7.48(m,7H),7.43-7.38(m,1H),7.37-7.30(m,2H),7.17(br.s.,1H),6.97(d,J=8.1Hz,1H),5.37(d,J=7.7Hz,1H),3.57(d,J=11.2Hz,1H),2.62-2.56(m,1H),2.38-2.24(m,1H),2.18(s,3H),2.10(d,J=2.9Hz,1H),1.82-1.68(m,2H)。
实施例12
(2R,3R)-N-((3S)-2-氧代-5-苯基-1-(2-吡啶基)-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺
实施例12由中间体B-15(37.9mg,0.115mmol)和中间体S-1(40.0mg,0.115mmol)根据实施例5所显示的一般程序制备。在分离非对映异构体(制备型SFC色谱,Berger SFC MGII,手性IB 250x 21mm ID,5μm,80/20CO2/MeOH,50mL/min)之后,得到实施例12(39.2mg,58.1%)。HPLC:RT=9.28min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=600[M+H+];1H NMR(400MHz,DMSO-d6)δ9.37(d,J=7.5Hz,1H),8.46(dd,J=4.8,1.1Hz,1H),7.98(td,J=7.8,1.9Hz,1H),7.75-7.65(m,3H),7.58-7.47(m,6H),7.44-7.36(m,3H),7.32-7.20(m,4H),6.95(d,J=8.4Hz,2H),5.21(d,J=7.3Hz,1H),3.71(d,J=11.2Hz,1H),3.49(td,J=10.7,3.7Hz,1H),2.63-2.54(m,1H),2.40-2.23(m,1H),1.85-1.60(m,2H)。
实施例13
(2R,3R)-3-(3-甲基-4-异噁唑基)-N-((7S)-6-氧代-9-苯基-6,7-二氢-5H-[1,3]二氧杂环戊烯并[4,5-h][1,4]苯并二氮杂-7-基)-2-(3,3,3-三氟丙基)琥珀酰胺
实施例13由中间体B-14(20.0mg,0.068mmol)和中间体S-2(23.8mg,0.068mmol)根据实施例5所显示的一般程序制备。得到实施例13(9.12mg,24.1%)。HPLC:RT=7.64min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=572[M+H+];1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),9.33(d,J=7.5Hz,1H),8.67(s,1H),7.82(br.s.,1H),7.54-7.48(m,1H),7.46-7.40(m,7H),7.16(br.s.,1H),6.78(s,1H),6.67(s,1H),6.15(s,1H),6.11(s,1H),5.03(d,J=7.5Hz,1H),3.56(d,J=11.2Hz,1H),3.26-3.16(m,1H),2.70-2.62(m,1H),2.36-2.25(m,1H),2.18(s,3H),1.75(d,J=12.8Hz,2H)。
实施例14
(2R,3R)-N-((3S)-1-(5-甲氧基-2-吡啶基)-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-(3-甲基-4-异噁唑基)-2-(3,3,3-三氟丙基)琥珀酰胺
实施例14由中间体B-17(55.0mg,0.153mmol)和中间体S-2(59.3mg,0.169mmol)根据实施例5所显示的一般程序制备。得到实施例14(26.0mg,51.4%)。HPLC:RT=9.09min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=635[M+H+];1H NMR(400MHz,DMSO-d6)δppm 9.48(1H,d,J=7.48Hz),8.71(1H,s),8.17(1H,d,J=2.86Hz),7.84(1H,br.s.),7.43-7.65(9H,m),7.28-7.38(2H,m),7.17(1H,br.s.),6.97(1H,d,J=7.92Hz),5.34(1H,d,J=7.48Hz),3.86(3H,s),3.56(1H,d,J=11.22Hz),2.56(1H,br.s.),2.26-2.40(1H,m),2.18(3H,s),1.68-1.82(2H,m)。
实施例15
(2R,3R)-N-((3S)-1-(5-甲氧基-2-吡啶基)-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺
实施例15由中间体B-17(30.0mg,0.084mmol)和中间体S-1(30.5mg,0.088mmol)根据实施例5所显示的一般程序制备。在分离非对映异构体(制备型SFC色谱,Berger SFC MGII,手性IC 250x 30mm ID,5μm,80/20CO2/MeOH,85mL/min)之后,得到实施例15(18.5mg,34.0%)。HPLC:RT=9.65min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=630[M+H+];1H NMR(400MHz,氯仿-d)δ8.13(s,1H),7.57-7.34(m,13H),7.31(d,J=5.1Hz,4H),7.23-7.15(m,1H),6.94(d,J=8.1Hz,1H),5.41(s,1H),3.87(s,3H),3.69(d,J=10.6Hz,1H),3.36-3.25(m,1H),2.41-2.22(m,2H),2.03-1.86(m,2H)。
实施例16
(2R,3R)-N-((3S)-1-(6-甲氧基-2-吡啶基)-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺
实施例16由中间体B-18(48.0mg,0.134mmol)和中间体S-1(44.1mg,0.127mmol)根据实施例5所显示的一般程序制备。在分离非对映异构体(制备型SFC色谱,Berger SFC MGII,手性IC 250x 30mm ID,5μm,83/17CO2/MeOH,85mL/min)之后,得到实施例16(11.5mg,17.5%)。HPLC:RT=10.46min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=630[M+H+];1H NMR(400MHz,MeOD)δ7.77(t,J=7.8Hz,1H),7.58-7.49(m,4H),7.47-7.38(m,4H),7.33-7.24(m,5H),7.16(d,J=7.5Hz,1H),7.08(d,J=8.1Hz,1H),6.73(d,J=8.1Hz,1H),5.21(s,1H),3.73(d,J=11.2Hz,1H),3.63(s,3H),3.49-3.39(m,1H),2.64-2.50(m,1H),2.43-2.29(m,1H),2.00-1.84(m,2H)。
实施例17
(2R,3R)-N1-((S)-9-氯-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酰胺
实施例17由中间体B-12(200mg,0.7mmol)和中间体S-2(246mg,0.7mmol)根据实施例5所显示的一般程序制备。得到实施例17(17mg,13.9%)。LC/MS,m/z562.2(M+1)。HPLC RT=0.86min。LC/MS(BEH C182.1x 50mm,1.7μm,0至100%B,于1min内,包括0.5min保持时间,流速=1ml/min,于254nm检测,溶剂A:100%水/0.1%TFA;溶剂B:100%ACN/0.1%TFA).1H NMR(400MHz,MeOD)δppm 8.64-8.72(1H,m),7.69-7.82(1H,m),7.49-7.58(3H,m),7.40-7.49(2H,m),7.17-7.35(2H,m),5.12-5.22(1H,m),3.59-3.68(1H,m),3.17-3.32(1H,m),2.49-2.70(1H,m),2.31-2.42(1H,m),2.28(3H,s),1.79-1.99(2H,m)。
实施例18
(2R,3R)-N1-((S)-9-氟-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酰胺
实施例18由中间体B-11(30mg,0.111mmol)和中间体S-2(39.1mg,0.111mmol)根据实施例5所显示的一般程序制备。在通过制备型HPLC(YMCODS C185μm 20x 100mm,以0%-100%甲醇水溶液洗脱20分钟,含0.1%TFA,20mL/min,检测器254nm)分离非对映异构体之后,得到实施例18(8.9mg,14%)。HPLC:RT=7.206min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=546[M+H+];1H NMR(400MHz,甲醇-d4)δ8.68(s,1H),7.59-7.38(m,6H),7.31-7.20(m,1H),7.15(s,1H),5.24(s,1H),3.66(s,1H),3.29-3.18(m,1H),2.69-2.49(m,1H),2.44-2.21(m,4H),2.01-1.81(m,2H)。
实施例19
(2R,3R)-N1-((S)-9-氟-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺
实施例19由中间体B-11(30mg,0.111mmol)和中间体S-1(38.6mg,0.111mmol)根据实施例5所显示的一般程序制备。在通过制备型SFC色谱分离非对映异构体后(仪器:Berger SFC MGII,柱:手性IC 25x 3cm,5μm;移动相:82/18CO2/MeOH流速:85mL/min;在220nm检测.)得到实施例19(8.5mg,14%)。HPLC:RT=7.793min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=541[M+H+];1H NMR(400MHz,甲醇-d4)δ7.54-7.40(m,8H),7.34-7.18(m,4H),7.08(d,J=7.9Hz,1H),5.03(s,1H),3.73(d,J=11.4Hz,1H),3.43(td,J=10.5,4.4Hz,1H),3.37(s,1H),2.68-2.47(m,1H),2.46-2.22(m,1H),2.03-1.79(m,2H)。
实施例20
(2R,3R)-N1-((S)-9-甲氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酰胺
实施例20由中间体B-10(50mg,0.178mmol)和中间体S-2(68.7mg,0.196mmol)根据实施例5所显示的一般程序制备。得到实施例20(29mg,29%)。HPLC:RT=8.128min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=558.5[M+H+];1H NMR(400MHz,甲醇-d4)δ8.67(s,1H),7.53-7.45(m,3H),7.44-7.36(m,2H),7.29-7.23(m,1H),7.22-7.15(m,1H),6.86(dd,J=7.7,1.3Hz,1H),5.17(s,1H),3.99(s,3H),3.62(d,J=11.2Hz,1H),3.22(dt,J=10.9,7.2Hz,1H),2.64-2.48(m,1H),2.41-2.27(m,1H),2.26(s,3H),1.97-1.83(m,2H)。
实施例21
(2R,3R)-N1-((S)-9-甲氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺
实施例21由制备中间体B-10(270mg,0.96mmol)和中间体S-1(332mg,0.96mmol)根据实施例5所显示的一般程序。实施例21(340mg,62%)得到。HPLC:RT=10.251min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=553.3[M+H+];1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),9.24(d,J=7.5Hz,1H),7.69(br.s.,1H),7.56-7.31(m,7H),7.30-7.12(m,5H),6.91(br.s.,1H),6.75(d,J=7.9Hz,1H),4.86(dd,J=7.5,1.8Hz,1H),3.89(s,3H),3.70(d,J=11.4Hz,1H),3.43(t,J=10.3Hz,1H),2.80-2.63(m,1H),2.43-2.25(m,1H),1.88-1.60(m,2H)。
实施例22
(2R,3R)-N-((3S)-1-(5-氯-2-吡啶基)-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺
实施例22由中间体B-16(50.0mg,0.138mmol)和中间体S-1(57.3mg,0.165mmol)根据实施例5所显示的一般程序制备。得到实施例22(44.0mg,47.8%)。HPLC:RT=10.43min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=634[M+H+];1H NMR(500MHz,DMSO-d6)δ9.36(d,J=7.5Hz,1H),8.51(dd,J=2.8,0.6Hz,1H),8.12(dd,J=8.6,2.8Hz,1H),7.69(br.s.,1H),7.66-7.63(m,1H),7.59-7.52(m,2H),7.51-7.45(m,4H),7.42-7.38(m,2H),7.35-7.19(m,5H),6.99(d,J=7.8Hz,1H),6.91(s,1H),5.22(d,J=7.5Hz,1H),3.71(d,J=11.4Hz,1H),3.49(td,J=10.6,3.7Hz,1H),2.60-2.54(m,1H),2.40-2.29(m,1H),1.84-1.64(m,2H)。
实施例23
(2R,3R)-N-((3S)-1-(5-氯-2-吡啶基)-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-(3-甲基-4-异噁唑基)-2-(3,3,3-三氟丙基)琥珀酰胺
实施例23由中间体B-16(50.0mg,0.138mmol)和中间体S-2(58.1mg,0.165mmol)根据实施例5所显示的一般程序制备。得到实施例23(38.0mg,42.3%)。HPLC:RT=9.85min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=639[M+H+];1H NMR(400MHz,DMSO-d6)δ9.52(d,J=7.5Hz,1H),8.71(s,1H),8.54-8.50(m,1H),8.14(dd,J=8.6,2.6Hz,1H),7.84(s,1H),7.68(dd,J=8.6,0.4Hz,1H),7.61-7.48(m,6H),7.39-7.33(m,2H),7.18(s,1H),7.01(d,J=8.1Hz,1H),5.38(d,J=7.5Hz,1H),3.56(d,J=11.2Hz,1H),3.28-3.23(m,1H),2.38-2.27(m,2H),2.18(s,3H),1.81-1.69(m,2H)。
实施例24
(2R,3R)-N1-((S)-9-氯-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺
实施例24由中间体B-12(44mg,0.12mmol)和中间体S-1(41.6mg,0.12mmol)根据实施例5所显示的一般程序制备。得到实施例24(8.7mg,12.52%)。HPLC:RT=9.023min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=557.1[M+H+];1H NMR(500MHz,DMSO-d6)δ10.40(s,1H),9.27(d,J=7.5Hz,1H),7.80(dd,J=7.8,1.4Hz,1H),7.69(br.s.,1H),7.56-7.50(m,1H),7.46(t,J=7.5Hz,2H),7.38(d,J=8.9Hz,4H),7.29-7.23(m,3H),7.22-7.16(m,2H),6.91(br.s.,1H),4.89(d,J=7.2Hz,1H),3.70(d,J=11.7Hz,1H),3.50-3.41(m,1H),2.70(d,J=12.2Hz,1H),1.85-1.75(m,1H),1.74-1.63(m,1H)。
实施例25
(2R,3R)-N1-((S)-7-氰基-9-甲氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺
实施例25由中间体B-19(60mg,0.196mmol)和中间体S-1(79mg,0.229mmol)根据实施例5所显示的一般程序制备。该物质通过制备型SFC色谱纯化(Berger SFC MGII,手性IB 250x 21mm ID,5μm,83/17CO2/MeOH,50mL/min)。得到实施例25(13mg,11%)。HPLC:RT=8.548min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=578.3[M+H+];1H NMR(400MHz,甲醇-d4)δ7.56-7.48(m,2H),7.46-7.35(m,6H),7.27-7.13(m,4H),5.01(s,1H),4.00(s,3H),3.75(d,J=11.2Hz,1H),3.54-3.43(m,1H),2.44(qd,J=10.7,7.0Hz,2H),2.05-1.89(m,2H)。
实施例26
(2R,3R)-N1-((S)-9-环丙氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺
实施例26由中间体B-8(1.35g,2.88mmol)和中间体S-1(0.6g,1.73mmol)根据实施例5所显示的一般程序制备。在通过制备型SFC色谱(Berger SFCMGII,手性IC 250x 20mm ID,5μm,82/18CO2/MeOH,85mL/min)分离非对映异构体后,得到实施例26(193mg,19%)。HPLC:RT=9.28min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=579[M+H+];1H NMR(400MHz,甲醇-d4)δ7.56(dd,J=8.1,1.1Hz,1H),7.52-7.35(m,7H),7.35-7.13(m,4H),6.82(dd,J=7.9,1.1Hz,1H),4.97(s,1H),3.95(d,J=2.6Hz,1H),3.73(d,J=11.2Hz,1H),2.68-2.24(m,2H),2.03-1.80(m,1H),1.52-1.23(m,1H),0.97(s,1H),0.91-0.82(m,1H)。
实施例27
(2R,3R)-N1-((S)-5-(4-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺
实施例27由中间体B-3(160mg,0.439mmol)和中间体S-1(152mg,0.439mmol)根据实施例5所显示的一般程序制备。在通过制备型SFC色谱(仪器:Berger SFC MGII,柱:Lux Cellulose 225x 3cm,5μm;移动相:80/20CO2/MeOH流速:85mL/min;在220nm检测.)分离非对映异构体后,得到实施例27(mg,%)。HPLC:RT=8.864min(H2O/CH3CN,含TFA,SunFireC183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=555.1[M+H+];1H NMR(400MHz,甲醇-d4)δ7.52-7.40(m,5H),7.34-7.22(m,3H),7.19-7.02(m,4H),4.93(s,1H),3.70(d,J=11.2Hz,1H),3.43-3.31(m.,1H),2.65-2.49(m,1H),2.42(s,3H),2.38-2.25(m,1H),1.98-1.82(m,2H)。
实施例28
(2R,3R)-N1-((S)-9-甲基-2-氧代-5-(3-(三氟甲基)苯基)-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酰胺
实施例28由中间体B-4(100mg,0.241mmol)和中间体S-2(85mg,0.241mmol)根据实施例5所显示的一般程序制备。得到实施例28(38mg,58%)。HPLC:RT=8.911min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=610.1[M+H+];1H NMR(400MHz,甲醇-d4)δ8.66(s,1H),7.85(s,1H),7.80(d,J=7.9Hz,1H),7.74(s,1H),7.67-7.59(m,1H),7.56-7.49(m,1H),7.22-7.15(m,1H),7.15-7.10(m,1H),5.16(s,1H),3.63(d,J=11.2Hz,1H),3.23(dt,J=11.2,7.0Hz,1H),2.67-2.53(m,1H),2.46(s,3H),2.38-2.28(m,1H),2.24(s,3H),1.96-1.84(m,2H)。
实施例29
(2R,3R)-N1-((S)-9-甲基-2-氧代-5-(3-(三氟甲基)苯基)-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺
实施例29由中间体B-4(100mg,0.241mmol)和中间体S-1(84mg,0.241mmol)根据实施例5所显示的一般程序制备。在通过制备型SFC色谱(仪器:Berger SFC MGII,柱:Regis Welk-O R,R 25x 3cm,5μm;移动相:88/12CO2/MeOH流速:85mL/min;在220nm检测.)分离非对映异构体后,得到实施例29(30mg,31%)。HPLC:RT=9.419min(H2O/CH3CN,含TFA,SunFireC183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=605.1[M+H+];1H NMR(400MHz,甲醇-d4)δ7.84(s,1H),7.81(dd,J=5.0,3.4Hz,1H),7.62-7.59(m,2H),7.52(d,J=6.8Hz,1H),7.48-7.43(m,2H),7.32-7.24(m,3H),7.21-7.14(m,1H),7.09(dd,J=7.9,0.9Hz,1H),4.97(s,1H),3.72(d,J=11.2Hz,1H),3.46-3.40(m,1H),2.64-2.50(m,1H),2.46(s,3H),2.40-2.28(m,1H),1.98-1.87(m,2H)。
实施例30
(2R,3R)-N1-((S)-9-甲基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺
实施例30由中间体B-9(62mg,0.144mmol)和中间体S-1(50mg,0.144mmol)根据实施例5所显示的一般程序制备。得到实施例30(36mg,25%)。HPLC:RT=10.173min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=537.3[M+H+];1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),9.19(d,J=7.7Hz,1H),7.69(s,1H),7.55-7.41(m,4H),7.39-7.32(m,4H),7.29-7.18(m,3H),7.16-7.09(m,1H),7.03(d,J=7.3Hz,1H),6.91(s,1H),4.89-4.84(m,1H),3.69(d,J=11.4Hz,1H),3.45(t,J=10.2Hz,1H),2.75-2.62(m,1H),2.38(s,3H),2.01-1.61(m,3H)。
实施例31
(2R,3R)-N1-((S)-5-(3-氯苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺
实施例31由中间体B-5(560mg,1.471mmol)和中间体S-1(510mg,1.471mmol)根据实施例5所显示的一般程序制备。在通过制备型SFC色谱(仪器:Berger SFC MGIII,柱:手性IC 25x 3cm,5μm;移动相:90/10CO2/MeOH流速:180mL/min;在220nm检测.)分离非对映异构体后,得到实施例31(190mg,34%)。HPLC:RT=9.151min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=571.1[M+H+];1H NMR(400MHz,甲醇-d4)δ7.55-7.51(m,2H),7.50(dd,J=2.1,1.0Hz,1H),7.48-7.44(m,2H),7.39(t,J=7.8Hz,1H),7.36-7.29(m,3H),7.29-7.24(m,1H),7.20-7.14(m,1H),7.12-7.06(m,1H),4.96(s,1H),3.72(d,J=11.2Hz,1H),3.47-3.39(m,1H),2.62-2.48(m,1H),2.44(s,3H),2.42-2.27(m,1H),1.98-1.85(m,2H)。
实施例32
(2R,3R)-N1-((S)-5-(3-氯苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酰胺
实施例32由中间体B-5(100mg,0.263mmol)和中间体S-2(92mg,0.263mmol)根据实施例5所显示的一般程序制备。得到实施例32(36mg,52%)。HPLC:RT=8.633min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=576.2[M+H+];1H NMR(400MHz,甲醇-d4)δ8.68(s,1H),7.59-7.56(m,1H),7.55-7.49(m,2H),7.45-7.38(m,2H),7.23-7.13(m,2H),5.14(s,1H),3.64(d,J=11.2Hz,1H),3.24(dt,J=11.1,7.1Hz,1H),2.66-2.53(m,1H),2.47(s,3H),2.43-2.28(m,1H),2.26(s,3H),1.97-1.86(m,2H)。
实施例33
(2R,3R)-N1-((S)-5-(4-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酰胺
实施例33由中间体B-3(100mg,0.275mmol)和中间体S-2(96mg,0.2775mmol)根据实施例5所显示的一般程序制备。得到实施例33(17mg,11%)。HPLC:RT=8.204min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=560.3[M+H+];1H NMR(400MHz,甲醇-d4)δ8.67(s,1H),7.60-7.48(m,3H),7.23-7.12(m,4H),5.14(s,1H),3.64(d,J=11.2Hz,1H),3.24(dt,J=11.4,7.1Hz,1H),2.64-2.50(m,1H),2.46(s,3H),2.41-2.28(m,1H),2.26(s,3H),1.97-1.85(m,2H)。
实施例34
(2R,3R)-N1-((S)-5-(3-(二氟甲基)苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺
实施例34由中间体B-6(100mg,0.252mmol)和中间体S-1(87mg,0.252mmol)根据实施例5所显示的一般程序制备。在通过制备型SFC色谱(仪器:Berger SFC MGII,柱:手性IC 25x 3cm,5μm;移动相:88/12CO2/MeOH流速:85mL/min;在220nm检测)分离非对映异构体后,得到实施例34(30mg,20%)。HPLC:RT=8.869min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=587.3[M+H+];1H NMR(400MHz,甲醇-d4)δ7.72-7.65(m,2H),7.64-7.58(m,1H),7.52(dd,J=14.7,7.0Hz,2H),7.42(dd,J=7.8,1.4Hz,2H),7.29-7.11(m,5H),6.69(t,J=56.6Hz,1H),4.98(s,1H),3.74(d,J=11.0Hz,1H),3.53-3.45(m,1H),2.54-2.43(m,2H),2.41(s,3H),2.04-1.95(m,2H)。
实施例35
(2R,3R)-N1-((S)-9-环丙氧基-5-(3-氟苯基)-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺
实施例35由中间体B-7(1106mg,0.326mmol)和中间体S-1(101mg,0.358mmol)根据实施例5所显示的一般程序制备。在通过制备型SFC色谱(Berger SFC MGII,Cel4,250x 20mm ID,5μm,83/17CO2/MeOH,85mL/min)分离非对映异构体后,得到实施例35(15mg,7%)。HPLC:RT=10.684min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=597[M+H+];1H NMR(400MHz,甲醇-d4)δ7.62-7.35(m,4H),7.35-7.08(m,7H),6.85(dd,J=8.0,1.2Hz,1H),5.00(s,1H),3.96(s,1H),3.72(d,J=11.2Hz,1H),3.37(s,1H),2.68-2.23(m,2H),1.92(d,J=4.4Hz,2H),1.01-0.79(m,4H)。
实施例36
(2R,3R)-3-(4-氯苯基)-N1-((S)-9-甲氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-2-(3,3,3-三氟丙基)琥珀酰胺
实施例36由中间体B-10(35mg,0.079mmol)和中间体S-4(30mg,0.079mmol)根据实施例5所显示的一般程序制备。得到实施例36(3mg,8%)。HPLC:RT=9.079min(H2O/CH3CN,含TFA,SunFire C183.5μm,4.6x150mm,梯度=15min,波长=220和254nm);MS(ES):m/z=587[M+H+];1H NMR(400MHz,甲醇-d4)δ7.51-7.27(m,10H),7.25-7.21(m,1H),7.20-7.13(m,1H),6.81(dd,J=7.7,1.3Hz,1H),5.02(s,1H),3.97(s,3H),3.69(d,J=11.4Hz,1H),2.53-2.39(m,1H),2.38-2.25(m,1H),1.95-1.81(m,2H)。
比较化合物37至40
比较化合物37至40可根据美国专利第7,053,084号中分别针对实施例8、12a、38及45a所阐述的程序制备。
表1
生物学分析
本发明化合物的药理学性质可藉由许多生物分析证实。利用本发明化合物进行下文所例示的生物分析。
Notch-CBF1转活化分析
基于Notch-CBF1(C-启动子结合因子I)细胞的转活化分析为基于所释放的Notch细胞内结构域片段(NICD)连同CBF1及其他核因子一起作为转录因子功能的能力。使用荧光素酶分析来测量对于Notch-CBF1转录活性的拮抗作用。使用含有截短Notch 1、Notch 2、Notch 3或Notch 4受体的pCDNA3.1/Hygro质粒及含有CBF1结合位点的4个拷贝的PGL3荧光素酶报导子载体瞬时共转染HeLa子宫颈癌细胞。然后测试这些细胞在测试化合物的不存在或存在下的Notch-CBF1活性。取维持于DMEM(高葡萄糖,含HEPES)、1×谷氨酰胺/青霉素/链霉素及10%胎牛血清中的HeLa细胞,根据制造商说明书,使用Monster转染套组(Mirus编号MIR2906),于T175烧瓶中进行过渡性转染(4.5×106个细胞/烧瓶)。表2表示用于转染的各个DNA量。
表2
DNA(μg) | CBF1(μg) | 载体(μg) | 总DNA(μg) | |
人类Notch 1 | 6 | 14.4 | 15.6 | 36.0 |
人类Notch 2 | 2 | 14.4 | 19.6 | 36.0 |
人类Notch 3 | 0.3 | 14.4 | 21.3 | 36.0 |
人类Notch 4 | 4 | 14.4 | 17.6 | 36.0 |
转染后6小时,使用胰蛋白酶处理细胞,并依5×103个细胞/孔的密度平铺至经聚-D-赖氨酸涂覆的384孔黑色组织培养板中的95μL分析培养基(DMEM(高葡萄糖,含HEPES)、1×谷氨酰胺/青霉素/链霉素、0.0125%BSA、1X非必需氨基酸)中。将含有最终浓度在5μM至8.4×10-5μM(3倍连续稀释)的范围内的测试化合物的分析培养基(5μL)添加至这些细胞中,且然后在37℃及5%CO2下将这些细胞板温育18小时。对照孔含有DMSO媒剂(总计数)或0.5μM的自行使用的小分子抑制剂(背景计数)。每一样品均一式两份。在与50μlSTEADY-荧光素酶试剂一起温育20分钟后,根据制造商说明书(Promega,目录编号E2550)测量荧光素酶活性,并藉由Envision板读数器(PerkinElmer,Boston,MA)分析。
化合物的拮抗效应为表示为100×[1-(平均样品-平均背景)/(平均总量-平均背景)],其中样品为在测试化合物的存在下的荧光素酶活性,背景等于在小分子抑制剂对照的存在下的荧光素酶活性,且总量为DMSO孔中所诱导的信号。使用四参数逻辑拟合等式对数据作图,且IC50值为定义为抑制50%荧光素酶活性的化合物浓度。
下表3列示上文Notch-CBF1转活化分析中所测量的本发明实施例1至36及比较化合物37-40的Notch 1及Notch 3IC50值。在一些情形下,该值为多个实验的平均值,其中N为所实施的实验数。由实施例1至36所例示的本发明化合物显示24.2nM或更少的Notch 1值及22.9nM或更少的Notch 3IC50值。
表3
高通量(HT)代谢稳定性组
胃肠外给药的化合物进入血流,并一或多次穿过肝。不易于被肝代谢的化合物可以治疗上有效血浆含量给药并持续治疗上有效时间。
经口给药的化合物通常经吸收穿过肠壁进入血流中,并第一次穿过肝。在此第一次穿过肝时不易代谢的化合物可以治疗上有效量分布至身体的其他部位。
10分钟温育后,代谢稳定性分析使用人类、大鼠、小鼠、狗和/或猴微粒体评价活体外的CYP介导的代谢稳定性。一式两份测试每一化合物。
这些分析的结果为表示为该10分钟温育后反应混合物中所剩余的母体化合物的分数(剩余百分比)。一般而言,这些结果为用于仅评价测试化合物的CYP介导或NADPH依赖性代谢的程度。当该化合物明显代谢(剩余<40%至50%)时,此指示由CYP介导的代谢导致的该化合物在活体内的高清除率。然而,若该化合物在这些活体外分析中展示中等(50%至80%)或低(>85%)代谢,则在活体内经由其他代谢及消除路径高清除率仍为可能的。
这些分析的剩余百分比结果预测活体内化合物清除率,此假设CYP介导的代谢为主要消除路径。在不同微粒体种类中,结果范围为大概如表4中所显示。
表4
代谢稳定性结果解释指南
方法及材料
利用肝微粒体的温育
以存于100%DMSO中的3.5mM储备溶液形式接受测试化合物。稀释该测试化合物以产生含有1.4%DMSO的50μM乙腈(ACN)溶液,然后作为100×储备溶液用于利用微粒体的温育。在代谢稳定性-人类、大鼠及小鼠成套分析中,在三个物种中的每一者中单独地以一式两份测试每一化合物,或在代谢稳定性-狗或代谢稳定性-猴成套分析中的个别物种中以一式两份测试每一化合物。在3个步骤中将化合物、NADPH及肝微粒体溶液合并用于温育:
1.在37℃,使152μl的肝微粒体悬浮液(蛋白质浓度为存于100mM NaPi,pH 7.4,5mM MgCl2缓冲液中1.1mg/ml)预升温。
2.将1.7μl的50μM化合物(98.6%ACN,1.4%DMSO)添加至同一管中,并在37℃预温育5分钟。
3.藉由添加17μl存于100mM NaPi中的经预升温10mM NADPH溶液(pH 7.4)来起始该反应。
将这些反应组份充分混合,且将75μl的反应混合物立即转移至150μl淬灭/停止溶液中(0时间点,T0)。在37℃将反应温育10分钟,且然后将另一75μl等份试样转移至150μl淬灭溶液中。使用含有乙腈的100μM DMN(用于注射质量控制的UV标准物)作为终止代谢反应的淬灭溶液。
在X-12离心机(SX4750转子,Beckman Coulter公司,Fullerton,CA)中以1500rpm(约500×g)对经淬灭混合物离心15分钟,以使变性微粒体沉淀。然后将90μl的体积的上清液萃取物(含有母体化合物与其代谢物的混合物)转移至单独96孔板用于UV-LC/MS-MS分析,以测定该混合物中所剩余的母体化合物百分比。
表5
代谢稳定性分析-反应组份
反应组份 | 代谢稳定性分析中的最终浓度 |
化合物(底物) | 0.5μM |
NaPi缓冲液,pH 7.4 | 100mM |
DMSO | 0.014% |
乙腈 | 0.986% |
微粒体(人类、大鼠、小鼠)(BD/Gentest) | 1mg/ml蛋白质 |
NADPH | 1.0mM |
MgCl2 | 5.0mM |
37℃温育时间 | 0分钟和10分钟 |
淬灭/停止溶液(ACN+100μM DMN) | 150μl |
反应组份 | 代谢稳定性分析中的最终浓度 |
反应样品 | 75μl |
变性微粒体的沉降 | 15分钟 |
上清液的UV-LC/MS分析 | 0.17μM |
样品分析-仪器
HPLC:泵-Thermo Surveyor;自动取样器-CTC/LEAP HTS;UV检测器-Thermo Surveyor PDA plus;管柱-具有0.5μm直列式滤器的C18,3μm,2×20mm;用于结构完整性预分析的流动相:(A)98%水,2%乙腈,具有10mM乙酸铵;(B)10%水,90%乙腈,具有10mM乙酸铵;用于反应样品分析的流动相:(A)98%水,2%乙腈,具有0.1%甲酸;(B)2%水,98%乙腈,具有0.1%甲酸;(C)存于水中的0.1%氢氧化铵;(D)存于乙腈中的0.1%氢氧化铵。
质谱仪:Thermo TSQUltra三重四极柱质谱仪;
样品分析-结构完整性预分析
使用代谢稳定性结构完整性预分析来评估所分析化合物的纯度。化合物为以57μl的3.5mM DMSO溶液形式接受于96孔板中。利用含有相等体积的乙腈、异丙醇及MilliQ-H2O的溶液将3.5mM化合物DMSO储备溶液稀释至1/18。藉由LC-UV/MS于Thermo LCQ Deca XP Plus ion trap质谱仪上使用具有WatersSentry 2.1mm保护管柱的Waters XBridge C18管柱(5μm,2×50mm)及下表中所阐述的LC条件(其中5μl注射及1ml/min的流速)针对结构完整性分析所得溶液(200μM)。所获得数据藉由220nm下的UV吸亮度反映纯度。仅报告那些具有大于50%的纯度的化合物的结果。
表6
代谢稳定性-结构完整性梯度
梯度时间(min) | A% | B% |
0.00 | 100 | 0 |
4.00 | 0 | 100 |
5.00 | 0 | 100 |
5.10 | 100 | 0 |
6.00 | 100 | 0 |
样品分析-所温育的样品
于配备有加热电喷雾(H-ESI)来源的Thermo TSQ三重四极柱质谱仪上藉由自动化输注实施MS/MS条件优化,以获得SRM跃迁及其相应的碰撞能量值。以90μL/min的流速输注浓度为存于1:1甲醇:水中20μM的化合物溶液,然后与流速为50μL/min的流动相合并,然后引入该来源中。先使用流动相A及B(50%A及50%B)且若需要则使用流动相C及D(亦为50:50组成)使所有化合物优化。将经优化参数(包括极性、SRM跃迁及碰撞能量)储存于MICROSOFT数据库中。
使用自动化输注获得的质谱条件来分析来自代谢稳定性分析的温育样品。注射体积为5μl,且流速为0.8ml/min。所使用梯度为显示于下表中。以该梯度先使用流动相A及B注射所有样品。若需要(例如,出于层析的原因),则以相同梯度、但使用流动相C及D再注射样品。在原始数据文文件中以电子方式捕获所有LC-MS/MS分析参数。
表7
代谢稳定性-样品分析梯度
梯度时间(min) | A%(或C%) | B%(或D%) |
0.00 | 95 | 5 |
0.20 | 95 | 5 |
0.30 | 0 | 100 |
1.05 | 0 | 100 |
1.10 | 95 | 5 |
1.50 | 95 | 5 |
数据分析
利用软件实施峰整合。对于每一化合物,藉由比较来自T10min样品的LC-MS/MS峰面积与来自T0min样品的峰面积来实施剩余百分比计算。
质量控制
于每一分析板中测试一组3种化合物以及测试化合物。仅在这些对照化合物属于下文所显示的预期范围内时,才接受并上传数据。
表8
代谢稳定性分析-藉由微粒体种类得到的对照化合物值
SD=标准偏差
代谢稳定性半衰期组
使用活体外所测定于人类或动物肝微粒体中的代谢速率及半衰期来测定化合物的固有清除率(CLint)及肝清除率(CLh,b)。这些参数可用于预测活体内人类清除率,该清除率界定活体内药物暴露含量(Obach等,1997、1999)。
代谢稳定性半衰期分析组评价CYP介导的(NADPH依赖性)代谢在活体外于人类、大鼠、小鼠、狗及猴微粒体中的时程及速率。该时程贯穿45分钟温育,且包括0分钟、5分钟、10分钟、15分钟、30分钟及45分钟时间点,在每一时间点处测量混合物中所剩余的测试化合物的量。
结果解释指南
代谢稳定性半衰期分析的结果为表示为半衰期(T1/2,min)。一般而言,这些结果应用于仅评价测试化合物的CYP介导或NADPH依赖性代谢的程度。当该化合物明显代谢(T1/2<14分钟)时,此指示由CYP介导的代谢导致的活体内高清除率。然而,若该化合物在这些活体外分析中展示中等(14分钟至70分钟)或低(>70分钟)代谢,则在活体内经由其他代谢及消除路径高清除率仍为可能的。
这些分析的结果预测活体内化合物清除率,此假设CYP介导的代谢为主要消除路径。在人类微粒体中,结果范围为大概如下表中所显示:
表9
代谢稳定性半衰期-结果解释指南
方法及材料
肝微粒体系购自BD-Biosciences(Woburn,MA),且NADPH购自AppliChem Inc;所有其他试剂为获得自Sigma。
利用肝微粒体的温育
以存于100%DMSO中的3.5mM储备溶液形式接受测试化合物。稀释该测试化合物以产生含有1.4%DMSO的50μM乙腈(ACN)溶液,然后作为100倍储备溶液用于利用微粒体的温育。于人类、大鼠、小鼠、狗及猴肝微粒体中测试每一化合物。在3个步骤中将化合物、NADPH及肝微粒体溶液合并用于温育:
1.在37℃,使450μl的肝微粒体悬浮液(蛋白质浓度为存于100mM NaPi,pH 7.4,5mM MgCl2缓冲液中1.1mg/ml)预升温。
2.将5μl的50μM化合物(98.6%ACN,1.4%DMSO)添加至同一管中,并在37℃预温育5分钟。
3.藉由添加50μl存于100mM NaPi中的经预升温10mM NADPH溶液(pH 7.4)来起始该反应。
将反应组份充分混合,且将65μl立即转移至130μl淬灭/停止溶液中(0时间点,T0)。在37℃,将反应温育5分钟、10分钟、15分钟、30分钟及45分钟,且在每一时间点处将65μl等份试样转移至130μl的淬灭溶液中。使用含有乙腈的内标准物(100ng/ml)作为终止代谢反应的淬灭溶液。
在X-12离心机(SX4750转子,Beckman Coulter公司,Fullerton,CA)中以1500rpm(约500×g)对经淬灭混合物离心15分钟,以使变性微粒体沉淀。然后将90μl的体积的上清液萃取物(含有母体化合物与其代谢物的混合物)转移至单独96孔板用于LC/MS-MS分析,以测定该混合物中所剩余的母体化合物百分比。
表10
代谢稳定性半衰期分析-反应组份
反应组份 | 代谢稳定性分析中的最终浓度 |
化合物(底物) | 0.5μM |
NaPi缓冲液,pH 7.4 | 100mM |
DMSO | 0.014% |
乙腈 | 0.986% |
微粒体(人类、大鼠、小鼠)(BD/Gentest) | 1mg/ml蛋白质 |
NADPH | 1.0mM |
MgCl2 | 5.0mM |
37℃温育时间 | 0、5、10、15、30和45分钟 |
淬灭/停止溶液(ACN+100μM DMN) | 130μl |
反应样品 | 65μl |
变性微粒体的沉降 | 15分钟 |
样品分析-仪器
HPLC:泵-Shimadzu LC-20AD系列二元泵;自动取样器-CTC/LEAP HTS
下表11列示于人类代谢稳定性半衰期分析中所测量的本发明实施例1至36及比较化合物37至40的CYP介导的代谢半衰期值。在一些情形下,该值为多个实验的平均值,其中N为所实施的实验数。由实施例1至36所例示的本发明化合物具有30分钟或更长的代谢稳定性半衰期值。相比之下,比较化合物37至40具有8分钟或更少的代谢稳定性半衰期值。
表11
实施例 | HLM(t1/2,min) | N |
1 | 64 | 3 |
2 | >109 | 2 |
3 | 73 | 1 |
4 | >120 | 2 |
5 | 44 | 4 |
6 | 41 | 2 |
7 | 71 | 1 |
8 | 86 | 1 |
9 | 30 | 3 |
10 | 67 | 1 |
11 | 41 | 3 |
12 | 93 | 1 |
13 | 31 | 1 |
14 | 45 | 1 |
15 | >120 | 1 |
16 | 85 | 1 |
17 | 58 | 2 |
18 | 78 | 2 |
19 | >120 | 1 |
20 | 58 | 2 |
21 | 52 | 5 |
22 | >120 | 1 |
23 | 39 | 1 |
24 | >120 | 1 |
25 | 78 | 2 |
26 | 46 | 3 |
27 | 54 | 2 |
28 | 37 | 1 |
29 | 47 | 2 |
30 | 45 | 3 |
31 | 54 | 2 |
32 | 32 | 1 |
33 | 49 | 1 |
34 | 48 | 1 |
35 | 47 | 2 |
36 | 31 | 1 |
比较化合物37 | 8 | 1 |
比较化合物38 | 6 | 1 |
比较化合物39 | 6 | 1 |
比较化合物40 | 3 | 1 |
所列示的本发明化合物在人类代谢稳定性半衰期分析中显示由CYP介导的代谢导致的低清除率的惊奇优势。由实施例1至36所例示的本发明化合物在人类代谢稳定性半衰期分析中具有在30分钟或更大的范围的代谢半衰期数值。相比之下,比较化合物37至40在人类代谢稳定性分析中具有8分钟或更少的代谢半衰期。比较化合物37至40在人类代谢稳定性分析中显示高清除率,此指示这些化合物为藉由肝微粒体来去除。
已将本发明化合物(实施例1至36)与美国专利第7,456,172号中所公开的比较化合物37至40相比较,且发现其尤其有利。本发明的化合物具有作为Notch 1及Notch 3的抑制剂的活性及优于肝微粒体的代谢稳定性的组合的惊奇优势。如表3及11中所显示,在所报告测试中,本发明的实施例1至36具有24.2nM或更少的Notch 1IC50值及22.9nM或更少的Notch 3IC50值;及在人类代谢稳定性半衰期分析中30分钟或更长的人类代谢稳定性半衰期。相比之下,在类似测试中,比较化合物37至40具有在5.1nM至64.1nM的范围内的Notch 1IC50值及在12.5nM至74.5nM的范围内的Notch 3IC50值;及8分钟或更少的人类代谢稳定性半衰期。
小鼠中的人类肿瘤异种移植模型
所有啮齿动物为获得自Harlan Sprague Dawley公司(Indianapolis,Indiana),且于无氨水环境中维持于经界定且无病原体群落中。在用于肿瘤传播及药物效力测试前大约1周对所有小鼠进行隔离。给小鼠随意饲喂食物及水。百时美施贵宝药品研究所(Bristol-Myers Squibb Pharmaceutical Research Institute)的动物照护计划经美国实验动物照护评鉴协会(American Association forAccreditation of Laboratory Animal Care,AAALAC)完全认可。依照百时美施贵宝(Bristol-Myers Squibb,BMS)动物测试方法及指南实施所有实验。
使肿瘤异种移植物生长,并经皮下(SC)维持于免疫受损的balb/c nu/nu裸或NOD-SCID小鼠(Harlan Sprague Dawley)中。使用自供体小鼠获得的肿瘤片段以皮下移植物形式于适当小鼠品为(表12)中传播肿瘤。
表12
用于各种人类肿瘤异种移植物于小鼠中的繁殖的组织学类型及宿主小鼠品系/性别要求
肿瘤类型 | 组织学 | 小鼠品系 | 性别 |
TALL-1 | ALL | NOD-SCID | 雌性 |
MDA-MB-157 | 乳房 | NOD-SCID | 雌性 |
MDA-MB-468 | 乳房 | NOD-SCID | 雌性 |
临床前化学疗法试验
在实验开始时将需要检测有意义反应的所需数量的动物集合在一起,且利用13号套管针向每一者给予肿瘤片段(约20mg)的皮下植入物。使肿瘤生长至预定大小窗口(排除该范围外面的肿瘤),且将动物均匀分布至各种治疗及对照群组。通常每个治疗及对照群组有8只小鼠,以SAL-IGF(此不包括于表12中)肿瘤模型实施的实验(其中每个治疗及对照群组有5只小鼠)除外。每一动物的治疗为基于个别体重。每天检查经治疗动物的治疗相关的毒性/死亡率。在起始治疗之前(Wt1)且然后在最后一次治疗剂量之后再次(Wt2)对每组动物称重。体重的差异(Wt2-Wt1)提供治疗相关的毒性的量度。
肿瘤反应为藉由每周两次利用卡尺测量肿瘤来测定,直至肿瘤达到预定0.5gm或1gm(取决于肿瘤类型)的“目标”大小为止。自下式估计肿瘤重量(mg):
肿瘤重量=(长度×宽度2)÷2
用肿瘤生长抑制(%TGI)表示肿瘤反应标准。肿瘤生长延迟为定义为经治疗肿瘤(T)达到预定目标大小所需要的时间(天)与对照群组(C)的时间相比的差异。出于此目的,一群组的肿瘤重量为表示为中等肿瘤重量(MTW)。
肿瘤生长抑制为如以下计算:
其中,
Ct=治疗结束时的对照肿瘤大小中值
C0=治疗起始时的对照肿瘤大小中值
Tt=治疗结束时治疗群组的肿瘤大小中值
T0=治疗起始时治疗群组的肿瘤大小中值
活性为定义为达成50%或更大的持久肿瘤生长抑制(即,TGI≥50%)或0.5或更大的细胞对数杀灭(LCK≥0.5)并持续相当于至少1个肿瘤体积倍增时间的时期,且药物治疗必须持续相当于至少2个肿瘤体积倍增时间的时期。
亦用肿瘤生长延迟(TGD值)表示肿瘤反应,肿瘤生长延迟为定义为经治疗肿瘤(T)达到预定目标大小所需要的时间(天)与对照群组(C)的时间相比的差异。
只要可能时,在高达最大耐受剂量(MTD)的剂量值范围内测定抗肿瘤活性,该最大耐受剂量为定义为刚刚高于发生过高毒性(即,超过一个死亡)的剂量值。当发生死亡时,记录死亡的日期。认为在肿瘤达到目标大小之前死亡的经治疗小鼠死于药物毒性。死亡对照小鼠所携带肿瘤皆不小于目标大小。认为具有超过一个由药物毒性引起的死亡的治疗群组已进行过高毒性治疗,且其数据不包括于化合物的抗肿瘤效力的评价中。
影响治疗耐受性的潜在药物毒性相互作用在组合化学疗法试验中为重要考虑因素。组合治疗结果的解释必须基于对同等耐受剂量的单一药剂与该组合的最佳可能反应的抗肿瘤活性的比较。因此,治疗协同作用为定义为利用超过在单一疗法的任一耐受剂量下达成的最佳效应的组合药剂的耐受方案达成的治疗效应。使用格翰氏广义威尔卡森检定(Gehan's generalizedWilcoxon test)实施数据的统计学评价。在P<0.05下宣布统计显著性。
药物给药
在活体外研究中,将所有药剂溶解于100%DMSO中,并连续稀释于培养基/10%胎牛血清中。使用以下赋形剂来向啮齿动物给药Notch抑制剂:ETOH/TPGS/PEG300(10:10:80)。通常根据QD×15、10天给药-2天停药-5天给药的时间表经口给药Notch抑制剂,但亦评价其他时间表,且显示为有效的。例如,显示由QD×12、4天给药-3天停药组成的给药方案与QD×15、10天给药-2天停药-5天给药同样有效。在BID研究中,在第一剂量后6小时至12小时给予第二剂量。
活体内抗肿瘤活性
于小鼠中所植入的人类肿瘤异种移植物中评价经口给药(PO)的实施例1的抗肿瘤活性。
下表13列示于小鼠中以人类肿瘤异种移植模型测量的本发明实施例的抗肿瘤活性。实施例1、21、26、30和31所示例的本发明化合物显示利用经口给药(PO)的抗肿瘤活性。
表13
安排:QDx10-14,或BIDx10经口给药
TALL1:QDx10.QD–每天一次;BID–每天两次
LCK–细胞对数杀死
Claims (11)
1.式(I)化合物:
其中:
R2为苯基、氟苯基、氯苯基、三氟苯基、甲基异噁唑基或吡啶基;
R3为H、-CH3、-CH2(环丙基)、吡啶基、氯吡啶基或甲氧基吡啶基;
各Ra独立地为F、Cl、-CH3、-OCH3、-CN和/或-O(环丙基);
或者两个Ra与它们连接的碳原子一起形成间二氧杂环戊烯(dioxole)环;
各Rb独立地为F、Cl、-CHF2和/或-CF3;
y为零、1或2;和
z为零、1或2。
2.权利要求1的化合物,其中:
R2为苯基、氟苯基、氯苯基或三氟苯基。
3.权利要求1的化合物,其中:
R2为甲基异噁唑基。
4.权利要求1的化合物,其中:
R2为吡啶基。
5.权利要求1的化合物,其中:
R3为H或-CH3。
6.权利要求1的化合物,其中:
R3为-CH2(环丙基)、吡啶基、氯吡啶基或甲氧基吡啶基。
7.权利要求1的化合物,其选自:(2R,3R)-N-((3S)-1-甲基-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(1);(2R,3R)-3-(4-氟苯基)-N-((3S)-1-甲基-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-2-(3,3,3-三氟丙基)琥珀酰胺(2);(2R,3R)-N-((3S)-1-甲基-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-(2,3,4-三氟苯基)-2-(3,3,3-三氟丙基)琥珀酰胺(3);(2R,3R)-N-((3S)-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(4);(2R,3R)-N1-((S)-5-(3-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(5);(2R,3R)-N1-((S)-1-甲基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酰胺(6);(2R,3R)-N1-((S)-1-(环丙基甲基)-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(7);(2R,3R)-N1-((S)-1-(环丙基甲基)-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(4-氟苯基)-2-(3,3,3-三氟丙基)琥珀酰胺(8);(2R,3R)-3-(3-甲基异噁唑-4-基)-N1-((S)-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-2-(3,3,3-三氟丙基)琥珀酰胺(9);(2R,3R)-N1-((S)-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(吡啶-3-基)-2-(3,3,3-三氟丙基)琥珀酰胺(10);(2R,3R)-3-(3-甲基-4-异噁唑基)-N-((3S)-2-氧代-5-苯基-1-(2-吡啶基)-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-2-(3,3,3-三氟丙基)琥珀酰胺(11);(2R,3R)-N-((3S)-2-氧代-5-苯基-1-(2-吡啶基)-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(12);(2R,3R)-3-(3-甲基-4-异噁唑基)-N-((7S)-6-氧代-9-苯基-6,7-二氢-5H-[1,3]二氧杂环戊并[4,5-h][1,4]苯并二氮杂-7-基)-2-(3,3,3-三氟丙基)琥珀酰胺(13);(2R,3R)-N-((3S)-1-(5-甲氧基-2-吡啶基)-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-(3-甲基-4-异噁唑基)-2-(3,3,3-三氟丙基)琥珀酰胺(14);(2R,3R)-N-((3S)-1-(5-甲氧基-2-吡啶基)-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(15);(2R,3R)-N-((3S)-1-(6-甲氧基-2-吡啶基)-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(16);(2R,3R)-N1-((S)-9-氯-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酰胺(17);(2R,3R)-N1-((S)-9-氟-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酰胺(18);(2R,3R)-N1-((S)-9-氟-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(19);(2R,3R)-N1-((S)-9-甲氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酰胺(20);(2R,3R)-N1-((S)-9-甲氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(21);(2R,3R)-N-((3S)-1-(5-氯-2-吡啶基)-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(22);(2R,3R)-N-((3S)-1-(5-氯-2-吡啶基)-2-氧代-5-苯基-2,3-二氢-1H-1,4-苯并二氮杂-3-基)-3-(3-甲基-4-异噁唑基)-2-(3,3,3-三氟丙基)琥珀酰胺(23);(2R,3R)-N1-((S)-9-氯-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(24);(2R,3R)-N1-((S)-7-氰基-9-甲氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(25);(2R,3R)-N1-((S)-9-环丙氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(26);(2R,3R)-N1-((S)-5-(4-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(27);(2R,3R)-N1-((S)-9-甲基-2-氧代-5-(3-(三氟甲基)苯基)-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酰胺(28);(2R,3R)-N1-((S)-9-甲基-2-氧代-5-(3-(三氟甲基)苯基)-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(29);(2R,3R)-N1-((S)-9-甲基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(30);(2R,3R)-N1-((S)-5-(3-氯苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(31);(2R,3R)-N1-((S)-5-(3-氯苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酰胺(32);(2R,3R)-N1-((S)-5-(4-氟苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-(3-甲基异噁唑-4-基)-2-(3,3,3-三氟丙基)琥珀酰胺(33);(2R,3R)-N1-((S)-5-(3-(二氟甲基)苯基)-9-甲基-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(34);(2R,3R)-N1-((S)-9-环丙氧基-5-(3-氟苯基)-2-氧代-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-3-苯基-2-(3,3,3-三氟丙基)琥珀酰胺(35);和(2R,3R)-3-(4-氯苯基)-N1-((S)-9-甲氧基-2-氧代-5-苯基-2,3-二氢-1H-苯并[e][1,4]二氮杂-3-基)-2-(3,3,3-三氟丙基)琥珀酰胺(36)。
8.一种药物组合物,其包含至少一种权利要求1至7中任一项的化合物和药学上可接受的载体。
9.权利要求1至8中任一项的化合物或其药学上可接受的盐,其用于治疗癌症的疗法中。
10.权利要求9的化合物或其药学上可接受的盐,其中该疗法进一步包含一种或多种选自达沙替尼、紫杉醇、他莫昔芬、地塞米松及卡铂的额外药剂,供依序或同时给药治疗癌症。
11.权利要求1至8中任一项的化合物或其药学上可接受的盐,用于制造治疗癌症的药品。
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PCT/US2013/060833 WO2014047392A1 (en) | 2012-09-21 | 2013-09-20 | Fluoroalkyl-1,4-benzodiazepinone compounds |
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US9273075B2 (en) | 2012-09-21 | 2016-03-01 | Bristol-Myers Squibb Company | Prodrugs of 1,4-benzodiazepinone compounds |
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2013
- 2013-09-20 JP JP2015533206A patent/JP2015529252A/ja active Pending
- 2013-09-20 WO PCT/US2013/060833 patent/WO2014047392A1/en active Application Filing
- 2013-09-20 US US14/429,941 patent/US9133139B2/en active Active
- 2013-09-20 EP EP13770811.1A patent/EP2897954B1/en not_active Not-in-force
- 2013-09-20 CN CN201380060053.6A patent/CN104822677A/zh active Pending
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023241738A3 (zh) * | 2022-06-15 | 2024-02-15 | 复旦大学 | 1,4-苯二氮䓬类化合物及其在制备抗肿瘤药物中的用途 |
Also Published As
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JP2015529252A (ja) | 2015-10-05 |
WO2014047392A1 (en) | 2014-03-27 |
EP2897954A1 (en) | 2015-07-29 |
US20150218111A1 (en) | 2015-08-06 |
US9133139B2 (en) | 2015-09-15 |
EP2897954B1 (en) | 2016-10-26 |
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