CN110997668B - Kras g12c抑制剂及其使用方法 - Google Patents
Kras g12c抑制剂及其使用方法 Download PDFInfo
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- CN110997668B CN110997668B CN201880047910.1A CN201880047910A CN110997668B CN 110997668 B CN110997668 B CN 110997668B CN 201880047910 A CN201880047910 A CN 201880047910A CN 110997668 B CN110997668 B CN 110997668B
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- alkylene
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- aryl
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Abstract
本文提供KRAS G12C抑制剂、其组合物及其使用方法。这些抑制剂可用于治疗多种病症,包括胰腺癌、结肠直肠癌及肺癌。
Description
技术领域
本文提供KRAS G12C抑制剂、其组合物及其使用方法。这些抑制剂可用于治疗多种病症,包括胰腺癌、结肠直肠癌及肺癌。
背景技术
KRAS基因突变在胰腺癌、肺腺癌、结肠直肠癌、胆囊癌、甲状腺癌及胆管癌中常见。在约25%的NSCLC患者中也观察到KRAS突变,并且一些研究表明,KRAS突变是NSCLC患者的不良预后因子。近来,已发现V-Ki-ras2 Kirsten大鼠肉瘤病毒癌基因同源物(Kirsten ratsarcoma viral oncogene homolog,KRAS)突变在结肠直肠癌中赋予对表皮生长因子受体(EGFR)靶向疗法的抗性;因此,KRAS的突变状态可以在开具TKI疗法之前提供重要信息。总而言之,需要用于胰腺癌、肺腺癌或结肠直肠癌患者,尤其是已确诊患有此类以KRAS突变为特征的癌症的患者,并且包括在化学疗法后疾病进展的患者的新颖医学治疗方法。
发明内容
本文提供具有式(I)的结构的化合物
其中
E1及E2各自独立地为N或CR1;
R1独立地为H、羟基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、NH-C1-6烷基、N(C1-6烷基)2、氰基或卤基;
R2是卤基、C1-6烷基、C1-6卤代烷基、OR’、N(R’)2、C2-3烯基、C2-3炔基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、芳基、杂芳基、C0-3亚烷基芳基或C0-3亚烷基杂芳基,并且各R’独立地为H、C1-6烷基、C1-6卤代烷基、C3-14环烷基、C2-14杂环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基,或两个R’取代基连同其所附接的氮原子一起形成3-7元环;
R3是卤基、C1-3烷基、C1-2卤代烷基、C1-3烷氧基、C3-4环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基;
R4是
环A是单环4-7元环或双环、桥连、稠合或螺环6-11元环;
L是键、C1-6亚烷基、-O-C0-5亚烷基、-S-C0-5亚烷基或-NH-C0-5亚烷基,并且对于C2-6亚烷基、-O-C2-5亚烷基、-S-C2-5亚烷基及NH-C2-5亚烷基,该亚烷基基团的一个碳原子可任选地经O、S或NH替代;
R4’是H、C1-6烷基、C2-6炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、环烷基、杂环烷基、C0-3亚烷基-C3-4环烷基、C0-3亚烷基-C2-14杂环烷基、芳基、杂芳基、C0-3亚烷基-C6-14芳基,或选自
R5及R6各自独立地为H、卤基、C1-6烷基、C2-6炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、C1-6亚烷基胺、C0-6亚烷基-酰胺、C0-3亚烷基-C(O)OH、C0-3亚烷基-C(O)OC1-4烷基、C1-6亚烷基-O-芳基、C0-3亚烷基-C(O)C1-4亚烷基-OH、环烷基、杂环烷基、芳基、杂芳基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、C0-3亚烷基-C6-14芳基、C0-3亚烷基-C2-14杂芳基或氰基,或R5及R6连同其所附接的原子一起形成4-6元环;并且
R7是H或C1-8烷基,或R7及R5连同其所附接的原子一起形成4-6元环,或其药学上可接受的盐。
在另一个实施例中,本文提供具有式(I)的结构的化合物
其中
E1及E2各自独立地为N或CR1;
R1独立地为H、羟基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、NH-C1-6烷基、N(C1-4烷基)2、氰基或卤基;
R2是卤基、C1-6烷基、C1-6卤代烷基、OR’、N(R’)2、C2-3烯基、C2-3炔基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、芳基、杂芳基、C0-3亚烷基-C6-14芳基或C0-3亚烷基-C2-14杂芳基,并且各R’独立地为H、C1-6烷基、C1-6卤代烷基、C3-14环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基,或两个R’取代基连同其所附接的氮原子一起形成3-7元环;
R3是卤基、C1-3烷基、C1-2卤代烷基、C1-3烷氧基、C3-14环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基;
环A是单环4-7元环或双环、桥连、稠合或螺环6-11元环;
L是键、C1-6亚烷基、-O-C0-5亚烷基、-S-C0-5亚烷基或-NH-C0-5亚烷基,并且对于C2-6亚烷基、-O-C2-5亚烷基、-S-C2-5亚烷基及NH-C2-5亚烷基,该亚烷基基团的一个碳原子可任选地经O、S或NH替代;
R5及R6各自独立地为H、卤基、C1-8烷基、C2-8炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、C1-6亚烷基胺、C0-6亚烷基-酰胺、C0-3亚烷基-C(O)OH、C0-3亚烷基-C(O)OC1-4烷基、C1-6亚烷基-O-芳基、C0-3亚烷基-C(O)C1-4亚烷基-OH、环烷基、杂环烷基、芳基、杂芳基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、C0-3亚烷基-C6-14芳基、C0-3亚烷基-C2-14杂芳基或氰基,或R5及R6连同其所附接的原子一起形成4-6元环;并且
R7是H或C1-6烷基,或R7及R5连同其所附接的原子一起形成4-6元环,或其药学上可接受的盐。
另外提供具有式(II)的化合物或其药学上可接受的盐:
其中E1及E2各自独立地为N或CR1;J是N、NR10或CR10;M是N、NR13或CR13;根据需要而为单键或双键以使其每个原子呈现其正常价态;R1独立地为H、羟基、C1-6烷基、C1-4卤代烷基、C1-4烷氧基、NH-C1-4烷基、N(C1-4烷基)2、氰基或卤基;R2是卤基、C1-6烷基、C1-6卤代烷基、OR’、N(R’)2、C2-3烯基、C2-3炔基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、芳基、杂芳基、C0-3亚烷基-C6-14芳基或C0-3亚烷基-C2-14杂芳基,并且各R’独立地为H、C1-6烷基、C1-6卤代烷基、C3-14环烷基、C2-14杂环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基,或两个R’取代基连同其所附接的氮原子一起形成3-7元环;R3是卤基、C1-3烷基、C1-2卤代烷基、C1-3烷氧基、C3-4环烷基、C2-14杂环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基;
R4是 环A是单环4-7元环或双环、桥连、稠合或螺环6-11元环;L是键、C1-6亚烷基、-O-C0-5亚烷基、-S-C0-5亚烷基或-NH-C0-5亚烷基,并且对于C2-6亚烷基、-O-C2-5亚烷基、-S-C2-5亚烷基及NH-C2-5亚烷基,该亚烷基基团的一个碳原子可任选地经O、S或NH替代;R4’是H、C1-8烷基、C2-8炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、环烷基、杂环烷基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、芳基、杂芳基、C0-3亚烷基-C6-14芳基,或选自
R5及R6各自独立地为H、卤基、C1-6烷基、C2-6炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、C1-6亚烷基胺、C0-6亚烷基-酰胺、C0-3亚烷基-C(O)OH、C0-3亚烷基-C(O)OC1-4烷基、C1-6亚烷基-O-芳基、C0-3亚烷基-C(O)C1-4亚烷基-OH、环烷基、杂环烷基、芳基、杂芳基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、C0-3亚烷基-C6-14芳基、C0-3亚烷基-C2-14杂芳基或氰基,或R5及R6连同其所附接的原子一起形成4-6元环;R7是H或C1-8烷基,或R7及R5连同其所附接的原子一起形成4-6元环;Q是CR8R9、C=CR8R9、C=O、C=S或C=NR8;R8及R9各自独立地为H、C1-3烷基、羟基、C1-3烷氧基、氰基、硝基或C3-6环烷基,或R8及R9连同其所附接的碳原子一起可以形成3-6元环;R10是C1-8烷基、C0-3亚烷基-C6-14芳基、C0-3亚烷基-C3-14杂芳基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、C1-6烷氧基、O-C0-3亚烷基-C6-14芳基、O-C0-3亚烷基-C3-14杂芳基、O-C0-3亚烷基-C3-14环烷基、O-C0-3亚烷基-C2-14杂环烷基、NH-C1-8烷基、N(C1-8烷基)2、NH-C0-3亚烷基-C6-14芳基、NH-C0-3亚烷基-C2-14杂芳基、NH-C0-3亚烷基-C3-14环烷基、NH-C0-3亚烷基-C2-14杂环烷基、卤基、氰基或C1-6亚烷基-胺;并且
R13是C1-6烷基、C1-6卤代烷基、C1-6亚烷基胺或C3-14环烷基,
或其药学上可接受的盐,其限制条件为
(1)当J是NR10时,M是N或CR13;
(2)当M是NR13时,J是N或CR10;
(3)当J是CR10时,M是N或NR13;并且
(4)当M是CR13时,J是N或NR10。
在一些实施例中,当Q是C=O,并且E1及E2各自为CR1时,则(1)R10是C1–3亚烷基芳基、C1–3亚烷基杂芳基、C0-3亚烷基-C3-8环烷基、C1-3亚烷基-C2-7杂环烷基或卤基;或(2)R13是C1-3卤代烷基或C3-5环烷基。在各个实施例中,J是NR10并且M是CR13。在一些实施例中,J是CR10并且M是NR13。在一些实施例中,J是N并且M是NR13。在各个实施例中,J是NR10并且M是N。
另外提供具有式(II)的结构的化合物
其中
E1及E2各自独立地为N或CR1;
J是N、NR10或CR10;
M是N、NR13或CR13;
R1独立地为H、羟基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、NH-C1-4烷基、N(C1-4烷基)2、氰基或卤基;
R2是卤基、C1-6烷基、C1-6卤代烷基、OR’、N(R’)2、C2-3烯基、C2-3炔基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、芳基、杂芳基、C0-3亚烷基-C6-14芳基或C0-3亚烷基-C2-14杂芳基,并且各R’独立地为H、C1-6烷基、C1-6卤代烷基、C3-14环烷基、C2-14杂环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基,或两个R’取代基连同其所附接的氮原子一起形成3-7元环;
R3是卤基、C1-3烷基、C1-2卤代烷基、C1-3烷氧基、C3-4环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基;
环A是单环4-7元环或双环、桥连、稠合或螺环6-11元环;
L是键、C1-6亚烷基、-O-C0-5亚烷基、-S-C0-5亚烷基或-NH-C0-5亚烷基,并且对于C2-6亚烷基、-O-C2-5亚烷基、-S-C2-5亚烷基及NH-C2-5亚烷基,该亚烷基基团的一个碳原子可任选地经O、S或NH替代;
R5及R6各自独立地为H、卤基、C1-6烷基、C2-6炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、C1-6亚烷基胺、C0-6亚烷基-酰胺、C0-3亚烷基-C(O)OH、C0-3亚烷基-C(O)OC1-4烷基、C1-6亚烷基-O-芳基、C0-3亚烷基-C(O)C1-4亚烷基-OH、环烷基、杂环烷基、芳基、杂芳基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、C0-3亚烷基-C6-14芳基、C0-3亚烷基-C2-14杂芳基或氰基,或R5及R6连同其所附接的原子一起形成4-6元环;
R7是H或C1-8烷基,或R7及R5连同其所附接的原子一起形成4-6元环;
Q是CR8R9、C=CR8R9、C=O、C=S或C=NR8;
R8及R9各自独立地为H、C1-3烷基、羟基、C1-3烷氧基、氰基、硝基或C3-6环烷基,或R8及R9连同其所附接的碳原子一起可以形成3-6元环;
R10是C1-8烷基、C0-3亚烷基-C6-14芳基、C0-3亚烷基-C3-14杂芳基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、C1-6烷氧基、O-C0-3亚烷基-C6-14芳基、O-C0-3亚烷基-C3-14杂芳基、O-C0-3亚烷基-C3-14环烷基、O-C0-3亚烷基-C2-14杂环烷基、NH-C1-8烷基、N(C1-8烷基)2、NH-C0-3亚烷基-C6-14芳基、NH-C0-3亚烷基-C2-14杂芳基、NH-C0-3亚烷基-C3-14环烷基、NH-C0-3亚烷基-C2-14杂环烷基、卤基、氰基或C1-6亚烷基-胺;
其限制条件为
(1)当J是NR10时,M是N或CR13;
(2)当M是NR13时,J是N或CR10;
(3)当J是CR10时,M是N或NR13;并且
(4)当M是CR13时,J是N或NR10。
在一些实施例中,当Q是C=O,并且E1及E2各自为CR1时,则(1)R10是C1–3亚烷基芳基、C1–3亚烷基杂芳基、C0-3亚烷基-C3-8环烷基、C1-3亚烷基-C2-7杂环烷基或卤基;或(2)R13是C1-3卤代烷基或C3-5环烷基。在各个实施例中,J是NR10并且M是CR13。在一些实施例中,J是CR10并且M是NR13。在一些实施例中,J是N并且M是NR13。在各个实施例中,J是NR10并且M是N。
另外提供具有式(III)或(III’)的化合物或其药学上可接受的盐:
其中E1及E2各自独立地为N或CR1;
R1独立地为H、羟基、C1-6烷基、C1-4卤代烷基、C1-4烷氧基、NH-C1-4烷基、N(C1-4烷基)2、氰基或卤基;
R2是卤基、C1-6烷基、C1-6卤代烷基、OR’、N(R’)2、C2-3烯基、C2-3炔基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、芳基、杂芳基、C0-3亚烷基-C6-14芳基或C0-3亚烷基-C2-14杂芳基,并且各R’独立地为H、C1-6烷基、C1-6卤代烷基、C3-14环烷基、C2-14杂环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基,或两个R’取代基连同其所附接的氮原子一起形成3-7元环;
R3是卤基、C1-3烷基、C1-2卤代烷基、C1-3烷氧基、C3-4环烷基、C2-14杂环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基;
环A是单环4-7元环或双环、桥连、稠合或螺环6-11元环;
L是键、C1-6亚烷基、-O-C0-5亚烷基、-S-C0-5亚烷基或-NH-C0-5亚烷基,并且对于C2-6亚烷基、-O-C2-5亚烷基、-S-C2-5亚烷基及NH-C2-5亚烷基,该亚烷基基团的一个碳原子可任选地经O、S或NH替代;
R4’是H、C1-8烷基、C2-8炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、环烷基、杂环烷基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、芳基、杂芳基、C0-3亚烷基-C6-14芳基,或选自
R5及R6各自独立地为H、卤基、C1-6烷基、C2-6炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、C1-6亚烷基胺、C0-6亚烷基-酰胺、C0-3亚烷基-C(O)OH、C0-3亚烷基-C(O)OC1-4烷基、C1-6亚烷基-O-芳基、C0-3亚烷基-C(O)C1-4亚烷基-OH、环烷基、杂环烷基、芳基、杂芳基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、C0-3亚烷基-C6-14芳基、C0-3亚烷基-C2-14杂芳基或氰基,或R5及R6连同其所附接的原子一起形成4-6元环;
R7是H或C1-8烷基,或R7及R5连同其所附接的原子一起形成4-6元环;
Q是CR8R9、C=CR8R9、C=O、C=S或C=NR8;
R8及R9各自独立地为H、C1–6烷基、羟基、C1–6烷氧基、氰基、硝基或C3–14环烷基,或R8及R9连同其所附接的碳原子一起可以形成3-6元环;
R10是C1-8烷基、C0-3亚烷基-C6-14芳基、C0-3亚烷基-C3-14杂芳基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、C1-6烷氧基、O-C0-3亚烷基-C6-14芳基、O-C0-3亚烷基-C3-14杂芳基、O-C0-3亚烷基-C3-14环烷基、O-C0-3亚烷基-C2-14杂环烷基、NH-C1-8烷基、N(C1-8烷基)2、NH-C0-3亚烷基-C6-14芳基、NH-C0-3亚烷基-C2-14杂芳基、NH-C0-3亚烷基-C3-14环烷基、NH-C0-3亚烷基-C2-14杂环烷基、卤基、氰基或C1-6亚烷基-胺。
另外提供具有式(III)或(III’)的化合物或其药学上可接受的盐:
其中
E1及E2各自独立地为N或CR1;
R1独立地为H、羟基、C1-6烷基、C1-4卤代烷基、C1-4烷氧基、NH-C1-4烷基、N(C1-4烷基)2、氰基或卤基;
R2是卤基、C1-6烷基、C1-6卤代烷基、OR’、N(R’)2、C2-3烯基、C2-3炔基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、芳基、杂芳基、C0-3亚烷基-C6-14芳基或C0-3亚烷基-C2-14杂芳基,并且各R’独立地为H、C1-6烷基、C1-6卤代烷基、C3-14环烷基、C2-14杂环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基,或两个R’取代基连同其所附接的氮原子一起形成3-7元环;
R3是卤基、C1-3烷基、C1-2卤代烷基、C1-3烷氧基、C3-4环烷基、C2-14杂环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基;
L是键、C1-6亚烷基、-O-C0-5亚烷基、-S-C0-5亚烷基或-NH-C0-5亚烷基,并且对于C2-6亚烷基、-O-C2-5亚烷基、-S-C2-5亚烷基及NH-C2-5亚烷基,该亚烷基基团的一个碳原子可任选地经O、S或NH替代;
R5及R6各自独立地为H、卤基、C1-6烷基、C2-6炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、C1-6亚烷基胺、C0-6亚烷基-酰胺、C0-3亚烷基-C(O)OH、C0-3亚烷基-C(O)OC1-4烷基、C1-6亚烷基-O-芳基、C0-3亚烷基-C(O)C1-4亚烷基-OH、环烷基、杂环烷基、芳基、杂芳基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、C0-3亚烷基-C6-14芳基、C0-3亚烷基-C2-14杂芳基或氰基,或R5及R6连同其所附接的原子一起形成4-6元环;
R7是H或C1-8烷基,或R7及R5连同其所附接的原子一起形成4-6元环;
Q是CR8R9、C=CR8R9、C=O、C=S或C=NR8;
R8及R9各自独立地为H、C1–6烷基、羟基、C1–6烷氧基、氰基、硝基或C3–14环烷基,或R8及R9连同其所附接的碳原子一起可以形成3-6元环;
R10是C1-8烷基、C0-3亚烷基-C6-14芳基、C0-3亚烷基-C3-14杂芳基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、C1-6烷氧基、O-C0-3亚烷基-C6-14芳基、O-C0-3亚烷基-C3-14杂芳基、O-C0-3亚烷基-C3-14环烷基、O-C0-3亚烷基-C2-14杂环烷基、NH-C1-8烷基、N(C1-8烷基)2、NH-C0-3亚烷基-C6-14芳基、NH-C0-3亚烷基-C2-14杂芳基、NH-C0-3亚烷基-C3-14环烷基、NH-C0-3亚烷基-C2-14杂环烷基、卤基、氰基或C1-6亚烷基-胺。
在一些实施例中,这些化合物具有式(III)的结构。在其他实施例中,这些化合物具有式(III’)的结构。
本文所披露的具有式(II)或(III)的化合物可以具有以下特征中的一个或多个。在一些实施例中,Q是C=O。在一些实施例中,Q是C=S。在一些实施例中,Q是C=NR8。在各个实施例中,R8是C1-2烷基。在一些实施例中,Q是CR8R9。在各个实施例中,Q是C=CR8R9。在一些实施例中,R8及R9连同其所附接的碳原子一起形成3–4元环。在一些实施例中,R8是C1-2烷基,并且R9是H。
还提供具有式(IV)或(IV’)的化合物或其药学上可接受的盐:
R1独立地为H、羟基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、NH-C1-6烷基、N(C1-6烷基)2、氰基或卤基;
R2是卤基、C1-6烷基、C1-6卤代烷基、OR’、N(R’)2、C2-3烯基、C2-3炔基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、芳基、杂芳基、C0-3亚烷基-C6-14芳基或C0-3亚烷基-C2-14杂芳基,并且各R’独立地为H、C1-6烷基、C1-6卤代烷基、C3-14环烷基、C2-14杂环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基,或两个R’取代基连同其所附接的氮原子一起形成3-7元环;
R3是卤基、C1-2卤代烷基、C1-3烷氧基、C3-4环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基;
环A是单环4-7元环或双环、桥连、稠合或螺环6-11元环;
L是键、C1-6亚烷基、-O-C0-5亚烷基、-S-C0-5亚烷基或-NH-C0-5亚烷基,并且对于C2-6亚烷基、-O-C2-5亚烷基、-S-C2-5亚烷基及NH-C2-5亚烷基,该亚烷基基团的一个碳原子可任选地经O、S或NH替代;
R4’是H、C1-8烷基、C2-8炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、环烷基、杂环烷基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、芳基、杂芳基、C0-3亚烷基-C6-14芳基,或选自
R5及R6各自独立地为H、卤基、C1-6烷基、C2-6炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、C1-6亚烷基胺、C0-6亚烷基-酰胺、C0-3亚烷基-C(O)OH、C0-3亚烷基-C(O)OC1-4烷基、C1-6亚烷基-O-芳基、C0-3亚烷基-C(O)C1-4亚烷基-OH、环烷基、杂环烷基、芳基、杂芳基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、C0-3亚烷基-C6-14芳基、C0-3亚烷基-C2-14杂芳基或氰基,或R5及R6连同其所附接的原子一起形成4-6元环;
R7是H或C1-8烷基,或R7及R5连同其所附接的原子一起形成4-6元环;
R8是H、C1-3烷基、羟基、C1-3烷氧基、卤基、氰基、硝基、C3–14环烷基或NR11R12;
R11及R12各自独立地为H、C1–8烷基或C3-14环烷基;并且
R10是C1-8烷基、C0-3亚烷基-C6-14芳基、C0-3亚烷基-C2-14杂芳基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、C1-6烷氧基、O-C0-3亚烷基-C6-14芳基、O-C0-3亚烷基-C2-14杂芳基、O-C0-3亚烷基-C3-14环烷基、O-C0-3亚烷基-C2-14杂环烷基、NH-C1-8烷基、N(C1-8烷基)2、NH-C0-3亚烷基-C6-14芳基、NH-C0-3亚烷基-C2-14杂芳基、N-C0-3亚烷基-C3-14环烷基、N-C0-3亚烷基-C2-14杂环烷基、卤基、氰基或C1-6亚烷基-胺;
在一些实施例中,本文所披露的化合物具有式(IV)的结构。在各个实施例中,本文所披露的化合物具有式(IV’)的结构。在一些实施例中,E1及E2各自为CR1,并且R8是羟基、卤基、硝基或C3-6环烷基。
在一些实施例中,R8是甲基。
另外提供具有式(IV)或(IV’)的结构的化合物:
其中
E1及E2各自独立地为CR1或N;
R1独立地为H、羟基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、NH-C1-6烷基、N(C1-6烷基)2、氰基或卤基;
R2是卤基、C1-6烷基、C1-6卤代烷基、OR’、N(R’)2、C2-3烯基、C2-3炔基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、芳基、杂芳基、C0-3亚烷基-C6-14芳基或C0-3亚烷基-C2-14杂芳基,并且各R’独立地为H、C1-6烷基、C1-6卤代烷基、C3-14环烷基、C2-14杂环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基,或两个R’取代基连同其所附接的氮原子一起形成3-7元环;
R3是卤基、C1-2卤代烷基、C1-3烷氧基、C3-14环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基;
环A是单环4-7元环或双环、桥连、稠合或螺环6-11元环;
L是键、C1-6亚烷基、-O-C0-5亚烷基、-S-C0-5亚烷基或-NH-C0-5亚烷基,并且对于C2-6亚烷基、-O-C2-5亚烷基、-S-C2-5亚烷基及NH-C2-5亚烷基,该亚烷基基团的一个碳原子可任选地经O、S或NH替代;
R5及R6各自独立地为H、卤基、C1-6烷基、C2-6炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、C1-6亚烷基胺、C0-6亚烷基-酰胺、C0-3亚烷基-C(O)OH、C0-3亚烷基-C(O)OC1-4烷基、C1-6亚烷基-O-芳基、C0-3亚烷基-C(O)C1-4亚烷基-OH、环烷基、杂环烷基、芳基、杂芳基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、C0-3亚烷基-C6-14芳基、C0-3亚烷基-C2-14杂芳基或氰基,或R5及R6连同其所附接的原子一起形成4-6元环;
R7是H或C1-8烷基,或R7及R5连同其所附接的原子一起形成4-6元环;
R8是H、C1-3烷基、羟基、C1-3烷氧基、卤基、氰基、硝基、C3-14环烷基或NR11R12;
R11及R12各自独立地为H、C1–8烷基或C3-15环烷基;并且
R10是C1-8烷基、C0-3亚烷基-C6-14芳基、C0-3亚烷基-C3-14杂芳基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、C1-6烷氧基、O-C0-3亚烷基-C6-14芳基、O-C0-3亚烷基-C3-14杂芳基、O-C0-3亚烷基-C3-14环烷基、O-C0-3亚烷基-C2-14杂环烷基、NH-C1-8烷基、N(C1-8烷基)2、NH-C0-3亚烷基-C6-14芳基、NH-C0-3亚烷基-C2-14杂芳基、NH-C0-3亚烷基-C3-14环烷基、NH-C0-3亚烷基-C2-14杂环烷基、卤基、氰基或C1-6亚烷基-胺;
或其药学上可接受的盐。
在一些实施例中,本文所披露的化合物具有式(IV)的结构。在各个实施例中,本文所披露的化合物具有式(IV’)的结构。在一些实施例中,E1及E2各自为CR1,并且R8是羟基、卤基、硝基或C3-6环烷基。
在一些实施例中,R8是甲基。
另外提供具有式(V)的结构的化合物或其药学上可接受的盐:
其中
E1及E2各自独立地为CR1或N;
R1独立地为H、羟基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、NH-C1-6烷基、N(C1-6烷基)2、氰基或卤基;
R2是卤基、C1-6烷基、C1-6卤代烷基、OR’、N(R’)2、C2-3烯基、C2-3炔基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、芳基、杂芳基、C0-3亚烷基-C6-14芳基或C0-3亚烷基-C2-14杂芳基,并且各R’独立地为H、C1-6烷基、C1-6卤代烷基、C3-14环烷基、C2-14杂环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基,或两个R’取代基连同其所附接的氮原子一起形成3-7元环;
R3是卤基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-14环烷基、C2-6烯基、C2-6炔基、芳基或杂芳基;
环A是单环4-7元环或双环、桥连、稠合或螺环6-11元环;
L是键、C1-6亚烷基、-O-C0-5亚烷基、-S-C0-5亚烷基或-NH-C0-5亚烷基,并且对于C2-6亚烷基、-O-C2-5亚烷基、-S-C2-5亚烷基及NH-C2-5亚烷基,该亚烷基基团的一个碳原子可任选地经O、S或NH替代;
R4’是H、C1-8烷基、C2-8炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、环烷基、杂环烷基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、芳基、杂芳基、C0-3亚烷基-C6-14芳基,或选自
R5及R6各自独立地为H、卤基、C1-6烷基、C2-6炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、C1-6亚烷基胺、C0-6亚烷基-酰胺、C0-3亚烷基-C(O)OH、C0-3亚烷基-C(O)OC1-4烷基、C1-6亚烷基-O-芳基、C0-3亚烷基-C(O)C1-4亚烷基-OH、环烷基、杂环烷基、芳基、杂芳基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、C0-3亚烷基-C6-14芳基、C0-3亚烷基-C2-14杂芳基或氰基,或R5及R6连同其所附接的原子一起形成4-6元环;
R7是H或C1-8烷基,或R7及R5连同其所附接的原子一起形成4-6元环;并且
R10是C1-8烷基、C0-3亚烷基-C6-14芳基、C0-3亚烷基-C3-14杂芳基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、C1-6烷氧基、O-C0-3亚烷基-C6-14芳基、O-C0-3亚烷基-C3-14杂芳基、O-C0-3亚烷基-C3-14环烷基、O-C0-3亚烷基-C2-14杂环烷基、NH-C1-8烷基、N(C1-8烷基)2、NH-C0-3亚烷基-C6-14芳基、NH-C0-3亚烷基-C2-14杂芳基、NH-C0-3亚烷基-C3-14环烷基、NH-C0-3亚烷基-C2-14杂环烷基、卤基、氰基或C1-6亚烷基-胺;或其药学上可接受的盐。
另外提供具有式(V)的结构的化合物:
其中
E1及E2各自独立地为CR1或N;
R1独立地为H、羟基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、NH-C1-6烷基、N(C1-6烷基)2、氰基或卤基;
R2是卤基、C1-6烷基、C1-6卤代烷基、OR’、N(R’)2、C2-3烯基、C2-3炔基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、芳基、杂芳基、C0-3亚烷基-C6-14芳基或C0-3亚烷基-C2-14杂芳基,并且各R’独立地为H、C1-6烷基、C1-6卤代烷基、C3-14环烷基、C2-14杂环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基,或两个R’取代基连同其所附接的氮原子一起形成3-7元环;
R3是卤基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C3-14环烷基、C2-8烯基、C2-8炔基、芳基或杂芳基;
环A是单环4-7元环或双环、桥连、稠合或螺环6-11元环;
L是键、C1-6亚烷基、-O-C0-5亚烷基、-S-C0-5亚烷基或-NH-C0-5亚烷基,并且对于C2-6亚烷基、-O-C2-5亚烷基、-S-C2-5亚烷基及NH-C2-5亚烷基,该亚烷基基团的一个碳原子可任选地经O、S或NH替代;
R5及R6各自独立地为H、卤基、C1-6烷基、C2-6炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、C1-6亚烷基胺、C0-6亚烷基-酰胺、C0-3亚烷基-C(O)OH、C0-3亚烷基-C(O)OC1-4烷基、C1-6亚烷基-O-芳基、C0-3亚烷基-C(O)C1-4亚烷基-OH、环烷基、杂环烷基、芳基、杂芳基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、C0-3亚烷基-C6-14芳基、C0-3亚烷基-C2-14杂芳基或氰基,或R5及R6连同其所附接的原子一起形成4-6元环;
R7是H或C1-8烷基,或R7及R5连同其所附接的原子一起形成4-6元环;并且
R10是C1-8烷基、C0-3亚烷基-C6-14芳基、C0-3亚烷基-C3-14杂芳基、C0-3亚烷基-C3-14环烷基、C0-3亚烷基-C2-14杂环烷基、C1-6烷氧基、O-C0-3亚烷基-C6-14芳基、O-C0-3亚烷基-C3-14杂芳基、O-C0-3亚烷基-C3-14环烷基、O-C0-3亚烷基-C2-14杂环烷基、NH-C1-8烷基、N(C1-8烷基)2、NH-C0-3亚烷基-C6-14芳基、NH-C0-3亚烷基-C2-14杂芳基、NH-C0-3亚烷基-C3-14环烷基、NH-C0-3亚烷基-C2-14杂环烷基、卤基、氰基或C1-6亚烷基-胺;或其药学上可接受的盐。
本文所披露的具有式(I)、(II)、(III)、(III’)、(IV)、(IV’)或(V)的化合物可以具有以下特征中的一个或多个。在一些实施例中,E1及E2中的每一个为CR1。在其他实施例中,E1是CR1并且E2是N。在一些实施例中,E1是N并且E2是CR1。在各个实施例中,E1及E2中的每一个为N。
本文所披露的具有式(II)、(III)、(III’)、(IV)、(IV’)或(V)的化合物可以具有以下特征中的一个或多个。在各个实施例中,R10是C1-6烷基、芳基、杂芳基、C3-14环烷基、C2-14杂环烷基、C1-6烷氧基、O-C0-6亚烷基-C6-14芳基、O-C0-6亚烷基-C2-14杂芳基、O-C0-6亚烷基-C3-14环烷基、O-C0-6亚烷基-C2-14杂环烷基、N-C1-8烷基、N(C1-8烷基)2、NH-C0-6亚烷基-C6-14芳基、NH-C0-6亚烷基-C2-14杂芳基、NH-C0-6亚烷基-C3-14环烷基或NH-C0-6亚烷基-C2-14杂环烷基。在各个实施例中,R10是C1-8烷基。在一些实施例中,R10是C0-3亚烷基-C6-14杂芳基。在一些实施例中,R10是C0-3亚烷基-C2-14杂芳基。在一些实施例中,R10是C0-3亚烷基-C3-14环烷基。在一些实施例中,R10是C0-3亚烷基-C2-14杂环烷基。在其他实施例中,R10是C0-6亚烷基胺。例如,R10可以为i-Pr、t-Bu、苯基、苄基、OCH3、Cl、环丙基、环丁基、环戊基、环己基、
本文所披露的具有式(I)、(II)、(III)、(III’)、(IV)、(IV’)或(V)的化合物可以具有以下特征中的一个或多个。在一些实施例中,R1是H。在一些实施例中,R1是F。在一些实施例中,R1是甲基。
本文所披露的具有式(I)、(II)、(III)、(III’)、(IV)、(IV’)或(V)的化合物可以具有以下特征中的一个或多个。在各个实施例中,R2是芳基。在一些实施例中,R2是杂芳基。在各个实施例中,R2是苯基、萘基、吡啶基、吲唑基、吲哚基、氮杂吲哚基、二氢吲哚基、苯并三唑基、苯并噁二唑基、咪唑基、噌啉基、咪唑并吡啶基、吡唑并吡啶基、喹啉基、异喹啉基、喹唑啉基、喹唑啉酮基、吲哚啉酮基、异吲哚啉酮基、四氢萘基、四氢喹啉基或四氢异喹啉基。例如,R2可以为Cl、Br、CF3、环丙基、环丁基、环戊基、环己基、哌啶、吡咯啶、氮杂环丁烷、OCH3、OCH2CH3、苯基、
本文所披露的具有式(I)、(II)、(III)、(III’)、(IV)、(IV’)或(V)的化合物可以具有以下特征中的一个或多个。在各个实施例中,R3是卤基。在各个实施例中,R3是Cl。在各个实施例中,R3是F。在一些实施例中,R3是C1-2烷基。在一些实施例中,R3是甲基。在一些实施例中,R3是C1-2卤代烷基。在各个实施例中,R3是CF3。
本文所披露的具有式(I)、(II)、(III)、(III’)、(IV)、(IV’)或(V)的化合物可以具有以下特征中的一个或多个。在一些实施例中,R4是在各个实施例中,R4是在一些实施例中,R4是在一些实施例中,R4是在一些实施例中,R4是在一些实施例中,R4是在一些实施例中,R4可以为
在各个实施例中,R4’是H、C1-8烷基、C2-8炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、C0-3亚烷基-C3-8环烷基、C0-3亚烷基-C2-7杂环烷基、C0-3亚烷基-C6-14芳基,或选自
在一些实施例中,环A包含哌啶基、哌嗪基、吡咯烷基或氮杂环丁烷基。在一些实施例中,环A包含哌啶基。
本文所披露的具有式(I)、(II)、(III)、(III’)、(IV)、(IV’)或(V)的化合物可以具有以下特征中的一个或多个。
在一些实施例中,L是键。
在一些实施例中,L是C1-2亚烷基。
在各个实施例中,L是O。在一些实施例中,L是S。
在各个实施例中,L是NH。
在一些实施例中,R5是H或卤基。
在一些实施例中,R5是H、Br、Cl、F、CN、CH3、CF3、CH2Br、CH2OH、CH2CH2OH、CH2OCH2苯基、环丙基、苯基、CH2苯基、CH2OCH3、CH2N(CH3)2、CH2N(CH2CH3)2、CH2CO2H、CH2CO2CH3、CH2NHC(O)CH3、CH2C(O)NHCH3、CH2OC(O)CH3或
在一些实施例中,R6是C1-6烷基、C1-6亚烷基-O-C1-6烷基、C1-6亚烷基-OH、C1-3卤代烷基、C1-6亚烷基-胺、C0-6亚烷基-酰胺、C0-1亚烷基C(O)OC1-3烷基、C0-1亚烷基-C2-14杂环烷基、C0-1亚烷基-C3-14环烷基或C0-3亚烷基-C6-14芳基。
在各个实施例中,R6是C0-6亚烷基-胺或C0-3亚烷基-酰胺并且为CH2NH2、CH(CH3)NH2、CH(CH3)2NH2、CH2CH2NH2、CH2CH2N(CH3)2、CH2NHCH3、C(O)NHCH3、C(O)N(CH3)2、CH2C(O)NH苯基、CH2NHC(O)CH3、CH2NHCH2CH2OH、CH2NHCH2CO2H、CH2NH(CH3)CH2CO2CH3、CH2NHCH2CH2OCH3、CH2NH(CH3)CH2CH2OCH3、CH2NH(CH3)CH2C(O)N(CH3)2、CH2NH(CH3)CH2C(O)NHCH3、CH2NMe2、CH2NH(CH3)CH2CH2OH、CH2NH(CH3)CH2CH2F、CH2N+(CH3)3、CH2NHCH2CHF2、CH2NHCH2CH3、
在各个实施例中,R6是苯基、环丙基、CH3、CF3、CH2CH3、CH2NH2、CH(CH3)NH2、CH(CH3)2NH2、CH2Cl、CH2Br、CH2OCH3、CH2O苯基、CH2OH、CO2H、CO2CH2CH3、CH2CO2H、CH2CH2NH2、CH2CH2OH、CH2CH2N(CH3)2、CH2NHCH3、C(O)NHCH3、C(O)N(CH3)2、CH2C(O)NH苯基、CH2CHF2、CH2F、CHF2、CH2NHC(O)CH3、CH2NHCH2CH2OH、CH2NHCH2CO2H、CH2NH(CH3)CH2CO2CH3、CH2NHCH2CH2OCH3、CH2NH(CH3)CH2CH2OCH3、CH2NH(CH3)CH2C(O)N(CH3)2、CH2NH(CH3)CH2C(O)NHCH3、CH2CH2CCH、CH2NMe2、CH2NH(CH3)CH2CH2OH、CH2NH(CH3)CH2CH2F、CH2N+(CH3)3、CH2NHCH2CHF2、CH2NHCH2CH3、
在一些实施例中,R5及R6中的每一个为H。
在一些实施例中,R7是H。
在一些实施例中,R7是甲基。
在各个实施例中,R7及R5一起为-CH2-或-C(O)CH2-。
本文所披露的化合物可以呈药学上可接受的盐形式。所提供的化合物可以配制为包含本文所披露的化合物及药学上可接受的赋形剂的药物配制品。
还提供一种抑制细胞中的KRAS G12C的方法,该方法包括使该细胞与本文所披露的化合物或组合物接触。另外提供一种治疗受试者的癌症的方法,该方法包括向该受试者施用治疗有效量的本文所披露的化合物或组合物。在一些实施例中,该癌症是肺癌、胰腺癌或结肠直肠癌。
具体实施方式
定义
缩写:在本文可以使用以下缩写:
除非另外指示,否则在描述本发明的上下文中(尤其是在申请专利范围的上下文中)术语“一个(种)”及“该(这些)”及类似参考物的使用应解释为涵盖单数及复数两者。除非本文另外指示,否则本文有关值的范围的陈述仅意欲用作个别地提及在该范围内的每一独立值的简写方法,且每一独立值是并入说明书中,就如同在本文个别地陈述该值一般。除非另外要求,否则本文所提供的任何及所有实例,或示例性语言(例如“诸如”)的使用旨在更好地说明本发明且并非对本发明范围的限制。本说明书中的语言均不应解释为指示任何非要求的要素为实践本发明必不可少的。
如本文所使用,术语“烷基”是指直链及支链C1-C8烃基基团,包括但不限于,甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、3-甲基丁基、2,2-二甲基丙基、正己基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,2-二甲基丁基、2,3-二甲基丁基、3,3-二甲基丁基及2-乙基丁基。术语Cm-n意指该烷基基团具有“m”至“n”个碳原子。术语“亚烷基”是指具有取代基的烷基基团。烷基(例如甲基)或亚烷基(例如-CH2-)基团可以经一个或多个,且典型地一个至三个独立地选自例如以下的基团取代:卤基、三氟甲基、三氟甲氧基、羟基、烷氧基、硝基、氰基、烷基氨基、C1-8烷基、C2-8烯基、C2-8炔基、-NC、氨基、-CO2H、-CO2C1-C8烷基、-OCOC1-C8烷基、C3-C10环烷基、C3-C10杂环烷基、C5-C10芳基及C5-C10杂芳基。术语“卤代烷基”特别地指烷基基团,其中该烷基基团的至少一个(例如,1至6个)或所有氢被卤基原子取代。
术语“烯基”及“炔基”分别指另外包括双键及三键的烷基基团。
如本文所使用,术语“卤基”是指氟、氯、溴及碘。术语“烷氧基”定义为-OR,其中R是烷基。
如本文所使用,术语“氨基”或“胺”可互换地指-NR2基团,其中各R是例如H或取代基。在一些实施例中,氨基基团进一步经取代以形成铵离子,例如NR3 +。铵部分特别地包括在“氨基”或“胺”的定义中。取代基可以例如为烷基、烷氧基、环烷基、杂环烷基、酰胺或羧酸酯。R基团可以进一步例如经一个或多个(例如一个至四个)选自以下的基团取代:卤基、氰基、烯基、炔基、烷基、环烷基、杂环烷基、芳基、杂芳基、脲、羰基、羧酸酯、胺及酰胺。“酰胺”或“酰氨基”基团可互换地指与胺或氨基基团类似但另外包括C(O)的基团,例如-C(O)NR2。一些预期的氨基或酰氨基(一些具有可选亚烷基,例如亚烷基-氨基或亚烷基-酰氨基)包括:CH2NH2、CH(CH3)NH2、CH(CH3)2NH2、CH2CH2NH2、CH2CH2N(CH3)2、CH2NHCH3、C(O)NHCH3、C(O)N(CH3)2、CH2C(O)NH苯基、CH2NHC(O)CH3、CH2NHCH2CH2OH、CH2NHCH2CO2H、CH2NH(CH3)CH2CO2CH3、CH2NHCH2CH2OCH3、CH2NH(CH3)CH2CH2OCH3、CH2NH(CH3)CH2C(O)N(CH3)2、CH2NH(CH3)CH2C(O)NHCH3、CH2CH2CCH、CH2NMe2、CH2NH(CH3)CH2CH2OH、CH2NH(CH3)CH2CH2F、CH2N+(CH3)3、CH2NHCH2CHF2、CH2NHCH2CH3、
如本文所使用,术语“芳基”是指C6-14单环或多环芳香族基团,优选地C6-10单环或双环芳香族基团,或C10-14多环芳香族基团。芳基基团的实例包括但不限于苯基、萘基、芴基、薁基、蒽基、菲基、芘基、联苯基及联三苯基。芳基还指C10-14双环及三环碳环,其中一个环是芳香族的且其他环是饱和的、部分不饱和的或芳香族的,例如二氢萘基、茚基、二氢茚基或四氢萘基(四氢化萘基)。除非另外指示,否则芳基基团可以未经取代或经一个或多个且特别是一个至四个独立地选自例如以下的基团取代:卤基、C1-8烷基、C2-8烯基、C2-8炔基、-CF3、-OCF3、-NO2、-CN、-NC、-OH、烷氧基、氨基、-CO2H、-CO2C1-C8烷基、-OCOC1-C8烷基、C3-C10环烷基、C3-C10杂环烷基、C5-C10芳基及C5-C10杂芳基。
如本文所使用,术语“环烷基”是指单环或多环非芳香族碳环,其中该多环可以为稠合的、桥接的或螺环的。碳环可以具有3至10个碳环原子。考虑到的碳环包括但不限于,环丙基、环丁基、环戊基、环己基、环庚基、环辛基及环壬基。
如本文所用,术语“杂环烷基”意指单环或多环(例如,二环)、饱和的或部分不饱和的环系统,其含有3个或更多个(例如,3至12、4至10、4至8或5至7个)总原子,其中1-5个(例如,1、2、3、4或5个)原子独立地选自氮、氧和硫。杂环烷基的非限制性实例包括氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、二氢吡咯基、吗啉基、硫代吗啉基、二氢吡啶基、氧杂环庚基、二氧杂环庚基、硫杂环庚基及二氮杂环庚基。
除非另外指示,否则环烷基或杂环烷基基团可以未经取代或经一个或多个且特别是一个至四个基团取代。一些预期的取代基包括卤基、C1-8烷基、C2-8烯基、C2-8炔基、-OCF3、-NO2、-CN、-NC、-OH、烷氧基、氨基、-CO2H、-CO2C1-C8烷基、-OCOC1-C8烷基、C3-C10环烷基、C3-C10杂环烷基、C5-C10芳基及C5-C10杂芳基。
如本文所使用,术语“杂芳基”是指含有一个至三个芳香族环且在芳香族环中含有一个至四个(例如1、2、3或4个)选自氮、氧及硫的杂原子的单环或多环系统(例如双环)。在某些实施例中,杂芳基基团具有5至20个、5至15个、5至10个或5至7个环原子。杂芳基还指C10-14双环及三环,其中一个环是芳香族的且其他环是饱和、部分不饱和或芳香族的。杂芳基的实例包括但不限于,呋喃基、咪唑基、异噻唑基、异噁唑基、噁二唑基、噁唑基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、噻二唑基、噻唑基、噻吩基、四唑基、三嗪基、三唑基、苯并呋喃基、苯并咪唑基、苯并异噁唑基、苯并吡喃基、苯并噻二唑基、苯并噻唑基、苯并噻吩基、苯并苯硫基、苯并三唑基、苯并噁唑基、呋喃并吡啶基、咪唑并吡啶基、咪唑并噻唑基、吲哚嗪基、吲哚基、吲唑基、异苯并呋喃基、异苯并噻吩基、异吲哚基、异喹啉基、异噻唑基、萘啶基、噁唑并吡啶基、酞嗪基、喋啶基、嘌呤基、吡啶并吡啶基、吡咯并吡啶基、喹啉基、喹喔啉基、喹唑啉基、噻二唑并嘧啶基及噻吩并吡啶基。除非另外指示,否则杂芳基基团可以未经取代或经一个或多个且特别是一个至四个或一个或两个取代基取代。考虑到的取代基包括卤基、C1-8烷基、C2-8烯基、C2-8炔基、-OCF3、-NO2、-CN、-NC、-OH、烷氧基、氨基、-CO2H、-CO2C1-C8烷基、-OCOC1-C8烷基、C3-C10环烷基、C3-C10杂环烷基、C5-C10芳基及C5-C10杂芳基。
本披露的化合物
本文提供具有式I-V之一的结构的KRAS抑制剂,这些结构将于下文更详细地论述。
本文所披露的化合物包括所有药学上可接受的同位素标记的化合物,其中本文所披露的化合物的一个或多个原子经具有相同原子数但原子质量或质量数不同于自然界通常发现的原子质量或质量数的原子替代。可以并入所披露的化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟、氯及碘的同位素,诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、36Cl、123I及125I。这些放射性标记的化合物可用于通过表征例如作用位点或方式,或与药理学上重要的作用位点的结合亲和力来帮助确定或测量化合物的有效性。本披露的某些同位素标记的化合物,例如并入放射性同位素的化合物可用于药物及/或底物组织分布研究中。放射性同位素氚,即3H,及碳-14,即14C因其易于并入及现有检测手段而特别适用于此目的。
经较重同位素,诸如氘,即2H取代可由于代谢稳定性较高,例如活体内半衰期增加或剂量要求降低而提供某些治疗益处,且因此在一些情况下是优选的。
用正电子发射同位素,诸如11C、18F、15O及13N取代可用于正电子发射断层扫描(PET)研究中以检查底物受体占有率。同位素标记的结构(I)化合物一般可以通过本领域技术人员已知的常规技术,或通过与以下所述制备及实例中所描述的方法类似的方法,使用适当同位素标记的试剂代替先前采用的未标记的试剂来制备。
本文所披露的同位素标记的化合物一般可以通过本领域技术人员已知的常规技术,或通过所附实例及方案中所描述的方法类似的方法,使用适当同位素标记的试剂代替先前采用的未标记的试剂来制备。
如本文所披露的某些化合物可以作为立体异构体(即,只有原子的空间排布不同的异构体)存在,包括光学异构体和构象异构体(或构象体)。本文所披露的化合物包括作为纯的个别立体异构体制剂和每一种的富集制剂的所有立体异构体、以及此类立体异构体的外消旋混合物以及可以根据本领域技术人员已知的方法分离的个别非对映异构体和对映异构体。另外,本文所披露的化合物包括这些化合物的所有互变异构形式。
某些本文所披露的化合物可以作为阻转异构体存在,其为在由于与分子其他部分的空间相互作用,围绕分子中单键的旋转被阻止或大大减慢时出现的构象立体异构体。本文所披露的化合物包括作为纯的个别阻转异构体制剂、每一种的富集制剂或者每一种的非特定混合物的所有阻转异构体。如果围绕单键的旋转势垒足够高,并且构象之间的互变足够缓慢,那么可以容许异构体种类的分离和分开。例如,基团诸如但不限于以下R10基团 可能展现受限的旋转。
本披露提供一种具有式(I)的结构的化合物
其中E1及E2各自独立地为N或CR1;R1独立地为H、羟基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、NH-C1-4烷基、N(C1-4烷基)2、氰基或卤基;R2是卤基、C1-6烷基、C1-6卤代烷基、OR’、N(R’)2、C2-3烯基、C2-3炔基、C0-3亚烷基-C3-8环烷基、C0-3亚烷基-C2-7杂环烷基、C0-3亚烷基芳基或C0-3亚烷基杂芳基,并且各R’独立地为H、C1-6烷基、C1-6卤代烷基、C3-4环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基,或两个R’取代基连同其所附接的氮原子一起形成3-7元环;R3是卤基、C1-3烷基、C1-2卤代烷基、C1-3烷氧基、C3-4环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基;R4是
环A是单环4-7元环或双环、桥连、稠合或螺环6-11元环;L是键、C1-6亚烷基、-O-C0-5亚烷基、-S-C0-5亚烷基或-NH-C0-5亚烷基,并且对于C2-6亚烷基、-O-C2-5亚烷基、-S-C2-5亚烷基及NH-C2-5亚烷基,该亚烷基基团的一个碳原子可任选地经O、S或NH替代;R4’是H、C1-8烷基、C2-8炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、C0-3亚烷基-C3-8环烷基、C0-3亚烷基-C2-7杂环烷基、C0-3亚烷基芳基,或选自 R5及R6各自独立地为H、卤基、C1-8烷基、C2-8炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、C1-6亚烷基胺、C0-6亚烷基酰胺、C0-3亚烷基-C(O)OH、C0-3亚烷基-C(O)OC1-4烷基、C1-6亚烷基-O-芳基、C0-3亚烷基-C(O)C1-4亚烷基-OH、C0-3亚烷基-C3-8环烷基、C0-3亚烷基-C2-7杂环烷基、C0-3亚烷基芳基或氰基,或R5及R6连同其所附接的原子一起形成4-6元环;并且R7是H或C1-3烷基,或R7及R5连同其所附接的原子一起形成4-6元环,或其药学上可接受的盐。
式I的化合物可以呈式(I-A)、(I-B)、(I-C)或(I-D)的形式:
本披露还提供一种具有式(II)的结构的化合物
其中E1及E2各自独立地为N或CR1;J是N、NR10或CR10;M是N、NR13或CR13;视需要是单键或双键以施用每个原子其正常化合价;R1独立地为H、羟基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、NH-C1-4烷基、N(C1-4烷基)2、氰基或卤基;R2是卤基、C1-6烷基、C1-6卤代烷基、OR’、N(R’)2、C2-3烯基、C2-3炔基、C0-3亚烷基-C3-8环烷基、C0-3亚烷基-C2-7杂环烷基、C0-3亚烷基芳基或C0-3亚烷基杂芳基,并且各R’独立地为H、C1-6烷基、C1-6卤代烷基、C3-4环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基,或两个R’取代基连同其所附接的氮原子一起形成3-7元环;R3是卤基、C1-3烷基、C1-2卤代烷基、C1-3烷氧基、C3-4环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基;R4是
环A是单环4-7元环或双环、桥连、稠合或螺环6-11元环;L是键、C1-6亚烷基、-O-C0-5亚烷基、-S-C0-5亚烷基或-NH-C0-5亚烷基,并且对于C2-6亚烷基、-O-C2-5亚烷基、-S-C2-5亚烷基及NH-C2-5亚烷基,该亚烷基基团的一个碳原子可任选地经O、S或NH替代;R4’是H、C1-8烷基、C2-8炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、C0-3亚烷基-C3-8环烷基、C0-3亚烷基-C2-7杂环烷基、C0-3亚烷基芳基,或选自 R5及R6各自独立地为H、卤基、C1-8烷基、C2-8炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、C1-6亚烷基胺、C0-6亚烷基酰胺、C0-3亚烷基-C(O)OH、C0-3亚烷基-C(O)OC1-4烷基、C1-6亚烷基-O-芳基、C0-3亚烷基-C(O)C1-4亚烷基-OH、C0-3亚烷基-C3-8环烷基、C0-3亚烷基-C2-7杂环烷基、C0-3亚烷基芳基或氰基,或R5及R6连同其所附接的原子一起形成4-6元环;R7是H或C1-3烷基,或R7及R5连同其所附接的原子一起形成4-6元环;Q是CR8R9、C=CR8R9、C=O、C=S或C=NR8;R8及R9各自独立地为H、C1-3烷基、羟基、C1-3烷氧基、氰基、硝基或C3-6环烷基,或R8及R9连同其所附接的碳原子一起可以形成3-6元环;R10是C1-8烷基、C0-3亚烷基芳基、C0-3亚烷基杂芳基、C0-3亚烷基-C3-8环烷基、C0-3亚烷基-C2-7杂环烷基、C1-6烷氧基、O-C0-3亚烷基芳基、O-C0-3亚烷基杂芳基、O-C0-3亚烷基-C3-8环烷基、O-C0-3亚烷基芳基、O-C0-3亚烷基-C2-7杂环烷基、NH-C1-8烷基、N(C1-8烷基)2、NH-C0-3亚烷基芳基、NH-C0-3亚烷基杂芳基、NH-C0-3亚烷基-C3-8环烷基、NH-C0-3亚烷基-C2-7杂环烷基、卤基、氰基或C1-6亚烷基胺;并且R13是C1-4烷基、C1-3卤代烷基、C1-3亚烷基胺及C3-5环烷基,或其药学上可接受的盐,其限制条件为(1)当J是NR10时,M是N或CR13;(2)当M是NR13时,J是N或CR10;(3)当J是CR10时,M是N或NR13;并且(4)当M是CR13时,J是N或NR10。
在各个实施例中,J是NR10并且M是CR13。在一些实施例中,J是CR10并且M是NR13。在一些实施例中,J是CR10且M是N。在各个实施例中,J是N且M是NR13。在一些实施例中,J是N且M是CR13。一些特别预期的R13包括甲基、乙基、丙基、异丙基、丁基、仲丁基、三氟甲基、CH2NH2及环丙基。在一些实施例中,J是NR10且M是N。在一些实施例中,当Q是C=O且E1及E2中的每一个为CR1时,则(1)R10是C1-3亚烷基芳基、C1-3亚烷基杂芳基、C0-3亚烷基-C3-8环烷基、C1-3亚烷基-C2-7杂环烷基或卤基;或(2)R13是C1-3卤代烷基或C3-5环烷基。
式II的化合物可以呈式(II-A)、(II-B)、(II-C)、(II-D)、(II-E)、(II-F)、(II-G)、(II-H)、(II-J)、(II-K)、(II-L)、(II-M)、(II-N)、(II-O)、(II-P)或(II-Q)的形式:
本披露亦提供一种具有式(III)或式(III’)的结构的化合物:
其中各R1独立地为H、羟基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、NH-C1-4烷基、N(C1-4烷基)2、氰基或卤基;R2是卤基、C1-6烷基、C1-6卤代烷基、OR’、N(R’)2、C2-3烯基、C2-3炔基、C0-3亚烷基-C3-8环烷基、C0-3亚烷基-C2-7杂环烷基、C0-3亚烷基芳基或C0-3亚烷基杂芳基,并且各R’独立地为H、C1-6烷基、C1-6卤代烷基、C3-4环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基,或两个R’取代基连同其所附接的氮原子一起形成3-7元环;R3是卤基、C1-3烷基、C1-2卤代烷基、C1-3烷氧基、C3-4环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基;R4是
环A是单环4-7元环或双环、桥连、稠合或螺环6-11元环;L是键、C1-6亚烷基、-O-C0-5亚烷基、-S-C0-5亚烷基或-NH-C0-5亚烷基,并且对于C2-6亚烷基、-O-C2-5亚烷基、-S-C2-5亚烷基及NH-C2-5亚烷基,该亚烷基基团的一个碳原子可任选地经O、S或NH替代;R4’是H、C1-8烷基、C2-8炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、C0-3亚烷基-C3-8环烷基、C0-3亚烷基-C2-7杂环烷基、C0-3亚烷基芳基,或选自 R5及R6各自独立地为H、卤基、C1-8烷基、C2-8炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、C1-6亚烷基胺、C0-6亚烷基酰胺、C0-3亚烷基-C(O)OH、C0-3亚烷基-C(O)OC1-4烷基、C1-6亚烷基-O-芳基、C0-3亚烷基-C(O)C1-4亚烷基-OH、C0-3亚烷基-C3-8环烷基、C0-3亚烷基-C2-7杂环烷基、C0-3亚烷基芳基或氰基,或R5及R6连同其所附接的原子一起形成4-6元环;R7是H或C1-3烷基,或R7及R5连同其所附接的原子一起形成4-6元环;Q是CR8R9、C=CR8R9、C=O、C=S或C=NR8;R8及R9各独立地为H、C1-3烷基、羟基、C1-3烷氧基、氰基、硝基或C3-6环烷基,或R8及R9连同其所附接的碳原子一起可以形成3-6元环;并且R10是C1-8烷基、C0-3亚烷基芳基、C0-3亚烷基杂芳基、C0-3亚烷基-C3-8环烷基、C0–3亚烷基-C2-7杂环烷基、C1-6烷氧基、C1-6烷氧基、O-C0-3亚烷基芳基、O-C0-3亚烷基杂芳基、O-C0-3亚烷基-C3-8环烷基、O-C0-3亚烷基-C2-7杂环烷基、NH-C1-8烷基、N(C1-8烷基)2、NH-C0-3亚烷基芳基、NH-C0-3亚烷基杂芳基、NH-C0-3亚烷基-C3-8环烷基、NH-C0-3亚烷基-C2-7杂环烷基、卤基、氰基或C1-6亚烷基胺,或其药学上可接受的盐。
式III的化合物可以呈式(III-A)、(III-B)、(III-C)或(III-D)的形式:
本披露亦提供一种具有式(IV)或式(IV’)的结构的化合物:
其中E1及E2各自独立地为CR1或N;R1独立地为H、羟基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、NH-C1-4烷基、N(C1-4烷基)2、氰基或卤基;R2是卤基、C1-6烷基、C1-6卤代烷基、OR’、N(R’)2、C2-3烯基、C2-3炔基、C0-3亚烷基-C3-8环烷基、C0-3亚烷基-C2-7杂环烷基、C0-3亚烷基芳基或C0-3亚烷基杂芳基,并且各R’独立地为H、C1-6烷基、C1-6卤代烷基、C3-4环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基,或两个R’取代基连同其所附接的氮原子一起形成3-7元环;R3是卤基、C1-2卤代烷基、C1-3烷氧基、C3-4环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基;R4是 环A是单环4-7元环或双环、桥连、稠合或螺环6-11元环;L是键、C1-6亚烷基、-O-C0-5亚烷基、-S-C0-5亚烷基或-NH-C0-5亚烷基,并且对于C2-6亚烷基、-O-C2-5亚烷基、-S-C2-5亚烷基及NH-C2-5亚烷基,该亚烷基基团的一个碳原子可任选地经O、S或NH替代;R4’是H、C1-8烷基、C2-8炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、C0-3亚烷基-C3-8环烷基、C0-3亚烷基-C2-7杂环烷基、C0-3亚烷基芳基,或选自 R5及R6各自独立地为H、卤基、C1-8烷基、C2-8炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、C1-6亚烷基胺、C0-6亚烷基酰胺、C0-3亚烷基-C(O)OH、C0-3亚烷基-C(O)OC1-4烷基、C1-6亚烷基-O-芳基、C0-3亚烷基-C(O)C1-4亚烷基-OH、C0-3亚烷基-C3-8环烷基、C0-3亚烷基-C2-7杂环烷基、C0-3亚烷基芳基或氰基,或R5及R6连同其所附接的原子一起形成4-6元环;R7是H或C1-3烷基,或R7及R5连同其所附接的原子一起形成4-6元环;R8是C1-3烷基、羟基、C1-3烷氧基、卤基、氰基、硝基、C3-6环烷基或NR11R12;R11及R12各自独立地为H、C1-4烷基或C3-5环烷基;并且R10是C1-8烷基、C0-3亚烷基芳基、C0-3亚烷基杂芳基、C0-3亚烷基-C3-8环烷基、C0-3亚烷基-C2-7杂环烷基、C1-6烷氧基、O-C0-3亚烷基芳基、O-C0-3亚烷基杂芳基、O-C0-3亚烷基-C3-8环烷基、O-C0-3亚烷基-C2-7杂环烷基、NH-C1-8烷基、N(C1-8烷基)2、NH-C0-3亚烷基芳基、NH-C0-3亚烷基杂芳基、NH-C0-3亚烷基-C3-8环烷基、NH-C0-3亚烷基-C2-7杂环烷基、卤基、氰基或C1-6亚烷基胺,或其药学上可接受的盐。在一些实施例中,E1及E2各自为CR1,并且R8是羟基、卤基、硝基或C3-6环烷基。在一些实施例中,R8是甲基。该化合物可以具有式(IV-A)、(IV’-A)、(IV-B)、(IV’-B)、(IV-C)、(IV’-C)、(IV-D)或(IV’-D)的结构:
本文还提供具有式(V)的结构的化合物:
其中E1及E2各自独立地为CR1或N;R1独立地为H、羟基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、NH-C1-4烷基、N(C1-4烷基)2、氰基或卤基;R2是卤基、C1-6烷基、C1-6卤代烷基、OR’、N(R’)2、C2-3烯基、C2-3炔基、C0-3亚烷基-C3-8环烷基、C0-3亚烷基-C2-7杂环烷基、C0-3亚烷基芳基或C0-3亚烷基杂芳基,并且各R’独立地为H、C1-6烷基、C1-6卤代烷基、C3-4环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基,或两个R’取代基连同其所附接的氮原子一起形成3-7元环;R3是卤基、C1-3烷基、C1-2卤代烷基、C1-3烷氧基、C3-4环烷基、C2-3烯基、C2-3炔基、芳基或杂芳基;R4是 环A是单环4-7元环或双环、桥连、稠合或螺环6-11元环;L是键、C1-6亚烷基、-O-C0-5亚烷基、-S-C0-5亚烷基或-NH-C0-5亚烷基,并且对于C2-6亚烷基、-O-C2-5亚烷基、-S-C2-5亚烷基及NH-C2-5亚烷基,该亚烷基基团的一个碳原子可任选地经O、S或NH替代;R4’是H、C1-8烷基、C2-8炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、C0-3亚烷基-C3-8环烷基、C0-3亚烷基-C2-7杂环烷基、C0-3亚烷基芳基,或选自 R5及R6各自独立地为H、卤基、C1-8烷基、C2-8炔基、C1-6亚烷基-O-C1-4烷基、C1-6亚烷基-OH、C1-6卤代烷基、C1-6亚烷基胺、C0-6亚烷基酰胺、C0-3亚烷基-C(O)OH、C0-3亚烷基-C(O)OC1-4烷基、C1-6亚烷基-O-芳基、C0-3亚烷基-C(O)C1-4亚烷基-OH、C0-3亚烷基-C3-8环烷基、C0-3亚烷基-C2-7杂环烷基、C0-3亚烷基芳基或氰基,或R5及R6连同其所附接的原子一起形成4-6元环;R7是H或C1-3烷基,或R7及R5连同其所附接的原子一起形成4-6元环;并且R10是C1-8烷基、C0-3亚烷基芳基、C0-3亚烷基杂芳基、C0-3亚烷基-C3-8环烷基、C0-3亚烷基-C2-7杂环烷基、C1-6烷氧基、O-C0-3亚烷基芳基、O-C0-3亚烷基杂芳基、O-C0-3亚烷基-C3-8环烷基、O-C0-3亚烷基-C2-7杂环烷基、NH-C1-8烷基、N-C1-8烷基、NH-C0-3亚烷基芳基、NH-C0-3亚烷基杂芳基、NH-C0-3亚烷基-C3-8环烷基、NH-C0-3亚烷基-C2-7杂环烷基、卤基、氰基或C1-6亚烷基胺;或其药学上可接受的盐。
对于具有式(II)、(III)及(III’)的化合物:在一些实施例中,Q是C=O。在一些实施例中,Q是C=S。在一些实施例中,Q是C=NR8。R8可以为C1-2烷基,例如甲基。
Q可以为CR8R9或C=CR8R9。R8及R9连同其所附接的碳原子一起可以形成3-4元环,例如环丙基环。在一些实施例中,R8是C1-2烷基(例如甲基),且R9是H。
对于具有式(II)、(III)、(III’)、(IV)、(IV’)及(V)的化合物:在各个实施例中,R10是C1-4烷基、芳基、杂芳基、C3-6环烷基、C3-6杂环烷基、C1-4烷氧基或芳氧基。在各个实施例中,R10是C1-8烷基、C1-5烷基或C1-3烷基。在各个实施例中,R10是C0-3亚烷基芳基、C0-1亚烷基芳基或苯基。在各个实施例中,R10是C0-3亚烷基杂芳基或C0-1亚烷基杂芳基,并且杂芳基可以为例如吡啶基。在各个实施例中,R10是C0-3亚烷基-C3-8环烷基、C0-1亚烷基-C3-8环烷基或C3-8环烷基,并且环烷基可以为例如环己基。在各个实施例中,R10是C0-3亚烷基-C3-8杂环烷基或C0-1亚烷基-C3-8杂环烷基。在各个实施例中,R10是C0-6亚烷基胺或C0-3亚烷基胺或胺。一些特别预期的R10包括i-Pr、t-Bu、苯基、苄基、OCH3、Cl、环丙基、环丁基、环戊基、环己基、
对于所有化合物:
R1可以为较小部分。例如,R1可以为H、C1–2烷基(例如甲基)、C1-2卤代烷基(例如CF3)或卤基(例如F)。一些特别预期的R1包括H、F、Me、Cl及CF3。
R2可以为C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C0-1亚烷基-C3-8环烷基、C3-6环烷基、C0-1亚烷基芳基(例如芳基)或C0-1亚烷基杂芳基(例如杂芳基)。一些特别预期的R2基团包括苯基、萘基、吡啶基、吲唑基、吲哚基、氮杂吲哚基、二氢吲哚基、苯并三唑基、苯并噁二唑基、咪唑基、噌啉基、咪唑并吡啶基、吡唑并吡啶基、喹啉基、异喹啉基、喹唑啉基、喹唑啉酮基、吲哚啉酮基、异吲哚啉酮基、四氢萘基、四氢喹啉基或四氢异喹啉基。一些其他特定的R2包括Cl、Br、CF3、环丙基、环丁基、环戊基、环己基、哌啶、吡咯啶、氮杂环丁烷、OCH3、OCH2CH3、苯基、
R3可以为卤基(例如Cl、F)、C1-2烷基(例如甲基)或C1-2卤代烷基(例如CF3)。一些特别预期的R3包括Cl、F、Me、CF3、OMe、Et、C=CH2及环丙基。
L是键、C1-6亚烷基、-O-C0-5亚烷基、-S-C0-5亚烷基或-NH-C0-5亚烷基,并且对于C2-6亚烷基、-O-C2-5亚烷基、-S-C2-5亚烷基及NH-C2-5亚烷基,该亚烷基基团的一个碳原子可任选地经O、S或NH替代。例如,在C2亚烷基基团上的碳被NH替代时,L可以是-CH2-NH-,或者在O-C3亚烷基基团上的碳被O替代时,是–O-CH2CH2-O-。具体考虑到了C3、C4、C5或C6亚烷基经O、S或NH取代的其他选择。在一些实施例中,L是C1-2亚烷基、O、S或NH。在一些实施例中,L是键。
环A是单环4-7元环或双环、桥连、稠合或螺环6-11元环。一些特别预期的环包括环丁基、环戊基、环己基、环庚基、吡咯烷基、哌啶基、氮杂环庚烷基、咪唑烷基、六氢嘧啶基、六氢哒嗪基、四氢呋喃基、四氢硫代呋喃基、氮杂环丁烷基、螺庚基、螺辛基、螺壬基、螺癸基、二氮杂双环癸基、二氮杂双环壬基、二氮杂双环辛基、二氮杂双环庚基、六氢吡咯并吡啶基、八氢吡咯并吡啶基及八氢吡咯并嘧啶基。在各个实施例中,环A可以包含哌啶基、哌嗪基、吡咯烷基或氮杂环丁烷基。在一些实施例中,环A包含哌啶基。环A可以进一步经一个至三个取代基取代。环A上的取代的一些非限制性实例包括一个至三个选自以下的取代基:烷基、烯基、炔基、羟基烷基、羧酸或酯、卤代烷基、烷基胺、C(O)NH2、氧代、卤基、氰基及异氰基。
R5及R6是本文所披露的KRAS抑制剂的丙烯酰胺部分上的取代基。在一些实施例中,R5及R6中的每一个为H。一些特别预期的R5取代基包括H、Br、Cl、F、CN、CH3、CF3、CH2Br、CH2OH、CH2CH2OH、CH2OCH2苯基、环丙基、苯基、CH2苯基、CH2OCH3、CH2N(CH3)2、CH2N(CH2CH3)2、CH2CO2H、CH2CO2CH3、CH2NHC(O)CH3、CH2C(O)NHCH3、CH2OC(O)CH3或
一些特别预期的R6取代基包括苯基、环丙基、CH3、CF3、CH2CH3、CH2NH2、CH(CH3)NH2、CH(CH3)2NH2、CH2Cl、CH2Br、CH2OCH3、CH2O苯基、CH2OH、CO2H、CO2CH2CH3、CH2CO2H、CH2CH2NH2、CH2CH2OH、CH2CH2N(CH3)2、CH2NHCH3、C(O)NHCH3、C(O)N(CH3)2、CH2C(O)NH苯基、CH2CHF2、CH2F、CHF2、CH2NHC(O)CH3、CH2NHCH2CH2OH、CH2NHCH2CO2H、CH2NH(CH3)CH2CO2CH3、CH2NHCH2CH2OCH3、CH2NH(CH3)CH2CH2OCH3、CH2NH(CH3)CH2C(O)N(CH3)2、CH2NH(CH3)CH2C(O)NHCH3、CH2CH2CCH、CH2NMe2、CH2NH(CH3)CH2CH2OH、CH2NH(CH3)CH2CH2F、CH2N+(CH3)3、CH2NHCH2CHF2、CH2NHCH2CH3、
R5及R6连同其所附接的原子一起可以形成4-6元环,例如5元或6元环。
在大多数实施例中,R7是H。然而,在一些实施例中,R7是甲基。在其他实施例中,R7及R5一起为-CH2-或-C(O)CH2-。
在另一个实施例中,本发明披露具有选自以下的结构的化合物:
在另一个实施例中,本发明披露具有选自以下的结构的化合物:
在另一个实施例中,本发明披露具有选自以下的结构的化合物:
在另一个实施例中,本发明披露具有选自以下的结构的化合物:
在另一个实施例中,本发明披露具有选自以下的结构的化合物:
在另一个实施例中,本发明披露具有选自以下的结构的化合物:
在另一个实施例中,本发明披露具有选自以下的结构的化合物:
在另一个实施例中,本发明披露具有选自以下的结构的化合物:
在另一个实施例中,本发明披露具有选自以下的结构的化合物:
在另一个实施例中,本发明披露具有选自以下的结构的化合物:
在另一个实施例中,本发明披露具有选自以下的结构的化合物:
在另一个实施例中,本发明披露具有选自以下的结构的化合物:
在另一个实施例中,本发明披露具有选自以下的结构的化合物:
在另一个实施例中,本发明披露具有选自以下的结构的化合物:
在另一个实施例中,本发明披露具有选自以下的结构的化合物:
在另一个实施例中,本发明披露具有选自以下的结构的化合物:
在另一个实施例中,本发明披露具有选自以下的结构的化合物:
在另一个实施例中,这些化合物可用作制备本申请案中的化合物的方法中的中间体。
在另一个实施例中,这些化合物可以呈药学上可接受的盐形式。
在另一个实施例中,这些化合物可以呈包含任一种或多种化合物及药学上可接受的赋形剂的药物配制品形式。
在另一个实施例中,这些化合物可以用于抑制细胞中的KRAS G12C的方法中,该方法包括使细胞与这些化合物中的任一种化合物或与该药物配制品接触。
在另一个实施例中,这些化合物可用于治疗受试者的癌症的方法中,该方法包括向受试者施用治疗有效量的这些化合物中的任一种或组合物。
在另一个实施例中,该癌症是肺癌、胰腺癌或结肠直肠癌。
在另一个实施例中,该癌症是肺癌。
在另一个实施例中,该癌症是胰腺癌。
在另一个实施例中,该癌症是结肠直肠癌。
在另一个实施例中,该方法进一步包括向有需要的患者施用治疗有效量的其他药学活性化合物。
在另一个实施例中,该其他药学活性化合物是卡非佐米(carfilzomib)。
在另一个实施例中,该其他药学活性化合物是阿糖胞苷(cytarabine)。
在另一个实施例中,本发明包含一种或多种化合物用于治疗受试者的癌症的用途。
在另一个实施例中,本发明包含一种或多种化合物用于制备供治疗癌症用的药物的用途。
在另一个实施例中,该癌症是血液恶性病。
在另一个实施例中,本发明包含一种或多种化合物用于治疗癌症的用途,其中该癌症是血液恶性病。
以下实例1-11是使用经典系统标记,其中第一个数字是指用于合成化合物的方法,第二个数字是标识数字,并且若存在第三个数字,则是指化合物在色谱分离程序中的洗脱次序。若不存在第三个数字,则该化合物是单一化合物或异构体混合物。实例12-53使用经典系统,其中第一个数字是标识数字,并且若存在第二个数字,则指化合物在色谱分离程序中的洗脱次序。若不存在第二个数字,则该化合物是单一化合物或异构体混合物。实例的顺序编号是间断的且出于格式考虑,有意地省略某些实例编号。“-”表示未发生变化,或在相关框中无条目。特别预期的化合物包括表1及表1(a)中所列的那些:
表1
表1(a)
合成所披露的化合物
本文所披露的化合物可以经由多种特定方法合成。下文概述具体合成途径和一般方案的实例意欲向普通合成化学家提供指导,他们将容易了解,可以视需要修改溶剂、浓度、试剂、保护基团、合成步骤的顺序、时间、温度等,这些完全在普通技术人员的技术和判断范围内。
方法1
方法1合成:本文所披露的具有式(I)的化合物可以如方法1中所略述来合成。在步骤1中,使适当芳香族或杂芳香族酸与卤化剂反应以形成卤化芳香族或杂芳香族酸。然后,在步骤2中使该酸与酰胺化剂反应以形成酰胺中间体。然后,在步骤3中使酰胺中间体与硫化剂反应以形成硫代酰胺中间体。接下来,在步骤4中使硫代酰胺中间体与氧化剂反应以形成所示噻唑环。然后,在步骤5中,使用活化剂将噻唑的胺转化成离去基团。然后,如步骤6中所示,用经保护的R4基团替代离去基团。然后,在步骤7中通过使适当R2(经保护)试剂与噻唑中间体上的X卤化物发生交叉偶联反应,引入R2部分。然后,在步骤8中,取决于所用保护基团,在适当条件下使R4基团脱保护,然后使R4基团酰基化以引入如所示的丙烯酰胺部分,并且最后,使R2脱保护。适当保护基团及脱保护试剂是本领域技术人员已知的,例如,如Greene’s Protective Groups in Organic Synthesis[Greene的有机合成中的保护基团]中所论述。
考虑到的卤化剂包括但不限于,氯、溴、N-氯代琥珀酰亚胺及N-溴代琥珀酰亚胺,任选地存在催化剂,例如铁或铝存在下。普通合成化学家将容易理解,可以使用其他卤化剂和催化剂。
考虑到的酰胺化剂包括但不限于,N,N’-二异丙基碳化二亚胺、N-(3-二甲氨基丙基)-N’-乙基碳化二亚胺、六氟磷酸苯并三唑-1-基-氧基三吡啶基膦鎓盐、六氟磷酸O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓盐、亚硫酰氯、氯甲酸异丁酯、氰基膦酸二乙酯、羰基二咪唑及聚膦酸酐。普通合成化学家将容易理解,可以使用其他酰胺化剂。
考虑到的硫化剂包括但不限于硫、五硫化二磷和劳森试剂。普通合成化学家将容易理解,可以使用其他硫化剂。
考虑到的氧化剂包括但不限于过氧化氢、二乙酸碘苯、叔丁基过氧化氢、N-溴代琥珀酰亚胺和过氧二硫酸铵。普通合成化学家将容易理解,可以使用其他氧化剂。
考虑到的激活剂包括但不限于亚硝酸钠和亚硝酸叔丁酯。普通合成化学家将容易理解,可以使用其他激活剂。
考虑到的交叉偶联反应包括但不限于Suzuki偶联、Negishi偶联、Hiyama偶联、Kumada偶联和Stille偶联。普通化学家将容易理解,如方法1中所示的偶联可以在多种条件下进行。
方法2
方法2合成:方法2提供用于形成本文所披露的具有式(I)的化合物的替代性方法。在步骤1中卤化后,在步骤2通过在偶联反应中与酸反应引入经保护的R4基团。在步骤3中,使用硫化剂将氧代基团转变成硫。接着,在步骤4中,在氧化剂存在下,形成噻唑环。其余步骤5–8与以上描述的方法1中的步骤7及8类似。
方法3
方法3合成:方法3提供用于形成本文所披露的具有式(I)的化合物的替代性方法。异噻唑中间体的R4基团在步骤1中脱保护及酰基化以引入丙烯酰胺部分。然后,在步骤2中通过使适当R2(经保护)试剂与异噻唑中间体上的X卤化物发生交叉偶联反应,引入R2部分。最后,在步骤3中使R2基团脱保护。
方法4
方法4合成:方法4提供用于形成本文所披露的具有式(I)的化合物的替代性方法。在如步骤1中所描绘,用经保护的R4基团取代异噻唑中间体上的离去基团后,在步骤2中使R4基团中间体脱保护并酰基化,以引入丙烯酰胺部分。与方法1中相同,在步骤3中通过交叉偶联反应引入R2部分,且在步骤4中使R2基团脱保护。
方法5
方法5合成:方法5提供用于形成本文所披露的具有式(I)的化合物的替代性方法。在此替代方法中,先通过与步骤1中所示的芳香族或杂芳香族酰胺中间体上的X卤化物交叉偶联来引入R2部分。然后,在步骤2中使酰胺中间体与硫化剂反应以形成硫代酰胺中间体。在步骤3中,使此中间体氧化得到异噻唑环。然后,在步骤4中将氨基基团转化成离去基团且随后在步骤5中,用经保护的R4基团取代。最后,在步骤6中,使R4基团脱保护且与酰基化剂反应,且然后使R2基团脱保护。
方法6
方法6合成:方法6提供用于形成本文所披露的具有式(I)的化合物的替代性方法。在此替代方法中,使异噻唑中间体与金属化剂反应以活化X卤化物。然后,通过使活化的中间体与适当R2(经保护)试剂反应来引入R2基团。在最后一个步骤中,使R4基团脱保护并酰基化以引入丙烯酰胺部分。
所预期的金属化剂包括但不限于,双(频哪醇根基)二硼、镁、锌、六甲基二锡烷及正丁基锂。有普通技能的合成化学家将易于了解,亦可使用其他金属化剂及催化剂。
方法7
方法7合成:方法7提供用于形成本文所披露的具有式(I)的化合物的替代性方法。先通过与步骤1中所示的芳香族或杂芳香族酸中间体上的X卤化物交叉偶联来引入R2部分。然后,在步骤2中使该酸部分与适当R4(经保护)试剂在酰胺化剂存在下反应。然后,在步骤3中,使用硫化剂将酸衍生物的羰基基团转化成硫羰基基团。然后,在步骤4中使硫代酸衍生物与氧化剂反应以形成异噻唑中间体。最后,使R4基团脱保护并酰基化以引入丙烯酰胺部分,且使R2基团脱保护。
方法8
方法8合成:本文所披露的具有式(II)的化合物可以如方法8中所略述来合成。在步骤1中,使适当芳香族或杂芳香族酸与酰胺化剂反应以形成主要酰胺中间体。然后,使该酰胺与异氰酸酯形成试剂及R10-经取代胺反应以形成脲中间体。考虑到的异氰酸酯形成剂包括草酰氯、亚硫酰氯和三氯氧磷。然后,在步骤3中使脲中间体与环化剂反应以形成所示的喹唑啉二酮环。考虑到的环化剂包括但不限于碱,例如六甲基二硅基胺基钾、叔丁醇钾、氢化钠和磷腈碱。然后,在步骤4中通过使适当R2(经保护)试剂与喹唑啉二酮中间体上的X卤化物发生交叉偶联反应,引入R2部分。然后,在步骤5中使用活化剂将喹唑啉二酮的氧代基基团转化成离去基团。考虑到的激活剂包括但不限于亚硫酰氯、三氟甲磺酸酐、三氯氧磷和五氯化磷。然后,如步骤6中所示,用经保护的R4基团替代离去基团以形成经取代的喹唑啉酮。步骤7-9中所示的其余脱保护-酰基化-脱保护工序类似于方法1中的步骤8。
方法9
方法9合成:方法9提供用于形成本文所披露的具有式(II)的化合物的替代性方法。在步骤1中,将喹唑啉二酮的氧代基基团转化成离去基团。步骤2涉及引入R4(经保护)基团、R4基团脱保护及游离R4基团的酰基化。在步骤3中通过使适当R2(经保护)试剂与喹唑啉二酮中间体上的X卤化物发生交叉偶联反应,引入R2基团。最后,使R2基团脱保护。
方法10
方法10合成:本文所披露的具有式(V)的化合物可以如方法10中所略述来合成。如步骤1中所示,使适当酸酐与肼反应以形成酞嗪二酮环。在步骤2中通过使适当R2试剂与喹唑啉二酮中间体上的X卤化物发生交叉偶联反应,引入R2部分。然后,在步骤3中,保护R2基团。使酞嗪二酮环卤化两次。考虑到的卤化剂包括亚硫酰氯、三氯氧磷和草酰氯。然后,如步骤5中所示,用经保护的R4基团替代一个卤素基团以形成经取代的酞嗪环。然后,在步骤6及7中,取决于所用保护基团,在适当条件下使R4基团脱保护,且然后,使游离R4基团酰基化以引入丙烯酰胺部分。在步骤8中,使R2脱保护。最后,在步骤9中通过使适当R10试剂与酞嗪中间体上的X卤化物发生交叉偶联反应,引入R10部分。
方法11
方法11合成:方法11提供用于形成本文所披露的具有式(II)的化合物的替代性方法。在步骤1中,将喹唑啉二酮的氧代基基团转化成离去基团。在步骤2中,引入R4(经保护)基团。在步骤3中通过使适当R2(经保护)试剂与喹唑啉二酮中间体上的X卤化物发生交叉偶联反应,引入R2基团。最后,在步骤4及5中,使R4基团脱保护且随后酰基化。
药物组合物、给药及施用途径
本文还提供了药物组合物,这些药物组合物包含如本文所披露的化合物以及药学上可接受的赋形剂,例如稀释剂或载体。适用于本发明中的化合物及药物组合物包括可以按有效量施用该化合物以实现其预定目的的那些化合物及药物组合物。以下将更详细地描述该化合物的施用。
适合药物配制品可以由技术人员根据施用途径及所需剂量决定。参见例如,Remington’s Pharmaceutical Sciences[雷明顿药物科学],1435-712(第18版,宾夕法尼亚州伊斯顿市马克出版公司(Mack Publishing Co),1990)。配制品可以影响所施用的药剂的物理状态、稳定性、或体内释放速率及活体内清除速率。取决于施用途径,可以根据体重、体表面积或器官大小来计算适合剂量。本领域普通技术人员在不进行过度实验的情况下,尤其根据本文所披露的剂量信息和测定以及可通过动物或人类临床试验获得的药物代谢动力学数据,以常规方式进行决定适当治疗剂量所需计算的进一步精化。
短语“药学上可接受的”或“药理学上可接受的”是指在施用动物或人类时不产生不良反应、过敏反应或其他不利反应的分子实体和组合物。如本文所使用,“药学上可接受”包括任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。此类赋形剂用于药学活性物质的使用是本领域所熟知的。除了任何常规介质或剂与治疗组合物不相容的情况外,其在治疗组合物中的使用是有所考虑的。还可以将补充性活性成分掺入组合物中。在示例性实施例中,配制品可以包含玉米糖浆固体、高油酸红花油、椰子油、大豆油、L-亮氨酸、磷酸三钙、L-酪氨酸、L-脯氨酸、乙酸L-赖氨酸、DATEM(乳化剂)、L-谷氨酰胺、L-缬氨酸、磷酸氢二钾、L-异亮氨酸、L-精氨酸、L-丙氨酸、甘氨酸、L-天冬酰胺一水合物、L-丝氨酸、柠檬酸钾、L-苏氨酸、柠檬酸钠、氯化镁、L-组氨酸、L-甲硫氨酸、抗坏血酸、碳酸钙、L-谷氨酸、L-胱氨酸二盐酸盐、L-色氨酸、L-天冬氨酸、氯化胆碱、牛磺酸、m-肌醇、硫酸亚铁、抗坏血酸棕榈酸酯、硫酸锌、L-肉碱、α-生育酚乙酸酯、氯化钠、烟酰胺、混合生育酚、泛酸钙、硫酸酮、氯化硫胺素盐酸盐、维生素A棕榈酸酯、硫酸锰、核黄素、盐酸吡哆辛、叶酸、β-胡萝卜素、碘化钾、叶绿醌、生物素、硒酸钠、氯化铬、钼酸钠、维生素D3和氰钴胺。
化合物可以作为药学上可接受的盐存在于药物组合物中。如本文所使用,“药学上可接受的盐”包括例如碱加成盐和酸加成盐。
药学上可接受的碱加成盐可以用金属或胺(例如碱金属和碱土金属或有机胺)来形成。化合物的药学上可接受的盐也可以用药学上可接受的阳离子来制备。适合的药学上可接受的阳离子是本领域技术人员熟知的且包括碱金属、碱土金属、铵及四级铵阳离子。碳酸盐或碳酸氢盐也有可能。用作阳离子的金属的实例是钠、钾、镁、铵、钙或三价铁等。适合的胺的实例包括异丙胺、三甲胺、组氨酸、N,N’-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、二环己胺、乙二胺、N-甲基葡糖胺和普鲁卡因。
药学上可接受的酸加成盐包括无机酸盐或有机酸盐。适合的酸盐的实例包括盐酸盐、甲酸盐、乙酸盐、柠檬酸盐、水杨酸盐、硝酸盐、磷酸盐。其他适合的药学上可接受的盐是本领域技术人员所熟知的并且包括例如甲酸、乙酸、柠檬酸、草酸、酒石酸或扁桃酸、盐酸、氢溴酸、硫酸或磷酸;与有机羧酸、磺酸、磺酸基酸或磷酸基酸或N-取代的氨基磺酸,例如乙酸、三氟乙酸(TFA)、丙酸、乙醇酸、琥珀酸、马来酸、羟基马来酸、甲基马来酸、富马酸、苹果酸、酒石酸、乳酸、草酸、葡糖酸、葡糖二酸、葡糖醛酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、水杨酸、4-氨基水杨酸、2-苯氧基苯甲酸、2-乙酰氧基苯甲酸、扑酸、烟酸或异烟酸的盐;以及与氨基酸,例如在自然界中参与蛋白质合成所涉及的20种α氨基酸,例如谷氨酸或天冬氨酸,以及与苯乙酸、甲磺酸、乙磺酸、2-羟基乙磺酸、乙烷1,2-二磺酸、苯磺酸、4-甲基苯磺酸、萘2-磺酸、萘1,5-二磺酸、2-磷酸甘油酸或3-磷酸甘油酸、葡萄糖6-磷酸、N-环己基氨基磺酸(用于环己氨磺酸盐的形成),或与其他酸性有机化合物,例如抗坏血酸的盐。
含有本文所披露的化合物的药物组合物能以常规方式来制造,例如通过常规混合、溶解、造粒、糖衣丸制备、磨细、乳化、囊封、捕集或冻干工艺。适当的配制品取决于所选的施用途径。
对于口服施用,可以通过将本文所披露的化合物与本领域熟知的药学上可接受的赋形剂(例如载体)组合来容易地配制适合的组合物。此类赋形剂和载体使得能将本发明化合物配制为片剂、丸剂、糖衣丸、胶囊、液体、凝胶、糖浆、浆液、悬浮液等,以供要治疗的患者口服摄食。用于口服使用的药物制剂可以通过以下方式来获得:向如本文所披露的化合物添加固体赋形剂,任选地研磨所得混合物,并且在添加适合的辅助剂后(如果需要)加工颗粒混合物,获得片剂或糖衣丸核心。适合赋形剂包括例如填充剂及纤维素制剂。必要时,可以添加崩解剂。用于各种类型的配制品的药学上可接受的成分是熟知的,并且可以是例如用于各种配制品类型的粘合剂(例如,天然或合成聚合物)、润滑剂、表面活性剂、甜味和矫味剂、包衣材料、防腐剂、染料、增稠剂、佐剂、抗微生物剂、抗氧化剂和载体。
在口服施用治疗有效量的本文所披露的化合物时,组合物典型地呈固体(例如,片剂、胶囊、丸剂、粉末或糖锭)或液体配制品(例如,水性悬浮液、溶液、酏剂或糖浆)的形式。
在以片剂形式施用时,组合物可以另外含有功能性固体和/或固体载体,例如明胶或佐剂。片剂、胶囊和粉末可以含有约1%至约95%化合物,并且优选地约15%至约90%化合物。
在以液体或悬浮液形式施用时,可以添加功能性液体和/或液体载体,例如水、石油或动物或植物来源的油。组合物的液体形式可以进一步含有生理盐水溶液、糖醇溶液、右旋糖或其他糖溶液或二醇。在以液体或悬浮液形式施用时,组合物可以含有以重量计约0.5%至约90%的本文所披露的化合物,并且优选地约1%至约50%的本文所披露的化合物。在考虑到的一个实施例中,液体载体是非水性的或基本上非水性的。对于以液体形式施用,组合物可以作为快速溶解的固体配制品来供应,用于在即将施用前溶解或悬浮。
在通过静脉内、经皮肤或皮下注射施用治疗有效量的本文所披露的化合物时,组合物呈无热原、肠胃外可接受的水溶液的形式。此类肠胃外可接受的溶液的制备应充分考虑pH、等渗性、稳定性等,是在本领域技术范围的。除了本文所披露的化合物以外,用于静脉内、经皮肤或皮下注射的优选组合物典型地含有等渗媒剂。此类组合物可以经制备用于作为与表面活性剂(例如羟丙基纤维素)适当混合的游离碱或药理学上可接受的盐于水中的溶液来施用。还可以在甘油、液体聚乙二醇及其混合物中以及在油中制备分散液。在普通的储存和使用条件下,这些制剂可以任选地含有防腐剂以防止微生物生长。
可注射组合物可以包括无菌水性溶液、悬浮液或分散液,以及用于临时制备无菌可注射溶液、悬浮液或分散液的无菌粉末。在所有实施例中,该形式必须是无菌的,并且流动性必须达到存在易可注射性的程度。其必须在制造和储存条件下稳定,并且必须通过任选地包括防腐剂来抵抗微生物(例如细菌和真菌)的污染作用。载体可以是溶剂或分散介质,其含有例如水、乙醇、多元醇(例如,甘油、丙二醇和液体聚乙二醇等)、其适合的混合物以及植物油。在考虑到的一个实施例中,载体是非水性的或基本上非水性的。适当流动性可以例如通过以下方式来维持:通过使用包衣,例如卵磷脂;在分散液的实施例中通过维持化合物的所需粒径;以及通过使用表面活性剂。对微生物作用的防止可以通过各种抗细菌剂和抗真菌剂来实现,例如对羟苯甲酸酯、氯丁醇、酚、山梨酸、硫柳汞等。在许多实施例中,包括等渗剂(例如,糖或氯化钠)将是优选的。可注射组合物的延长吸收可以通过在组合物中使用吸收延迟剂(例如,单硬脂酸铝和明胶)来实现。
无菌可注射溶液通过以下方式来制备:将活性化合物以所需量掺入视需要含有上文所列举的各种其他成分的适当溶剂中,之后过滤灭菌。通常,分散液通过以下方式来制备:将各种经灭菌活性成分掺入无菌媒剂中,该媒剂含有基础分散介质和来自上文所列举的那些的其他所需成分。在用于制备无菌可注射溶液的无菌粉末的实施例中,优选的制备方法是真空干燥和冷冻干燥技术,其产生活性成分加来自其预先经无菌过滤的溶液的任何所需的其他成分的粉末。
还可以制备缓慢释放或持续释放配制品,以实现在胃肠道中与体液接触的活性化合物的受控释放,并且在血浆中提供基本上恒定且有效的活性化合物水平。例如,可以通过溶解、扩散和离子交换中的一种或多种来控制释放。另外,缓慢释放方法可以通过胃肠道内的可饱和或限制途径促进吸收。例如,出于这个目的,可以将化合物包埋于生物可降解聚合物、水溶性聚合物或二者的混合物以及任选地适合的表面活性剂的聚合物基质中。在这种情况下,包埋可以意指在聚合物基质中掺入微粒。还通过经由已知的分散液或乳液包衣技术囊封经分散的微粒或经乳化的微滴来获得受控释放配制品。
对于通过吸入施用,本发明的化合物便捷地以气溶胶喷雾呈递的形式从加压包装或雾化器使用适合的推进剂来递送。在加压气溶胶的实施例中,可以通过提供阀来确定剂量单位,以递送经计量的量。用于吸入器或吹入器的例如明胶的胶囊和药筒可以经配制含有化合物与适合的粉末基质(例如乳糖或淀粉)的粉末混合物。
本文所披露的化合物可以经配制用于通过注射(例如,通过推注或连续输注)肠胃外施用。注射用配制品能以单位剂型(例如,于安瓿中或于多剂量容器中)呈现,并添加有防腐剂。组合物可以采取诸如以下等形式:于油性或水性媒剂中的悬浮液、溶液或乳液,并且可以含有配制剂,例如悬浮剂、稳定剂和/或分散剂。
用于肠胃外施用的药物配制品包括呈水溶性形式的化合物的水溶液。另外,可以将化合物的悬浮液制备为适当的油性注射悬浮液。适合的亲脂性溶剂或媒剂包括脂肪油或合成脂肪酸酯。水性注射悬浮液可以含有提高悬浮液粘度的物质。任选地,悬浮液还可以含有适合的稳定剂或提高化合物的溶解度并允许制备高度浓缩的溶液的剂。可替代地,本发明组合物可以呈粉末形式以供在使用前用适合的媒剂(例如,无菌无热原水)构造。
本文所披露的化合物还可以配制于直肠组合物中,例如栓剂或滞留型灌肠剂(例如,含有常规栓剂基质)。除了先前所述的配制品以外,还可以将化合物配制为长效制剂。此类长效配制品可以通过植入(例如,皮下或肌内)或通过肌内注射来施用。因此,例如,化合物可以用适合的聚合或疏水材料(例如,作为可接受的油中的乳液)或离子交换树脂,或作为微溶衍生物(例如,作为微溶盐)来配制。
特别地,本文所披露的化合物能以含有赋形剂(例如淀粉或乳糖)的片剂的形式,或以单独的或与赋形剂混合的胶囊或珠囊(ovule),或以含有矫味剂或着色剂的酏剂或悬浮液的形式,口服、经颊或舌下施用。此类液体制剂可以用药学上可接受的添加剂(例如悬浮剂)来制备。还可以肠胃外注射化合物,例如静脉内、肌内、皮下或冠状动脉内。对于肠胃外施用,化合物最佳地以无菌水溶液的形式来使用,其可以含有其他物质,例如盐或糖醇(例如甘露醇)或葡萄糖,以使溶液与血液等渗。
对于兽用,本文所披露的化合物根据正规兽医实践作为适合地可接受的配制品来施用。兽医可以容易地确定对于特定动物最合适的给药方案和施用途径。
在一些实施例中,可以将用于使用如本文所披露的化合物(单独的或与传统地用于治疗这种疾病的另一种药剂或干预组合的)治疗KRAS相关障碍的所有所需组分包装至剂盒中。具体地,本发明提供了用于疾病的治疗干预的剂盒,该剂盒包含经包装的成套药物,包括本文所披露的化合物以及用于制备所述药物的可递送形式的缓冲液和其他组分;和/或用于递送此类药物的装置;和/或用于与本文所披露的化合物的组合疗法的任何药剂;和/或与药物一起包装的疾病治疗说明书。说明书可以固定于任何可触摸介质中,例如印刷纸张、或计算机可读取的磁性或光学介质、或参考远程计算机数据源的说明,例如可通过互联网访问的万维网网页。
“治疗有效量”意指有效治疗或预防所治疗受试者的已有症状的发展或减轻已有症状的量。尤其根据本文所提供的详细披露,有效量的确定完全在本领域技术人员的能力范围内。通常,“治疗有效剂量”是指导致实现所需效果的化合物的量。例如,在一个优选实施例中,本文所披露的化合物的治疗有效量使KRAS活性相较于对照组降低至少5%、至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%或至少90%。
所施用的化合物的量可以取决于所治疗的受试者、受试者的年龄、健康状况、性别和体重、并行治疗(如果有)的种类、病情的严重程度、所需效果的性质、治疗的方式和频率以及开处方医师的判断。给药频率亦可取决于针对动脉血氧压力的药效学作用。然而,可以根据个别受试者调整最优选的剂量,如本领域技术人员所理解并且不经过度实验即可确定的。这典型地涉及调整标准剂量(例如,如果患者体重低,那么减小剂量)。
虽然个体需求不同,但化合物的有效量的最佳范围的确定是在本领域技术范围的。对于在本文所鉴别的病症和障碍的治愈性或预防性治疗中施用人类,例如,本发明的化合物的典型剂量可以是约0.05mg/kg/天至约50mg/kg/天,例如至少0.05mg/kg、至少0.08mg/kg、至少0.1mg/kg、至少0.2mg/kg、至少0.3mg/kg、至少0.4mg/kg或至少0.5mg/kg,并且优选地50mg/kg或更少、40mg/kg或更少、30mg/kg或更少、20mg/kg或更少或10mg/kg或更少,例如,其可以是约2.5mg/天(0.5mg/kgx5kg)至约5000mg/天(50mg/kgx100kg)。例如,化合物的剂量可以是约0.1mg/kg/天至约50mg/kg/天、约0.05mg/kg/天至约10mg/kg/天、约0.05mg/kg/天至约5mg/kg/天、约0.05mg/kg/天至约3mg/kg/天、约0.07mg/kg/天至约3mg/kg/天、约0.09mg/kg/天至约3mg/kg/天、约0.05mg/kg/天至约0.1mg/kg/天、约0.1mg/kg/天至约1mg/kg/天、约1mg/kg/天至约10mg/kg/天、约1mg/kg/天至约5mg/kg/天、约1mg/kg/天至约3mg/kg/天、约3mg/天至约500mg/天、约5mg/天至约250mg/天、约10mg/天至约100mg/天、约3mg/天至约10mg/天或约100mg/天至约250mg/天。此类剂量能以单一剂量来施用,或者可以将其分为多个剂量。
使用KRAS G12C抑制剂的方法
本披露提供了抑制RAS介导的细胞信号传导的方法,该方法包括使细胞与有效量的一种或多种本文所披露的化合物接触。对RAS介导的信号转导的抑制可以通过本领域已知的众多种方式来评估和证实。非限制性实例包括显示以下项:(a)RAS的GTP酶活性的降低;(b)GTP结合亲和性的降低或GDP结合亲和性的增加;(c)GTP的K解离的增加或GDP的K解离的减小;(d)RAS途径中下游的信号传导转导分子水平的降低,例如pMEK、pERK或pAKT水平的降低;和/或(e)RAS复合物与下游信号传导分子(包括但不限于Raf)的结合的降低。可以利用试剂盒和市售测定来确定上述项中的一种或多种。
本披露还提供了使用本披露的化合物或药物组合物治疗疾病病症的方法,这些疾病病症包括但不限于受累于G12C KRAS、HRAS或NRAS突变的病症(例如,癌症)。
在一些实施例中,提供了治疗癌症的方法,该方法包括向有需要的受试者施用有效量的任一种包含如本文所披露的化合物的前述药物组合物。在一些实施例中,癌症是由KRAS、HRAS或NRAS G12C突变介导的。在各个实施例中,癌症是胰腺癌、结肠直肠癌或肺癌。在一些实施例中,癌症是胆囊癌、甲状腺癌和胆管癌。
在一些实施例中,本披露提供了治疗有需要的受试者的障碍的方法,其中所述方法包括确定受试者是否具有KRAS、HRAS或NRAS G12C突变,以及如果确定受试者具有KRAS、HRAS或NRAS G12C突变,那么向受试者施用治疗有效剂量的至少一种如本文所披露的化合物或其药学上可接受的盐。
所披露化合物抑制非锚定依赖性细胞生长,并且因此具有抑制肿瘤转移的潜力。因此,本披露的另一个实施例提供一种抑制肿瘤转移的方法,该方法包括施用有效量的本文所披露的化合物。
还已经在血液恶性肿瘤(例如,影响血液、骨髓和/或淋巴结的癌症)中鉴别出KRAS、HRAS或NRAS G12C突变。因此,某些实施例涉及将所披露化合物(例如,呈药物组合物形式)施用需要治疗血液恶性肿瘤的患者。此类恶性肿瘤包括但不限于白血病和淋巴瘤。例如,当前所披露的化合物可以用于治疗诸如以下等疾病:急性淋巴细胞性白血病(ALL)、急性髓性白血病(AML)、慢性淋巴细胞白血病(CLL)、小淋巴细胞淋巴瘤(SLL)、慢性髓性白血病(CML)、急性单核细胞白血病(AMoL)和/或其他白血病。在其他实施例中,这些化合物可用于治疗淋巴瘤,例如所有亚型的霍奇金淋巴瘤或非霍奇金淋巴瘤。在各个实施例中,这些化合物可用于治疗浆细胞恶性肿瘤,例如多发性骨髓瘤、套细胞淋巴瘤和华氏巨球蛋白血症。
确定肿瘤或癌症是否包含G12C KRAS、HRAS或NRAS突变可以通过评估编码KRAS、HRAS或NRAS蛋白的核苷酸序列,通过评估KRAS、HRAS或NRAS蛋白的氨基酸序列,或通过评估推定的KRAS、HRAS或NRAS突变体蛋白的特征来进行。野生型人类KRAS、HRAS或NRAS的序列是本领域已知的(例如,登录号NP203524)。
检测KRAS、HRAS或NRAS核苷酸序列中的突变的方法是本领域技术人员已知的。这些方法包括但不限于聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)测定、聚合酶链式反应-单链构象多态性(PCR-SSCP)测定、实时PCR测定、PCR测序、突变体等位基因特异性PCR扩增(MASA)测定、直接测序、引物延伸反应、电泳、寡核苷酸连接测定、杂交测定、TaqMan测定、SNP基因分型测定、高分辨率熔解测定和微阵列分析。在一些实施例中,通过实时PCR针对G12C KRAS、HRAS或NRAS突变评价样品。在实时PCR中,使用对KRAS、HRAS或NRAS G12C突变具特异性的荧光探针。在突变存在时,探针结合并检测到荧光。在一些实施例中,使用KRAS、HRAS或NRAS基因中的特定区域(例如,外显子2和/或外显子3)的直接测序方法来鉴别KRAS、HRAS或NRAS G12C突变。这种技术将鉴别所测序区域中所有可能的突变。
用于检测KRAS、HRAS或NRAS蛋白中的突变的方法是本领域技术人员已知的。这些方法包括但不限于使用对突变体蛋白具特异性的结合剂(例如,抗体)检测KRAS、HRAS或NRAS突变体、蛋白质电泳和蛋白质印迹法、以及直接肽测序。
用于确定肿瘤或癌症是否包含G12C KRAS、HRAS或NRAS突变的方法可以使用多种样品。在一些实施例中,样品取自患有肿瘤或癌症的受试者。在一些实施例中,样品是新鲜肿瘤/癌症样品。在一些实施例中,样品是冷冻肿瘤/癌症样品。在一些实施例中,样品是福尔马林固定且石蜡包埋的样品。在一些实施例中,样品是循环肿瘤细胞(CTC)样品。在一些实施例中,样品经处理成细胞溶解产物。在一些实施例中,样品经处理成DNA或RNA。
本披露还涉及治疗哺乳动物的过度增生障碍的方法,该方法包括向所述哺乳动物施用治疗有效量的如本文所披露的化合物或其药学上可接受的盐。在一些实施例中,所述方法涉及治疗患有癌症的受试者,该癌症是例如急性髓样白血病、青少年癌症、儿童肾上腺皮质癌、AIDS相关癌症(例如,淋巴瘤和卡波西肉瘤)、肛门癌、阑尾癌、星形细胞瘤、非典型畸胎样瘤、基底细胞癌、胆管癌、膀胱癌、骨癌、脑干细胞神经胶质瘤、脑瘤、乳腺癌、支气管肿瘤、伯基特淋巴瘤、类癌瘤、非典型畸胎样瘤、胚胎瘤、胚细胞瘤、原发性淋巴瘤、宫颈癌、儿童癌症、脊索瘤、心脏肿瘤、慢性淋巴细胞白血病(CLL)、慢性髓性白血病(CML)、慢性骨髓增生性障碍、结肠癌、结肠直肠癌、颅咽管瘤、皮肤T细胞淋巴瘤、肝外导管原位癌(DCIS)、胚胎瘤、CNS癌症、子宫内膜癌、室管膜瘤、食管癌、鼻腔神经胶质瘤、尤文肉瘤、颅外胚细胞瘤、性腺外胚细胞瘤、眼癌、骨纤维组织细胞瘤、胆囊癌、胃癌、胃肠类癌瘤、胃肠道间质瘤(GIST)、胚细胞瘤、妊娠滋养细胞瘤、毛细胞白血病、头颈癌、心脏癌症、肝癌、霍奇金淋巴瘤、下咽癌、眼内黑色素瘤、胰岛细胞瘤、胰腺神经内分泌肿瘤、肾癌、喉癌、嘴唇和口腔癌、肝癌、小叶原位癌(LCIS)、肺癌、淋巴瘤、转移性伴隐匿性原发性鳞状颈癌、中线癌、口腔癌、多发性内分泌瘤综合征、多发性骨髓瘤/浆细胞肿瘤、蕈样真菌病、骨髓增生异常综合征、脊髓发育不良/骨髓增生肿瘤、多发性骨髓瘤、梅克尔细胞癌、恶性间皮瘤、骨恶性纤维组织细胞瘤和骨肉瘤、鼻腔和副鼻窦癌、鼻咽癌、神经母细胞瘤、非霍奇金淋巴瘤、非小细胞肺癌(NSCLC)、口癌、嘴唇和口腔癌、口咽癌、卵巢癌、胰腺癌、乳头瘤病、副神经节瘤、副鼻窦和鼻腔癌、甲状旁腺癌、阴茎癌、咽癌、胸膜肺母细胞瘤、原发性中枢神经系统(CNS)淋巴瘤、前列腺癌、直肠癌、移行细胞癌、视网膜母细胞瘤、横纹肌肉瘤、涎腺癌、皮肤癌、胃(stomach/gastric)癌、小细胞肺癌、小肠癌、软组织肉瘤、T细胞淋巴瘤、睾丸癌、咽喉癌、胸腺瘤和胸腺癌、甲状腺癌、肾盂和输尿管移行细胞癌、滋养细胞瘤、儿童罕见癌症、尿道癌、子宫肉瘤、阴道癌、外阴癌或病毒诱发的癌症。在一些实施例中,所述方法涉及治疗非癌性过度增生障碍,例如皮肤的良性增生(例如,银屑病)、再狭窄或前列腺(例如,良性前列腺肥大(BPH))。
在一些实施例中,治疗方法涉及治疗肺癌,这些方法包括向有需要的受试者施用有效量的任一种上述化合物(或包含该化合物的药物组合物)。在某些实施例中,肺癌是非小细胞肺癌(NSCLC),例如腺癌、鳞状细胞肺癌或大细胞肺癌。在一些实施例中,肺癌是小细胞肺癌。可用所披露化合物治疗的其他肺癌包括但不限于腺瘤、类癌瘤和未分化癌。
本披露进一步提供了调节G12C突变体KRAS、HRAS或NRAS蛋白活性的方法,其通过使该蛋白质与有效量的本披露的化合物接触来进行。调节可以为抑制或活化蛋白质活性。在一些实施例中,本披露提供了抑制蛋白质活性的方法,其通过使G12C突变体KRAS、HRAS或NRAS蛋白与有效量的本披露的化合物在溶液中接触来进行。在一些实施例中,本披露提供了抑制G12C突变体KRAS、HRAS或NRAS蛋白活性的方法,其通过接触表达感兴趣的蛋白质的细胞、组织或器官来进行。在一些实施例中,本披露提供了在包括但不限于啮齿动物和哺乳动物(例如,人类)的受试者中抑制蛋白质活性的方法,其通过向该受试者施用有效量的本披露的化合物来进行。在一些实施例中,调节百分比超过25%、30%、40%、50%、60%、70%、80%或90%。在一些实施例中,抑制百分比超过25%、30%、40%、50%、60%、70%、80%或90%。
在一些实施例中,本披露提供了抑制细胞中的KRAS、HRAS或NRAS G12C活性的方法,其通过使所述细胞与一定量的本披露的化合物接触来进行,该量足以抑制所述细胞中KRAS、HRAS或NRAS G12C的活性。在一些实施例中,本披露提供了抑制组织中的KRAS、HRAS或NRAS G12C活性的方法,其通过使所述组织与一定量的本披露的化合物接触来进行,该量足以抑制所述组织中KRAS、HRAS或NRAS G12C的活性。在一些实施例中,本披露提供了抑制生物体中的KRAS、HRAS或NRAS G12C活性的方法,其通过使所述生物体与一定量的本披露的化合物接触来进行,该量足以抑制所述生物体中KRAS、HRAS或NRAS G12C的活性。在一些实施例中,本披露提供了抑制动物中的KRAS、HRAS或NRAS G12C活性的方法,其通过使所述动物与一定量的本披露的化合物接触来进行,该量足以抑制所述动物中KRAS、HRAS或NRAS G12C的活性。在一些实施例中,本披露提供了抑制哺乳动物中的KRAS、HRAS或NRAS G12C活性的方法,其通过使所述哺乳动物与一定量的本披露的化合物接触来进行,该量足以抑制所述哺乳动物中KRAS、HRAS或NRAS G12C的活性。在一些实施例中,本披露提供了抑制人类中的KRAS、HRAS或NRAS G12C活性的方法,其通过使所述人类与一定量的本披露的化合物接触来进行,该量足以抑制所述人类中KRAS、HRAS或NRAS G12C的活性。本披露提供了治疗需要这种治疗的受试者的由KRAS、HRAS或NRAS G12C活性介导的疾病的方法。
组合疗法:
本披露还提供了用于组合疗法的方法,其中将已知可调节其他途径或相同途径的其他组分、或甚至靶标酶的重叠集合的药剂与本披露的化合物或其药学上可接受的盐组合使用。在一个方面中,这种疗法包括但不限于一种或多种本披露的化合物与化学治疗剂、治疗性抗体和辐射治疗的组合,以提供协同或累加的治疗效果。
许多化学治疗剂目前是本领域已知的,并且可以与本披露的化合物组合使用。在一些实施例中,化学治疗剂选自由以下组成的组:有丝分裂抑制剂、烷基化剂、抗代谢药、嵌入抗生素、生长因子抑制剂、细胞周期抑制剂、酶、拓扑异构酶抑制剂、生物反应修饰剂、抗激素药、血管发生抑制剂和抗雄激素。非限制性实例是化学治疗剂、细胞毒性剂和非肽小分子,例如(甲磺酸伊马替尼)、(卡非佐米(carfilzomib))、(硼替佐米)、Casodex(比卡鲁胺)、(吉非替尼)和阿霉素(Adriamycin)以及多种化学治疗剂。化学治疗剂的非限制性实例包括烷基化剂,例如噻替派和环磷酰胺(CYTOXANTM);烷基磺酸酯,例如白消安、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶,例如苯佐替哌(benzodopa)、卡波醌、美妥替哌(meturedopa)和乌瑞替哌(uredopa);乙烯亚胺和甲基蜜胺(methylamelamine),包括六甲蜜胺、三亚乙基蜜胺、三亚乙基磷酰胺、三亚乙基硫代磷酰胺(triethylenethiophosphaoramide)和三羟甲基蜜胺(trimethylolomelamine);氮芥,例如苯丁酸氮芥、萘氮芥、氯磷酰胺(cholophosphamide)、雌氮芥、异环磷酰胺、二氯甲基二乙胺、盐酸甲氧氮芥(mechlorethamine oxide hydrochloride)、美法仑、新恩比兴(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀、曲磷胺、尿嘧啶氮芥;亚硝基脲,例如卡莫司汀、氯脲霉素、福莫司汀、洛莫司汀、尼莫司汀、雷莫司汀;抗生素,例如阿克拉霉素(aclacinomysin)、放线菌素(actinomycin)、安曲霉素(authramycin)、重氮丝氨酸、博来霉素、放线菌素(cactinomycin)、卡奇霉素(calicheamicin)、卡柔比星(carabicin)、洋红霉素、嗜癌菌素(carzinophilin)、CasodexTM、色霉素、更生霉素、道诺霉素、地托比星、6-重氮基-5-氧代-L-正亮氨酸、多柔比星、表柔比星、依索比星、伊达比星、麻西罗霉素(marcellomycin)、丝裂霉素、霉酚酸、诺加霉素、橄榄霉素、培洛霉素、泊非霉素(potfiromycin)、嘌呤霉素、三铁阿霉素(quelamycin)、罗多比星、链黑菌素、链脲霉素、杀结核菌素、乌苯美司、净司他丁、佐柔比星;抗代谢药,例如甲氨蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物,例如二甲叶酸(denopterin)、甲氨蝶呤、蝶罗呤、三甲曲沙;嘌呤类似物,例如氟达拉滨、6-巯嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物,例如安西他滨(azacitidine)、阿扎胞苷、6-氮杂尿苷、卡莫氟(carmofur)、阿糖胞苷、二脱氧尿苷、去氧氟尿苷、依诺他滨、氟尿苷,雄激素例如卡普睾酮、屈他雄酮丙酸酯(dromostanolone propionate)、环硫雄醇、美雄烷、睾内酯;抗肾上腺药,例如氨鲁米特、米托坦、曲洛司坦;叶酸补充剂,例如亚叶酸(frolinic acid);醋葡醛内酯;醛磷酰胺糖苷;氨基乙酰丙酸;安吖啶;贝曲布昔(bestrabucil);比生群;伊达曲沙(edatraxate);地磷酰胺(defofamine);秋水仙胺;地吖醌;依氟鸟氨酸(elfomithine);依利醋铵;依托格鲁;硝酸镓;羟基脲;香菇多糖;氯尼达明;米托胍腙;米托蒽醌;莫哌达醇;硝氨丙吖啶(nitracrine);喷司他汀;蛋胺氮芥(phenamet);吡柔比星;鬼臼酸(podophyllinic acid);2-乙基酰肼;丙卡巴肼;PSK;丙亚胺;西佐喃;锗螺胺;细交链孢菌酮酸;三亚胺醌;2,2’,2”-三氯三乙胺;乌拉坦(urethan);长春地辛;达卡巴嗪;甘露莫司汀;二溴甘露醇;二溴卫矛醇;哌泊溴烷;加赛特辛(gacytosine);阿拉伯糖苷(“Ara-C”);环磷酰胺;噻替派;紫杉烷,例如紫杉酚和多西他赛;视黄酸;埃斯波霉素(esperamicins);卡培他滨;以及上述任何一种的药学上可接受的盐、酸或衍生物。
作为适合的化学治疗性细胞调理剂还包括用于调节或抑制激素对肿瘤的作用的抗激素剂,例如抗雌激素药,包括例如他莫昔芬(NolvadexTM)、雷洛昔芬、芳香酶抑制性4(5)-咪唑、4-羟基他莫昔芬、曲沃昔芬、可莫昔芬(keoxifene)、LY 117018、奥那司酮和托瑞米芬(法乐通);和抗雄激素药,例如氟他胺、尼鲁米特、比卡鲁胺、亮丙瑞林和戈舍瑞林;苯丁酸氮芥;吉西他滨;6-硫鸟嘌呤;巯嘌呤;甲胺喋呤;铂类似物,例如顺铂和卡铂;长春碱;铂;依托泊苷(VP-16);异环磷酰胺;丝裂霉素C;米托蒽醌;长春新碱;长春瑞滨;诺维本;诺安托(novantrone);替尼泊苷;道诺霉素;氨基蝶呤;希罗达(xeloda);伊班膦酸盐;喜树碱-11(CPT-11);拓扑异构酶抑制剂RFS2000;二氟甲基鸟氨酸(DMFO)。
如果需要,本披露的化合物或药物组合物可以与通常开具的抗癌药物组合使用,例如 ABVD、阿维金(AVICINE)、阿巴伏单抗(Abagovomab)、吖啶羧酰胺(Acridinecarboxamide)、阿德木单抗(Adecatumumab)、17-N-烯丙基氨基-17-去甲氧基格尔德霉素、阿法雷丁(Alpharadin)、阿瓦昔地(Alvocidib)、3-氨基吡啶-2-甲醛氨基硫脲、氨萘非特(Amonafide)、蒽二酮(Anthracenedione)、抗CD22免疫毒素、抗肿瘤药、抗肿瘤发生草药(Antitumorigenic herbs)、阿帕兹醌(Apaziquone)、阿替莫德(Atiprimod)、硫唑嘌呤(Azathioprine)、贝洛替康(Belotecan)、苯达莫司汀(Bendamustine)、BIBW 2992、比立考达(Biricodar)、伯斯塔利辛(Brostallicin)、苔藓抑素(Bryostatin)、丁硫氨酸亚砜胺(Buthionine sulfoximine)、CBV(化学疗法)、花萼海绵诱癌素(Calyculin)、细胞周期非特异性抗肿瘤剂、二氯乙酸、圆皮海绵内酯(Discodermolide)、依沙芦星(Elsamitrucin)、依诺他滨(Enocitabine)、埃博霉素(Epothilone)、艾日布林(Eribulin)、依维莫司(Everolimus)、依沙替康(Exatecan)、依昔舒林(Exisulind)、铁锈醇(Ferruginol)、氟罗德辛(Forodesine)、磷雌酚(Fosfestrol)、ICE化学治疗方案、IT-101、伊美克(Imexon)、咪喹莫特(Imiquimod)、吲哚并咔唑(Indolocarbazole)、伊罗夫文(Irofulven)、拉尼喹达(Laniquidar)、拉洛他赛(Larotaxel)、来那度胺(Lenalidomide)、硫蒽酮(Lucanthone)、勒托替康(Lurtotecan)、马磷酰胺(Mafosfamide)、米托唑胺(Mitozolomide)、萘福昔定(Nafoxidine)、奈达铂(Nedaplatin)、奥拉帕尼(Olaparib)、沃塔紫杉醇(Ortataxel)、PAC-1、木瓜(Pawpaw)、匹杉琼(Pixantrone)、蛋白酶体抑制剂、蝴蝶霉素(Rebeccamycin)、瑞喹莫德(Resiquimod)、鲁比特康(Rubitecan)、SN-38、盐孢菌酰胺A(Salinosporamide A)、沙帕他滨(Sapacitabine)、斯坦福V(Stanford V)、苦马豆素(Swainsonine)、他拉泊芬(Talaporfin)、塔利喹达(Tariquidar)、优福定(Tegafur-uracil)、特莫多(Temodar)、替司他赛(Tesetaxel)、四硝酸三铂(Triplatin tetranitrate)、三(2-氯乙基)胺、曲沙他滨(Troxacitabine)、乌拉莫司汀(Uramustine)、瓦帝莫泽(Vadimezan)、长春氟宁(Vinflunine)、ZD6126或唑喹达(Zosuquidar)。
本披露进一步涉及使用本文所提供的化合物或药物组合物与放射疗法的组合在哺乳动物中抑制异常细胞生长或治疗过度增生障碍的方法。施用放射疗法的技术是本领域已知的,并且这些技术可以用于本文所述的组合疗法中。这种组合疗法中本披露的化合物的施用可以如本文所述来确定。
放射疗法可以通过若干种方法之一或方法的组合来施用,包括但不限于外射束疗法、内放射疗法、植入物放射、立体定位性放射外科手术、全身放射疗法、放射疗法和永久性或临时性间质近距离放射疗法。如本文所使用,术语“近距离放射疗法”是指通过空间受限的放射性材料递送的放射疗法,该放射性材料是在肿瘤或其他增生性组织患病位点处或附近插入体内的。该术语意图不受限制地包括暴露于放射性同位素(例如,At-211、I-131、I-125、Y-90、Re-186、Re-188、Sm-153、Bi-212、P-32和Lu的放射性同位素)。用作本披露的细胞调理剂的适合的放射源包括固体和液体。通过非限制性实例,放射源可以是放射性核素,例如作为固体来源的I-125、I-131、Yb-169、Ir-192,作为固体来源的I-125,或发射光子、β粒子、γ辐射或其他治疗性射线的其他放射性核素。放射性材料还可以是从一种或多种放射性核素的任何溶液(例如,I-125或I-131的溶液)制备的流体,或者放射性流体可以使用含有固体放射性核素(例如Au-198、Y-90)的小颗粒的适合的流体的浆液产生。此外,可以将一种或多种放射性核素包埋于凝胶或放射性微球中。
本披露的化合物或药物组合物可以与一定量的一种或多种选自以下的物质组合使用:抗血管发生剂、信号转导抑制剂、抗增殖剂、糖酵解抑制剂或自体吞噬抑制剂。
抗血管发生剂可以结合本披露的化合物和本文所述的药物组合物使用,这些抗血管发生剂是例如MMP-2(基质金属蛋白酶2)抑制剂、MMP-9(基质金属蛋白酶9)抑制剂和COX-11(环氧酶11)抑制剂。抗血管发生剂包括例如雷帕霉素、替西罗莫司(temsirolimus,CCI-779)、依维莫司(RAD001)、索拉非尼、舒尼替尼和贝伐单抗。有用COX-II抑制剂的实例包括阿来昔布(alecoxib)、伐地昔布和罗非昔布。有用基质金属蛋白酶抑制剂的实例描述于以下专利中:WO 96/33172、WO 96/27583、欧洲专利公开案EP 0818442、欧洲专利公开案EP1004578、WO 98/07697、WO 98/03516、WO 98/34918、WO 98/34915、WO 98/33768、WO 98/30566、欧洲专利公开案606046、欧洲专利公开案931 788、WO 90/05719、WO 99/52910、WO99/52889、WO 99/29667、WO 1999007675、欧洲专利公开案EP 1786785、欧洲专利公开案号EP1181017、美国公开案号US 20090012085、美国公开案US 5863 949、美国公开案US 5861510和欧洲专利公开案EP 0780386,将所有这些专利通过引用以其整体并入本文。优选的MMP-2和MMP-9抑制剂是具有极小或无抑制MMP-1的活性的那些。更优选的是相对于其他基质金属蛋白酶(即,MAP-1、MMP-3、MMP-4、MMP-5、MMP-6、MMP-7、MMP-8、MMP-10、MMP-11、MMP-12和MMP-13)选择性抑制MMP-2和/或AMP-9的那些。可用于本披露中的MMP抑制剂的一些具体实例是AG-3340、RO 32-3555和RS 13-0830。
本发明化合物还可以用于与其他抗瘤剂的共同疗法中,这些其他抗瘤剂是例如醋孟南(acemannan)、阿柔比星、阿地白介素、阿仑单抗(alemtuzumab)、阿利维A酸(alitretinoin)、六甲蜜胺、氨磷汀、氨基乙酰丙酸、氨柔比星、安吖啶、阿那格雷、阿那曲唑、ANCER、安西司亭(ancestim)、阿加来必(ARGLABIN)、三氧化二砷、BAM002(诺夫洛斯公司(Novelos))、贝沙罗汀(bexarotene)、比卡鲁胺、溴尿苷、卡培他滨、西莫白介素、西曲瑞克、克拉屈滨、克霉唑、阿糖胞苷十八烷基磷酸盐(cytarabine ocfosfate)、DA 3030(Dong-A)、达克珠单抗(daclizumab)、地尼白介素(denileukin diftitox)、地洛瑞林(deslorelin)、右雷佐生、地拉卓(dilazep)、多西他赛、二十二醇、度骨化醇(doxercalciferol)、去氧氟尿苷、多柔比星、溴隐亭、卡莫司汀、阿糖胞苷、氟尿嘧啶、HIT双氯酚酸、干扰素-α、道诺霉素、多柔比星、维甲酸、依地福新、依决洛单抗、依氟鸟氨酸(eflornithine)、乙嘧替氟、表柔比星、红细胞生成素β、磷酸依托泊苷、依西美坦、依昔舒林(exisulind)、法倔唑、非格司亭(filgrastim)、非那雄胺、磷酸氟达拉滨、福美司坦(formestane)、福莫司汀、硝酸镓、吉西他滨、吉妥珠单抗奥唑米星(gemtuzumab zogamicin)、吉美拉西(gimeracil)/奥替拉西(oteracil)/替加氟组合、格莱克滨(glycopine)、戈舍瑞林、庚铂(heptaplatin)、人绒毛膜促性腺素、人类胎儿甲胎蛋白、伊班膦酸、伊达比星、咪喹莫特、干扰素-α、干扰素-α、天然干扰素-α-2、干扰素-α-2a、干扰素-α-2b、干扰素-α-N1、干扰素-α-n3、干扰素alfacon-1、干扰素α、天然干扰素β、干扰素β-1a、干扰素β-1b、干扰素γ、天然干扰素γ-1a、干扰素γ-1b、白介素-1β、碘苄胍、伊立替康、伊索拉定(irsogladine)、兰瑞肽(lanreotide)、LC 9018(养乐多集团(Yakult))、来氟米特、来格司亭(lenograstim)、硫酸香菇多糖、来曲唑、白细胞α干扰素、亮丙瑞林、左旋咪唑+氟尿嘧啶、利阿唑(liarozole)、洛铂、氯尼达明、洛伐他汀、马索罗酚、美拉胂醇、甲氧氯普胺、米非司酮、米替福新、米立司亭、错配双链RNA、米托胍腙、二溴卫矛醇、米托蒽醌、莫拉司亭(molgramostim)、那法瑞林、纳洛酮+喷他佐辛、那托司亭(nartograstim)、奈达铂、尼鲁米特(nilutamide)、那可丁、新颖红细胞生成刺激蛋白、NSC631570奥曲肽、奥普瑞白介素(oprelvekin)、奥沙特隆、奥沙利铂(oxaliplatin)、紫杉酚、帕米膦酸(pamidronic acid)、培门冬酶、聚乙二醇干扰素-α-2b、木聚硫钠(pentosanpolysulfate sodium)、喷司他丁、毕西巴尼(picibanil)、吡柔比星、兔抗胸腺细胞多克隆抗体、聚乙二醇干扰素-α-2a、卟吩姆钠、雷洛昔芬、雷替曲塞、拉斯伯门特(rasburiembodiment)、羟乙膦酸铼(Re 186)、RII维甲酰酚胺(RII retinamide)、利妥昔单抗、罗莫肽、来昔决南钐(153 Sm)(samarium(153 Sm)lexidronam)、沙格司亭(sargramostim)、西佐喃、索布佐生、索纳明(sonermin)、氯化锶-89、苏拉明、他索那明(tasonermin)、他扎罗汀、替加氟、替莫泊芬(temoporfin)、替莫唑胺、替尼泊苷、四氯十氧化物、沙利度胺、胸腺法新、促甲状腺素α、托泊替康(topotecan)、托瑞米芬、托西莫单抗(tositumomab)-碘131、曲妥珠单抗、曲奥舒凡、维甲酸、曲洛司坦、三甲曲沙、曲普瑞林、肿瘤坏死因子α、天然乌苯美司、膀胱癌疫苗、丸山(Maruyama)疫苗、黑色素瘤裂解物疫苗、戊柔比星(valrubicin)、维替泊芬、长春瑞滨、维鲁利秦(VIRULIZIN)、净司他丁斯酯(zinostatin stimalamer)或唑来膦酸;阿巴瑞克;AE 941(依特纳公司(Aeterna))、氨莫司汀(ambamustine)、反义寡核苷酸、bcl-2(珍塔公司(Genta))、APC 8015(丹德里昂公司(Dendreon))、西妥昔单抗、地西他滨(decitabine)、德氨鲁米特(dexaminoglutethimide)、地吖醌、EL 532(义隆公司(Elan))、EM 800(英杜里奇公司(Endorecherche))、恩尿嘧啶、依他硝唑、芬维A铵(fenretinide)、非格司亭SD01(安进公司(Amgen))、氟维司群、加洛他滨、胃泌素17免疫原、HLA-B7基因疗法(伟科公司(Vical))、粒细胞-巨噬细胞集落刺激因子、组胺二盐酸盐、替伊莫单抗、伊洛马司他、IM 862(兴创公司(Cytran))、白介素-2、艾泼昔芬(iproxifene)、LDI 200(米克豪公司(Milkhaus))、来立司亭(leridistim)、林妥珠单抗(lintuzumab)、CA 125 MAb(巴米拉公司(Biomira))、癌症MAb(日本制药发展公司(JapanPharmaceutical Development))、HER-2和Fc MAb(梅达拉公司(Medarex))、独特型105AD7MAb(CRC技术公司(CRC Technology))、独特型CEA MAb(特里莱公司(Trilex))、LYM-1-碘131 MAb(特尼克隆公司(Techniclone))、多态性上皮粘液素-钇90 MAb(安特索玛公司(Antisoma))、马立马司他(marimastat)、美诺立尔、米妥莫单抗(mitumomab)、莫特沙芬钆(motexafin gadolinium)、MX 6(高德美公司(Galderma))、奈拉滨(nelarabine)、诺拉曲塞(nolatrexed)、P 30蛋白、培维索孟(pegvisomant)、培美曲塞、泊非霉素(porfiromycin)、普马司他(prinomastat)、RL 0903(夏尔公司(Shire))、鲁吡替康、沙铂(satraplatin)、苯乙酸钠、斯帕磷酸(sparfosic acid)、SRL 172(SR制药公司(SR Pharma))、SU 5416(苏根公司(SUGEN))、TA 077(田边公司(Tanabe))、四硫钼酸盐、厚果糖松草碱(thaliblastine)、血小板生成素、本紫红素乙酯锡(tinethyl etiopurpurin)、替拉扎明、癌症疫苗(巴米拉公司)、黑色素瘤疫苗(纽约大学(New York University))、黑色素瘤疫苗(斯隆-凯特琳研究所(Sloan Kettering Institute))、黑色素瘤肿瘤裂解物疫苗(纽约医学院(New YorkMedical College))、病毒黑色素瘤细胞裂解物疫苗(皇家纽卡斯尔医院(Royal NewcastleHospital))或伐司朴达(valspodar)。
本发明的化合物可以进一步与VEGFR抑制剂一起使用。以下专利和专利申请案中所述的其他化合物可以用于组合疗法中:US 6,258,812、US 2003/0105091、WO 01/37820、US 6,235,764、WO 01/32651、US 6,630,500、US 6,515,004、US 6,713,485、US 5,521,184、US 5,770,599、US 5,747,498、WO 02/68406、WO 02/66470、WO 02/55501、WO 04/05279、WO04/07481、WO 04/07458、WO 04/09784、WO 02/59110、WO 99/45009、WO 00/59509、WO 99/61422、US 5,990,141、WO 00/12089和WO 00/02871。
在一些实施例中,该组合包含本发明的组合物与至少一种抗血管发生剂的组合。药剂包括但不限于在体外以合成方式制备的化学组合物、抗体、抗原结合区、放射性核素及其组合和缀合物。药剂可以是激动剂、拮抗剂、变构调节剂、毒素,或者更通常地,可以用于抑制或刺激其靶标(例如,受体或酶激活或抑制),并且由此促进细胞死亡或阻止细胞生长。
示例性抗血管发生剂包括ERBITUXTM(IMC-C225)、KDR(激酶结构域受体)抑制剂(例如,特异性结合至激酶结构域受体的抗体和抗原结合区)、抗VEGF剂(例如,特异性结合VEGF的抗体或抗原结合区、或可溶VEGF受体或其配体结合区)(例如AVASTINTM或VEGF-TRAPTM)和抗VEGF受体剂(例如,与其特异性结合的抗体或抗原结合区)、EGFR抑制剂(例如,与其特异性结合的抗体或抗原结合区)(例如维克替比(Vectibix)(帕尼单抗)、IRESSATM(吉非替尼)、TARCEVATM(厄洛替尼)、抗Ang1剂和抗Ang2剂(例如,与其或与其受体(例如Tie2/Tek)特异性结合的抗体或抗原结合区)以及抗Tie2激酶抑制剂(例如,与其特异性结合的抗体或抗原结合区)。本发明的药物组合物还可以包含一种或多种特异性结合生长因子并抑制生长因子的活性的药剂(例如,抗体、抗原结合区或可溶受体),例如肝细胞生长因子(HGF,还称为散射因子)的拮抗剂、以及特异性结合其受体“c-met”的抗体或抗原结合区。
其他抗血管发生剂包括坎帕斯(Campath)、IL-8、B-FGF、Tek拮抗剂(Ceretti等人,美国公开案号2003/0162712;美国专利号6,413,932)、抗TWEAK剂(例如,特异性结合抗体或抗原结合区,或可溶TWEAK受体拮抗剂;参见Wiley,美国专利号6,727,225)、用于拮抗整联蛋白与其配体的结合的ADAM去整合素结构域(Fanslow等人,美国公开案号2002/0042368)、特异性结合抗eph受体和/或抗蝶素(ephrin)抗体或抗原结合区(美国专利号5,981,245;5,728,813;5,969,110;6,596,852;6,232,447;6,057,124和其专利族成员)和抗PDGF-BB拮抗剂(例如,特异性结合抗体或抗原结合区)以及特异性结合PDGF-BB配体的抗体或抗原结合区和PDGFR激酶抑制剂(例如,与其特异性结合的抗体或抗原结合区)。
其他抗血管发生/抗肿瘤剂包括:SD-7784(美国辉瑞公司(Pfizer));西仑吉肽(cilengitide)(德国默克集团(Merck KGaA),EPO 770622);哌加他尼八钠(pegaptaniboctasodium)(美国吉利德科学公司(Gilead Sciences));阿耳法他汀(Alphastatin)(英国百克塔公司(BioActa));M-PGA(美国赛尔基因公司(Celgene),US 5712291);伊洛马司他(美国爱瑞发公司(Arriva),US 5892112);艾玛夏尼(emaxanib)(美国辉瑞公司,US5792783);瓦他拉尼(vatalanib)(瑞士诺华公司(Novartis));2-甲氧基雌二醇(美国安翠梅德公司(EntreMed));TLC ELL-12(爱尔兰义隆公司);乙酸阿奈可他(anecortaveacetate)(美国爱尔康公司(Alcon));α-D148 Mab(美国安进公司);CEP-7055(美国瑟法隆公司(Cephalon));抗Vn Mab(荷兰克鲁赛尔公司(Crucell));DAC:抗血管发生剂(加拿大康久化学公司(ConjuChem));安吉西丁(Angiocidin)(美国英可因制药公司(InKinePharmaceutical));KM-2550(日本协和发酵工业株式会社(Kyowa Hakko));SU-0879(美国辉瑞公司);CGP-79787(瑞士诺华公司,EP 970070);ARGENT技术(美国阿瑞雅德公司(Ariad));YIGSR-Stealth(美国强生公司(Johnson&Johnson));纤维蛋白原-E片段(英国百克塔公司);血管发生抑制剂(英国三杰公司(Trigen));TBC-1635(美国恩赛斯夫制药公司(Encysive Pharmaceuticals));SC-236(美国辉瑞公司);ABT-567(美国雅培公司(Abbott));转移抑制素(Metastatin)(美国安翠梅德公司);血管发生抑制剂(瑞典瑞派公司(Tripep));乳腺丝抑蛋白(maspin)(日本创成公司(Sosei));2-甲氧基雌二醇(美国肿瘤学公司(Oncology Sciences Corporation));ER-68203-00(美国爱华克斯公司(IVAX));氟草胺(美国莱恩实验室公司(Lane Labs));Tz-93(日本津村株式会社(Tsumura));TAN-1120(日本武田株式会社(Takeda));FR-111142(日本藤泽株式会社(Fujisawa),JP 02233610);血小板因子4(美国瑞普利金公司(RepliGen),EP 407122);血管内皮生长因子拮抗剂(丹麦波伦公司(Borean));贝伐单抗(pINN)(美国基因泰克公司(Genentech));血管发生抑制剂(美国苏根公司);XL 784(美国伊克塞利克斯公司(Exelixis));XL 647(美国伊克塞利克斯公司);第二代MAbα5β3整联蛋白(美国应用分子进化基金会(Applied MolecularEvolution)和美国米迪缪妮公司(MedImmune));视网膜病变的基因疗法(英国牛津生物医药公司(Oxford BioMedica));盐酸恩扎妥林(enzastaurin hydrochloride)(USAN)(美国礼来公司(Lilly));CEP 7055(美国瑟法隆公司和法国赛诺菲圣德拉堡集团(Sanofi-Synthelabo));BC 1(意大利热那亚癌症研究所(Genoa Institute of CancerResearch));血管发生抑制剂(澳大利亚沃奇米亚公司(Alchemia));VEGF拮抗剂(美国再生元公司(Regeneron));rBPI 21和BPI衍生的抗血管发生剂(美国逍马公司(XOMA));PI 88(澳大利亚普健公司(Progen));西仑吉肽(pINN)(德国默克集团;德国慕尼黑技术大学(Munich Technical University),美国斯克里普斯诊所和研究基金会(Scripps Clinicand Research Foundation));西妥昔单抗(INN)(法国安万特公司(Aventis));AVE 8062(日本味之素公司(Ajinomoto));AS 1404(新西兰癌症研究实验室(Cancer ResearchLaboratory));SG 292(美国泰利奥斯公司(Telios));内皮抑素(美国波士顿儿童医院(Boston Childrens Hospital));ATN 161(美国阿特纽公司(Attenuon));血管抑素(美国波士顿儿童医院);2-甲氧基雌二醇(美国波士顿儿童医院);ZD 6474(英国阿斯利康公司(AstraZeneca));ZD 6126(英国安吉奥金尼制药公司(Angiogene Pharmaceuticals));PPI2458(美国普雷西斯公司(Praecis));AZD 9935(英国阿斯利康公司);AZD 2171(英国阿斯利康公司);瓦他拉尼(pINN)(瑞士诺华公司和德国先灵公司(Schering AG));组织因子途径抑制剂(美国安翠梅德公司);哌加他尼(Pinn)(美国吉利德科学公司);束骨姜黄醇(xanthorrhizol)(韩国延世大学(Yonsei University));基于基因的VEGF-2疫苗(美国斯克里普斯诊所和研究基金会);SPV5.2(加拿大萨普泰克公司(Supratek));SDX 103(美国圣地亚哥的加利福尼亚大学(University of California));PX478(美国派克斯公司(ProlX));转移抑制素(美国安翠梅德公司);肌钙蛋白I(美国哈佛大学(HarvardUniversity));SU 6668(美国苏根公司);OXI 4503(美国奥克斯吉尼公司(OXiGENE));邻胍(美国维度制药公司(Dimensional Pharmaceuticals));莫托普胺C(motuporamine C)(加拿大不列颠哥伦比亚大学(British Columbia University));CDP 791(英国细胞科技集团(Celltech Group));阿替莫德(pINN)(英国葛兰素史克公司(GlaxoSmithKline));E 7820(日本卫材株式会社(Eisai));CYC 381(美国哈佛大学);AE 941(加拿大依特纳公司);血管发生疫苗(美国安翠梅德公司);尿激酶纤溶酶原激活剂抑制剂(美国丹德里昂公司);奥谷法奈(oglufanide)(pINN)(美国麦尔墨特公司(Melmotte));HIF-1α抑制剂(英国新诺瓦公司(Xenova));CEP 5214(美国瑟法隆公司);BAY RES 2622(德国拜耳公司(Bayer));安吉西丁(美国英可因公司);A6(美国奥创公司(Angstrom));KR 31372(韩国的韩国化学技术研究所(Korea Research Institute of Chemical Technology));GW 2286(英国葛兰素史克公司);EHT 0101(法国埃克森海特公司(ExonHit));CP 868596(美国辉瑞公司);CP 564959(美国OSI公司);CP 547632(美国辉瑞公司);786034(英国葛兰素史克公司);KRN 633(日本麒麟啤酒株式会社(Kirin Brewery));眼内2-甲氧基雌二醇药物递送系统(美国安翠梅德公司);安吉尼克(anginex)(荷兰马斯特里赫特大学(Maastricht University)和美国明尼苏达大学(Minnesota University));ABT 510(美国雅培公司);AAL 993(瑞士诺华公司);VEGI(美国普若技术公司(ProteomTech));肿瘤坏死因子-α抑制剂(美国国立衰老研究所(National Institute on Aging));SU 11248(美国辉瑞公司和美国苏根公司);ABT 518(美国雅培公司);YH16(中国烟台荣昌公司(Yantai Rongchang));S-3APG(美国波士顿儿童医院和美国安翠梅德公司);MAb,KDR(美国英克隆系统公司(ImClone Systems));MAbα5β1(美国蛋白质设计公司(Protein Design));KDR激酶抑制剂(英国细胞科技集团和美国强生公司);GFB 116(美国南佛罗里达大学(South Florida University)和美国耶鲁大学(YaleUniversity));CS 706(日本三协株式会社(Sankyo));康普瑞汀(combretastatin)A4前药(美国亚利桑那州立大学(Arizona State University));软骨素酶AC(chondroitinaseAC)(加拿大阿卑斯公司(IBEX));BAY RES 2690(德国拜耳公司);AGM 1470(美国哈佛大学、日本武田株式会社和美国TAP公司);AG 13925(美国阿古伦公司(Agouron));四硫钼酸盐(美国密歇根大学(University of Michigan));GCS 100(美国韦恩州立大学(Wayne StateUniversity));CV 247(英国常春藤医疗公司(Ivy Medical));CKD 732(韩国钟根堂公司(Chong Kun Dang));血管内皮生长因子MAb(英国新诺瓦公司);伊索拉定(irsogladine)(INN)(日本新药株式会社(Nippon Shinyaku));RG 13577(法国安万特公司);WX 360(德国威莱克斯公司(Wilex));角鲨胺(pINN)(美国吉纳诺公司(Genaera));RPI 4610(美国瑟纳公司(Sirna));癌症疗法(澳大利亚马力诺瓦公司(Marinova));类肝素酶抑制剂(以色列洞见公司(InSight));KL 3106(韩国科隆公司(Kolon));和厚朴酚(美国埃默里大学(EmoryUniversity));ZK CDK(德国先灵公司);ZK Angio(德国先灵公司);ZK 229561(瑞士诺华公司和德国先灵公司);XMP 300(美国逍马公司);VGA 1102(日本大正株式会社(Taisho));VEGF受体调节剂(美国药典公司(Pharmacopeia));VE-钙粘蛋白-2拮抗剂(美国英克隆系统公司);伐索他汀(Vasostatin)(美国国立卫生研究院(National Institutes ofHealth));Flk-1疫苗(美国英克隆系统公司);TZ93(日本津村株式会社);肿瘤抑素(美国贝斯以色列医院(Beth Israel Hospital));截短型可溶FLT 1(血管内皮生长因子受体1)(美国默克公司(Merck&Co));Tie-2配体(美国再生元公司);和血小板反应蛋白1抑制剂(美国阿列格尼健康、教育和研究基金会(Allegheny Health,Education and ResearchFoundation))。
自体吞噬抑制剂包括但不限于氯喹、3-甲基腺嘌呤、羟氯喹(PlaquenilTM)、巴弗洛霉素A1(bafilomycin A1)、5-氨基-4-咪唑甲酰胺核糖核苷(AICAR)、冈田酸、抑制2A型或1型蛋白磷酸酶的自体吞噬抑制性海藻毒素、cAMP类似物以及升高cAMP水平的药物例如腺苷、LY204002、N6-巯嘌呤核糖核苷和长春碱。另外,还可以使用抑制蛋白质表达的反义或siRNA,这些蛋白质包括但不限于ATG5(其参与自体吞噬)。
可以用于治疗癌症并且可以与本发明的一种或多种化合物组合使用的其他药学活性化合物/药剂包括:阿法依伯汀(epoetin alfa);阿法达贝泊汀(darbepoetin alfa);帕尼单抗;培非格司亭(pegfilgrastim);帕利夫明(palifermin);非格司亭;地诺单抗(denosumab);安西司亭;AMG 102;AMG 386;AMG 479;AMG 655;AMG 745;AMG 951;及AMG706或其药学上可接受的盐。
在某些实施例中,将本文所提供的组合物与化学治疗剂联合施用。适合的化学治疗剂可以包括天然产物,例如长春花生物碱(例如,长春碱、长春新碱和长春瑞滨)、紫杉酚、表鬼臼毒素(Epidipodophyllotoxin)(例如,依托泊苷和替尼泊苷)、抗生素(例如,更生霉素(放线菌素D)、道诺霉素、多柔比星和伊达比星)、蒽环类抗生素、米托蒽醌、博来霉素、普卡霉素(光辉霉素)、丝裂霉素、酶(例如,L-天冬酰胺酶,其系统性地代谢L-天冬酰胺并剥夺不具有合成自身天冬酰胺的能力的细胞)、抗血小板剂、抗增殖/抗有丝分裂烷基化剂(例如氮芥,例如,二氯甲基二乙胺、环磷酰胺和类似物、美法仑和苯丁酸氮芥)、乙烯亚胺和甲基蜜胺(例如,六甲基蜜胺(hexaamethylmelaamine)和噻替派)、CDK抑制剂(例如,塞利西利(seliciclib)、UCN-01、P1446A-05、PD-0332991、迪那西利(dinaciclib)、P27-00、AT-7519、RGB286638和SCH727965)、烷基磺酸酯(例如,白消安)、亚硝基脲(例如,卡莫司汀(BCNU)和类似物和链脲霉素)、三氮烯-达卡巴嗪(Trazenes-dacarbazinine)(DTIC)、抗增殖/抗有丝分裂抗代谢药例如叶酸类似物(例如,甲氨蝶呤)、嘧啶类似物(例如,氟尿嘧啶、氟尿苷和阿糖胞苷)、嘌呤类似物和相关抑制剂(例如,巯嘌呤、硫鸟嘌呤、喷司他丁和2-氯脱氧腺苷)、芳香酶抑制剂(例如,阿那曲唑、依西美坦和来曲唑)和铂配位络合物(例如,顺铂和卡铂)、丙卡巴肼、羟基脲、米托坦、氨鲁米特、组蛋白脱乙酰酶(HDAC)抑制剂(例如,曲古抑菌素、丁酸钠、阿匹西坦(apicidan)、辛二酰苯胺异羟肟酸(hydroamic acid)、伏立诺他(vorinostat)、LBH 589、罗米地辛(romidepsin)、ACY-1215和帕比司他(panobinostat))、mTor抑制剂(例如,替西罗莫司、依维莫司、地磷莫司(ridaforolimus)和西罗莫司)、KSP(Eg5)抑制剂(例如,Array 520)、DNA结合剂(例如,扎利普斯(Zalypsis))、PI3Kδ抑制剂(例如,GS-1101和TGR-1202)、PI3Kδ和γ抑制剂(例如,CAL-130)、多激酶抑制剂(例如,TG02和索拉非尼)、激素(例如,雌激素)和激素激动剂例如黄体化激素释放激素(LHRH)激动剂(例如,戈舍瑞林、亮丙瑞林和曲普瑞林)、BAFF中和性抗体(例如,LY2127399)、IKK抑制剂、p38MAPK抑制剂、抗IL-6(例如,CNTO328)、端粒酶抑制剂(例如,GRN 163L)、极光激酶抑制剂(例如,MLN8237)、细胞表面单克隆抗体(例如,抗CD38(HUMAX-CD38)、抗CS1(例如,埃罗妥珠单抗(elotuzumab))、HSP90抑制剂(例如,17 AAG和KOS 953)、P13K/Akt抑制剂(例如,哌立福辛(perifosine))、Akt抑制剂(例如,GSK-2141795)、PKC抑制剂(例如,恩扎妥林)、FTI(例如,ZarnestraTM)、抗CD138(例如,BT062)、Torc1/2特异性激酶抑制剂(例如,INK128)、激酶抑制剂(例如,GS-1101)、ER/UPR靶向剂(例如,MKC-3946)、cFMS抑制剂(例如,ARRY-382)、JAK1/2抑制剂(例如,CYT387)、PARP抑制剂(例如,奥拉帕尼和维利帕尼(veliparib)(ABT-888))、BCL-2拮抗剂。其他化学治疗剂可以包括二氯甲基二乙胺、喜树碱、异环磷酰胺、他莫昔芬、雷洛昔芬、吉西他滨、诺维本、索拉非尼或前述项的任何类似物或衍生物变体。
本发明化合物亦可与放射疗法、激素疗法、手术及免疫疗法结合使用,这些疗法是本领域技术人员熟知的。
在某些实施例中,将本文所提供的药物组合物与类固醇联合施用。适合的类固醇可以包括但不限于21-乙酰氧基孕烯醇酮、阿氯米松、阿尔孕酮、安西奈德、倍氯米松(beclomethasone)、倍他米松、布地奈德、氯泼尼松(chloroprednisone)、氯倍他索(clobetasol)、氯可托龙、氯泼尼醇、皮质酮、可的松、可的伐唑、地夫可特、地奈德、去羟米松、地塞米松、二氟拉松(diflorasone)、二氟可龙(diflucortolone)、二氟孕甾丁酯(difuprednate)、甘草次酸、氟扎可特、氟氯奈德(flucloronide)、氟米松(flumethasone)、氟尼缩松、氟轻松(fluocinolone acetonide)、醋酸氟轻松、氟考丁酯(fluocortinbutyl)、氟可龙、氟米龙(fluorometholone)、醋酸甲氟龙(fluperolone acetate)、醋酸氟泼尼定(fluprednidene acetate)、氟泼尼龙(fluprednisolone)、氟氢缩松(flurandrenolide)、丙酸氟替卡松、福莫可他(formocortal)、氯氟舒松(halcinonide)、丙酸卤倍他索(halobetasol propionate)、卤米松(halometasone)、氢化可的松(hydrocortisone)、依碳酸氯替泼诺(loteprednol etabonate)、马泼尼酮、甲羟松、甲泼尼松、甲泼尼龙(methylprednisolone)、糠酸莫米松(mometasone furoate)、帕拉米松、泼尼卡酯、泼尼松龙(prednisolone)、泼尼松龙25-二乙氨基乙酸酯、泼尼松龙磷酸钠、泼尼松(prednisone)、泼尼松龙戊酸酯(prednival)、泼尼立定(prednylidene)、利美索龙、替可的松(tixocortol)、曲安西龙(triamcinolone)、曲安奈德(triamcinolone acetonide)、苯曲安奈德(triamcinolone benetonide)、己曲安奈德(triamcinolone hexacetonide)及其盐和/或衍生物。在一个特定实施例中,本发明的化合物还可以与治疗恶心的其他药学活性剂组合使用。可以用于治疗恶心的药剂的实例包括:屈大麻酚(dronabinol)、格拉司琼(granisetron)、甲氧氯普胺(metoclopramide)、昂丹司琼(ondansetron)及丙氯拉嗪(prochlorperazine)、或其药学上可接受的盐。
本披露的化合物或药物组合物还可以与一定量的一种或多种选自以下的物质组合使用:EGFR抑制剂、MEK抑制剂、PI3K抑制剂、AKT抑制剂、TOR抑制剂和免疫疗法,包括抗PD-1、抗PDL-1、抗CTLA4、抗LAG1和抗OX40剂、GITR激动剂、CAR-T细胞和BiTE。
EGFR抑制剂包括但不限于小分子拮抗剂、抗体抑制剂或特定反义核苷酸或siRNA。有用的EGFR抗体抑制剂包括西妥昔单抗(爱必妥)、帕尼单抗(维克替比)、扎鲁木单抗(zalutumumab)、尼妥珠单抗(nimotuzumab)和马妥珠单抗(matuzumab)。EGFR的小分子拮抗剂包括吉非替尼、厄洛替尼(特罗凯(Tarceva))和最近的拉帕替尼(lapatinib)(泰克博(TykerB))。参见例如,Yan L等人,Pharmacogenetics and Pharmacogenomics InOncology Therapeutic Antibody Development[肿瘤治疗抗体研发中的遗传药理学和药物基因组学],BioTechniques[生物技术]2005;39(4):565-8,和Paez J G等人,EGFRMutations In Lung Cancer Correlation With Clinical Response To GefitinibTherapy[肺癌中的EGFR突变与对吉非替尼疗法的临床反应的关联],Science[科学]2004;304(5676):1497-500。
小分子EGFR抑制剂的非限制性实例包括以下专利公开案中描述的任何EGFR抑制剂、以及所述EGFR抑制剂的所有药学上可接受的盐和溶剂化物:欧洲专利申请案EP520722,1992年12月30日公开;欧洲专利申请案EP 566226,1993年10月20日公开;PCT国际公开案WO 96/33980,1996年10月31日公开;美国专利号5,747,498,1998年5月5日授权;PCT国际公开案WO 96/30347,1996年10月3日公开;欧洲专利申请案EP 787772,1997年8月6日公开;PCT国际公开案WO 97/30034,1997年8月21日公开;PCT国际公开案WO 97/30044,1997年8月21日公开;PCT国际公开案WO 97/38994,1997年10月23日公开;PCT国际公开案WO 97/49688,1997年12月31日公开;欧洲专利申请案EP837063,1998年4月22日公开;PCT国际公开案WO 98/02434,1998年1月22日公开;PCT国际公开案WO 97/38983,1997年10月23日公开;PCT国际公开案WO 95/19774,1995年7月27日公开;PCT国际公开案WO 95/19970,1995年7月27日公开;PCT国际公开案WO 97/13771,1997年4月17日公开;PCT国际公开案WO 98/02437,1998年1月22日公开;PCT国际公开案WO 98/02438,1998年1月22日公开;PCT国际公开案WO97/32881,1997年9月12日公开;德国申请案DE 19629652,1998年1月29日公开;PCT国际公开案WO 98/33798,1998年8月6日公开;PCT国际公开案WO 97/32880,1997年9月12日公开;PCT国际公开案WO 97/32880,1997年9月12日公开;欧洲专利申请案EP 682027,1995年11月15日公开;PCT国际公开案WO 97/02266,197年1月23日公开;PCT国际公开案WO 97/27199,1997年7月31日公开;PCT国际公开案WO 98/07726,1998年2月26日公开;PCT国际公开案WO97/34895,1997年9月25日公开;PCT国际公开案WO 96/31510’,1996年10月10日公开;PCT国际公开案WO 98/14449,1998年4月9日公开;PCT国际公开案WO 98/14450,1998年4月9日公开;PCT国际公开案WO 98/14451,1998年4月9日公开;PCT国际公开案WO 95/09847,1995年4月13日公开;PCT国际公开案WO 97/19065,1997年5月29日公开;PCT国际公开案WO 98/17662,1998年4月30日公开;美国专利号5,789,427,1998年8月4日授权;美国专利号5,650,415,1997年7月22日授权;美国专利号5,656,643,1997年8月12日授权;PCT国际公开案WO99/35146,1999年7月15日公开;PCT国际公开案WO 99/35132,1999年7月15日公开;PCT国际公开案WO 99/07701,1999年2月18日公开;和PCT国际公开案WO 92/20642,1992年11月26日公开。小分子EGFR抑制剂的其他非限制性实例包括描述于Traxler,P.,1998,Exp.Opin.Ther.Patents[治疗术专利专家评述]8(12):1599-1625中的任何EGFR抑制剂。
基于抗体的EGFR抑制剂包括可以部分或完全阻断EGFR被其天然配体激活的任何抗EGFR抗体或抗体片段。基于抗体的EGFR抑制剂的非限制性实例包括以下文献中描述的那些:Modjtahedi,H.等人,1993,Br.J.Cancer[英国癌症杂志]67:247-253;Teramoto,T.等人,1996,Cancer[癌症]77:639-645;Goldstein等人,1995,Clin.Cancer Res.[临床癌症研究]1:1311-1318;Huang,S.M.等人,1999,Cancer Res.[癌症研究]15:59(8):1935-40;和Yang,X.等人,1999,Cancer Res.[癌症研究]59:1236-1243。因此,EGFR抑制剂可以是单克隆抗体Mab E7.6.3(Yang,1999,同上)、或Mab C225(ATCC登录号HB-8508)、或具有其结合特异性的抗体或抗体片段。
MEK抑制剂包括但不限于CI-1040、AZD6244、PD318088、PD98059、PD334581、RDEA119、ARRY-142886、ARRY-438162和PD-325901。
PI3K抑制剂包括但不限于渥曼青霉素、WO 06/044453中描述的17-羟基渥曼青霉素类似物、4-[2-(1H-吲唑-4-基)-6-[[4-(甲磺酰基)哌嗪-1-基]甲基]噻吩并[3,2-d]嘧啶-4-基]吗啉(还称为GDC 0941,并且描述于PCT公开案号WO 09/036,082和WO 09/055,730中)、2-甲基-2-[4-[3-甲基-2-氧代-8-(喹啉-3-基)-2,3-二氢咪唑并[4,5-c]喹啉-1-基]苯基]丙腈(还称为BEZ 235或NVP-BEZ 235,并且描述于PCT公开案号WO 06/122806中)、(S)-1-(4-((2-(2-氨基嘧啶-5-基)-7-甲基-4-吗啉代噻吩并[3,2-d]嘧啶-6-基)甲基)哌嗪-1-基)-2-羟基丙-1-酮(描述于PCT公开案号WO 2008/070740中)、LY294002(2-(4-吗啉基)-8-苯基-4H-1-苯并吡喃-4-酮,可从艾克松医学化学公司(Axon Medchem)获得)、PI103盐酸盐(3-[4-(4-吗啉基吡啶并-[3’,2’:4,5]呋喃并[3,2-d]嘧啶-2-基]苯酚盐酸盐,可从艾克松医学化学公司获得)、PIK 75(N’-[(1E)-(6-溴代咪唑并[1,2-a]吡啶-3-基)亚甲基]-N,2-二甲基-5-硝基苯磺酰基-酰肼盐酸盐,可从艾克松医学化学公司获得)、PIK 90(N-(7,8-二甲氧基-2,3-二氢-咪唑并[1,2-c]喹唑啉-5-基)-烟酰胺,可从艾克松医学化学公司获得)、GDC-0941二甲磺酸盐(2-(1H-吲唑-4-基)-6-(4-甲烷磺酰基-哌嗪-1-基甲基)-4-吗啉-4-基-噻吩并[3,2-d]嘧啶二甲磺酸盐,可从艾克松医学化学公司获得)、AS-252424(5-[1-[5-(4-氟-2-羟基-苯基)-呋喃-2-基]-甲-(Z)-亚基]-噻唑烷-2,4-二酮,可从艾克松医学化学公司获得)以及TGX-221(7-甲基-2-(4-吗啉基)-9-[1-(苯基氨基)乙基]-4H-吡啶并-[1,2-a]嘧啶-4-酮,可从艾克松医学化学公司获得)、XL-765和XL-147。其他PI3K抑制剂包括去甲氧基绿胶霉素(demethoxyviridin)、哌立福辛、CAL101、PX-866、BEZ235、SF1126、INK1117、IPI-145、BKM120、XL147、XL765、帕罗米德529(Palomid 529)、GSK1059615、ZSTK474、PWT33597、IC87114、TG100-115、CAL263、PI-103、GNE-477、CUDC-907和AEZS-136。
AKT抑制剂包括但不限于Akt-1-1(抑制Akt1)(Barnett等人(2005)Biochem.J.[生物化学杂志],385(Pt.2),399-408);Akt-1-1,2(抑制Ak1和2)(Barnett等人(2005)Biochem.J.[生物化学杂志]385(Pt.2),399-408);API-59CJ-Ome(例如,Jin等人(2004)Br.J.Cancer[英国癌症杂志]91,1808-12);1-H-咪唑并[4,5-c]吡啶基化合物(例如,WO05011700);吲哚-3-甲醇(carbinol)及其衍生物(例如,美国专利号6,656,963;Sarkar和Li(2004)J Nutr.[营养学杂志]134(12增刊),3493S-3498S);哌立福辛(例如,干扰Akt膜定位;Dasmahapatra等人(2004)Clin.Cancer Res.[临床癌症研究]10(15),5242-52,2004);磷脂酰肌醇醚脂质类似物(例如,Gills和Dennis(2004)Expert.Opin.Investig.Drugs[研究药物专家评论]13,787-97);和曲西立滨(TCN或API-2或NCI标识符:NSC154020;Yang等人(2004)Cancer Res.[癌症研究]64,4394-9)。
TOR抑制剂包括但不限于,抑制剂包括AP-23573、CCI-779、依维莫司、RAD-001、雷帕霉素、替西罗莫司、ATP竞争性TORC1/TORC2抑制剂,包括PI-103、PP242、PP30和托林1(Torin 1)。其他TOR抑制剂包括FKBP12增强剂;雷帕霉素及其衍生物,包括:CCI-779(替西罗莫司)、RAD001(依维莫司;WO 9409010)和AP23573;雷帕霉素类似物(rapalog),例如如WO98/02441和WO 01/14387中所披露,例如AP23573、AP23464或AP23841;40-(2-羟乙基)雷帕霉素、40-[3-羟基(羟甲基)甲基丙酸酯]-雷帕霉素(还称为CC1779)、40-表-(四唑基)-雷帕霉素(还称为ABT578)、32-脱氧雷帕霉素、16-戊炔氧基-32(S)-二氢雷帕霉素和WO05005434中披露的其他衍生物;以下专利中披露的衍生物:美国专利号5,258,389、WO 94/090101、WO 92/05179、美国专利号5,118,677、美国专利号5,118,678、美国专利号5,100,883、美国专利号5,151,413、美国专利号5,120,842、WO 93/111130、WO 94/02136、WO 94/02485、WO 95/14023、WO 94/02136、WO 95/16691、WO 96/41807、WO 96/41807和美国专利号5,256,790;含磷雷帕霉素衍生物(例如,WO 05016252);4H-1-苯并吡喃-4-酮衍生物(例如,美国临时申请案号60/528,340)。
免疫疗法包括但不限于抗PD-1剂、抗PDL-1剂、抗CTLA-4剂、抗LAG1剂和抗OX40剂。示例性抗PD-1抗体及其使用方法描述于以下文献中:Goldberg等人,Blood[血液]110(1):186-192(2007);Thompson等人,Clin.Cancer Res.[临床癌症研究]13(6):1757-1761(2007);和Korman等人,国际申请案号PCT/JP 2006/309606(公开案号WO 2006/121168A1),将其各自通过引用明确并入本文。包括:YervoyTM(伊匹单抗(ipilimumab))或曲美目单抗(Tremelimumab)(针对CTLA-4)、加利昔单抗(galiximab)(针对B7.1)、BMS-936558(针对PD-1)、MK-3475(针对PD-1)、AMP224(针对B7DC)、BMS-936559(针对B7-H1)、MPDL3280A(针对B7-H1)、MEDI-570(针对ICOS)、AMG557(针对B7H2)、MGA271(针对B7H3)、IMP321(针对LAG-3)、BMS-663513(针对CD137)、PF-05082566(针对CD137)、CDX-1127(针对CD27)、抗OX40(普罗维登斯卫生服务(Providence Health Services))、huMAbOX40L(针对OX40L)、阿塞西普(Atacicept)(针对TACI)、CP-870893(针对CD40)、鲁卡木单抗(Lucatumumab)(针对CD40)、达西珠单抗(Dacetuzumab)(针对CD40)、莫罗单抗-CD3(Muromonab-CD3)(针对CD3)、伊匹单抗(针对CTLA-4)。免疫疗法还包括遗传工程化的T细胞(例如,CAR-T细胞)和双特异性抗体(例如,BiTE)。
GITR激动剂包括但不限于GITR融合蛋白和抗GITR抗体(例如,二价抗GITR抗体),例如描述于以下专利中的GITR融合蛋白:美国专利号6,111,090box.c、欧洲专利号:090505B1、美国专利号8,586,023、PCT公开案号:WO 2010/003118和2011/090754;或描述于例如以下专利中的抗GITR抗体:美国专利号7,025,962、欧洲专利号:1947183B1、美国专利号7,812,135、美国专利号8,388,967、美国专利号8,591,886、欧洲专利号:EP 1866339、PCT公开案号:WO 2011/028683、PCT公开案号:WO 2013/039954、PCT公开案号:WO 2005/007190、PCT公开案号:WO 2007/133822、PCT公开案号:WO 2005/055808、PCT公开案号:WO99/40196、PCT公开案号:WO 2001/03720、PCT公开案号:WO 99/20758、PCT公开案号:WO2006/083289、PCT公开案号:WO 2005/115451、美国专利号7,618,632和PCT公开案号:WO2011/051726。
在一些实施例中,将具有结构的化合物或其立体异构体、其阻转异构体、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其阻转异构体的药学上可接受的盐以及治疗有效量的其他药物活性化合物施用有需要的患者,例如,阿糖胞苷、蛋白酶体抑制剂(例如,卡非佐米或奥普佐米)、BCl-2抑制剂(例如,维奈妥拉)、MCl-1抑制剂(例如,AMG-176)、单克隆抗体(例如,雷妥木单抗)、和免疫调节酰亚胺药物(IMiD)(例如,沙利度胺、来那度胺、泊马度胺和阿普斯特)。
在一些实施例中,将具有结构的化合物或其立体异构体、其阻转异构体、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其阻转异构体的药学上可接受的盐以及治疗有效量的其他药物活性化合物施用有需要的患者,例如,阿糖胞苷、蛋白酶体抑制剂(例如,卡非佐米或奥普佐米)、BCl-2抑制剂(例如,维奈妥拉)、MCl-1抑制剂(例如,AMG-176)、单克隆抗体(例如,雷妥木单抗)、和免疫调节酰亚胺药物(IMiD)(例如,沙利度胺、来那度胺、泊马度胺和阿普斯特)。
在一些实施例中,将具有结构的化合物或其立体异构体、其阻转异构体、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其阻转异构体的药学上可接受的盐以及治疗有效量的其他药物活性化合物施用有需要的患者,例如,阿糖胞苷、蛋白酶体抑制剂(例如,卡非佐米或奥普佐米)、BCl-2抑制剂(例如,维奈妥拉)、MCl-1抑制剂(例如,AMG-176)、单克隆抗体(例如,雷妥木单抗)、和免疫调节酰亚胺药物(IMiD)(例如,沙利度胺、来那度胺、泊马度胺和阿普斯特)。
在一些实施例中,将具有结构的化合物或其立体异构体、其阻转异构体、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其阻转异构体的药学上可接受的盐以及治疗有效量的其他药物活性化合物施用有需要的患者,例如,阿糖胞苷、蛋白酶体抑制剂(例如,卡非佐米或奥普佐米)、BCl-2抑制剂(例如,维奈妥拉)、MCl-1抑制剂(例如,AMG-176)、单克隆抗体(例如,雷妥木单抗)、和免疫调节酰亚胺药物(IMiD)(例如,沙利度胺、来那度胺、泊马度胺和阿普斯特)。
在一些实施例中,将具有结构的化合物或其立体异构体、其阻转异构体、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其阻转异构体的药学上可接受的盐以及治疗有效量的其他药物活性化合物施用有需要的患者,例如,阿糖胞苷、蛋白酶体抑制剂(例如,卡非佐米或奥普佐米)、BCl-2抑制剂(例如,维奈妥拉)、MCl-1抑制剂(例如,AMG-176)、单克隆抗体(例如,雷妥木单抗)、和免疫调节酰亚胺药物(IMiD)(例如,沙利度胺、来那度胺、泊马度胺和阿普斯特)。
在一些实施例中,将具有结构的化合物或其立体异构体、其阻转异构体、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其阻转异构体的药学上可接受的盐以及治疗有效量的其他药物活性化合物施用有需要的患者,例如,阿糖胞苷、蛋白酶体抑制剂(例如,卡非佐米或奥普佐米)、BCl-2抑制剂(例如,维奈妥拉)、MCl-1抑制剂(例如,AMG-176)、单克隆抗体(例如,雷妥木单抗)、和免疫调节酰亚胺药物(IMiD)(例如,沙利度胺、来那度胺、泊马度胺和阿普斯特)。
在一些实施例中,将具有结构的化合物或其立体异构体、其阻转异构体、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其阻转异构体的药学上可接受的盐以及治疗有效量的其他药物活性化合物施用有需要的患者,例如,阿糖胞苷、蛋白酶体抑制剂(例如,卡非佐米或奥普佐米)、BCl-2抑制剂(例如,维奈妥拉)、MCl-1抑制剂(例如,AMG-176)、单克隆抗体(例如,雷妥木单抗)、和免疫调节酰亚胺药物(IMiD)(例如,沙利度胺、来那度胺、泊马度胺和阿普斯特)。
在一些实施例中,将具有结构的化合物或其立体异构体、其阻转异构体、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其阻转异构体的药学上可接受的盐以及治疗有效量的其他药物活性化合物施用有需要的患者,例如,阿糖胞苷、蛋白酶体抑制剂(例如,卡非佐米或奥普佐米)、BCl-2抑制剂(例如,维奈妥拉)、MCl-1抑制剂(例如,AMG-176)、单克隆抗体(例如,雷妥木单抗)、和免疫调节酰亚胺药物(IMiD)(例如,沙利度胺、来那度胺、泊马度胺和阿普斯特)。
在一些实施例中,将具有结构的化合物或其立体异构体、其阻转异构体、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其阻转异构体的药学上可接受的盐以及治疗有效量的其他药物活性化合物施用有需要的患者,例如,阿糖胞苷、蛋白酶体抑制剂(例如,卡非佐米或奥普佐米)、BCl-2抑制剂(例如,维奈妥拉)、MCl-1抑制剂(例如,AMG-176)、单克隆抗体(例如,雷妥木单抗)、和免疫调节酰亚胺药物(IMiD)(例如,沙利度胺、来那度胺、泊马度胺和阿普斯特)。
在一些实施例中,将具有结构的化合物或其立体异构体、其阻转异构体、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其阻转异构体的药学上可接受的盐以及治疗有效量的其他药物活性化合物施用有需要的患者,例如,阿糖胞苷、蛋白酶体抑制剂(例如,卡非佐米或奥普佐米)、BCl-2抑制剂(例如,维奈妥拉)、MCl-1抑制剂(例如,AMG-176)、单克隆抗体(例如,雷妥木单抗)、和免疫调节酰亚胺药物(IMiD)(例如,沙利度胺、来那度胺、泊马度胺和阿普斯特)。
在一些实施例中,将具有结构的化合物或其立体异构体、其阻转异构体、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其阻转异构体的药学上可接受的盐以及治疗有效量的其他药物活性化合物施用有需要的患者,例如,阿糖胞苷、蛋白酶体抑制剂(例如,卡非佐米或奥普佐米)、BCl-2抑制剂(例如,维奈妥拉)、MCl-1抑制剂(例如,AMG-176)、单克隆抗体(例如,雷妥木单抗)、和免疫调节酰亚胺药物(IMiD)(例如,沙利度胺、来那度胺、泊马度胺和阿普斯特)。
在一些实施例中,将具有结构的化合物或其立体异构体、其阻转异构体、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其阻转异构体的药学上可接受的盐以及治疗有效量的其他药物活性化合物施用有需要的患者,例如,阿糖胞苷、蛋白酶体抑制剂(例如,卡非佐米或奥普佐米)、BCl-2抑制剂(例如,维奈妥拉)、MCl-1抑制剂(例如,AMG-176)、单克隆抗体(例如,雷妥木单抗)、和免疫调节酰亚胺药物(IMiD)(例如,沙利度胺、来那度胺、泊马度胺和阿普斯特)。
在一些实施例中,将具有结构的化合物或其立体异构体、其阻转异构体、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其阻转异构体的药学上可接受的盐以及治疗有效量的其他药物活性化合物施用有需要的患者,例如,阿糖胞苷、蛋白酶体抑制剂(例如,卡非佐米或奥普佐米)、BCl-2抑制剂(例如,维奈妥拉)、MCl-1抑制剂(例如,AMG-176)、单克隆抗体(例如,雷妥木单抗)、和免疫调节酰亚胺药物(IMiD)(例如,沙利度胺、来那度胺、泊马度胺和阿普斯特)。
在一些实施例中,将具有结构的化合物或其立体异构体、其阻转异构体、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其阻转异构体的药学上可接受的盐以及治疗有效量的其他药物活性化合物施用有需要的患者,例如,阿糖胞苷、蛋白酶体抑制剂(例如,卡非佐米或奥普佐米)、BCl-2抑制剂(例如,维奈妥拉)、MCl-1抑制剂(例如,AMG-176)、单克隆抗体(例如,雷妥木单抗)、和免疫调节酰亚胺药物(IMiD)(例如,沙利度胺、来那度胺、泊马度胺和阿普斯特)。
在一些实施例中,将具有结构的化合物或其立体异构体、其阻转异构体、其药学上可接受的盐、其立体异构体的药学上可接受的盐或其阻转异构体的药学上可接受的盐以及治疗有效量的其他药物活性化合物施用有需要的患者,例如,阿糖胞苷、蛋白酶体抑制剂(例如,卡非佐米或奥普佐米)、BCl-2抑制剂(例如,维奈妥拉)、MCl-1抑制剂(例如,AMG-176)、单克隆抗体(例如,雷妥木单抗)、和免疫调节酰亚胺药物(IMiD)(例如,沙利度胺、来那度胺、泊马度胺和阿普斯特)。
本文所述的化合物可以与本文所披露的药剂或其他适合的药剂组合使用,这取决于所治疗的病症。因此,在一些实施例中,本披露的一种或多种化合物将与如上所述的其他药剂共施用。在用于组合疗法中时,本文所述的化合物与第二药剂同时或分开施用。这种组合施用可以包括以相同剂型同时施用两种药剂、以单独剂型同时施用和分开施用。也就是说,本文所述的化合物和上述任何药剂可以一起配制于相同剂型中并同时施用。可替代地,本披露的化合物和上述任何药剂可以同时施用,其中两种药剂存在于单独配制品中。在另一个替代方案中,可以在施用本披露的化合物后立即施用上述任何药剂,或反之亦然。在单独施用方案的一些实施例中,本披露的化合物和上述任何药剂的施用相隔几分钟,或相隔几小时,或相隔几天。
由于本发明的一个方面考虑了用可以分开施用的药学活性化合物的组合治疗疾病/病症,本发明进一步涉及以试剂盒形式组合单独的药物组合物。该试剂盒包含两种单独的药物组合物:本发明的化合物和第二药物化合物。该试剂盒包含用于容纳单独组合物的容器,例如分开的瓶子或分开的箔袋。容器的其他实例包括注射器、盒和袋。在一些实施例中,该试剂盒包含单独组分的使用说明。在优选地以不同剂型(例如,口服和肠胃外)施用单独组分时,以不同剂量间隔施用时,或在开方的医护专业人员需要组合中个别组分的滴定时,试剂盒形式特别有利。
实例
方法1
实例1-1:1-(4-(6-(2-溴-5-羟苯基)-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-基)丙-2-烯-1-酮
步骤1:2-氨基-4-溴-5-氯-3-氟苯甲酸(中间体A)。将2-氨基-4-溴-3-氟苯甲酸(3.91g,16.71mmol,英国斯托克波特市(Stockport)阿波罗科学有限公司(ApolloScientific Ltd.))和N-氯代琥珀酰亚胺(1.36mL,16.7mmol)于N,N-二甲基甲酰胺(33mL)中的混合物在70℃下搅拌20h。然后允许反应混合物冷却至室温,添加冰水(40mL),并将所得混合物搅拌1h。将所得沉淀通过过滤收集,用水洗涤,并在真空中干燥,以得到2-氨基-4-溴-5-氯-3-氟苯甲酸。1H NMR(400MHz,DMSO-d6)δ7.69(1H,d,J=2.0Hz),6.48–7.23(2H,brs)。19F NMR(376MHz,DMSO-d6)δ–119.70(1F,s)。m/z(ESI,+ve)270.0(M+H)+。
步骤2:2-氨基-4-溴-5-氯-3-氟苯甲酰胺(中间体B)。将氯化铵(1.10g,20.6mmol)和二异丙基乙胺(5.13mL,29.5mmol)依序添加至2-氨基-4-溴-5-氯-3-氟苯甲酸(中间体A,3.96g,14.7mmol)和TBTU(4.97g,15.5mmol,美国肯塔基州路易斯维尔(Louisville)先进化学技术公司(Advanced Chem Tech))于N,N-二甲基甲酰胺(30mL)中的混合物中,并将所得物在室温下搅拌30min。然后将反应混合物添加至饱和碳酸氢钠水溶液中并搅拌15min。将所得沉淀通过过滤收集,用水洗涤,并在真空中干燥,以得到2-氨基-4-溴-5-氯-3-氟苯甲酰胺。1H NMR(400MHz,DMSO-d6)δ8.03(1H,br s),7.72(1H,d,J=2.0Hz),7.47(1H,br s),6.86(2H,s)。19F NMR(376MHz,DMSO-d6)δ–120.79(1F,s)。m/z(ESI,+ve)268.9(M+H)+。
步骤3:2-氨基-4-溴-5-氯-3-氟苯并硫酰胺将劳森试剂(2.81g,6.95mmol)添加至THF(77mL)中的2-氨基-4-溴-5-氯-3-氟苯甲酰胺(中间体B,3.10g,11.59mmol)中,并将所得混合物在室温下搅拌1h。然后将反应混合物用EtOAc(75mL)稀释,并依序用2M HCl水溶液(50mL)、饱和碳酸氢钠水溶液(50mL)和盐水(50mL)洗涤。然后将有机萃取物经Na2SO4干燥,通过过滤收集,并在真空中浓缩。残余物的色谱纯化(硅胶,DCM中的0-3%MeOH)提供2-氨基-4-溴-5-氯-3-氟苯并硫酰胺:1H NMR(400MHz,DMSO-d6)δ9.93-10.15(1H,m),9.63(1H,brs),7.28(1H,d,J=1.96Hz),6.34(2H,s)。19F NMR(376MHz,DMSO-d6)δ-119.52(1F,s)。m/z(ESI,+ve)284.8(M+H)+。
步骤4:6-溴-5-氯-7-氟苯并[c]异噻唑-3-胺将过氧化氢(30wt%于水中,2.93mL,28.7mmol)逐滴添加至2-氨基-4-溴-5-氯-3-氟苯并硫酰胺(2.71g,9.55mmol)于吡啶(32mL)中的冰冷却溶液中,并且随后允许所得混合物升温至室温并搅拌24h。添加水(50mL),并且将沉淀的固体通过过滤收集,用水洗涤,并在真空中干燥,以得到6-溴-5-氯-7-氟苯并[c]异噻唑-3-胺:1H NMR(400MHz,DMSO-d6)δ8.12-8.26(2H,m),7.95-8.06(1H,m)。19FNMR(376MHz,DMSO-d6)δ–114.32(1F,s)。m/z(ESI,+ve)283.0(M+H)+。
步骤5:6-溴-3,5-二氯-7-氟苯并[c]异噻唑(中间体C)向6-溴-5-氯-7-氟苯并[c]异噻唑-3-胺(2.47g,8.78mmol)、水(12mL)和浓盐酸(37wt%,12mL,395mmol)的冰冷却混合物中缓慢添加亚硝酸钠(0.788g,11.4mmol)于水(2.0mL)中的溶液。将所得混合物在0℃下搅拌2.5h,然后在0℃下添加氯化铜(I)(1.39g,14.1mmol)于浓盐酸(37wt%,12mL,395mmol)中的混合物。随后允许反应混合物升温至室温并搅拌20h。将反应混合物用水(50mL)稀释,并且将沉淀的固体通过过滤收集,并在真空中干燥。将所收集的材料吸收于(3:1)DCM:MeOH(200mL)中,并依序用水(200mL)和盐水(100mL)洗涤。然后将有机层经Na2SO4干燥,过滤,并在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0-20%EtOAc)得到6-溴-3,5-二氯-7-氟苯并[c]异噻唑:1H NMR(400MHz,DMSO-d6)δ7.99(1H,d,J=1.57Hz)。19F NMR(376MHz,DMSO-d6)δ–111.48(1F,s)。m/z(ESI,+ve)425.0(M+H)+。
步骤6:4-(6-溴-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯(中间体D)将6-溴-3,5-二氯-7-氟苯并[c]异噻唑(中间体C,150mg,0.497mmol)和1-Boc-哌嗪(204mg,1.09mmol)于N,N-二甲基甲酰胺(2.0mL)中的混合物在室温下搅拌20h。然后使反应混合物吸附至硅胶上并进行色谱纯化(硅胶,庚烷中的0-20%EtOAc),以提供4-(6-溴-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯。1H NMR(400MHz,氯仿-d)δ7.60(1H,d,J=1.56Hz),3.68-3.79(4H,m),3.40-3.51(4H,m),1.26(9H,s)。m/z(ESI,+ve)451.8(M+H)+。
步骤7:4-(6-(2-溴-5-甲氧基苯基)-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯将4-(6-溴-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯(中间体D,111mg,0.247mmol)、2-溴-5-甲氧基苯硼酸(0.114mL,0.494mmol)、碳酸钠(0.041mL,0.988mmol)和四(三苯膦)钯(14.3mg,0.012mmol)于1,4-二噁烷(1.6mL)和水(0.4mL)中的混合物在90℃下加热21h。然后将反应混合物在真空中浓缩,吸附至硅胶上,并通过柱色谱(硅胶,庚烷中的0-20%(3:1)EtOAc/EtOH)纯化,以供给4-(6-(2-溴-5-甲氧基苯基)-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯:m/z(ESI,+ve)558.1(M+H)+。
步骤8:1-(4-(6-(2-溴-5-羟苯基)-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-基)丙-2-烯-1-酮将氯化氢(4M于1,4-二噁烷中,2.0mL,8.0mmol)添加至4-(6-(2-溴-5-甲氧基苯基)-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯(107mg,0.192mmol)和甲醇(2.0mL)的混合物中,并将所得混合物在室温下搅拌1h。然后将反应混合物在真空中浓缩,以得到6-(2-溴-5-甲氧基苯基)-5-氯-7-氟-3-(哌嗪-1-基)苯并[c]异噻唑:m/z(ESI,+ve)458.0(M+1)+。
向此材料(88mg)中添加二氯甲烷(2mL)中的N,N-二异丙基乙胺(0.101mL,0.578mmol),并使所得混合物冷却至0℃。添加丙烯酰氯(0.26M于DCM中,0.75mL,0.19mmol),并将所得混合物在0℃下搅拌10min。将反应混合物在真空中浓缩,以提供1-(4-(6-(2-溴-5-甲氧基苯基)-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-基)丙-2-烯-1-酮:m/z(ESI,+ve)512.0(M+H)+。
对于不含甲醚保护基团的化合物,在这个阶段纯化粗材料。对于带有甲醚保护基团的化合物,将粗材料不经纯化即用于接下来的转化中:
将所得1-(4-(6-(2-溴-5-甲氧基苯基)-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-基)丙-2-烯-1-酮吸收于1,2-二氯乙烷(2.0mL)中并冷却至0℃。添加三溴化硼溶液(1.0M于己烷中,0.97mL,0.97mmol),并将所得混合物在0℃下搅拌1h。然后将反应混合物添加至饱和碳酸氢钠水溶液(2.0mL)中并用(2:1)DCM/MeOH(10mL)萃取。将有机萃取物经Na2SO4干燥,过滤,并在真空中浓缩。残余物的色谱纯化(硅胶,DCM中的0-3%MeOH)提供1-(4-(6-(2-溴-5-羟苯基)-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-基)丙-2-烯-1-酮:1H NMR(400MHz,DMSO-d6)δ9.99(br s,1H),8.04(s,1H),7.55(d,J=8.7Hz,1H),6.81-6.94(m,2H),6.79(d,J=2.9Hz,1H),6.19(dd,J=16.7,2.2Hz,1H),5.77(dd,J=10.5,2.2Hz,1H),3.87(br d,J=19.5Hz,4H),3.63(br t,J=5.1Hz,4H)。19F NMR(376MHz,DMSO-d6)δ–124.16(1F,s)。m/z(ESI,+ve)498.0(M+H)+
表1(b):遵循上文方法1步骤1-8中所述的程序制备化合物1-2至1-28,如下:
方法2
实例2-1:1-(4-(5-氯-6-(3-羟基-1-萘基)[1,2]噻唑并[3,4-b]吡啶-3-基)-1-哌嗪基)-2-丙烯-1-酮
步骤1:2-氨基-6-溴-5-氯烟酸。将N-氯代琥珀酰亚胺(2.78g,20.8mmol)添加至2-氨基-6-溴烟酸(4.51g,20.8mmol,美国伊利诺伊州阿灵顿海茨市方舟制药公司)于DMF(75mL)中的溶液中,并将所得混合物在70℃下加热2.5h。然后停止加热,并继续搅拌16h。随后将反应混合物倾倒至冰水中。在冰已融化后,将所得浆液经由烧结玻璃漏斗过滤。将所收集的固体风干,提供2-氨基-6-溴-5-氯烟酸:1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.64(br.s,2H)。m/z(ESI,+ve)250.9(M+H)+。
步骤2:4-(2-氨基-6-溴-5-氯烟酰基)哌嗪-1-甲酸叔丁酯。向2-氨基-6-溴-5-氯烟酸(1.12g,4.5mmol)于DMF(14mL)中的溶液中添加TBTU(1.93g,6.0mmol)。在5min后,将反应依序用1-Boc-哌嗪(912mg,4.9mmol)和DIPEA(2.33mL,13.4mmol)处理。将所得溶液在室温下搅拌25h,添加饱和NaHCO3水溶液(75mL),并将所得混合物用DCM萃取。将有机层分离并依序用水(2×)洗涤,经无水硫酸钠干燥,并在真空中浓缩。残余物的色谱纯化(硅胶,DCM中的0至7%MeOH)供给4-(2-氨基-6-溴-5-氯烟酰基)哌嗪-1-甲酸叔丁酯:1H NMR(400MHz,DMSO-d6)δ7.58(s,1H),6.66(s,2H),3.33(s,8H),1.40(s,9H)。m/z(ESI,+ve)419.0(M+H)+。
步骤3:4-(2-氨基-6-溴-5-氯吡啶-3-硫羰基)哌嗪-1-甲酸叔丁酯。将劳森试剂(353mg,0.87mmol)添加至4-(2-氨基-6-溴-5-氯烟酰基)哌嗪-1-甲酸叔丁酯(610mg,1.45mmol)于THF(7.5mL)中的溶液中,并将所得溶液在50℃下搅拌2.5h。然后允许反应混合物冷却至室温,并依序用水(10mL)和1N HCl水溶液(4mL)处理。将所得混合物用EtOAc(2×)萃取,并将合并的萃取物经无水硫酸钠干燥,过滤,并在真空中浓缩。残余物的色谱纯化(硅胶,DCM中的0-6%MeOH)提供4-(2-氨基-6-溴-5-氯吡啶-3-硫羰基)哌嗪-1-甲酸叔丁酯:1HNMR(400MHz,DMSO-d6)δ7.47(s,1H),6.58(br.s,2H),4.30(ddd,J=13.3,6.3,3.3Hz,1H),4.01-4.13(m,2H),3.68-3.77(m,1H),3.51-3.59(m,1H),3.40-3.50(m,3H),1.41(s,9H)。m/z(ESI,+ve)434.9(M+H)+。
步骤4:4-(5,6-二氯异噻唑并[3,4-b]吡啶-3-基)哌嗪-1-甲酸叔丁酯。将NCS(116mg,0.87mmol)添加至4-(2-氨基-6-溴-5-氯吡啶-3-硫羰基)哌嗪-1-甲酸叔丁酯(343mg,0.79mmol)于THF(8mL)中的溶液中,并将所得溶液在室温下搅拌20min。然后添加水(10mL)与1M亚硫酸钠水溶液(5mL)的混合物,并将所得混合物用EtOAc(2×)萃取。将合并的萃取物经无水硫酸钠干燥,过滤,并在真空中浓缩。残余物的色谱纯化(硅胶,DCM中的0至4%MeOH)提供4-(5,6-二氯异噻唑并[3,4-b]吡啶-3-基)哌嗪-1-甲酸叔丁酯:1H NMR(400MHz,氯仿-d)δ8.10(s,1H),3.69-3.80(m,4H),3.50-3.57(m,4H),1.51(s,9H)。m/z(ESI,+ve)389.0(M+H)+。
步骤5:4-(5-氯-6-(3-甲氧基萘-1-基)异噻唑并[3,4-b]吡啶-3-基)哌嗪-1-甲酸叔丁酯。将4-(5,6-二氯异噻唑并[3,4-b]吡啶-3-基)哌嗪-1-甲酸叔丁酯(154mg,0.36mmol)、(3-甲氧基萘-1-基)硼酸(287mg,1.42mmol)和碳酸铯(463mg,1.42mmol)于1,4-二噁烷(8mL)和水(2mL)中的混合物用氩鼓泡,之后添加四(三苯膦)钯(41mg,0.04mmol)。将反应混合物再次用氩鼓泡,然后在密封管中在100℃下加热25h。在冷却至室温后,将反应混合物用盐水(40mL)稀释并用EtOAc(2×)萃取。将合并的萃取物经硫酸钠干燥,过滤,并在真空中浓缩。残余物的色谱纯化(硅胶,DCM中的0-3.5%MeOH)得到4-(5-氯-6-(3-甲氧基萘-1-基)异噻唑并[3,4-b]吡啶-3-基)哌嗪-1-甲酸叔丁酯:m/z(ESI,+ve)511.1(M+H)+。
步骤6:5-氯-6-(3-甲氧基萘-1-基)-3-(哌嗪-1-基)异噻唑并[3,4-b]吡啶。将三氟乙酸(560μL,7.6mmol)添加至4-(5-氯-6-(3-甲氧基萘-1-基)异噻唑并[3,4-b]吡啶-3-基)哌嗪-1-甲酸叔丁酯(155mg,0.30mmol)于DCM(6mL)中的溶液中,并将所得溶液在室温下搅拌2.3h,然后在真空中浓缩。残余物的色谱纯化(硅胶,DCM中的0-25%MeOH)供给作为TFA盐的5-氯-6-(3-甲氧基萘-1-基)-3-(哌嗪-1-基)异噻唑并[3,4-b]吡啶:1H NMR(400MHz,DMSO-d6)δ8.78(s,1H),7.94(d,J=8.2Hz,1H),7.46-7.53(m,2H),7.31(d,J=3.7Hz,2H),7.19(d,J=2.4Hz,1H),3.95(s,3H),3.76-3.83(m,4H),3.35-3.43(m,4H)。m/z(ESI,+ve)411.0(M+H)+。
步骤7:1-(4-(5-氯-6-(3-甲氧基-1-萘基)[1,2]噻唑并[3,4-b]吡啶-3-基)-1-哌嗪基)-2-丙烯-1-酮。向5-氯-6-(3-甲氧基萘-1-基)-3-(哌嗪-1-基)异噻唑并[3,4-b]吡啶(TFA盐;100mg,0.19mmol)于DCM(5mL)中的冰冷却浆液中依序添加DIPEA(100μL,0.57mmol)和丙烯酰氯(23μL,0.29mmol)。将所得溶液在0℃下搅拌70min,并添加饱和NaHCO3水溶液(15mL)。将所得混合物用DCM(3×)萃取,并将合并的萃取物经硫酸钠干燥,过滤,并在真空中浓缩。残余物的色谱纯化(硅胶,DCM中的0至7%MeOH)提供1-(4-(5-氯-6-(3-甲氧基-1-萘基)[1,2]噻唑并[3,4-b]吡啶-3-基)-1-哌嗪基)-2-丙烯-1-酮:1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),7.93(d,J=8.2Hz,1H),7.45-7.54(m,2H),7.25-7.39(m,2H),7.19(d,J=2.5Hz,1H),6.86(dd,J=16.7,10.3Hz,1H),6.19(dd,J=16.7,2.3Hz,1H),5.77(dd,J=10.5,2.3Hz,1H),3.94(s,3H),3.81-3.94(m,4H),3.69-3.76(m,4H)。m/z(ESI,+ve)465.0(M+H)+。
步骤8:1-(4-(5-氯-6-(3-羟基-1-萘基)[1,2]噻唑并[3,4-b]吡啶-3-基)-1-哌嗪基)-2-丙烯-1-酮。将三溴化硼(1.0M于己烷中,400μL,0.40mmol)(逐滴)添加至1-(4-(5-氯-6-(3-甲氧基萘-1-基)异噻唑并[3,4-b]吡啶-3-基)哌嗪-1-基)丙-2-烯-1-酮(37.3mg,0.08mmol)于1,2-二氯乙烷(4mL)中的冰冷却溶液中,并将所得混合物在0℃下搅拌2.3h。然后添加饱和NaHCO3水溶液(5mL),并将所得混合物用(4:1)DCM:MeOH(2×)萃取。将合并的萃取物经硫酸钠干燥,过滤,并在真空中浓缩。残余物的色谱纯化(硅胶,DCM中的0-6%MeOH)提供1-(4-(5-氯-6-(3-羟基-1-萘基)[1,2]噻唑并[3,4-b]吡啶-3-基)-1-哌嗪基)-2-丙烯-1-酮:1H NMR(400MHz,DMSO-d6)δ9.97(br.s,1H),8.72(s,1H),7.79(d,J=8.6Hz,1H),7.42(t,J=7.1Hz,1H),7.17-7.28(m,3H),7.09(d,J=2.1Hz,1H),6.86(dd,J=16.7,10.5Hz,1H),6.19(dd,J=16.7,2.3Hz,1H),5.74-5.79(m,1H),3.81-3.95(m,4H),3.68-3.76(m,4H)。m/z(ESI,+ve)451.0(M+H)+。
表2:遵循上文方法2步骤1-8中所述的程序制备化合物2-2至2-6,如下:
方法3
实例3-1:1-(4-(5-氯-7-氟-6-(3-羟基萘-1-基)苯并[c]异噻唑-3-基)哌嗪-1-基)丙-2-烯-1-酮
步骤1:1-(4-(6-溴-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-基)丙-2-烯-1-酮。将DCM中的0.2M丙烯酰氯(1.240mL,0.248mmol)添加至6-溴-5-氯-7-氟-3-(哌嗪-1-基)苯并[c]异噻唑(中间体D,87mg,0.248mmol)和N,N-二异丙基乙胺(0.129mL,0.744mmol)于二氯甲烷(2.3mL)中的冰冷却溶液中,并将所得混合物在0℃下搅拌10min。然后将混合物在真空中浓缩,并将残余物在MeOH(2mL)中进行超声波处理。将悬浮的固体通过过滤收集,用MeOH洗涤,并在真空中干燥,以提供1-(4-(6-溴-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-基)丙-2-烯-1-酮:1H NMR(400MHz,DMSO-d6)δ8.13(1H,d,J=1.56Hz),6.84(1H,dd,J=10.47,16.73Hz),6.17(1H,dd,J=2.35,16.63Hz),5.66-5.82(1H,m),3.73-3.93(4H,m),3.55-3.67(4H,m)。19F NMR(376MHz,DMSO-d6)δ–113.39(s,1F)。m/z(ESI,+ve)405.8(M+H)+。
步骤2:1-(4-(5-氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-基)哌嗪-1-基)丙-2-烯-1-酮(中间体E)。将1-(4-(6-溴-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-基)丙-2-烯-1-酮(中间体D,79mg,0.20mmol)、(3-甲氧基萘-1-基)硼酸(47.3mg,0.234mmol)、四(三苯膦)钯(22.5mg,0.020mmol)和碳酸钠(83mg,0.78mmol)于水(0.500mL)和1,4-二噁烷(2.0mL)中的混合物在100℃下加热16h。然后使反应混合物吸附至硅胶上并进行色谱纯化(硅胶,DCM中的0-3%MeOH),以得到1-(4-(5-氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-基)哌嗪-1-基)丙-2-烯-1-酮:m/z(ESI,+ve)482.0(M+H)+。
步骤3:1-(4-(5-氯-7-氟-6-(3-羟基萘-1-基)苯并[c]异噻唑-3-基)哌嗪-1-基)丙-2-烯-1-酮。将三溴化硼(1.0M于己烷中,0.664mL,0.664mmol)添加至1-(4-(5-氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-基)哌嗪-1-基)丙-2-烯-1-酮(64mg,0.13mmol)于1,2-二氯乙烷(2.0mL)中的冰冷却溶液中,并将所得混合物在0℃下搅拌1h。然后将反应混合物添加至饱和碳酸氢钠水溶液(2.0mL)中,并将所得混合物用(2:1)DCM:MeOH(10mL)萃取。将有机萃取物经Na2SO4干燥,过滤,并在真空中浓缩。残余物的色谱纯化(硅胶,DCM中的0-3%MeOH)得到1-(4-(5-氯-7-氟-6-(3-羟基萘-1-基)苯并[c]异噻唑-3-基)哌嗪-1-基)丙-2-烯-1-酮:1H NMR(400MHz,DMSO-d6)δ9.90-10.04(1H,m),8.10(1H,s),7.80(1H,d,J=8.41Hz),7.43(1H,ddd,J=1.96,6.11,8.17Hz),7.16-7.31(3H,m),7.07(1H,d,J=2.35Hz),6.87(1H,dd,J=10.47,16.73Hz),6.19(1H,dd,J=2.25,16.73Hz),5.77(1H,dd,J=2.25,10.47Hz),3.88(4H,br d,J=19.56Hz),3.61-3.72(4H,m)。19F NMR(376MHz,DMSO-d6)δ–123.78(s,1F)。m/z(ESI,+ve)468.0(M+H)+。
中间体E的替代合成
1-(4-(5-氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-基)哌嗪-1-基)丙-2-烯-1-酮(中间体E,替代合成):向6-溴-3,5-二氯-7-氟苯并[c]异噻唑(中间体C,715mg,2.37mmol)于N,N-二甲基甲酰胺(5.6mL)中的溶液中依序添加1-(哌嗪-1-基)丙-2-烯-1-酮双(2,2,2-三氟乙酸盐)(961mg,2.61mmol,美国新泽西州布里奇沃特市(Bridgewater)艾诺威化学有限公司(eNovation Chemicals LLC))于N,N-二甲基甲酰胺(5.6mL)中的溶液和N,N-二异丙基乙胺(1.243mL,7.12mmol)。将所得混合物在室温下搅拌1h,然后在50℃下加热22h。在冷却至室温后,将反应混合物添加至冰水(10mL)中,并将所得沉淀通过过滤收集,并用水洗涤。将所收集的固体吸附至硅胶上并进行色谱纯化(硅胶,DCM中的0-3%MeOH),以供给1-(4-(6-溴-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-基)丙-2-烯-1-酮。
表3:遵循上文方法3步骤1-3中所述的程序制备化合物3-2至3-24,如下:
方法4
实例4-1:1-(6-(5-氯-7-氟-6-(3-羟基萘-1-基)苯并[c]异噻唑-3-基)-2,6-二氮杂螺[3.3]庚-2-基)丙-2-烯-1-酮。
步骤1:6-(6-溴-5-氯-7-氟苯并[c]异噻唑-3-基)-2,6-二氮杂螺[3.3]庚烷-2-甲酸叔丁酯。将6-溴-3,5-二氯-7-氟苯并[c]异噻唑(中间体C,169mg,0.562mmol)和2-Boc-2,6-二氮杂螺[3.3]庚烷(212mg,1.07mmol,美国宾夕法尼亚州布里斯托尔市爱思特公司)于DMF(3.5mL)中的混合物在室温下搅拌5h。添加冰水(5mL),并将所得混合物搅拌15min。将所得沉淀通过过滤收集,用水洗涤,并在真空中干燥,以提供6-(6-溴-5-氯-7-氟苯并[c]异噻唑-3-基)-2,6-二氮杂螺[3.3]庚烷-2-甲酸叔丁酯:1H NMR(400MHz,DMSO-d6)δ7.52-7.74(1H,m),4.55(4H,s),4.09(4H,s),1.38(9H,s)。19F NMR(376MHz,DMSO-d6)δ–113.55(1F,s)。m/z(ESI,+ve)464.0(M+1)。
步骤2:1-(6-(6-溴-5-氯-7-氟苯并[c]异噻唑-3-基)-2,6-二氮杂螺[3.3]庚烷-2-基)丙-2-烯-1-酮。将氯化氢溶液(4M于1,4-二噁烷中,5.0mL,20mmol)添加至甲醇(10mL)中的6-(6-溴-5-氯-7-氟苯并[c]异噻唑-3-基)-2,6-二氮杂螺[3.3]庚烷-2-甲酸叔丁酯(249mg,0.538mmol)中,并将所得混合物在室温下搅拌2h。然后将反应混合物在真空中浓缩,以提供6-溴-5-氯-7-氟-3-(2,6-二氮杂螺[3.3]庚烷-2-基)苯并[c]异噻唑:m/z(ESI,+ve)363.8(M+1)+。
向此材料中添加二氯甲烷(3.0mL)中的N,N-二异丙基乙胺(0.281mL,1.61mmol),并使所得混合物冷却至0℃。然后添加丙烯酰氯(0.2M于DCM中,2.69mL,0.538mmol),并将所得混合物在0℃下搅拌10min。然后将反应混合物在真空中浓缩,并将残余物进行色谱纯化(硅胶,DCM中的0-10%(3:1)EtOAc/EtOH),以提供1-(6-(6-溴-5-氯-7-氟苯并[c]异噻唑-3-基)-2,6-二氮杂螺[3.3]庚烷-2-基)丙-2-烯-1-酮:1H NMR(400MHz,DMSO-d6)δ7.65(1H,d,J=1.4Hz),6.25-6.36(1H,m),6.10(1H,dd,J=17.0,2.3Hz),5.64-5.72(1H,m),4.58(4H,s),4.47(2H,s),4.18(2H,s)。19F NMR(376MHz,DMSO-d6)δ–113.54(1F,s)。m/z(ESI,+ve)418.0(M+H)+。
步骤3:1-(6-(5-氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-基)-2,6-二氮杂螺[3.3]庚烷-2-基)丙-2-烯-1-酮。将1-(6-(6-溴-5-氯-7-氟苯并[c]异噻唑-3-基)-2,6-二氮杂螺[3.3]庚烷-2-基)丙-2-烯-1-酮(102mg,0.245mmol)、(3-甲氧基萘-1-基)硼酸(59.3mg,0.294mmol)、四(三苯膦)钯(28.3mg,0.024mmol)和碳酸钠(104mg,0.979mmol)于水(0.5mL)和1,4-二噁烷(2.0mL)中的混合物在100℃下加热1h。然后使反应混合物吸附至硅胶上并进行色谱纯化(硅胶,DCM中的0-5%MeOH)。将经纯化材料在MeOH中进行超声波处理,并将悬浮的固体通过过滤收集,用MeOH洗涤,并在真空中干燥,以提供1-(6-(5-氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-基)-2,6-二氮杂螺[3.3]庚烷-2-基)丙-2-烯-1-酮:1H NMR(400MHz,DMSO-d6)δ7.93(1H,d,J=8.4Hz),7.67(1H,s),7.45-7.57(2H,m),7.23-7.36(2H,m),7.16(1H,d,J=2.5Hz),6.27-6.39(1H,m),6.11(1H,dd,J=17.0,2.2Hz),5.65-5.76(1H,m),4.58-4.67(4H,m),4.50(2H,s),4.22(2H,s),3.93(3H,s)。19FNMR(376MHz,DMSO-d6)δ–123.88(1F,s)。m/z(ESI,+ve)494.0(M+H)+。
步骤4:1-(6-(5-氯-7-氟-6-(3-羟基萘-1-基)苯并[c]异噻唑-3-基)-2,6-二氮杂螺[3.3]庚烷-2-基)丙-2-烯-1-酮。将三溴化硼(1.0M于己烷中,0.638mL,0.638mmol)添加至1,2-二氯乙烷(2.0mL)中的冰冷却的1-(6-(5-氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-基)-2,6-二氮杂螺[3.3]庚烷-2-基)丙-2-烯-1-酮(63mg,0.128mmol)中,并将所得混合物在0℃下搅拌2h。然后将反应混合物添加至饱和碳酸氢钠水溶液(2.0mL)中,并将所得混合物用(2:1)DCM:MeOH(10mL)萃取。将有机萃取物经Na2SO4干燥,过滤,并在真空中浓缩。残余物的色谱纯化(硅胶,DCM中的0-2%MeOH(含有2M氨))得到1-(6-(5-氯-7-氟-6-(3-羟基萘-1-基)苯并[c]异噻唑-3-基)-2,6-二氮杂螺[3.3]庚烷-2-基)丙-2-烯-1-酮:1HNMR(400MHz,DMSO-d6)δ9.82-10.04(1H,m),7.79(1H,d,J=8.2Hz),7.66(1H,s),7.43(1H,dt,J=8.3,4.0Hz),7.26(1H,d,J=2.3Hz),7.22(2H,d,J=3.7Hz),7.05(1H,d,J=2.3Hz),6.26–6.38(1H,m),6.12(1H,dd,J=16.8,2.2Hz),5.66–5.72(1H,m),4.58–4.67(4H,m),4.50(2H,s),4.22(2H,s)。19F NMR(376MHz,DMSO-d6)δ–123.98(1F,s)。m/z(ESI,+ve)480.0(M+H)+。表4:遵循上文方法4步骤1-4中所述的程序制备化合物4-2至4-9,如下:
方法5
实例5-1:N-(1-(5-氯-7-氟-6-(3-羟基-1-萘基)-2,1-苯并噻唑-3-基)-3-氮杂环丁烷基)-N-甲基-2-丙烯酰胺
步骤1:2-氨基-5-氯-3-氟-4-(3-甲氧基萘-1-基)苯甲酰胺。将(3-甲氧基萘-1-基)硼酸(2.04g,10.1mmol)、2-氨基-4-溴-5-氯-3-氟苯甲酰胺(中间体B(1.93g,7.20mmol))、四(三苯膦)钯(0.832g,0.720mmol)、碳酸钠(1.2mL,28.8mmol)于水(9.6mL)和1,4-二噁烷(38.4mL)中的混合物在90℃下加热2天。然后将反应混合物通过硅藻土垫过滤,用EtOAc洗涤。将滤液用饱和NaHCO3水溶液(50mL)稀释,并用EtOAc(3×50mL)萃取。将有机萃取物用盐水(30mL)洗涤,并经Na2SO4干燥。然后将溶液过滤并将滤液在真空中浓缩。使残余物悬浮于MeOH(5mL)中,并将悬浮的固体通过过滤收集,用MeOH洗涤,并干燥,以得到2-氨基-5-氯-3-氟-4-(3-甲氧基萘-1-基)苯甲酰胺。经浓缩滤液的色谱纯化(硅胶,庚烷中的0%至100%(3:1)EtOAc-EtOH)提供另外的2-氨基-5-氯-3-氟-4-(3-甲氧基萘-1-基)苯甲酰胺。1H NMR(400MHz,DMSO-d6)δ8.01-8.17(m,1H),7.92(d,J=8.2Hz,1H),7.75(s,1H),7.43-7.55(m,3H),7.23-7.34(m,2H),7.10(d,J=2.5Hz,1H),6.73(s,2H),3.93(s,3H)。m/z(ESI,+ve)345.0(M+H)+。
步骤2:2-氨基-5-氯-3-氟-4-(3-甲氧基萘-1-基)硫代苯甲酰胺。向2-氨基-5-氯-3-氟-4-(3-甲氧基萘-1-基)苯甲酰胺(2.11g,6.12mmol)于四氢呋喃(41mL)中的溶液中添加劳森试剂(1.49mL,3.67mmol),并将所得混合物在室温下搅拌1h。然后将反应混合物用EtOAc(60mL)稀释,并依序用2MHCl(60mL)、饱和NaHCO3水溶液(60mL)和盐水(60mL)洗涤。将有机萃取物经Na2SO4干燥,过滤,并在真空中浓缩。将残余物在DCM(5mL)中进行超声波处理,并将所得沉淀通过过滤收集,用DCM洗涤,并在真空中干燥,提供2-氨基-5-氯-3-氟-4-(3-甲氧基萘-1-基)硫代苯甲酰胺。滤液的色谱纯化(硅胶,庚烷中的0%至100%(3:1)EtOAc-EtOH)得到另外的2-氨基-5-氯-3-氟-4-(3-甲氧基萘-1-基)硫代苯甲酰胺:m/z(ESI,+ve)361.0(M+H)+。
步骤3:5-氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-胺。将过氧化氢溶液(30%于水中,2.2mL,21.3mmol)缓慢添加至2-氨基-5-氯-3-氟-4-(3-甲氧基萘-1-基)硫代苯甲酰胺(1.92g,5.33mmol)于吡啶(18mL)中的冰冷却溶液中。允许所得混合物升温至室温并在室温下搅拌18h。然后将反应混合物用水(60mL)稀释,并将所得沉淀通过过滤收集,依序用水和MeOH洗涤,并在真空中干燥,以得到5-氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-胺:1H NMR(400MHz,DMSO-d6)δ8.14(s,2H),7.99-8.03(m,1H),7.93(d,J=8.3Hz,1H),7.48-7.55(m,1H),7.47(d,J=2.3Hz,1H),7.31(d,J=3.9Hz,2H),7.16(d,J=2.5Hz,1H),3.94(s,3H)。19F NMR(376MHz,DMSO-d6)δ-124.71(s,1F)。m/z(ESI,+ve)359.0(M+H)+。
步骤4:3,5-二氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑。在65℃下将5-氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-胺(1.55g,4.31mmol)经15min逐份添加至氯化铜(II)(0.870g,6.47mmol)和亚硝酸叔丁酯(0.77mL,6.47mmol)于乙腈(43mL)中的悬浮液中。将所得混合物在65℃下搅拌30min,然后冷却至环境温度,并用冰水(50mL)稀释。将沉淀的固体通过过滤收集,用水洗涤,并在真空中干燥。将残余物在DCM(10mL)中进行超声波处理,并将悬浮的固体通过过滤收集,用DCM洗涤,并在真空中干燥,以回收未反应的5-氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-胺。将滤液在真空中浓缩,以得到3,5-二氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑。1H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.96(d,J=8.2Hz,1H),7.49-7.56(m,2H),7.28-7.36(m,2H),7.24-7.28(m,1H),3.95(s,3H)。19FNMR(376MHz,DMSO-d6)δ–122.17(s,1F)。m/z(ESI,+ve)378.0(M+H)+。
步骤5:(1-(5-氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯。将3,5-二氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑(100mg,0.264mmol)、DIPEA(0.14mL,0.793mmol)和3-Boc-3-甲基氨基氮杂环丁烷(0.098mL,0.529mmol,贝达医药科学公司(Beta Pharma Scientific,Inc.))于DMF(1.3mL)中的混合物在室温下搅拌18h。然后添加冰水(3mL),并将所得混合物搅拌15min。然后将沉淀的固体通过过滤收集,用水洗涤,并在真空中干燥,以供给(1-(5-氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯:m/z(ESI,+ve)528.0(M+H)+。
步骤6:N-(1-(5-氯-7-氟-6-(3-羟基-1-萘基)-2,1-苯并噻唑-3-基)-3-氮杂环丁烷基)-N-甲基-2-丙烯酰胺。遵循方法1步骤8中报告的程序以三个步骤从(1-(5-氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-基)氮杂环丁烷-3-基)(甲基)氨基甲酸叔丁酯(131.1mg,0.248mmol)制备标题化合物:1H NMR(400MHz,DMSO-d6)δ9.89-10.10(m,1H),7.79(d,J=8.4Hz,1H),7.73(s,1H),7.43(ddd,J=8.2,5.1,2.9Hz,1H),7.20-7.30(m,3H),7.05(d,J=2.2Hz,1H),6.81(dd,J=16.7,10.5Hz,1H),6.10-6.23(m,1H),5.69-5.81(m,1H),5.37-5.59(m,1H),4.63-4.74(m,3H),4.53-4.61(m,1H),3.14-3.23(m,3H)。19F NMR(376MHz,DMSO-d6)δ-124.10(s,1F)。m/z(ESI,+ve)468.0(M+H)+。
表5:遵循上文方法5步骤1-6中所述的程序制备化合物5-2至5-9,如下:
方法6
实例6-1:1-(4-(6-(6-氨基-3-氯-2-吡啶基)-5-氯-7-氟-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮
步骤1:4-(5-氯-7-氟-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯。将4-(6-溴-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯(中间体D,1.10g,2.45mmol)、双(频哪醇合)二硼(1.86g,7.34mmol)、乙酸钾(0.61mL,9.8mmol)和Pd(dppf)Cl2·DCM(0.537g,0.734mmol)于1,4-二噁烷(12mL)中的混合物在100℃下加热40h。然后将反应混合物在真空中浓缩并进行色谱纯化(硅胶,庚烷中的0%至100%(3:1)EtOAc-EtOH),以提供4-(5-氯-7-氟-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯:1H NMR(400MHz,DMSO-d6)δ7.85(s,1H),3.59(br d,J=4.7Hz,4H),3.44-3.54(m,4H),1.43(s,9H),1.35(s,5H),1.15(s,7H)。19F NMR(376MHz,DMSO-d6)δ-125.11(s,1F)。m/z(ESI,+ve)498.0(M+H)+。
步骤2:4-(6-(6-氨基-3-氯吡啶-2-基)-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯。将4-(5-氯-7-氟-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯(99.5mg,0.200mmol)、SPhos Pd G3(17.3mg,0.020mmol)、6-溴-5-氯吡啶-2-胺(美国加利福尼亚州圣地亚哥康比乐公司,124mg,0.6mmol)、碳酸钠(85mg,0.80mmol)于水(0.25mL)和1,2-DCE(0.75mL)中的混合物在50℃下加热2h。将反应混合物在真空中浓缩并进行色谱纯化(硅胶,庚烷中的0%至100%(3:1)EtOAc-EtOH),以得到4-(6-(6-氨基-3-氯吡啶-2-基)-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯:m/z(ESI,+ve)498.0(M+H)+。
步骤3:1-(4-(6-(6-氨基-3-氯-2-吡啶基)-5-氯-7-氟-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮。遵循方法1步骤8中报告的程序以两个步骤从4-(6-(6-氨基-3-氯吡啶-2-基)-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯(31.6mg,0.063mmol)制备标题化合物:1H NMR(400MHz,DMSO-d6)δ7.97-8.10(m,1H),7.60(d,J=8.9Hz,1H),6.86(dd,J=16.6,10.6Hz,1H),6.57(d,J=8.9Hz,1H),6.38(s,2H),6.19(dd,J=16.8,2.3Hz,1H),5.71-5.84(m,1H),3.86(br d,J=19.9Hz,4H),3.63(br d,J=1.0Hz,4H)。19F NMR(376MHz,DMSO-d6)δ-126.04(s,1F)。m/z(ESI,+ve)452.0(M+H)+。
表6:遵循上文方法6步骤1-3中所述的程序制备化合物6-2,如下:
方法7
实例7-1:1-((3R)-4-(5-氯-7-氟-6-(3-羟基-1-萘基)-2,1-苯并噻唑-3-基)-3-(二氟甲基)-1-哌嗪基)-2-丙烯-1-酮|1-((3S)-4-(5-氯-7-氟-6-(3-羟基-1-萘基)-2,1-苯并噻唑-3-基)-3-(二氟甲基)-1-哌嗪基)-2-丙烯-1-酮
步骤1:2-氨基-5-氯-3-氟-4-(3-甲氧基萘-1-基)苯甲酸。使用与方法1步骤7中所述类似的程序从中间体A制备:m/z(ESI,+ve)346.0(M+H)+。
步骤2:4-(2-氨基-5-氯-3-氟-4-(3-甲氧基萘-1-基)苯甲酰基)-3-(二氟甲基)哌嗪-1-甲酸叔丁酯。将2-氨基-5-氯-3-氟-4-(3-甲氧基萘-1-基)苯甲酸(0.150g,0.434mmol)、TBTU(0.188g,0.586mmol)、3-(二氟甲基)哌嗪-1-甲酸叔丁酯(0.123g,0.521mmol)和DIPEA(0.23mL,1.302mmol)于DMF(4mL)中的混合物在环境温度下搅拌3h。然后将反应混合物用饱和NaHCO3水溶液洗涤,并将水性洗液用EtOAc萃取。将合并的有机层经Na2SO4干燥,过滤,并在真空中浓缩。残余物的色谱纯化(硅胶,0-40%EtOAc/庚烷)提供4-(2-氨基-5-氯-3-氟-4-(3-甲氧基萘-1-基)苯甲酰基)-3-(二氟甲基)哌嗪-1-甲酸叔丁酯:m/z(ESI,+ve)586(M+Na)+。
步骤3:4-(2-氨基-5-氯-3-氟-4-(3-甲氧基萘-1-基)苯基硫羰基)-3-(二氟甲基)哌嗪-1-甲酸叔丁酯。将劳森试剂(0.041mL,0.10mmol)添加至4-(2-氨基-5-氯-3-氟-4-(3-甲氧基萘-1-基)苯甲酰基)-3-(二氟甲基)哌嗪-1-甲酸叔丁酯(0.095g,0.168mmol)于THF(4mL)中的溶液中,并将所得混合物在50℃下搅拌18h。然后将反应混合物在真空中浓缩,并通过柱色谱(硅胶,0-30%EtOAc/庚烷)纯化,以得到4-(2-氨基-5-氯-3-氟-4-(3-甲氧基萘-1-基)苯基硫羰基)-3-(二氟甲基)哌嗪-1-甲酸叔丁酯:m/z(ESI,+ve)602.2(M+Na)+。
步骤4:4-(5-氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-基)-3-(二氟甲基)哌嗪-1-甲酸叔丁酯。将NBS(0.022g,0.17mmol)添加至4-(2-氨基-5-氯-3-氟-4-(3-甲氧基萘-1-基)苯基硫羰基)-3-(二氟甲基)哌嗪-1-甲酸叔丁酯于THF(7mL)中的溶液中,并将所得混合物在环境温度下搅拌15min。将反应混合物用水稀释并用10%硫代硫酸钠洗涤。将水性洗液用EtOAc萃取,然后将合并的有机层在真空中浓缩,以得到4-(5-氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-基)-3-(二氟甲基)哌嗪-1-甲酸叔丁酯:m/z(ESI,+ve)578.2(M+H)+。
步骤5:1-((3R)-4-(5-氯-7-氟-6-(3-羟基-1-萘基)-2,1-苯并噻唑-3-基)-3-(二氟甲基)-1-哌嗪基)-2-丙烯-1-酮|1-((3S)-4-(5-氯-7-氟-6-(3-羟基-1-萘基)-2,1-苯并噻唑-3-基)-3-(二氟甲基)-1-哌嗪基)-2-丙烯-1-酮。使用与方法1步骤8中所述类似的程序来制备:1H NMR(400MHz,DMSO-d6)δ10.13(br.s.,1H)8.12(d,J=2.2Hz,1H)7.80(d,J=8.2Hz,1H)7.43(br t,J=7.0Hz,1H)7.20-7.30(m,3H)7.08(dd,J=5.8,2.2Hz,1H)6.78-6.91(m,1H)6.27-6.70(m,1H)6.20(dd,J=16.6,2.0Hz,1H)5.76-5.84(m,1H)4.73-4.87(m,1H)4.19-4.72(m,2H)3.55-3.90(m,3H)3.36-3.47(m,1H)。m/z(ESI,+ve)518.0(M+H)+。
表7:遵循上文方法7步骤1-5中所述的程序制备化合物7-2和7-3,如下:
方法8
实例8-1:6-氯-7-(2-氟-6-羟苯基)-1-(2-(2-丙烷基)苯基)-4-(4-(2-丙烯酰基)-1-哌嗪基)-2(1H)-喹唑啉酮
步骤1:4-溴-5-氯-2-氟苯甲酰胺。将4-溴-5-氯-2-氟苯甲酸(23.3g,92mmol)于亚硫酰氯(67mL,0.92mol)中的混合物在70℃下在回流冷凝器下搅拌1h。然后将反应混合物在真空中浓缩,并将残余物吸收于1,4-二噁烷(200mL)中,用氢氧化铵(30%水溶液,82mL,0.64mol)处理,并在室温下搅拌15min。将反应混合物在真空中浓缩,以得到4-溴-5-氯-2-氟苯甲酰胺:m/z(ESI,+ve)251.8(M+H)+。
步骤2:4-溴-5-氯-2-氟-N-((2-异丙基苯基)氨甲酰基)苯甲酰胺。将4-溴-5-氯-2-氟苯甲酰胺(5.90g,23.4mmol)和草酰氯(1M于DCM中;12.9mL,25.7mmol)于DCE(100mL)中的混合物在80℃下在回流冷凝器下搅拌1h。然后将反应混合物冷却至室温并添加2-异丙基苯胺(6.62mL,46.7mmol)。将所得混合物在室温下搅拌15min,然后冷却至0℃。将沉淀的固体通过过滤移除,并将所收集滤液在真空中浓缩,以得到4-溴-5-氯-2-氟-N-((2-异丙基苯基)氨甲酰基)苯甲酰胺:1H NMR(400MHz,DMSO-d6)δ11.06(br.s.,1H)10.31(s,1H)7.97-8.05(m,2H)7.82(d,J=7.2Hz,1H)7.32-7.38(m,1H)7.14-7.25(m,2H)3.11(spt,J=6.8Hz,1H)1.24(d,J=6.8Hz,6H)。19F NMR(376MHz,DMSO-d6)δ–113.6(s,1F)。m/z(ESI,+ve)412.7及414.6(M+H)+。
步骤3:7-溴-6-氯-1-(2-异丙基苯基)喹唑啉-2,4(1H,3H)-二酮(中间体F)。在-20℃下将KHMDS(1M于THF中,8.30mL,8.30mmol)添加至4-溴-5-氯-2-氟-N-((2-异丙基苯基)氨甲酰基)苯甲酰胺(1.56g,3.77mmol)于THF(19mL)中的混合物中,并允许所得混合物经1h升温至室温。然后将反应混合物用EtOAc(150mL)稀释,并用饱和氯化铵水溶液(2×100mL)洗涤。将有机层经Na2SO4干燥,过滤,并在真空中浓缩。将残余物悬浮于DCM(5mL)中,进行超声波处理,通过过滤收集,并在真空中干燥,以得到7-溴-6-氯-1-(2-异丙基苯基)喹唑啉-2,4(1H,3H)-二酮:1H NMR(400MHz,CDCl3)δ9.43(br.s.,1H)8.29(s,1H)7.55-7.59(m,2H)7.39-7.44(m,1H)7.16(d,J=7.8Hz,1H)6.75(s,1H)2.59-2.77(m,1H)1.17-1.24(m,3H)1.11(d,J=6.8Hz,3H)。m/z(ESI,+ve)392.9及395.0(M+H)+。
步骤4:6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基苯基)喹唑啉-2,4(1H,3H)-二酮。将7-溴-6-氯-1-(2-异丙基苯基)喹唑啉-2,4(1H,3H)-二酮(中间体F,1.17g,2.96mmol)、(2-氟-6-甲氧基苯基)硼酸(2.02g,11.9mmol)、SPhos Pd G3(0.128g,0.148mmol)和碳酸钾(2M于水中,4.45mL,8.90mmol)于DME(30mL)中的混合物在85℃下搅拌16h。然后将反应混合物用EtOAc(150mL)稀释,并用饱和NaHCO3水溶液(3×100mL)洗涤。将有机层经Na2SO4干燥,过滤,并在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0-50%EtOAc)得到6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基苯基)喹唑啉-2,4(1H,3H)-二酮:1H NMR(400MHz,DMSO-d6)δ11.90(d,J=1.2Hz,1H)8.11(d,J=3.3Hz,1H)7.53-7.59(m,1H)7.48(tt,J=7.0,2.2Hz,1H)7.38-7.44(m,1H)7.32-7.37(m,2H)6.93(dd,J=8.4,4.3Hz,1H)6.86(t,J=8.7Hz,1H)6.15(s,1H)3.66(d,J=30Hz,3H)2.73(dq,J=14.2,7.0Hz,1H)1.11(t,J=7.1Hz,3H)1.03(dd,J=12.7,6.8Hz,3H)。19F NMR(376MHz,DMSO-d6)δ–113.8(s,1F)–115.2(s,1F)。m/z(ESI,+ve)439.1(M+H)+。
步骤5:4,6-二氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基苯基)喹唑啉-2(1H)-酮。向6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基苯基)喹唑啉-2,4(1H,3H)-二酮(0.395g,0.900mmol)和Et3N(0.753mL,5.40mmol)于乙腈(9mL)中的溶液中添加三氯氧磷(0.503mL,5.40mmol),并将所得溶液在80℃下搅拌1.5h。将反应混合物在真空中浓缩,以得到4,6-二氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基苯基)喹唑啉-2(1H)-酮:m/z(ESI,+ve)457.1(M+H)+。
步骤5的替代程序(如下表中所述来使用):向步骤4产物(1.0当量)、三乙胺(18.0当量)和1H-苯并[d][1,2,3]三唑(12当量)于乙腈(0.07M)中的经搅拌混合物中添加三氯氧磷(6.0当量),并将所得反应混合物在80℃下搅拌3.5h。然后在10℃下将反应混合物缓慢倾倒至快速搅拌的水(100mL)中。将水性悬浮液搅拌15min,之后用EtOAc(100mL)萃取。将有机层用盐水(100mL)洗涤,经MgSO4干燥,过滤,并在真空中浓缩,以得到苯并三唑加合物中间体,将其直接用于步骤6中。
步骤6:4-(6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基苯基)-2-氧代-1,2-二氢喹唑啉-4-基)哌嗪-1-甲酸叔丁酯。将4,6-二氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基苯基)喹唑啉-2(1H)-酮(从方法8步骤5获得)、哌嗪-1-甲酸叔丁酯(0.335g,1.80mmol)和Et3N(0.753mL,5.40mmol)于DCE(9mL)中的溶液在60℃下搅拌20min。将反应混合物用EtOAc(100mL)稀释,并用饱和NaHCO3水溶液(3×75mL)洗涤。将有机层经Na2SO4干燥并在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0-60%(3:1)EtOAc-EtOH)提供4-(6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基苯基)-2-氧代-1,2-二氢喹唑啉-4-基)哌嗪-1-甲酸叔丁酯:m/z(ESI,+ve)607.3(M+H)+。
注释:在使用(S)-1-(3-甲基哌嗪-1-基)丙-2-烯-1-酮2,2,2-三氟乙酸盐时,其是如下来合成:
(S)-1-(3-甲基哌嗪-1-基)丙-2-烯-1-酮2,2,2-三氟乙酸盐
步骤6-a:(S)-叔丁基4-丙烯酰基-2-甲基哌嗪-1-甲酸酯。在-10℃下将丙烯酰氯(1.34mL,16.5mmol)添加至(S)-1-boc-2-甲基-哌嗪(3.00g,15.0mmol,纽约州雪利市(Shirley)Boc科学公司(BocSciences))于THF(30.0mL)中的溶液中,并将所得混合物在-10℃下搅拌5min。然后缓慢添加三乙胺(6.26mL,44.9mmol),并将所得混合物在-10℃下搅拌15min,然后允许其升温至室温。将反应混合物在EtOAc与饱和NaHCO3水溶液之间分配。将水层用EtOAc(3×)萃取,然后将有机层合并,经MgSO4干燥,过滤,并在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0-100%EtOAc)供给(S)-叔丁基4-丙烯酰基-2-甲基哌嗪-1-甲酸酯:1H NMR(400MHz,DMSO-d6)δ6.72–6.85(m,1H)6.10–6.18(m,1H)5.68–5.76(m,1H)4.08–4.32(m,2H)3.68–4.03(m,2H)2.86–3.14(m,2H)2.66–2.80(m,1H)1.38–1.43(s,9H)0.96–1.04(m,3H)。m/z(ESI,+ve)277.3(M+Na)+。
步骤6-b:(S)-1-(3-甲基哌嗪-1-基)丙-2-烯-1-酮2,2,2-三氟乙酸盐。将(S)-叔丁基4-丙烯酰基-2-甲基哌嗪-1-甲酸酯(3.21g,12.62mmol)和TFA(4.7mL,63.1mmol)于DCM(16mL)中的混合物在室温下搅拌24h。然后将反应混合物在真空中浓缩,以得到(S)-1-(3-甲基哌嗪-1-基)丙-2-烯-1-酮2,2,2-三氟乙酸盐:1H NMR(400MHz,DMSO-d6)δ8.70–8.99(m,1H)6.74–6.91(m,1H)6.12–6.26(m,1H)5.70–5.84(m,1H)4.25–4.44(m,1H)4.07–4.25(m,1H)3.49–3.53(m,1H)3.22–3.32(m,2H)2.92–3.08(m,2H)1.14–1.29(m,3H)。m/z(ESI,+ve)155.1(M+H)+。
步骤7:6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基苯基)-4-(哌嗪-1-基)喹唑啉-2(1H)-酮。将4-(6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基苯基)-2-氧代-1,2-二氢喹唑啉-4-基)哌嗪-1-甲酸叔丁酯(0.594g,0.978mmol)于TFA(4mL)中的溶液在环境温度下搅拌30min。将反应混合物在真空中浓缩,以得到6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基苯基)-4-(哌嗪-1-基)喹唑啉-2(1H)-酮:m/z(ESI,+ve)507.2(M+H)+。
步骤8:4-(4-丙烯酰基哌嗪-1-基)-6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基苯基)喹唑啉-2(1H)-酮。在0℃下向6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基苯基)-4-(哌嗪-1-基)喹唑啉-2(1H)-酮和DIPEA(0.85mL,4.9mmol)于DCM(10mL)中的冰冷却溶液中添加丙烯酰氯(0.079mL,0.98mmol),并将所得混合物在0℃下搅拌30min。然后将反应混合物用EtOAc(100mL)稀释,并用饱和NaHCO3水溶液(3×75mL)洗涤。将有机层经Na2SO4干燥,倾析,并在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0-100%(3:1)EtOAc-EtOH)得到4-(4-丙烯酰基哌嗪-1-基)-6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基苯基)喹唑啉-2(1H)-酮:1H NMR(400MHz,CDCl3)δ7.86(d,J=1.2Hz,1H)7.41-7.54(m,2H)7.29-7.37(m,2H)7.14(dt,J=7.8,1.7Hz,1H)6.70-6.79(m,2H)6.58-6.68(m,1H)6.50(d,J=7.4Hz,1H)6.39(dd,J=16.8,1.8Hz,1H)5.75-5.84(m,1H)3.79-4.06(m,8H)3.75(s,2H)3.66(s,1H)2.69(tt,J=13.4,6.8Hz,1H)1.20-1.24(m,3H)1.07(dd,J=6.8,3.9Hz,3H)。19F NMR(377MHz,CDCl3)δ–113.05(s,1F)–113.55(s,1F)。m/z(ESI,+ve)561.2(M+H)+。
步骤9:6-氯-7-(2-氟-6-羟苯基)-1-(2-(2-丙烷基)苯基)-4-(4-(2-丙烯酰基)-1-哌嗪基)-2(1H)-喹唑啉酮。将BBr3(1M于DCE中,3.3mL,3.3mmol)添加至4-(4-丙烯酰基哌嗪-1-基)-6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基苯基)喹唑啉-2(1H)-酮(0.372g,0.663mmol)于DCE(1.7mL)中的冰冷却溶液中,并将所得混合物在0℃下搅拌20min,然后允许其升温至室温并在室温下搅拌2h。将饱和NaHCO3水溶液添加至反应混合物中,之后添加EtOAc(150mL)。将有机层分离并用饱和NaHCO3水溶液(3×100mL)洗涤。然后将有机层经Na2SO4干燥,过滤,并在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0-100%(3:1)EtOAc-EtOH)提供6-氯-7-(2-氟-6-羟苯基)-1-(2-(2-丙烷基)苯基)-4-(4-(2-丙烯酰基)-1-哌嗪基)-2(1H)-喹唑啉酮:1H NMR(400MHz,DMSO-d6)δ10.06(br.d.,J=15.1Hz,1H)8.03(d,J=1.2Hz,1H)7.51–7.56(m,1H)7.45(t,J=7.6Hz,1H)7.33(tdd,J=7.5,7.5,3.8,1.4Hz,1H)7.14–7.25(m,2H)6.84(dd,J=16.8,10.4Hz,1H)6.62–6.74(m,2H)6.14–6.26(m,2H)5.71–5.78(m,1H)3.71–3.99(m,8H)2.52–2.59(m,1H)1.02–1.12(m,6H)。19F NMR(377MHz,DMSO-d6)δ–113.6(s,1F)–114.8(s,1F)。m/z(ESI,+ve)547.1(M+H)+。
表8:遵循上文方法8步骤1-9中所述的程序制备化合物8-2至8-6,如下:
方法9
实例9-1:6-氯-7-(2,3-二氯-5-羟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)-1-(2-(2-丙烷基)苯基)-2(1H)-喹唑啉酮
步骤1:7-溴-4,6-二氯-1-(2-异丙基苯基)喹唑啉-2(1H)-酮。向7-溴-6-氯-1-(2-异丙基苯基)喹唑啉-2,4(1H,3H)-二酮(中间体F,470mg,1.194mmol)和DIPEA(0.623mL,3.58mmol)于乙腈(11.4mL)中的混合物中添加三氯氧磷(0.915mL,5.97mmol)。将所得混合物在80℃下加热2h,然后冷却至环境温度并在真空中浓缩,以得到7-溴-4,6-二氯-1-(2-异丙基苯基)喹唑啉-2(1H)-酮:m/z(ESI,+ve)413.0(M+H)+。
步骤2:(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-7-溴-6-氯-1-(2-异丙基苯基)喹唑啉-2(1H)-酮。将7-溴-4,6-二氯-1-(2-异丙基苯基)喹唑啉-2(1H)-酮(492mg,1.19mmol)、(S)-4-N-boc-2-甲基哌嗪(478mg,2.39mmol)和DIPEA(0.623mL,3.58mmol)于DMF(2.3mL)中的混合物在室温下搅拌10min。然后添加冰水(10mL),并将所得混合物搅拌15min。将沉淀的固体通过过滤收集,用水洗涤,并在真空中干燥,以得到(S)-叔丁基4-(7-溴-6-氯-1-(2-异丙基苯基)-2-氧代-1,2-二氢喹唑啉-4-基)-3-甲基哌嗪-1-甲酸酯:m/z(ESI,+ve)577.1(M+H)+。
将TFA(2.0mL,26.8mmol)添加至(S)-叔丁基4-(7-溴-6-氯-1-(2-异丙基苯基)-2-氧代-1,2-二氢喹唑啉-4-基)-3-甲基哌嗪-1-甲酸酯(297mg,0.516mmol)于DCM(2.0mL)中的溶液中,并将所得混合物在室温下搅拌15min。将所得混合物在真空中浓缩,提供(S)-7-溴-6-氯-1-(2-异丙基苯基)-4-(2-甲基哌嗪-1-基)喹唑啉-2(1H)-酮:m/z(ESI,+ve)477.0(M+H)+。
将丙烯酰氯(0.258M于DCM中,4.0mL,1.031mmol)添加至(S)-7-溴-6-氯-1-(2-异丙基苯基)-4-(2-甲基哌嗪-1-基)喹唑啉-2(1H)-酮和DIPEA(0.269mL,1.547mmol)于DCM(2.0mL)中的冰冷却混合物中,并将所得混合物在0℃下搅拌20min。将残余物在真空中浓缩,之后进行色谱纯化(硅胶,庚烷中的0-100%(3:1)EtOAc-EtOH),得到(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-7-溴-6-氯-1-(2-异丙基苯基)喹唑啉-2(1H)-酮:1H NMR(400MHz,DMSO-d6)δ7.91-8.08(m,1H),7.49-7.67(m,2H),7.41(br d,J=5.8Hz,1H),7.21(br s,1H),6.76-6.98(m,1H),6.52-6.67(m,1H),6.09-6.29(m,1H),5.75(br s,1H),4.61-4.96(m,1H),4.23-4.48(m,1H),3.93-4.21(m,2H),3.50-3.77(m,1H),3.33-3.49(m,1H),3.23-3.28(m,1H),2.94-3.24(m,1H),1.27(br d,J=9.3Hz,6H),1.09(br s,3H)。m/z(ESI,+ve)531.1(M+H)+。
步骤3:(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-氯-7-(2,3-二氯-5-甲氧基苯基)-1-(2-异丙基苯基)喹唑啉-2(1H)-酮。将(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-7-溴-6-氯-1-(2-异丙基苯基)喹唑啉-2(1H)-酮(120mg,0.226mmol)、2-(2,3-二氯-5-甲氧基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(82mg,0.272mmol)、Na2CO3(96mg,0.906mmol)和Pd(PPh3)4(26.2mg,0.023mmol)于1,4-二噁烷(1.6mL)和水(0.4mL)中的混合物在90℃下加热17h。然后将反应混合物在真空中浓缩并进行色谱纯化(硅胶,庚烷中的0-100%(3:1)EtOAc-EtOH),以提供(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-氯-7-(2,3-二氯-5-甲氧基苯基)-1-(2-异丙基苯基)喹唑啉-2(1H)-酮:m/z(ESI,+ve)627.0(M+H)+。
步骤4:6-氯-7-(2,3-二氯-5-羟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)-1-(2-(2-丙烷基)苯基)-2(1H)-喹唑啉酮。将BBr3(1M于己烷中,0.32mL,0.320mmol)添加至(S)-4-(4-丙烯酰基-2-甲基哌嗪-1-基)-6-氯-7-(2,3-二氯-5-甲氧基苯基)-1-(2-异丙基苯基)喹唑啉-2(1H)-酮(40mg,0.064mmol)和DCE(1.0mL)的冰冷却混合物中,并将所得混合物在0℃下搅拌30min。添加饱和NaHCO3水溶液(2.0mL),并将所得混合物用(2:1)DCM/MeOH(5mL)萃取。将有机萃取物经Na2SO4干燥,过滤,并在真空中浓缩。残余物的色谱纯化(硅胶,DCM中的0-10%MeOH)得到6-氯-7-(2,3-二氯-5-羟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)-1-(2-(2-丙烷基)苯基)-2(1H)-喹唑啉酮:1H NMR(400MHz,DMSO-d6)δ10.42(br d,J=17.0Hz,1H),7.86-8.11(m,1H),7.50-7.63(m,1H),7.47(br t,J=6.0Hz,1H),7.36(t,J=7.5Hz,1H),7.15-7.26(m,1H),7.05(d,J=2.3Hz,1H),6.78-6.96(m,1H),6.44-6.58(m,1H),6.11-6.29(m,2H),5.71-5.82(m,1H),4.68-4.98(m,1H),3.96-4.52(m,3H),3.52-3.85(m,2H),3.34-3.51(m,1H),2.95-3.26(m,1H),1.27-1.41(m,3H),0.95-1.13(m,6H)。m/z(ESI,+ve)611.0(M+H)+。
表9:遵循上文方法9步骤1-4中所述的程序制备化合物9-2至9-14,如下:
方法10
实例10-1:1-(4-(7-氯-6-(2-氟-6-羟苯基)-4-(2-甲基苯基)-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮。
步骤1:6,7-二氯-2,3-二氢酞嗪-1,4-二酮(中间体G)。将肼(0.232mL,10.1mmol)添加至5,6-二氯异苯并呋喃-1,3-二酮(2.00g,9.22mmol,美国俄勒冈州波特兰市TCI美国公司(TCI America))和乙醇(30mL)的混合物中,并将所得混合物在回流下加热2h,之后冷却至室温。将所得沉淀通过过滤收集,并用水洗涤,以得到6,7-二氯-2,3-二氢酞嗪-1,4-二酮:m/z(ESI,+ve)231.1(M+H)+。
步骤2:6-氯-7-(2-氟-6-羟苯基)-2,3-二氢酞嗪-1,4-二酮。将6,7-二氯-2,3-二氢酞嗪-1,4-二酮(中间体G,3.80g,16.45mmol)、2-氟-6-羟苯基硼酸(10.26g,65.8mmol,美国加利福尼亚州圣地亚哥康比乐公司)、SPhos Pd G3(1.423g,1.645mmol)和2M Na2CO3水溶液(32.9mL,65.8mmol)于DME(60mL)中的混合物在80℃下搅拌16h。使反应混合物冷却至室温并用水(200mL)和EtOAc(300mL)稀释。将水层分离,用5NHCl酸化,并用EtOAc(300mL)萃取。将合并的有机层用盐水(200mL)洗涤,经MgSO4干燥,过滤且在真空中浓缩。使残余物悬浮于DCM(50mL)中并通过过滤收集,以得到6-氯-7-(2-氟-6-羟苯基)-2,3-二氢酞嗪-1,4-二酮:m/z(ESI,+ve)307.0(M+H)+。
步骤3:6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-2,3-二氢酞嗪-1,4-二酮。将叔丁基(氯)二苯基甲硅烷(2.67mL,10.25mmol)添加至6-氯-7-(2-氟-6-羟苯基)-2,3-二氢酞嗪-1,4-二酮(2.62g,8.54mmol)和TEA(4.75mL,34.2mmol)于乙腈(40mL)中的冰冷却混合物中,并将所得混合物在0℃下搅拌15min,然后升温至室温并搅拌1.5h。添加另外的叔丁基(氯)二苯基甲硅烷(2.67mL,10.25mmol),并将所得混合物在室温下搅拌16h。随后将反应混合物用水(300mL)稀释,用5N HCl酸化,并用EtOAc(300mL)萃取。将有机层分离并依序用盐水(250mL)洗涤,经MgSO4干燥,过滤,并在真空中浓缩。将残余物吸收于DCM(200mL)中,添加TFA(20mL),并将所得混合物在室温下搅拌45min。然后将反应混合物用饱和NaHCO3水溶液(200mL)稀释并用DCM(2×250mL)萃取。将合并的有机萃取物经MgSO4干燥,过滤,并在真空中浓缩,以得到6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-2,3-二氢酞嗪-1,4-二酮:m/z(ESI,+ve)545.2(M+H)+。
步骤4:6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-1,4,7-三氯酞嗪。将吡啶(1.45mL,17.1mmol)添加至6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-2,3-二氢酞嗪-1,4-二酮(4.66g,8.55mmol)和三氯氧磷(6.39mL,68.4mmol)的混合物中,并将所得混合物在100℃下加热1.5h。然后使反应混合物冷却至室温,并缓慢倾倒至经搅拌水(300mL)中,同时维持内部温度<10℃。在搅拌15min后,将所得混合物用EtOAc(400mL)萃取,并将有机萃取物依序用盐水(250mL)洗涤,经MgSO4干燥,过滤,并在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0-25%EtOAc)提供6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-1,4,7-三氯酞嗪:m/z(ESI,+ve)581.1(M+H)+。
步骤5:4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-4,7-二氯酞嗪-1-基)哌嗪-1-甲酸叔丁酯(中间体H)。将1-Boc-哌嗪(5.00g,26.9mmol)添加至6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-1,4,7-三氯酞嗪(5.21g,8.95mmol)和三乙胺(3.77mL,26.9mmol)于DCM(35mL)中的混合物中,并将所得混合物在室温下搅拌19h。然后将反应混合物在DCM(300mL)与饱和NaHCO3水溶液(200mL)之间分配。分离有机层,经MgSO4干燥,过滤且在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0-50%EtOAc)得到4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-4,7-二氯酞嗪-1-基)哌嗪-1-甲酸叔丁酯与4-(7-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-4,6-二氯酞嗪-1-基)哌嗪-1-甲酸叔丁酯的混合物。将个别位置异构体通过手性SFC纯化(OJ-H柱(30×250mm,5μm),15%(20mM NH3于MeOH中)于超临界CO2中)分离,提供作为第二洗脱异构体的4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-4,7-二氯酞嗪-1-基)哌嗪-1-甲酸叔丁酯:1H NMR(400MHz,CDCl3)δ8.27(s,1H)8.17(s,1H)7.56-7.61(m,4H)7.40-7.46(m,2H)7.31-7.37(m,4H)6.99-7.07(m,1H)6.77(t,J=8.61Hz,1H)6.42(d,J=8.22Hz,1H)3.72-3.77(m,4H)3.53-3.59(m,4H)1.51(s,9H)0.66(s,9H)。m/z(ESI,+ve)731.2(M+H)+。
步骤6:6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-4,7-二氯-1-(哌嗪-1-基)酞嗪。将三氟乙酸(2mL,26.8mmol)添加至4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-4,7-二氯酞嗪-1-基)哌嗪-1-甲酸叔丁酯(中间体H,1.21g,1.654mmol)于DCM(10mL)中的经搅拌溶液中,并将所得混合物在室温下搅拌1.5h。然后将反应混合物用饱和NaHCO3水溶液(75mL)稀释并用DCM(2×100mL)萃取。将合并的有机萃取物经MgSO4干燥,过滤,并在真空中浓缩,以得到6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-4,7-二氯-1-(哌嗪-1-基)酞嗪:m/z(ESI,+ve)631.3(M+H)+。
步骤7:1-(4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-4,7-二氯酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮。将丙烯酰氯(0.148mL,1.81mmol)添加至6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-4,7-二氯-1-(哌嗪-1-基)酞嗪(1.04g,1.647mmol)和三乙胺(0.694mL,4.94mmol)于DCM(10mL)中的混合物中,并将所得混合物在室温下搅拌45min。添加饱和NaHCO3水溶液(75mL),并将所得混合物用DCM(3×100mL)萃取。将合并的有机萃取物经MgSO4干燥,过滤,并在真空中浓缩,以得到1-(4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-4,7-二氯酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮:m/z(ESI,+ve)685.1(M+H)+。
步骤8:1-(4-(4,7-二氯-6-(2-氟-6-羟苯基)酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮(中间体I)。将TBAF(1M于THF中,3.3mL,3.30mmol)添加至1-(4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-4,7-二氯酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮(1.13g,1.648mmol)于THF(10mL)中的溶液中,并将所得混合物在室温下搅拌15min。将反应混合物在真空中浓缩,并将残余物通过柱色谱(硅胶,庚烷中的0-100%EtOAc)纯化,以得到1-(4-(4,7-二氯-6-(2-氟-6-羟苯基)酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮:1H NMR(400MHz,DMSO-d6)δ10.26(br s,1H)8.31(s,1H)8.14(s,1H)7.31-7.40(m,1H)6.78-6.92(m,3H)6.17(dd,J=16.63,2.35Hz,1H)5.74(dd,J=10.37,2.35Hz,1H)3.79-3.92(m,4H)3.46-3.55(m,4H)。m/z(ESI,+ve)447.0(M+H)+。
步骤9:1-(4-(7-氯-6-(2-氟-6-羟苯基)-4-(邻甲苯基)酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮。将1-(4-(4,7-二氯-6-(2-氟-6-羟苯基)酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮(中间体I,25mg,0.056mmol)、2-甲苯基硼酸(30.4mg,0.224mmol,美国犹他州洛根市前沿科学公司)、Pd(PPh3)4(6.46mg,5.59μmol,美国马萨诸塞州纽伯里波特市(NewburyPort)斯特雷姆化学公司(Strem Chemicals Inc.))和2M Na2CO3水溶液(0.084mL,0.168mmol)于1,4-二噁烷(0.3mL)中的混合物在40℃下搅拌18h。然后将反应混合物用EtOAc(20mL)稀释并用水(15mL)洗涤。将有机层分离并依序用盐水(15mL)洗涤,经MgSO4干燥,过滤,并在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0-100%EtOAc)供给1-(4-(7-氯-6-(2-氟-6-羟苯基)-4-(邻甲苯基)酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮:1H NMR(400MHz,DMSO-d6)δ10.15(br s,1H)8.33(s,1H)7.36-7.45(m,2H)7.24-7.36(m,4H)6.90(dd,J=16.63,10.37Hz,1H)6.70-6.80(m,2H)6.18(dd,J=16.73,2.25Hz,1H)5.75(dd,J=10.56,2.15Hz,1H)3.83-3.97(m,4H)3.47-3.62(m,4H)1.98-2.06(m,3H)。m/z(ESI,+ve)503.1(M+H)+。
表10:遵循上文方法10步骤1-9中所述的程序制备化合物10-2至10-13,如下:
方法11
实例11-1:6-氯-7-(5-甲基-1H-吲唑-4-基)-1-(2-(2-丙烷基)苯基)-4-(4-(2-丙烯酰基)-1-哌嗪基)-2(1H)-喹唑啉酮
步骤1:4-(1H-苯并[d][1,2,3]三唑-1-基)-7-溴-6-氯-1-(2-异丙基苯基)喹唑啉-2(1H)-酮。将三氯氧磷(1.204mL,7.85mmol)添加至7-溴-6-氯-1-(2-异丙基苯基)喹唑啉-2,4(1H,3H)-二酮(中间体F,515mg,1.308mmol)、三乙胺(3.31mL,23.55mmol)和1H-苯并[d][1,2,3]三唑(2.01g,16.87mmol)于乙腈(15mL)中的经搅拌混合物中。将反应混合物加热至80℃并搅拌1h。使反应混合物冷却至室温并过滤。然后在约10℃下将滤液缓慢倾倒至快速搅拌的水(150mL)中。将水性悬浮液搅拌15min,之后用EtOAc(150mL)萃取两次。将有机层合并,用盐水(150mL)洗涤,经MgSO4干燥,过滤,并在真空中浓缩,以得到粗4-(1H-苯并[d][1,2,3]三唑-1-基)-7-溴-6-氯-1-(2-异丙基苯基)喹唑啉-2(1H)-酮。m/z(ESI)M+H:494.0。
步骤2:4-(7-溴-6-氯-1-(2-异丙基苯基)-2-氧代-1,2-二氢喹唑啉-4-基)哌嗪-1-甲酸叔丁酯。将哌嗪-1-甲酸叔丁酯(268mg,1.438mmol)添加至粗4-(1H-苯并[d][1,2,3]三唑-1-基)-7-溴-6-氯-1-(2-异丙基苯基)喹唑啉-2(1H)-酮(647mg,1.308mmol)和三乙胺(3.68mL,26.2mmol)于二甲亚砜(6mL)中的经搅拌混合物中。将反应混合物在80℃下搅拌30min。将反应混合物用EtOAc(100mL)稀释并用水(75mL)洗涤。将有机层分离,用盐水(75mL)洗涤,经MgSO4干燥,过滤且在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至100%EtOAc)得到4-(7-溴-6-氯-1-(2-异丙基苯基)-2-氧代-1,2-二氢喹唑啉-4-基)哌嗪-1-甲酸叔丁酯。1H NMR(400MHz,氯仿-d)δ7.79(1H,s)7.49-7.59(2H,m)7.36-7.42(1H,m)7.11(1H,d,J=7.63Hz)6.80(1H,s)3.79-3.92(4H,m)3.62-3.73(4H,m)2.60(1H,spt,J=6.80Hz)1.49-1.54(9H,m)1.22(3H,d,J=6.85Hz)1.08(3H,d,J=6.85Hz)。m/z(ESI)M+H:561.0。
步骤3:4-(6-氯-1-(2-异丙基苯基)-7-(5-甲基-1H-吲唑-4-基)-2-氧代-1,2-二氢喹唑啉-4-基)哌嗪-1-甲酸叔丁酯。将4-(7-溴-6-氯-1-(2-异丙基苯基)-2-氧代-1,2-二氢喹唑啉-4-基)哌嗪-1-甲酸叔丁酯(115mg,0.205mmol)、4-硼基-5-甲基-1h-吲唑(0.144mL,0.819mmol,美国伊利诺伊州阿灵顿海茨市方舟制药公司)、Sphos Pd G3(0.016mL,0.020mmol)和碳酸钠(2M水溶液,0.409mL,0.819mmol)在1,2-二甲氧基乙烷(1mL)中在氩气氛下在密封小瓶中混合。将反应混合物在100℃下搅拌24h。使反应混合物冷却至室温并用EtOAc(50mL)和水(40mL)稀释。将有机层分离,用盐水(40mL)洗涤,经MgSO4干燥,过滤且在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至50%(3:1EtOAc/EtOH))得到4-(6-氯-1-(2-异丙基苯基)-7-(5-甲基-1H-吲唑-4-基)-2-氧代-1,2-二氢喹唑啉-4-基)哌嗪-1-甲酸叔丁酯。m/z(ESI)M+H:613.2。
步骤4:6-氯-1-(2-异丙基苯基)-7-(5-甲基-1H-吲唑-4-基)-4-(哌嗪-1-基)喹唑啉-2(1H)-酮。将三氟乙酸(0.5mL,6.71mmol)添加至4-(6-氯-1-(2-异丙基苯基)-7-(5-甲基-1H-吲唑-4-基)-2-氧代-1,2-二氢喹唑啉-4-基)哌嗪-1-甲酸叔丁酯(78mg,0.127mmol)于二氯甲烷(1mL)中的经搅拌混合物中。将反应混合物在室温下搅拌1h。将反应混合物在真空中浓缩,以得到粗6-氯-1-(2-异丙基苯基)-7-(5-甲基-1H-吲唑-4-基)-4-(哌嗪-1-基)喹唑啉-2(1H)-酮。m/z(ESI)M+H:513.2。
步骤5:6-氯-7-(5-甲基-1H-吲唑-4-基)-1-(2-(2-丙烷基)苯基)-4-(4-(2-丙烯酰基)-1-哌嗪基)-2(1H)-喹唑啉酮。在0℃下将丙烯酰氯(10.33μl,0.127mmol)添加至6-氯-1-(2-异丙基苯基)-7-(5-甲基-1H-吲唑-4-基)-4-(哌嗪-1-基)喹唑啉-2(1H)-酮(65mg,0.127mmol)和三乙胺(0.178mL,1.267mmol)于二氯甲烷(2mL)中的经搅拌混合物中。将反应混合物在0℃下搅拌20min。添加另外的丙烯酰氯(5.17μl,0.064mmol),并将反应混合物在0℃下再搅拌20min。将反应混合物用DCM(25mL)稀释并用饱和碳酸氢钠水溶液(20mL)淬灭。分离有机层,经MgSO4干燥,过滤且在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至80%(3:1 EtOAc/EtOH))得到不纯产物。不纯产物的进一步色谱纯化(硅胶,庚烷中的0至100%丙酮)得到分离的非对映异构体。6-氯-7-(5-甲基-1H-吲唑-4-基)-1-(2-(2-丙烷基)苯基)-4-(4-(2-丙烯酰基)-1-哌嗪基)-2(1H)-喹唑啉酮(实例11-1-1)是要洗脱的第一非对映异构体。1H NMR(400MHz,氯仿-d)δ10.28(1H,br s)7.94(1H,s)7.35-7.49(4H,m)7.25-7.31(2H,m)7.11(1H,d,J=7.67Hz)6.64(1H,dd,J=16.79,10.57Hz)6.54(1H,s)6.41(1H,dd,J=16.79,1.87Hz)5.81(1H,dd,J=10.57,1.66Hz)3.83-4.07(8H,m)2.74(1H,spt,J=6.84Hz)2.13(3H,s)1.23(3H,d,J=6.84Hz)1.04(3H,d,J=6.84Hz)。m/z(ESI)M+H:567.2。将要洗脱的第二非对映异构体通过柱色谱(硅胶,庚烷中的0至80%(3:1 EtOAc/EtOH))进一步纯化,以得到6-氯-7-(5-甲基-1H-吲唑-4-基)-1-(2-(2-丙烷基)苯基)-4-(4-(2-丙烯酰基)-1-哌嗪基)-2(1H)-喹唑啉酮(实例11-1-2)。1H NMR(400MHz,氯仿-d)δ10.37(1H,br s)7.94(1H,s)7.34-7.50(4H,m)7.21-7.31(2H,m)7.13(1H,d,J=7.67Hz)6.64(1H,dd,J=16.90,10.68Hz)6.55(1H,s)6.41(1H,dd,J=16.79,1.66Hz)5.81(1H,dd,J=10.47,1.55Hz)3.83-4.08(8H,m)2.70(1H,spt,J=6.84Hz)2.13(3H,s)1.22(3H,d,J=6.84Hz)1.03(3H,d,J=6.84Hz)。m/z(ESI)M+H:567.2。
遵循上文方法11步骤1-5:
第2部分-个别实例
实例121-(4-(7-氯-4-环丙基-6-(2-氟-6-羟苯基)-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮
步骤1:4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-环丙基酞嗪-1-基)哌嗪-1-甲酸叔丁酯。向装填有4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-4,7-二氯酞嗪-1-基)哌嗪-1-甲酸叔丁酯(中间体H,0.060g,0.082mmol)的20mL小瓶中添加[1,1’-双(二苯基膦基)二茂铁]二氯化钯(II)与二氯甲烷的络合物(0.033g,0.041mmol)和2-甲基四氢呋喃(2.0mL)。将所得混合物加盖并在室温下搅拌10min,之后通过注射器添加环丙基溴化锌(0.5M于THF中,0.820mL,0.410mmol;美国内布拉斯加州林肯市雷基金属公司(Rieke Metals))。将反应混合物在80℃下加热3h,之后冷却至室温并在EtOAc(30mL)与水(10mL)之间分配。将水层用EtOAc(20mL)再萃取一次。将合并的有机层经MgSO4干燥,过滤,并在真空中浓缩。将粗品通过柱色谱(24g硅胶,庚烷中的0至30%丙酮)纯化,以获得4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-环丙基酞嗪-1-基)哌嗪-1-甲酸叔丁酯。1H NMR(氯仿-d)δ:8.31-8.38(m,1H),8.15-8.23(m,1H),7.55-7.64(m,4H),7.39-7.47(m,2H),7.29-7.38(m,4H),6.99-7.09(m,1H),6.74-6.85(m,1H),6.36-6.47(m,1H),3.68-3.79(m,4H),3.37-3.51(m,4H),2.37-2.48(m,1H),1.48-1.54(m,9H),1.37-1.45(m,1H),1.30-1.33(m,1H),1.00-1.15(m,2H),0.61-0.71(m,9H)。m/z(ESI)M+H:737.4。
步骤2:6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-环丙基-1-(哌嗪-1-基)酞嗪。将三氟乙酸(0.316mL,4.10mmol)添加至4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-环丙基酞嗪-1-基)哌嗪-1-甲酸叔丁酯于DCM(0.7mL)中的溶液中。将所得混合物加盖并在室温下搅拌30min。将反应混合物用DCM(10mL)稀释并使用饱和NaHCO3水溶液(5mL)碱化。将水层用DCM(10mL)再萃取一次。将合并的有机层经MgSO4干燥,过滤,并在真空中浓缩,以获得6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-环丙基-1-(哌嗪-1-基)酞嗪。1H NMR(氯仿-d)δ:8.30-8.36(m,1H),8.18-8.24(m,1H),7.55-7.64(m,4H),7.40-7.46(m,2H),7.33(q,J=7.1Hz,4H),6.97-7.09(m,1H),6.74-6.83(m,1H),6.36-6.46(m,1H),3.45-3.55(m,4H),3.16-3.26(m,4H),2.35-2.49(m,1H),1.37-1.46(m,1H),1.30-1.33(m,1H),1.06-1.12(m,2H),0.61-0.70(m,9H)。m/z(ESI)M+H:637.2。
步骤3:1-(4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-环丙基酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮。向装填有6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-环丙基-1-(哌嗪-1-基)酞嗪(0.023g,0.036mmol)的20mL小瓶中添加三乙胺(16μl,0.114mmol)和二氯甲烷(1.0mL)。将所得混合物加盖并在室温下搅拌10min,之后通过注射器添加丙烯酰氯(4.0μl,0.049mmol)。将反应混合物加盖并在室温下继续搅拌20min。将反应用饱和NaHCO3水溶液(3mL)淬灭并用DCM(10mL)稀释。将水层用DCM(5mL)再萃取一次。将合并的有机层经MgSO4干燥,过滤,并在真空中浓缩,以获得1-(4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-环丙基酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮。1H NMR(氯仿-d)δ:8.32-8.38(m,1H),8.16-8.24(m,1H),7.55-7.65(m,4H),7.40-7.48(m,2H),7.31-7.38(m,4H),6.98-7.10(m,1H),6.75-6.84(m,1H),6.60-6.72(m,1H),6.41-6.47(m,1H),6.31-6.40(m,1H),5.72-5.82(m,1H),3.79-4.08(m,4H),3.44-3.62(m,4H),2.38-2.49(m,1H),1.40-1.45(m,1H),1.33-1.37(m,1H),1.04-1.13(m,2H),0.62-0.68(m,9H)。m/z(ESI)M+H:691.2。
步骤4:1-(4-(7-氯-4-环丙基-6-(2-氟-6-羟苯基)-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮。向装填有1-(4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-环丙基酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮(0.022g,0.032mmol)的20mL小瓶中添加四氢呋喃(2.0mL),之后添加四丁基氟化铵(1.0M THF溶液,0.070mL,0.070mmol)。将小瓶加盖并在室温下搅拌30min。将反应混合物在真空中浓缩。将粗品通过柱色谱(24g二氧化硅,DCM中的0至5%MeOH)纯化,以获得1-(4-(7-氯-4-环丙基-6-(2-氟-6-羟苯基)-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮。1H NMR(氯仿-d)δ:8.30-8.37(m,1H),8.11-8.18(m,1H),7.29-7.38(m,1H),6.96-7.18(m,1H),6.88-6.94(m,1H),6.76-6.85(m,1H),6.59-6.72(m,1H),6.31-6.42(m,1H),5.73-5.84(m,1H),3.73-4.05(m,4H),3.35-3.62(m,4H),2.40-2.52(m,1H),1.35-1.42(m,1H),1.29-1.34(m,1H),1.03-1.14(m,2H)。m/z(ESI)M+H:453.2。
实例13
1-(4-(4-苯胺基-7-氯-6-(2-氟-6-羟苯基)-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮
步骤1:4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-(苯基氨基)酞嗪-1-基)哌嗪-1-甲酸叔丁酯。向装填有4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-4,7-二氯酞嗪-1-基)哌嗪-1-甲酸叔丁酯(0.060g,0.082mmol)的20mL小瓶中添加二甲亚砜(2.0mL),之后添加苯胺(0.075mL,0.820mmol)。将小瓶加盖并在80℃下回流3h。将反应冷却至室温并在EtOAc(30mL)与水(10mL)之间分配。将有机层分离并用水(2×10mL)洗涤。将有机层经MgSO4干燥,过滤,并在真空中浓缩。将粗品通过柱色谱(40g二氧化硅,庚烷中的0至30%EtOAc)纯化,以获得4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-(苯基氨基)酞嗪-1-基)哌嗪-1-甲酸叔丁酯。1H NMR(氯仿-d)δ:8.17-8.25(m,1H),7.76-7.81(m,1H),7.60-7.69(m,5H),7.50-7.55(m,2H),7.40-7.46(m,2H),7.31-7.37(m,5H),7.06-7.11(m,2H),6.76-6.83(m,1H),6.57-6.66(m,1H),6.39-6.50(m,1H),3.66-3.81(m,4H),3.32-3.43(m,4H),1.51-1.53(m,9H),0.69-0.75(m,9H)。m/z(ESI)M+H:788.2。
步骤2:7-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-6-氯-N-苯基-4-(哌嗪-1-基)酞嗪-1-胺。与实例12步骤2类似,4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-(苯基氨基)酞嗪-1-基)哌嗪-1-甲酸叔丁酯的反应产生7-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-6-氯-N-苯基-4-(哌嗪-1-基)酞嗪-1-胺。1H NMR(氯仿-d)δ:8.19-8.26(m,1H),7.75-7.80(m,1H),7.60-7.68(m,5H),7.49-7.55(m,2H),7.39-7.46(m,3H),7.32-7.37(m,5H),7.02-7.11(m,2H),6.75-6.84(m,1H),6.59-6.67(m,1H),6.43-6.53(m,1H),3.35-3.47(m,4H),3.16-3.27(m,4H),0.70-0.76(m,9H)。m/z(ESI)M+H:688.2。
步骤3:1-(4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-(苯基氨基)酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮。与实例12步骤3类似,7-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-6-氯-N-苯基-4-(哌嗪-1-基)酞嗪-1-胺的反应产生1-(4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-(苯基氨基)酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮。1H NMR(氯仿-d)δ:8.16-8.24(m,1H),7.77-7.84(m,1H),7.62-7.67(m,4H),7.52-7.55(m,1H),7.41-7.46(m,3H),7.32-7.38(m,6H),7.02-7.11(m,2H),6.77-6.84(m,1H),6.65-6.71(m,1H),6.46-6.51(m,1H),6.30-6.39(m,2H),5.73-5.81(m,1H),3.86-4.05(m,4H),3.37-3.53(m,4H),0.69-0.75(m,9H)。m/z(ESI)M+H:742.3。
步骤4:1-(4-(4-苯胺基-7-氯-6-(2-氟-6-羟苯基)-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮。与实例12步骤4类似,1-(4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-(苯基氨基)酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮的反应产生1-(4-(4-苯胺基-7-氯-6-(2-氟-6-羟苯基)-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮。1H NMR(氯仿-d)δ:7.96-8.09(m,2H),7.46-7.57(m,2H),7.37-7.44(m,1H),7.29-7.33(m,1H),7.20-7.26(m,1H),6.96-7.07(m,1H),6.81-6.87(m,1H),6.70-6.77(m,1H),6.54-6.67(m,1H),6.29-6.41(m,1H),5.68-5.82(m,1H),3.74-3.96(m,4H),3.12-3.43(m,4H)。m/z(ESI)M+H:504.2。
实例14
1-(4-(7-氯-4-环戊基-6-(2-氟-6-羟苯基)-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮
步骤1:4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-环戊基酞嗪-1-基)哌嗪-1-甲酸叔丁酯。与实例12步骤1类似,4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-4,7-二氯酞嗪-1-基)哌嗪-1-甲酸叔丁酯(中间体H)和环戊基溴化锌(0.5M于THF中,内布拉斯加州林肯市雷基金属公司)的反应产生4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-环戊基酞嗪-1-基)哌嗪-1-甲酸叔丁酯。1H NMR(氯仿-d)δ:8.18-8.22(m,1H),8.12-8.16(m,1H),7.60-7.66(m,2H),7.50-7.56(m,2H),7.39-7.47(m,2H),7.34-7.38(m,2H),7.28-7.33(m,2H),7.09(br d,J=1.2Hz,1H),6.75-6.82(m,1H),6.37-6.44(m,1H),3.72-3.78(m,4H),3.44-3.51(m,4H),2.03-2.23(m,4H),1.87-1.96(m,2H),1.67-1.79(m,3H),1.51-1.54(m,9H),0.62-0.67(m,9H)。m/z(ESI)M+H:765.2。
步骤2:6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-环戊基-1-(哌嗪-1-基)酞嗪。与实例12步骤2类似,4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-环戊基酞嗪-1-基)哌嗪-1-甲酸叔丁酯的反应产生6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-环戊基-1-(哌嗪-1-基)酞嗪。1H NMR(氯仿-d)δ:8.17-8.21(m,1H),8.12-8.16(m,1H),7.61-7.66(m,2H),7.51-7.56(m,2H),7.40-7.46(m,2H),7.34-7.38(m,2H),7.29-7.33(m,2H),6.99-7.08(m,1H),6.74-6.82(m,1H),6.37-6.45(m,1H),3.58-3.67(m,4H),3.27-3.36(m,4H),2.18-2.22(m,1H),2.08-2.12(m,2H),1.86-1.91(m,3H),1.69-1.77(m,3H),0.59-0.67(m,9H)。m/z(ESI)M+H:665.2。
步骤3:1-(4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-环戊基酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮。与实例12步骤3类似,6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-环戊基-1-(哌嗪-1-基)酞嗪的反应产生1-(4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-环戊基酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮。1H NMR(氯仿-d)δ:8.18-8.25(m,1H),8.13-8.17(m,1H),7.61-7.67(m,2H),7.50-7.57(m,2H),7.39-7.48(m,2H),7.28-7.37(m,4H),6.99-7.10(m,1H),6.75-6.83(m,1H),6.62-6.71(m,1H),6.33-6.43(m,2H),5.73-5.81(m,1H),3.84-4.07(m,4H),3.71-3.82(m,1H),3.49-3.65(m,4H),1.80-1.96(m,4H),1.67-1.77(m,4H),0.62-0.67(m,9H)。m/z(ESI)M+H:719.2。
步骤4:1-(4-(7-氯-4-环戊基-6-(2-氟-6-羟苯基)-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮。与实例12步骤4类似,1-(4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-7-氯-4-环戊基酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮的反应产生1-(4-(7-氯-4-环戊基-6-(2-氟-6-羟苯基)-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮。1H NMR(氯仿-d)δ:8.10-8.22(m,2H),7.29-7.38(m,1H),6.86-6.93(m,1H),6.77-6.85(m,1H),6.61-6.72(m,1H),6.33-6.44(m,1H),5.74-5.85(m,1H),3.82-4.05(m,4H),3.75-3.82(m,1H),3.40-3.63(m,4H),2.06-2.24(m,4H),1.81-1.96(m,2H),1.67-1.79(m,2H)。m/z(ESI)M+H:481.2。
实例15
1-(4-(7-氯-6-(2-氟-6-羟苯基)-4-(1-哌啶基)-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮
步骤1:4-(7-氯-6-(2-氟-6-羟苯基)-4-(哌啶-1-基)酞嗪-1-基)哌嗪-1-甲酸叔丁酯。向装填有4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-4,7-二氯酞嗪-1-基)哌嗪-1-甲酸叔丁酯(中间体H,0.060g,0.082mmol)的20mL小瓶中添加哌啶(1.0mL,10.10mmol)。将小瓶加盖并在80℃下加热2h。将反应冷却至室温并在EtOAc(30mL)与水(10mL)之间分配。将有机层分离并用水(2x10mL)洗涤。将合并的有机层经MgSO4干燥,过滤,并在真空中浓缩,以获得4-(7-氯-6-(2-氟-6-羟苯基)-4-(哌啶-1-基)酞嗪-1-基)哌嗪-1-甲酸叔丁酯。1H NMR(氯仿-d)δ:8.09-8.14(m,1H),7.97-8.03(m,1H),7.28-7.35(m,1H),6.75-6.88(m,2H),3.65-3.76(m,4H),3.30-3.44(m,8H),1.72-1.81(m,4H),1.61-1.71(m,3H),1.48-1.53(m,9H)。m/z(ESI)M+H:542.2。
步骤2:2-(7-氯-1-(哌嗪-1-基)-4-(哌啶-1-基)酞嗪-6-基)-3-氟苯酚。与实例12步骤2类似,4-(7-氯-6-(2-氟-6-羟苯基)-4-(哌啶-1-基)酞嗪-1-基)哌嗪-1-甲酸叔丁酯的反应产生2-(7-氯-1-(哌嗪-1-基)-4-(哌啶-1-基)酞嗪-6-基)-3-氟苯酚。1H NMR(氯仿-d)δ:8.09-8.13(m,1H),7.95-8.03(m,1H),7.28-7.38(m,1H),6.83-6.89(m,1H),6.75-6.82(m,1H),3.39-3.48(m,4H),3.31-3.38(m,4H),3.12-3.21(m,4H),1.75-1.80(m,4H),1.64-1.69(m,2H)。m/z(ESI)M+H:442.2。
步骤3:1-(4-(7-氯-6-(2-氟-6-羟苯基)-4-(1-哌啶基)-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮。与实例12步骤3类似,2-(7-氯-1-(哌嗪-1-基)-4-(哌啶-1-基)酞嗪-6-基)-3-氟苯酚的反应产生1-(4-(7-氯-6-(2-氟-6-羟苯基)-4-(1-哌啶基)-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮。1H NMR(氯仿-d)δ:8.08-8.15(m,1H),7.98-8.05(m,1H),7.29-7.39(m,1H),6.86-6.94(m,1H),6.76-6.85(m,1H),6.59-6.70(m,1H),6.30-6.43(m,1H),5.72-5.84(m,1H),3.77-4.05(m,4H),3.40-3.56(m,4H),3.32-3.38(m,4H),1.73-1.85(m,4H),1.64-1.70(m,2H)。m/z(ESI)M+H:496.2。
实例16
1-(4-(7-氯-6-(2-氟-6-羟苯基)-4-苯氧基-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮
步骤1:4-(7-氯-6-(2-氟-6-羟苯基)-4-苯氧基酞嗪-1-基)哌嗪-1-甲酸叔丁酯。在干燥50mL圆底烧瓶中装填苯酚(0.130g,1.381mmol)和四氢呋喃(3.0mL)。使混合物冷却至0℃,之后添加叔丁醇钾(0.153g,1.367mmol)。将混合物在0℃下搅拌10min,之后升温至室温并搅拌30min。添加4-(6-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-4,7-二氯酞嗪-1-基)哌嗪-1-甲酸叔丁酯(中间体H,0.100g,0.137mmol),并将所得混合物在60℃下加热2h。将反应冷却至室温并用水淬灭。将所得混合物在EtOAc(30mL)与水(15mL)之间分配。将水层用EtOAc(20mL)再萃取一次。将合并的有机层经MgSO4干燥,过滤,并在真空中浓缩。将粗品通过柱色谱(40g二氧化硅,10至50%丙酮)纯化,以获得4-(7-氯-6-(2-氟-6-羟苯基)-4-苯氧基酞嗪-1-基)哌嗪-1-甲酸叔丁酯:m/z(ESI)M+H:551.2。
步骤2:2-(7-氯-4-苯氧基-1-(哌嗪-1-基)酞嗪-6-基)-3-氟苯酚。与实例12步骤2类似,4-(7-氯-6-(2-氟-6-羟苯基)-4-苯氧基酞嗪-1-基)哌嗪-1-甲酸酯的反应产生。2-(7-氯-4-苯氧基-1-(哌嗪-1-基)酞嗪-6-基)-3-氟苯酚。1H NMR(氯仿-d)δ:8.37-8.42(m,1H),8.14-8.19(m,1H),7.37-7.45(m,2H),7.29-7.34(m,1H),7.19-7.25(m,2H),6.89-6.98(m,1H),6.76-6.87(m,4H),3.36-3.45(m,4H),3.13-3.22(m,4H)。m/z(ESI)M+H:451.2。
步骤3:1-(4-(7-氯-6-(2-氟-6-羟苯基)-4-苯氧基-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮。与实例12步骤3类似,2-(7-氯-4-苯氧基-1-(哌嗪-1-基)酞嗪-6-基)-3-氟苯酚的反应产生1-(4-(7-氯-6-(2-氟-6-羟苯基)-4-苯氧基-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮。1H NMR(氯仿-d)δ:8.41-8.45(m,1H),8.17-8.20(m,1H),7.40-7.45(m,2H),7.28-7.37(m,2H),7.20-7.26(m,1H),6.78-6.87(m,2H),6.59-6.70(m,1H),6.31-6.41(m,1H),5.97-6.06(m,1H),5.74-5.81(m,1H),3.76-4.03(m,4H),3.38-3.53(m,4H)。m/z(ESI)M+H:505.2。
实例17-1和17-2
(2E)-1-(4-(5-氯-7-氟-6-(3-甲氧基-1-萘基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-4-(二甲基氨基)-2-丁烯-1-酮(实例17-1)和(2E)-1-(4-(5-氯-7-氟-6-(3-羟基-1-萘基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-4-(二甲基氨基)-2-丁烯-1-酮(实例17-2)
步骤1:4-(5-氯-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯。用氩流对4-(6-溴-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯(中间体D,459mg,1.02mmol)、(3-甲氧基萘-1-基)硼酸(823mg,4.07mmol)和碳酸铯(1.33g,4.07mmol)于1,4-二噁烷(8mL)与水(2mL)的混合物中的浆液进行脱气。添加四(三苯膦)钯(118mg,0.10mmol),并用氩流再次对混合物进行脱气。将反应混合物密封并在100℃下加热23h。允许反应冷却至室温,用盐水(60mL)稀释,并用EtOAc萃取两次。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:DCM中的0-2%MeOH)纯化,以提供4-(5-氯-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯。m/z(ESI)M+H:528.0。
步骤2:5-氯-6-(3-甲氧基萘-1-基)-3-(哌嗪-1-基)苯并[c]异噻唑。通过注射器向4-(5-氯-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯(327mg,0.56mmol)于DCM(6mL)中的溶液中添加三氟乙酸(1.04mL,13.9mmol)。将所得黄色溶液在室温下搅拌4h,然后浓缩。将残余物通过硅胶色谱(洗脱液:DCM中的0-25%MeOH)纯化,以提供5-氯-6-(3-甲氧基萘-1-基)-3-(哌嗪-1-基)苯并[c]异噻唑的单TFA盐。m/z(ESI)M+H:428.0.
步骤3:(2E)-1-(4-(5-氯-7-氟-6-(3-甲氧基-1-萘基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-4-(二甲基氨基)-2-丁烯-1-酮。通过注射器向5-氯-6-(3-甲氧基萘-1-基)-3-(哌嗪-1-基)苯并[c]异噻唑(74mg单TFA盐,0.14mmol)和反式-4-二甲基氨基巴豆酸盐酸盐(38mg,0.23mmol)于DMA(2mL)中的溶液中添加亚硫酰氯(41μL,0.69mmol)。将所得褐色溶液在室温下搅拌2.5h。将反应混合物用水(50mL)淬灭并用8:1 DCM/MeOH萃取。将有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:DCM中的0-15%MeOH)纯化,以提供(2E)-1-(4-(5-氯-7-氟-6-(3-甲氧基-1-萘基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-4-(二甲基氨基)-2-丁烯-1-酮。1H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.94(d,J=8.4Hz,1H),7.46-7.55(m,2H),7.27-7.35(m,2H),7.19(d,J=2.5Hz,1H),6.61-6.72(m,2H),3.94(s,3H),3.80-3.93(m,4H),3.62-3.68(m,4H),3.07(d,J=4.3Hz,2H),2.18(s,6H)。m/z(ESI)M+H:539.2。
步骤4:(2E)-1-(4-(5-氯-7-氟-6-(3-羟基-1-萘基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-4-(二甲基氨基)-2-丁烯-1-酮。在0℃下通过注射器向(2E)-1-(4-(5-氯-7-氟-6-(3-甲氧基-1-萘基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-4-(二甲基氨基)-2-丁烯-1-酮(23.5mg,0.044mmol)于1,2-二氯乙烷(4mL)中的溶液中逐滴添加三溴化硼(1.0M于己烷中,218μL,0.22mmol)。将所得黄色浆液在0℃下搅拌2.75h,然后用饱和NaHCO3水溶液(4mL)淬灭。将混合物用DCM/MeOH的4:1混合物萃取两次。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:DCM中的0-18%MeOH)纯化,以提供(2E)-1-(4-(5-氯-7-氟-6-(3-羟基-1-萘基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-4-(二甲基氨基)-2-丁烯-1-酮。1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),8.10(s,1H),7.80(d,J=8.4Hz,1H),7.40-7.46(m,1H),7.19-7.30(m,3H),7.07(d,J=2.4Hz,1H),6.62-6.71(m,2H),3.80-3.93(m,4H),3.62-3.69(m,4H),3.07(d,J=4.1Hz,2H),2.17(s,6H)。m/z(ESI)M+H:525.0。
实例18-1至18-3
1-(4-(5-氯-7-氟-6-(3-甲氧基-1-萘基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-(羟甲基)-2-丙烯-1-酮。(实例18-1)和2-(溴甲基)-1-(4-(5-氯-7-氟-6-(3-羟基-1-萘基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮(实例18-2)和1-(4-(5-氯-7-氟-6-(3-羟基-1-萘基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-(羟甲基)-2-丙烯-1-酮(实例18-3)
步骤1:1-(4-(5-氯-7-氟-6-(3-甲氧基-1-萘基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-(羟甲基)-2-丙烯-1-酮。在小瓶中装填1-(4-(5-氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-基)哌嗪-1-基)丙-2-烯-1-酮(中间体O,29mg,0.06mmol)于叔丁醇(0.4mL)和水(0.4mL)中的溶液。依序添加苯酚(5.7mg,0.06mmol)、DABCO(20.3mg,0.18mmol)和甲醛(37%水溶液,24μL,0.24mmol)。将所得溶液密封并在55℃下加热29h。将反应冷却至室温并在水(6mL)与10:1 DCM/MeOH之间分配。分离有机层,且水层再用10:1 DCM/MeOH萃取两次。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:DCM中的0-3.5%MeOH)纯化,以提供1-(4-(5-氯-7-氟-6-(3-甲氧基-1-萘基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-(羟甲基)-2-丙烯-1-酮。1H NMR(400MHz,DMSO-d6)δ8.12(s,1H),7.94(d,J=8.2Hz,1H),7.47-7.55(m,2H),7.25-7.34(m,2H),7.19(d,J=2.5Hz,1H),5.43(br.s,1H),5.20(br.s,1H),5.14(t,J=5.8Hz,1H),4.12(d,J=5.7Hz,2H),3.94(s,3H),3.78-3.85(m,4H),3.54-3.66(m,4H)。m/z(ESI)M+H:512.0。
步骤2:2-(溴甲基)-1-(4-(5-氯-7-氟-6-(3-羟基-1-萘基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮和1-(4-(5-氯-7-氟-6-(3-羟基-1-萘基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-(羟甲基)-2-丙烯-1-酮。在0℃下通过注射器向1-(4-(5-氯-7-氟-6-(3-甲氧基-1-萘基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-(羟甲基)-2-丙烯-1-酮(17.1mg,0.033mmol)于1,2-二氯乙烷(4mL)中的溶液中逐滴添加三溴化硼溶液(1.0M于己烷中,167μL,0.17mmol)。将所得浆液在0℃下搅拌40min,之后用饱和NaHCO3水溶液(5mL)淬灭。将混合物用DCM/MeOH的4:1混合物萃取两次。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:DCM中的0-7%MeOH)纯化,以得到两种产物。
第一洗脱峰:2-(溴甲基)-1-(4-(5-氯-7-氟-6-(3-羟基萘-1-基)苯并[c]异噻唑-3-基)哌嗪-1-基)丙-2-烯-1-酮。1H NMR(400MHz,DMSO-d6)δ9.96(br.s,1H),8.13(s,1H),7.80(d,J=8.2Hz,1H),7.40-7.47(m,1H),7.19-7.29(m,3H),7.07(d,J=2.4Hz,1H),5.78(s,1H),5.41(s,1H),4.38(s,2H),3.84-3.93(m,4H),3.62-3.72(m,4H)。m/z(ESI)M+H:560.0
第二洗脱峰:1-(4-(5-氯-7-氟-6-(3-羟基萘-1-基)苯并[c]异噻唑-3-基)哌嗪-1-基)-2-(羟甲基)丙-2-烯-1-酮。1H NMR(400MHz,DMSO-d6)δ9.98(br.s,1H),8.11(s,1H),7.79(d,J=8.2Hz,1H),7.37-7.48(m,1H),7.17-7.28(m,3H),7.07(d,J=2.4Hz,1H),5.43(br.s,1H),5.20(br.s,1H),5.07-5.14(m,1H),4.12(br.s,2H),3.78-3.86(m,4H),3.57-3.66(m,4H)。m/z(ESI)M+H:498.0
实例19-1至19-3
1-(4-(5-氯-7-氟-6-(5-甲氧基-1-甲基-1H-吲唑-7-基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮(实例19-1)和1-(4-(5-氯-7-氟-6-(5-羟基-1-甲基-1H-吲唑-7-基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮(实例19-2)和1-(4-(5-氯-7-氟-6-(5-羟基-2-甲基-2H-吲唑-7-基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮(实例19-3)
步骤1:4-(5-氯-7-氟-6-(5-甲氧基-1H-吲唑-7-基)苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯。用氩流对中间体D(232mg,0.51mmol)、5-甲氧基-7-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吲唑(535mg,1.95mmol,参见下文的合成)和碳酸铯(636mg,1.95mmol)于1,4-二噁烷(8mL)与水(2mL)的混合物中的浆液进行脱气。添加四(三苯膦)钯(59mg,0.05mmol)并用氩流再次对混合物进行脱气。将反应混合物密封并在100℃下加热18h。允许反应冷却至室温并在盐水(40mL)与EtOAc之间分配。将水层用EtOAc萃取两次,并将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-4.5%DCM/MeOH)纯化,以提供4-(5-氯-7-氟-6-(5-甲氧基-1H-吲唑-7-基)苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯。LCMS-ESI(POS.)m/z:518.2(M+H)+。1H NMR(400MHz,DMSO-d6)δ12.90(br.s,1H),8.06(s,1H),8.03(s,1H),7.31(d,J=1.4Hz,1H),6.99(d,J=2.2Hz,1H),3.83(s,3H),3.61-3.69(m,4H),3.54-3.60(m,4H),1.45(s,9H)。
5-甲氧基-7-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吲唑。用氩流对7-溴-5-甲氧基-1H-吲唑(1.00g,4.40mmol,美国伊利诺伊州阿灵顿海茨市方舟制药公司)、乙酸钾(1.30g,13.2mmol)和双(频哪醇合)二硼(1.23g,4.84mmol)于1,4-二噁烷(18mL)中的悬浮液进行脱气。添加[1,1’-双(二苯基膦基)二茂铁]二氯化钯(ii)与二氯甲烷的络合物(108mg,0.13mmol),并用氩流再次进行脱气。将反应混合物密封并在80℃下加热2d。允许反应冷却至室温并在水(50mL)与EtOAc之间分配。将水层用EtOAc萃取两次,并将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:2%-65%EtOAc/庚烷)纯化,以提供5-甲氧基-7-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吲唑。LCMS-ESI(POS.)m/z:275.1(M+H)+。
步骤2:4-(5-氯-7-氟-6-(5-甲氧基-1-甲基-1H-吲唑-7-基)苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯和4-(5-氯-7-氟-6-(5-甲氧基-2-甲基-2H-吲唑-7-基)苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯。向4-(5-氯-7-氟-6-(5-甲氧基-1H-吲唑-7-基)苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯(115mg,0.22mmol)于THF(5mL)中的溶液中添加氢化钠(矿物油中的60%分散体,44.5mg,1.1mmol)。在10min后,添加碘甲烷(69μL,1.1mmol)并将反应在室温下再搅拌15min,之后在饱和氯化铵水溶液(10mL)与DCM之间分配。将水层用DCM萃取两次,并将合并的有机层经无水硫酸钠干燥并浓缩,得到4-(5-氯-7-氟-6-(5-甲氧基-1-甲基-1H-吲唑-7-基)苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯与4-(5-氯-7-氟-6-(5-甲氧基-2-甲基-2H-吲唑-7-基)苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯的混合物。将粗混合物不经纯化即用于下一步骤中。LCMS-ESI(POS.)m/z:532.0(M+H)+。
步骤3:5-氯-7-氟-6-(5-甲氧基-1-甲基-1H-吲唑-7-基)-3-(哌嗪-1-基)苯并[c]异噻唑(中间体J)和5-氯-7-氟-6-(5-甲氧基-2-甲基-2H-吲唑-7-基)-3-(哌嗪-1-基)苯并[c]异噻唑(中间体K)。通过注射器向4-(5-氯-7-氟-6-(5-甲氧基-1-甲基-1H-吲唑-7-基)苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯和4-(5-氯-7-氟-6-(5-甲氧基-2-甲基-2H-吲唑-7-基)苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯的混合物(143mg)于DCM(6mL)中的粗混合物溶液中添加三氟乙酸(484μL,6.5mmol)。将所得溶液在室温下搅拌25min,然后浓缩。将残余物通过硅胶色谱(洗脱液:0-25%DCM/MeOH)纯化。
第一洗脱峰:5-氯-7-氟-6-(5-甲氧基-1-甲基-1H-吲唑-7-基)-3-(哌嗪-1-基)苯并[c]异噻唑的单TFA盐(中间体J)。LCMS-ESI(POS.)m/z:432.0(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),8.03(s,1H),7.35(d,J=2.4Hz,1H),6.99(d,J=2.4Hz,1H),3.84(s,3H),3.67-3.76(m,4H),3.56(s,3H),3.36-3.42(m,4H)。
第二洗脱峰:5-氯-7-氟-6-(5-甲氧基-2-甲基-2H-吲唑-7-基)-3-(哌嗪-1-基)苯并[c]异噻唑的单TFA盐(中间体K)。LCMS-ESI(POS.)m/z:432.0(M+H)+。
步骤4:1-(4-(5-氯-7-氟-6-(5-甲氧基-1-甲基-1H-吲唑-7-基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮。通过注射器向中间体J的单TFA盐(108mg,0.20mmol)于DCM(5mL)中的冰冷却浆液中逐滴添加DIPEA(104μL,0.60mmol),之后添加丙烯酰氯(24μL,0.30mmol)。将所得溶液在0℃下搅拌3h,然后用饱和NaHCO3水溶液(15mL)淬灭,并用DCM萃取两次。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-7%DCM/MeOH)纯化,以提供1-(4-(5-氯-7-氟-6-(5-甲氧基-1-甲基-1H-吲唑-7-基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮。LCMS-ESI(POS.)m/z:486.0(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.13(s,1H),8.02(s,1H),7.33(d,J=2.2Hz,1H),6.99(d,J=2.4Hz,1H),6.85(dd,J=16.6,10.6Hz,1H),6.18(dd,J=16.7,2.3Hz,1H),5.76(dd,J=10.5,2.3Hz,1H),3.85-3.95(m,4H),3.84(s,3H),3.62-3.72(m,4H),3.56(s,3H)。
步骤5:1-(4-(5-氯-7-氟-6-(5-羟基-1-甲基-1H-吲唑-7-基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮。通过注射器向1-(4-(5-氯-7-氟-6-(5-甲氧基-1-甲基-1H-吲唑-7-基)苯并[c]异噻唑-3-基)哌嗪-1-基)丙-2-烯-1-酮(72.5mg,0.15mmol)于1,2-二氯乙烷(5mL)中的冰冷却溶液中逐滴添加三溴化硼溶液(1.0M于己烷中,746μL,0.75mmol)。将所得浆液在0℃下搅拌3.75h,然后用饱和NaHCO3水溶液(5mL)淬灭,并用DCM/MeOH的4:1混合物萃取两次。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-6%DCM/MeOH)纯化,以提供1-(4-(5-氯-7-氟-6-(5-羟基-1-甲基-1H-吲唑-7-基)苯并[c]异噻唑-3-基)哌嗪-1-基)丙-2-烯-1-酮。LCMS-ESI(POS.)m/z:472.0(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.12(s,1H),7.92(s,1H),7.12(d,J=2.2Hz,1H),6.81-6.91(m,2H),6.18(dd,J=16.7,2.5Hz,1H),5.76(dd,J=10.4,2.4Hz,1H),3.81-3.94(m,4H),3.62-3.70(m,4H),3.52(s,3H)。
对于1-(4-(5-氯-7-氟-6-(5-羟基-2-甲基-2H-吲唑-7-基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮的合成。
使用来自步骤3的中间体K,如上文进行步骤4和5以产生1-(4-(5-氯-7-氟-6-(5-羟基-2-甲基-2H-吲唑-7-基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮。LCMS-ESI(POS.)m/z:472.0(M+H)+。1H NMR(400MHz,DMSO-d6)δ9.28(s,1H),8.11(s,1H),8.01(s,1H),6.95(d,J=2.0Hz,1H),6.77-6.90(m,2H),6.18(dd,J=16.7,2.5Hz,1H),5.76(dd,J=10.4,2.2Hz,1H),4.03(s,3H),3.80-3.94(m,4H),3.58-3.66(m,4H)。
实例20
1-(4-(5-氯-7-氟-6-(3-羟基-1-萘基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-4-羟基-2-亚甲基-1-丁酮
步骤1:4-((叔丁基二苯基甲硅烷基)氧基)-1-(4-(5-氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-基)哌嗪-1-基)-2-亚甲基丁-1-酮。在0℃下向4-((叔丁基二苯基甲硅烷基)氧基)-2-亚甲基丁酸(101mg,0.29mmol,根据以下文献制备:Pihko,P.M.,J.Org.Chem.[有机化学杂志],2006,71,2538-2541和Greaney,M.F.,Org.Lett.[有机化学通讯],2007,9,1931-1934)于DCM(2mL)中的溶液中添加2M草酰氯溶液(0.21mL,0.43mmol),之后添加催化量的DMF(5μL)。允许反应混合物升温至室温并搅拌2h。将反应混合物在真空中浓缩,然后用DCM(1mL)稀释,并将其添加至5-氯-7-氟-6-(3-甲氧基萘-1-基)-3-(哌嗪-1-基)苯并[c]异噻唑(中间体N,122mg,0.29mmol)、三乙胺(0.20mL,1.43mmol)和DCM(2mL)的溶液中。允许反应混合物升温至室温,并添加DMAP(2mg,0.016mmol)。将反应混合物在室温下搅拌15h,然后在真空中浓缩,并通过硅胶柱色谱(洗脱液:0-50%EtOAc:庚烷)纯化,以得到4-((叔丁基二苯基甲硅烷基)氧基)-1-(4-(5-氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-基)哌嗪-1-基)-2-亚甲基丁-1-酮。1H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.94(d,J=8.0Hz,1H),7.63-7.61(m,4H),7.52-7.49(m,2H),7.47-7.40(m,6H),7.33-7.28(m,2H),7.20-7.19(m,1H),5.37(s,1H),5.24(s,1H),3.94(s,3H),3.83-3.76(m,6H),3.53(brs,2H),3.31(s,4H),1.01(s,9H)。m/z(ESI)M+H:764。
步骤2:1-(4-(5-氯-7-氟-6-(3-羟基-1-萘基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-4-羟基-2-亚甲基-1-丁酮。在0℃下向4-((叔丁基二苯基甲硅烷基)氧基)-1-(4-(5-氯-7-氟-6-(3-甲氧基萘-1-基)苯并[c]异噻唑-3-基)哌嗪-1-基)-2-亚甲基丁-1-酮(85mg,0.11mmol)和DCM(2mL)的溶液中添加BBr3(0.28mL,0.56mmol)于DCM中的2M溶液。将反应混合物用水淬灭,在真空中浓缩,并通过硅胶柱色谱(用0-50%庚烷/3:1 EtOAc:EtOH洗脱),得到1-(4-(5-氯-7-氟-6-(3-羟基-1-萘基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-4-羟基-2-亚甲基-1-丁酮。1H NMR(400MHz,DMSO-d6)δ9.93(br s,1H),8.11(s,1H),7.80(d,J=12Hz,1H),7.43(m,1H),7.26-7.20(m,3H),7.07(s,1H),5.32(s,1H),5.16(s,1H),3.83(br s,4H),3.63(br s,4H),3.53(t,J=8.0Hz,2H),2.42(t,J=8.0Hz,2H)。19FNMR(377MHz,DMSO-d6)δ-123.8(s,1F)。m/z(ESI)M+H:512。
实例21
1-(4-(5-氯-7-氟-6-(7-羟基-5-喹啉基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮
1-(4-(5-氯-7-氟-6-(7-羟基-5-喹啉基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮是通过方法1使用7-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)喹啉(下文合成)从中间体D制备,其中有以下变化:在步骤7中,使用S-Phos Pd G3、碳酸钾水溶液和DME;在步骤8-1中,使用TFA/DCM;在步骤8-2中,使用DCE作为溶剂;并且在步骤8-3中,使用三溴化硼溶液(1.0M于DCE中),以得到1-(4-(5-氯-7-氟-6-(7-羟基-5-喹啉基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮。1H NMR(400MHz,CDCl3)δ8.81(dd,J=4.2,1.3Hz,1H)7.72-7.78(m,2H)7.64(s,1H)7.28(d,J=2.2Hz,1H)7.16(dd,J=8.4,4.3Hz,1H)6.56-6.66(m,1H)6.40(dd,J=16.8,1.6Hz,1H)5.78-5.87(m,1H)4.01(br.s.,2H)3.89(br.s.,2H)3.50-3.60(m,4H)。19F NMR(376MHz,CDCl3)δ–121.33(s,1F)。MS(ESI,+ve)m/z:469.1(M+1)+。
7-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)喹啉。将5-溴-7-甲氧基喹啉(0.407g,1.71mmol,美国伊利诺伊州伍德戴尔市奥科化学公司(OxChem))、4,4,4’,4’,5,5,5’,5’-八甲基-2,2’-二(1,3,2-二氧杂硼烷)(0.912g,3.59mmol)、PdCl2(dppf)(0.051g,0.070mmol)和乙酸钾(0.503g,5.13mmol)于DMF(9mL)中的溶液在90℃下搅拌1h,然后在100℃下搅拌45min。将反应混合物用EtOAc(100mL)稀释,并用饱和碳酸氢钠水溶液(2×75mL)洗涤。将有机层分离,经无水Na2SO4干燥,并在真空中浓缩。将粗品吸附至二氧化硅上,并通过柱色谱(硅胶,0-80%庚烷/EtOAc)纯化,以得到7-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)喹啉。MS(ESI,+ve)m/z:286.1(M+1)+。
实例22
1-(5-氯-7-氟-6-(3-羟基-1-萘基)-2,1-苯并噻唑-3-基)-4-(2-丙烯酰基)-2-哌嗪甲酸
在0℃下向4-丙烯酰基-1-(5-氯-7-氟-6-(3-羟基萘-1-基)苯并[c]异噻唑-3-基)哌嗪-2-甲酸甲酯(实例7-3,0.022g,0.042mmol)于THF/EtOH(1:1;6mL)中的溶液中添加NaOH(5N水溶液;1.0mL,5.0mmol),并将所得混合物在0℃下搅拌5min。将反应在0℃下用5NHCl酸化,用EtOAc萃取,并通过HPLC纯化,得到1-(5-氯-7-氟-6-(3-羟基-1-萘基)-2,1-苯并噻唑-3-基)-4-(2-丙烯酰基)-2-哌嗪甲酸。m/z(ESI,+ve)512.0(M+H)+。1H NMR(400MHz,DMSO-d6)δ3.14-3.28(m,1H)3.52-3.87(m,3H)4.15-5.03(m,2H)5.15-5.23(m,1H)5.77-5.83(m,1H)6.13-6.24(m,1H)6.86(br.s.,1H)7.06-7.12(m,1H)7.20-7.30(m,3H)7.38-7.49(m,1H)7.76-7.84(m,1H)8.07-8.13(m,1H)9.98(br.s.,1H)13.42(br.s.,1H)。
实例23
1-(4-(5-氯-6-(5-环丙基-1H-吲唑-4-基)-7-氟-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮
实例23是如方法1中所描述,在步骤7中使用(5-环丙基-1H-吲唑-4-基)硼酸(参见以下合成),并省略步骤8-3制备。m/z(ESI,+ve)482.0(M+H)+。1H NMR(400MHz,DMSO-d6)δ12.92-13.19(1H,m),8.02-8.21(1H,m),7.47-7.60(2H,m),7.02-7.09(1H,m),6.80-6.93(1H,m),6.15-6.25(1H,m),5.71-5.82(1H,m),3.80-3.96(4H,m),3.60-3.72(4H,m),1.55-1.74(1H,m),0.72-0.79(2H,m),0.58-0.71(2H,m)。
(5-环丙基-1H-吲唑-4-基)硼酸
步骤1:2-溴-1-环丙基-4-氟苯。在环境温度下向2-L圆底烧瓶中添加环戊基甲醚(1.1L)中的2-溴-4-氟-1-碘苯(22g,73.1mmol)和环丙基硼酸(12.6g,146mmol)。添加Na2CO3(2M水溶液;183mL),并用N2气将反应脱气20分钟。添加Tetrakis(8.45g,7.31mmol),并用N2气将反应再次脱气20分钟。然后将反应混合物在N2气氛下转移至5-L高压釜中并加热至130℃持续40h。使反应混合物冷却至环境温度,经硅藻土垫过滤,并用乙醚(200mL)洗涤。向滤液中添加水(500mL),并将有机层分离。将水层用乙醚(2×300mL)萃取,并将合并的有机层经无水硫酸钠干燥,并在减压下蒸发。将粗材料吸附至硅胶塞上并进行色谱纯化(硅胶,100%石油醚),以提供2-溴-1-环丙基-4-氟苯。GC-MS m/z:214/2161H NMR(400MHz,CDCl3)δ7.36–7.23(m,1H),6.95(dt,J=7.0,1.5Hz,2H),2.09(ddd,J=13.8,8.5,5.4Hz,1H),1.12–0.88(m,2H),0.76–0.50(m,2H)。
步骤2:2-溴-3-环丙基-6-氟苯甲醛。在N2气氛下向500-mL圆底烧瓶中添加四氢呋喃(130mL)中的2-溴-1-环丙基-4-氟苯(6.5g,30.2mmol)。在-78℃下(内部温度维持在-65℃至-70℃之间)逐滴添加LDA(18.1mL,36.3mmol,2M于THF中,1.2当量),并将反应混合物搅拌1h。然后将DMF(6mL)逐滴添加至反应混合物(内部温度维持在-65℃至-70℃之间)中,并将反应在-78℃下再搅拌3h。将反应用饱和氯化铵水溶液(100mL)淬灭并缓慢升温至环境温度。将混合物用乙醚(200mL)稀释,并将有机层分离,并用盐水溶液(2×50mL)洗涤。将合并的有机层经无水Na2SO4干燥,并在减压下蒸发。将粗材料吸附至硅胶塞上并进行色谱纯化(硅胶,0-2%EtOAc/己烷),以提供2-溴-3-环丙基-6-氟苯甲醛。GC-MSm/z:2421H NMR(400MHz,CDCl3)δ10.43(d,J=1.5Hz,1H),7.26–7.12(m,1H),7.06(t,J=9.3Hz,1H),2.15(td,J=8.4,4.3Hz,1H),1.17–0.94(m,2H),0.78–0.52(m,2H)。
步骤3:4-溴-5-环丙基-1H-吲唑。向100mL密封管中添加乙二醇(40mL)中的2-溴-3-环丙基-6-氟苯甲醛(4g,16.5mmol)和水合肼(4.0mL,82mmol)。将反应在90℃下搅拌2h,然后加热至150℃持续16h。使反应混合物冷却至环境温度,并添加冰冷水(40mL)和EtOAc(50mL)。将有机层分离并将水层用EtOAc(2×40mL)萃取。将合并的有机层用水(2×40mL)和盐水溶液(40mL)洗涤,经无水硫酸钠干燥,并在真空中浓缩。将粗材料吸附至硅胶塞上并进行色谱纯化(硅胶,0-20%EtOAc/己烷),以提供4-溴-5-环丙基-1H-吲唑。将化合物通过反相制备型液相色谱(YMC:C18,150×20mm,5μm;流动相:水和乙腈中的0.1%TFA;流速:15mL/min)纯化,得到纯化合物。MS(ESI阳离子)m/z:237/239.0(M+1)。1H NMR(400MHz,DMSO-d6)δ13.31(s,1H),7.97(s,1H),7.46(d,J=8.6Hz,1H),6.97(d,J=8.6Hz,1H),2.21(tt,J=8.5,5.3Hz,1H),1.24–0.87(m,2H),0.93–0.33(m,2H)。
步骤4:5-环丙基-1H-吲唑-4-基)硼酸。向100-mL圆底烧瓶中添加1,4-二噁烷(25mL)中的4-溴-5-环丙基-1H-吲唑(0.62g,2.6mmol)和双(频哪醇合)二硼(0.996g,3.92mmol);添加乙酸钾(0.77g,7.84mmol),并用N2气将反应混合物脱气10分钟。将PdCl2(dppf)·DCM加合物(0.213g,0.261mmol)添加至反应混合物中;再次用N2气将反应混合物脱气10分钟,然后加热至100℃持续16h。使反应混合物冷却至环境温度,经硅藻土垫过滤,并用EtOAc(50mL)洗涤。将滤液在真空中浓缩,并将粗材料吸附至硅胶塞上并进行色谱纯化(硅胶,0-50%EtOAc/己烷)。将化合物通过反相制备型液相色谱(Grace柱;0-70%MeCN/水)进一步纯化,以提供5-环丙基-1H-吲唑-4-基)硼酸。MS(ESI阳离子)m/z:285.2(M+1)。1HNMR(400MHz,DMSO-d6)δ12.88(s,1H),8.13(q,J=1.3Hz,1H),7.50(d,J=8.7Hz,1H),6.83(dd,J=8.8,1.4Hz,1H),2.78–2.60(m,1H),1.38(d,J=1.4Hz,12H),1.07–0.85(m,2H),0.75–0.48(m,2H)。
实例24
1-(4-(5-氯-7-氟-6-(3-(甲基氨基)-1-异喹啉基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮
步骤1:1-(5-氯-7-氟-3-(哌嗪-1-基)苯并[c]异噻唑-6-基)-N-甲基异喹啉-3-胺。在0℃下向4-(6-溴-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯(中间体D,30mg,0.067mmol)于四氢呋喃(0.6mL)中的溶液中添加异丙基氯化镁的溶液(四氢呋喃中的2.0M溶液,0.050mL,0.100mmol)。将混合物搅拌5min,之后添加氯化锌(2-甲基四氢呋喃中的1.9M溶液,0.053mL,0.100mmol),并使反应混合物升温至室温并搅拌40min。然后将反应混合物转移至含有Sphos Pd G3(5.76mg,6.66μmol)和(1-溴异喹啉-3-基)(甲基)氨基甲酸叔丁酯(24.7mg,0.073mmol,参见下文合成)的小瓶中,并加热至70℃过夜。将粗反应用饱和NH4Cl水溶液(50mL)和EtOAc(50mL)稀释。将有机层分离,经Na2SO4干燥,过滤并浓缩。通过硅胶柱色谱(用DCM中的6%-20%MeOH洗脱)纯化提供1-(5-氯-7-氟-3-(哌嗪-1-基)苯并[c]异噻唑-6-基)-N-甲基异喹啉-3-胺。m/z(ESI,+ve)428.1(M+H)+。
(1-溴异喹啉-3-基)(甲基)氨基甲酸叔丁酯的合成:在室温下向1-溴异喹啉-3-胺(200mg,0.897mmol,英国奥尔特灵厄姆市(Altrincham)美布雷化学公司(MaybridgeChemical Co.))于四氢呋喃(5mL)中的溶液中添加双(三甲基甲硅烷基)酰胺钠(四氢呋喃中的1M溶液,1.79mL,1.79mmol)。将混合物搅拌10min,之后添加Boc-酸酐(0.208mL,0.897mmol)于THF(1mL)中的溶液。将反应混合物搅拌5min,之后用饱和NH4Cl水溶液(50mL)和EtOAc(50mL)稀释。将有机层分离,经Na2SO4干燥,过滤并浓缩。通过硅胶柱色谱(用庚烷中的0-20%EtOAc洗脱)提供(1-溴异喹啉-3-基)氨基甲酸叔丁酯。m/z(ESI,+ve)345.0(M+Na)+。
在室温下向(1-溴异喹啉-3-基)氨基甲酸叔丁酯(140mg,0.433mmol)于四氢呋喃(3mL)中的溶液中添加氢化钠(矿物油中的60%分散体,22.52mg,0.563mmol)。将混合物搅拌15min,之后添加碘代甲烷(0.033mL,0.520mmol)。在搅拌过夜后,将反应用饱和NH4Cl水溶液(50mL)和EtOAc(50mL)稀释。将有机层分离,经Na2SO4干燥,过滤并浓缩。通过硅胶柱色谱(用庚烷中的0-10%EtOAc洗脱)提供(1-溴异喹啉-3-基)(甲基)氨基甲酸叔丁酯。1H NMR(400MHz,甲醇-d4)δ8.25(d,J=8.61Hz,1H),7.88-7.95(m,2H),7.79(t,J=7.5Hz,1H),7.70(t,J=7.6Hz,1H),3.42(s,3H),1.54(s,9H)。m/z(ESI,+ve)359.1(M+H)+。
步骤2:1-(4-(5-氯-7-氟-6-(3-(甲基氨基)-1-异喹啉基)-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮。与方法1步骤8-2类似的程序。通过硅胶柱色谱(用DCM中的0-14%MeOH洗脱)经15min纯化。1H NMR(400MHz,甲醇-d4)δ7.90(s,1H),7.63(d,J=8.5Hz,1H),7.43(t,J=7.4Hz,1H),7.24(d,J=8.5Hz,1H),7.05(t,J=7.4Hz,1H),6.72-6.84(m,1H),6.67(s,1H),6.15-6.28(m,1H),5.68-5.81(m,1H),3.87-3.97(m,4H),3.63(m,4H),2.90(s,3H)。m/z(ESI,+ve)482.0(M+H)+。
实例25
1-(4-(6-(3-氨基-1-异喹啉基)-5-氯-7-氟-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮
步骤1:4-(6-(3-((叔丁氧基羰基)氨基)异喹啉-1-基)-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯。与实例25步骤1类似的程序,使用1.3M异丙基氯化镁锂于THF中的溶液代替异丙基氯化镁溶液,并使用双(2-甲基-2-丙烷基)(1-溴-3-异喹啉基)-2-亚氨基二碳酸酯(下文合成)代替(1-溴异喹啉-3-基)(甲基)氨基甲酸叔丁酯。m/z(ESI,+ve)614.2(M+H)+。
双(2-甲基-2-丙烷基)(1-溴-3-异喹啉基)-2-亚氨基二碳酸酯的合成:在0℃下向1-溴异喹啉-3-胺(1.0g,4.48mmol,英国奥尔特灵厄姆市美布雷化学公司)于DCM(50mL)中的溶液中添加Boc-酸酐(3.12mL,13.45mmol)和DMAP(0.055g,0.448mmol)。将反应升温至室温并搅拌过夜。然后将反应混合物用饱和NH4Cl水溶液(100mL)和DCM(50mL)稀释。将有机层分离,经Na2SO4干燥,过滤并浓缩。通过硅胶柱色谱(用庚烷中的0-10%EtOAc洗脱)经15min纯化,提供双(2-甲基-2-丙烷基)(1-溴-3-异喹啉基)-2-亚氨基二碳酸酯。1H NMR(400MHz,甲醇-d4)δ8.36(d,J=8.5Hz,1H),8.03(d,J=8.1Hz,1H),7.77-7.92(m,3H),1.44(s,18H)。m/z(ESI,+ve)267.0(M+H)+。
步骤2:1-(4-(6-(3-氨基-1-异喹啉基)-5-氯-7-氟-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮。与方法1步骤8-1和8-2类似的程序,其中在步骤8-1中使用DCM中的TFA代替二噁烷/MeOH中的4M HCl。通过硅胶柱色谱(用DCM中的0-12%MeOH洗脱)纯化。然后使此材料经历SFC纯化:二醇柱(21.2x250mm,5μm),使用超临界CO2中的17%(20mM NH3于MeOH中)(总流速为7g/min),得到1-(4-(6-(3-氨基-1-异喹啉基)-5-氯-7-氟-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮。1H NMR(400MHz,甲醇-d4)δ7.85(s,1H),7.53(d,J=8.5Hz,1H),7.39(t,J=7.6Hz,1H),7.23(d,J=8.5Hz,1H),7.03(t,J=7.8Hz,1H),6.82(s,1H),6.71(dd,J=10.8,16.8Hz,1H),6.2(dd,J=1.5,16.8Hz,1H),5.70(dd,J=1.5,10.8Hz,1H),3.82-3.93(m,4H),3.50-3.66(m,4H)。m/z(ESI,+ve)468.0(M+H)+。
实例26
1-(4-(6-(2-氨基-4-喹啉基)-5-氯-7-氟-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮
步骤1:4-(5-氯-7-氟-6-(三丁基锡烷基)苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯。将4-(6-溴-5-氯-7-氟苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯(中间体D,320mg,0.710mmol)、1,1,1,2,2,2-六丁基二锡烷(824mg,1.420mmol)和四(三苯膦)钯(0)(82mg,0.071mmol,美国马萨诸塞州纽伯里波特市斯特雷姆化学公司)于N,N-二甲基乙酰胺(5mL)中的溶液在密封小瓶中在微波炉中在160℃下加热40min。将反应混合物用饱和NaHCO3水溶液(50mL)、盐水(50mL)和EtOAc(100mL)稀释。将有机层分离,经Na2SO4干燥,过滤并浓缩。通过硅胶柱色谱(用庚烷中的0-30%EtOAc洗脱)纯化,提供4-(5-氯-7-氟-6-(三丁基锡烷基)苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯。m/z(ESI,+ve)662.2(M+H)+。
步骤2:2-甲基-2-丙烷基4-(6-(2-(双(((2-甲基-2-丙烷基)氧基)羰基)氨基)-4-喹啉基)-5-氯-7-氟-2,1-苯并噻唑-3-基)-1-哌嗪甲酸酯。将(4-溴喹啉-2-基)-2-亚氨基二碳酸二叔丁酯(19.2mg,0.045mmol,以与实例26中的双(2-甲基-2-丙烷基)(1-溴-3-异喹啉基)-2-亚氨基二碳酸酯类似的方式,使用4-溴喹啉-2-胺(美国伊利诺伊州阿灵顿海茨市方舟制药公司)作为起始材料来制备)、4-(5-氯-7-氟-6-(三丁基锡烷基)苯并[c]异噻唑-3-基)哌嗪-1-甲酸叔丁酯(20mg,0.030mmol)、四(三苯膦)钯(0)(6.99mg,6.05μmol,美国马萨诸塞州纽伯里波特市斯特雷姆化学公司)、碘化铜(I)(1.153mg,6.05μmol)和氟化铯(13.79mg,0.091mmol)于DMF(0.5mL)中的溶液在密封小瓶中在60℃下加热30min。将粗反应用饱和NaHCO3水溶液(50mL)和EtOAc(100mL)稀释。将有机层分离,经Na2SO4干燥,过滤并浓缩。通过硅胶柱色谱(用庚烷中的0-50%EtOAc洗脱),提供2-甲基-2-丙烷基4-(6-(2-(双(((2-甲基-2-丙烷基)氧基)羰基)氨基)-4-喹啉基)-5-氯-7-氟-2,1-苯并噻唑-3-基)-1-哌嗪甲酸酯。m/z(ESI,+ve)714.2(M+H)+。
步骤3:1-(4-(6-(2-氨基-4-喹啉基)-5-氯-7-氟-2,1-苯并噻唑-3-基)-1-哌嗪基)-2-丙烯-1-酮。与方法1步骤8-1和8-2类似的程序,在步骤8-1中使用DCM中的TFA代替二噁烷/MeOH中的4M HCl。1H NMR(400MHz,甲醇-d4)δ7.90(s,1H),7.53(d,J=8.2Hz,1H),7.42-7.49(m,1H),7.10(d,J=8.0Hz,1H),7.03-7.08(m,J=7.6Hz,1H),6.67-6.81(m,2H),6.19(dd,J=1.8,16.6Hz,1H),5.72(dd,J=1.8,10.6Hz,1H),3.87-3.93(m,4H),3.56-3.66(m,4H)。m/z(ESI,+ve)468.0(M+H)+。
实例27
1-(4-(3-(2-氟-6-羟苯基)-2-甲基-5-(2-(2-丙烷基)苯基)吡啶并[2,3-d]哒嗪-8-基)-1-哌嗪基)-2-丙烯-1-酮
步骤1:6,7-二氢吡啶并[2,3-d]哒嗪-5,8-二酮。将肼(1.26mL,40.2mmol)添加至2,3-吡啶二甲酸酐(4.00g,26.8mmol)于乙醇(100mL)中的经搅拌溶液中。将反应混合物回流16h,之后冷却至室温并在真空中浓缩,以得到粗6,7-二氢吡啶并[2,3-d]哒嗪-5,8-二酮,将其直接用于下一步骤中。m/z(ESI)M+H:164.1。
步骤2:5,8-二氯吡啶并[2,3-d]哒嗪。将吡啶(4.57mL,53.7mmol)添加至粗6,7-二氢吡啶并[2,3-d]哒嗪-5,8-二酮(4.38g,26.8mmol)于三氯氧磷(v)(20.1mL,215mmol)中的混合物中。将反应混合物在100℃下搅拌2h。将反应混合物冷却并在约10℃下缓慢倾倒至快速搅拌的水(250mL)中。将水性悬浮液搅拌15min,之后用EtOAc(250mL)萃取。将有机层分离,用盐水(200mL)洗涤,经MgSO4干燥,过滤且在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至100%EtOAc)得到5,8-二氯吡啶并[2,3-d]哒嗪。1H NMR(400MHz,氯仿-d)δ9.41(1H,dd,J=4.30,1.56Hz)8.65(1H,dd,J=8.41,1.56Hz)8.02(1H,dd,J=8.41,4.30Hz)。m/z(ESI)M+H:200.0。
步骤3:3,5-二氯吡啶并[2,3-d]哒嗪-8(7H)-酮和3,8-二氯吡啶并[2,3-d]哒嗪-5(6H)-酮。将N-氯代琥珀酰亚胺(1268mg,9.50mmol,美国俄勒冈州波特兰市TCI美国公司)添加至5,8-二氯吡啶并[2,3-d]哒嗪(950mg,4.75mmol)于乙酸(20mL)中的经搅拌溶液中,并将反应混合物加热至100℃持续16h。添加另外的N-氯代琥珀酰亚胺(1268mg,9.50mmol,美国俄勒冈州波特兰市TCI美国公司),并将反应混合物在100℃下再搅拌4h。添加另外的N-氯代琥珀酰亚胺(634mg,4.75mmol,美国俄勒冈州波特兰市TCI美国公司),并将反应混合物再搅拌4h。然后将反应混合物用水(75mL)稀释,并用EtOAc(100mL)萃取三次。将合并的有机层用盐水(150mL)洗涤,经MgSO4干燥,过滤且在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至75%EtOAc)得到3,5-二氯吡啶并[2,3-d]哒嗪-8(7H)-酮化合物和3,8-二氯吡啶并[2,3-d]哒嗪-5(6H)-酮的位置异构体混合物。m/z(ESI)M+H:215.9。
步骤4:3,5,8-三氯吡啶并[2,3-d]哒嗪。将吡啶(2.024mL,23.79mmol)添加至3,5-二氯吡啶并[2,3-d]哒嗪-8(7H)-酮与3,8-二氯吡啶并[2,3-d]哒嗪-5(6H)-酮(2.57g,11.90mmol)于三氯氧磷(8.90mL,95mmol)中的位置异构体混合物中。将反应混合物在100℃下搅拌1.5h。将反应混合物冷却并在约10℃下缓慢倾倒至快速搅拌的水(150mL)中。将水性悬浮液搅拌15min,之后用EtOAc(200mL)萃取。将有机层分离,用盐水(150mL)洗涤,经MgSO4干燥,过滤且在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至50%EtOAc)得到3,5,8-三氯吡啶并[2,3-d]哒嗪。1H NMR(400MHz,氯仿-d)δ9.27(1H,d,J=2.35Hz)8.58(1H,d,J=2.35Hz)。m/z(ESI)M+H:233.9。
步骤5:4-(3,5-二氯吡啶并[2,3-d]哒嗪-8-基)哌嗪-1-甲酸叔丁酯。将1-Boc-哌嗪(278mg,1.494mmol)添加至3,5,8-三氯吡啶并[2,3-d]哒嗪(292mg,1.245mmol)和三乙胺(0.350mL,2.491mmol)于二甲亚砜(5mL)中的经搅拌混合物中。将反应混合物在室温下搅拌3h,之后用EtOAc(75mL)稀释,并用饱和碳酸氢钠水溶液(75mL)洗涤。将有机层分离,用盐水(50mL)洗涤,经MgSO4干燥,过滤且在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至25%丙酮)得到4-(3,5-二氯吡啶并[2,3-d]哒嗪-8-基)哌嗪-1-甲酸叔丁酯,其为两种位置异构体首先洗脱的。1H NMR(400MHz,氯仿-d)δ9.01(1H,d,J=2.54Hz)8.43(1H,d,J=2.54Hz)4.04-4.15(4H,m)3.64-3.70(4H,m)1.50(9H,s)。m/z(ESI)M+H:384.0。
步骤6:4-(3-氯-5-(2-异丙基苯基)吡啶并[2,3-d]哒嗪-8-基)哌嗪-1-甲酸叔丁酯。将4-(3,5-二氯吡啶并[2,3-d]哒嗪-8-基)哌嗪-1-甲酸叔丁酯(199mg,0.518mmol)、2-异丙基苯基硼酸(93mg,0.570mmol,美国马萨诸塞州哈弗希尔市阿法埃莎公司)、四(三苯膦)钯(59.8mg,0.052mmol,美国马萨诸塞州纽伯里波特市斯特雷姆化学公司)和碳酸钠(2M水溶液,1.036mL,2.072mmol)在1,4-二噁烷(4mL)中在氩气氛下混合。将反应混合物在40℃下搅拌16h。使反应混合物冷却至室温,用EtOAc(50mL)稀释,并用水(40mL)洗涤。将有机层分离,用盐水(50mL)洗涤,经MgSO4干燥,过滤且在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至50%EtOAc)得到起始材料与所需产物的混合物。使混合物再次经历初始反应条件,使用较少2-异丙基苯基硼酸(56mg,0.342mmol,美国马萨诸塞州哈弗希尔市阿法埃莎公司)。将混合物在40℃下搅拌16h。添加另外的2-异丙基苯基硼酸(28mg,0.171mmol,美国马萨诸塞州哈弗希尔市阿法埃莎公司),并将反应混合物再搅拌6h。使反应混合物冷却至室温,用EtOAc(50mL)稀释,并用水(40mL)洗涤。将有机层分离,用盐水(50mL)洗涤,经MgSO4干燥,过滤且在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至50%EtOAc)得到4-(3-氯-5-(2-异丙基苯基)吡啶并[2,3-d]哒嗪-8-基)哌嗪-1-甲酸叔丁酯。1H NMR(400MHz,氯仿-d)δ8.95(1H,d,J=2.35Hz)7.72(1H,d,J=2.54Hz)7.45-7.53(2H,m)7.26-7.33(1H,m)7.16-7.21(1H,m)4.04-4.23(4H,m)3.66-3.73(4H,m)2.67(1H,spt,J=6.75Hz)1.48(9H,s)1.16(3H,d,J=6.85Hz)1.03(3H,d,J=6.85Hz)。m/z(ESI)M+H:468.2。
步骤7:4-(3-氯-5-(2-异丙基苯基)-2-甲基吡啶并[2,3-d]哒嗪-8-基)哌嗪-1-甲酸叔丁酯。在-78℃下将甲基锂(乙醚中的1.6M溶液,0.137mL,0.219mmol)添加至4-(3-氯-5-(2-异丙基苯基)吡啶并[2,3-d]哒嗪-8-基)哌嗪-1-甲酸叔丁酯(93mg,0.199mmol)于四氢呋喃(1mL)中的经搅拌溶液中。将反应混合物在-78℃下搅拌5min,之后允许其升温至0℃并搅拌30min。使反应混合物冷却回至-78℃,并添加另外的甲基锂(乙醚中的1.6M溶液,0.068mL,0.109mmol)。将反应混合物在-78℃下搅拌5min,之后允许其升温至0℃并再搅拌15min。将反应混合物用水(20mL)淬灭并用EtOAc(30mL)萃取。将有机层分离,用盐水(20mL)洗涤,经MgSO4干燥,过滤,并在真空中浓缩,以得到粗4-(3-氯-5-(2-异丙基苯基)-2-甲基-1,2-二氢吡啶并[2,3-d]哒嗪-8-基)哌嗪-1-甲酸叔丁酯。m/z(ESI)M+H:484.3。
将4,5-二氯-3,6-二氧代-1,4-环己二烯-1,2-二腈(45.0mg,0.198mmol)添加至粗4-(3-氯-5-(2-异丙基苯基)-2-甲基-1,2-二氢吡啶并[2,3-d]哒嗪-8-基)哌嗪-1-甲酸叔丁酯(96mg,0.198mmol)于二氯甲烷(2mL)中的经搅拌混合物中。将反应混合物在室温下搅拌10min。将反应混合物用DCM(30mL)稀释并用水(20mL)洗涤。分离有机层,经MgSO4干燥,过滤且在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至50%EtOAc)得到4-(3-氯-5-(2-异丙基苯基)-2-甲基吡啶并[2,3-d]哒嗪-8-基)哌嗪-1-甲酸叔丁酯。1H NMR(400MHz,氯仿-d)δ7.72(1H,s)7.51-7.55(2H,m)7.32-7.37(1H,m)7.22-7.27(1H,m)4.08-4.25(4H,m)3.71-3.79(4H,m)2.87(3H,s)2.73(1H,spt,J=6.68Hz)1.54(9H,s)1.21(3H,d,J=6.85Hz)1.07(3H,d,J=6.85Hz)。m/z(ESI)M+H:482.1。
步骤8:4-(3-(2-氟-6-羟苯基)-5-(2-异丙基苯基)-2-甲基吡啶并[2,3-d]哒嗪-8-基)哌嗪-1-甲酸叔丁酯。将4-(3-氯-5-(2-异丙基苯基)-2-甲基吡啶并[2,3-d]哒嗪-8-基)哌嗪-1-甲酸叔丁酯(78mg,0.162mmol)、(2-氟-6-羟苯基)硼酸(101mg,0.647mmol,康比乐公司)、Sphos Pd G3(14.00mg,0.016mmol)和碳酸钠(2M水溶液,0.324mL,0.647mmol)在1,2-二甲氧基乙烷(1mL)中在氩气氛下混合,然后在80℃下加热2.5h。使反应混合物冷却,用EtOAc(30mL)稀释,并用水(25mL)洗涤。将有机层分离,用盐水(25mL)洗涤,经MgSO4干燥,过滤且在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至50%EtOAc)得到4-(3-(2-氟-6-羟苯基)-5-(2-异丙基苯基)-2-甲基吡啶并[2,3-d]哒嗪-8-基)哌嗪-1-甲酸叔丁酯(66mg,0.118mmol,73.1%产率)。m/z(ESI)M+H:558.2。
步骤9:3-氟-2-(5-(2-异丙基苯基)-2-甲基-8-(哌嗪-1-基)吡啶并[2,3-d]哒嗪-3-基)苯酚。将三氟乙酸(0.2mL,2.68mmol)添加至4-(3-(2-氟-6-羟苯基)-5-(2-异丙基苯基)-2-甲基吡啶并[2,3-d]哒嗪-8-基)哌嗪-1-甲酸叔丁酯(64mg,0.115mmol)于二氯甲烷(0.5mL)中的经搅拌溶液中。将反应混合物在室温下搅拌30min。将反应混合物用DCM(30mL)稀释并用饱和碳酸氢钠水溶液(20mL)淬灭。将有机层分离,经MgSO4干燥,过滤,并在真空中浓缩,以得到粗3-氟-2-(5-(2-异丙基苯基)-2-甲基-8-(哌嗪-1-基)吡啶并[2,3-d]哒嗪-3-基)苯酚。m/z(ESI)M+H:458.1。
步骤10:1-(4-(3-(2-氟-6-羟苯基)-5-(2-异丙基苯基)-2-甲基吡啶并[2,3-d]哒嗪-8-基)哌嗪-1-基)丙-2-烯-1-酮。在0℃下将丙烯酰氯(9.45μl,0.116mmol)添加至3-氟-2-(5-(2-异丙基苯基)-2-甲基-8-(哌嗪-1-基)吡啶并[2,3-d]哒嗪-3-基)苯酚(53mg,0.116mmol)和三乙胺(0.049mL,0.348mmol)于二氯甲烷(1mL)中的经搅拌混合物中。将反应混合物在0℃下搅拌10min。将反应混合物用DCM(25mL)稀释并用饱和碳酸氢钠水溶液(20mL)淬灭。分离有机层,经MgSO4干燥,过滤且在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至100%EtOAc)得到1-(4-(3-(2-氟-6-羟苯基)-2-甲基-5-(2-(2-丙烷基)苯基)吡啶并[2,3-d]哒嗪-8-基)-1-哌嗪基)-2-丙烯-1-酮。1H NMR(400MHz,氯仿-d)δ9.51(0.6H,br s)8.98(0.4H,br s)7.63(0.4H,s)7.58(0.6H,s)7.35-7.43(2H,m)7.10-7.26(3H,m)6.78(1H,dd,J=16.63,8.22Hz)6.59-6.71(2H,m)6.36(1H,dd,J=16.82,1.57Hz)5.78(1H,dd,J=10.56,1.37Hz)4.10-4.38(4H,m)3.80-4.03(4H,m)2.60-2.72(1H,m)2.61(1.2H,s)2.59(1.8H,s)0.91-1.08(6H,m)。m/z(ESI)M+H:512.3。
实例28
1-(4-(7-氯-6-(2-氟-6-羟苯基)-4-((1R)-1-苯乙基)-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮和1-(4-(7-氯-6-(2-氟-6-羟苯基)-4-((1S)-1-苯乙基)-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮
将α-甲基苄基溴化锌(0.5M于THF中,492μl,0.246mmol)、四(三苯膦)钯(5.68mg,4.92μmol,美国马萨诸塞州纽伯里波特市斯特雷姆化学公司)和1-(4-(4,7-二氯-6-(2-氟-6-羟苯基)酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮(中间体I,22mg,0.049mmol)的混合物在60℃下在密封小瓶中搅拌16h。将反应混合物浓缩,并且残余物的色谱纯化(硅胶,庚烷中的0至100%EtOAc)得到1-(4-(7-氯-6-(2-氟-6-羟苯基)-4-((1R)-1-苯乙基)-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮与1-(4-(7-氯-6-(2-氟-6-羟苯基)-4-((1S)-1-苯乙基)-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮的混合物。1H NMR(400Mhz,甲醇-d4)δ8.27(1H,s)8.15(0.33H,s)8.10(0.67H,s)7.19-7.31(5H,m)7.10-7.16(1H,m)6.86(1H,dd,J=16.73,10.66Hz)6.62-6.78(2H,m)6.27(1H,dd,J=16.82,1.96Hz)5.80(1H,dd,J=10.66,1.86Hz)4.94-5.01(1H,m)3.93-4.03(4H,m)3.49-3.60(4H,m)1.81(3H,d,J=7.04Hz)。m/z(ESI)M+H:517.1。
实例29
1-(4-(7-氯-4-(4-氟苄基)-6-(2-氟-6-羟苯基)-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮
在密封小瓶中在氩气氛下将4-氟苄基氯化锌(0.5M于THF中,0.089mL,0.044mmol)添加至1-(4-(4,7-二氯-6-(2-氟-6-羟苯基)酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮(中间体I,18mg,0.040mmol)和四(三苯膦)钯(4.65mg,4.02μmol,美国马萨诸塞州纽伯里波特市斯特雷姆化学公司)于四氢呋喃(0.1mL)中的经搅拌混合物中。将反应混合物在室温下搅拌2h,之后加热至40℃持续3h。添加另外的4-氟苄基氯化锌(0.089mL,0.044mmol),并将反应混合物在40℃下再搅拌16h。添加另外的4-氟苄基氯化锌(0.089mL,0.044mmol),并将反应混合物加热至60℃并搅拌6h。将反应混合物在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至100%EtOAc)得到1-(4-(7-氯-4-(4-氟苄基)-6-(2-氟-6-羟苯基)-1-酞嗪基)-1-哌嗪基)-2-丙烯-1-酮。1H NMR(400MHz,甲醇-d4)δ8.32(1H,s)8.19(1H,s)7.26-7.34(3H,m)6.98(2H,t,J=8.71Hz)6.69-6.91(3H,m)6.28(1H,dd,J=16.92,1.86Hz)5.82(1H,dd,J=10.56,1.76Hz)4.54-4.65(2H,m)3.99(4H,m)3.58(4H,m)。m/z(ESI)M+H:521.2。
实例30和31
2-(1-(4-丙烯酰基-1-哌嗪基)-7-氯-4-苯基-6-酞嗪基)-3-氟苯酚(实例30)和2-(4-(4-丙烯酰基-1-哌嗪基)-7-氯-1-苯基-6-酞嗪基)-3-氟苯酚(实例31)
步骤1:1,4,6,7-四氯酞嗪(中间体L)。将吡啶(431μl,5.28mmol)添加至6,7-二氯-2,3-二氢酞嗪-1,4-二酮(中间体G,610mg,2.64mmol)于三氯氧磷(2.4mL,26.4mmol)中的经搅拌混合物中。将反应混合物加热至100℃持续2h,然后冷却并在约10℃下缓慢倾倒至快速搅拌的水(75mL)中。将所得悬浮液过滤,并将固体用水洗涤,以得到1,4,6,7-四氯酞嗪。1HNMR(400MHz,氯仿-d)δ8.43(2H,s)。m/z(ESI)M+H:266.9。
步骤2:4-(4,6,7-三氯酞嗪-1-基)哌嗪-1-甲酸叔丁酯(中间体M)。将1-Boc-哌嗪(340mg,1.824mmol)添加至1,4,6,7-四氯酞嗪(中间体L,543mg,2.027mmol)和三乙胺(0.846mL,6.08mmol)于二氯甲烷(8mL)中的经搅拌混合物中。将反应混合物在室温下搅拌2天。添加另外的1-boc-哌嗪(340mg,1.824mmol),并将反应混合物在室温下再搅拌23h。将反应混合物用饱和碳酸氢钠水溶液(20mL)淬灭并用DCM(30mL)萃取。将有机层分离,用盐水(20mL)洗涤,经MgSO4干燥,过滤且在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至50%EtOAc)得到4-(4,6,7-三氯酞嗪-1-基)哌嗪-1-甲酸叔丁酯。1H NMR(400MHz,氯仿-d)δ8.35(1H,s)8.12(1H,s)3.68-3.75(4H,m)3.45-3.52(4H,m)1.51(9H,s)。m/z(ESI)M+H:417.0。
步骤3:4-(6,7-二氯-4-苯基酞嗪-1-基)哌嗪-1-甲酸叔丁酯。将4-(4,6,7-三氯酞嗪-1-基)哌嗪-1-甲酸叔丁酯(中间体M,95mg,0.227mmol)、四(三苯膦)钯(26.3mg,0.023mmol,美国马萨诸塞州纽伯里波特市斯特雷姆化学公司)、苯基硼酸(27.7mg,0.227mmol)和碳酸钠(2M水溶液,0.341mL,0.682mmol)在1,4-二噁烷(1mL)中在密封小瓶中在氩气氛下混合。将反应混合物在40℃下搅拌24h。添加另外的四(三苯膦)钯(26.3mg,0.023mmol)和苯基硼酸(13.5mg,0.113mmol),并将反应混合物在40℃下再搅拌24h。将反应混合物用饱和碳酸氢钠水溶液(20mL)淬灭并用EtOAc(25mL)萃取。将有机层分离,用盐水(20mL)洗涤,经MgSO4干燥,过滤且在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至100%EtOAc)得到4-(6,7-二氯-4-苯基酞嗪-1-基)哌嗪-1-甲酸叔丁酯。1H NMR(400MHz,氯仿-d)δ8.13(1H,s)8.07(1H,s)7.62-7.67(2H,m)7.50-7.55(3H,m)3.65-3.74(4H,m)3.44-3.53(4H,m)1.47(9H,s)。m/z(ESI)M+H:459.1。
步骤4:6,7-二氯-1-苯基-4-(哌嗪-1-基)酞嗪。将4-(6,7-二氯-4-苯基酞嗪-1-基)哌嗪-1-甲酸叔丁酯(68mg,0.148mmol)在三氟乙酸(1mL,13.46mmol)中在室温下搅拌20min。将反应混合物用饱和碳酸氢钠水溶液(20mL)淬灭并用DCM(25mL)萃取两次。将有机层分离,经MgSO4干燥,过滤,并在真空中浓缩,以得到粗6,7-二氯-1-苯基-4-(哌嗪-1-基)酞嗪,将其直接用于下一步骤中。m/z(ESI)M+H:359.0。
步骤5:1-(4-(6,7-二氯-4-苯基酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮。将丙烯酰氯(0.013mL,0.162mmol)添加至6,7-二氯-1-苯基-4-(哌嗪-1-基)酞嗪(53mg,0.148mmol)和三乙胺(0.062mL,0.443mmol)于二氯甲烷(1mL)中的经搅拌混合物中。将反应混合物在室温下搅拌30min。将反应混合物用饱和碳酸氢钠水溶液(15mL)淬灭并用DCM(20mL)萃取。分离有机层,经MgSO4干燥,过滤且在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至100%EtOAc)得到1-(4-(6,7-二氯-4-苯基酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮。1H NMR(400MHz,氯仿-d)δ8.20(1H,s)8.14(1H,s)7.66-7.75(2H,m)7.54-7.62(3H,m)6.66(1H,dd,J=16.63,10.37Hz)6.37(1H,dd,J=16.82,1.96Hz)5.78(1H,dd,J=10.56,1.96Hz)3.85-4.04(1H,m)3.53-3.72(1H,m)。m/z(ESI)M+H:431.2。
步骤6:2-(1-(4-丙烯酰基-1-哌嗪基)-7-氯-4-苯基-6-酞嗪基)-3-氟苯酚和2-(4-(4-丙烯酰基-1-哌嗪基)-7-氯-1-苯基-6-酞嗪基)-3-氟苯酚。将1-(4-(6,7-二氯-4-苯基酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮(43mg,0.104mmol)、2-氟-6-羟苯基硼酸(17.84mg,0.114mmol,美国加利福尼亚州圣地亚哥康比乐公司)、Sphos Pd G3(9.00mg,10.40μmol)和碳酸钠(2M水溶液,0.156mL,0.312mmol)在1,2-二甲氧基乙烷(0.5mL)中在密封小瓶中在氩气氛下混合。将反应混合物在60℃下搅拌3h。添加另外的2-氟-6-羟苯基硼酸(8.92mg,0.057mmol,美国加利福尼亚州圣地亚哥康比乐公司)和SPhos Pd G3(9.00mg,10.40μmol),并将反应混合物在60℃下再搅拌2h。将反应混合物用饱和碳酸氢钠水溶液(15mL)淬灭并用EtOAc(20mL)萃取。将有机层分离,用盐水(10mL)洗涤,经MgSO4干燥,过滤且在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至100%EtOAc)得到两种位置异构体产物的混合物。反相制备型色谱(XBridge Prep C18 5μmOBD,150×30mm;35至55%(水中的0.1%TFA)于(乙腈中的0.1%TFA)中;流速=30mL/min)得到分离的位置异构体产物。将含有个别位置异构体的级分用饱和碳酸氢钠水溶液中和并用DCM萃取,并将有机萃取物在真空中浓缩。将分离的位置异构体通过柱色谱(硅胶,庚烷中的0至100%EtOAc)进一步个别地纯化。2-(1-(4-丙烯酰基-1-哌嗪基)-7-氯-4-苯基-6-酞嗪基)-3-氟苯酚(实例30)是从反相制备型色谱洗脱的第一位置异构体。1H NMR(400MHz,氯仿-d)δ8.21(1H,s)8.06(1H,s)7.62-7.69(2H,m)7.45-7.51(3H,m)7.24-7.32(1H,m)6.81-6.90(1H,m)6.75(1H,t,J=8.41Hz)6.65(1H,dd,J=16.82,10.56Hz)6.38(1H,dd,J=16.82,1.76Hz)5.79(1H,dd,J=10.56,1.76Hz)3.86-4.02(4H,m)3.57-3.76(4H,m)。m/z(ESI)M+H:489.0。2-(4-(4-丙烯酰基-1-哌嗪基)-7-氯-1-苯基-6-酞嗪基)-3-氟苯酚(实例31)是从反相柱洗脱的第二位置异构体。1H NMR(400MHz,氯仿-d)δ8.15(1H,s)8.12(1H,s)7.68-7.73(2H,m)7.53-7.58(3H,m)7.30(1H,brtd,J=8.22,6.65Hz)6.88(1H,d,J=8.22Hz)6.78(1H,t,J=8.61Hz)6.57(1H,dd,J=16.82,10.56Hz)6.28(1H,dd,J=16.73,1.66Hz)5.71(1H,dd,J=10.56,1.56Hz)3.78-3.89(4H,m)3.51-3.73(4H,m)。m/z(ESI)M+H:489.1。
实例32和33
2-(1-(4-丙烯酰基-1-哌嗪基)-7-氯-4-甲氧基-6-酞嗪基)-3-氟苯酚(实例32)和2-(4-(4-丙烯酰基-1-哌嗪基)-7-氯-1-甲氧基-6-酞嗪基)-3-氟苯酚(实例33)
实例32和33是以与实例30和31类似的方法来制备,但步骤3的改变如下:
步骤3:4-(6,7-二氯-4-甲氧基酞嗪-1-基)哌嗪-1-甲酸叔丁酯。将4-(4,6,7-三氯酞嗪-1-基)哌嗪-1-甲酸叔丁酯(中间体M,198mg,0.474mmol)和甲醇钠(甲醇中的25%溶液,2mL,8.75mmol)在密封小瓶中混合。将反应混合物在60℃下搅拌2h。将反应混合物用饱和碳酸氢钠水溶液(25mL)淬灭并用EtOAc(25mL)萃取。将有机层分离,用盐水(20mL)洗涤,经MgSO4干燥,过滤且在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至50%EtOAc)得到4-(6,7-二氯-4-甲氧基酞嗪-1-基)哌嗪-1-甲酸叔丁酯。1H NMR(400MHz,氯仿-d)δ8.29(1H,s)8.08(1H,s)4.22(3H,s)3.68-3.73(4H,m)3.33-3.38(4H,m)1.51(9H,s)。m/z(ESI)M+H:413.1。
来自步骤6:第一洗脱位置异构体:2-(1-(4-丙烯酰基-1-哌嗪基)-7-氯-4-甲氧基-6-酞嗪基)-3-氟苯酚(实例32)1H NMR(400MHz,氯仿-d)δ8.23(1H,s)8.11(1H,s)7.32(1H,td,J=8.31,6.46Hz)6.88(1H,d,J=8.22Hz)6.77-6.83(1H,m)6.65(1H,dd,J=16.82,10.56Hz)6.37(1H,dd,J=16.82,1.76Hz)5.79(1H,dd,J=10.47,1.86Hz)4.18(3H,s)3.79-4.05(4H,m)3.34-3.54(4H,m)。m/z(ESI)M+H:443.1。
第二洗脱位置异构体:2-(4-(4-丙烯酰基-1-哌嗪基)-7-氯-1-甲氧基-6-酞嗪基)-3-氟苯酚(实例33)。1H NMR(400MHz,氯仿-d)δ8.32(1H,s)8.01(1H,s)7.32(1H,td,J=8.27,6.55Hz)6.89(1H,d,J=8.22Hz)6.77-6.83(1H,m)6.60(1H,dd,J=17.02,10.56Hz)6.30(1H,dd,J=16.82,1.76Hz)5.75(1H,dd,J=10.56,1.76Hz)4.22(3H,s)3.67-3.98(4H,m)3.25-3.55(4H,m)。m/z(ESI)M+H:443.1。
实例34:
1-(4-丙烯酰基-1-哌嗪基)-4-苄基-6,7-二氯酞嗪
实例34是以与实例30及31类似的方法制备,不过省略步骤6,并且步骤2及3作如下变化:
步骤2和3:4-(4-苄基-6,7-二氯酞嗪-1-基)哌嗪-1-甲酸叔丁酯。在氩气氛下将苄基溴化锌(0.5M于THF中,1.926mL,0.963mmol)添加至含有1,4,6,7-四氯酞嗪(中间体L,258mg,0.963mmol)和四(三苯膦)钯(111mg,0.096mmol,美国马萨诸塞州纽伯里波特市斯特雷姆化学公司)的小瓶中。将反应混合物在室温下搅拌16h。添加1-Boc-哌嗪(1.79g,9.63mmol),并将反应混合物在60℃下搅拌5h。将反应混合物用饱和碳酸氢钠水溶液(40mL)淬灭并用EtOAc(50mL)萃取。将有机层分离,用盐水(40mL)洗涤,经MgSO4干燥,过滤且在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至50%EtOAc)得到4-(4-苄基-6,7-二氯酞嗪-1-基)哌嗪-1-甲酸叔丁酯。1H NMR(400MHz,氯仿-d)δ8.11(1H,s)8.10(1H,s)7.27-7.35(4H,m)7.20-7.25(1H,m)4.59(2H,s)3.69-3.74(4H,m)3.44-3.49(4H,m)1.52(9H,s)。m/z(ESI)M+H:473.1。m/z(ESI)M+H:473.1。
来自步骤5:1-(4-丙烯酰基-1-哌嗪基)-4-苄基-6,7-二氯酞嗪。1H NMR(400MHz,氯仿-d)δppm 8.13(1H,s)8.12(1H,s)7.28-7.36(4H,m)7.20-7.26(1H,m)6.65(1H,dd,J=16.82,10.56Hz)6.37(1H,dd,J=16.82,1.57Hz)5.78(1H,dd,J=10.56,1.56Hz)4.61(2H,s)3.83-4.01(4H,m)3.48-3.62(4H,m)。m/z(ESI)M+H:427.1。
实例35及36:
2-(1-(4-丙烯酰基-1-哌嗪基)-4-苄基-7-氯-6-酞嗪基)-3-氟苯酚(实例35)和2-(4-(4-丙烯酰基-1-哌嗪基)-1-苄基-7-氯-6-酞嗪基)-3-氟苯酚(实例36)
1-(4-(4-苄基-6,7-二氯酞嗪-1-基)哌嗪-1-基)丙-2-烯-1-酮。将(实例34,35mg,0.082mmol)、2-氟-6-羟苯基硼酸(12.77mg,0.082mmol,美国加利福尼亚州圣地亚哥康比乐公司)、SPhos Pd G3(7.09mg,8.19μmol)和碳酸钠(2M水溶液,0.123mL,0.246mmol)在1,2-二甲氧基乙烷(0.3mL)中在密封小瓶中在氩气氛下混合。将反应混合物在60℃下搅拌1h。将反应混合物用饱和碳酸氢钠水溶液(15mL)淬灭并用EtOAc(20mL)萃取。将有机层分离,用盐水(10mL)洗涤,经MgSO4干燥,过滤且在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至100%EtOAc)得到两种位置异构体产物的混合物。反相制备型色谱(XBridge Prep C18 5μmOBD,150×30mm;20至90%(水中的0.1%TFA)于(乙腈中的0.1%TFA)中;流速=30mL/min)得到部分分离的位置异构体产物。将含有位置异构体的级分用饱和碳酸氢钠水溶液中和并用DCM萃取,并将有机萃取物在真空中浓缩。2-(1-(4-丙烯酰基-1-哌嗪基)-4-苄基-7-氯-6-酞嗪基)-3-氟苯酚(实例35)是在反相制备型色谱期间洗脱的第一位置异构体,并且含有约36%的要洗脱的第二位置异构体。1H NMR(400MHz,氯仿-d)δ8.13(1H,s)8.11(1H,s)7.12-7.37(6H,m)6.91(1H,d,J=8.22Hz)6.77(1H,t,J=8.61Hz)6.64(1H,dd,J=16.82,10.56Hz)6.37(1H,dd,J=16.82,1.76Hz)5.79(1H,dd,J=10.56,1.96Hz)4.55(2H,s)3.34-4.01(8H,m)。m/z(ESI)M+H:503.1。2-(4-(4-丙烯酰基-1-哌嗪基)-1-苄基-7-氯-6-酞嗪基)-3-氟苯酚(实例36)是要洗脱的第二位置异构体。1H NMR(400MHz,氯仿-d)δ8.12(1H,s)8.05(1H,s)7.26-7.36(5H,m)7.19-7.24(1H,m)6.93(1H,d,J=8.41Hz)6.76(1H,t,J=8.31Hz)6.58(1H,dd,J=16.82,10.76Hz)6.28(1H,dd,J=16.82,1.76Hz)5.75(1H,dd,J=10.56,1.76Hz)4.54(2H,s)3.32-3.93(8H,m)。m/z(ESI)M+H:503.1。
实例37
1-(4-丙烯酰基-1-哌嗪基)-4-苄基-6-氯-7-(5-甲基-1H-吲唑-4-基)酞嗪和1-(4-丙烯酰基-1-哌嗪基)-4-苄基-7-氯-6-(5-甲基-1H-吲唑-4-基)酞嗪
实例37是以与实例35和36类似的方法来制备,用5-甲基-1h-吲唑-4-基硼酸(美国加利福尼亚州圣地亚哥康比乐公司)代替2-氟-6-羟苯基硼酸。在这个实施例中,不分离两种位置异构体产物。1H NMR(400MHz,氯仿-d)δ8.23(0.6H,s)8.22(0.4H,s)8.02(0.4H,s)8.00(0.6H,s)7.19-7.57(8H,m)6.68(0.4H,dd,J=16.82,10.56Hz)6.60(0.6H,dd,J=16.82,10.56Hz)6.38(0.4H,dd,J=16.63,1.76Hz)6.32(0.6H,dd,J=16.82,1.76Hz)5.79(0.4H,dd,J=10.56,1.76Hz)5.73(0.6H,dd,J=10.56,1.76Hz)4.67(1.2H,s)4.60(0.8H,s)3.74-4.06(4H,m)3.46-3.70(4H,m)2.21(1.8H,s)2.06(1.2H,s)。m/z(ESI)M+H:523。
实例38
6-氯-1-(环丙基甲基)-7-(2-氟-6-羟苯基)-4-(4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮
用于实例38的起始材料是使用方法8步骤1-4用试剂2,5,6-三氯烟酸(步骤1)、氨甲基环丙烷(步骤2)、2-氟-6-羟苯基硼酸(步骤4,美国加利福尼亚州圣地亚哥康比乐公司)和碳酸钠(步骤4)来制备。
步骤1:7-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-6-氯-1-(环丙基甲基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。将叔丁基氯二苯基甲硅烷(0.036mL,0.139mmol)添加至6-氯-1-(环丙基甲基)-7-(2-氟-6-羟苯基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(42mg,0.116mmol)和三乙胺(0.065mL,0.464mmol)于乙腈(0.5mL)中的经搅拌混合物中。将反应混合物在室温下搅拌1h。用饱和NH4Cl水溶液(25mL)使反应混合物淬灭且用EtOAc(30mL)萃取。将有机层分离,用盐水(25mL)洗涤,经MgSO4干燥,过滤,并在真空中浓缩,以得到粗7-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-6-氯-1-(环丙基甲基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮,将其直接用于下一步骤中。m/z(ESI)M+H:599.8。
步骤2:4-(4-丙烯酰基哌嗪-1-基)-7-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-6-氯-1-(环丙基甲基)吡啶并[2,3-d]嘧啶-2(1H)-酮。将三氯氧磷(0.087mL,0.933mmol)添加至粗7-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-6-氯-1-(环丙基甲基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(70mg,0.117mmol)、三乙胺(0.295mL,2.099mmol)和1H-苯并[d][1,2,3]三唑(167mg,1.400mmol)于乙腈(2mL)中的经搅拌混合物中。将反应混合物在80℃下搅拌4h。将反应混合物在真空中浓缩。将所得残余物吸收于1,2-二氯乙烷(2mL)中,并添加三乙胺(0.295mL,2.099mmol)和1-(哌嗪-1-基)丙-2-烯-1-酮(32.7mg,0.233mmol,美国新泽西州布里奇沃特市艾诺威化学有限公司)。将反应混合物在室温下搅拌16h。添加另外的三乙胺(0.148mL,1.050mmol)和1-(哌嗪-1-基)丙-2-烯-1-酮(32.7mg,0.233mmol,美国新泽西州布里奇沃特市艾诺威化学有限公司),并将反应混合物在室温下搅拌1h,之后加热至60℃并搅拌4h。将反应混合物用饱和NaHCO3水溶液(40mL)稀释并用DCM(50mL)萃取。分离有机层,经MgSO4干燥,过滤且在真空中浓缩。将所得残余物再次吸收于1,2-二氯乙烷(2mL)中,并添加三乙胺(0.295mL,2.099mmol)和1-(哌嗪-1-基)丙-2-烯-1-酮(32.7mg,0.233mmol,美国新泽西州布里奇沃特市艾诺威化学有限公司)。将反应混合物在60℃下搅拌6h。将反应混合物用饱和NaHCO3水溶液(40mL)稀释并用DCM(50mL)萃取。分离有机层,经MgSO4干燥,过滤且在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至100%(3:1 EtOAc/EtOH))得到4-(4-丙烯酰基哌嗪-1-基)-7-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-6-氯-1-(环丙基甲基)吡啶并[2,3-d]嘧啶-2(1H)-酮,将其不经进一步纯化即用于下一步骤中。m/z(ESI)M+H:721.8。
步骤3:4-(4-丙烯酰基哌嗪-1-基)-6-氯-1-(环丙基甲基)-7-(2-氟-6-羟苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮。将四丁基氟化铵(四氢呋喃中的1.0M溶液,0.025mL,0.025mmol)添加至4-(4-丙烯酰基哌嗪-1-基)-7-(2-((叔丁基二苯基甲硅烷基)氧基)-6-氟苯基)-6-氯-1-(环丙基甲基)吡啶并[2,3-d]嘧啶-2(1H)-酮(6mg,8.31μmol)于四氢呋喃(0.2mL)中的经搅拌混合物中。将反应混合物在室温下搅拌20min,之后在真空中浓缩。残余物的色谱纯化(硅胶,庚烷中的0至100%(3:1 EtOAc/EtOH))得到6-氯-1-(环丙基甲基)-7-(2-氟-6-羟苯基)-4-(4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。1H NMR(400MHz,氯仿-d)δ8.04(1H,s)7.26-7.33(1H,m)6.82(1H,d,J=8.29Hz)6.71(1H,t,J=8.91Hz)6.51(1H,dd,J=16.79,10.57Hz)6.30(1H,dd,J=16.79,1.45Hz)5.72(1H,dd,J=10.47,1.55Hz)4.15(2H,br d,J=6.43Hz)3.69-3.90(8H,m)1.14-1.27(4H,m)0.73-0.88(1H,m)。m/z(ESI)M+H:483.8。
实例39
6-氯-7-(2-氟-6-羟苯基)-1-(2-甲基-6-(2-丙烷基)苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮
步骤1:2,5,6-三氯烟酰胺(中间体P)。将1,1’-羰基二咪唑(40g,247mmol)分批添加至于THF(400mL)中的2,5,6-三氯烟酸(50.7g,224mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-blocks))中,使每次添加之间的气体放出停止。将所得混合物搅拌5min且然后用室内真空脱气并用氮气吹扫(×2)。将所得混合物加热至50℃,持续60min,然后用甲苯(100mL)稀释并浓缩至一半体积。将所得混合物冷却至0℃并经由注射器缓慢添加氢氧化铵(60mL,437mmol)。将反应在室温下搅拌10min,用EtOAc(200mL)稀释并用水(3×100mL)洗涤。将有机层经无水硫酸钠干燥并浓缩。将残余物悬浮于9:1庚烷/EtOAc(300mL)中并过滤。收集过滤的固体且将其余母液部分蒸发至一半体积,冷却至0℃,并过滤。合并两批过滤的固体,以提供2,5,6-三氯烟酰胺。
步骤2:2,5,6-三氯-N-((2-异丙基-6-甲基苯基)胺甲酰基)烟酰胺。向2,5,6-三氯烟酰胺(中间体P,1.13g,5.0mmol)于THF(30mL)中的混合物中添加草酰氯(DCM中的2M溶液,2.7mL,5.4mmol)。将所得浆液在65℃下加热40min,然后停止加热并允许反应冷却至室温。添加2-异丙基-6-甲基苯胺(0.80mL,5.36mmol,美国新泽西州蒙茅斯交界处烯胺公司(Enamine))并将反应在室温下搅拌14h。将反应浓缩并使残余物在EtOAc(50mL)与饱和碳酸氢钠水溶液(10mL)之间分配。将有机层用盐水(10mL)洗涤,经无水硫酸钠干燥并浓缩。将残余物悬浮于5:1庚烷/EtOAc(10mL)中并过滤。收集过滤的固体,以提供2,5,6-三氯-N-((2-异丙基-6-甲基苯基)胺甲酰基)烟酰胺。1H NMR(400MHz,氯仿-d)δppm 9.63(s,1H),9.35(br s,1H),8.25(s,1H),7.19-7.26(m,2H),7.13(d,J=7.3Hz,1H),3.14(quin,J=6.9Hz,1H),2.29(s,3H),1.23(d,J=6.8Hz,6H)。m/z(ESI,+ve离子):400.0(M+H)+。
步骤3:6,7-二氯-1-(2-异丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。向2,5,6-三氯-N-((2-异丙基-6-甲基苯基)胺甲酰基)烟酰胺(1.45g,3.6mmol)于THF(20mL)中的混合物中添加KHMDS(THF中的1M溶液,7.5mL,7.5mmol)。在室温下搅拌30min后,将反应浓缩至1/3体积并用饱和氯化铵水溶液(10mL)淬灭。将混合物用EtOAc(40mL)萃取。将有机层用盐水(10mL)洗涤,经无水硫酸钠干燥并浓缩,以提供6,7-二氯-1-(2-异丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。该材料不经进一步纯化即用于下一步骤中。m/z(ESI,+ve离子):364.0(M+H)+。
步骤4:(S)-叔丁基4-(6,7-二氯-1-(2-异丙基-6-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。向粗6,7-二氯-1-(2-异丙基-6-甲基苯基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(3.6mmol)于乙腈(10mL)中的混合物中添加DIPEA(1.50mL,8.6mmol),随后添加氧氯化磷(0.50mL,5.3mmol)。将所得混合物在80℃下加热1h,然后冷却至室温并浓缩。将残余物溶解于DMF(15mL)中并用DIPEA(1.50mL,8.6mmol),随后(S)-4-N-Boc-2-甲基哌嗪(900mg,4.5mmol,美国伊利诺伊州阿灵顿海茨市方舟制药公司(ArkPharm Inc.))处理。将所得溶液在室温下搅拌14h且然后用EtOAc(30mL)稀释。将混合物用水(10mL)及盐水(10mL)洗涤,且有机层经无水硫酸镁干燥并浓缩。将残余物通过硅胶色谱(洗脱液:10%-50%3:1 EtOAc-EtOH/庚烷)纯化,以提供(S)-叔丁基4-(6,7-二氯-1-(2-异丙基-6-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。1H NMR(400MHz,MeOH-d4)δppm 8.45(s,1H),7.34-7.43(m,2H),7.23(d,J=7.3Hz,1H),4.97(br s,1H),4.34(br d,J=13.3Hz,1H),4.15(br d,J=12.0Hz,1H),4.01(br d,J=13.7Hz,1H),3.80(br s,1H),3.09-3.32(m,2H),2.49-2.59(m,1H),1.99(d,J=3.7Hz,3H),1.55(s,9H),1.50(dd,J=1.7,6.6Hz,3H),1.18(dd,J=6.7,1.8Hz,3H),1.09(dd,J=6.8,2.3Hz,3H)。m/z(ESI,+ve离子):546.1(M+H)+。
步骤5:(3S)-叔丁基4-(6-氯-7-(2-氟-6-羟苯基)-1-(2-异丙基-6-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。向圆底烧瓶中装入(S)-叔丁基4-(6,7-二氯-1-(2-异丙基-6-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯(8.3g,15.19mmol)、乙酸钾(7.50g,76mmol)及[1,1’-双(二苯基膦基)二茂铁]-二氯钯(II)与二氯甲烷的络合物(0.495g,0.606mmol)。添加1,4-二噁烷(40mL)及水(8mL)并将混合物加热至90℃。添加三氟硼酸(2-氟-6-羟苯基)钾(中间体Q,7.45g,34.2mmol)且再添加[1,1’-双(二苯基膦基)二茂铁]-二氯钯(II)与二氯甲烷的络合物(0.176g)。将所得混合物在室温下搅拌2.5h,然后冷却至室温,用EtOAc(200mL)稀释并用水(1×)及盐水(1×)洗涤。将有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:5%-40%3:1 EtOAc-EtOH/庚烷)纯化,以提供(3S)-叔丁基4-(6-氯-7-(2-氟-6-羟苯基)-1-(2-异丙基-6-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。1H NMR(400MHz,氯仿-d)δppm 8.68(br s,1H),8.14(br s,1H),7.33-7.45(m,2H),7.25(d,J=6.3Hz,2H),6.64-6.73(m,2H),3.91-5.15(m,4H),3.67(br s,1H),3.32(br s,2H),2.49-2.76(m,1H),1.95-2.08(m,3H),1.53(s,12H),1.14-1.29(m,3H),0.95-1.07(m,3H)。19F NMR(377MHz,氯仿-d)δppm-104.56(br s,1F)。m/z(ESI,+ve离子):622.1(M+H)+。
步骤6:6-氯-7-(2-氟-6-羟苯基)-1-(2-甲基-6-(2-丙烷基)苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。向(3S)-叔丁基4-(6-氯-7-(2-氟-6-羟苯基)-1-(2-异丙基-6-甲基苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯(680mg,1.1mmol)于DCM(10mL)中的溶液中添加三氟乙酸(1.5mL,19.6mmol)。将反应在室温下搅拌1.5h,且然后浓缩。使残余物在EtOAc(40mL)与饱和碳酸氢钠水溶液(2×15mL)之间分配。将有机层用盐水(5mL)洗涤,经无水硫酸钠干燥并浓缩。将残余物溶解于DCM(10mL)中并用DIPEA(0.5mL,2.9mmol),随后丙烯酰氯(0.09mL,1.1mmol)处理。将反应在室温下搅拌10min,然后用EtOAc(30mL)稀释并用饱和碳酸氢钠水溶液(10mL)及盐水(5mL)洗涤。将有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:10%-60%3:1 EtOAc-EtOH/庚烷)纯化,以提供6-氯-7-(2-氟-6-羟苯基)-1-(2-甲基-6-(2-丙烷基)苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。1H NMR(400MHz,DMSO-d6)δppm 10.07(s,1H),8.40(br s,1H),7.17-7.25(m,3H),7.06-7.13(m,1H),6.79-6.91(m,1H),6.69(d,J=8.0Hz,1H),6.65(t,J=8.8Hz,1H),6.20(br d,J=16.8Hz,1H),5.73-5.78(m,1H),4.91(br s,1H),4.21-4.46(m,2H),3.95-4.20(m,1H),3.42-3.80(m,2H),3.03-3.27(m,1H),2.53-2.63(m,1H),1.85(br s,3H),1.32(br t,J=5.9Hz,3H),1.05(d,J=6.8Hz,3H),0.91(br d,J=6.6Hz,3H)。19F NMR(377MHz,DMSO-d6)δppm-115.71--115.50(m,1F),-116.16(br s,1F)。m/z(ESI,+ve离子):576.0(M+H)+。
三氟硼酸(2-氟-6-羟苯基)钾(中间体Q)。将氟化钾(44.7g,770mmol)于水(75mL)中的溶液添加至(2-氟-6-羟苯基)硼酸(30g,192mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-blocks))于乙腈(750mL)中的悬浮液中。将混合物搅拌2min且然后经10min时间经由加料漏斗添加L-(+)-酒石酸(72.2g,481mmol)于THF(375mL)中的溶液。将混合物用机械搅拌器剧烈搅拌1h,且然后将所得悬浮液过滤,且将过滤的固体用少量THF洗涤。丢弃固体并部分浓缩滤液,直至固体开始从溶液沉淀析出。然后将混合物冷却至-20℃并搅拌16h。将反应缓慢升温并添加2-丙烷醇(20mL)。过滤所得悬浮液且将过滤的固体用2-丙烷醇洗涤。将滤液再部分浓缩直至形成悬浮液,且然后冷却至-20℃并再搅拌20min。将所得悬浮液用2-丙烷醇稀释并过滤,且用2-丙烷醇洗涤过滤的固体。合并两批固体,以提供三氟硼酸2-氟-6-羟苯基)钾(中间物Q)。1H NMR(400MHz,DMSO-d6)δppm 8.07(q,J=14.7Hz,1H)6.93(q,J=7.5Hz,1H)6.30-6.38(m,2H)。
实例40
6-氯-7-(2-氟苯基)-1-(4-甲基-2-(2-丙烷基)-3-吡啶基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮
步骤1:2-异丙基-4-甲基吡啶-3-胺(中间体R)。向3-氨基-2-溴-4-甲基吡啶(360mg,1.9mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-blocks))于THF(4mL)中的浆液中添加[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)与二氯甲烷的络合物(79mg,0.10mmol)。将所得浆液用氩气脱氧2min且然后添加溴化2-丙基锌(THF中的0.5M溶液,5.40mL,2.7mmol,密苏里州圣路易斯西格玛-奥德里奇(Sigma-Aldrich))。将所得溶液在60℃下加热17h,然后停止加热并允许反应冷却至室温。将反应混合物用水(10mL)及1N NaOH溶液(20mL)淬灭且然后用EtOAc(2x)萃取。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-15%MeOH/DCM)纯化,以提供2-异丙基-4-甲基吡啶-3-胺。1HNMR(400MHz,DMSO-d6)δppm 7.66(d,J=4.6Hz,1H),6.78(d,J=4.8Hz,1H),4.72(br s,2H),3.14-3.25(m,1H),2.08(s,3H),1.14(d,J=6.8Hz,6H)。m/z(ESI,+ve离子):151.1(M+H)+。
步骤2:2,5,6-三氯-N-((2-异丙基-4-甲基吡啶-3-基)胺甲酰基)烟酰胺。经由注射器向2,5,6-三氯烟酰胺(中间物P,3.10g,13.8mmol)于THF(46mL)中的-78℃浆液中缓慢添加草酰氯(DCM中的2M溶液,7.4mL,14.7mmol)。将所得浆液在60℃下加热3.5h,然后停止加热并将反应冷却至-78℃。添加三乙胺(6.0mL,42.6mmol),随后经由导管添加2-异丙基-4-甲基吡啶-3-胺的溶液(中间体R,2.12g,14.1mmol)。将所得浆液升温至室温并搅拌1h,然后使其在水(120mL)与EtOAc(175mL)之间分配。将有机层经无水硫酸钠干燥并浓缩。将残余物悬浮于9:1庚烷/EtOAc中并过滤。收集过滤的固体,以提供2,5,6-三氯-N-((2-异丙基-4-甲基吡啶-3-基)胺甲酰基)烟酰胺。1H NMR(400MHz,DMSO-d6)δppm 11.31(s,1H),9.54(s,1H),8.66(s,1H),8.34(d,J=4.8Hz,1H),7.16(d,J=5.0Hz,1H),3.24-3.33(m,1H),2.22(s,3H),1.17(d,J=6.6Hz,6H)。m/z(ESI,+ve离子):400.9(M+H)+。
步骤3:6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。经由注射器向2,5,6-三氯-N-((2-异丙基-4-甲基吡啶-3-基)胺甲酰基)烟酰胺(4.71g,11.7mmol)于THF(55mL)中的冰冷溶液中缓慢添加KHMDS(THF中的1M溶液,23.5mL,23.5mmol)。10min后,移除冰浴并将所得溶液在室温下再搅拌30min。将反应用饱和氯化铵水溶液(125mL)淬灭并用EtOAc(250mL)萃取。将有机层用盐水(1x)洗涤,经无水硫酸钠干燥,并浓缩。将残余物通过硅胶色谱(洗脱液:0-11%MeOH/DCM)纯化,以提供6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。1H NMR(400MHz,DMSO-d6)δppm 12.27(br s,1H),8.59(s,1H),8.52(d,J=5.0Hz,1H),7.28(d,J=5.0Hz,1H),2.82-2.92(m,1H),2.04(s,3H),1.08(d,J=6.6Hz,3H),1.01(d,J=6.8Hz,3H)。m/z(ESI,+ve离子):365.0(M+H)+。
步骤4:4,6,7-三氯-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮。向6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(2.52g,6.9mmol)于乙腈(45mL)中的浆液中添加DIPEA(1.80mL,10.3mmol),随后经由注射器缓慢添加氧氯化磷(1.58mL,10.3mmol)。将所得混合物在80℃下加热1.75h,且然后冷却至室温并浓缩,以提供4,6,7-三氯-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮。该材料不经进一步纯化即用于下一步骤中。
步骤5:(S)-叔丁基4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。向4,6,7-三氯-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(2.64g,6.9mmol)于THF(40mL)中的溶液中添加DIPEA(3.61mL,20.7mmol),随后添加(S)-4-N-Boc-2-甲基哌嗪(2.07g,10.3mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-Blocks,Inc.))。将所得溶液在室温下搅拌1.5h,且然后添加冰水(60mL)。将混合物再搅拌5min,然后用EtOAc(3x)萃取。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-11%MeOH/DCM)纯化,以提供(S)-叔丁基4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。1H NMR(400MHz,DMSO-d6)δppm 8.46(dd,J=11.6,5.2Hz,2H),7.25(d,J=4.8Hz,1H),4.79-4.93(m,1H),4.10-4.24(m,1H),3.87-4.05(m,1H),3.77-3.87(m,1H),3.62-3.76(m,1H),2.99-3.25(m,2H),2.55-2.69(m,1H),1.94(d,J=2.5Hz,3H),1.45(s,9H),1.32(br t,J=5.7Hz,3H),1.06(d,J=6.8Hz,3H),1.00(d,J=6.6Hz,3H)。m/z(ESI,+ve离子):547.2(M+H)+。
步骤6:(S)-叔丁基-4-(6-氯-7-(2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。向(S)-叔丁基4-(6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯(1.02g,1.8mmol)于1,4-二噁烷(17mL)中的溶液中添加乙酸钾(914mg,9.3mmol)及(2-氟苯基)硼酸(313mg,2.2mmol,美国密苏里州圣路易斯西格玛-奥德里奇(Sigma-Aldrich))。向混合物充入氩气,且然后添加[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)与二氯甲烷的络合物(76mg,0.093mmol)。将混合物再次充入氩气并在90℃下加热。30秒后,将三滴水添加至反应混合物中。在90℃下继续加热40min,且然后允许反应冷却至室温。添加水(50mL)及盐水(4mL)且将所得混合物用EtOAc(2x)萃取。将合并的有机层用盐水(1x)洗涤,经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-9%MeOH/DCM)纯化,以提供(S)-叔丁基4-(6-氯-7-(2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。1H NMR(400MHz,DMSO-d6)δppm8.43(d,J=2.5Hz,1H),8.39(d,J=4.8Hz,1H),7.47-7.55(m,1H),7.16-7.33(m,4H),4.86-4.97(m,1H),4.21-4.30(m,1H),3.90-4.06(m,2H),3.80-3.89(m,1H),3.67-3.78(m,1H),3.04-3.16(m,1H),2.65-2.75(m,1H),1.93(s,3H),1.48(s,9H),1.36(br d,J=6.6Hz,3H),1.06(d,J=6.6Hz,3H),0.94(dd,J=6.6,2.1Hz,3H)。m/z(ESI,+ve离子):607.0(M+H)+。
步骤7:6-氯-7-(2-氟苯基)-1-(4-甲基-2-(2-丙烷基)-3-吡啶基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。将三氟乙酸(4.0mL,53.9mmol)添加至(S)-叔丁基4-(6-氯-7-(2-氟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯(935mg,1.54mmol)于DCM(20mL)中的溶液中。将所得溶液在室温下搅拌1.5h且然后浓缩。将残余物溶解于DCM(12mL)中,冷却至0℃,并用DIPEA(0.807mL,4.62mmol),随后丙烯酰氯(0.131mL,1.62mmol;经由注射器逐滴添加)处理。将所得溶液在0℃下搅拌35min,然后用饱和碳酸氢钠水溶液(35mL)淬灭并用DCM(2x)萃取。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-11%MeOH/DCM)纯化,以提供6-氯-7-(2-氟苯基)-1-(4-甲基-2-(2-丙烷基)-3-吡啶基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。1HNMR(400MHz,DMSO-d6)δppm 8.46(br d,J=4.6Hz,1H),8.39(d,J=4.8Hz,1H),7.47-7.55(m,1H),7.16-7.34(m,4H),6.78-6.94(m,1H),6.15-6.26(m,1H),5.73-5.80(m,1H),4.95(br s,1H),4.36-4.45(m,0.5H),4.24-4.36(m,1.5H),4.11-4.21(m,0.5H),3.98-4.08(m,0.5H),3.71-3.85(m,1H),3.60-3.69(m,0.5H),3.41-3.53(m,0.5H),3.06-3.27(m,1H),2.65-2.75(m,1H),1.94(d,J=1.7Hz,3H),1.34(d,J=6.2Hz,3H),1.07(d,J=6.6Hz,3H),0.94(dd,J=6.5,0.9Hz,3H)。m/z(ESI,+ve离子):560.9(M+H)+。
实例41
6-氟-7-(2-氟-6-羟苯基)-1-(4-甲基-2-(2-丙烷基)-3-吡啶基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮
步骤1:2,6-二氯-5-氟烟酰胺(中间体S)。向2,6-二氯-5-氟-烟酸(4.0g,19.1mmol,宾夕法尼亚州布里斯托尔市爱思特公司(AstaTechInc.))于二氯甲烷(48mL)中的混合物中添加草酰氯(DCM中的2M溶液,11.9mL,23.8mmol),随后添加催化量的DMF(0.05mL)。将反应在室温下搅拌过夜且然后浓缩。将残余物溶解于1,4-二噁烷(48mL)中并冷却至0℃。经由注射器缓慢添加氢氧化铵溶液(28.0%-30%NH3计,3.6mL,28.6mmol)。将所得混合物在0℃下搅拌30min且然后浓缩。将残余物用1:1的EtOAc/庚烷混合物稀释并搅动5min,然后过滤。丢弃过滤的固体,且其余母液部分浓缩至一半体积并过滤。将过滤的固体用庚烷洗涤并在减压烘箱(45℃)中干燥过夜,以提供2,6-二氯-5-氟烟酰胺。1H NMR(400MHz,DMSO-d6)δppm 8.23(d,J=7.9Hz,1H)8.09(br s,1H)7.93(br s,1H)。m/z(ESI,+ve离子):210.9(M+H)+。
步骤2:2,6-二氯-5-氟-N-((2-异丙基-4-甲基吡啶-3-基)胺甲酰基)烟酰胺。经由注射器向2,6-二氯-5-氟烟酰胺(中间体S,5.0g,23.9mmol)于THF(20mL)中的冰冷浆液中缓慢添加草酰氯(DCM中的2M溶液,14.4mL,28.8mmol)。将所得混合物在75℃下加热1h,然后停止加热,并将反应浓缩至一半体积。冷却至0℃后,经由导管逐滴添加添加THF(20mL),随后添加2-异丙基-4-甲基吡啶-3-胺(中间体R,3.59g,23.92mmol)于THF(10mL)中的溶液。将所得混合物在0℃下搅拌1h且然后用1:1的盐水及饱和氯化铵水溶液的混合物淬灭。将混合物用EtOAc(3x)萃取且将合并的有机层经无水硫酸钠干燥并浓缩,以提供2,6-二氯-5-氟-N-((2-异丙基-4-甲基吡啶-3-基)胺甲酰基)烟酰胺。该材料不经进一步纯化即用于下一步骤中。m/z(ESI,+ve离子):385.1(M+H)+。
步骤3:7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。经由注射器向2,6-二氯-5-氟-N-((2-异丙基-4-甲基吡啶-3-基)胺甲酰基)烟酰胺(9.2g,24.0mmol)于THF(40mL)中的冰冷溶液中缓慢添加KHMDS(THF中的1M溶液,50.2mL,50.2mmol)。将冰浴移除并将所得混合物在室温下搅拌40min。将反应用饱和氯化铵水溶液淬灭并用EtOAc(3x)萃取。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-50%3:1 EtOAc-EtOH/庚烷)纯化,以提供7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。1H NMR(400MHz,DMSO-d6)δppm 12.27(brs,1H),8.48-8.55(m,2H),7.29(d,J=4.8Hz,1H),2.87(quin,J=6.6Hz,1H),1.99-2.06(m,3H),1.09(d,J=6.6Hz,3H),1.01(d,J=6.6Hz,3H)。19F NMR(376MHz,DMSO-d6)δ:-126.90(s,1F)。m/z(ESI,+ve离子):349.1(M+H)+。
步骤4:4,7-二氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮。经由注射器向7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(4.7g,13.5mmol)及DIPEA(3.5mL,20.2mmol)于乙腈(20mL)中的溶液中逐滴添加氧氯化磷(1.63mL,17.5mmol)。将所得混合物在80℃下加热1h,且然后冷却至室温并浓缩,以提供4,7-二氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮。该材料不经进一步纯化即用于下一步骤中。m/z(ESI,+ve离子):367.1(M+H)+。
步骤5:(S)-叔丁基4-(7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。向4,7-二氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(13.5mmol)于乙腈(20mL)中的冰冷溶液中添加DIPEA(7.1mL,40.3mmol),随后添加(S)-4-N-Boc-2-甲基哌嗪(3.23g,16.1mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-Blocks,Inc.))。将所得混合物升温至室温并搅拌1h,然后用冷饱和碳酸氢钠水溶液(200mL)及EtOAc(300mL)稀释。将混合物再搅拌混合物5min,分离各层,且将水层再用EtOAc(1x)萃取。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-50%EtOAc/庚烷)纯化,以提供(S)-叔丁基4-(7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。m/z(ESI,+ve离子):531.2(M+H)+。
步骤6:(3S)-叔丁基4-(6-氟-7-(2-氟-6-羟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。用氮气使(S)-叔丁基4-(7-氯-6-氟-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯(4.3g,8.1mmol)、三氟(2-氟-6-羟苯基)硼酸钾(中间体Q,2.9g,10.5mmol)、乙酸钾(3.2g,32.4mmol)及[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)与二氯甲烷的络合物(661mg,0.81mmol)于1,4-二噁烷(80mL)中的混合物脱气1min。添加脱氧水(14mL),且将所得混合物在90℃下加热1h。允许反应冷却至室温,用半饱和碳酸氢钠水溶液淬灭,并用EtOAc(2x)及DCM(1x)萃取。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-60%3:1 EtOAc-EtOH/庚烷)纯化,以提供(3S)-叔丁基4-(6-氟-7-(2-氟-6-羟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。1H NMR(400MHz,DMSO-d6)δppm 10.19(br s,1H),8.38(d,J=5.0Hz,1H),8.26(dd,J=12.5,9.2Hz,1H),7.23-7.28(m,1H),7.18(d,J=5.0Hz,1H),6.72(d,J=8.0Hz,1H),6.68(t,J=8.9Hz,1H),4.77-4.98(m,1H),4.24(br t,J=14.2Hz,1H),3.93-4.08(m,1H),3.84(br d,J=12.9Hz,1H),3.52-3.75(m,1H),3.07-3.28(m,1H),2.62-2.74(m,1H),1.86-1.93(m,3H),1.43-1.48(m,9H),1.35(dd,J=10.8,6.8Hz,3H),1.26-1.32(m,1H),1.07(dd,J=6.6,1.7Hz,3H),0.93(dd,J=6.6,2.1Hz,3H)。19F NMR(376MHz,DMSO-d6)δ:-115.65(s,1F),-128.62(s,1F)。m/z(ESI,+ve离子):607.3(M+H)+。
步骤7:6-氟-7-(2-氟-6-羟苯基)-1-(4-甲基-2-(2-丙烷基)-3-吡啶基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。将三氟乙酸(25mL,324mmol)添加至(3S)-叔丁基4-(6-氟-7-(2-氟-6-羟苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯(6.3g,10.4mmol)于DCM(30mL)中的溶液中。将所得混合物在室温下搅拌1h且然后浓缩。将残余物溶解于DCM(30mL)中,冷却至0℃,并依序用DIPEA(7.3mL,41.7mmol)以及丙烯酰氯(0.849mL,10.4mmol)于DCM(3mL;经由注射器逐滴添加)中的溶液处理。将反应在0℃下搅拌10min,然后用半饱和碳酸氢钠水溶液淬灭并用DCM(2x)萃取。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-100%3:1 EtOAc-EtOH/庚烷)纯化,以提供6-氟-7-(2-氟-6-羟苯基)-1-(4-甲基-2-(2-丙烷基)-3-吡啶基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。1H NMR(400MHz,DMSO-d6)δppm10.20(s,1H),8.39(d,J=4.8Hz,1H),8.24-8.34(m,1H),7.23-7.32(m,1H),7.19(d,J=5.0Hz,1H),6.87(td,J=16.3,11.0Hz,1H),6.74(d,J=8.6Hz,1H),6.69(t,J=8.6Hz,1H),6.21(br d,J=16.2Hz,1H),5.74-5.80(m,1H),4.91(br s,1H),4.23-4.45(m,2H),3.97-4.21(m,1H),3.44-3.79(m,2H),3.11-3.31(m,1H),2.67-2.77(m,1H),1.91(s,3H),1.35(d,J=6.8Hz,3H),1.08(d,J=6.6Hz,3H),0.94(d,J=6.8Hz,3H)。19F NMR(376MHz,DMSO-d6)δppm-115.64(s,1F),-128.63(s,1F)。m/z(ESI,+ve离子):561.2(M+H)+。
实例42
1-(2-环丙基-4-甲基-3-吡啶基)-6-氟-7-(2-氟-6-羟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮
步骤1:2-环丙基-4-甲基吡啶-3-胺(中间体T)。经由加料漏斗向3-氨基-2-溴-4-甲基吡啶(4.0g,21.4mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-blocks))及二氯[1,1’-双(二苯基膦基)二茂铁]二氯化钯(II)二氯甲烷加合物(1.78g,2.1mmol)于THF(100mL)中的浆液中缓慢添加溴化环丙基锌(THF中的0.5M溶液,68.4mL,34.2mmol,密苏里州圣路易斯西格玛-奥德里奇(Sigma-Aldrich))。允许所得混合物在70℃下加热6h,然后停止加热并允许反应冷却至室温。用5N NaOH溶液淬灭反应混合物并用EtOAc(1x)萃取。将有机层经无水硫酸镁干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-50%3:1 EtOAc-EtOH/庚烷)纯化,以提供2-环丙基-4-甲基吡啶-3-胺。1H NMR(400MHz,氯仿-d)δppm 7.84(d,J=4.8Hz,1H),6.82(d,J=4.8Hz,1H),3.82(br s,2H),2.17(s,3H),1.85(quin,J=6.7Hz,1H),0.92-0.99(m,4H)。m/z(ESI,+ve离子):149.1(M+H)+。
步骤2:2,6-二氯-N-((2-环丙基-4-甲基吡啶-3-基)胺甲酰基)-5-氟烟酰胺。经由注射器向2,6-二氯-5-氟烟酰胺(中间体S,3.0g,14.4mmol)于THF(30mL)中的溶液中缓慢添加草酰氯(DCM中的2M溶液,10.7mL,21.5mmol)。将所得混合物在65℃下加热2h,然后停止加热,并将反应浓缩。将残余物溶解于THF(30mL)中并经由导管添加至2-环丙基-4-甲基吡啶-3-胺(中间体T,2.1g,14.4mmol)于THF(105mL)中的溶液中。将所得混合物在室温下搅拌3h,然后用水淬灭并用EtOAc(3x)萃取。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-50%EtOAc/庚烷)纯化,以提供2,6-二氯-N-((2-环丙基-4-甲基吡啶-3-基)胺甲酰基)-5-氟烟酰胺。1H NMR(400MHz,氯仿-d)δppm 9.85(s,1H),9.68(s,1H),8.29(d,J=4.8Hz,1H),7.97(d,J=7.0Hz,1H),6.99(d,J=4.8Hz,1H),2.29(s,3H),2.08-2.16(m,1H),1.08-1.13(m,2H),0.95-1.02(m,2H)。m/z(ESI,+ve离子):383.0(M+H)+。
步骤3:7-氯-1-(2-环丙基-4-甲基吡啶-3-基)-6-氟吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。经由注射器向2,6-二氯-N-((2-环丙基-4-甲基吡啶-3-基)胺甲酰基)-5-氟烟酰胺(3.35g,8.7mmol)于THF(30mL)中的冰冷溶液中缓慢添加KHMDS(THF中的1M溶液,17.5mL,17.5mmol)。将冰浴移除并将所得混合物在室温下搅拌14h。将反应用饱和氯化铵水溶液淬灭并用EtOAc(3x)萃取。合并的有机层经无水硫酸钠干燥并浓缩,以提供7-氯-1-(2-环丙基-4-甲基吡啶-3-基)-6-氟吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。该材料不经进一步纯化即用于下一步骤中。m/z(ESI,+ve离子):347.0(M+H)+。
步骤4:4,7-二氯-1-(2-环丙基-4-甲基吡啶-3-基)-6-氟吡啶并[2,3-d]嘧啶-2(1H)-酮。经由注射器向7-氯-1-(2-环丙基-4-甲基吡啶-3-基)-6-氟吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(8.7mmol)及DIPEA(2.32mL,13.1mmol)于乙腈(25mL)中的溶液中逐滴添加氧氯化磷(1.22mL,13.1mmol)。在80℃下加热所得混合物3h,且然后冷却至室温并浓缩,以提供4,7-二氯-1-(2-环丙基-4-甲基吡啶-3-基)-6-氟吡啶并[2,3-d]嘧啶-2(1H)-酮。该材料不经进一步纯化即用于下一步骤中。m/z(ESI,+ve离子):365.0(M+H)+。
步骤5:(S)-叔丁基4-(7-氯-1-(2-环丙基-4-甲基吡啶-3-基)-6-氟-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。向4,7-二氯-1-(2-环丙基-4-甲基吡啶-3-基)-6-氟吡啶并[2,3-d]嘧啶-2(1H)-酮(8.7mmol)于DCM(25mL)中的冰冷溶液中添加DIPEA(7.74mL,43.7mmol),随后添加(S)-4-N-Boc-2-甲基哌嗪(1.75g,8.7mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-Blocks,Inc.))。在0℃下搅拌所得混合物2h,然后用水淬灭并用EtOAc(3x)萃取。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-60%EtOAc/庚烷)纯化,以提供(S)-叔丁基4-(7-氯-1-(2-环丙基-4-甲基吡啶-3-基)-6-氟-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。1HNMR(400MHz,DMSO-d6)δppm 8.31-8.39(m,2H),7.18(d,J=4.8Hz,1H),4.82(br s,1H),4.10-4.21(m,1H),3.96(br s,1H),3.82(br d,J=13.3Hz,1H),3.62-3.72(m,1H),3.19-3.52(m,2H),1.94(s,3H),1.62(dq,J=8.2,4.0Hz,1H),1.45(s,9H),1.32(dd,J=6.5,3.6Hz,3H),0.87-0.98(m,1H),0.69-0.84(m,2H),0.57-0.68(m,1H)。m/z(ESI,+ve离子):529.0(M+H)+。
步骤6:(3S)-叔丁基4-(1-(2-环丙基-4-甲基吡啶-3-基)-6-氟-7-(2-氟-6-羟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。向(S)-叔丁基4-(7-氯-1-(2-环丙基-4-甲基吡啶-3-基)-6-氟-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯(987mg,1.87mmol)、(2-氟-6-羟苯基)硼酸(524mg,3.36mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-blocks))、乙酸钾(916mg,9.33mmol)及[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)与二氯甲烷的络合物(152mg,0.19mmol)于1,4-二噁烷(10mL)中的混合物中充入氩气并在80℃下加热。2min后,将三滴水添加至反应混合物中并将温度升高至90℃。在90℃下继续加热1h,且然后允许反应冷却至室温。添加水且将所得混合物用EtOAc(3x)萃取。将合并的有机层用盐水(1x)洗涤,经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-65%EtOAc/庚烷)纯化,以提供(3S)-叔丁基4-(1-(2-环丙基-4-甲基吡啶-3-基)-6-氟-7-(2-氟-6-羟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。1H NMR(400MHz,DMSO-d6)δppm 10.22(s,1H),8.19-8.31(m,2H),7.23-7.32(m,1H),7.10(d,J=5.0Hz,1H),6.74(d,J=8.3Hz,1H),6.69(t,J=8.8Hz,1H),4.76-4.98(m,1H),4.15-4.31(m,1H),3.99(br s,1H),3.78-3.89(m,1H),3.55-3.77(m,1H),2.99-3.29(m,2H),1.91(d,J=2.7Hz,3H),1.68(td,J=8.0,4.5Hz,1H),1.45(s,9H),1.35(dd,J=18.7,6.6Hz,3H),0.82-0.89(m,1H),0.71-0.82(m,2H),0.57-0.66(m,1H)。m/z(ESI,+ve离子):605.0(M+H)+。
步骤7:1-(2-环丙基-4-甲基-3-吡啶基)-6-氟-7-(2-氟-6-羟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。将三氟乙酸(2.17mL,28.1mmol)添加至(3S)-叔丁基4-(1-(2-环丙基-4-甲基吡啶-3-基)-6-氟-7-(2-氟-6-羟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯(850mg,1.41mmol)于DCM(10mL)中的溶液中。将所得混合物在室温下搅拌3h且然后浓缩。将残余物溶解于DCM(10mL)中,冷却至0℃,并经由注射器用DIPEA(1.23mL,7.03mmol),随后丙烯酰氯(0.103mL,1.27mmol)逐滴处理。将反应在0℃下搅拌2h,然后用水淬灭并用DCM(3x)萃取。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-80%3:1EtOAc-EtOH/庚烷)纯化,以提供1-(2-环丙基-4-甲基-3-吡啶基)-6-氟-7-(2-氟-6-羟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。1H NMR(400MHz,DMSO-d6)δppm 8.32(br t,J=10.1Hz,1H),8.28(d,J=5.0Hz,1H),7.51-7.60(m,1H),7.27-7.38(m,3H),7.14(d,J=4.8Hz,1H),6.80-6.92(m,1H),6.20(br d,J=16.6Hz,1H),5.69-5.80(m,1H),4.92(br d,J=1.5Hz,1H),4.24-4.46(m,2H),3.97-4.19(m,1H),3.71(br s,1H),3.42-3.66(m,1H),3.05-3.30(m,1H),1.97(s,3H),1.65(br s,1H),1.33(d,J=6.6Hz,3H),0.90(td,J=5.4,2.6Hz,1H),0.80-0.87(m,1H),0.70-0.79(m,1H),0.60-0.70(m,1H)。m/z(ESI,+ve离子):559.0(M+H)+。
实例43
6-氯-1-(4,6-二(2-丙烷基)-5-嘧啶基)-7-(2-氟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮
步骤1:4,6-二异丙基嘧啶-5-胺(中间体U)。通过使氩气鼓泡进入混合物中,使4,6-二氯-5-氨基嘧啶(3.00g,18.29mmol,美国加利福尼亚州圣地亚哥康比乐公司)于THF(18mL)中的溶液脱氧5min。经由注射器添加溴化2-丙基锌(THF中的0.5M溶液,91.0mL,45.5mmol,密苏里州圣路易斯西格玛-奥德里奇(Sigma-Aldrich)),随后添加XantPhos PdG3(434mg,0.46mmol,美国密苏里州圣路易斯西格玛-奥德里奇(Sigma-Aldrich))。将所得混合物在室温下搅拌16h且然后经硅藻土垫过滤。用EtOAc冲洗滤饼,且收集滤液并浓缩,得到4,6-二异丙基嘧啶-5-胺(3.45g)。该材料不经进一步纯化即用于下一步骤中。m/z(ESI,+ve离子):180.2(M+H)+。
步骤2:2,5,6-三氯-N-((4,6-二异丙基嘧啶-5-基)胺甲酰基)烟酰胺。将2,5,6-三氯烟酰胺(中间体P,3.30g,14.6mmol)于1,2-二氯乙烷(49mL)中的溶液用草酰氯(DCM中的2M溶液,11.0mL,22.0mmol)处理。将混合物在80℃下加热45min,然后停止加热,并将反应浓缩。将残余物溶解于乙腈(49mL)中,冷却至-10℃,并经由导管添加4,6-二异丙基嘧啶-5-胺(中间体U,3.15g,17.6mmol)于乙腈(5mL)中的溶液。将所得混合物在室温下搅拌过夜且然后浓缩。将残余物悬浮于温10:1庚烷/EtOAc(110mL)中并过滤。将滤液浓缩且残余物通过硅胶色谱(洗脱液:0-40%EtOAc/庚烷)纯化,以提供2,5,6-三氯-N-((4,6-二异丙基嘧啶-5-基)胺甲酰基)烟酰胺。1H NMR(400MHz,DMSO-d6)δppm 11.30-11.46(m,1H),9.66(br s,1H),8.95-9.01(m,1H),8.65-8.72(m,1H),3.26(s,2H),1.17(d,J=6.6Hz,12H)。m/z(ESI,+ve离子):432.0(M+H)+。
步骤3:6,7-二氯-1-(4,6-二异丙基嘧啶-5-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。向2,5,6-三氯-N-((4,6-二异丙基嘧啶-5-基)胺甲酰基)烟酰胺(2.10g,4.9mmol)于THF(49mL)中的-20℃溶液中添加KHMDS(THF中的1M溶液,12.2mL,12.2mmol)。将冷却浴移除并将所得混合物在室温下搅拌2h。将反应混合物用饱和氯化铵水溶液(50mL)淬灭,用盐水稀释,并用3:1EtOAc/MeOH(1x)萃取。分离各层并将水层再用EtOAc(1x)萃取。将合并的有机层经无水硫酸镁干燥并浓缩。将残余物悬浮于庚烷/EtOAc中并过滤。将滤液浓缩,以提供6,7-二氯-1-(4,6-二异丙基嘧啶-5-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。1H NMR(400MHz,DMSO-d6)δppm 12.33(s,1H),9.18(s,1H),8.61(s,1H),2.90-3.02(m,2H),1.10(d,J=6.6Hz,6H),0.99(d,J=6.6Hz,6H)。m/z(ESI,+ve离子):394.0(M+H)+。
步骤4:(S)-叔丁基4-(6,7-二氯-1-(4,6-二异丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。经由注射器向6,7-二氯-1-(4,6-二异丙基嘧啶-5-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(900mg,2.28mmol)及DIPEA(0.518mL,2.97mmol)于乙腈(15mL)中的溶液缓慢添加氧氯化磷(0.255mL,2.74mmol)。将所得混合物在80℃下加热45min,且然后冷却至-10℃。添加DIPEA(1.2mL,6.88mmol),随后经由导管添加(S)-4-N-Boc-2-甲基哌嗪(1.37g,6.85mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-Blocks,Inc.))于乙腈(5mL)中的溶液。将所得混合物升温至室温并搅拌10min,并且然后再添加DIPEA(1.2mL,6.88mmol)。将反应混合物倒入冰水中并用EtOAc(2x)萃取。将合并的有机层用盐水(1x)洗涤,经无水硫酸镁干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-80%EtOAc/庚烷)纯化,以提供(S)-叔丁基4-(6,7-二氯-1-(4,6-二异丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。1H NMR(400MHz,DMSO-d6)δppm 9.15(s,1H),8.48(s,1H),5.75(s,1H),4.90(br s,1H),4.21(brd,J=14.1Hz,1H),3.91-4.06(m,1H),3.83(br d,J=13.3Hz,1H),3.73(br t,J=10.6Hz,1H),3.03-3.19(m,1H),2.69(dq,J=13.4,6.7Hz,2H),1.45(s,9H),1.31-1.36(m,3H),1.09(d,J=6.6Hz,6H),1.00(d,J=6.6Hz,6H)。m/z(ESI,+ve离子):576.2(M+H)+。
步骤5:(S)-叔丁基4-(6-氯-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。通过使氩气鼓泡进入混合物中,使(S)-叔丁基4-(6,7-二氯-1-(4,6-二异丙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯(500mg,0.87mmol)及乙酸钾(426mg,4.34mmol)于1,4-二噁烷(4.3mL)中的混合物脱氧5min。添加[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)与二氯甲烷的络合物(63mg,0.087mmol)并在90℃下加热混合物10min。缓慢添加2-氟苯基硼酸(243mg,1.735mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-Blocks,Inc.))于1,4-二噁烷(2mL)中的溶液,随后添加6滴水。将所得混合物在90℃下加热1h。将反应混合物吸附至硅胶塞上并通过硅胶色谱(洗脱液:0-8%MeOH/DCM)纯化,以提供(S)-叔丁基4-(6-氯-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。1H NMR(400MHz,DMSO-d6)δppm 9.05(s,1H),8.46(s,1H),8.15(s,1H),7.49-7.54(m,1H),7.27-7.32(m,1H),7.12-7.16(m,1H),4.93(br s,1H),4.29(br d,J=13.9Hz,1H),4.07(br d,J=4.6Hz,1H),3.85(br d,J=13.7Hz,1H),3.75(br t,J=11.0Hz,1H),3.56(s,2H),3.08-3.22(m,3H),2.67-2.78(m,2H),1.45(s,9H),1.08(d,J=6.6Hz,6H),0.92(d,J=6.6Hz,6H)。m/z(ESI,+ve离子):636.2(M+H)+。
步骤6.6-氯-1-(4,6-二(2-丙烷基)-5-嘧啶基)-7-(2-氟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。将三氟乙酸(0.176mL,2.36mmol)添加至(S)-叔丁基4-(6-氯-1-(4,6-二异丙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯(150mg,0.24mmol)于DCM(2.4mL)中的溶液。将所得混合物在38℃下加热2h且然后浓缩。将残余物溶解于DCM(2.4mL)中,冷却至0℃,并用DIPEA(0.494mL,2.83mmol)处理。2min后,经由注射器逐滴添加丙烯酰氯(0.019mL,0.24mmol),并将反应在0℃下再搅拌10min。将反应混合物浓缩且使残余物在饱和碳酸氢钠水溶液与EtOAc(2x)之间分配。将合并的有机层经无水硫酸镁干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-100%EtOAc/庚烷,随后0-8%MeOH/DCM)纯化,以提供6-氯-1-(4,6-二(2-丙烷基)-5-嘧啶基)-7-(2-氟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。1H NMR(400MHz,DMSO-d6)δppm 9.06(s,1H),8.46-8.52(m,1H),7.48-7.55(m,1H),7.26-7.34(m,2H),7.17(td,J=7.4,1.6Hz,1H),6.82-6.93(m,1H),6.22(br d,,J=16.6Hz,1H),5.75-5.80(m,1H),5.00(br s,1H),4.31-4.43(m,2H),4.02-4.21(m,1H),3.81(br d,J=8.9Hz,1H),3.45-3.70(m,1H),3.10-3.30(m,1H),2.73(br d,J=6.4Hz,2H),1.36(d,J=6.6Hz,3H),1.09(d,J=6.6Hz,6H),0.93(d,J=6.4Hz,6H)。m/z(ESI,+ve离子):590.2(M+H)+。
实例44
6-氯-1-(2-环丙基-4-甲基-3-吡啶基)-7-(2-氟-6-羟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮
步骤1:2,5,6-三氯-N-((2-环丙基-4-甲基吡啶-3-基)胺甲酰基)烟酰胺。经由注射器向2,5,6-三氯烟酰胺(中间体P,3.5g,15.5mmol)于THF(30mL)中的溶液中缓慢添加草酰氯(DCM中的2M溶液,11.6mL,23.3mmol)。将所得混合物在65℃下加热2h,然后停止加热,并将反应浓缩。将残余物溶解于THF(30mL)中并经由导管用2-环丙基-4-甲基吡啶-3-胺(中间体T,2.5g,17.1mmol)于THF(15mL)中的溶液处理。将所得混合物在室温下搅拌2h,然后用水淬灭并用EtOAc(3x)萃取。将合并的有机层经无水硫酸钠干燥并浓缩,以提供2,5,6-三氯-N-((2-环丙基-4-甲基吡啶-3-基)胺甲酰基)烟酰胺。该材料不经进一步纯化即用于下一步骤中。1H NMR(400MHz,DMSO-d6)δppm 11.30(br s,1H),9.44-9.73(m,1H),8.64(s,1H),8.21(d,J=5.0Hz,1H),7.07(d,J=5.0Hz,1H),2.22(s,3H),0.92(s,2H),0.91(d,J=3.5Hz,2H)。m/z(ESI,+ve离子):400.9(M+H)+。
步骤2:6,7-二氯-1-(2-环丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。经由注射器向2,5,6-三氯-N-((2-环丙基-4-甲基吡啶-3-基)胺甲酰基)烟酰胺(460mg,1.15mmol)于THF(5mL)中的冰冷溶液中缓慢添加KHMDS(THF中的1M溶液,2.30mL,2.30mmol)。将所得混合物在0℃下搅拌2h,然后用饱和氯化铵水溶液淬灭并用EtOAc(3x)萃取。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-40%3:1EtOAc-EtOH/庚烷)纯化,以提供6,7-二氯-1-(2-环丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。1H NMR(400MHz,DMSO-d6)δppm 12.26(br s,1H),8.59(s,1H),8.36(d,J=5.0Hz,1H),7.19(d,J=5.0Hz,1H),2.05(s,3H),1.86-1.96(m,1H),0.88-0.95(m,1H),0.79-0.87(m,1H),0.73-0.79(m,1H),0.62-0.70(m,1H)。m/z(ESI,+ve离子):362.9(M+H)+。
步骤3:4,6,7-三氯-1-(2-环丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮。向6,7-二氯-1-(2-环丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(4.60g,12.7mmol)及DIPEA(3.32mL,19.0mmol)于乙腈(25mL)中的溶液中添加氧氯化磷(1.77mL,19.0mmol)。将所得混合物在80℃下加热3h,且然后冷却至室温并浓缩,以提供4,6,7-三氯-1-(2-环丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮。该材料不经进一步纯化即用于下一步骤中。m/z(ESI,+ve离子):380.9(M+H)+。
步骤4:(S)-叔丁基4-(6,7-二氯-1-(2-环丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯(中间体V)。向4,6,7-三氯-1-(2-环丙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(12.7mmol)于DCM(40mL)中的冰冷溶液中添加DIPEA(11.1mL,63.3mmol),随后添加(S)-4-N-Boc-2-甲基哌嗪(2.54g,12.7mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-Blocks,Inc.))。将所得混合物在0℃下搅拌1h,然后用水淬灭并用DCM(3x)萃取。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-50%3:1 EtOAc-EtOH/庚烷)纯化,以提供(S)-叔丁基4-(6,7-二氯-1-(2-环丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。1H NMR(400MHz,DMSO-d6)δppm 8.44(d,J=7.0Hz,1H),8.33(d,J=5.0Hz,1H),7.17(d,J=5.2Hz,1H),4.85(br s,1H),4.16(br d,J=11.0Hz,1H),3.96(br dd,J=3.4,2.2Hz,1H),3.82(br d,J=13.3Hz,1H),3.69(q,J=12.0Hz,1H),3.19-3.29(m,1H),3.03-3.19(m,1H),1.95(d,J=3.9Hz,3H),1.58-1.68(m,1H),1.45(s,9H),1.32(dd,J=6.6,2.5Hz,3H),0.88-0.97(m,1H),0.77-0.86(m,1H),0.70-0.77(m,1H),0.59-0.69(m,1H)。m/z(ESI,+ve离子):544.9(M+H)+。
步骤5:(3S)-叔丁基4-(6-氯-1-(2-环丙基-4-甲基吡啶-3-基)-7-(2-氟-6-羟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。用氩气使(S)-叔丁基4-(6,7-二氯-1-(2-环丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸叔丁酯(中间体V,992mg,1.82mmol)、(2-氟-6-羟苯基)硼酸(510mg,3.27mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-blocks))、乙酸钾(892mg,9.09mmol)及[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)与二氯甲烷的络合物(119mg,0.15mmol)于1,4-二噁烷(16mL)中的混合物脱气并在80℃下加热。2min后,将两滴水添加至反应混合物中并将温度升高至90℃。在90℃下继续加热1h,且然后允许反应冷却至室温。添加水且将所得混合物用EtOAc(3x)萃取。将合并的有机层经无水硫酸镁干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-50%3:1 EtOAc-EtOH/庚烷)纯化,以提供(3S)-叔丁基4-(6-氯-1-(2-环丙基-4-甲基吡啶-3-基)-7-(2-氟-6-羟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。1H NMR(400MHz,DMSO-d6)δppm 10.04-10.22(m,1H),8.31-8.45(m,1H),8.23(d,J=5.0Hz,1H),7.19-7.31(m,1H),7.09(br s,1H),6.60-6.76(m,2H),4.75-5.02(m,1H),4.10-4.36(m,1H),3.92-4.06(m,1H),3.56-3.89(m,2H),2.91-3.30(m,2H),1.90(br d,J=19.3Hz,3H),1.61-1.77(m,1H),1.45(s,9H),1.30-1.40(m,3H),0.59-0.90(m,4H)。m/z(ESI,+ve离子):620.9(M+H)+。
步骤6:1-(2-环丙基-4-甲基-3-吡啶基)-6-氯-7-(2-氟-6-羟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。将三氟乙酸(2.47mL,33.2mmol)添加至(3S)-叔丁基4-(6-氯-1-(2-环丙基-4-甲基吡啶-3-基)-7-(2-氟-6-羟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯(1.03g,1.66mmol)于DCM(10mL)中的溶液中。将所得混合物在室温下搅拌3h且然后浓缩。将残余物溶解于DCM(10mL)中,冷却至0℃,并经由注射器用DIPEA(1.45mL,8.29mmol),随后丙烯酰氯(0.120mL,1.49mmol)逐滴处理。将反应在0℃下搅拌2h,然后用水淬灭并用DCM(3x)萃取。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-50%3:1EtOAc-EtOH/庚烷)纯化,以提供6-氯-1-(2-环丙基-4-甲基-3-吡啶基)-7-(2-氟-6-羟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。1H NMR(400MHz,DMSO-d6)δppm 10.06-10.26(m,1H),8.33-8.49(m,1H),8.23(d,J=4.8Hz,1H),7.20-7.34(m,1H),7.09(br d,J=2.1Hz,1H),6.79-6.92(m,1H),6.63-6.78(m,2H),6.16-6.29(m,1H),5.76(dd,J=10.4,2.3Hz,1H),4.77-5.08(m,1H),4.21-4.47(m,2H),3.98-4.20(m,1H),3.39-3.92(m,2H),2.92-3.28(m,1H),1.85-1.99(m,3H),1.62-1.79(m,1H),1.34(br d,J=19.5Hz,3H),0.74-0.88(m,3H),0.56-0.68(m,1H)。m/z(ESI,+ve离子):574.9(M+H)+。
实例45
6-氯-1-(2-环丙基-4-甲基-3-吡啶基)-7-(2-氟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮
步骤1:(S)-叔丁基4-(6-氯-1-(2-环丙基-4-甲基吡啶-3-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。用氩气使(S)-叔丁基4-(6,7-二氯-1-(2-环丙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯(中间体V,500mg,0.92mmol)、(2-氟苯基)硼酸(269mg,1.92mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-blocks))、乙酸钾(450mg,4.58mmol)及[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)与二氯甲烷的络合物(75mg,0.09mmol)于1,4-二噁烷(7mL)中的混合物脱气并在80℃下加热。2min后,将三滴水添加至反应混合物中并将温度升高至90℃。在90℃下继续加热1h,且然后允许反应冷却至室温。添加水且将所得混合物用EtOAc(3x)萃取。将合并的有机层经无水硫酸镁干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-40%3:1 EtOAc-EtOH/庚烷)纯化,以提供(S)-叔丁基4-(6-氯-1-(2-环丙基-4-甲基吡啶-3-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。1H NMR(400MHz,DMSO-d6)δppm 8.41(d,J=2.5Hz,1H),8.25(d,J=5.0Hz,1H),7.49-7.56(m,1H),7.25-7.35(m,3H),7.11(d,J=4.8Hz,1H),4.90(br d,J=1.5Hz,1H),4.24(br d,J=13.7Hz,1H),3.93-4.07(m,1H),3.85(br d,J=13.9Hz,1H),3.65-3.79(m,1H),3.21-3.30(m,1H),3.09-3.20(m,1H),1.96(s,3H),1.60-1.70(m,1H),1.45(s,9H),1.36(d,J=6.6Hz,3H),0.86-0.93(m,1H),0.72-0.83(m,2H),0.61-0.71(m,1H)。m/z(ESI,+ve离子):605.0(M+H)+。
步骤2:6-氯-1-(2-环丙基-4-甲基-3-吡啶基)-7-(2-氟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。将三氟乙酸(1.28mL,17.2mmol)添加至(S)-叔丁基4-(6-氯-1-(2-环丙基-4-甲基吡啶-3-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯(521mg,0.86mmol)于DCM(10mL)中的溶液中。将所得混合物在室温下搅拌3h且然后浓缩。将残余物溶解于DCM(10mL)中,冷却至0℃,并经由注射器用DIPEA(0.762mL,4.31mmol),随后丙烯酰氯(0.440mL,0.86mmol)逐滴处理。将反应在0℃下搅拌2h,然后用水淬灭并用DCM(1x)萃取。将有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-50%3:1 EtOAc-EtOH/庚烷)纯化,以提供6-氯-1-(2-环丙基-4-甲基-3-吡啶基)-7-(2-氟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。1H NMR(400MHz,DMSO-d6)δppm 8.44(br s,1H),8.25(d,J=5.0Hz,1H),7.48-7.56(m,1H),7.24-7.35(m,3H),7.11(d,J=5.0Hz,1H),6.78-6.92(m,1H),6.20(br d,J=16.2Hz,1H),5.72-5.79(m,1H),4.94(br s,1H),4.25-4.44(m,2H),3.99-4.20(m,1H),3.43-3.69(m,2H),3.02-3.15(m,1H),1.96(d,J=3.3Hz,3H),1.60-1.71(m,1H),1.34(d,J=6.8Hz,3H),0.89(br dd,J=8.3,4.6Hz,1H),0.72-0.84(m,2H),0.61-0.71(m,1H)。m/z(ESI,+ve离子):559.0(M+H)+。
实例46
6-氯-1-(2-乙基-4-甲基-3-吡啶基)-7-(2-氟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。
步骤1:2-乙基-4-甲基吡啶-3-胺(中间体W)。经由注射器将溴化乙基镁(乙醚中的3M溶液,3.5mL,10.5mmol)缓慢添加至氯化锌(0.5M于THF中,18mL,9.0mmol)中的溶液中。该添加是放热的。将溶液在室温下搅拌10min,且然后添加3-氨基-2-溴-4-甲基吡啶(1.5g,8.0mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-blocks))及二氯[1,1’-双(二苯基膦基)二茂铁]二氯化钯(ii)二氯甲烷加合物(120mg,0.16mmol)。将所得混合物在50℃下加热20min,然后停止加热并允许反应冷却至室温。用10%氢氧化铵溶液(30mL)淬灭反应混合物并用EtOAc(80mL,2×40mL)萃取。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:1%-5%MeOH/DCM)纯化,以提供2-乙基-4-甲基吡啶-3-胺。1H NMR(400MHz,氯仿-d)δppm 7.92(d,J=5.0Hz,1H),6.87(d,J=4.8Hz,1H),3.59(br s,2H),2.74(q,J=7.6Hz,2H),2.19(s,3H),1.33(t,J=7.6Hz,3H)。m/z(ESI,+ve离子):137.1(M+H)+。
步骤2:2,5,6-三氯-N-((2-乙基-4-甲基吡啶-3-基)胺甲酰基)烟酰胺。经由注射器向2,5,6-三氯烟酰胺(中间体P,2.5g,11.1mmol)于THF(20mL)中的溶液中缓慢添加草酰氯(DCM中的2M溶液,5.4mL,10.8mmol)。将所得混合物在65℃下加热1.5h,然后停止加热并允许反应冷却至室温。经由导管添加2-乙基-4-甲基吡啶-3-胺(中间体W,1.5g,10.7mmol)于THF(15mL)中的溶液。将所得混合物在室温下搅拌1h,且然后部分浓缩以移除大部分THF。使残余物在饱和碳酸氢钠水溶液(30mL)与EtOAc(50mL)之间分配。将有机层用盐水(1x)洗涤,经无水硫酸钠干燥并浓缩。将残余物悬浮于10:1庚烷/EtOAc(60mL)中并过滤,以提供2,5,6-三氯-N-((2-乙基-4-甲基吡啶-3-基)胺甲酰基)烟酰胺。将产物直接用于下一步骤中。
步骤3:6,7-二氯-1-(2-乙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。经由注射器向2,5,6-三氯-N-((2-乙基-4-甲基吡啶-3-基)胺甲酰基)烟酰胺(10.7mmol)于THF(60mL)中的冰冷溶液中缓慢添加KHMDS(THF中的1M溶液,16.0mL,16.0mmol)。将所得溶液在0℃下搅拌10min,然后用饱和氯化铵水溶液(20mL)淬灭并用EtOAc(60mL)萃取。将有机层用盐水(1x)洗涤,经无水硫酸钠干燥并浓缩。将残余物悬浮于9:1庚烷/EtOAc(60mL)中并过滤,以提供6,7-二氯-1-(2-乙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。1H NMR(400MHz,DMSO-d6)δppm 12.14-12.39(m,1H),8.54(s,1H),8.47(d,J=5.0Hz,1H),7.28(d,J=5.0Hz,1H),2.41-2.49(m,2H),2.03(s,3H),1.07(t,J=7.5Hz,3H)。m/z(ESI,+ve离子):350.9(M+H)+。
步骤4:(S)-叔丁基4-(6,7-二氯-1-(2-乙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。向6,7-二氯-1-(2-乙基-4-甲基吡啶-3-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(1.0g,2.9mmol)及DIPEA(1.5mL,8.6mmol)于乙腈(8mL)中的溶液中添加氧氯化磷(0.40mL,4.3mmol)。将所得溶液在80℃下加热30min,且然后冷却至0℃。添加DIPEA(1.5mL,8.6mmol),随后添加(S)-4-N-Boc-2-甲基哌嗪(800mg,4.0mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-Blocks,Inc.))。将所得混合物升温至室温并搅拌30min,然后用EtOAc(30mL)稀释并用饱和碳酸氢钠水溶液(10mL)及盐水(10mL)洗涤。将有机层经无水硫酸镁干燥并浓缩。将残余物通过硅胶色谱(洗脱液:10%-50%3:1 EtOAc-EtOH/庚烷)纯化,以提供(S)-叔丁基4-(6,7-二氯-1-(2-乙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。1HNMR(400MHz,DMSO-d6)δppm 8.46(d,J=5.0Hz,1H),8.44(s,1H),7.27(d,J=5.0Hz,1H),4.85(br s,1H),4.12-4.21(m,1H),3.95(br s,1H),3.82(br d,J=12.9Hz,1H),3.69(brd,J=11.4Hz,1H),2.94-3.27(m,2H),2.25-2.43(m,2H),1.94(d,J=1.7Hz,3H),1.45(s,9H),1.32(t,J=6.2Hz,3H),1.05(t,J=7.6Hz,3H)。m/z(ESI,+ve离子):533.0(M+H)+。
步骤5:(S)-叔丁基4-(6-氯-1-(2-乙基-4-甲基吡啶-3-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。用氮气使(S)-叔丁基4-(6,7-二氯-1-(2-乙基-4-甲基吡啶-3-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯(450mg,0.84mmol)、(2-氟苯基)硼酸(199mg,1.43mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-blocks))、乙酸钾(250mg,2.55mmol)及[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)与二氯甲烷的络合物(33mg,0.04mmol)于1,4-二噁烷(5mL)及水(1mL)中的混合物脱气并在65℃下加热1.5h。允许反应冷却至室温,然后用EtOAc(40mL)稀释并用饱和碳酸氢钠水溶液(10mL)及盐水(10mL)洗涤。将有机层经无水硫酸镁干燥并浓缩。将残余物通过硅胶色谱(洗脱液:10%-50%3:1EtOAc-EtOH/庚烷)纯化,以提供(S)-叔丁基4-(6-氯-1-(2-乙基-4-甲基吡啶-3-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。1H NMR(400MHz,DMSO-d6)δppm 8.43(s,1H),8.36(d,J=5.0Hz,1H),7.47-7.55(m,1H),7.20-7.33(m,4H),4.90(br s,1H),4.24(br s,1H),3.99(br s,1H),3.85(br d,J=13.3Hz,1H),3.72(br d,J=11.6Hz,1H),3.33-3.47(m,1H),3.03-3.21(m,1H),2.30-2.43(m,2H),1.95(s,3H),1.46(s,9H),1.36(t,J=6.1Hz,3H),1.04(dt,J=7.5,2.3Hz,3H)。19F NMR(377MHz,氯仿-d)δppm-113.84--113.85(2s,1F)。m/z(ESI,+ve离子):592.9(M+H)+。
步骤6:6-氯-1-(2-乙基-4-甲基-3-吡啶基)-7-(2-氟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。将三氟乙酸(3.0mL,40.3mmol)添加至(S)-叔丁基4-(6-氯-1-(2-乙基-4-甲基吡啶-3-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯(500mg,0.84mmol)于DCM(10mL)中的溶液中。将所得混合物在室温下搅拌30min且然后浓缩。将残余物溶解于DCM(10mL)中并用DIPEA(0.500mL,2.86mmol),随后丙烯酰氯(0.100mL,1.23mmol)于DCM(2mL)中的溶液处理。将反应在室温下搅拌30min,且然后用饱和碳酸氢钠水溶液(10mL)及盐水(5mL)淬灭。用EtOAc(2x15mL)萃取混合物且将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:10%-60%3:1 EtOAc-EtOH/庚烷)纯化,以提供6-氯-1-(2-乙基-4-甲基-3-吡啶基)-7-(2-氟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。1H NMR(400MHz,氯仿-d)δppm 8.45(d,J=5.0Hz,1H),8.10(s,1H),7.38-7.46(m,1H),7.08-7.20(m,4H),6.62(br s,1H),6.42(dd,J=16.7,1.6Hz,1H),5.82(dd,J=10.5,1.8Hz,1H),4.24-5.21(m,3H),3.60-4.15(m,3H),3.00-3.36(m,1H),2.41-2.60(m,2H),2.00-2.12(m,3H),1.45-1.61(m,3H),1.15-1.22(m,3H)。19F NMR(377MHz,氯仿-d)δppm-111.94--113.08(m,1F)。m/z(ESI,+ve离子):547.2(M+H)+。
实例47
6-氯-1-(4,6-二乙基-5-嘧啶基)-7-(2-氟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮
步骤1:4,6-二乙烯基嘧啶-5-胺。用氮气使4,6-二氯-5-氨基嘧啶(5.0g,30.5mmol,密苏里州圣路易斯西格玛奥德里奇(Sigma Aldrich))、乙烯基三氟硼酸钾(16.3g,122mmol,密苏里州圣路易斯西格玛奥德里奇(Sigma Aldrich))、Pd(dppf)Cl2(1.12g,1.52mmol)及碳酸铯(49.7g,152mmol)于1,4-二噁烷(130mL)及水(13mL)中的混合物脱气并在100℃下加热4h。允许反应冷却至室温且然后用水稀释并依序用EtOAc(3×100mL)及DCM(5×100mL)萃取。将合并的有机层经无水硫酸镁干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-20%4:1 DCM-MeOH/DCM)纯化,以提供4,6-二乙烯基嘧啶-5-胺。1H NMR(400MHz,氯仿-d)δppm 8.62(s,1H),6.80-6.89(m,2H),6.46(dd,J=17.0,1.7Hz,2H),5.71(dd,J=10.9,1.8Hz,2H),3.86(br s,2H)。m/z(ESI,+ve离子):148.1(M+H)+。
步骤2:4,6-二乙基嘧啶-5-胺(中间体X)。用钯(10wt.%于活性碳上,1.12g,1.05mmol)处理4,6-二乙烯基嘧啶-5-胺(3.1g,21.1mmol)于乙醇(50mL)中的溶液。用20psi氢气净化混合物(4x)并在20psi氢气下,在室温下搅拌4h。将反应混合物经硅藻土垫过滤并浓缩,得到4,6-二乙基嘧啶-5-胺。1H NMR(400MHz,氯仿-d)δppm 8.59(s,1H),3.62(br s,2H),2.70(q,J=7.6Hz,4H),1.34(t,J=7.6Hz,6H)。m/z(ESI,+ve离子):152.2(M+H)+。
步骤3:2,5,6-三氯-N-((4,6-二乙基嘧啶-5-基)胺甲酰基)烟酰胺。向2,5,6-三氯烟酰胺(中间体P,4.67g,20.7mmol)于THF(100mL)中的悬浮液中添加草酰氯(DCM中的2M溶液,15.5mL,31.0mmol)。将所得混合物在65℃下加热1h,然后停止加热,并将反应浓缩至三分的一体积。添加甲苯(100mL)并将混合物冷却至0℃。经由导管逐滴添加4,6-二乙基嘧啶-5-胺(中间体X,3.13g,20.7mmol)于1,2-二氯乙烷(20mL)中的溶液。将所得混合物升温至室温并搅拌15min,且然后浓缩。将残余物悬浮于MTBE(50mL)中并过滤。在真空烘箱中,在50℃下短时间干燥过滤的固体,以提供2,5,6-三氯-N-((4,6-二乙基嘧啶-5-基)胺甲酰基)烟酰胺。m/z(ESI,+ve离子):402.1(M+H)+。
步骤4:6,7-二氯-1-(4,6-二乙基嘧啶-5-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。经由注射器向2,5,6-三氯-N-((4,6-二乙基嘧啶-5-基)胺甲酰基)烟酰胺(7.28g,18.1mmol)于THF(100mL)中的冰冷溶液中缓慢添加KHMDS(THF中的1M溶液,36.2mL,36.2mmol)。将所得混合物升温至室温并搅拌5min,然后用饱和氯化铵水溶液淬灭并用EtOAc(5×100mL)萃取。将合并的有机层经无水硫酸镁干燥并浓缩。将残余物在真空烘箱中在45℃下干燥过夜,以提供6,7-二氯-1-(4,6-二乙基嘧啶-5-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。该材料不经进一步纯化即用于下一步骤中。m/z(ESI,+ve离子):366.0(M+H)+。
步骤5:(S)-叔丁基4-(6,7-二氯-1-(4,6-二乙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。
用三乙胺(3.71mL,26.4mmol),随后氧氯化磷(1.26mL,12.7mmol)处理6,7-二氯-1-(4,6-二乙基嘧啶-5-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(3.87g,10.6mmol)于乙腈(30mL)中的溶液。将所得混合物在60℃下加热30min,且然后冷却至0℃。添加三乙胺(1.50mL,10.7mmol),随后添加(S)-4-N-Boc-2-甲基哌嗪(2.22g,11.1mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-Blocks,Inc.))。将反应混合物升温至室温并搅拌30min,然后使其在EtOAc(100mL)与盐水(40mL)之间分配。将有机层用水(30mL)及盐水(50mL)洗涤,经无水硫酸镁干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-100%EtOAc/庚烷)纯化,以提供(S)-叔丁基4-(6,7-二氯-1-(4,6-二乙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。1H NMR(400MHz,DMSO-d6)δppm 9.09(s,1H),8.48(s,1H),4.88(br s,1H),4.19(br d,J=13.7Hz,1H),3.90-4.00(m,1H),3.83(br d,J=13.7Hz,1H),3.66-3.78(m,1H),3.05-3.35(m,2H),2.35-2.46(m,4H),1.45(s,9H),1.33(d,J=6.6Hz,3H),1.08(t,J=7.5Hz,6H)。m/z(ESI,+ve离子):548.2(M+H)+。
步骤6:(S)-叔丁基4-(6-氯-1-(4,6-二乙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。用氩气使(S)-叔丁基4-(6,7-二氯-1-(4,6-二乙基嘧啶-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯(354mg,0.65mmol)、(2-氟苯基)硼酸(108mg,0.78mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-blocks))、乙酸钾(317mg,3.23mmol)及[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)与二氯甲烷的络合物(23mg,0.03mmol)于1,4-二噁烷(6.5mL)中的混合物脱气5min。添加四滴水并将混合物在90℃下加热30min。允许反应冷却至室温,且然后使其在水(10mL)与EtOAc(20mL)之间分配。将水层用DCM(20mL)萃取。合并的有机层用盐水(20mL)洗涤,经无水硫酸镁干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-30%4:1 DCM-MeOH/DCM)纯化,以提供(S)-叔丁基4-(6-氯-1-(4,6-二乙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。1H NMR(400MHz,DMSO-d6)δppm 9.01(s,1H),8.45(s,1H),7.49-7.57(m,1H),7.26-7.34(m,2H),7.20-7.26(m,1H),4.88-4.98(m,1H),4.27(br d,J=13.7Hz,1H),3.93-4.03(m,1H),3.85(br d,J=13.5Hz,1H),3.70-3.81(m,1H),3.05-3.35(m,2H),2.35-2.46(m,4H),1.46(s,9H),1.37(d,J=6.6Hz,3H),1.06(td,J=7.5,1.6Hz,6H)。19F NMR(377MHz,DMSO-d6)δppm-114.01(s,1F)。m/z(ESI,+ve离子):608.2(M+H)+。
步骤7:6-氯-1-(4,6-二乙基-5-嘧啶基)-7-(2-氟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。将三氟乙酸(3.0mL,38.9mmol)添加至(S)-叔丁基4-(6-氯-1-(4,6-二乙基嘧啶-5-基)-7-(2-氟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸(酯(327mg,0.54mmol)于DCM5mL)中的溶液中。将所得混合物在室温下搅拌15min且然后浓缩。将残余物溶解于DCM(10mL)中,冷却至0℃,并用DIPEA(0.470mL,2.69mmol),随后丙烯酰氯(0.048mL,0.59mmol)处理。将反应在0℃下搅拌10min,且然后再添加DIPEA(0.300mL,1.71mmol),随后再添加丙烯酰氯(0.020mL,0.25mmol)。在0℃下又保持20min之后,用饱和碳酸氢钠水溶液(10mL)淬灭反应并用DCM(2×30mL)萃取。将合并的有机层经无水硫酸镁干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-60%4:1 DCM-MeOH/DCM)纯化,以提供6-氯-1-(4,6-二乙基-5-嘧啶基)-7-(2-氟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。1H NMR(400MHz,DMSO-d6)δppm 9.01(s,1H),8.48(br d,J=5.0Hz,1H),7.50-7.57(m,1H),7.27-7.35(m,3H),7.20-7.27(m,1H),6.79-6.93(m,1H),6.17-6.26(m,1H),5.65-5.80(m,1H),4.92-5.02(m,1H),4.23-4.44(m,2H),3.99-4.20(m,1H),3.72-3.88(m,1H),3.40-3.71(m,1H),2.35-2.48(m,4H),1.36(d,J=6.6Hz,3H),1.06(t,J=7.5Hz,6H)。19F NMR(377MHz,DMSO-d6)δppm-114.01(s,1F)。m/z(ESI,+ve离子):562.1(M+H)+。
实例48
6-氯-7-(2-氟-6-羟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)-1-(4-(2-丙烷基)-1,3-噻唑-5-基)吡啶并[2,3-d]嘧啶-2(1H)-酮
步骤1:2,5,6-三氯-N-((4-异丙基噻唑-5-基)胺甲酰基)烟酰胺。向2,5,6-三氯烟酰胺(中间体P,1.00g,4.5mmol)于THF(20mL)中的混合物中添加草酰氯(DCM中的2M溶液,2.4mL,4.9mmol)。将所得混合物在70℃下加热30min,然后停止加热并允许反应冷却至室温。添加4-(丙烷-2-基)-1,3-噻唑-5-胺(715mg,5.0mmol,美国新泽西州蒙茅斯交界处烯胺公司(Enamine))。将反应混合物在室温下搅拌10min且然后浓缩。将残余物悬浮于MeOH中并过滤。丢弃过滤的固体并浓缩滤液,以提供2,5,6-三氯-N-((4-异丙基噻唑-5-基)胺甲酰基)烟酰胺。1H NMR(400MHz,DMSO-d6)δppm 11.69(br s,1H),10.64(br s,1H),8.71(s,1H),8.58(s,1H),3.13(br d,J=6.4Hz,1H),1.25(d,J=6.8Hz,6H)。m/z(ESI,+ve离子):393.0(M+H)+。
步骤2:6,7-二氯-1-(4-异丙基噻唑-5-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。向2,5,6-三氯-N-((4-异丙基噻唑-5-基)胺甲酰基)烟酰胺(1.75g,4.5mmol)于THF(20mL)中的冰冷溶液中添加KHMDS(THF中的1M溶液,9.3mL,9.3mmol)。将所得混合物升温至室温并搅拌30min,然后将其再冷却至0℃并用KHMDS(THF中的1M溶液,1.0mL,1.0mmol)处理。将反应升温至室温并搅拌15min,然后用半饱和氯化铵水溶液(60mL)淬灭并用EtOAc(2×50mL)萃取。将合并的有机层用水(60mL)洗涤,通过经Chem Elut萃取筒(加利福尼亚州圣克拉拉安捷伦科技有限公司(Agilent Technology))洗脱进行干燥并浓缩。将残余物通过硅胶色谱(洗脱液:5%-70%EtOAc/庚烷)纯化,以提供6,7-二氯-1-(4-异丙基噻唑-5-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。1H NMR(400MHz,DMSO-d6)δppm 12.20(s,1H),9.14(s,1H),8.54(s,1H),2.86(quin,J=6.8Hz,1H),1.11(t,J=7.4Hz,6H)。m/z(ESI,+ve离子):357.0(M+H)+。
步骤3:(S)-叔丁基4-(6,7-二氯-1-(4-异丙基噻唑-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。向6,7-二氯-1-(4-异丙基噻唑-5-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(3.01g,8.4mmol)于乙腈(40mL)中的混合物中添加DIPEA(4.40mL,25.3mmol),随后添加氧氯化磷(1.57mL,16.8mmol)。将所得混合物在80℃下加热15min,然后冷却至室温并浓缩。将残余物溶解于DMF(30mL)中并用DIPEA(7.34mL,42.2mmol),随后(S)-4-N-Boc-2-甲基哌嗪(1.89g,9.5mmol,美国密苏里州圣路易斯西格玛-奥德里奇(Sigma-Aldrich))处理。将所得溶液在室温下搅拌5min,然后添加冰水(100mL)并且再将混合物搅拌15min。将混合物过滤且将过滤的固体用DCM溶解,通过使其通过Chem Elut萃取筒(加利福尼亚州圣克拉拉安捷伦科技有限公司(Agilent Technology))进行干燥并浓缩。将残余物通过硅胶色谱(洗脱液:40%-100%EtOAc/庚烷)纯化,以提供(S)-叔丁基4-(6,7-二氯-1-(4-异丙基噻唑-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。1H NMR(400MHz,DMSO-d6)δppm 9.10(s,1H),8.40(d,J=1.7Hz,1H),4.85(br s,1H),4.07-4.18(m,1H),3.88-4.00(m,1H),3.81(br d,J=13.9Hz,1H),3.64-3.77(m,1H),3.28(s,1H),3.01-3.19(m,1H,),2.65(t,J=13.3,6.6Hz,1H),1.44(s,9H),1.31(dd,J=6.4,3.3Hz,3H),1.09-1.13(m,6H)。m/z(ESI,+ve离子):539.2(M+H)+。
步骤4:(3S)-叔丁基4-(6-氯-7-(2-氟-6-羟苯基)-1-(4-异丙基噻唑-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。用氩气使(S)-叔丁基4-(6,7-二氯-1-(4-异丙基噻唑-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯(2.03g,3.76mmol)、乙酸钾(1.86g,18.9mmol)、(2-氟-6-羟苯基)硼酸(911mg,5.84mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-blocks))及[1,1’-双(二苯基膦基)二茂铁]-二氯钯(II)与二氯甲烷的络合物(282mg,0.39mmol)于1,4-二噁烷(36mL)中的混合物脱气5min。添加一滴水并将所得混合物加热至90℃,持续1.5h。允许反应冷却至室温,且然后使其在水(50mL)与EtOAc(2x50mL)之间分配。将合并的有机提取物用水(60mL)洗涤,通过经Chem Elut萃取筒(加利福尼亚州圣克拉拉安捷伦科技有限公司(Agilent Technology))洗脱进行干燥并浓缩。将残余物通过硅胶色谱(洗脱液:50%-100%EtOAc/庚烷)纯化,以提供(3S)-叔丁基4-(6-氯-7-(2-氟-6-羟苯基)-1-(4-异丙基噻唑-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。1H NMR(400MHz,DMSO-d6)δppm 10.10(s,1H),9.00(s,1H),8.31-8.39(m,1H),7.21-7.32(m,1H),6.65-6.77(m,2H),4.88(br s,1H),4.11-4.33(m,1H),3.91-3.98(m,1H),3.83(br d,J=13.9Hz,1H),3.64-3.78(m,1H),3.28(br s,1H),3.03-3.21(m,1H),2.63(br s,1H),1.45(s,9H),1.36(br s,3H),1.09(br d,J=6.8Hz,3H),1.01(d,J=6.8Hz,3H)。19F NMR(376MHz,DMSO-d6)δppm-115.41(br s,1F)。m/z(ESI,+ve离子):615.2(M+H)+。
步骤5:6-氯-7-(2-氟-6-羟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)-1-(4-(2-丙烷基)-1,3-噻唑-5-基)吡啶并[2,3-d]嘧啶-2(1H)-酮。将三氟乙酸(10mL,130mmol)添加至(3S)-叔丁基4-(6-氯-7-(2-氟-6-羟苯基)-1-(4-异丙基噻唑-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯(2.15g,3.50mmol)于DCM(20mL)中的溶液中。在室温下搅拌反应30min且然后浓缩。将残余物溶解于DCM(20mL)中,冷却至0℃,并用DIPEA(3.05mL,17.5mmol),随后丙烯酰氯溶液(0.258M于DCM中,10.84mL,2.8mmol)处理。将反应混合物升温至室温并搅拌15min,然后将其再冷却至0℃并用丙烯酰氯溶液(0.258M于DCM中,2.0mL,0.52mmol)处理。升温至室温并再搅拌10min后,将反应浓缩。将残余物通过硅胶色谱(洗脱液:40%-100%3:1 EtOAc-EtOH/庚烷)纯化,以提供6-氯-7-(2-氟-6-羟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)-1-(4-(2-丙烷基)-1,3-噻唑-5-基)吡啶并[2,3-d]嘧啶-2(1H)-酮。1H NMR(400MHz,DMSO-d6)δppm 10.10(s,1H),9.01(s,1H),8.37(br s,1H),7.22-7.32(m,1H),6.80-6.93(m,1H),6.66-6.77(m,2H),6.20(br d,J=16.6Hz,1H),5.71-5.81(m,1H),4.83-5.04(m,1H),3.98-4.45(m,3H),3.56-3.87(m,2H),3.07(br dd,J=4.1,2.9Hz,1H),2.59-2.70(m,1H),1.33(br d,J=5.8Hz,3H),1.07-1.14(m,3H),1.01(br d,J=6.6Hz,3H)。19F NMR(376MHz,DMSO-d6)δppm-115.41(brs,1F)。m/z(ESI,+ve离子):569.2(M+H)+。
实例49
6-氯-7-(2-氟-6-羟苯基)-1-(2-(2-甲基-2-丙烷基)苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮
步骤1:N-((2-(叔丁基)苯基)胺甲酰基)-2,5,6-三氯烟酰胺。向2,5,6-三氯烟酰胺(中间体P,1.02g,4.5mmol)于THF(20mL)中的混合物中添加草酰氯(DCM中的2M溶液,2.5mL,5.0mmol)。将所得混合物在70℃下加热40min,然后停止加热并允许反应冷却至室温。添加2-叔丁基苯胺(0.708mL,4.5mmol,美国伊利诺伊州阿灵顿海茨市方舟制药公司)。将反应混合物在室温下搅拌10min且然后浓缩。将残余物悬浮于MeOH中并过滤。收集过滤的固体,以提供N-((2-(叔丁基)苯基)胺甲酰基)-2,5,6-三氯烟酰胺。1H NMR(400MHz,DMSO-d6)δppm 11.43(br s,1H),9.79-10.16(m,1H),8.65(s,1H),7.49(br dd,J=7.5,1.7Hz,1H),7.43(br d,J=7.7Hz,1H),7.18-7.28(m,2H),1.40(s,9H)。m/z(ESI,+ve离子):422.0(M+Na)+。
步骤2:1-(2-(叔丁基)苯基)-6,7-二氯吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。向N-((2-(叔丁基)苯基)胺甲酰基)-2,5,6-三氯烟酰胺(1.26g,3.1mmol)于THF(20mL)中的冰冷的混合物中添加KHMDS(THF中的1M溶液,6.6mL,6.6mmol)。将所得混合物升温至室温并搅拌10min,然后通过添加半饱和氯化铵水溶液(60mL)淬灭并用EtOAc(2×50mL)萃取。将合并的有机层用水(60mL)洗涤,通过经Chem Elut萃取筒(加利福尼亚州圣克拉拉安捷伦科技有限公司(Agilent Technology))洗脱进行干燥并浓缩。将残余物悬浮于MeOH中并过滤。收集过滤的固体,以提供1-(2-(叔丁基)苯基)-6,7-二氯吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。1H NMR(400MHz,DMSO-d6)δppm 12.19(s,1H),8.56(s,1H),7.65(dd,J=8.2,1.3Hz,1H),7.41-7.46(m,1H),7.33(td,J=7.5,1.2Hz,1H),7.21(dd,J=7.8,1.3Hz,1H),1.17(s,9H)。m/z(ESI,+ve离子):364.0(M+H)+。
步骤3:(S)-叔丁基4-(1-(2-(叔丁基)苯基)-6,7-二氯-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。向1-(2-(叔丁基)苯基)-6,7-二氯吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(925mg,2.54mmol)于乙腈(20mL)中的混合物中添加DIPEA(0.574mL,3.30mmol),随后添加氧氯化磷(0.284mL,3.05mmol)。将所得混合物在80℃下加热45min,然后冷却至0℃。添加DIPEA(1.33mL,7.62mmol),随后添加(S)-4-N-Boc-2-甲基哌嗪(0.522g,2.61mmol,美国密苏里州圣路易斯西格玛-奥德里奇(Sigma-Aldrich))。允许所得溶液经40min时间逐渐升温至室温,然后将其倒入冷饱和碳酸氢钠水溶液(50mL)中并再搅拌10min。将混合物用EtOAc(2×30mL)萃取且将合并的有机萃取物通过经Chem Elut萃取筒(加利福尼亚州圣克拉拉安捷伦科技有限公司(Agilent Technology))洗脱进行干燥并浓缩。将残余物通过硅胶色谱(洗脱液:30%-80%EtOAc/庚烷)纯化,以提供(S)-叔丁基4-(1-(2-(叔丁基)苯基)-6,7-二氯-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。1H NMR(400MHz,DMSO-d6)δppm 8.33-8.48(m,1H),7.61(d,J=7.9Hz,1H),7.36-7.42(m,1H),7.29(td,J=7.5,1.2Hz,1H),7.00(dd,J=7.7,1.0Hz,1H),4.68-4.89(m,1H),3.88-4.25(m,2H),3.77-3.86(m,1H),3.52-3.71(m,1H),3.09-3.26(m,1H),2.84-3.07(m,1H),1.44(s,9H),1.24(s,3H),1.13(d,J=2.3Hz,9H)。m/z(ESI,+ve离子):546.2(M+H)+。
步骤4:(3S)-叔丁基4-(1-(2-(叔丁基)苯基)-6-氯-7-(2-氟-6-羟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。用氩气使(S)-叔丁基4-(1-(2-(叔丁基)苯基)-6,7-二氯-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯(1.00g,1.83mmol)、乙酸钾(905mg,9.22mmol)、(2-氟-6-羟苯基)硼酸(347mg,2.22mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-blocks))及[1,1’-双(二苯基膦基)二茂铁]-二氯钯(II)与二氯甲烷的络合物(137mg,0.19mmol)于1,4-二噁烷(20mL)中的混合物脱气5min。添加一滴水并将所得混合物加热至90℃,持续1.5h。允许反应冷却至室温,且然后使其在水(40mL)与EtOAc(2x40mL)之间分配。将合并的有机提取物用水(40mL)洗涤,通过经Chem Elut萃取筒(加利福尼亚州圣克拉拉安捷伦科技有限公司(AgilentTechnology))洗脱进行干燥并浓缩。将残余物通过硅胶色谱(洗脱液:40%-100%EtOAc/庚烷)纯化,以提供(3S)-叔丁基4-(1-(2-(叔丁基)苯基)-6-氯-7-(2-氟-6-羟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。1H NMR(400MHz,DMSO-d6)δppm10.03-10.09(m,1H),8.31-8.39(m,1H),7.53(d,J=8.1Hz,1H),7.25-7.32(m,1H),7.18-7.24(m,2H),6.94(br d,J=6.6Hz,1H),6.61-6.73(m,2H),4.80(br d,J=1.2Hz,1H),4.09-4.25(m,1H),3.92-4.01(m,1H),3.84(br d,J=12.9Hz,1H),3.63(br d,J=9.1Hz,1H),2.99-3.26(m,2H),1.45(s,9H),1.29-1.37(m,3H),1.11(s,9H)。19F NMR(376MHz,DMSO-d6)δppm-115.35--115.44(m,1F)。m/z(ESI,+ve离子):622.2(M+H)+。
步骤5:6-氯-7-(2-氟-6-羟苯基)-1-(2-(2-甲基-2-丙烷基)苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。将三氟乙酸(5.0mL,64.9mmol)添加至(3S)-叔丁基4-(1-(2-(叔丁基)苯基)-6-氯-7-(2-氟-6-羟苯基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯(984mg,1.58mmol)于DCM(10mL)中的溶液中。将所得混合物在室温下搅拌30min且然后浓缩。将残余物溶解于DCM(10mL)中,冷却至0℃,并用DIPEA(1.38mL,7.91mmol),随后丙烯酰氯溶液(0.258M于DCM中,4.90mL,1.27mmol)处理。将反应混合物升温至室温并搅拌30min,然后将其再冷却至0℃并用丙烯酰氯溶液(0.258M于DCM中,1.0mL,0.26mmol)处理。升温至室温并再搅拌5min后,将反应浓缩。将残余物通过硅胶色谱(洗脱液:40%-100%3:1EtOAc-EtOH/庚烷)纯化,以提供6-氯-7-(2-氟-6-羟苯基)-1-(2-(2-甲基-2-丙烷基)苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。1H NMR(400MHz,DMSO-d6)δppm 10.06(br d,J=5.4Hz,1H),8.38(br d,J=12.2Hz,1H),7.54(d,J=7.7Hz,1H),7.17-7.32(m,3H),6.91-7.02(m,1H),6.83(br dd,J=10.2,16.4Hz,1H),6.61-6.74(m,2H),6.20(br d,J=16.6Hz,1H),5.72-5.80(m,1H),4.85(br d,J=2.1Hz,1H),4.07-4.51(m,3H),3.59-3.81(m,3H),1.24-1.37(m,3H),1.06-1.13(m,9H)。19F NMR(376MHz,DMSO-d6)δppm-115.42(m,1F)。m/z(ESI,+ve离子):576.2(M+H)+。
实例50
6-氯-7-(2-氟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)-1-(2-(2-丙烷基)苯基)-2(1H)-喋啶酮
步骤1:3-氨基-6-氯-5-(2-氟苯基)吡嗪-2-甲酸甲酯。用氮气使3-氨基-5,6-二氯吡嗪-2-甲酸甲酯(10.0g,45mmol,伊利诺伊州阿灵顿海茨市方舟制药公司)、(2-氟苯基)硼酸(6.93g,49.5mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-blocks))及碳酸钾(13.1g,95mmol)于10:1的DME/水混合物(220mL)中的混合物脱气5min且然后添加四(三苯基膦)钯(0)(1.04g,0.90mmol)。将反应混合物在90℃下搅拌16h,然后允许其冷却至室温并在EtOAc(200mL)与1N HCl(200mL)之间分配。将有机层经无水硫酸钠干燥并浓缩,以提供3-氨基-6-氯-5-(2-氟苯基)吡嗪-2-甲酸甲酯。m/z(ESI,+ve):282.1(M+H)+。
步骤2:3,6-二氯-5-(2-氟苯基)吡嗪-2-甲酸甲酯。向3-氨基-6-氯-5-(2-氟苯基)吡嗪-2-甲酸甲酯(22.0g,78mmol)于t-BuOH(220mL)中的溶液中添加亚硝酸异戊酯(15.8mL,117mmol)及氯化铜(12.6g,94mmol)。将所得混合物在60℃下搅拌16h且然后使其在水(1L)与EtOAc(2L)之间分配。将有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-5%EtOAc/己烷)纯化,以提供3,6-二氯-5-(2-氟苯基)吡嗪-2-甲酸甲酯。m/z(ESI,+ve离子):300.9(M+H)+。
步骤3:3,6-二氯-5-(2-氟苯基)吡嗪-2-甲酰胺。向3,6-二氯-5-(2-氟苯基)吡嗪-2-甲酸甲酯(13.5g,44.8mmol)于THF(150mL)中的溶液中添加氢氧化铵溶液(30%,150mL,44.8mmol)。将所得混合物在50℃下加热4h,然后允许其冷却至室温并在水与EtOAc(500mL)之间分配。将有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-30%EtOAc/己烷)纯化,以提供3,6-二氯-5-(2-氟苯基)吡嗪-2-甲酰胺。1H NMR(400MHz,DMSO-d6)δppm 8.32(br s,1H),8.16(br s,1H),7.64-7.77(m,2H),7.41-7.47(m,2H)。m/z(ESI,+ve):286.0(M+H)+。
步骤4:3,6-二氯-5-(2-氟苯基)-N-((2-异丙基苯基)胺甲酰基)吡嗪-2-甲酰胺。在80℃下,将3,6-二氯-5-(2-氟苯基)吡嗪-2-甲酰胺(704mg,2.46mmol)及草酰氯溶液(2M于DCM中,1.35mL,2.71mmol)于DCE(15mL)中的混合物加热1h。将反应冷却至室温并添加2-异丙基苯胺(0.35mL,2.46mmol)。将所得混合物在室温下搅拌3h且然后浓缩。将残余物用EtOAc处理,用音波处理并过滤。收集过滤的固体,以提供3,6-二氯-5-(2-氟苯基)-N-((2-异丙基苯基)胺甲酰基)吡嗪-2-甲酰胺。m/z(ESI,+ve):446.8(M+H)+。
步骤5:6-氯-7-(2-氟苯基)-1-(2-异丙基苯基)喋啶-2,4(1H,3H)-二酮(中间体Y)。将KHMDS(THF中的1M溶液,0.93mL,0.93mmol)添加至3,6-二氯-5-(2-氟苯基)-N-((2-异丙基苯基)胺甲酰基)吡嗪-2-甲酰胺(208mg,0.46mmol)于THF(4mL)中的冰冷混合物中。允许所得混合物升温至室温且搅拌2h。使反应在EtOAc(10mL)与饱和氯化铵水溶液(2×5mL)之间分配。将有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-50%EtOAc/庚烷)纯化,以提供6-氯-7-(2-氟苯基)-1-(2-异丙基苯基)喋啶-2,4(1H,3H)-二酮。1HNMR(400MHz,氯仿-d)δppm 8.50(br s,1H),7.40–7.47(m,3H),7.31(dt,J=8.3,4.2Hz,1H),7.17-7.24(m,2H),7.09-7.16(m,2H),2.69(quin,J=6.8Hz,1H),1.22(d,J=6.8Hz,3H),1.06(d,J=6.8Hz,3H)。m/z(ESI,+ve):410.9(M+H)+。
步骤6:6-氯-7-(2-氟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)-1-(2-(2-丙烷基)苯基)-2(1H)-喋啶酮。向6-氯-7-(2-氟苯基)-1-(2-异丙基苯基)喋啶-2,4(1H,3H)-二酮(373mg,0.91mmol)于乙腈(5mL)中的溶液中添加DIPEA(0.269mL,1.54mmol),随后添加氧氯化磷(0.127mL,1.36mmol)。将所得溶液在80℃下搅拌30min且然后浓缩。将残余物溶解于DMF(5mL)中,冷却至0℃,并用DIPEA(0.54mL,3.08mmol),随后(S)-1-(3-甲基哌嗪-1-基)丙-2-烯-1-酮2,2,2-三氟乙酸盐(582mg,1.00mmol)于DMF(0.5mL)中的溶液处理。将所得溶液在0℃下搅拌30min且然后允许其逐渐升温至室温。使反应在EtOAc(10mL)与水(2×10mL)之间分配。将有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-3%MeOH/DCM)纯化,以提供6-氯-7-(2-氟苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)-1-(2-(2-丙烷基)苯基)-2(1H)-喋啶酮。1H NMR(400MHz,DMSO-d6)δppm 7.51-7.61(m,1H),7.44(dt,J=7.9,1.9Hz,1H),7.33-7.38(m,2H),7.27-7.32(m,2H),7.24(br t,J=7.7Hz,1H),7.13(br dt,J=7.9,1.7Hz,1H),6.89(br dd,J=16.4,10.4Hz,1H),6.22(brd,J=16.4Hz,1H),5.76(dd,J=10.2,1.2Hz,1H),4.68-5.54(m,1H),4.21-4.44(m,6H),2.69-2.83(m,1H),1.21-1.31(m,3H),1.10(t,J=6.3Hz,3H),0.99(dd,J=6.7,3.4Hz,3H)。m/z(ESI,+ve):546.8(M+H)+。
实例51
7-(2-氟苯基)-6-甲基-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)-1-(2-(2-丙烷基)苯基)-2(1H)-喋啶酮
步骤1:7-(2-氟苯基)-1-(2-异丙基苯基)-6-甲基喋啶-2,4(1H,3H)-二酮。向玻璃微波反应容器中装入6-氯-7-(2-氟苯基)-1-(2-异丙基苯基)喋啶-2,4(1H,3H)-二酮(中间体Y,930mg,2.27mmol)、[1,1’-双(二苯基膦基)二茂铁]-二氯钯(II)与二氯甲烷的络合物(166mg,0.28mmol)、三甲基硼氧六环(0.64mL,4.54mmol,美国密苏里州圣路易斯西格玛-奥德里奇(Sigma-Aldrich))及碳酸钾(0.63g,4.54mmol)于10:1二噁烷/水(11mL)中的混合物。用氮气使反应脱气5min并在Emrys Optimizer微波反应器(瑞典乌普萨拉拜泰齐公司(Biotage))中,在100℃下加热1.5h。允许反应冷却至室温,且然后使其在水(10mL)与EtOAc(10mL)之间分配。将有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-40%EtOAc/庚烷)纯化,以提供7-(2-氟苯基)-1-(2-异丙基苯基)-6-甲基喋啶-2,4(1H,3H)-二酮。1H NMR(400MHz,氯仿-d)δppm 8.53(br s,1H),7.38-7.48(m,3H),7.30(dt,J=8.3,4.2Hz,1H),7.08-7.20(m,4H),2.71(quin,J=6.8Hz,1H),2.61(d,J=2.3Hz,3H),1.21(d,J=6.8Hz,3H),1.05(d,J=6.8Hz,3H)。m/z(ESI,+ve):391.0(M+H)+。
步骤2:7-(2-氟苯基)-6-甲基-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)-1-(2-(2-丙烷基)苯基)-2(1H)-喋啶酮。向7-(2-氟苯基)-1-(2-异丙基苯基)-6-甲基喋啶-2,4(1H,3H)-二酮(330mg,0.85mmol)于乙腈(5mL)中的溶液中添加DIPEA(0.252mL,1.44mmol),随后添加氧氯化磷(0.119mL,1.27mmol)。将所得溶液在60℃下搅拌1h且然后浓缩。将残余物溶解于DMF(5mL)中,冷却至0℃并经由导管用DIPEA(0.51mL,2.88mmol),随后(S)-1-(3-甲基哌嗪-1-基)丙-2-烯-1-酮2,2,2-三氟乙酸盐(544mg,0.93mmol)于DMF(0.5mL)中的溶液处理。将所得混合物在0℃下搅拌30min且然后允许其逐渐升温至室温。使反应在EtOAc(10mL)与水(2×10mL)之间分配。将有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-3%MeOH/DCM)纯化,以提供7-(2-氟苯基)-6-甲基-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)-1-(2-(2-丙烷基)苯基)-2(1H)-喋啶酮。1H NMR(400MHz,DMSO-d6)δppm7.48-7.57(m,1H),7.42(dt,J=7.7,1.9Hz,1H),7.32-7.37(m,2H),7.20-7.31(m,3H),7.10(br dt,J=7.1,1.0Hz,1H),6.80-6.95(m,1H),6.20(br d,J=16.6Hz,1H),5.75(dd,J=10.3,2.0Hz,1H),4.66-5.57(m,1H),4.13-4.46(m,3H),3.44-3.73(m,3H),2.56-2.70(m,1H),2.42(s,3H),1.25(br s,3H),1.09(t,J=6.1Hz,3H),0.97(dd,J=6.6,1.7Hz,3H)。m/z(ESI,+ve):527.0(M+H)+。
实例52
7-(2-氟-6-羟苯基)-6-甲基-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)-1-(2-(2-丙烷基)苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮
步骤1:2,6-二氯-5-甲基烟酸。在90℃下,将2,6-二氯-5-甲基烟碱酸乙酯(6.49g,27.7mmol,美国加利福尼亚州森尼维耳市药石公司(Pharmablock Inc..)A)于TFA(30mL)及5N HCl(24mL)中的混合物加热16h。允许反应冷却至室温且然后部分浓缩。添加水并过滤混合物。收集过滤的固体并真空干燥,以提供2,6-二氯-5-甲基烟酸。m/z(ESI,+ve):205.9(M+H)+。
步骤2:2,6-二氯-5-甲基烟酰胺。向2,6-二氯-5-甲基烟酸(4.55g,22.1mmol)于DCM(30mL)中的冰冷的混合物中添加草酰氯(DCM中的2M溶液,16.6mL,33.1mmol),随后添加数滴DMF。允许反应混合物逐渐升温至室温并搅拌1h且然后浓缩。将残余物悬浮于甲苯(15mL)中,冷却至0℃,并用氢氧化铵(30%,9.1mL,62mmol)处理。将反应在室温下搅拌30min且然后过滤。将过滤的固体用水洗涤并真空干燥,以提供2,6-二氯-5-甲基烟酰胺。m/z(ESI,+ve):204.9(M+H)+。
步骤3:2,6-二氯-N-((2-异丙基苯基)胺甲酰基)-5-甲基烟酰胺。在65℃下,将2,6-二氯-5-甲基烟酰胺(513mg,2.50mmol)及草酰氯(DCM中的2M溶液,1.38mL,2.63mmol)于THF(10mL)中的混合物加热1h。将反应冷却至室温并添加2-异丙基苯胺(0.36mL,2.63mmol)。将所得混合物在室温下搅拌1h且然后浓缩。使残余物在EtOAc(50mL)与饱和碳酸氢钠水溶液(15mL)之间分配。将有机层经无水硫酸钠干燥并浓缩。将残余物悬浮于5:1庚烷/EtOAc中并过滤。收集过滤的固体,以提供2,6-二氯-N-((2-异丙基苯基)胺甲酰基)-5-甲基烟酰胺。m/z(ESI,+ve):365.8(M+H)+。
步骤4:7-氯-1-(2-异丙基苯基)-6-甲基吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。经由注射器将KHMDS(THF中的1M溶液,4.54mL,4.54mmol)添加至2,6-二氯-N-((2-异丙基苯基)胺甲酰基)-5-甲基烟酰胺(831mg,2.27mmol)于THF(10mL)中的冰冷混合物中。允许所得混合物升温至室温且搅拌2h。使反应在EtOAc(20mL)与饱和氯化铵水溶液(2×10mL)之间分配。将有机层经无水硫酸钠干燥并浓缩。将残余物悬浮于5:1庚烷/EtOAc中并过滤。收集过滤的固体,以提供7-氯-1-(2-异丙基苯基)-6-甲基吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。1HNMR(400MHz,DMSO-d6)δppm 8.36(s,1H),7.49(dd,J=8.5,1.4Hz,1H),7.44(td,J=6.8,1.2Hz,1H),7.26-7.33(m,1H),7.23(dd,J=7.9,1.7Hz,1H),2.68(quin,J=6.8Hz,1H),2.34(s,3H),1.08(d,J=6.8Hz,3H),1.02(d,J=6.6Hz,3H)。m/z(ESI,+ve):329.9(M+H)+。
步骤5:(S)-4-(7-氯-1-(2-异丙基苯基)-6-甲基-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸叔丁酯。向7-氯-1-(2-异丙基苯基)-6-甲基吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(444mg,1.35mmol)于乙腈(5mL)中的溶液中添加DIPEA(0.70mL,4.04mmol),随后添加氧氯化磷(0.125mL,1.35mmol)。将所得溶液在80℃下搅拌2h且然后浓缩。将残余物溶解于乙腈(5mL)中,冷却至0℃,并用DIPEA(0.70mL,4.04mmol),随后(S)-4-N-Boc-2-甲基哌嗪(297mg,1.48mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-Blocks,Inc.))处理。将所得混合物在0℃下搅拌30min且然后允许其逐渐升温至室温。使反应在EtOAc(10mL)与水(2×10mL)之间分配。将有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-30%3:1 EtOAc-EtOH/庚烷)纯化,以提供(S)-4-(7-氯-1-(2-异丙基苯基)-6-甲基-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸叔丁酯。1H NMR(400MHz,DMSO-d6)δppm 8.16(d,J=16.2Hz,1H),7.47(dd,J=6.8,1.2Hz,1H),7.41(br t,J=7.3Hz,1H),7.28(dt,J=7.7,1.2Hz,1H),7.09(dt,J=7.8,1.6Hz,1H),4.70-4.90(m,1H),3.89-4.20(m,2H),3.97-4.09(m,2H),3.76-3.88(m,1H),3.53-3.72(m,1H),2.44(td,J=6.8,4.9Hz,1H),2.35(d,J=0.8Hz,3H),1.45(s,9H),1.25(br s,3H),1.06(d,J=6.8,3H),1.02(dd,J=6.8,1.7Hz,3H)。m/z(ESI,+ve):511.9(M+H)+。
步骤6:(3S)-4-(7-(2-氟-6-羟苯基)-1-(2-异丙基苯基)-6-甲基-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸叔丁酯。在90℃下,将(S)-4-(7-氯-1-(2-异丙基苯基)-6-甲基-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸叔丁酯(458mg,0.89mmol)、乙酸钾(439mg,4.47mmol)、(2-氟-6-羟苯基)硼酸(418mg,2.68mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-blocks))及[1,1’-双(二苯基膦基)二茂铁]-二氯钯(II)与二氯甲烷的络合物(65mg,0.09mmol)于1,4-二噁烷(7mL)及水(0.05mL)中的混合物加热2h。允许反应冷却至室温,且然后使其在饱和碳酸氢钠水溶液(15mL)与EtOAc(20mL)之间分配。将有机层用盐水(10mL)洗涤,经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-30%3:1 EtOAc-EtOH/庚烷)纯化,以提供(3S)-4-(7-(2-氟-6-羟苯基)-1-(2-异丙基苯基)-6-甲基-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸叔丁酯。m/z(ESI,+ve):587.9(M+H)+。
步骤7:7-(2-氟-6-羟苯基)-6-甲基-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)-1-(2-(2-丙烷基)苯基)吡啶并[2,3-d]嘧啶-2(1H)-酮。将三氟乙酸(1.7mL,14.7mmol)添加至(3S)-4-(7-(2-氟-6-羟苯基)-1-(2-异丙基苯基)-6-甲基-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸叔丁酯(288mg,0.49mmol)于DCM(5mL)中的溶液中。将所得混合物在室温下搅拌30min且然后浓缩。将残余物溶解于DCM(3mL)中,冷却至0℃,并用DIPEA(0.34mL,1.96mmol),随后丙烯酰氯(0.042mL,0.51mmol)于DCM(0.5mL)中的溶液处理。将反应混合物升温至室温并搅拌30min,然后用饱和碳酸氢钠水溶液(5mL)淬灭并用EtOAc(10mL)萃取。将有机层用盐水(5mL)洗涤,经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-50%3:1 EtOAc-EtOH/庚烷)纯化,以提供7-(2-氟-6-羟苯基)-6-甲基-1-(2-甲基-6-(2-丙烷基)苯基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。1H NMR(400MHz,DMSO-d6)δppm 9.94(s,1H),8.10-8.19(m,1H),7.38(dd,J=7.5,1.0Hz,1H),7.31(td,J=7.1,0.8Hz,1H),7.16-7.24(m,2H),7.06(br dt,J=7.9,1.9Hz,1H),6.75-6.97(m,1H),6.71(d,J=8.1Hz,1H),6.64(t,J=8.8Hz,1H),6.21(br dd,J=16.9,5.7Hz,1H),5.76(dd,J=10.2,2.5Hz,1H),4.76-4.98(m,1H),4.10-4.51(m,2H),3.24-3.81(m,4H),2.43-2.49(m,1H),2.12(d,J=2.9Hz,3H),1.22-1.33(m,3H),1.05(d,J=6.8Hz,3H),0.96(d,J=6.8Hz,3H)。m/z(ESI,+ve):541.8(M+H)+。
实例53
6-氯-7-(2-氟苯基)-1-(4-甲基-1-(2-丙烷基)-1H-吡唑-5-基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮
步骤1:2,5,6-三氯-N-((1-异丙基-4-甲基-1H-吡唑-5-基)胺甲酰基)烟酰胺。在室温下,向2,5,6-三氯烟酰胺(中间体P,2.43g,10.8mmol)于THF(21.5mL)中的混合物中添加草酰氯溶液(2M于DCM中,5.70mL,11.4mmol)。将所得混合物在65℃下加热3h,然后停止加热并允许反应冷却至0℃。经由导管添加1-异丙基-4-甲基-1H-吡唑-5-胺(1.50g,10.8mmol,美国加利福尼亚州圣地亚哥ChemBridge公司)于THF(15mL)中的溶液。将反应混合物在0℃下搅拌30min且然后升温至室温并再搅拌16h。将反应混合物过滤,且收集过滤的固体并用乙腈(20mL)洗涤,以提供2,5,6-三氯-N-((1-异丙基-4-甲基-1H-吡唑-5-基)胺甲酰基)烟酰胺。1H NMR(400MHz,DMSO-d6)δppm 11.39(br s,1H),9.51(br s,1H),8.62(s,1H),7.29(s,1H),4.33-4.44(m,1H),1.87(s,3H),1.33(d,J=6.6Hz,6H)。m/z(ESI,+ve离子):389.9(M+H)+。
步骤2:6,7-二氯-1-(1-异丙基-4-甲基-1H-吡唑-5-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。经由注射器将KHMDS(THF中的1M溶液,18.0mL,18.0mmol)缓慢添加至2,5,6-三氯-N-((1-异丙基-4-甲基-1H-吡唑-5-基)胺甲酰基)烟酰胺(3.52g,9.0mmol)于THF(30mL)中的冰冷混合物中。10min后,允许所得反应混合物升温至室温并搅拌18h。将所得浆液用饱和氯化铵水溶液(50mL)及盐水(50mL)淬灭,且然后用EtOAc(2x50mL)萃取。将合并的有机层用盐水(50mL)洗涤,经硫酸钠干燥并浓缩,以提供6,7-二氯-1-(1-异丙基-4-甲基-1H-吡唑-5-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮。该材料不经进一步纯化即用于下一步骤中。1H NMR(400MHz,DMSO-d6)δppm 12.22(br s,1H),8.55(s,1H),7.45(s,1H),4.22-4.34(m,1H),1.78(s,3H),1.25(t,J=6.6Hz,6H)。m/z(ESI,+ve离子):353.9(M+H)+。
步骤3:4,6,7-三氯-1-(1-异丙基-4-甲基-1H-吡唑-5-基)吡啶并[2,3-d]嘧啶-2(1H)-酮。向6,7-二氯-1-(1-异丙基-4-甲基-1H-吡唑-5-基)吡啶并[2,3-d]嘧啶-2,4(1H,3H)-二酮(3.19g,9.0mmol)及DIPEA(4.71mL,27.0mmol)于乙腈(60mL)中的溶液中添加氧氯化磷(1.68mL,18.0mmol)。将所得混合物在80℃下加热30min,且然后冷却至室温并浓缩,以提供4,6,7-三氯-1-(1-异丙基-4-甲基-1H-吡唑-5-基)吡啶并[2,3-d]嘧啶-2(1H)-酮。该材料不经进一步纯化即用于下一步骤中。
步骤4:(S)-叔丁基4-(6,7-二氯-1-(1-异丙基-4-甲基-1H-吡唑-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。向4,6,7-三氯-1-(1-异丙基-4-甲基-1H-吡唑-5-基)吡啶并[2,3-d]嘧啶-2(1H)-酮(3.36g,9.0mmol)于THF(45mL)中的溶液中添加DIPEA(4.71mL,27.1mmol),随后添加(S)-4-N-Boc-2-甲基哌嗪(2.71g,13.6mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-Blocks,Inc.))。将所得混合物在室温下搅拌1h,然后用冰冷的饱和碳酸氢钠水溶液(100mL)淬灭并用EtOAc(100mL,2×50mL)萃取。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-50%3:1 EtOAc-EtOH/庚烷)纯化,以提供(S)-叔丁基4-(6,7-二氯-1-(1-异丙基-4-甲基-1H-吡唑-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸酯。1HNMR(400MHz,DMSO-d6)δppm 8.43(d,J=19.1Hz,1H),7.42(s,1H),4.77-4.98(m,1H),4.15(br dd,J=26.7,13.5Hz,1H),3.61-4.07(m,4H),2.94-3.28(m,2H),1.72(d,J=5.2Hz,3H),1.44(s,9H),1.32(br dd,J=13.0,6.7Hz,3H),1.21-1.28(m,6H)。m/z(ESI,+ve离子):536.0(M+H)+。
步骤5:(S)-4-(6-氯-7-(2-氟苯基)-1-(1-异丙基-4-甲基-1H-吡唑-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸叔丁酯。在80℃下,将(S)-4-(6,7-二氯-1-(1-异丙基-4-甲基-1H-吡唑-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸叔丁酯(703mg,1.31mmol)、(2-氟苯基)硼酸(330mg,2.36mmol,美国加利福尼亚州圣地亚哥康比乐公司(Combi-blocks))、无水碳酸钠(416mg,3.93mmol)及四(三苯基膦)钯(0)(151mg,0.13mmol)于1,4-二噁烷(3.5mL)及水(0.87mL)中的混合物加热2h。将反应浓缩且将残余物通过硅胶色谱(洗脱液:0-100%EtOAc/庚烷)纯化,以提供(S)-4-(6-氯-7-(2-氟苯基)-1-(1-异丙基-4-甲基-1H-吡唑-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸叔丁酯。1H NMR(400MHz,DMSO-d6)δppm 8.41(d,J=8.9Hz,1H),7.50-7.66(m,1H),7.24-7.37(m,4H),4.92(br s,1H),4.24(br t,J=12.4Hz,1H),3.95-4.12(m,2H),3.67-3.89(m,2H),3.00-3.29(m,2H),1.70(s,3H),1.45(s,9H),1.36(t,J=6.6Hz,3H),1.14-1.28(m,6H)。19F NMR(376MHz,DMSO-d6)δppm-113.95(d,J=6.9Hz,1F)。m/z(ESI,+ve离子):596.0(M+H)+。
步骤6:6-氯-7-(2-氟苯基)-1-(4-甲基-1-(2-丙烷基)-1H-吡唑-5-基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。将三氟乙酸(7.4mL,63.6mmol)添加至(S)-4-(6-氯-7-(2-氟苯基)-1-(1-异丙基-4-甲基-1H-吡唑-5-基)-2-氧代-1,2-二氢吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-甲酸叔丁酯(532mg,0.74mmol)于DCM(7.4mL)中的溶液中。将所得混合物在室温下搅拌1h且然后浓缩。将残余物溶解于DCM(7.4mL)中,冷却至0℃,并用DIPEA(1.28mL,7.35mmol),随后丙烯酰氯(DCM中的0.2M溶液,3.67mL,0.74mmol)处理。将所得混合物在0℃下搅拌20min,然后用饱和碳酸氢钠水溶液(50mL)淬灭并用DCM(2×50mL)萃取。将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶色谱(洗脱液:0-50%EtOAc/庚烷,随后0-50%4:1DCM-MeOH/DCM)纯化,以提供6-氯-7-(2-氟苯基)-1-(4-甲基-1-(2-丙烷基)-1H-吡唑-5-基)-4-((2S)-2-甲基-4-(2-丙烯酰基)-1-哌嗪基)吡啶并[2,3-d]嘧啶-2(1H)-酮。1H NMR(400MHz,DMSO-d6)δppm 8.44(brd,J=7.5Hz,1H),7.50-7.59(m,1H),7.23-7.41(m,4H),6.77-6.93(m,1H),6.21(br d,J=16.4Hz,1H),5.71-5.81(m,1H),4.96(br s,1H),4.22-4.46(m,2H),3.96-4.21(m,2H),3.37-3.89(m,2H),3.00-3.28(m,1H),1.71(d,J=2.5Hz,3H),1.34(t,J=6.8Hz,3H),1.12-1.29(m,6H)。19F NMR(376MHz,DMSO-d6)δppm-113.96(d,J=9.5Hz,1F)。m/z(ESI,+ve离子):550.2(M+H)+。
表12:包括立体异构体的分离的化合物实例,其中有一些为阻转异构体
表12(b)包括阻转异构体的分离的化合物实例
表13:通用程序的分析数据
表14:个别实例的分析数据
表14(b):个别实例的分析数据
生物测定资料
对于表15中的化合物,采用以下测定条件:
偶联核苷酸交换测定:将含有G12C及C118A氨基酸取代及N末端His标签的纯化的GDP结合KRAS蛋白(aa 1-169)与化合物剂量反应滴定液一起在测定缓冲液(25mM HEPES pH7.4、10mM MgCl2及0.01%Triton X-100)中预孵育2小时。化合物预孵育后,将纯化的SOS蛋白(aa 564-1049)及GTP(罗氏公司(Roche)10106399001)添加至测定孔中并且再孵育一小时。为了确定对SOS介导的核苷酸交换的抑制程度,将纯化的GST标记的cRAF(aa 1-149)、镍螯合剂AlphaLISA受体珠粒(PerkinElmer AL 108R)及AlphaScreen谷胱甘肽供体珠粒(PerkinElmer 6765302)添加至测定孔中并孵育10分钟。然后在PerkinElmer EnVision多标记读取器上,使用技术读取测定盘,并使用4参数逻辑模型分析数据以计算IC50值。
磷酸ERK1/2 MSD测定:在含有10%胎牛血清(赛默飞世尔科技公司(ThermoFisherScientific)16000044)及1x青霉素-链霉素-谷酰氨酸(赛默飞世尔科技公司(ThermoFisher Scientific)10378016)的RPMI 1640培养基(赛默飞世尔科技公司(ThermoFisher Scientific)11875093)中培养MIA PaCa-2(CRL-1420TM)及A549(CCL-185TM)细胞。在化合物处理前十六小时,将MIA PaCa-2或A549细胞以25,000个细胞/孔的密度接种于96孔细胞培养盘中并在37℃、5%CO2下孵育。在生长培养基中稀释化合物剂量反应滴定液,将其添加至细胞培养盘的适当孔中,且然后在37℃、5%CO2下孵育4小时。在化合物处理后,用10ng/mLEGF(罗氏公司(Roche)11376454001)刺激细胞10min,用不含Ca2+或Mg2+的冰冷杜贝卡式磷酸盐缓冲生理食盐水(赛默飞世尔科技公司(ThermoFisher Scientific)14190144)洗涤,且然后将其溶解于含有蛋白酶抑制剂(罗氏公司(Roche)4693132001)及磷酸酶抑制剂(罗氏公司(Roche)4906837001)的RIPA缓冲液(50mM Tris-HCl pH 7.5、1%Igepal、0.5%脱氧胆酸钠、150mM NaCl及0.5%十二烷基硫酸钠)中。将细胞裂解物冷冻储存于-80℃下过夜。根据制造商的方案,使用磷酸ERK1/2全细胞溶解产物试剂盒(Meso Scale Discovery K151DWD)测定化合物处理的溶解产物中ERK1/2的磷酸化情况。在Meso Scale Discovery Sector Imager 6000上读取测定盘,并使用4参数逻辑模型分析数据以计算IC50值。
表15:化合物的生物化学及细胞活性
对于表16中的化合物,采用以下测定条件:
偶联核苷酸交换测定:将含有G12C及C118A氨基酸取代及N末端His标签的纯化的GDP结合KRAS蛋白(aa 1-169)与化合物剂量反应滴定液一起在测定缓冲液(25mM HEPES pH7.4、10mM MgCl2及0.01%Triton X-100)中预孵育5min。化合物预孵育后,将纯化的SOS蛋白(aa 564-1049)及GTP(罗氏公司(Roche)10106399001)添加至测定孔中并且再孵育30min。为了确定对SOS介导的核苷酸交换的抑制程度,将纯化的GST标记的cRAF(aa 1-149)、镍螯合剂AlphaLISA受体珠粒(PerkinElmer AL108R)及AlphaScreen谷胱甘肽供体珠粒(PerkinElmer 6765302)添加至测定孔中并孵育5分钟。然后在PerkinElmer EnVision多标记读取器上,使用技术读取测定盘,并使用4参数逻辑模型分析数据以计算IC50值。
磷酸ERK1/2 MSD测定:在含有10%胎牛血清(赛默飞世尔科技公司(ThermoFisherScientific)16000044)及1x青霉素-链霉素-谷酰氨酸(赛默飞世尔科技公司(ThermoFisher Scientific)10378016)的RPMI 1640培养基(赛默飞世尔科技公司(ThermoFisher Scientific)11875093)中培养MIA PaCa-2(CRL-1420TM)及A549(CCL-185TM)细胞。在化合物处理前十六小时,将MIA PaCa-2或A549细胞以25,000个细胞/孔的密度接种于96孔细胞培养盘中并在37℃、5%CO2下孵育。在生长培养基中稀释化合物剂量反应滴定液,将其添加至细胞培养盘的适当孔中,且然后在37℃、5%CO2下孵育2小时。在化合物处理后,用10ng/mL EGF(罗氏公司(Roche)11376454001)刺激细胞10min,用不含Ca2+或Mg2+的冰冷杜贝卡式磷酸盐缓冲生理食盐水(赛默飞世尔科技公司(ThermoFisher Scientific)14190144)洗涤,且然后将其溶解于含有蛋白酶抑制剂(罗氏公司(Roche)4693132001)及磷酸酶抑制剂(罗氏公司(Roche)4906837001)的RIPA缓冲液(50mM Tris-HCl pH 7.5、1%Igepal、0.5%脱氧胆酸钠、150mM NaCl及0.5%十二烷基硫酸钠)中。根据制造商的方案,使用磷酸ERK1/2全细胞溶解产物试剂盒(Meso ScaleDiscovery K151DWD)测定化合物处理的溶解产物中ERK1/2的磷酸化情况。在Meso ScaleDiscovery Sector Imager 6000上读取测定盘,并使用4参数逻辑模型分析数据以计算IC50值。
表16:化合物的生物化学及细胞活性
(-)=未测试
本发明结合优选实施例进行描述。然而,应了解,本发明并不限于所披露的实施例。应了解,根据本文本发明实施例的描述,本领域技术人员可以做出多种修改。此类修改涵盖于下文的权利要求书中。
Claims (12)
7.一种药物组合物,其包含如权利要求1至6中任一项所述的化合物及药学上可接受的赋形剂。
8.如权利要求1至6中任一项所述的化合物在制备药物中的用途,所述药物用于治疗特征在于KRAS G12C突变的癌症。
9.如权利要求8所述的用途,其中该癌症是非小细胞肺癌、小肠癌、阑尾癌、结肠直肠癌、子宫内膜癌、胰腺癌、皮肤癌、胃癌、鼻腔癌或胆管癌。
10.如权利要求9所述的用途,其中该癌症是非小细胞肺癌。
11.如权利要求9所述的用途,其中该癌症是结肠直肠癌。
12.如权利要求9所述的用途,其中该癌症是胰腺癌。
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Families Citing this family (157)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RS62456B1 (sr) * | 2016-12-22 | 2021-11-30 | Amgen Inc | Derivati benzizotiazola, izotiazolo[3,4-b]piridina, hinazolina, ftalazina, pirido[2,3-d]piridazina i pirido[2,3-d]pirimidina kao kras g12c inhibitori za tretman raka pluća, pankreasa ili debelog creva |
JOP20190272A1 (ar) | 2017-05-22 | 2019-11-21 | Amgen Inc | مثبطات kras g12c وطرق لاستخدامها |
SG11202001499WA (en) | 2017-09-08 | 2020-03-30 | Amgen Inc | Inhibitors of kras g12c and methods of using the same |
CN112218859A (zh) | 2018-04-04 | 2021-01-12 | 阿尔维纳斯运营股份有限公司 | 蛋白水解调节剂及相关使用方法 |
EP3788038B1 (en) * | 2018-05-04 | 2023-10-11 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
US11045484B2 (en) | 2018-05-04 | 2021-06-29 | Amgen Inc. | KRAS G12C inhibitors and methods of using the same |
TW202012415A (zh) | 2018-05-08 | 2020-04-01 | 瑞典商阿斯特捷利康公司 | 化學化合物 |
WO2019217691A1 (en) * | 2018-05-10 | 2019-11-14 | Amgen Inc. | Kras g12c inhibitors for the treatment of cancer |
US11096939B2 (en) | 2018-06-01 | 2021-08-24 | Amgen Inc. | KRAS G12C inhibitors and methods of using the same |
EP3802537A1 (en) * | 2018-06-11 | 2021-04-14 | Amgen Inc. | Kras g12c inhibitors for treating cancer |
MX2020012261A (es) * | 2018-06-12 | 2021-03-31 | Amgen Inc | Inhibidores de kras g12c que comprenden un anillo de piperazina y uso de estos en el tratamiento del cancer. |
LT3814348T (lt) | 2018-06-27 | 2023-10-10 | Bristol-Myers Squibb Company | Pakeistieji naftiridinono junginiai, naudotini kaip t ląstelių aktyvatoriai |
EA202190137A1 (ru) | 2018-06-27 | 2021-05-17 | Бристол-Маерс Сквибб Компани | Нафтиридиноновые соединения для применения в качестве активаторов t-клеток |
JP2020090482A (ja) * | 2018-11-16 | 2020-06-11 | アムジエン・インコーポレーテツド | Kras g12c阻害剤化合物の重要な中間体の改良合成法 |
JP7377679B2 (ja) * | 2018-11-19 | 2023-11-10 | アムジエン・インコーポレーテツド | がん治療のためのkrasg12c阻害剤及び1種以上の薬学的に活性な追加の薬剤を含む併用療法 |
CA3117222A1 (en) | 2018-11-19 | 2020-05-28 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
MA54452A (fr) | 2018-12-10 | 2022-03-16 | Ideaya Biosciences Inc | Dérivés de 2-oxoquinazoline utilisés en tant qu'inhibiteurs de la méthionine adénosyltransférase 2a |
JP2022518591A (ja) * | 2019-01-29 | 2022-03-15 | 博瑞生物医薬(蘇州)股▲分▼有限公司 | 複素環式化合物であるベンゾピリドンおよびその使用 |
EP3924053A1 (en) | 2019-02-12 | 2021-12-22 | Novartis AG | Pharmaceutical combination comprising tno155 and a krasg12c inhibitor |
WO2020219603A1 (en) * | 2019-04-22 | 2020-10-29 | University Of Pittsburgh-Of The Commonwealth System Of Higher Education | Use of tg02 for treating gliomas in pediatric subjects |
EP3964516A4 (en) * | 2019-04-28 | 2023-01-11 | Genfleet Therapeutics (Shanghai) Inc. | OXAAZACHUINAZOLINE-7( 8H)-KETONE COMPOUND, PROCESS FOR ITS PRODUCTION AND ITS PHARMACEUTICAL APPLICATION |
EP3738593A1 (en) | 2019-05-14 | 2020-11-18 | Amgen, Inc | Dosing of kras inhibitor for treatment of cancers |
AU2020279287A1 (en) * | 2019-05-21 | 2021-12-16 | InventisBio Co., Ltd. | Heterocyclic compounds, preparation methods and uses thereof |
AU2020277398A1 (en) | 2019-05-21 | 2021-12-09 | Amgen Inc. | Solid state forms |
EP3972973A1 (en) | 2019-05-21 | 2022-03-30 | Amgen Inc. | Solid state forms |
EP3978490A4 (en) * | 2019-05-29 | 2023-04-19 | Shanghai Hansoh Biomedical Co., Ltd. | HETEROCYCLIC DERIVATIVE REGULATOR CONTAINING NITROGEN, METHOD FOR PREPARATION AND APPLICATION |
CN112552294B (zh) * | 2019-09-10 | 2023-12-19 | 上海翰森生物医药科技有限公司 | 含哌嗪杂环类衍生物抑制剂、其制备方法和应用 |
CN113396147A (zh) * | 2019-05-31 | 2021-09-14 | 上海翰森生物医药科技有限公司 | 芳香杂环类衍生物调节剂、其制备方法和应用 |
WO2020259513A1 (en) * | 2019-06-24 | 2020-12-30 | Guangdong Newopp Biopharmaceuticals Co., Ltd. | Heterocyclic compounds as inhibitors of kras g12c |
CN113993860B (zh) * | 2019-06-25 | 2023-08-01 | 正大天晴药业集团股份有限公司 | 作为kras g12c突变蛋白抑制剂的七元杂环类衍生物 |
CN110256421A (zh) * | 2019-06-26 | 2019-09-20 | 微境生物医药科技(上海)有限公司 | Kras-g12c抑制剂 |
WO2021000885A1 (zh) * | 2019-07-01 | 2021-01-07 | 江苏恒瑞医药股份有限公司 | 喹唑啉酮类衍生物、其制备方法及其在医药上的应用 |
CN112300194B (zh) * | 2019-07-30 | 2022-01-14 | 上海凌达生物医药有限公司 | 一类稠环吡啶酮类化合物、制备方法和用途 |
EP4011886A4 (en) * | 2019-08-02 | 2023-07-26 | Shanghai Jemincare Pharmaceuticals Co., Ltd. | TETRACYCLIC COMPOUND, METHOD OF PRODUCTION THEREOF AND USE THEREOF |
CN112341457A (zh) * | 2019-08-07 | 2021-02-09 | 北京加科思新药研发有限公司 | Kras突变蛋白抑制剂 |
CN112390788A (zh) * | 2019-08-13 | 2021-02-23 | 苏州闻天医药科技有限公司 | 一种用于抑制krasg12c突变蛋白的化合物及其制备方法和用途 |
CN112390797A (zh) * | 2019-08-15 | 2021-02-23 | 微境生物医药科技(上海)有限公司 | 新型螺环类K-Ras G12C抑制剂 |
CN112390796B (zh) * | 2019-08-19 | 2023-06-27 | 贝达药业股份有限公司 | Kras g12c抑制剂及其在医药上的应用 |
AR119821A1 (es) | 2019-08-28 | 2022-01-12 | Bristol Myers Squibb Co | Compuestos de piridopirimidinonilo sustituidos útiles como activadores de células t |
US20220259150A1 (en) * | 2019-09-11 | 2022-08-18 | Chiral Quest (Suzhou) Co., Ltd. | Synthesis method applied to kras inhibitor drug heterocyclic intermediate |
US20220389029A1 (en) * | 2019-09-20 | 2022-12-08 | Shanghai Jemincare Pharmaceuticals Co., Ltd | Fused pyridone compound, and preparation method therefor and use thereof |
KR20220091480A (ko) * | 2019-09-24 | 2022-06-30 | 미라티 테라퓨틱스, 인크. | 병용 요법 |
EP4045047A1 (en) | 2019-10-15 | 2022-08-24 | Amgen Inc. | Combination therapy of kras inhibitor and shp2 inhibitor for treatment of cancers |
WO2021081212A1 (en) | 2019-10-24 | 2021-04-29 | Amgen Inc. | Pyridopyrimidine derivatives useful as kras g12c and kras g12d inhibitors in the treatment of cancer |
CN112225734B (zh) * | 2019-10-25 | 2021-12-07 | 南京瑞捷医药科技有限公司 | Kras g12c抑制剂及其用途 |
IL292438A (en) * | 2019-10-28 | 2022-06-01 | Merck Sharp & Dohme | Small molecules that inhibit the g12c mutant of kras |
CN115057872A (zh) * | 2019-10-30 | 2022-09-16 | 劲方医药科技(上海)有限公司 | 取代的杂环并环类化合物,其制法与医药上的用途 |
TW202132314A (zh) | 2019-11-04 | 2021-09-01 | 美商銳新醫藥公司 | Ras抑制劑 |
CA3159559A1 (en) | 2019-11-04 | 2021-05-14 | Revolution Medicines, Inc. | Ras inhibitors |
EP4054719A1 (en) | 2019-11-04 | 2022-09-14 | Revolution Medicines, Inc. | Ras inhibitors |
WO2021097212A1 (en) * | 2019-11-14 | 2021-05-20 | Amgen Inc. | Improved synthesis of kras g12c inhibitor compound |
AR120456A1 (es) | 2019-11-14 | 2022-02-16 | Amgen Inc | Síntesis mejorada del compuesto inhibidor de g12c de kras |
CN114630832A (zh) * | 2019-11-15 | 2022-06-14 | 四川海思科制药有限公司 | 一种嘧啶并环衍生物及其在医药上的应用 |
JP2023505100A (ja) | 2019-11-27 | 2023-02-08 | レボリューション メディシンズ インコーポレイテッド | 共有ras阻害剤及びその使用 |
EP4065125A4 (en) | 2019-11-27 | 2024-01-03 | Turning Point Therapeutics Inc | COMBINATION THERAPY WITH DIARYL MACROCYCLIC COMPOUNDS |
WO2021106231A1 (en) * | 2019-11-29 | 2021-06-03 | Taiho Pharmaceutical Co., Ltd. | A compound having inhibitory activity against kras g12d mutation |
CN113614080B (zh) * | 2019-11-29 | 2022-06-28 | 苏州信诺维医药科技股份有限公司 | Kras g12c抑制剂化合物及其用途 |
CN111377918B (zh) * | 2019-11-29 | 2021-03-02 | 苏州信诺维医药科技有限公司 | 一种kras抑制剂化合物 |
WO2021113595A1 (en) * | 2019-12-06 | 2021-06-10 | Beta Pharma, Inc. | Phosphorus derivatives as kras inhibitors |
US20230124492A1 (en) * | 2019-12-10 | 2023-04-20 | The Board Of Regents Of The University Of Texas System | Compositions and methods for substituted 7-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine analogs as inhibitors of kras |
US20230028414A1 (en) | 2019-12-16 | 2023-01-26 | Amgen Inc. | Dosing regimen of kras g12c inhibitor |
WO2021120045A1 (en) * | 2019-12-18 | 2021-06-24 | InventisBio Co., Ltd. | Heterocyclic compounds, preparation methods and uses thereof |
CN115192577B (zh) * | 2019-12-19 | 2024-03-29 | 北京加科思新药研发有限公司 | Kras突变蛋白抑制剂 |
WO2021120890A1 (en) | 2019-12-20 | 2021-06-24 | Novartis Ag | Pyrazolyl derivatives useful as anti-cancer agents |
AR120823A1 (es) | 2019-12-23 | 2022-03-23 | Bristol Myers Squibb Co | Compuestos bicíclicos sustituidos útiles como activadores de células t |
WO2021139678A1 (zh) * | 2020-01-07 | 2021-07-15 | 广州百霆医药科技有限公司 | 吡啶并嘧啶类kras g12c突变蛋白抑制剂 |
TWI770760B (zh) * | 2020-01-08 | 2022-07-11 | 大陸商蘇州亞盛藥業有限公司 | 螺環四氫喹唑啉 |
CN111205286B (zh) * | 2020-01-13 | 2022-12-13 | 中科苏州药物研究院 | 作为kras g12c突变蛋白抑制剂的腈甲基哌嗪类衍生物及其应用 |
CN114671866A (zh) * | 2020-12-25 | 2022-06-28 | 苏州泽璟生物制药股份有限公司 | 芳基或杂芳基并吡啶酮或嘧啶酮类衍生物及其制备方法和应用 |
WO2021150613A1 (en) | 2020-01-20 | 2021-07-29 | Incyte Corporation | Spiro compounds as inhibitors of kras |
WO2021147965A1 (zh) * | 2020-01-21 | 2021-07-29 | 南京明德新药研发有限公司 | 作为kras抑制剂的大环类化合物 |
GB202001344D0 (en) | 2020-01-31 | 2020-03-18 | Redx Pharma Plc | Ras Inhibitors |
CN112159405B (zh) * | 2020-02-04 | 2021-09-14 | 广州必贝特医药技术有限公司 | 吡啶并嘧啶酮类化合物及其应用 |
CN113248521B (zh) * | 2020-02-11 | 2023-07-18 | 上海和誉生物医药科技有限公司 | 一种k-ras g12c抑制剂及其制备方法和应用 |
WO2021169963A1 (zh) | 2020-02-24 | 2021-09-02 | 上海喆邺生物科技有限公司 | 芳香类化合物及其在制备抗肿瘤药物中的应用 |
CN114901663A (zh) * | 2020-03-02 | 2022-08-12 | 上海喆邺生物科技有限公司 | 一类芳香杂环类化合物及其在药物中的应用 |
WO2021185233A1 (en) * | 2020-03-17 | 2021-09-23 | Jacobio Pharmaceuticals Co., Ltd. | Kras mutant protein inhibitors |
AU2021248363B2 (en) * | 2020-04-03 | 2024-02-15 | Medshine Discovery Inc. | Octahydropyrazinodiazanaphthyridine dione compounds |
US20230203055A1 (en) * | 2020-04-28 | 2023-06-29 | Betta Pharmaceuticals Co., Ltd | Fused ring compound and application thereof in medicine |
US11739102B2 (en) | 2020-05-13 | 2023-08-29 | Incyte Corporation | Fused pyrimidine compounds as KRAS inhibitors |
JP2023526443A (ja) | 2020-05-18 | 2023-06-21 | ウェルマーカー バイオ カンパニー リミテッド | Ron変異が関与する非小細胞肺がんの予防又は治療用医薬組成物及びその使用方法 |
WO2021236920A1 (en) * | 2020-05-20 | 2021-11-25 | Teva Pharmaceuticals International Gmbh | Solid state forms of amg-510 and process for preparation thereof |
CN112574199B (zh) * | 2020-05-20 | 2021-05-18 | 首药控股(北京)股份有限公司 | Kras-G12C抑制剂杂环化合物 |
CN116034106A (zh) | 2020-06-02 | 2023-04-28 | 勃林格殷格翰国际有限公司 | 用于治疗癌症的环状2-氨基-3-氰基噻吩及衍生物 |
WO2021244555A1 (zh) * | 2020-06-02 | 2021-12-09 | 上海喆邺生物科技有限公司 | 一种手性中间体及其制备方法 |
WO2021249563A1 (zh) * | 2020-06-12 | 2021-12-16 | 苏州泽璟生物制药股份有限公司 | 芳基或杂芳基并吡啶酮或嘧啶酮类衍生物及其制备方法和应用 |
CN115916194A (zh) | 2020-06-18 | 2023-04-04 | 锐新医药公司 | 用于延迟、预防和治疗针对ras抑制剂的获得性抗性的方法 |
WO2021259972A1 (en) | 2020-06-24 | 2021-12-30 | Boehringer Ingelheim International Gmbh | Anticancer combination therapy comprising a sos1 inhibitor and a kras g12c inhibitor |
KR20230028798A (ko) * | 2020-06-25 | 2023-03-02 | 톨레모 테라퓨틱스 아게 | 암 치료를 위한 CBP/p300 브로모도메인 억제제 및 KRAS 억제제의 조합물 |
CN113980032B (zh) * | 2020-07-27 | 2023-06-16 | 江苏恒瑞医药股份有限公司 | 稠合四环类衍生物、其制备方法及其在医药上的应用 |
CN115052870B (zh) | 2020-08-02 | 2024-02-20 | 上海喆邺生物科技有限公司 | 一种芳香类化合物及其在抗肿瘤药物中的应用 |
US20230295163A1 (en) * | 2020-08-21 | 2023-09-21 | Zhejiang Hisun Pharmaceutical Co., Ltd. | Tetracyclic derivative, method for preparing same and use thereof in medicine |
CN114075195A (zh) * | 2020-08-21 | 2022-02-22 | 广东东阳光药业有限公司 | 嘧啶酮衍生物及其在药物中的应用 |
WO2022047093A1 (en) * | 2020-08-28 | 2022-03-03 | Incyte Corporation | Vinyl imidazole compounds as inhibitors of kras |
AU2021344830A1 (en) | 2020-09-03 | 2023-04-06 | Revolution Medicines, Inc. | Use of SOS1 inhibitors to treat malignancies with SHP2 mutations |
KR20230067635A (ko) | 2020-09-15 | 2023-05-16 | 레볼루션 메디슨즈, 인크. | 암의 치료에서 ras 억제제로서 인돌 유도체 |
WO2022072783A1 (en) | 2020-10-02 | 2022-04-07 | Incyte Corporation | Bicyclic dione compounds as inhibitors of kras |
MX2023003983A (es) | 2020-10-07 | 2023-04-24 | Amgen Inc | Procedimiento para racemizar y aislar atropisomeros de 7-cloro-6-fluoro-1-(2-isopropil-4-metilpiridin-3-il)pirido[2,3-d] pirimidin-2,4(1h,3h)-diona. |
CA3199082A1 (en) | 2020-10-27 | 2022-05-05 | Amgen Inc. | Heterocyclic spiro compounds and methods of use |
TW202224682A (zh) * | 2020-11-13 | 2022-07-01 | 美商建南德克公司 | 用於治療實性瘤之方法與包含krasg12c抑制劑及vegf抑制劑之組成物 |
TW202237598A (zh) | 2020-11-20 | 2022-10-01 | 美商安進公司 | 用於製備7—氯—6—氟—1—(2—異丙基—4—甲吡啶—3—基)吡啶并[2,3—d]嘧啶—2,4(1h,3h)—二酮之方法 |
TW202227438A (zh) * | 2020-11-24 | 2022-07-16 | 大陸商杭州多域生物技術有限公司 | 一種芳香化合物、其製備方法及應用 |
WO2022111513A1 (zh) * | 2020-11-24 | 2022-06-02 | 杭州多域生物技术有限公司 | 一种芳香化合物、其制备方法及应用 |
CN116490188A (zh) * | 2020-11-26 | 2023-07-25 | 上海翰森生物医药科技有限公司 | 含氮杂环类衍生物的盐、晶型及其制备方法和应用 |
CN116171155A (zh) * | 2020-12-08 | 2023-05-26 | 上海和誉生物医药科技有限公司 | 吡啶并[2,3-d]嘧啶-2(1H)-酮衍生物及其制备方法和应用 |
AU2021397319A1 (en) * | 2020-12-11 | 2023-07-27 | Erasca, Inc. | Combination therapies for the treatment of cancer |
CN114644628A (zh) * | 2020-12-17 | 2022-06-21 | 广东东阳光药业有限公司 | 嘧啶酮衍生物及其在药物中的应用 |
US20230107642A1 (en) | 2020-12-18 | 2023-04-06 | Erasca, Inc. | Tricyclic pyridones and pyrimidones |
WO2022127915A1 (zh) * | 2020-12-18 | 2022-06-23 | 正大天晴药业集团股份有限公司 | 吡啶并嘧啶酮类化合物 |
WO2022140246A1 (en) | 2020-12-21 | 2022-06-30 | Hangzhou Jijing Pharmaceutical Technology Limited | Methods and compounds for targeted autophagy |
CN114685502A (zh) * | 2020-12-25 | 2022-07-01 | 由理生物医药(上海)有限公司 | 作为kras-g12c抑制剂的螺环类化合物 |
AU2022205969A1 (en) | 2021-01-08 | 2023-07-06 | Amgen Inc. | Use of a kras g12c inhibitor in treating cancers |
AU2022234388A1 (en) * | 2021-03-10 | 2023-10-26 | Beta Pharma, Inc. | Pyridopyrimidine derivatives as kras inhibitors |
CN116940346A (zh) * | 2021-03-11 | 2023-10-24 | 益方生物科技(上海)股份有限公司 | 固体分散体 |
CN113018415B (zh) * | 2021-03-17 | 2022-07-01 | 遵义医科大学 | 一种药物组合及其应用 |
CN117479942A (zh) | 2021-04-09 | 2024-01-30 | 勃林格殷格翰国际有限公司 | 抗癌疗法 |
EP4329749A1 (en) * | 2021-04-27 | 2024-03-06 | Merck Sharp & Dohme LLC | Small molecule inhibitors of kras g12c mutant |
EP4329888A1 (en) | 2021-04-29 | 2024-03-06 | Amgen Inc. | 2-aminobenzothiazole compounds and methods of use thereof |
WO2022235870A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Ras inhibitors for the treatment of cancer |
CR20230570A (es) | 2021-05-05 | 2024-01-22 | Revolution Medicines Inc | Inhibidores de ras |
EP4341260A1 (en) | 2021-05-19 | 2024-03-27 | Teva Pharmaceuticals International GmbH | Process for preparation of sotorasib and solid state form thereof |
CN117337193A (zh) * | 2021-05-19 | 2024-01-02 | 基因泰克公司 | 组合疗法 |
AU2022280025A1 (en) * | 2021-05-25 | 2023-12-07 | Erasca, Inc. | Sulfur-containing heteroaromatic tricyclic kras inhibitors |
WO2022266206A1 (en) | 2021-06-16 | 2022-12-22 | Erasca, Inc. | Kras inhibitor conjugates |
AR126166A1 (es) * | 2021-06-18 | 2023-09-27 | Antengene Discovery Ltd | Combinación de un inhibidor de erk y un inhibidor de kras y usos de estos |
TW202317100A (zh) | 2021-06-23 | 2023-05-01 | 瑞士商諾華公司 | 包含kras g12c抑制劑的藥物組合及其用於治療癌症之用途 |
WO2022269008A1 (en) | 2021-06-24 | 2022-12-29 | Sandoz Ag | Crystalline form of sotorasib |
EP4227305A1 (en) | 2022-02-10 | 2023-08-16 | Sandoz AG | Crystalline form of sotorasib |
CA3228338A1 (en) * | 2021-08-10 | 2023-02-16 | Amgen Inc. | Heterocyclic compounds and methods of use |
CA3224341A1 (en) | 2021-09-01 | 2023-03-09 | Novartis Ag | Pharmaceutical combinations comprising a tead inhibitor and uses thereof for the treatment of cancers |
CN114605406B (zh) * | 2021-09-18 | 2023-05-26 | 都创(上海)医药开发有限公司 | Amg510化合物的晶型及其制备方法和用途 |
TW202322807A (zh) | 2021-10-01 | 2023-06-16 | 美商辛瑟拉股份有限公司 | 吖丁啶及吡咯啶parp1抑制劑及其用途 |
AR127308A1 (es) | 2021-10-08 | 2024-01-10 | Revolution Medicines Inc | Inhibidores ras |
CA3235146A1 (en) | 2021-10-14 | 2023-04-20 | Incyte Corporation | Quinoline compounds as inhibitors of kras |
WO2023078252A1 (en) | 2021-11-02 | 2023-05-11 | Flare Therapeutics Inc. | Pparg inverse agonists and uses thereof |
WO2023078424A1 (zh) * | 2021-11-05 | 2023-05-11 | 苏州信诺维医药科技股份有限公司 | Kras突变体抑制剂的晶型、其制备方法及其应用 |
WO2023097195A1 (en) | 2021-11-24 | 2023-06-01 | Genentech, Inc. | Therapeutic indazole compounds and methods of use in the treatment of cancer |
US20230203062A1 (en) | 2021-11-24 | 2023-06-29 | Genentech, Inc. | Therapeutic compounds and methods of use |
TW202340214A (zh) | 2021-12-17 | 2023-10-16 | 美商健臻公司 | 做為shp2抑制劑之吡唑并吡𠯤化合物 |
WO2023117681A1 (en) | 2021-12-22 | 2023-06-29 | Boehringer Ingelheim International Gmbh | Heteroaromatic compounds for the treatment of cancer |
WO2023122662A1 (en) | 2021-12-22 | 2023-06-29 | The Regents Of The University Of California | Covalently binding inhibitors of g12s, g12d and/or g12e mutants of k-ras gtpase |
US11939329B2 (en) | 2022-01-21 | 2024-03-26 | Xinthera, Inc. | PARP1 inhibitors and uses thereof |
EP4227307A1 (en) | 2022-02-11 | 2023-08-16 | Genzyme Corporation | Pyrazolopyrazine compounds as shp2 inhibitors |
WO2023159086A1 (en) | 2022-02-16 | 2023-08-24 | Amgen Inc. | Quinazoline compounds and use thereof as inhibtors of mutant kras proteins |
WO2023159087A1 (en) | 2022-02-16 | 2023-08-24 | Amgen Inc. | Quinazoline compounds and use thereof as inhibtors of mutant kras proteins |
TW202346267A (zh) | 2022-03-07 | 2023-12-01 | 美商安進公司 | 用於製備4-甲基-2-丙-2-基-吡啶-3-甲腈之方法 |
WO2023172940A1 (en) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Methods for treating immune refractory lung cancer |
US11618751B1 (en) | 2022-03-25 | 2023-04-04 | Ventus Therapeutics U.S., Inc. | Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives |
WO2023194310A1 (en) | 2022-04-04 | 2023-10-12 | Sanofi | Therapeutic combination of kras g12c inhibitor and tead inhibitor |
WO2023199180A1 (en) | 2022-04-11 | 2023-10-19 | Novartis Ag | Therapeutic uses of a krasg12c inhibitor |
WO2023205701A1 (en) | 2022-04-20 | 2023-10-26 | Kumquat Biosciences Inc. | Macrocyclic heterocycles and uses thereof |
TW202400596A (zh) | 2022-04-28 | 2024-01-01 | 美商辛瑟拉股份有限公司 | 三環parp1抑制劑及其用途 |
WO2023240263A1 (en) | 2022-06-10 | 2023-12-14 | Revolution Medicines, Inc. | Macrocyclic ras inhibitors |
WO2024040131A1 (en) | 2022-08-17 | 2024-02-22 | Treeline Biosciences, Inc. | Pyridopyrimidine kras inhibitors |
GB202212641D0 (en) | 2022-08-31 | 2022-10-12 | Jazz Pharmaceuticals Ireland Ltd | Novel compounds |
CN115368358A (zh) * | 2022-09-01 | 2022-11-22 | 浙江九洲药业股份有限公司 | 一种Sotorasib新晶型及其制备方法与应用 |
WO2024081674A1 (en) | 2022-10-11 | 2024-04-18 | Aadi Bioscience, Inc. | Combination therapies for the treatment of cancer |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011075747A1 (en) * | 2009-12-18 | 2011-06-23 | Glaxosmithkline Llc | Therapeutic compounds |
WO2015054572A1 (en) * | 2013-10-10 | 2015-04-16 | Araxes Pharma Llc | Inhibitors of kras g12c |
Family Cites Families (233)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4232027A (en) | 1979-01-29 | 1980-11-04 | E. R. Squibb & Sons, Inc. | 1,2-Dihydro-2-oxo-4-phenyl-3-quinolinecarbonitrile derivatives |
DE3381783D1 (de) | 1982-03-03 | 1990-09-13 | Genentech Inc | Menschliches antithrombin iii, dns sequenzen dafuer, expressions- und klonierungsvektoren die solche sequenzen enthalten und damit transformierte zellkulturen, verfahren zur expression von menschlichem antithrombin iii und diese enthaltende pharmazeutische zusammensetzungen. |
GB8827305D0 (en) | 1988-11-23 | 1988-12-29 | British Bio Technology | Compounds |
JP2762522B2 (ja) | 1989-03-06 | 1998-06-04 | 藤沢薬品工業株式会社 | 血管新生阻害剤 |
GB8912336D0 (en) | 1989-05-30 | 1989-07-12 | Smithkline Beckman Intercredit | Compounds |
US5112946A (en) | 1989-07-06 | 1992-05-12 | Repligen Corporation | Modified pf4 compositions and methods of use |
PT98990A (pt) | 1990-09-19 | 1992-08-31 | American Home Prod | Processo para a preparacao de esteres de acidos carboxilicos de rapamicina |
US5892112A (en) | 1990-11-21 | 1999-04-06 | Glycomed Incorporated | Process for preparing synthetic matrix metalloprotease inhibitors |
US5120842A (en) | 1991-04-01 | 1992-06-09 | American Home Products Corporation | Silyl ethers of rapamycin |
US5100883A (en) | 1991-04-08 | 1992-03-31 | American Home Products Corporation | Fluorinated esters of rapamycin |
US5118678A (en) | 1991-04-17 | 1992-06-02 | American Home Products Corporation | Carbamates of rapamycin |
CA2066898A1 (en) | 1991-04-29 | 1992-10-30 | Chuan Shih | Pharmaceutical compounds |
SG64322A1 (en) | 1991-05-10 | 1999-04-27 | Rhone Poulenc Rorer Int | Bis mono and bicyclic aryl and heteroaryl compounds which inhibit egf and/or pdgf receptor tyrosine kinase |
US5118677A (en) | 1991-05-20 | 1992-06-02 | American Home Products Corporation | Amide esters of rapamycin |
NZ243082A (en) | 1991-06-28 | 1995-02-24 | Ici Plc | 4-anilino-quinazoline derivatives; pharmaceutical compositions, preparatory processes, and use thereof |
US5151413A (en) | 1991-11-06 | 1992-09-29 | American Home Products Corporation | Rapamycin acetals as immunosuppressant and antifungal agents |
GB9125660D0 (en) | 1991-12-03 | 1992-01-29 | Smithkline Beecham Plc | Novel compound |
AU661533B2 (en) | 1992-01-20 | 1995-07-27 | Astrazeneca Ab | Quinazoline derivatives |
US5521184A (en) | 1992-04-03 | 1996-05-28 | Ciba-Geigy Corporation | Pyrimidine derivatives and processes for the preparation thereof |
ZA935111B (en) | 1992-07-17 | 1994-02-04 | Smithkline Beecham Corp | Rapamycin derivatives |
ZA935112B (en) | 1992-07-17 | 1994-02-08 | Smithkline Beecham Corp | Rapamycin derivatives |
US5256790A (en) | 1992-08-13 | 1993-10-26 | American Home Products Corporation | 27-hydroxyrapamycin and derivatives thereof |
GB9221220D0 (en) | 1992-10-09 | 1992-11-25 | Sandoz Ag | Organic componds |
US5258389A (en) | 1992-11-09 | 1993-11-02 | Merck & Co., Inc. | O-aryl, O-alkyl, O-alkenyl and O-alkynylrapamycin derivatives |
DE69334100T2 (de) | 1992-11-13 | 2007-07-19 | Immunex Corp., Seattle | Elk ligand, ein cytokin |
US5455258A (en) | 1993-01-06 | 1995-10-03 | Ciba-Geigy Corporation | Arylsulfonamido-substituted hydroxamic acids |
US5629327A (en) | 1993-03-01 | 1997-05-13 | Childrens Hospital Medical Center Corp. | Methods and compositions for inhibition of angiogenesis |
US5516658A (en) | 1993-08-20 | 1996-05-14 | Immunex Corporation | DNA encoding cytokines that bind the cell surface receptor hek |
CA2148931A1 (en) | 1993-10-01 | 1995-04-13 | Jurg Zimmermann | Pyrimidineamine derivatives and processes for the preparation thereof |
US5656643A (en) | 1993-11-08 | 1997-08-12 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
EP0729471A1 (en) | 1993-11-19 | 1996-09-04 | Abbott Laboratories | Semisynthetic analogs of rapamycin (macrolides) being immunomodulators |
CN1046944C (zh) | 1993-12-17 | 1999-12-01 | 山道士有限公司 | 雷怕霉素类衍生物 |
US5700823A (en) | 1994-01-07 | 1997-12-23 | Sugen, Inc. | Treatment of platelet derived growth factor related disorders such as cancers |
IL112249A (en) | 1994-01-25 | 2001-11-25 | Warner Lambert Co | Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds |
IL112248A0 (en) | 1994-01-25 | 1995-03-30 | Warner Lambert Co | Tricyclic heteroaromatic compounds and pharmaceutical compositions containing them |
WO1995024190A2 (en) | 1994-03-07 | 1995-09-14 | Sugen, Inc. | Receptor tyrosine kinase inhibitors for inhibiting cell proliferative disorders and compositions thereof |
EP1464706A3 (en) | 1994-04-15 | 2004-11-03 | Amgen Inc., | HEK5, HEK7, HEK8, HEK11, EPH-like receptor protein tyrosine kinases |
EP0682027B1 (de) | 1994-05-03 | 1997-10-15 | Novartis AG | Pyrrolopyrimidinderivate mit antiproliferativer Wirkung |
US6303769B1 (en) | 1994-07-08 | 2001-10-16 | Immunex Corporation | Lerk-5 dna |
US5919905A (en) | 1994-10-05 | 1999-07-06 | Immunex Corporation | Cytokine designated LERK-6 |
US6057124A (en) | 1995-01-27 | 2000-05-02 | Amgen Inc. | Nucleic acids encoding ligands for HEK4 receptors |
US5863949A (en) | 1995-03-08 | 1999-01-26 | Pfizer Inc | Arylsulfonylamino hydroxamic acid derivatives |
EP2295415A1 (en) | 1995-03-30 | 2011-03-16 | OSI Pharmaceuticals, Inc. | Quinazoline derivatives |
EP0819129B1 (en) | 1995-04-03 | 2000-08-02 | Novartis AG | Pyrazole derivatives and processes for the preparation thereof |
CA2218503C (en) | 1995-04-20 | 2001-07-24 | Pfizer Inc. | Arylsulfonyl hydroxamic acid derivatives |
GB9508538D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
US5747498A (en) | 1996-05-28 | 1998-05-05 | Pfizer Inc. | Alkynyl and azido-substituted 4-anilinoquinazolines |
US5650415A (en) | 1995-06-07 | 1997-07-22 | Sugen, Inc. | Quinoline compounds |
US5880141A (en) | 1995-06-07 | 1999-03-09 | Sugen, Inc. | Benzylidene-Z-indoline compounds for the treatment of disease |
AU712193B2 (en) | 1995-06-09 | 1999-10-28 | Novartis Ag | Rapamycin derivatives |
SI9620103A (sl) | 1995-07-06 | 1998-10-31 | Novartis Ag | Pirolopirimidini in postopki za njihovo pripravo |
DE19534177A1 (de) | 1995-09-15 | 1997-03-20 | Merck Patent Gmbh | Cyclische Adhäsionsinhibitoren |
AR004010A1 (es) | 1995-10-11 | 1998-09-30 | Glaxo Group Ltd | Compuestos heterociclicos |
GB9523675D0 (en) | 1995-11-20 | 1996-01-24 | Celltech Therapeutics Ltd | Chemical compounds |
ATE225343T1 (de) | 1995-12-20 | 2002-10-15 | Hoffmann La Roche | Matrix-metalloprotease inhibitoren |
AU1441497A (en) | 1996-01-23 | 1997-08-20 | Novartis Ag | Pyrrolopyrimidines and processes for their preparation |
JP3406763B2 (ja) | 1996-01-30 | 2003-05-12 | 東レ・ダウコーニング・シリコーン株式会社 | シリコーンゴム組成物 |
GB9603097D0 (en) | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline compounds |
GB9603095D0 (en) | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline derivatives |
DE19608588A1 (de) | 1996-03-06 | 1997-09-11 | Thomae Gmbh Dr K | Pyrimido [5,4-d]pyrimidine, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
DE19629652A1 (de) | 1996-03-06 | 1998-01-29 | Thomae Gmbh Dr K | 4-Amino-pyrimidin-Derivate, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
PT888353E (pt) | 1996-03-15 | 2003-11-28 | Novartis Ag | Novas n-7-heterociclil-pirrolo¬2,3-d|pirimidinas e sua aplicacao |
PL190489B1 (pl) | 1996-04-12 | 2005-12-30 | Warner Lambert Co | Nieodwracalne inhibitory kinaz tyrozyny, kompozycja farmaceutyczna je zawierająca i ich zastosowanie |
GB9607729D0 (en) | 1996-04-13 | 1996-06-19 | Zeneca Ltd | Quinazoline derivatives |
EP0907642B1 (en) | 1996-06-24 | 2005-11-02 | Pfizer Inc. | Phenylamino-substituted tricyclic derivatives for treatment of hyperproliferative diseases |
US6258823B1 (en) | 1996-07-12 | 2001-07-10 | Ariad Pharmaceuticals, Inc. | Materials and method for treating or preventing pathogenic fungal infection |
EP0818442A3 (en) | 1996-07-12 | 1998-12-30 | Pfizer Inc. | Cyclic sulphone derivatives as inhibitors of metalloproteinases and of the production of tumour necrosis factor |
HRP970371A2 (en) | 1996-07-13 | 1998-08-31 | Kathryn Jane Smith | Heterocyclic compounds |
TR199900048T2 (xx) | 1996-07-13 | 1999-04-21 | Glaxo Group Limited | Protein tirozin kinaz inhibit�rleri olarak bisiklik heteroaromatik bile�ikler |
ES2186908T3 (es) | 1996-07-13 | 2003-05-16 | Glaxo Group Ltd | Compuestos heterociciclos condensados como inhibidores de pproteina-tirosina-quinasas. |
HUP9903014A3 (en) | 1996-07-18 | 2000-08-28 | Pfizer | Phosphinate derivatives having matrix metalloprotease inhibitor effect and medicaments containing the same |
EP1947183B1 (en) | 1996-08-16 | 2013-07-17 | Merck Sharp & Dohme Corp. | Mammalian cell surface antigens; related reagents |
US6111090A (en) | 1996-08-16 | 2000-08-29 | Schering Corporation | Mammalian cell surface antigens; related reagents |
JP4242928B2 (ja) | 1996-08-23 | 2009-03-25 | ノバルティス アクチエンゲゼルシャフト | 置換ピロロピリミジンおよびその製造方法 |
US6153609A (en) | 1996-08-23 | 2000-11-28 | Pfizer Inc | Arylsulfonylamino hydroxamic acid derivatives |
ID18494A (id) | 1996-10-02 | 1998-04-16 | Novartis Ag | Turunan pirazola leburan dan proses pembuatannya |
JP4205168B2 (ja) | 1996-10-02 | 2009-01-07 | ノバルティス アクチエンゲゼルシヤフト | ピリミジン誘導体およびその製造法 |
AU4779897A (en) | 1996-10-02 | 1998-04-24 | Novartis Ag | Fused pyrazole derivatives and processes for their preparation |
EP0837063A1 (en) | 1996-10-17 | 1998-04-22 | Pfizer Inc. | 4-Aminoquinazoline derivatives |
GB9621757D0 (en) | 1996-10-18 | 1996-12-11 | Ciba Geigy Ag | Phenyl-substituted bicyclic heterocyclyl derivatives and their use |
CA2277100C (en) | 1997-01-06 | 2005-11-22 | Pfizer Inc. | Cyclic sulfone derivatives |
TR199901849T2 (xx) | 1997-02-03 | 2000-02-21 | Pfizer Products Inc. | Arils�lfonilamino hidroksamik asit t�revleri. |
EP0964864B1 (en) | 1997-02-05 | 2008-04-09 | Warner-Lambert Company LLC | Pyrido 2,3-d pyrimidines and 4-aminopyrimidines as inhibitors of cellular proliferation |
CA2279863A1 (en) | 1997-02-07 | 1998-08-13 | Pfizer Inc. | N-hydroxy-beta-sulfonyl-propionamide derivatives and their use as inhibitors of matrix metalloproteinases |
NZ336836A (en) | 1997-02-11 | 2001-02-23 | Pfizer | Arylsulfonyl hydroxamic acid derivatives suitable for a broad range of medicinal treatments |
CO4950519A1 (es) | 1997-02-13 | 2000-09-01 | Novartis Ag | Ftalazinas, preparaciones farmaceuticas que las comprenden y proceso para su preparacion |
US6150395A (en) | 1997-05-30 | 2000-11-21 | The Regents Of The University Of California | Indole-3-carbinol (I3C) derivatives and methods |
WO1999007701A1 (en) | 1997-08-05 | 1999-02-18 | Sugen, Inc. | Tricyclic quinoxaline derivatives as protein tyrosine kinase inhibitors |
ATE263147T1 (de) | 1997-08-08 | 2004-04-15 | Pfizer Prod Inc | Derivate von aryloxyarylsulfonylamino hydroxyaminsäuren |
JP2001520039A (ja) | 1997-10-21 | 2001-10-30 | ヒューマン ジノーム サイエンシーズ, インコーポレイテッド | ヒト腫瘍壊死因子レセプター様タンパク質、tr11,tr11sv1およびtr11sv2 |
GB9725782D0 (en) | 1997-12-05 | 1998-02-04 | Pfizer Ltd | Therapeutic agents |
GB9800569D0 (en) | 1998-01-12 | 1998-03-11 | Glaxo Group Ltd | Heterocyclic compounds |
GB9800575D0 (en) | 1998-01-12 | 1998-03-11 | Glaxo Group Ltd | Heterocyclic compounds |
GB9801690D0 (en) | 1998-01-27 | 1998-03-25 | Pfizer Ltd | Therapeutic agents |
CA2319236A1 (en) | 1998-02-09 | 1999-08-12 | Genentech, Inc. | Novel tumor necrosis factor receptor homolog and nucleic acids encoding the same |
AU756838B2 (en) | 1998-03-04 | 2003-01-23 | Bristol-Myers Squibb Company | Heterocyclo-substituted imidazopyrazine protein tyrosine kinase inhibitors |
PA8469501A1 (es) | 1998-04-10 | 2000-09-29 | Pfizer Prod Inc | Hidroxamidas del acido (4-arilsulfonilamino)-tetrahidropiran-4-carboxilico |
PA8469401A1 (es) | 1998-04-10 | 2000-05-24 | Pfizer Prod Inc | Derivados biciclicos del acido hidroxamico |
HUP0103617A2 (hu) | 1998-05-29 | 2002-02-28 | Sugen, Inc. | Protein kinázt gátló, pirrolilcsoporttal helyettesített 2-indolszármazékok, e vegyületeket tartalmazó gyógyászati készítmények, valamint e vegyületek alkalmazása |
UA60365C2 (uk) | 1998-06-04 | 2003-10-15 | Пфайзер Продактс Інк. | Похідні ізотіазолу, спосіб їх одержання, фармацевтична композиція та спосіб лікування гіперпроліферативного захворювання у ссавця |
WO2000002871A1 (en) | 1998-07-10 | 2000-01-20 | Merck & Co., Inc. | Novel angiogenesis inhibitors |
AU760020B2 (en) | 1998-08-31 | 2003-05-08 | Merck & Co., Inc. | Novel angiogenesis inhibitors |
DK1004578T3 (da) | 1998-11-05 | 2004-06-28 | Pfizer Prod Inc | 5-oxo-pyrrolidin-2-carboxylsyrehydroxamidderivater |
EP2298311B1 (en) | 1999-01-13 | 2012-05-09 | Bayer HealthCare LLC | w-Carboxy aryl substituted diphenyl ureas as p38 kinase inhibitors |
DE60028740T2 (de) | 1999-03-30 | 2007-05-24 | Novartis Ag | Phthalazinderivate zur behandlung von entzündlichen erkrankungen |
GB9912961D0 (en) | 1999-06-03 | 1999-08-04 | Pfizer Ltd | Metalloprotease inhibitors |
IL146482A0 (en) | 1999-06-07 | 2002-07-25 | Immunex Corp | Tek antagonists |
US6521424B2 (en) | 1999-06-07 | 2003-02-18 | Immunex Corporation | Recombinant expression of Tek antagonists |
ATE376837T1 (de) | 1999-07-12 | 2007-11-15 | Genentech Inc | Stimulierung oder hemmung von angiogenese und herzvaskularisierung mit tumor nekrose faktor ligand/rezeptor homologen |
DE60010098T2 (de) | 1999-08-24 | 2005-03-31 | Ariad Gene Therapeutics, Inc., Cambridge | 28-epirapaloge |
UA72946C2 (uk) | 1999-11-05 | 2005-05-16 | Астразенека Аб | Похідні хіназоліну як інгібітори васкулярного ендотеліального фактора росту (vegf) |
WO2001037820A2 (en) | 1999-11-24 | 2001-05-31 | Sugen, Inc. | Ionizable indolinone derivatives and their use as ptk ligands |
US6515004B1 (en) | 1999-12-15 | 2003-02-04 | Bristol-Myers Squibb Company | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases |
US6727225B2 (en) | 1999-12-20 | 2004-04-27 | Immunex Corporation | TWEAK receptor |
NZ521437A (en) | 2000-02-25 | 2004-04-30 | Immunex Corp | Integrin antagonists suitable as inhibitors of angiogenesis |
AU2001273498B2 (en) | 2000-07-19 | 2006-08-24 | Warner-Lambert Company | Oxygenated esters of 4-iodo phenylamino benzhydroxamic acids |
US6630500B2 (en) | 2000-08-25 | 2003-10-07 | Cephalon, Inc. | Selected fused pyrrolocarbazoles |
ATE430742T1 (de) | 2000-12-21 | 2009-05-15 | Smithkline Beecham Corp | Pyrimidinamine als angiogenesemodulatoren |
US6995162B2 (en) | 2001-01-12 | 2006-02-07 | Amgen Inc. | Substituted alkylamine derivatives and methods of use |
US6878714B2 (en) | 2001-01-12 | 2005-04-12 | Amgen Inc. | Substituted alkylamine derivatives and methods of use |
US7105682B2 (en) | 2001-01-12 | 2006-09-12 | Amgen Inc. | Substituted amine derivatives and methods of use |
US7102009B2 (en) | 2001-01-12 | 2006-09-05 | Amgen Inc. | Substituted amine derivatives and methods of use |
US20020147198A1 (en) | 2001-01-12 | 2002-10-10 | Guoqing Chen | Substituted arylamine derivatives and methods of use |
JP2002233610A (ja) | 2002-02-18 | 2002-08-20 | Olympia:Kk | スロットマシン |
US7307088B2 (en) | 2002-07-09 | 2007-12-11 | Amgen Inc. | Substituted anthranilic amide derivatives and methods of use |
TWI329112B (en) | 2002-07-19 | 2010-08-21 | Bristol Myers Squibb Co | Novel inhibitors of kinases |
US20050009849A1 (en) | 2003-01-03 | 2005-01-13 | Veach Darren R. | Pyridopyrimidine kinase inhibitors |
CA2525717A1 (en) | 2003-05-23 | 2004-12-09 | Wyeth | Gitr ligand and gitr ligand-related molecules and antibodies and uses thereof |
AU2004255340B2 (en) | 2003-07-08 | 2008-05-01 | Novartis Ag | Use of rapamycin and rapamycin derivatives for the treatment of bone loss |
WO2005016252A2 (en) | 2003-07-11 | 2005-02-24 | Ariad Gene Therapeutics, Inc. | Phosphorus-containing macrocycles |
EP1660126A1 (en) | 2003-07-11 | 2006-05-31 | Schering Corporation | Agonists or antagonists of the clucocorticoid-induced tumour necrosis factor receptor (gitr) or its ligand for the treatment of immune disorders, infections and cancer |
AR045134A1 (es) | 2003-07-29 | 2005-10-19 | Smithkline Beecham Plc | Compuesto de 1h - imidazo [4,5-c] piridin-ilo, composicion farmaceutica que lo comprende, proceso para prepararla, su uso para preparar dicha composicion farmaceutica, combinacion farmaceutica, uso de la combinacion farmaceutica para la preparacion de un medicamento, procedimientos para preparar dic |
CN1839133A (zh) | 2003-08-22 | 2006-09-27 | 阿文尼尔药品公司 | 作为巨噬细胞移动抑制因子的抑制剂的取代的二氮杂萘衍生物及其在治疗人类疾病中的应用 |
WO2005055808A2 (en) | 2003-12-02 | 2005-06-23 | Genzyme Corporation | Compositions and methods to diagnose and treat lung cancer |
GB0409799D0 (en) | 2004-04-30 | 2004-06-09 | Isis Innovation | Method of generating improved immune response |
WO2006083289A2 (en) | 2004-06-04 | 2006-08-10 | Duke University | Methods and compositions for enhancement of immunity by in vivo depletion of immunosuppressive cell activity |
ATE463486T1 (de) | 2004-08-26 | 2010-04-15 | Pfizer | Enantiomerenreine aminoheteroaryl-verbindungen als proteinkinasehemmer |
WO2006044453A1 (en) | 2004-10-13 | 2006-04-27 | Wyeth | Analogs of 17-hydroxywortmannin as pi3k inhibitors |
KR20070073791A (ko) | 2004-10-18 | 2007-07-10 | 암젠 인코포레이티드 | 티아디아졸 화합물 및 이의 사용방법 |
EP1866339B8 (en) | 2005-03-25 | 2021-12-01 | GITR, Inc. | Gitr binding molecules and uses therefor |
LT2439273T (lt) | 2005-05-09 | 2019-05-10 | Ono Pharmaceutical Co., Ltd. | Žmogaus monokloniniai antikūnai prieš programuotos mirties 1(pd-1) baltymą, ir vėžio gydymo būdai, naudojant vien tik anti-pd-1 antikūnus arba derinyje su kitais imunoterapiniais vaistais |
GB0510390D0 (en) | 2005-05-20 | 2005-06-29 | Novartis Ag | Organic compounds |
US20090012085A1 (en) | 2005-09-20 | 2009-01-08 | Charles Michael Baum | Dosage forms and methods of treatment using a tyrosine kinase inhibitor |
BRPI0706621A2 (pt) | 2006-01-18 | 2011-04-05 | Amgen Inc | composto, composição farmacêutica, métodos para tratar um distúrbio mediado por quinase em um mamìfero e para tratar um distúrbio relacionado com a proliferação em um mamìfero, e , uso do composto |
EP1981969A4 (en) | 2006-01-19 | 2009-06-03 | Genzyme Corp | ANTI-GITRANT ANTIBODIES FOR THE TREATMENT OF CANCER |
US7888352B2 (en) | 2006-12-07 | 2011-02-15 | Piramed Limited | Phosphoinositide 3-kinase inhibitor compounds and methods of use |
PT2137186E (pt) | 2007-03-23 | 2016-03-30 | Amgen Inc | Compostos heterocíclicos e suas utilizações |
EP2139882B1 (en) | 2007-03-23 | 2013-12-25 | Amgen Inc. | 3- substituted quinoline or quinoxaline derivatives and their use as phosphatidylinositol 3-kinase (pi3k) inhibitors |
CA2680783C (en) | 2007-03-23 | 2012-04-24 | Amgen Inc. | Heterocyclic compounds and their uses |
US8557830B2 (en) | 2007-06-07 | 2013-10-15 | Amgen Inc. | RAF kinase modulators and methods of use |
ES2591281T3 (es) | 2007-07-12 | 2016-11-25 | Gitr, Inc. | Terapias de combinación que emplean moléculas de enlazamiento a GITR |
AU2008276521B2 (en) | 2007-07-17 | 2011-11-03 | Amgen Inc. | Heterocyclic modulators of PKB |
US7919504B2 (en) | 2007-07-17 | 2011-04-05 | Amgen Inc. | Thiadiazole modulators of PKB |
TW200911798A (en) | 2007-08-02 | 2009-03-16 | Amgen Inc | PI3 kinase modulators and methods of use |
MX338504B (es) | 2007-09-12 | 2016-04-20 | Genentech Inc | Combinaciones de compuestos inhibidores de fosfoinosituro 3-cinasa y agentes quimioterapeuticos, y metodos de uso. |
CA2701292C (en) | 2007-10-25 | 2015-03-24 | Genentech, Inc. | Process for making thienopyrimidine compounds |
EP2231661A1 (en) | 2007-12-19 | 2010-09-29 | Amgen, Inc. | Inhibitors of pi3 kinase |
EA201001030A1 (ru) | 2007-12-19 | 2011-02-28 | Амген Инк. | Конденсированные соединения пиридина, пиримидина и триазина в качестве ингибиторов клеточного цикла |
EP2278973B1 (en) | 2008-04-07 | 2011-11-02 | Amgen Inc. | Gem-disubstituted and spirocyclic amino pyridines/pyrimidines as cell cycle inhibitors |
WO2009155121A2 (en) | 2008-05-30 | 2009-12-23 | Amgen Inc. | Inhibitors of pi3 kinase |
KR20110044992A (ko) | 2008-07-02 | 2011-05-03 | 이머전트 프로덕트 디벨롭먼트 시애틀, 엘엘씨 | TGF-β 길항제 다중-표적 결합 단백질 |
CN102149820B (zh) | 2008-09-12 | 2014-07-23 | 国立大学法人三重大学 | 能够表达外源gitr配体的细胞 |
EP2387570A1 (en) | 2009-01-15 | 2011-11-23 | Amgen, Inc | Fluoroisoquinoline substituted thiazole compounds and methods of use |
JP2012518037A (ja) | 2009-02-18 | 2012-08-09 | アムジエン・インコーポレーテツド | mTORキナーゼ阻害剤としてのインドール/ベンゾイミダゾール化合物 |
WO2010108074A2 (en) | 2009-03-20 | 2010-09-23 | Amgen Inc. | Inhibitors of pi3 kinase |
UY32582A (es) | 2009-04-28 | 2010-11-30 | Amgen Inc | Inhibidores de fosfoinositida 3 cinasa y/u objetivo mamífero |
MX2011012037A (es) | 2009-05-13 | 2012-02-28 | Amgen Inc | Compuestos de heteroarilo como inhibidores de pikk. |
EA201270051A1 (ru) | 2009-06-25 | 2012-05-30 | Амген Инк. | Гетероциклические соединения и их применения |
JP2012531435A (ja) | 2009-06-25 | 2012-12-10 | アムジエン・インコーポレーテツド | PI3K阻害剤としての4H−ピリド[1,2−a]ピリミジン−4−オン誘導体 |
EP2445902A2 (en) | 2009-06-25 | 2012-05-02 | Amgen, Inc | Heterocyclic compounds and their uses as inhibitors of pi3k activity |
TW201111362A (en) | 2009-06-25 | 2011-04-01 | Amgen Inc | Heterocyclic compounds and their uses |
EP2266984A1 (en) * | 2009-06-26 | 2010-12-29 | Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts | Pyrido[2,3-d]pyrimidines as Wnt antagonists for treatment of cancer and arthritis |
LT3023438T (lt) | 2009-09-03 | 2020-05-11 | Merck Sharp & Dohme Corp. | Anti-gitr antikūnai |
EP2818170B1 (en) | 2009-09-11 | 2018-12-05 | Amgen, Inc | N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridin yl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine for use in the treatment of antimitotic agent resistant cancer |
GB0919054D0 (en) | 2009-10-30 | 2009-12-16 | Isis Innovation | Treatment of obesity |
SI2519543T1 (sl) | 2009-12-29 | 2016-08-31 | Emergent Product Development Seattle, Llc | Beljakovine, ki se vežejo s heterodimeri in njihova uporaba |
US9133164B2 (en) | 2011-04-13 | 2015-09-15 | Innov88 Llc | MIF inhibitors and their uses |
WO2013039954A1 (en) | 2011-09-14 | 2013-03-21 | Sanofi | Anti-gitr antibodies |
EP2836482B1 (en) | 2012-04-10 | 2019-12-25 | The Regents of The University of California | Compositions and methods for treating cancer |
EP2882746B1 (en) | 2012-08-07 | 2016-12-07 | Merck Patent GmbH | Pyridopyrimidine derivatives as protein kinase inhibitors |
WO2014143659A1 (en) | 2013-03-15 | 2014-09-18 | Araxes Pharma Llc | Irreversible covalent inhibitors of the gtpase k-ras g12c |
EP2970121B1 (en) | 2013-03-15 | 2017-12-13 | Araxes Pharma LLC | Covalent inhibitors of kras g12c |
US9227978B2 (en) | 2013-03-15 | 2016-01-05 | Araxes Pharma Llc | Covalent inhibitors of Kras G12C |
GB201312059D0 (en) | 2013-07-05 | 2013-08-21 | Univ Leuven Kath | Novel GAK modulators |
TWI659021B (zh) | 2013-10-10 | 2019-05-11 | 亞瑞克西斯製藥公司 | Kras g12c之抑制劑 |
GB201320729D0 (en) | 2013-11-25 | 2014-01-08 | Cancer Rec Tech Ltd | Therapeutic compounds and their use |
BR112016016421B1 (pt) | 2014-01-20 | 2022-10-18 | Cleave Biosciences, Inc | Composto de pirimidina fundida, composição farmacêutica e respectivos uso |
WO2016035008A1 (en) | 2014-09-04 | 2016-03-10 | Lupin Limited | Pyridopyrimidine derivatives as mek inhibitors |
JO3556B1 (ar) | 2014-09-18 | 2020-07-05 | Araxes Pharma Llc | علاجات مدمجة لمعالجة السرطان |
WO2016049565A1 (en) | 2014-09-25 | 2016-03-31 | Araxes Pharma Llc | Compositions and methods for inhibition of ras |
WO2016049524A1 (en) | 2014-09-25 | 2016-03-31 | Araxes Pharma Llc | Inhibitors of kras g12c mutant proteins |
US10011600B2 (en) | 2014-09-25 | 2018-07-03 | Araxes Pharma Llc | Methods and compositions for inhibition of Ras |
CN107835812A (zh) * | 2015-04-03 | 2018-03-23 | 南特生物科学股份有限公司 | 靶向突变体k‑ras 的组合物和方法 |
TW201702232A (zh) | 2015-04-10 | 2017-01-16 | 亞瑞克西斯製藥公司 | 經取代之喹唑啉化合物及其使用方法 |
US10428064B2 (en) | 2015-04-15 | 2019-10-01 | Araxes Pharma Llc | Fused-tricyclic inhibitors of KRAS and methods of use thereof |
MX2018000777A (es) | 2015-07-22 | 2018-03-23 | Araxes Pharma Llc | Compuestos de quinazolina sustituido y su uso como inhibidores de proteinas kras, hras y/o nras mutantes g12c. |
US10882847B2 (en) | 2015-09-28 | 2021-01-05 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
WO2017058768A1 (en) | 2015-09-28 | 2017-04-06 | Araxes Pharma Llc | Inhibitors of kras g12c mutant proteins |
US10730867B2 (en) | 2015-09-28 | 2020-08-04 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
US10858343B2 (en) | 2015-09-28 | 2020-12-08 | Araxes Pharma Llc | Inhibitors of KRAS G12C mutant proteins |
WO2017058807A1 (en) | 2015-09-28 | 2017-04-06 | Araxes Pharma Llc | Inhibitors of kras g12c mutant proteins |
WO2017058915A1 (en) | 2015-09-28 | 2017-04-06 | Araxes Pharma Llc | Inhibitors of kras g12c mutant proteins |
EP3356339A1 (en) | 2015-09-28 | 2018-08-08 | Araxes Pharma LLC | Inhibitors of kras g12c mutant proteins |
JP7015059B2 (ja) | 2015-11-16 | 2022-02-15 | アラクセス ファーマ エルエルシー | 置換複素環式基を含む2-置換キナゾリン化合物およびその使用方法 |
WO2017100546A1 (en) | 2015-12-09 | 2017-06-15 | Araxes Pharma Llc | Methods for preparation of quinazoline derivatives |
WO2017172979A1 (en) | 2016-03-30 | 2017-10-05 | Araxes Pharma Llc | Substituted quinazoline compounds and methods of use |
ES2863873T3 (es) | 2016-05-18 | 2021-10-11 | Mirati Therapeutics Inc | Inhibidores de KRAS G12C |
US10646488B2 (en) | 2016-07-13 | 2020-05-12 | Araxes Pharma Llc | Conjugates of cereblon binding compounds and G12C mutant KRAS, HRAS or NRAS protein modulating compounds and methods of use thereof |
EP3519402A1 (en) | 2016-09-29 | 2019-08-07 | Araxes Pharma LLC | Inhibitors of kras g12c mutant proteins |
CN110312711A (zh) | 2016-10-07 | 2019-10-08 | 亚瑞克西斯制药公司 | 作为ras抑制剂的杂环化合物及其使用方法 |
RS62456B1 (sr) * | 2016-12-22 | 2021-11-30 | Amgen Inc | Derivati benzizotiazola, izotiazolo[3,4-b]piridina, hinazolina, ftalazina, pirido[2,3-d]piridazina i pirido[2,3-d]pirimidina kao kras g12c inhibitori za tretman raka pluća, pankreasa ili debelog creva |
CN110382483A (zh) | 2017-01-26 | 2019-10-25 | 亚瑞克西斯制药公司 | 稠合的n-杂环化合物及其使用方法 |
JOP20190272A1 (ar) * | 2017-05-22 | 2019-11-21 | Amgen Inc | مثبطات kras g12c وطرق لاستخدامها |
US11639346B2 (en) | 2017-05-25 | 2023-05-02 | Araxes Pharma Llc | Quinazoline derivatives as modulators of mutant KRAS, HRAS or NRAS |
SG11202001499WA (en) | 2017-09-08 | 2020-03-30 | Amgen Inc | Inhibitors of kras g12c and methods of using the same |
EP3788038B1 (en) | 2018-05-04 | 2023-10-11 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
US11045484B2 (en) | 2018-05-04 | 2021-06-29 | Amgen Inc. | KRAS G12C inhibitors and methods of using the same |
WO2019217691A1 (en) | 2018-05-10 | 2019-11-14 | Amgen Inc. | Kras g12c inhibitors for the treatment of cancer |
US11096939B2 (en) | 2018-06-01 | 2021-08-24 | Amgen Inc. | KRAS G12C inhibitors and methods of using the same |
EP3802537A1 (en) | 2018-06-11 | 2021-04-14 | Amgen Inc. | Kras g12c inhibitors for treating cancer |
MX2020012261A (es) | 2018-06-12 | 2021-03-31 | Amgen Inc | Inhibidores de kras g12c que comprenden un anillo de piperazina y uso de estos en el tratamiento del cancer. |
MA52939A (fr) | 2018-06-21 | 2021-04-28 | Janssen Pharmaceutica Nv | Composés inhibiteurs d'oga |
EP3810586A1 (en) | 2018-06-21 | 2021-04-28 | Janssen Pharmaceutica NV | Oga inhibitor compounds |
JP2020090482A (ja) | 2018-11-16 | 2020-06-11 | アムジエン・インコーポレーテツド | Kras g12c阻害剤化合物の重要な中間体の改良合成法 |
JP7377679B2 (ja) | 2018-11-19 | 2023-11-10 | アムジエン・インコーポレーテツド | がん治療のためのkrasg12c阻害剤及び1種以上の薬学的に活性な追加の薬剤を含む併用療法 |
CA3117222A1 (en) | 2018-11-19 | 2020-05-28 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
EP3738593A1 (en) | 2019-05-14 | 2020-11-18 | Amgen, Inc | Dosing of kras inhibitor for treatment of cancers |
AU2020277398A1 (en) | 2019-05-21 | 2021-12-09 | Amgen Inc. | Solid state forms |
EP3972973A1 (en) | 2019-05-21 | 2022-03-30 | Amgen Inc. | Solid state forms |
WO2021081212A1 (en) | 2019-10-24 | 2021-04-29 | Amgen Inc. | Pyridopyrimidine derivatives useful as kras g12c and kras g12d inhibitors in the treatment of cancer |
WO2021097212A1 (en) | 2019-11-14 | 2021-05-20 | Amgen Inc. | Improved synthesis of kras g12c inhibitor compound |
AR120456A1 (es) | 2019-11-14 | 2022-02-16 | Amgen Inc | Síntesis mejorada del compuesto inhibidor de g12c de kras |
US20230028414A1 (en) | 2019-12-16 | 2023-01-26 | Amgen Inc. | Dosing regimen of kras g12c inhibitor |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011075747A1 (en) * | 2009-12-18 | 2011-06-23 | Glaxosmithkline Llc | Therapeutic compounds |
WO2015054572A1 (en) * | 2013-10-10 | 2015-04-16 | Araxes Pharma Llc | Inhibitors of kras g12c |
Non-Patent Citations (2)
Title |
---|
旋光化合物判别方法的研究;李大塘等;《当代教育理论与实践》;20110320(第03期);全文 * |
蓬勃发展的手性化学;张来新等;《化学工程师》;20161125(第11期);全文 * |
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