CN109661387B - 用于治疗肺纤维化的组合物 - Google Patents

用于治疗肺纤维化的组合物 Download PDF

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CN109661387B
CN109661387B CN201780046913.9A CN201780046913A CN109661387B CN 109661387 B CN109661387 B CN 109661387B CN 201780046913 A CN201780046913 A CN 201780046913A CN 109661387 B CN109661387 B CN 109661387B
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dichloromethane
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CN109661387A (zh
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卡伦·安妮特·达根
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Vectus Biosystems Pty Ltd
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Abstract

本发明涉及化合物及其在肺纤维化和/或相关病况的预防性和/或治疗性治疗中的用途。

Description

用于治疗肺纤维化的组合物
发明领域
本申请要求澳大利亚临时专利申请号2016902978(2016年7月28日提交)的优先权，其内容整体结合于此。
本发明涉及化合物及其在肺纤维化和相关病况的预防性和/或治疗性治疗中的用途。
发明背景
在整个说明书中的现有技术的任何讨论决不应被认为是承认这样的现有技术在该领域中是众所周知的或构成公知常识的一部分。
肺纤维化(pulmonary fibrosis)是其中过量的纤维状结缔组织在肺中积聚而导致肺壁增厚并且降低向血液的氧供给的呼吸疾病。因而，患有肺纤维化的受试者遭受呼吸短促。
肺纤维化可以是其他肺病如肺的自身免疫病症、病毒感染和细菌感染(如结核)的继发效应，或者接受了针对肺癌或乳腺癌的放射疗法。肺纤维化还可以是特发性的，并且吸烟、环境因素(例如职业性暴露于气体、烟、化学品、石棉纤维或灰尘)或遗传倾向性(genetic predisposition)被认为是风险因素。
针对肺纤维化的治疗选择非常有限。一些类型的肺纤维化对皮质类固醇或其他免疫抑制剂有反应。然而，这样的治疗产生可变的结果并且在患有特发性肺纤维化的受试者中无效。肺移植是目前在严重的特发性肺纤维化的情况中唯一可用的治疗选择。
肺纤维化可以导致发展肺动脉高压(pulmonary hypertension)、右侧心力衰竭(right-sided heart failure)、呼吸衰竭(respiratory failure)、缺氧(hypoxia)、咳嗽(cough)、血栓形成(formation of blood clots)、肺炎(pneumonia)和肺癌(lungcancer)。
对于预防或治疗肺纤维化和相关病况的药剂存在需求。特别地，对于预防、减轻或延缓肺纤维化的发展或者减轻已经形成的肺纤维化的药剂存在需求。
本发明的目的是克服或改善现有技术的缺点中的至少一个，或者提供有用的备选方案。
发明概述
根据一个方面，本发明提供下式的化合物：
Figure BDA0001960521980000021
或其药理学上可接受的盐、立体异构体、非对映异构体、对映异构体、外消旋体、水合物和/或溶剂化物，
其中：
B选自由下列各项组成的组：
Figure BDA0001960521980000022
R1、R3和R4独立地是C、CH、CH2、O、N、NH或S，
R2是C、CH、CH2、N、NH、C-CF3、CH-CF3或C＝O；
R5至R9独立地是C或N；
Q独立地选自卤素、烷基、羟基、氨基和取代的氨基；
n是0、1、2、3、4或5；
D是：
Figure BDA0001960521980000031
R10至R14独立地是C、N、O或S；
T独立地选自C1-6烷基、卤素、C0-6烷基羧酸、氨基、羟基和C1-6烷氧基；并且
m是0、1、2、3或4，
其中D不能是未取代的苯基，并且当n是1并且R5至R9都是C时Q不能是羟基。
根据另一个方面，本发明提供一种预防性地或治疗性地治疗肺纤维化或者在患有肺纤维化或处于发展肺纤维化的风险下的受试者中的相关病况的方法，所述方法包括向所述受试者施用有效量的下式的化合物：
Figure BDA0001960521980000032
或其药理学上可接受的盐、立体异构体、非对映异构体、对映异构体、外消旋体、水合物和/或溶剂化物，
其中：
B选自由下列各项组成的组：
Figure BDA0001960521980000033
R1、R3和R4独立地是C、CH、CH2、O、N、NH或S，
R2是C、CH、CH2、N、NH、C-CF3、CH-CF3或C＝O；
R5至R9独立地是C或N；
Q独立地选自卤素、烷基、羟基、氨基和取代的氨基；
n是0、1、2、3、4或5；
D是：
Figure BDA0001960521980000041
R10至R14独立地是C、N、O或S；
T独立地选自C1-6烷基、卤素、C0-6烷基羧酸、氨基、羟基和C1-6烷氧基；并且
m是0、1、2、3或4，
其中D不能是未取代的苯基，并且当n是1并且R5至R9都是C时Q不能是羟基。
根据另一个方面，本发明提供下式的化合物或其药理学上可接受的盐、立体异构体、非对映异构体、对映异构体、外消旋体、水合物和/或溶剂化物用于制备药物的用途：
Figure BDA0001960521980000042
所述药物用于预防性地或治疗性地治疗肺纤维化或者在患有肺纤维化或处于发展肺纤维化的风险下的受试者中的相关病况，
其中：
B选自由下列各项组成的组：
Figure BDA0001960521980000051
R1、R3和R4独立地是C、CH、CH2、O、N、NH或S，
R2是C、CH、CH2、N、NH、C-CF3、CH-CF3或C＝O；
R5至R9独立地是C或N；
Q独立地选自卤素、烷基、羟基、氨基和取代的氨基；
n是0、1、2、3、4或5；
D是：
Figure BDA0001960521980000052
R10至R14独立地是C、N、O或S；
T独立地选自C1-6烷基、卤素、C0-6烷基羧酸、氨基、羟基和C1-6烷氧基；并且
m是0、1、2、3或4，
其中D不能是未取代的苯基，并且当n是1并且R5至R9都是C时Q不能是羟基。
根据另一个方面，本发明提供下式的化合物：
Figure BDA0001960521980000053
其中：
B选自由下列各项组成的组：
Figure BDA0001960521980000061
Q独立地选自卤素、烷基、羟基、氨基和取代的氨基；
n是0、1、2、3、4或5；
R1、R3和R4独立地是C、CH、CH2、O、N、NH或S，
R2是C、CH、CH2、N、NH、C-CF3、CH-CF3或C＝O；
R5至R9独立地是C或N；
D是：
Figure BDA0001960521980000062
R10至R14独立地是C、N、O或S；
T独立地选自C1-6烷基、卤素、C0-6烷基羧酸、氨基、羟基和C1-6烷氧基；并且
m是0、1、2、3或4，
其中D不能是未取代的苯基，并且当n是1并且R5至R9都是C时Q不能是羟基，
其用于在预防性地或治疗性地治疗肺纤维化或者在患有肺纤维化或处于发展肺纤维化的风险下的受试者中的相关病况的方法中使用。
根据另一个方面，本发明提供下式的化合物：
Figure BDA0001960521980000071
或其药理学上可接受的盐、立体异构体、非对映异构体、对映异构体、外消旋体、水合物和/或溶剂化物。
根据另一个方面，本发明提供一种预防性地或治疗性地治疗肺纤维化或者在患有肺纤维化或处于发展肺纤维化的风险下的受试者中的相关病况的方法，所述方法包括向所述受试者施用有效量的下式的化合物：
Figure BDA0001960521980000072
或其药理学上可接受的盐、立体异构体、非对映异构体、对映异构体、外消旋体、水合物和/或溶剂化物。
根据另一个方面，本发明提供下式的化合物或其药理学上可接受的盐、立体异构体、非对映异构体、对映异构体、外消旋体、水合物和/或溶剂化物用于制备药物的用途：
Figure BDA0001960521980000073
所述药物用于预防性地或治疗性地治疗肺纤维化或者在患有肺纤维化或处于发展肺纤维化的风险下的受试者中的相关病况。
根据另一个方面，本发明提供下式的化合物：
Figure BDA0001960521980000081
或其药理学上可接受的盐、立体异构体、非对映异构体、对映异构体、外消旋体、水合物和/或溶剂化物，
其用于在预防性地或治疗性地治疗肺纤维化或者在患有肺纤维化或处于发展肺纤维化的风险下的受试者中的相关病况的方法中使用。
根据另一个方面，本发明提供一种预防性地或治疗性地治疗肺纤维化或者在患有肺纤维化或处于发展肺纤维化的风险下的受试者中的相关病况的方法，所述方法包括向所述受试者施用有效量的下式的化合物：
Figure BDA0001960521980000082
或其药理学上可接受的盐、立体异构体、非对映异构体、对映异构体、外消旋体、水合物和/或溶剂化物，
其中：
A选自任选取代的饱和、部分饱和或不饱和的5或6元杂环基；任选取代的C1-6烷氧基胺；任选取代的C1-6烷基胺；任选取代的C0-6烷基羧酸；任选取代的C1-6烷基羟基；任选取代的饱和或不饱和的C0-6烷基双环杂环基；和任选取代的饱和或不饱和的C1-6烷氧基双环杂环基；
B选自由下列各项组成的组：
Figure BDA0001960521980000091
Q独立地选自卤素、烷基、羟基、氨基和取代的氨基；
n是0、1、2、3、4或5；
R1、R3和R4独立地是C、CH、CH2、O、N、NH或S，
R2是C、CH、CH2、N、NH、C-CF3、CH-CF3或C＝O；
R5至R9独立地是C或N；
D是：
Figure BDA0001960521980000092
R10至R14独立地是C、N、O或S；
T独立地选自C1-6烷基、卤素、C0-6烷基羧酸、氨基、羟基和C1-6烷氧基；
m是0、1、2、3或4；并且
X是-OH或
Figure BDA0001960521980000101
根据另一个方面，本发明提供下式的化合物或其药理学上可接受的盐、立体异构体、非对映异构体、对映异构体、外消旋体、水合物和/或溶剂化物用于制备药物的用途：
Figure BDA0001960521980000102
所述药物用于预防性地或治疗性地治疗肺纤维化或者在患有肺纤维化或处于发展肺纤维化的风险下的受试者中的相关病况，
其中：
A选自任选取代的饱和、部分饱和或不饱和的5或6元杂环基；任选取代的C1-6烷氧基胺；任选取代的C1-6烷基胺；任选取代的C0-6烷基羧酸；任选取代的C1-6烷基羟基；任选取代的饱和或不饱和的C0-6烷基双环杂环基；和任选取代的饱和或不饱和的C1-6烷氧基双环杂环基；
B选自由下列各项组成的组：
Figure BDA0001960521980000111
Q独立地选自卤素、烷基、羟基、氨基和取代的氨基；
n是0、1、2、3、4或5；
R1、R3和R4独立地是C、CH、CH2、O、N、NH或S，
R2是C、CH、CH2、N、NH、C-CF3、CH-CF3或C＝O；
R5至R9独立地是C或N；
D是：
Figure BDA0001960521980000112
R10至R14独立地是C、N、O或S；
T独立地选自C1-6烷基、卤素、C0-6烷基羧酸、氨基、羟基和C1-6烷氧基；
m是0、1、2、3或4；并且
X是-OH或
Figure BDA0001960521980000113
根据另一个方面，本发明提供下式的化合物：
Figure BDA0001960521980000121
或其药理学上可接受的盐、立体异构体、非对映异构体、对映异构体、外消旋体、水合物和/或溶剂化物，
其中：
A选自任选取代的饱和、部分饱和或不饱和的5或6元杂环基；任选取代的C1-6烷氧基胺；任选取代的C1-6烷基胺；任选取代的C0-6烷基羧酸；任选取代的C1-6烷基羟基；任选取代的饱和或不饱和的C0-6烷基双环杂环基；和任选取代的饱和或不饱和的C1-6烷氧基双环杂环基；
B选自由下列各项组成的组：
Figure BDA0001960521980000122
Q独立地选自卤素、烷基、羟基、氨基和取代的氨基；
n是0、1、2、3、4或5；
R1、R3和R4独立地是C、CH、CH2、O、N、NH或S，
R2是C、CH、CH2、N、NH、C-CF3、CH-CF3或C＝O；
R5至R9独立地是C或N；
D是：
Figure BDA0001960521980000131
R10至R14独立地是C、N、O或S；
T独立地选自C1-6烷基、卤素、C0-6烷基羧酸、氨基、羟基和C1-6烷氧基；
m是0、1、2、3或4；并且
X是-OH或
Figure BDA0001960521980000132
其用于在预防性地或治疗性地治疗肺纤维化或者在患有肺纤维化或处于发展肺纤维化的风险下的受试者中的相关病况的方法中使用。
根据另一个方面，本发明提供下式的化合物
Figure BDA0001960521980000133
或其药理学上可接受的盐、立体异构体、非对映异构体、对映异构体、外消旋体、水合物和/或溶剂化物。
在一个实施方案中，饱和、部分饱和或不饱和的5或6元杂环基含有N、S或O中的一个或多个，并且被一个或多个氧代基、C1-6烷基、氨基、羟基或卤素取代基任选地取代。
在一个实施方案中，饱和、部分饱和或不饱和的5或6元杂环基选自吡咯基、吡唑基、咪唑基、三唑基、咪唑烷基、吡咯烷基、亚吡咯烷基(pyrrolidinylidene)、二氢吡咯基、异
Figure BDA0001960521980000142
唑基二氢/>
Figure BDA0001960521980000143
唑基、异/>
Figure BDA0001960521980000144
唑烷基、/>
Figure BDA0001960521980000145
唑烷基和/>
Figure BDA0001960521980000146
唑基，并且被一个或多个氧代基、C1-6烷基、氨基、羟基或卤素取代基任选地取代。
在一个实施方案中，C1-6烷氧基胺是氨基氧基甲基。
在一个实施方案中，C1-6烷基胺被C1-6烷基、C1-6卤代烷基、羟基或卤素中的一个或多个，优选单取代的、二取代的或三取代的卤代烷基，最优选三氟甲烷任选地取代。
在一个实施方案中，C0-6烷基羧酸是羧酸。
在一个实施方案中，C1-6烷基羟基是甲基羟基。
在一个实施方案中，C0-6烷基双环杂环基选自吲哚基、异吲哚基、吲哚啉基和异吲哚啉基，并且被一个或多个氧代基、优选二氧代基任选地取代。
在一个实施方案中，C1-6烷氧基双环杂环基选自吲哚基、异吲哚基、吲哚啉基和异吲哚啉，并且被一个或多个氧代基任选地取代，并且其中C1-6烷氧基是甲氧基或乙氧基。
在一个实施方案中，A选自：
Figure BDA0001960521980000141
Figure BDA0001960521980000151
在一个实施方案中，Q是选自由F、Cl、Br和I组成的组的卤素。
在一个实施方案中，Q是式-NHW的取代的氨基，并且其中：
W选自-CN、-SO2(X1)aY和-CO(X1)aY，
a是0或1，
X1选自-NH-和-O-，并且
Y选自-H、-CH3、-CH2CH3、-CH2OH和-CH2CH2OH。
在一个实施方案中，Q是选自由下列各项组成的组的取代的氨基：-NHSO2CH3、-NHCOH、-NHCONHCH3、-NHCONHCH2CH3、-NHSO2NHCH3、-NHSO2NHCH2CH3、-NHCOCH3、-NHCOOCH3、-NHCOOCH2CH2OH、-NHCONH2和-NHCN。
在一个实施方案中，Q是选自由甲基、乙基、丙基、丁基和戊基组成的组的烷基。
在一个实施方案中，B选自：
Figure BDA0001960521980000152
Figure BDA0001960521980000161
在一个实施方案中，B选自：
Figure BDA0001960521980000162
其中Q是取代的氨基，优选-NHSO2CH3、-NHCOH、-NHCONHCH3、-NHCONHCH2CH3、-NHSO2NHCH3、-NHSO2NHCH2CH3、-NHCOCH3、-NHCOOCH3、-NHCOOCH2CH2OH、-NHCONH2或-NHCN，并且n是1或2。
在一个实施方案中，B选自：
Figure BDA0001960521980000163
其中Q是氨基并且n是1或2。
在一个实施方案中，B选自：
Figure BDA0001960521980000171
其中Q是羟基并且n是1或2。
在一个实施方案中，B选自：
Figure BDA0001960521980000172
其中Q是卤素，优选-F或-Cl，并且n是1或2。
在一个实施方案中，B选自：
Figure BDA0001960521980000173
其中Q是烷基，优选-CH3，并且n是1或2。
在一个实施方案中，B选自：
Figure BDA0001960521980000181
其中R15至R17独立地选自卤素、烷基、羟基、氨基和取代的氨基。
在一个实施方案中，D选自：
Figure BDA0001960521980000182
在一个实施方案中，D选自：
Figure BDA0001960521980000183
Figure BDA0001960521980000191
其中T是烷基，优选-CH3，并且m是1或2。
在一个实施方案中，D选自：
Figure BDA0001960521980000192
其中T是C0-6烷基羧酸，优选-C(O)OH，并且m是1或2。
在一个实施方案中，D选自：
Figure BDA0001960521980000193
其中T是卤素，优选-F，并且m是1或2。
在一个实施方案中，D选自：
Figure BDA0001960521980000201
其中T是氨基并且m是1或2。
在一个实施方案中，D选自：
Figure BDA0001960521980000202
其中T是羟基并且m是1或2。
在一个实施方案中，D选自：
Figure BDA0001960521980000203
其中T是C1-6烷氧基，优选-OCH3，并且m是1或2。
在一个实施方案中，D选自：
Figure BDA0001960521980000211
在一个实施方案中，D选自：
Figure BDA0001960521980000212
其中T是烷基，优选-CH3，并且m是1或2。
在一个实施方案中，D选自：
Figure BDA0001960521980000213
其中T是C0-6烷基羧酸，优选-C(O)OH，并且m是1或2。
在一个实施方案中，D选自：
Figure BDA0001960521980000221
其中T是卤素，优选-F，并且m是1或2。
在一个实施方案中，D选自：
Figure BDA0001960521980000222
其中T是氨基并且m是1或2。
在一个实施方案中，D选自：
Figure BDA0001960521980000223
其中T是羟基并且m是1或2。
在一个实施方案中，D选自：
Figure BDA0001960521980000231
其中T是C1-6烷氧基，优选-OCH3，并且m是1或2。
在一个实施方案中，X是-OH。
在一个实施方案中，X是
Figure BDA0001960521980000232
在一个实施方案中，所述化合物选自由下列各项组成的组：
Figure BDA0001960521980000233
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Figure BDA0001960521980000241
/>
Figure BDA0001960521980000251
/>
Figure BDA0001960521980000261
或其药理学上可接受的盐、立体异构体、非对映异构体、对映异构体、外消旋体、水合物和/或溶剂化物。
在一个实施方案中，所述化合物选自由下列各项组成的组：
Figure BDA0001960521980000262
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Figure BDA0001960521980000271
/>
Figure BDA0001960521980000281
/>
Figure BDA0001960521980000291
/>
Figure BDA0001960521980000301
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Figure BDA0001960521980000311
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Figure BDA0001960521980000321
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Figure BDA0001960521980000331
或其药理学上可接受的盐、立体异构体、非对映异构体、对映异构体、外消旋体、水合物和/或溶剂化物。
在一个实施方案中，处于发展肺纤维化的风险下的受试者已经暴露于气体、烟、化学品、石棉纤维或灰尘。
在一个实施方案中，处于发展肺纤维化的风险下的受试者患有肺的自身免疫病症、病毒感染或细菌感染。
在一个实施方案中，处于发展肺纤维化的风险下的受试者已经接受了针对肺癌或乳腺癌的放射疗法。
在一个实施方案中，处于发展肺纤维化的风险下的受试者具有遗传倾向性。
在一个实施方案中，处于发展肺纤维化的风险下的受试者是吸烟者。
在一个实施方案中，所述相关病况选自肺动脉高压、右侧心力衰竭、呼吸衰竭、缺氧、咳嗽、血栓形成、肺炎和肺癌。
在一个实施方案中，预防、减轻或延缓了肺纤维化的发展。
在一个实施方案中，减轻了已经形成的肺纤维化。
除非上下文清楚地另外要求，在整个说明书和权利要求中，词语“包含”、“包括”等应当以与排他或穷举意义相对的包含意义进行解释；即以“包括但不限于”的意义解释。
附图简述
图1：在16周对照(在博来霉素(bleomycin)施用之后两周)中和在用VB0004、A6、A32、A79或赋形剂对照的4周治疗之后20周时的肺纤维化。所有药物以在饮用溶液(5％乙醇)中500pmol/kg/min施用。赋形剂对照是仅饮用溶液。*p<0.001相对于20周对照，#p<0.025相对于16周对照，##p<0.001相对于16周对照。
图2：在16周对照(在博来霉素(bleomycin)施用之后两周)中和在A32、A79、A6、VB0004、P13、D30、D6、A81和赋形剂对照(100％)中的4周治疗之后20周时的肺纤维化(以20周对照的百分数表示)。所有药物以在饮用溶液(5％乙醇)中500pmol/kg/min施用。赋形剂对照是仅饮用溶液。
图3：在人小气道上皮细胞中的细胞阻抗与相比于20周对照的纤维化的百分数降低(即，预防肺纤维化的发展)之间的线性关系(R2＝0.812)。
图4：在人小气道上皮细胞中的细胞阻抗与相比于16周对照的纤维化的百分数降低(即，使已经形成的肺纤维化逆转)之间的线性关系(R2＝0.802)。
图5：在用A6、A26、A27、A30、A32、A35、A56、A79、A81、D4、D5、D6、D10、D11、D12、D16、D17、D18、D28、D30、D31、D32、D35、D167、D171、D172、P13、P14、P25、P42、P43、P44和VB0004治疗的人小气道上皮细胞中测量的细胞阻抗。发现所观察到的负偏转与相比于20周对照的纤维化的百分数降低以及相比于16周对照的百分数降低相关。
发明详述
本发明涉及在预防、减轻或延缓肺纤维化的发展或者减轻已经形成的肺纤维化方面有效的化合物。
本发明的化合物由下式表示：
Figure BDA0001960521980000351
或其药理学上可接受的盐、立体异构体、非对映异构体、对映异构体、外消旋体、水合物和/或溶剂化物，
其中：
B选自由下列各项组成的组：
Figure BDA0001960521980000352
R1、R3和R4独立地是C、CH、CH2、O、N、NH或S，
R2是C、CH、CH2、N、NH、C-CF3、CH-CF3或C＝O；
R5至R9独立地是C或N；
Q独立地选自卤素、烷基、羟基、氨基和取代的氨基；
n是0、1、2、3、4或5；
D是：
Figure BDA0001960521980000361
R10至R14独立地是C、N、O或S；
T独立地选自C1-6烷基、卤素、C0-6烷基羧酸、氨基、羟基和C1-6烷氧基；并且
m是0、1、2、3或4，
其中D不能是未取代的苯基，并且当n是1并且R5至R9都是C时Q不能是羟基。
本发明的另外的化合物由下式表示：
Figure BDA0001960521980000362
或其药理学上可接受的盐、立体异构体、非对映异构体、对映异构体、外消旋体、水合物和/或溶剂化物，
其中：
A选自任选取代的饱和、部分饱和或不饱和的5或6元杂环基；任选取代的C1-6烷氧基胺；任选取代的C1-6烷基胺；任选取代的C0-6烷基羧酸；任选取代的C1-6烷基羟基；任选取代的饱和或不饱和的C0-6烷基双环杂环基；和任选取代的饱和或不饱和的C1-6烷氧基双环杂环基；
B选自由下列各项组成的组：
Figure BDA0001960521980000371
Q独立地选自卤素、烷基、羟基、氨基和取代的氨基；
n是0、1、2、3、4或5；
R1、R3和R4独立地是C、CH、CH2、O、N、NH或S，
R2是C、CH、CH2、N、NH、C-CF3、CH-CF3或C＝O；
R5至R9独立地是C或N；
D是：
Figure BDA0001960521980000372
R10至R14独立地是C、N、O或S；
T独立地选自C1-6烷基、卤素、C0-6烷基羧酸、氨基、羟基和C1-6烷氧基；
m是0、1、2、3或4；并且
X是-OH或
Figure BDA0001960521980000373
本发明的另外的化合物是：
Figure BDA0001960521980000381
以下化合物是本发明的化合物的具体但非限制性的实例：
Figure BDA0001960521980000382
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Figure BDA0001960521980000391
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Figure BDA0001960521980000401
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Figure BDA0001960521980000411
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Figure BDA0001960521980000421
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Figure BDA0001960521980000431
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Figure BDA0001960521980000441
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Figure BDA0001960521980000451
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Figure BDA0001960521980000461
如在本文中所使用的，术语“烷基”单独或组合地意指式-CnH(2n+1)的直链或支链烷基。烷基的实例包括甲基、乙基、正丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、己基、辛基等。
如在本文中所使用的，术语“烷氧基”单独或组合地意指与氧结合的烷基，其中术语烷基是如以上限定的。烷氧基的实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基等。
如在本文中所使用的，术语“卤素”表示-F、-Cl、-Br或-I。
如在本文中所使用的，术语“羟基”表示-OH。
如在本文中所使用的，术语“氨基”或“胺”表示-NH2。
如在本文中所使用的，术语“取代的氨基”包括-NHW，其中W选自-CN、-SO2(X)aY和-CO(X)aY，a是0或1，X选自-NH-和-O-，并且Y选自-H、-CH3、-CH2CH3、-CH2OH和-CH2CH2OH。
如在本文中所使用的，术语“羧酸”表示-C(O)OH。
如在本文中所使用的，术语“氧基”表示-O-。
如在本文中所使用的，术语“氧代基”表示＝O。
如在本文中所使用的，术语“葡糖苷酸(glucuronide)”包括其中葡糖醛酸通过糖苷键与化合物连接的化合物。
如在本文中所使用的，简写Me、Et、Ph、Ms分别表示甲基、乙基、苯基和甲磺酰基。具有本领域普通技术的有机化学家所使用的简写的更全面的列表出现在Journal ofOrganic Chemistry的每一卷的第一期中；该列表通常在题目为标准简写列表的表中给出。在所述列表中包含的简写以及具有本领域普通技术的有机化学家所使用的所有简写通过引用结合于此。
本发明的化合物可以以特定几何或立体异构形式存在。本发明构想了所有这样的化合物，包括顺式-和反式-异构体、(R)-和(S)-对映异构体、非对映异构体、(d)-异构体、(l)-异构体、它们的外消旋混合物以及它们的其他混合物，如落在本发明的范围内。所有这样的异构体以及它们的混合物意图包括在本发明中。
例如，如果需要本发明的化合物的特定对映异构体，则其可以通过非对称合成或通过利用手性助剂的衍生化来制备，其中所得的非对映混合物被分离并且助剂基团被裂开以提供纯的所需对映异构体。备选地，可以使用适当的光学活性的酸或碱来形成非对映盐，接着通过在本领域内公知的分级结晶(fractional crystallization)或色谱手段进行由此形成的非对映异构体的拆分，并且随后回收纯的对映异构体。
通常，通过在例如以下所述的通用反应方案中所示的方法或者通过其变形，使用容易获得的起始材料、试剂和常规合成工艺，可以制备本发明的化合物。在这些反应中，还可以利用本身已知但未在本文中提及的变体。
除了所指出的情况以外，化合物合成方法基于广泛接受的方法，例如其描述于：Michael B.Smith的March's Advanced Organic Chemistry:Reactions,Mechanisms,andStructure(高等有机化学：反应、机理和结构)(2013)；Francis A.Carey和RichardJ.Sunberg的Advanced Organic Chemistry,Part A:Structure and Mechanisms(高等有机化学，A部分：结构和机理)(2008)和Advanced Organic Chemistry:Part B:Reactionand Synthesis(高等有机化学：B部分：反应和合成)(2010)；以及Peter G.M.Wuts的Greene's Protective Groups in Organic Synthesis(有机合成中的保护基团)(2014)。
本发明还构想了化合物的药用盐。术语“药用盐”包括酸和碱加成盐二者并且是指这样的盐，其保留游离碱或酸的生物有效性和性质，并且不是生物学上或其他方面不合乎需要的。药用盐使用无机或有机酸或碱形成，并且可以在化合物的最终分离和纯化期间原位制备，或者通过分别使纯化的化合物以其游离碱或酸形式与适合的有机或无机酸或碱反应并且将由此形成的盐分离而制备。
如在本发明上下文中使用的术语“肺纤维化”是指在肺中过量纤维状结缔组织的形成。肺纤维化可以是其他肺病的继发效应。这样的疾病的实例包括自身免疫病症、病毒感染和细菌感染(如结核)。肺纤维化还可以是特发性的，并且吸烟、环境因素(例如职业性暴露于气体、烟、化学品或灰尘)或遗传倾向性被认为是风险因素。
除了已经形成的纤维化的治疗以外，可以在处于发展肺纤维化的风险下的受试者中预防性地使用本发明的化合物。作为处于发展肺纤维化的风险类别中的受试者的实例是患有肺病(如肺的自身免疫病症、病毒感染或细菌感染)，暴露于气体、烟、化学品、石棉纤维或粉尘，或具有遗传倾向性的受试者，或者吸烟的受试者。如在本发明上下文中使用的术语“预防性”尤其旨在涵盖用于预防或延缓在风险群体中的纤维化的发展的治疗。
在本发明上下文中的术语“相关病况”是指与肺纤维化有关或由肺纤维化引起的任何病况。相关病况的实例包括肺动脉高压、右侧心力衰竭、呼吸衰竭、缺氧、咳嗽、血栓形成、肺炎和肺癌。
本发明还构想了包含本发明的化合物连同药用赋形剂的药物组合物。如在本发明上下文中使用的术语“药用赋形剂”意指组合物的任何药用非活性组分。如在本领域内公知的，赋形剂包括稀释剂、缓冲液、粘合剂、润滑剂、崩解剂、着色剂、抗氧化剂/防腐剂、pH调节剂等。赋形剂基于最终形式的所需物理方面进行选择：例如，获得可迅速分散并且容易吞咽的具有所需硬度和脆性的片剂等。在摄入后活性物质从组合物的所需释放速率也在赋形剂的选择中起作用。药物组合物可以包括任何类型的剂型如片剂、胶囊剂、粉剂、液体制剂、延迟或持续释放剂、贴剂、嗅剂、鼻喷剂等。所考虑的药物组合物的物理形式和含量是可以由在药物制剂领域中的技术人员配制并且基于在例如Remington:The Science andPractice of Pharmacy(雷明顿：药剂科学与实践)，第19版，1995；英国药典2000和类似的制剂教科书和手册中描述的广泛接受的原理和组合物的常规制剂。
例如，在口服施用化合物或组合物的情况下，可以将它们配制为片剂、胶囊剂、颗粒剂、粉剂或糖浆剂；或者对于肠胃外施用，可以将它们配制为注射剂(静脉内、肌内或皮下)、滴注制剂或栓剂。对于通过眼黏膜途径的应用，可以将它们配制为滴眼液或眼软膏。这些制剂可以通过常规手段制备，并且如果需要，活性成分可以与任何常规添加剂(如赋形剂、粘合剂、崩解剂、润滑剂、矫味剂(corrigent)、增溶剂、悬浮助剂、乳化剂或包衣剂)混合。
当将本发明的化合物作为药物施用至人和动物时，它们可以以本身给予或作为含有与药用载体组合的例如0.1至99.5％(更优选0.5至90％)的活性成分的药物组合物给予。
也可以由执业医师容易地确定应当使用的化合物的剂量和施用频率，以产生所需响应。
尽管剂量将根据症状、患者的年龄和体重、待治疗或预防的病症的性质和严重性、施用途径以及药物的形式而变化，通常，0.0001mg至200mg的本发明的化合物的日剂量对于成年人患者可以是合适的有效量，并且其可以以单次剂量或以分次剂量施用。
要通过主题方法治疗的“患者”或“受试者”可以意指人或非人受试者。
对于治疗方法，主题化合物的“有效量”是指在制剂中的治疗剂的量，当作为所需剂量方案的一部分应用时，所述量提供根据用于治疗或预防特定病症的临床可接受的标准的益处。
现在将参照描述具体组合物和使用方法的具体但非限制性的实例来更详细地描述本发明。然而，应当理解，仅出于举例说明本发明的目的而包括具体程序、组合物和方法的详细描述。其不应以任何方式理解为对如上给出的发明构思的广义描述的限制。
实施例
实验例1：化合物的合成
在PCT/AU2014/000923(WO2015/039173)中描述了VB0004的合成，其内容通过引用整体结合于此。
在PCT/AU2016/000095(WO2016/145479)中描述了A32、A6、A30、A56f、A56g、A56、A56k、A26、A27、A31、A35、A45、A79和A81的合成，其内容通过引用整体结合于此。
在PCT/AU2014/000922(WO2015/039172)中描述了T1、T2、T3、T4、T5、T6、T10、T11、T12、T15、T16、T18、T20、T22、T23、T24、T25、T26、T27、T29、T30、T31、T32、T33、T35、T37、T38、T39、T48、T58、T63、T64、T65、T66、T67、T68、T69和T70的合成，其内容通过引用整体结合于此。
在PCT/AU2016/000094(WO2016/145478)中描述了P1、P3、P4、P5、P6、P8、P9、P11、P22、P26、P33、P38、P40、P41、P42、P43、P44、P45、P46、P47、P48、P49、P50和P104的合成，其内容通过引用整体结合于此。
以下示出了P13的合成方案。
Figure BDA0001960521980000501
步骤P13.01：3-[3’-羟基-4-(1-氧化吡嗪-2-基)联苯-2-基]丙酰胺的合成。在20mL微波瓶中装入吡嗪N-氧化物[Fagnou等，JACS 2005,127:18020-1](0.346g，3.60mmol)、碳酸钾(0.497g，3.60mmol)、乙酸钯(0.020g，0.089mmol)、三正丁基
Figure BDA0001960521980000512
四氟硼酸盐(0.052g，0.179mmol)和新戊酸(0.055g，0.541mmol)。加入2-(3-氨基-3-氧代丙基)-3’-羟基联苯-4-基三氟甲磺酸酯(0.700g，1.798mmol)在甲苯(4mL)中的溶液，将瓶在氮气下吹洗10分钟，密封并且回流加热4h。在冷却时，加入氯仿(10mL)，将所得沉淀过滤并且依次用二氯甲烷和乙酸乙酯/甲醇洗涤。将有机物合并，浓缩并且通过急骤色谱(丙酮/二氯甲烷/甲醇)纯化，得到标题化合物，为无色固体(0.460g，76％)。1H NMR(400MHz,DMSO-d6)δppm9.56(s,1H),8.81(s,1H),8.52-8.49(m,1H),8.45(d,J＝4.1Hz,1H),7.78-7.73(m,2H),7.30-7.26(m,1H),7.25(d,J＝8.0Hz,1H),7.22(br.s.,1H),6.80(ddd,J＝0.8,2.3,8.2Hz,1H),6.78-6.75(m,1H),6.75-6.70(m,2H),2.82(dd,J＝6.9,9.1Hz,2H),2.31-2.24(m,2H)。LCMS[M+H]+＝336.2。
步骤P13.02：3-[3’-羟基-4-(吡嗪-2-基)联苯-2-基]丙酰胺(P13)的合成。在氮气气氛下在圆底烧瓶中装入3-[3’-羟基-4-(1-氧化吡嗪-2-基)联苯-2-基]丙酰胺(0.460g，1.37mmol)和甲醇(10mL)。通过使氮气鼓泡通过5分钟将反应混合物脱气，加入10％钯碳(palladium on carbon)(0.046g)并且将反应混合物在氢气气氛下搅拌18h。将混合物通过尼龙过滤器过滤，浓缩并且通过急骤色谱(甲醇/二氯甲烷)纯化，得到浅黄色固体。将固体从氯仿/甲醇中重结晶，得到标题化合物，为无色粉末(0.245g，56％)。1H NMR(400MHz,DMSO-d6)δppm 9.54(s,1H),9.28(d,J＝1.6Hz,1H),8.74(dd,J＝1.6,2.5Hz,1H),8.62(d,J＝2.5Hz,1H),8.10(d,J＝1.8Hz,1H),8.00(dd,J＝2.0,8.0Hz,1H),7.30(d,J＝7.8Hz,1H),7.26(t,J＝7.8Hz,2H),6.83-6.71(m,4H),2.86(dd,J＝6.9,9.1Hz,2H),2.36-2.29(m,2H)。LCMS[M+H]+＝320.1,[M+Na]+＝342.1。
以下示出了P14的合成方案
Figure BDA0001960521980000511
步骤P14.01：3-[3’-羟基-4-(2-氧化哒嗪-3-基)联苯-2-基]丙酰胺的合成。根据步骤P13.01进行制备。将反应混合物回流加热12h。将粗制物料通过急骤色谱(二氯甲烷/丙酮/甲醇)纯化，得到标题化合物，为黄色泡沫状物(0.380g，63％)。1H NMR(400MHz,METHANOL-d4)δppm 8.60(dd,J＝2.3,5.3Hz,1H),8.12(dd,J＝2.3,8.0Hz,1H),7.80(d,J＝1.6Hz,1H),7.75(dd,J＝1.9,7.9Hz,1H),7.45(dd,J＝5.3,8.0Hz,1H),7.33(d,J＝8.0Hz,1H),7.27(t,J＝7.8Hz,1H),6.84-6.79(m,2H),6.78-6.76(m,1H),2.99(dd,J＝7.1,8.7Hz,2H),2.44-2.36(m,2H)。LCMS[M+H]+＝336.1,[M+Na]+＝358.1。
步骤P14.02：3-[3’-羟基-4-(哒嗪-3-基)联苯-2-基]丙酰胺(P14)的合成。根据步骤P13.02，通过在24h之后加入氢氧化铵溶液(2mL)进行制备，得到标题化合物，为无色粉末(0.105g，55％)。1H NMR(400MHz,DMSO-d6)δppm 9.54(s,1H),9.22(dd,J＝1.6,4.9Hz,1H),8.24(dd,J＝1.6,8.6Hz,1H),8.13(d,J＝1.8Hz,1H),8.00(dd,J＝2.0,8.0Hz,1H),7.80(dd,J＝4.9,8.6Hz,1H),7.32(d,J＝7.8Hz,1H),7.29-7.22(m,2H),6.83-6.71(m,4H),2.91-2.83(m,2H),2.36-2.30(m,2H)。LCMS[M+H]+＝320.2,[M+Na]+＝342.2。
以下示出了P25的合成方案
Figure BDA0001960521980000521
步骤P25.01：4-(6-氯嘧啶-4-基)苯酚的合成。在圆底烧瓶中装入在1,4-二
Figure BDA0001960521980000522
烷/水(9:1，100mL)的溶液中的4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(dioxaborolan)-2-基)苯酚(10.0g，0.045mol)、4,6-二氯嘧啶(8.12g，0.055mol)和碳酸铯(29.58g，0.092mol)，并且使氮气鼓泡通过混合物10分钟，之后加入与二氯甲烷复合的[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)(1.85g，2.27mmol)并且将反应混合物回流加热3h。将混合物冷却至室温，过滤，转移至分液漏斗并且在乙酸乙酯(100mL)和水(100mL)之间分配。将水层分离并且用乙酸乙酯(2x 50mL)重新萃取。将有机物合并，用硫酸镁干燥，过滤并且浓缩。将粗制物料通过急骤色谱(乙酸乙酯/己烷)半纯化，得到下一步直接采用的作为混合物的标题化合物(3.8g)。LCMS[M+H]+＝207.1。
步骤P25.02：4-(嘧啶-4-基)苯酚的合成在氮气气氛下在圆底烧瓶中装入4-(6-氯嘧啶-4-基)苯酚(0.20g，0.968mmol)、甲醇(10mL)和氨水(1.5mL的25％溶液)。通过使氮气鼓泡通过5分钟将反应混合物脱气，然后加入10％钯碳(0.020g)并且将反应混合物在氢气气氛下在室温搅拌3h，之后通过滤纸过滤。将滤液浓缩至干燥并且将残余物在乙酸乙酯(20mL)和水(10mL)之间分配。将水相分离，用10％氢氧化钠水溶液碱化，进一步用乙酸乙酯(3x 20mL)萃取，通过加入1M盐酸将pH调节至4，并且将混合物用9/1二氯甲烷/甲醇溶液萃取。将有机相分离，用硫酸镁干燥，过滤并且浓缩，得到标题化合物，为黄色固体(0.08g，80％)。1H NMR(400MHz,DMSO-d6)δppm 10.08(s,1H),9.13(d,J＝1.2Hz,1H),8.74(d,J＝5.5Hz,1H),8.12-8.06(m,2H),7.94(dd,J＝1.4,5.5Hz,1H),6.94-6.88(m,2H)。LCMS[M+H]+＝173.1。
步骤P25.03：2-羟基-5-(嘧啶-4-基)苯甲醛的合成。在圆底烧瓶中装入4-(嘧啶-4-基)苯酚(1.9g 11.04mmol)、三氟乙酸(22mL)和六胺(hexamine)(2.32g，16.5mmol)并且将反应混合物回流加热16h。在冷却至室温时，加入水(100mL)并且继续搅拌另外30分钟，然后将反应混合物转移至分液漏斗并且用二氯甲烷(100mL)萃取。将水层分离并且进一步用二氯甲烷(3x 100mL)萃取。将有机物合并，用水(150mL)、盐水(100mL)洗涤，用硫酸镁干燥，过滤并且浓缩。将粗制物料通过急骤色谱(乙酸乙酯/二氯甲烷/甲醇)纯化，得到标题化合物，为白色固体(0.750g，42％)。1H NMR(400MHz,DMSO-d6)δppm 11.32(br.s.,1H),10.35(s,1H),9.21(d,J＝1.3Hz,1H),8.82(d,J＝5.5Hz,1H),8.55(d,J＝2.3Hz,1H),8.38(dd,J＝2.4,8.7Hz,1H),8.06(dd,J＝1.4,5.5Hz,1H),7.17(d,J＝8.7Hz,1H)。LCMS[M+H]+＝201.1。
步骤P25.04：三氟甲磺酸2-甲酰基-4-(嘧啶-4-基)苯酯的合成。在圆底烧瓶中装入2-羟基-5-(嘧啶-4-基)苯甲醛(0.75g，3.75mmol)、乙腈(30mL)和碳酸钾(1.04g，17.5mmol)。加入N-苯基双(三氟甲磺酰亚胺)(1.47g，4.12mmol)并且将反应混合物在室温搅拌1h。将反应混合物浓缩，在乙酸乙酯(50mL)和水(50mL)之间分配，并且将水相进一步用乙酸乙酯(3x 40mL)萃取。将合并的有机萃取物用盐水洗涤，用硫酸镁干燥，过滤并且浓缩至干燥，得到标题化合物，为黄色固体(1.4g)，其在不进行进一步纯化的情况下使用。1HNMR(400MHz,CHLOROFORM-d)δppm 10.35(s,1H),9.34(d,J＝1.3Hz,1H),8.89(d,J＝5.3Hz,1H),8.69(d,J＝2.3Hz,1H),8.53(dd,J＝2.4,8.7Hz,1H),7.81(dd,J＝1.4,5.3Hz,1H),7.41(d,J＝7.9Hz,1H)。LCMS[M+H]+＝333.0。
步骤P25.05：3’-(苄氧基)-4-(嘧啶-4-基)联苯-2-甲醛的合成。将三氟甲磺酸2-甲酰基-4-(嘧啶-4-基)苯酯(1当量)、杂环硼酸(1.2当量)和碳酸钾(2当量)的混合物悬浮在1,4-二
Figure BDA0001960521980000541
烷(4mL/mmol)和水(5滴/mmol)中。使氮气鼓泡通过混合物15分钟。加入四(三苯基膦)钯(0)(0.1当量)并且将混合物在85℃在氮气下加热20h。将混合物用乙酸乙酯稀释并且过滤。将残余物用乙酸乙酯(2×)洗涤。将合并的滤液蒸发至干燥并且通过急骤色谱(甲醇/二氯甲烷)纯化。将产物悬浮在己烷(4mL)中并且通过过滤分离。将粗制物料通过急骤色谱(乙酸乙酯/二氯甲烷)纯化，得到标题化合物，为橙色油状物(0.400g，91％)。1H NMR(400MHz,CHLOROFORM-d)δppm 10.04(s,1H),9.32(d,J＝1.3Hz,1H),8.84(d,J＝5.4Hz,1H),8.66(d,J＝1.8Hz,1H),8.47(dd,J＝2.0,8.1Hz,1H),7.86(dd,J＝1.5,5.4Hz,1H),7.62(d,J＝8.5Hz,1H),7.47-7.43(m,2H),7.43-7.38(m,3H),7.30(m,1H),7.10(ddd,J＝0.9,2.6,8.4Hz,1H),7.07-7.03(m,1H),7.03-6.98(m,1H),5.13(s,2H)。LCMS[M+H]+＝367.2,[M+Na]+＝389.1。
步骤P25.0：(E)-3-(2-(3-(苄氧基)苯基)-5-(嘧啶-4-基)苯基)丙-2-烯酸的合成。在圆底烧瓶中装入3’-(苄氧基)-4-(嘧啶-4-基)联苯-2-甲醛(0.350g，0.96mmol)和吡啶(11mL)。加入丙二酸(0.120g，1.15mmol)，接着加入哌啶(9.8mg，0.11mmol)，并且将混合物回流加热48h。在冷却至室温时，加入1M盐酸直到达到pH 1-2。将所得悬浮液在冰浴中冷却，过滤，并且将残余物用乙酸乙酯(100ml)萃取并且用盐水(50mL)洗涤。将有机相用硫酸镁干燥，过滤并且浓缩至干燥，得到标题化合物，为橙色固体(0.280g，71％)，其在不进行进一步纯化的情况下使用。1H NMR(400MHz,DMSO-d6)δppm 9.31(d,J＝1.1Hz,1H),8.93(d,J＝5.4Hz,1H),8.65(d,J＝1.8Hz,1H),8.38-8.33(m,2H),7.60(d,J＝4.9Hz,1H),7.57(d,J＝2.9Hz,1H),7.49-7.38(m,5H),7.36-7.31(m,1H),7.13(ddd,J＝0.8,2.6,8.3Hz,1H),7.05-7.02(m,1H),6.97-6.93(m,1H),6.73(d,J＝15.9Hz,1H),5.17(s,2H)。LCMS[M+H]+＝409.2,[M+Na]+＝431.2。
步骤P25.07：(E)-3-(2-(3-(苄氧基)苯基)-5-(嘧啶-4-基)苯基)丙-2-烯酰胺的合成。将草酰氯(0.075mL，0.892mmol)逐滴加入至装有(E)-3-(2-(3’-(苄氧基)苯基)-5-(嘧啶-4-基)苯基)丙-2-烯酸(0.280g，0.686mmol)和二氯甲烷(2.3mL)的圆底烧瓶中。加入催化量的N,N-二甲基甲酰胺，并且将混合物在室温搅拌3h，并且然后浓缩。将残余物溶解在1,4-二
Figure BDA0001960521980000551
烷(10mL)中，在冰浴中冷却并且逐滴加入氨水(0.15mL，25％溶液)。在室温30分钟之后，将反应混合物浓缩至干燥，加入二乙醚并且将浆液过滤。将固体残余物溶解在热甲醇中，过滤并且浓缩至干燥，得到标题化合物，为无色固体(0.267g，96％)。1H NMR(400MHz,DMSO-d6)δppm 9.31(d,J＝1.2Hz,1H),8.93(d,J＝5.4Hz,1H),8.61(d,J＝1.8Hz,1H),8.26(dd,J＝1.9,8.1Hz,1H),8.23(dd,J＝1.4,5.5Hz,1H),7.60(br.s.,1H),7.55(d,J＝8.1Hz,1H),7.49-7.45(m,3H),7.45-7.37(m,3H),7.36-7.33(m,1H),7.16(br.s.,1H),7.12(ddd,J＝0.8,2.6,8.3Hz,1H),7.03-7.00(m,1H),6.94(td,J＝1.0,7.8Hz,1H),6.81(d,J＝15.6Hz,1H),5.16(s,2H)。LCMS[M+H]+＝408.1。
步骤P25.08.3-[3’-羟基-4-(嘧啶-4-基)联苯-2-基]丙酰胺(P25)的合成。在氮气气氛下在圆底烧瓶中装入(E)-3-(2-(3-(苄氧基)苯基)-5-(嘧啶-4-基)苯基)丙-2-烯酰胺(0.250g，0.164mmol)、甲醇(10mL)和氨水(1.5mL的25％溶液)。通过使氮气鼓泡通过5分钟将反应混合物脱气，然后加入10％钯碳(0.025g)并且将反应混合物在氢气气氛下在室温搅拌18h，之后通过滤纸过滤。将残余物用热甲醇洗涤并且将滤液浓缩至干燥，得到无色残余物，其通过反相急骤色谱(甲醇/水)纯化并且用甲醇研磨，得到标题化合物，为灰白色固体(0.036g，18％)。1H NMR(400MHz,METHANOL-d4)δppm 9.19(d,J＝1.2Hz,1H),8.80(d,J＝5.5Hz,1H),8.16(d,J＝1.8Hz,1H),8.07-8.00(m,2H),7.35(d,J＝8.0Hz,1H),7.27(t,J＝7.9Hz,1H),6.84-6.76(m,3H),3.05-2.99(m,2H),2.46-2.39(m,2H)。LCMS[M+H]+＝320.1,[M+Na]+＝342.1。
以下示出了用于制备D4-D18的试剂的合成方案
Figure BDA0001960521980000561
步骤R1.01：5-溴-1,3-二氨基苯的合成。在圆底烧瓶中装入5-溴-1,3-二硝基苯(5.0g，20.2mmol)、乙醇(240mL)和水(120mL)。加入铁粉(13.57g，24.3mmol)，之后加入氯化铵(1.30g，24.3mmol)，并且将所得混合物在85℃搅拌16h。将反应混合物过滤并且浓缩至干燥，得到标题化合物，为黄色固体(4.0g)，其在不进行纯化的情况下使用。1H NMR(400MHz,CHLOROFORM-d)δppm 6.26(d,J＝2.0Hz,2H),5.91(t,J＝2.0Hz,1H),3.59(br.s.,4H)。LCMS[M+H]+＝189.0。
步骤R1.02：(5-溴苯-1,3-二基)二氨基甲酸二叔丁酯的合成在圆底烧瓶中装入5-溴-1,3-二氨基苯(3.7g，19.8mmol)并且在水(20mL)中悬浮。加入二碳酸二叔丁酯(9.50g，43.56mmol)，导致加热和泡腾现象。将反应混合物进一步用水(80mL)稀释，然后在70℃加热5h。在冷却至室温时，加入水(100mL)，并且将沉淀通过过滤收集并且用水充分洗涤。将固体残余物萃取至二氯甲烷(100mL)中，用硫酸镁干燥，过滤并且浓缩至干燥，得到标题化合物，为浅黄色固体(7.4g，96％)。LCMS[M+Na]+＝411.0。
步骤R1.03：(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯-1,3-二基)二氨基甲酸二叔丁酯的合成。在圆底烧瓶中装入(5-溴苯-1,3-二基)二氨基甲酸二叔丁酯(4.00g，10.3mmol)、1,4-二
Figure BDA0001960521980000562
烷(50mL)、双(频哪醇)二硼(2.88g，11.36mmol)和乙酸钾(3.03g，30.9mmol)。使氮气鼓泡通过混合物5分钟，加入与二氯甲烷复合的[1,1’-双(二苯基膦基)-二茂铁]二氯钯(II)(0.420g，0.515mmol)，并且将反应混合物在100℃加热20h。在冷却时，将反应混合物在乙酸乙酯(150mL)和水(20mL)之间分配，将有机相用盐水(20mL)洗涤，用硫酸镁干燥，过滤并且浓缩。将残余物通过急骤色谱(乙酸乙酯/己烷)纯化，得到标题化合物，为浅黄色晶体粉末(0.55g，12％)。1H NMR(400MHz,CHLOROFORM-d)δppm 7.75(t,J＝2.1Hz,1H),7.35(d,J＝2.1Hz,2H),6.45(s,2H),1.50(s,18H),1.31(s,12H)。
步骤R1.04：1,3-二氨基-5-苯硼酸的合成。在圆底烧瓶中装入(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯-1,3-二基)二氨基甲酸二叔丁酯(1.34g，3.08mmol)和氯仿(10mL)，冷却至0℃并且加入三氟乙酸(2.4mL，30.8mmol)。将反应混合物温热至室温，搅拌24h，然后浓缩至干燥。将粗制残余物在氯仿(50mL)和水(50mL)之间分配，将水相用在氯仿(50mL)中的10％甲醇洗涤，通过加入碳酸氢钠将pH调节至7，并且用二氯甲烷洗涤。将水相浓缩至干燥，得到固体残余物，将其用二氯甲烷洗涤，溶解在甲醇中，过滤并且浓缩至干燥，得到标题化合物，为白色固体(0.50g，定量)。1H NMR(400MHz,METHANOL-d4)δppm7.62(br.s.,3H),7.40(br.s.,1H)。LCMS[M+H]+＝153.2。
步骤R1.05：5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-苯-1,3-二胺的合成在圆底烧瓶中装入1,3-二氨基-5-苯硼酸(0.50g，3.30mmol)，并且悬浮在四氢呋喃(10mL)中。加入2,3-二甲基-2,3-丁二醇(0.39g，3.30mmol)并且将反应混合物在室温搅拌24h，并且然后用在二氯甲烷(50mL)中的1％甲醇稀释，用硫酸钠干燥，过滤并且浓缩至干燥，得到标题化合物，为淡绿色固体(0.850g)，其在不进行纯化的情况下使用。LCMS[M+H]+＝235.2。
步骤R1.06：N,N’-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)(苯-1,3-二基)二甲磺酰胺的合成在圆底烧瓶中装入5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-苯-1,3-二胺(0.10g，0.427mmol)、氯仿(2mL)并且冷却至0℃。加入三乙胺(0.298mL，2.14mmol)，接着逐滴加入甲磺酰氯(0.165mL，2.14mmol)。将所得混合物搅拌2h，浓缩至干燥并且将残余物在氯仿(50mL)和水(50mL)之间分配。将水相用氯仿(3x 20mL)洗涤，将有机物合并，用硫酸镁干燥，过滤并且浓缩至干燥。将固体残余物用醚研磨，得到标题化合物，为白色固体(0.10g，43％)。1H NMR(400MHz,CHLOROFORM-d)δppm 7.90(d,J＝2.1Hz,2H),7.44(t,J＝2.1Hz,1H),3.40(s,12H),1.35(s,12H)。
以下示出了用于制备D4-D18的另外的试剂的合成方案
Figure BDA0001960521980000581
步骤R2.01：N-(4-溴吡啶-2-基)-N-(甲磺酰基)甲磺酰胺的合成。在圆底烧瓶中装入2-氨基-4-溴吡啶(1.0g，5.78mmol)和氯仿(10mL)，冷却至0℃并且加入三乙胺(2.41mL，17.34mmol)，接着逐滴加入甲磺酰氯(1.34mL，17.34mmol)。将反应混合物在0℃搅拌1h，在室温1h，并且然后浓缩至干燥。加入二乙醚(50mL)并且将悬浮液搅拌30分钟并且过滤。将固体残余物萃取至二氯甲烷(100mL)中，用水(50mL)洗涤，将有机相用硫酸镁干燥，过滤并且浓缩至干燥，得到含有大约15％的单磺酰化产物的标题化合物，为白色粉末(1.3g)。LCMS[M+H]+＝330.9,[M+Na]+＝352.9。
步骤R2.02：N-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-2-基)-N-(甲磺酰基)甲磺酰胺的合成。在20mL微波瓶中装入N-(4-溴吡啶-2-基)-N-(甲磺酰基)甲磺酰胺(0.500g，1.52mmol)、1,4-二
Figure BDA0001960521980000582
烷(5mL)、双(频哪醇)二硼(0.490g，1.67mmol)和乙酸钾(0.450g，4.56mmol)，并且使氮气鼓泡通过混合物5分钟。加入与二氯甲烷复合的[1,1’-双(二苯基膦基)-二茂铁]二氯钯(II)(0.062g，0.076mmol)，将瓶密封并且将混合物在90℃加热12h。在冷却时，加入乙酸乙酯(100mL)，将混合物转移至分液漏斗并且用水(50mL)洗涤。将有机相用0.01M盐酸洗涤，将合并的水相用乙酸乙酯(2x 20mL)重新萃取，将合并的有机物用盐水洗涤，干燥(硫酸镁)，过滤并且浓缩至干燥。将粗制残余物用乙酸乙酯/己烷洗涤并且过滤，得到标题化合物，为白色固体(0.120g，23％)。1H NMR(400MHz,DMSO-d6)δppm8.62(dd,J＝0.9,4.7Hz,1H),7.79(t,J＝0.9Hz,1H),7.71(dd,J＝0.9,4.7Hz,1H),3.65(s,6H),1.34(s,12H)。LCMS(硼酸)[M+H]+＝295.0,[M+Na]+＝317.0。
以下示出了D4的合成方案
Figure BDA0001960521980000591
步骤D4.01：3-(2-溴-5-(嘧啶-5-基)苯基)丙-2-烯酰胺的合成。在圆底烧瓶中装入3-(2-溴-5-碘苯基)丙-2-烯酰胺(1.0g，1.70mmol))、嘧啶5-硼酸(0.211g，1.7mmol)、碳酸铯(1.11g，3.4mmol)、1,4-二
Figure BDA0001960521980000592
烷(20mL)和水(3.5mL)，并且使氮气鼓泡通过混合物5分钟。加入与二氯甲烷复合的[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)(0.070g，0.08mmol)并且将混合物加热回流2h。在冷却时，加入乙酸乙酯(50mL)，将混合物转移至分液漏斗并且用水(25mL)洗涤。将水相用乙酸乙酯(25mL)重新萃取，将有机物合并，干燥(硫酸镁)，过滤并且浓缩至干燥。将残余物在二氯甲烷(50mL)中搅拌，将固体物料过滤，用二氯甲烷洗涤并且干燥，得到标题化合物，为灰色粉末(0.167g，32％)。1H NMR(400MHz,DMSO-d6)δppm 9.23(s,1H),9.22(s,2H),8.11(d,J＝2.15Hz,1H),7.86(d,J＝8.40Hz,1H),7.76(dd,J＝8.40,2.34Hz,1H),7.70(d,J＝15.63Hz,1H),7.56(bs,1H),6.83(d,J＝15.63Hz,1H),7.27(bs,1H)。LCMS[M+H]+＝304.1,306.1,[M+Na]+＝326.0,328.0。
步骤D4.02：3-(2-溴-5-(嘧啶-5-基)苯基)丙酰胺的合成[根据Monatshefte furChemie；vol.147；nb.3；(2016)；p.509-521调整]。在具有回流冷凝器的圆底烧瓶中装入3-(2-溴-5-(嘧啶-5-基)苯基)丙-2-烯酰胺(0.200g，0.658mmol)、二氯甲烷(10mL)、甲醇(10mL)、偶氮二甲酸钾(0.639g，3.29mmol)和乙酸(0.188mL，3.29mmol)。将反应混合物在45-50℃搅拌3天，然后冷却至室温并且用二氯甲烷(50mL)和水(50mL)稀释。将混合物振荡，然后将水层分离并且进一步用二氯甲烷(50mL)萃取。将有机物合并，用盐水(25mL)洗涤，用硫酸镁干燥，过滤并且浓缩，得到标题化合物，为棕色粉末(0.147g，73％)。1H NMR(400MHz,DMSO-d6)δppm 9.20(s,1H),9.14(s,2H),7.78(d,J＝2.34Hz,1H),7.74(d,J＝8.40Hz,1H),7.60(dd,J＝8.40,2.34Hz,1H),7.29-7.37(m,1H),6.83(bs,1H),2.94-3.02(m,2H),2.41-2.48(m,2H)。LCMS[M+H]+＝306.0,308.0,[M+Na]+＝328.0,330.0,[M-H+CH3OOH]-＝350.0,352.1。
步骤D4.03：3-(3’,5’-双((甲磺酰基)氨基)-4-(嘧啶-5-基)联苯-2-基)丙酰胺(D4)的合成。在氮气气氛下在微波瓶中装入3-(2-溴-5-(嘧啶-5-基)苯基)丙酰胺(0.147g，0.480mmol)、3,5-双((甲磺酰基)氨基)苯基硼酸、频哪醇酯(0.262g，0.480mmol)、1,4-二
Figure BDA0001960521980000602
烷(5mL)、水(0.5mL)和碳酸铯(0.626g，1.92mmol)。将混合物搅拌并且通过使氮气鼓泡通过5分钟进行脱气，然后加入与二氯甲烷复合的[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)(0.020g，0.024mmol)。将反应容器盖上并且将反应混合物在回流下搅拌2.5h。将反应混合物冷却至室温并且用乙酸乙酯(50mL)和水(25mL)稀释。用盐酸溶液将水层调节至pH 5-6，并且将两层充分混合。将水层分离并且用二氯甲烷/甲醇(100mL的1:1混合物)萃取。将有机物合并，用盐水(25mL)洗涤，用硫酸镁干燥，过滤并且浓缩。将残余物在热乙酸乙酯(50mL)中研磨10分钟，然后使其冷却至室温。将所得固体通过过滤收集，用乙酸乙酯(3x 15mL)洗涤并且风干。将固体在热二氯甲烷/甲醇(20mL的1:1混合物)中以相同方式研磨，得到标题化合物，为米黄色粉末(0.058g，25％)。来自第二研磨过程的滤液含有不纯的产物，其通过急骤色谱(二氯甲烷/甲醇)纯化，得到第二批标题化合物，为米黄色粉末(0.022g，9％)。将其与第一样品均化。1H NMR(400MHz,DMSO-d6)δppm 9.97(bs,2H),9.21(s,1H),9.19(s,2H),7.78(s,1H),7.71(d,J＝8.01Hz,1H),7.34(d,J＝8.01Hz,1H),7.24(bs,1H),7.18(s,1H),6.92(d,J＝1.56Hz,2H),6.76(bs,1H),3.06(s,6H),2.84(t,J＝7.91Hz,2H),2.28-2.41(m,2H)。LCMS[M+H]+＝490.1,[M+Na]+＝512.1,[M-H]-＝488.2。
以下示出了D5的合成方案：
Figure BDA0001960521980000601
步骤D5.01：(2E)-3-[2-(苄氧基)-5-(嘧啶-5-基)苯基]丙-2-烯酰胺的合成。在圆底烧瓶中装入(2E)-3-[2-(苄氧基)-5-溴苯基]丙-2-烯酰胺(1.5g，4.51mmol)、嘧啶5-硼酸(0.671g，5.41mmol)、碳酸钾(1.24g，9.0mmol)、1,4-二
Figure BDA0001960521980000611
烷(25mL)、乙醇(5mL)和水(2mL)，并且使氮气鼓泡通过混合物5分钟。加入四(三苯基膦)钯(0.26g，0.225mmol)并且将混合物在12h内加热至80℃。在冷却时，加入乙酸乙酯(20mL)，将混合物过滤，将有机相分离，干燥(硫酸镁)，过滤并且浓缩至干燥。将粗制物料用乙酸乙酯研磨，得到标题化合物，为灰白色固体(1.15g，77％)。LCMS[M+H]+＝332.2。
步骤D5.02：3-[2-羟基-5-(嘧啶-5-基)苯基]丙酰胺的合成。在圆底烧瓶中装入(2E)-3-[2-(苄氧基)-5-(嘧啶-5-基)苯基]丙-2-烯酰胺(0.440g，1.33mmol)、甲醇(25mL)和25％氨水溶液(2.5mL)。在氮气气氛下加入10重量％钯碳(0.044g)。将混合物用氢气冲灌并且在氢气气氛下在室温搅拌48h。将反应混合物通过硅藻土塞过滤，并且将硅藻土用沸腾甲醇(2x 50mL)冲洗。将滤液合并，浓缩并且在二氯甲烷(50mL)和水(50mL)之间分配。用稀盐酸(aq)将水相调节至pH 4-5并且用二氯甲烷(50mL)和乙酸乙酯(50mL)重新萃取。将有机物合并，干燥(硫酸镁)，过滤并且浓缩，得到标题化合物，为灰白色固体(0.025g，8％)。1HNMR(400MHz,DMSO-d6)δppm9.78(s,1H),9.08(s,1H),9.00-9.06(m,2H),7.53(d,J＝2.34Hz,1H),7.47(dd,J＝8.30,2.44Hz,1H),7.30(br.s.,1H),6.92(d,J＝8.40Hz,1H),6.79(br.s.,1H),2.80(t,J＝7.72Hz,2H),2.40(t,J＝7.81Hz,2H)。将水相浓缩至干燥，得到标题化合物，为粗制灰白色固体(0.298g)。
步骤D5.03：三氟甲磺酸2-(3-氨基-3-氧代丙基)-4-(嘧啶-5-基)苯酯的合成。在氮气气氛下在圆底烧瓶中装入3-(2-羟基-5-(嘧啶-5-基)苯基)丙酰胺(0.323g，1.33mmol)、碳酸钾(0.551g，3.98mmol)和乙腈(20mL)。将反应混合物在冰浴中冷却至<10℃并且加入N-苯基双(三氟甲磺酰亚胺)(0.498g，1.39mmol)。使反应混合物温热至室温并且搅拌12h。将反应混合物浓缩至干燥，在乙酸乙酯(100mL)和水(100mL)之间分配。将水相用乙酸乙酯(50mL)重新萃取，将有机相合并，用盐水(25mL)洗涤，干燥(硫酸镁)，过滤并且浓缩。将粗制物料通过急骤色谱(二氯甲烷/丙酮)纯化，得到标题化合物，为灰白色固体(0.314g，63％)。1H NMR(400MHz,DMSO-d6)δppm 9.23(s,1H),9.18(s,2H),7.90-7.98(m,1H),7.85(dd,J＝8.50,2.25Hz,1H),7.55(d,J＝8.40Hz,1H),7.35(bs,1H),6.84(bs,1H),2.96(t,J＝7.62Hz,2H),2.51-2.57(m,2H)。LCMS[M+H]+＝376.0,[M+Na]+＝398.0。
步骤D5.04：(2-(6-氨基嘧啶-4-基)-5-(嘧啶-5-基)苄基)丙二酸二乙酯(D5)的合成。在装有回流冷凝器并且在氮气气氛下的圆底烧瓶中装入三氟甲磺酸2-(3-氨基-3-氧代丙基)-4-(嘧啶-5-基)苯酯(0.244g，0.649mmol)、N-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)(吡啶-2-基)甲磺酰胺(0.513g，1.36mmol)、碳酸钾(0.351g 2.54mmol)、1,4-二
Figure BDA0001960521980000621
烷(10.2mL)、乙醇(3.9mL)和水(3.9mL)。通过使氮气鼓泡通过2分钟将反应混合物脱气，然后加入四(三苯基膦)钯(0.075g，0.652mmol)并且将反应混合物在85℃搅拌2.5h。将反应混合物冷却至室温并且在乙酸乙酯(75mL)和水(30mL)之间分配。将混合物转移至分液漏斗，将水层(pH 6-7)分离并且静置五天，在此期间固体析出。将固体通过过滤收集并且在二氯甲烷/甲醇(4:1，50mL)中搅拌。将固体通过过滤收集并且用甲醇(10mL)洗涤，得到标题化合物。将有机滤液浓缩并且将所得固体在沸腾的水/甲醇(5:1，24mL)中搅拌并且作为热混合物过滤。将滤液冷却至室温并且静置18h，在此期间固体析出(标题化合物)。将残余滤液浓缩至干燥，得到第三批标题化合物。将样品均化，得到标题化合物，为灰白色粉末(0.059g，23％)。1H NMR(400MHz,DMSO-d6)δppm 9.22(s,1H),9.19(s,2H),8.29(s,1H),7.82(d,J＝1.56Hz,1H),7.75(dd,J＝7.91,1.86Hz,1H),7.35(d,J＝8.01Hz,1H),7.27(bs,1H),7.01(bs,1H),6.92(s,1H),6.76(bs,1H),3.29(s,3H),2.84(t,J＝7.81Hz,2H),2.34-2.42(m,2H)。LCMS[M+H]+＝398.1,[M+Na]+＝420.1,[M-H]-＝396.1。
以下示出了D6的合成方案
Figure BDA0001960521980000631
步骤D6.01：2-(苄氧基)-5-溴-苯甲醛的合成。在装有回流冷凝器的圆底烧瓶中装入5-溴-2-羟基苯甲醛(10.0g，0.050mol)、碳酸钾(8.94g，0.065mol)、乙腈(100mL)和苄基溴(11.1g，0.065mol)。将反应混合物在70℃搅拌16h，然后冷却并且浓缩。将残余物在乙酸乙酯(100mL)和水(100mL)之间分配，并且将水层分离并且进一步用乙酸乙酯(100mL)萃取。将有机物合并，用盐水(50mL)洗涤，干燥(硫酸镁)，过滤并且浓缩。将油状物在己烷(250mL)中搅拌，在冰浴中冷却1h，并且将所得固体通过真空过滤收集，用己烷(3x 25mL)洗涤并且风干，得到标题化合物，为灰白色固体(10.5g，73％)。1H NMR(400MHz,CDCl3)δppm 10.46(s,1H),7.95(d,J＝2.54Hz,1H),7.60(dd,J＝8.89,2.64Hz,1H),7.32-7.46(m,5H),6.95(d,J＝8.99Hz,1H),5.18(s,2H)。LCMS[M+Na]+＝313.0,315.0。
步骤D6.02：苄基4-溴-2-(羟甲基)苯基醚的合成。在匹配的圆底烧瓶中装入2-(苄氧基)-5-溴-苯甲醛(10.5g，0.036mol)和甲醇(200mL)。将反应混合物在冰浴中搅拌并且冷却20分钟，然后在伴随气体释放的情况下逐份加入硼氢化钠(1.51g，0.040mol)。将反应混合物搅拌并且使其在1-2h内温热至室温。将反应混合物浓缩至接近干燥并且将残余物在乙酸乙酯(150mL)和碳酸氢钠溶液(150mL)之间分配。将水相分离并且进一步用乙酸乙酯(100mL)萃取。将有机物合并，用盐水(50mL)洗涤，干燥(硫酸镁)，过滤并且浓缩，得到标题化合物，为橙色油状物(10.6g，100％)。1H NMR(400MHz,CDCl3)δppm 7.46(d,J＝2.34Hz,1H),7.37-7.42(m,4H),7.31-7.37(m,2H),6.81(d,J＝8.79Hz,1H),5.09(s,2H),4.70(d,J＝6.25Hz,2H),2.17(t,J＝6.45Hz,1H)。LCMS[M-H2O+H]+＝275.0,277.0,[M+Na]+＝315.0,317.0。
步骤D6.03：苄基4-溴-2-(溴甲基)苯基醚的合成。在装有回流冷凝器并且在氮气气氛下的圆底烧瓶中装入苄基4-溴-2-(羟甲基)苯基醚(10.6g，0.036mol)和无水甲苯(110mL)。将反应混合物在冰浴中搅拌并且冷却20分钟，然后缓慢加入三溴化磷(11.3g，0.042mol)。将反应混合物在冰浴中搅拌并且冷却20分钟，然后使其在30分钟内温热至室温。然后将反应混合物在回流下搅拌1.5h并且冷却至室温。将水(110mL)加入至混合物中，将其搅拌15分钟，然后转移至具有乙酸乙酯(50mL)的分液漏斗并且剧烈振荡。将水层分离并且进一步用乙酸乙酯(50mL)萃取。将有机物合并，用水(50mL)、盐水(50mL)洗涤，干燥(硫酸镁)，过滤并且浓缩，得到标题化合物，为深色油状物(12.4g，96％)。1H NMR(400MHz,CDCl3)δppm 7.43-7.49(m,3H),7.37-7.43(m,2H),7.32–7.37(m,2H),6.79(d,J＝8.79Hz,1H),5.14(s,2H),4.52(s,2H)。GCMS m/z＝354,356,358。
步骤D6.04：2-(5-溴-2-(苯基甲氧基)苄基)丙二酸1,3-二乙酯的合成。在装有回流冷凝器并且在氮气气氛下的圆底烧瓶中装入丙二酸二乙酯(5.52g，0.034mol)和1,2-二甲氧基乙烷(50mL)。在伴随剧烈气体释放的情况下将氢化钠(1.26g的在油中的60％分散液，0.032mol)逐份加入至搅拌溶液中。将反应混合物搅拌20分钟，然后缓慢加入4-溴-2-(溴甲基)-1-(苯基甲氧基)苯(10.2g，0.029mol)在1,2-二甲氧基乙烷(50mL)中的溶液。将反应在回流下搅拌24h，然后冷却至室温并且用水(50mL)猝灭。将混合物用乙酸乙酯(2x100mL)萃取并且将有机物合并，用盐水(50mL)洗涤，干燥(硫酸镁)，过滤并且浓缩。将油状物通过急骤色谱(乙酸乙酯/己烷)纯化，得到标题化合物，为无色油状物(11.3g，90％)。1HNMR(400MHz,CDCl3)δppm 7.35-7.43(m,4H),7.27-7.35(m,3H),6.75(d,J＝8.40Hz,1H),5.09(s,2H),4.08-4.18(m,4H),3.83(t,J＝7.82Hz,1H),3.21(d,J＝7.62Hz,2H),1.16-1.23(m,6H)。LCMS[M+H]+＝435.0,437.0,[M+Na]+＝457.0,459.0。
步骤D6.05：2-(2-(苯基甲氧基)-5-(嘧啶-5-基)苄基)丙二酸1,3-二乙酯的合成。在装有回流冷凝器并且在氮气气氛下的圆底烧瓶中装入2-(5-溴-2-(苯基甲氧基)苄基)丙二酸1,3-二乙酯(7.37g，16.9mmol)、嘧啶-5-硼酸(2.73g，22.0mmol)、碳酸钾(7.02g，50.7mmol)、甲苯(290mL)、乙醇(185mL)和水(105mL)。通过使氮气鼓泡通过10分钟将反应混合物脱气，然后加入四(三苯基膦)钯(1.96g，1.69mmol)。将反应混合物在85℃搅拌2.5h，然后冷却至室温，用乙酸乙酯(100mL)稀释并且转移至分液漏斗。在剧烈振荡之后，将水层(pH～10)分离并且进一步用乙酸乙酯(100mL)萃取。将有机物合并，用盐水(3x 100mL)洗涤，干燥(硫酸镁)，过滤并且浓缩。将粗制油状物通过急骤色谱(乙酸乙酯/己烷)纯化，得到标题化合物，为深琥珀色油状物(3.18g，43％)。1H NMR(400MHz,CDCl3)δppm 9.15(s,1H),8.88(s,2H),7.30-7.49(m,7H),7.02(d,J＝8.21Hz,1H),5.19(s,2H),4.06-4.20(m,4H),3.92(t,J＝7.72Hz,1H),3.34(d,J＝7.62Hz,2H),1.17(t,J＝7.13Hz,6H)。LCMS[M+H]+＝435.2,[M+Na]+＝457.1。
步骤D6.06：2-(2-羟基-5-(嘧啶-5-基)苄基)丙二酸1,3-二乙酯的合成。在氮气气氛下在圆底烧瓶中装入2-(2-(苯基甲氧基)-5-(嘧啶-5-基)苄基)丙二酸1,3-二乙酯(0.659g，1.52mmol)和乙酸乙酯(10mL)。通过使氮气鼓泡通过5分钟将反应混合物脱气，然后加入10％钯碳(0.066g)，之后加入三乙胺(0.211mL)。将反应混合物在氢气气氛下在45℃搅拌3天，然后通过硅藻土过滤。将硅藻土用乙酸乙酯(3x 15mL)洗涤并且将滤液合并并且浓缩，得到标题化合物，为乳霜状固体(0.471g，90％)。1H NMR(400MHz,CDCl3)δppm 9.15(s,1H),8.88(s,2H),7.37(dd,J＝8.21,2.34Hz,1H),7.34(d,J＝2.34Hz,1H),7.03(d,J＝8.21Hz,1H),4.21(m,4H),3.78(t,J＝7.03Hz,1H),3.25(d,J＝7.03Hz,2H),1.24(t,J＝7.13Hz,6H)。LCMS[M+H]+＝345.2,[M+Na]+＝367.1。
步骤D6.07：2-(((2-三氟甲基)磺酰基)氧代)-5-(嘧啶-5-基)-苄基)丙二酸1,3-二乙酯的合成。在氮气气氛下在圆底烧瓶中装入2-(2-羟基-5-(嘧啶-5-基)苄基)丙二酸1,3-二乙酯(0.471g，1.37mmol)、碳酸钾(0.388g，2.80mmol)和乙腈(10mL)。将反应混合物在冰浴中冷却至<10℃并且加入N-苯基双(三氟甲磺酰亚胺)(0.513g，1.44mmol)。将反应混合物搅拌并且使其温热至室温。在4.5h之后，将反应混合物直接加载至二氧化硅上并且通过急骤色谱(乙酸乙酯/己烷)纯化，得到标题化合物，为黄色油状物(0.614g，94％)。1H NMR(400MHz,CDCl3)δppm 9.26(s,1H),8.92(s,2H),7.59(d,J＝2.1Hz,1H),7.54(dd,J＝2.2,8.5Hz,1H),7.46(d,J＝8.6Hz,1H),4.26-4.11(m,4H),3.76(t,J＝7.7Hz,1H),3.41(d,J＝7.8Hz,2H),1.22(t,J＝7.1Hz,6H)。LCMS[M+H]+＝477.1,[M+Na]+＝499.0。
步骤D6.08：2-(5-(嘧啶-5-基)-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)丙二酸1,3-二乙酯的合成。在微波瓶中装入2-(((2-三氟甲基)磺酰基)氧代)-5-(嘧啶-5-基)-苄基)丙二酸1,3-二乙酯(0.600g，1.26mmol)、双(频哪醇)二硼(0.800g，3.15mmol)、乙酸钾(0.371g，3.78mmol)和1,4-二
Figure BDA0001960521980000661
烷(10mL)。通过使氮气鼓泡通过5分钟将反应混合物脱气，然后加入与二氯甲烷复合的[1,1’-双(二苯基膦基)-二茂铁]二氯钯(II)(0.103g，0.126mmol)。将反应容器盖上并且在微波炉中将混合物在105℃加热3h。将反应混合物在乙酸乙酯(25mL)和水(25mL)之间分配并且用碳酸钠溶液将水相调节至pH>10。将有机物收集，用盐水(10mL)洗涤，干燥(硫酸镁)，过滤并且浓缩。将粗制固体通过急骤色谱(乙酸乙酯/己烷)纯化，得到标题化合物，为粉色油状物(0.457g，80％)。1H NMR(400MHz,CDCl3)δppm 9.21(s,1H),8.93(s,2H),7.95(d,J＝8.40Hz,1H),7.42-7.46(m,2H),4.09-4.20(m,4H),3.75-3.81(m,1H),3.54(d,J＝7.62Hz,2H),1.37(s,12H),1.16-1.22(m,6H)。LCMS[M+H]+＝455.2
步骤D6.09：2-(2-(6-氨基-嘧啶-4-基)-5-(嘧啶-5-基)苄基)丙二酸1,3-二乙酯的合成。在装有回流冷凝器并且在氮气气氛下的圆底烧瓶中装入2-(5-(嘧啶-5-基)-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基)丙二酸1,3-二乙酯(0.577g，1.27mmol)、4-氨基-6-氯嘧啶(0.181g 1.40mmol)、碳酸钾(0.351g 2.54mmol)、1,4-二
Figure BDA0001960521980000662
烷(4mL)、乙醇(1mL)和水(1mL)。通过使氮气鼓泡通过2分钟将反应混合物脱气，然后加入四(三苯基膦)钯(0.146g，0.127mmol)并且将反应混合物在85℃搅拌2.5h。将反应混合物冷却至室温并且在乙酸乙酯(100mL)和水(25mL)之间分配。将有机物收集，用盐水(25mL)洗涤，干燥(硫酸镁)，过滤并且浓缩。将残余物通过急骤色谱(二氯甲烷/甲醇)纯化，得到作为与3-(2-(6-氨基嘧啶-4-基)-5-(嘧啶-5-基)苯基)丙酸乙酯(LCMS[M+H]+＝350.2)的复杂混合物的标题化合物(0.093g，17％)(LCMS[M+H]+＝422.2)。将水性洗出液合并并且用2M盐酸酸化至pH～3，然后用二氯甲烷/甲醇(9:1，3x 25mL)萃取。将有机物合并，用盐水(10mL)洗涤，干燥(硫酸镁)，过滤并且浓缩，得到含有2-(2-(6-氨基嘧啶-4-基)-5-(嘧啶-5-基)苄基)-3-乙氧基-3-氧代丙酸(LCMS[M+H]+＝394.1)、标题化合物和其他杂质的残余物(0.202g)。将酸性水性洗出液浓缩至干燥并且将残余物用乙酸乙酯/甲醇(9:1，2x 25mL)萃取。将萃取物合并并且浓缩，得到含有(2-(6-氨基嘧啶-4-基)-5-(嘧啶-5-基)苄基)丙二酸(LCMS[M+H]+＝366.1)、2-(2-(6-氨基嘧啶-4-基)-5-(嘧啶-5-基)苄基)-3-乙氧基-3-氧代丙酸(LCMS[M+H]+＝394.1)和其他杂质的残余物(0.228g)。将含有标题化合物和其他水解类似物的残余物合并并且在下一步中使用。
步骤D6.10：3-(2-(6-氨基嘧啶-4-基)-5-(嘧啶-5-基)苯基)丙酸甲酯的合成。在装有回流冷凝器的圆底烧瓶中装入2-(2-(6-氨基嘧啶-4-基)-5-(嘧啶-5-基)苄基)丙二酸1,3-二乙酯(0.523g，1.24mmol)和硫酸(5mL的2M水溶液)。将反应混合物在回流下搅拌24h，然后冷却并且从甲醇(150mL)中浓缩三次。将残余物在甲醇中在室温搅拌过夜，然后浓缩。在伴随气体释放的情况下将残余物在乙酸乙酯(100mL)和碳酸氢钠溶液(50mL)之间分配。将有机物收集并且将碱性水层进一步用乙酸乙酯(50mL)萃取。将有机物合并，用盐水(50mL)洗涤，干燥(硫酸镁)，过滤并且浓缩。将残余物通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为灰白色粉末(0.075g，18％)。1H NMR(400MHz,DMSO-d6)δppm 9.17-9.23(m,3H),8.43(d,J＝0.98Hz,1H),7.81(d,J＝1.76Hz,1H),7.75(dd,J＝7.91,1.86Hz,1H),7.45(d,J＝8.01Hz,1H),6.96(s,2H),6.52(d,J＝1.17Hz,1H),3.55(s,3H),3.04(t,J＝7.91Hz,2H),2.67(t,J＝8.01Hz,2H)。LCMS[M+H]+＝336.2。
步骤D6.11：3-(2-(6-氨基嘧啶-4-基)-5-(嘧啶-5-基)苯基)丙酰胺(D6)的合成。在微波瓶中装入3-(2-(6-氨基嘧啶-4-基)-5-(嘧啶-5-基)苯基)丙酸甲酯(0.075g，0.224mmol)和氨溶液(5mL的在甲醇中的7N)。将容器盖上并且将反应混合物在60℃搅拌5天。将反应混合物冷却并且直接加载至二氧化硅上并且通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为粉色粉末(0.051g，71％)。1H NMR(400MHz,DMSO-d6)δppm 9.21(s,1H),9.19(s,2H),8.40-8.46(m,1H),7.76-7.80(m,1H),7.73(dd,J＝8.01,1.76Hz,1H),7.45(d,J＝8.01Hz,1H),7.26(bs,1H),6.96(s,2H),6.74(bs,1H),6.52(d,J＝1.17Hz,1H),2.95-3.02(m,2H),2.36-2.43(m,2H)。LCMS[M+H]+＝321.1。
以下示出了D10的合成方案
Figure BDA0001960521980000681
步骤D10.01：3-(2-溴-5-羟基苯基)丙-2-烯酰胺的合成[根据Monatshefte furChemie；vol.147；nb.3；(2016)；p.509-521调整]。在氮气气氛下在圆底烧瓶中装入(2-氨基-2-氧代乙基)(三苯基)氯化
Figure BDA0001960521980000682
(3.70g，10.4mmol)和甲醇(40mL)，并且将溶液在冰浴中冷却。加入叔丁醇钾(1.17g，10.4mmol)并且将混合物搅拌10分钟。加入2-溴-5-羟基苯甲醛(1.99g，9.90mmol)并且将反应混合物搅拌15分钟，在冰浴中冷却，然后使其温热至室温并且搅拌过夜。将反应混合物用水(125mL)稀释并且用盐酸溶液调节至pH<4。将水层用二氯甲烷(100mL)萃取并且将有机物收集并且浓缩。将残余物通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为深色粘性胶状物(2.30g，96％)，其由大约1:0.3比率的E和Z异构体二者组成。1H NMR(400MHz,DMSO-d6)δppm 9.88(s,1H),9.64(s,0.3H),7.67-7.53(m,2H),7.51-7.42(m,1.3H),7.36(d,J＝8.8Hz,0.3H),7.22(bs,1.3H),7.11-7.03(m,1.3H),7.00(d,J＝2.9Hz,0.3H),6.76(dd,J＝2.9,8.8Hz,1H),6.68-6.61(m,0.6H),6.52(d,J＝15.6Hz,1H),6.09(d,J＝15.6Hz,0.3H)。LCMS[M+H]+＝242.1,244.1,[M+Na]+＝264.0,266.0,[M-H]-＝240.0,242.0。
步骤D10.02：3-(5-羟基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)丙-2-烯酰胺的合成。在装有回流冷凝器并且在氮气气氛下的圆底烧瓶中装入3-(2-溴-5-羟基苯基)丙-2-烯酰胺(8.83g，0.036mol)、双(频哪醇)二硼(10.2g，0.040mol)、乙酸钾(14.3g，0.146mol)和无水二甲亚砜(250mL)。通过使氮气鼓泡通过10分钟将反应混合物脱气。加入与二氯甲烷复合的[1,1’-双(二苯基-膦基)二茂铁]二氯钯(II)(4.25g，0.005mol)并且将反应混合物在85℃搅拌过夜。将反应混合物冷却至室温并且加入水(600mL)。用盐酸溶液将水层的pH调节至pH<2，然后将混合物用乙酸乙酯(3x500mL)萃取。将有机物合并，用盐水(250mL)洗涤，用硫酸镁干燥，过滤并且浓缩。将残余物通过急骤色谱(乙酸乙酯/己烷)纯化，得到标题化合物，为橙色固体(5.57g，53％)，其为大约2:1比率的E和Z异构体的混合物。1H NMR(400MHz,CDCl3)δppm 8.36(d,J＝16.22Hz,1H),7.76(d,J＝8.21Hz,1H),7.59(d,J＝8.21Hz,0.5H),7.10(d,J＝2.15Hz,1.5H),7.00(s,0.5H),6.84(dd,J＝8.21,2.34Hz,1.5H),6.41(d,J＝15.63Hz,0.5H),6.32(d,J＝16.02Hz,1H),1.35(s,18H)。LCMS[M+H]+＝290.2,[M+Na]+＝312.1,[M-H]-＝288.2。
步骤D10.03：3-(5-羟基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)丙烯酰胺的合成。在装有回流冷凝器并且在氮气气氛下的圆底烧瓶中装入3-(5-羟基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)丙-2-烯酰胺(5.57g，0.019mol)和乙醇(250mL)。通过使氮气鼓泡通过10分钟将溶液脱气，然后加入10％钯碳(0.56g)。将反应混合物在回流下在氢气气氛下搅拌过夜，然后通过硅藻土床热过滤并且将残余物用乙醇(3x 50mL)洗涤。将滤液浓缩，得到标题化合物，为黄色固体(3.54g，63％)。1HNMR(400MHz,DMSO-d6)δppm 9.60(s,1H),7.47(d,J＝8.01Hz,1H),7.11(bs,1H),6.66(bs,1H),6.59(d,J＝2.34Hz,1H)6.56(dd,J＝8.11,2.44Hz,1H),2.94(t,J＝7.82Hz,2H),2.24(t,J＝7.82Hz,2H),1.27(s,12H)。LCMS[M+H]+＝292.2,[M+Na]+＝314.1,[M-H]-＝290.1。
步骤D10.04：3-(4-羟基-3’,5’-双((甲磺酰基)氨基)联苯-2-基)丙烯酰胺的合成。在微波瓶中装入3-(5-羟基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)丙酰胺(0.312g，1.07mmol)、N,N’-(5-溴苯-1,3-二基)双(N-(甲磺酰基)甲磺酰胺(0.562g，1.13mmol)、碳酸钾(0.889g，6.43mmol)、N,N-二甲基甲酰胺(12mL)和水(1.6mL)。通过使氮气鼓泡通过5分钟将反应混合物脱气，然后加入与二氯甲烷复合的[1,1’-双(二苯基-膦基)二茂铁]-二氯钯(II)(0.088g，0.107mmol)。将反应混合物在105℃加热1h，然后冷却至室温并且用水(10mL)稀释。用盐酸溶液将pH调节至pH<4，然后将混合物浓缩。将残余物通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为琥珀色胶状物(0.334g，73％)。1HNMR(400MHz,DMSO-d6)δppm9.45(bs,1H),7.20(bs,1H),7.11(t,J＝2.05Hz,1H),6.96(d,J＝8.21Hz,1H),6.82(d,J＝1.95Hz,2H),6.71(d,J＝2.54Hz,2H),6.66(dd,J＝8.21,2.54Hz,1H),3.02(s,6H),2.61-2.70(m,2H),2.14-2.24(m,2H)。LCMS[M+H]+＝428.1,[M+Na]+＝450.0,[M-H]-＝426.0。
步骤D10.05：三氟甲磺酸3-(3-氨基-3-氧代丙基)-3’,5’-双((甲磺酰基)氨基)联苯酯的合成。在圆底烧瓶中装入3-(4-羟基-3’,5’-双((甲磺酰基)-氨基)联苯-2-基)丙酰胺(0.796g，1.86mmol)、N,N-二甲基甲酰胺(30mL)、乙腈(50mL)和碳酸钾(2.06g，14.9mmol)。将反应混合物搅拌15分钟，然后加入N-苯基双(三氟甲磺酰亚胺)(0.698g，1.96mmol)。将反应混合物在室温搅拌2h，然后浓缩。将残余物在二氯甲烷/甲醇(5:1，100mL)和水(50mL)之间分配。用盐酸溶液将水层调节至pH～4并且将层充分混合。将水层分离并且用二氯甲烷/甲醇(5:1，100mL)洗涤。将有机物合并，用盐水(50mL)洗涤，用硫酸镁干燥，过滤并且浓缩。通过从二甲苯(150mL)中浓缩混合物将残余的N,N-二甲基甲酰胺移除，并且将残余物通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为灰白色玻璃状物(0.513g，49％)。1H NMR(400MHz,DMSO-d6)δppm 9.96(s,2H),7.45(d,J＝2.34Hz,1H),7.33-7.43(m,2H),7.23(bs,1H),7.16(s,1H),6.85(d,J＝1.95Hz,2H),6.77(bs,1H),3.04(s,6H),2.73-2.82(m,2H),2.23-2.31(m,2H)。LCMS[M+H]+＝560.0,[M+H]+＝582.0,[M-H]-＝558.0。
步骤D10.06：3-(3’,5’-双((甲磺酰基)氨基)-1-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)联苯-3-基)丙烯酰胺的合成。在微波瓶中装入三氟甲磺酸3-(3-氨基-3-氧代丙基)-3’,5’-双((甲磺酰基)氨基)-联苯酯(0.507g，0.906mmol)、双(频哪醇)二硼(0.230g，0.906mmol)、无水1,4-二
Figure BDA0001960521980000701
烷(10mL)和乙酸钾(0.445g，4.53mmol)。通过使氮气鼓泡通过2分钟将反应混合物脱气，然后加入与二氯甲烷复合的[1,1’-双(二苯基膦基)-二茂铁]二氯钯(II)(0.074g，0.091mmol)。将瓶盖上并且在微波炉中将反应混合物在105℃加热1h，然后冷却至室温并且用二氯甲烷/甲醇(5:1，25mL)稀释。用盐酸溶液将混合物调节至pH～4，然后过滤。将残余物用二氯甲烷/甲醇(5:1，75mL)洗涤并且将滤液合并，用硫酸镁干燥，过滤并且浓缩。将残余物通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为灰白色玻璃状物(0.324g，67％)。1H NMR(400MHz,DMSO-d6)δppm 9.91(bs,2H),7.64(s,1H),7.56(d,J＝7.42Hz,1H),7.22(bs,1H),7.13-7.20(m,2H),6.80-6.90(m,2H),6.72(bs,1H),3.03(s,6H),2.70-2.80(m,2H),2.15-2.26(m,2H),1.31(s,12H)。LCMS[M+H]+＝538.2,[M+H]+＝560.2,[M-H]-＝536.2。
步骤D10.07：3-(3’,5’-双((甲磺酰基)氨基)-1-(哒嗪-3-基)联苯-3-基)丙酰胺(D10)的合成。在微波瓶中装入3-(3’,5’-双((甲磺酰基)氨基)-1-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)联苯-3-基)丙酰胺(0.100g，0.186mmol)、3-溴哒嗪(0.030g，0.186mmol)、碳酸钾(0.129g，0.930mmol)、N,N-二甲基甲酰胺(2mL)和水(0.26mL)。通过使氮气鼓泡通过2分钟将反应混合物脱气，然后加入与二氯甲烷复合的[1,1’-双(二苯基-膦基)二茂铁]-二氯钯(II)(0.015g，0.019mmol)并且将瓶盖上。在微波炉中将反应混合物在105℃搅拌1h，然后冷却至室温并且用二氯甲烷/甲醇(5:1，25mL)稀释。用盐酸溶液将混合物调节至pH 5-6，然后过滤。将残余物用二氯甲烷/甲醇(5:1，50mL)洗涤并且将滤液合并，用硫酸镁干燥，过滤并且浓缩。将残余物通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为深色玻璃状物(0.029g，32％)。1H NMR(400MHz,DMSO-d6)δppm 9.95(s,2H),9.24(dd,J＝4.88,1.56Hz,1H),8.26(dd,J＝8.69,1.47Hz,1H),8.15(d,J＝1.76Hz,1H),8.03(dd,J＝8.01,1.95Hz,1H),7.77-7.85(m,1H),7.37(d,J＝7.82Hz,1H),7.24(bs,1H),7.19(t,J＝1.95Hz,1H),6.93(d,J＝1.95Hz,2H),6.75(bs,1H),3.06(s,6H),2.82-2.90(m,2H),2.30-2.38(m,2H)。LCMS[M+H]+＝490.1,[M+Na]+＝512.0,[M-H]-＝488.1。
以下示出了D16的合成方案
Figure BDA0001960521980000711
步骤D16.01：3-(3’,5’-双((甲磺酰基)氨基)-1-(吡嗪-2-基)联苯-3-基)丙酰胺(D16)的合成。根据步骤D10.07使用2-氯吡嗪进行制备，得到标题化合物，为深色玻璃状物(0.038g，39％)。1H NMR(400MHz,DMSO-d6)δppm9.96(s,2H),9.29(s,1H),8.74(s,1H),8.64(d,J＝2.34Hz,1H),8.12(s,1H),8.03(d,J＝8.01Hz,1H),7.34(d,J＝8.01Hz,1H),7.25(bs,1H),7.19(s,1H),6.93(d,J＝1.76Hz,2H),6.75(bs,1H),3.06(s,6H),2.81-2.89(m,2H),2.33(t,J＝7.91Hz,2H)。LCMS[M+H]+＝490.1,[M+Na]+＝512.0,[M-H]-＝488.1。
以下示出了D11的合成方案
Figure BDA0001960521980000721
步骤D11.01：3-(5-溴-2-羟基苯基)丙-2-烯酰胺的合成[根据Monatshefte furChemie；vol.147；nb.3；(2016)；p.509-521调整]。在氮气气氛下在圆底烧瓶中装入(2-氨基-2-氧代乙基)(三苯基)氯化
Figure BDA0001960521980000722
(5.70g，16.0mmol)和甲醇(60mL)，并且将溶液在冰浴中冷却。加入叔丁醇钾(1.80g，16.0mmol)并且将混合物搅拌20分钟。加入2-溴-5-羟基苯甲醛(3.07g，15.3mmol)并且将反应混合物搅拌20分钟，在冰浴中冷却，然后使其温热至室温并且搅拌过夜。将反应混合物用二氯甲烷(200mL)稀释并且搅拌20分钟，然后过滤。将残余物用二氯甲烷/甲醇(～5/1，50mL)洗涤并且将滤液合并并且浓缩。将残余物通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为乳霜状固体(3.11g，84％)。1H NMR(400MHz,DMSO-d6)δppm 10.35(s,1H),7.49-7.59(m,2H),7.46(bs,1H),7.33(dd,J＝8.69,2.44Hz,1H),7.05(bs,1H),6.86(d,J＝8.79Hz,1H),6.68(d,J＝16.02Hz,1H)。LCMS[M+H]+＝242.0,244.0,[M+Na]+＝263.9,265.9,[M-H]-＝240.0,242.0。
步骤D11.02：3-(2-羟基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)丙-2-烯酰胺的合成。在三个微波瓶中各自装入3-(5-溴-2-羟基苯基)丙-2-烯酰胺(1.04g，4.30mmol)、双(频哪醇)二硼(1.20g，4.73mmol)、乙酸钾(1.69g，17.2mmol)和无水1,4-二
Figure BDA0001960521980000731
烷(15mL)。通过使氮气鼓泡通过5分钟将反应混合物脱气，然后加入与二氯甲烷复合的[1,1’-双(二苯基-膦基)二茂铁]二氯钯(II)(0.351g，0.430mmol)并且在微波炉中将每个反应混合物在105℃加热1h。将反应混合物冷却至室温，合并并且过滤。将残余物用二氯甲烷/甲醇(5:1，250mL)洗涤并且将滤液合并并且浓缩。将残余物通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为棕色固体(2.22g，60％)。1H NMR(400MHz,DMSO-d6)δppm7.79(d,J＝1.37Hz,1H),7.66(d,J＝16.02Hz,1H),7.48(dd,J＝8.01,1.56Hz,2H),6.99(bs,1H),6.89(d,J＝8.21Hz,1H),6.65(d,J＝16.02Hz,1H),1.28(s,12H)。LCMS[M+H]+＝290.1,[M-H]-＝288.1。
步骤D11.03：3-(2-羟基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)丙烯酰胺的合成[根据Monatshefte fur Chemie；vol.147；nb.3；(2016)；p.509-521调整]。在圆底烧瓶中装入3-(2-羟基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)丙-2-烯酰胺(2.12g，7.33mmol)、二氯甲烷(50mL)、甲醇(50mL)、偶氮二甲酸钾(8.55g，44.1mmol)和冰醋酸(5.28g，87.9mmol)并且将混合物在室温搅拌过夜。将反应混合物直接加载至二氧化硅上并且通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为浅橙色晶体固体(0.982g，46％)。1H NMR(400MHz,DMSO-d6)δppm 9.75(s,1H),7.39(d,J＝1.56Hz,1H),7.34(dd,J＝8.01,1.76Hz,1H),7.27(bs,1H),6.71-6.80(m,2H),2.71(t,J＝7.81Hz,2H),2.26-2.34(m,2H),1.26(s,12H)。LCMS[M+H]+＝292.2,[M+Na]+＝314.1,[M-H]-＝290.2。
步骤D11.04：3-(2-羟基-5-(哒嗪-3-基)苯基)丙烯酰胺的合成。在装有回流冷凝器并且在氮气气氛下的圆底烧瓶中装入3-(2-羟基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)丙酰胺(0.982g，3.37mmol)、3-溴哒嗪(0.590g，3.71mmol)、碳酸铯(3.30g，10.1mmol)、1,4-二
Figure BDA0001960521980000732
烷(50mL)和水(9mL)。通过使氮气鼓泡通过5分钟将反应混合物脱气，然后加入与二氯甲烷复合的[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)(0.275g，0.337mmol)。将反应混合物在85℃搅拌3h，然后冷却至室温。将反应混合物用二氯甲烷/甲醇(5:1，50mL)稀释并且过滤。将残余物用二氯甲烷/甲醇(5:1，50mL)洗涤，将滤液合并并且浓缩。将残余物通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为深棕色固体(0.124g，15％)。1H NMR(400MHz,DMSO-d6)δppm 9.90(s,1H),9.10(dd,J＝4.79,1.47Hz,1H),8.07(dd,J＝8.69,1.47Hz,1H),7.93(d,J＝2.34Hz,1H),7.83(dd,J＝8.40,2.34Hz,1H),7.68(dd,J＝8.60,4.88Hz,1H),7.32(bs,1H),6.93(d,J＝8.40Hz,1H),6.77(bs,1H),2.82(t,J＝7.72Hz,2H),2.36-2.44(m,2H)。LCMS[M+H]+＝244.2,[M+Na]+＝266.1,[M-H]-＝242.2。
步骤D11.05：三氟甲磺酸2-(3-氨基-3-氧代丙基)-4-(哒嗪-3-基)苯酯的合成。在圆底烧瓶中装入3-(2-羟基-5-(哒嗪-3-基)苯基)丙酰胺(0.124g，0.510mmol)、乙腈(25mL)和碳酸钾(0.282g，2.04mmol)。加入N-苯基双(三氟甲磺酰亚胺)(0.191g，0.535mmol)并且将反应混合物在室温搅拌过夜。将混合物浓缩并且将残余物通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为深棕色固体(0.119g，62％)。1H NMR(400MHz,DMSO-d6)δppm9.27(dd,J＝4.88,1.56Hz,1H),8.25-8.31(m,2H),8.17(dd,J＝8.79,2.34Hz,1H),7.84(dd,J＝8.60,4.88Hz,1H),7.58(d,J＝8.60Hz,1H),7.24(d,J＝8.21Hz,1H),6.83(bs,1H),2.99(t,J＝7.62Hz,2H),2.51-2.55(m,2H)。LCMS[M+H]+＝376.0,[M+Na]+＝398.0,[M+HCO2H-H]-＝420.0。
步骤D11.06：3-(2-(2-((甲磺酰基)氨基)吡啶-4-基)-5-(哒嗪-3-基)苯基)丙酰胺(D11)的合成。在微波瓶中装入三氟甲磺酸2-(3-氨基-3-氧代丙基)-4-(哒嗪-3-基)苯酯(0.119g，0.317mmol)、N-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-吡啶-2-基)-N-(甲磺酰基)甲磺酰胺(0.131g，0.349mmol)、碳酸钾(0.088g，0.634mmol)、1,4-二
Figure BDA0001960521980000741
烷(6.7mL)、乙醇(1.7mL)和水(1.7mL)。通过使氮气鼓泡通过5分钟将反应混合物脱气，然后加入四(三苯基膦)钯(0)(0.037g，0.032mmol)并且将瓶盖上。在微波炉中将反应混合物在105℃搅拌3h，然后冷却至室温并且用二氯甲烷/甲醇(5:1，50mL)稀释。将混合物(pH～7)过滤并且将残余物用硫酸镁干燥，过滤并且浓缩。将残余物通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为棕色固体(0.056g，44％)。1H NMR(400MHz,DMSO-d6)δppm 9.25(dd,J＝1.6,4.9Hz,1H),8.32(bs,1H),8.27(dd,J＝1.6,8.6Hz,1H),8.18(d,J＝1.6Hz,1H),8.07(dd,J＝1.8,8.0Hz,1H),7.82(dd,J＝4.9,8.6Hz,1H),7.38(d,J＝8.0Hz,1H),7.28(bs,1H),7.07(d,J＝4.7Hz,1H),6.97(s,1H),6.76(bs,1H),3.33(bs,3H),2.91-2.82(m,2H),2.37(dd,J＝7.0,9.0Hz,2H)。LCMS[M+H]+＝398.1,[M+Na]+＝420.1,[M-H]-＝396.1。
以下示出了D12的合成方案
Figure BDA0001960521980000751
步骤D12.01：3-(2-(6-氨基嘧啶-4-基)-5-羟基苯基)丙酰胺的合成。在装有回流冷凝器并且在氮气气氛下的圆底烧瓶中装入3-(5-羟基-2-(频哪醇硼烷)苯基)丙酰胺(1.17g，4.02mmol)、4-氨基-6-氯嘧啶(0.573g，4.42mmol)、碳酸铯(3.93g，12.0mmol)、1,4-二
Figure BDA0001960521980000752
烷(50mL)和水(9mL)。通过使氮气鼓泡通过5分钟将反应混合物脱气，然后加入与二氯甲烷复合的[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)(0.328g，0.402mmol)。将反应混合物在85℃搅拌3h，然后冷却至室温。将反应混合物用乙酸乙酯(100mL)和水(100mL)稀释并且用盐酸溶液将水相调节至pH 4。收集有机物，用硫酸镁干燥，过滤并且浓缩，得到粗产物。将水层浓缩至干燥并且将残余物用二氯甲烷/甲醇(1:1，2x 50mL)萃取。将有机物浓缩，得到第二批粗产物，将其与第一批合并并且通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为棕色半固体(0.743g，72％)。1H NMR(400MHz,DMSO-d6)δppm9.87(bs,1H),8.55(bs,1H),7.75(bs,2H),7.41(bs,1H),7.18(d,J＝8.40Hz,1H),6.63-6.90(m,3H),6.54(s,1H),2.81(t,J＝7.62Hz,2H),2.35(t,J＝7.81Hz,2H)。LCMS[M+H]+＝259.1,[M-H]-＝257.2。
步骤D12.02：三氟甲磺酸3-(3-氨基-3-氧代丙基)-4-(6-氨基嘧啶-4-基)苯酯的合成。在圆底烧瓶中装入3-(2-(6-氨基嘧啶-4-基)-5-羟基苯基)丙酰胺(0.769g，2.98mmol)、乙腈(50mL)和N,N-二甲基甲酰胺(25mL)。加入碳酸钾(1.23g，8.93mmol)并且将反应混合物在冰浴中冷却15分钟。加入N-苯基双(三氟甲磺酰亚胺)(1.12g，3.13mmol)并且使反应混合物在数小时内缓慢温热至室温，然后在50℃加热3天。将反应混合物冷却至室温，浓缩，加入乙酸乙酯(250mL)并且搅拌30分钟。将所得固体通过过滤移除并且将滤液浓缩，然后从二甲苯(2x 150mL)中再次浓缩。将残余物通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为棕色蜡状固体(0.689g，59％)。1H NMR(400MHz,DMSO-d6)δppm 8.42(d,J＝0.98Hz,1H),7.38-7.50(m,3H),7.26(bs,1H),7.00(s,2H),6.75(bs,1H),6.48(d,J＝1.17Hz,1H),2.92(t,J＝7.81Hz,2H),2.33(t,J＝7.72Hz,2H)。LCMS[M+H]+＝391.1,[M-H]-＝389.0。
步骤D12.03：3-(2-(6-氨基嘧啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-丙酰胺的合成在微波瓶中装入三氟甲磺酸3-(3-氨基-3-氧代丙基)-4-(6-氨基嘧啶-4-基)苯酯(0.639g，1.64mmol)、双(频哪醇)二硼(1.04g，4.09mmol)、乙酸钾(0.482g，4.91mmol)和无水1,4-二
Figure BDA0001960521980000761
烷(15mL)。通过使氮气鼓泡通过5分钟将反应混合物脱气，然后加入与二氯甲烷复合的[1,1’-双(二苯基膦基)二茂铁]-二氯钯(II)(0.134g，0.164mmol)。在微波炉中将反应混合物在105℃加热1h，然后冷却至室温。将混合物过滤并且将残余物用二氯甲烷/甲醇(4:1，2x 50mL)洗涤。将滤液合并并且浓缩，并且将残余物通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为棕色固体(0.442g，73％)。1H NMR(400MHz,DMSO-d6)δppm 8.40(s,1H),7.62(s,1H),7.54-7.59(m,1H),7.28(d,J＝7.62Hz,1H),7.24(bs,1H),6.92(s,2H),6.69(bs,1H),6.45(d,J＝1.17Hz,1H),2.84-2.93(m,2H),2.24-2.33(m,2H),1.31(s,12H)。LCMS[M+H]+＝369.3。
步骤D12.04：3-(2-(6-氨基嘧啶-4-基)-5-(哒嗪-3-基)苯基)丙酰胺(D12)的合成。在微波瓶中装入3-(2-(6-氨基嘧啶-4-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)丙酰胺(0.224g，0.608mmol)、3-溴哒嗪(0.106g，0.669mmol)、碳酸铯(0.595g，1.82mmol)、1,4-二
Figure BDA0001960521980000762
烷(10mL)和水(1.8mL)。通过使氮气鼓泡通过2分钟将反应混合物脱气，然后加入与二氯甲烷复合的[1,1’-双(二苯基-膦基)二茂铁]-二氯钯(II)(0.050g，0.061mmol)并且将瓶盖上。在微波炉中将反应混合物在105℃搅拌80分钟，然后冷却至室温并且过滤。将残余物用乙酸乙酯(25mL)洗涤，然后用二氯甲烷/甲醇(5:1，2x25mL)洗涤。将滤液合并，用硫酸镁干燥，过滤并且浓缩。将残余物通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为深红色玻璃状物(0.088g，45％)。1H NMR(400MHz,DMSO-d6)δppm 9.24(dd,J＝1.5,5.0Hz,1H),8.44(d,J＝1.2Hz,1H),8.27(dd,J＝1.6,8.6Hz,1H),8.14(d,J＝1.8Hz,1H),8.05(dd,J＝2.0,8.0Hz,1H),7.81(dd,J＝4.9,8.6Hz,1H),7.47(d,J＝8.0Hz,1H),7.28(bs,1H),6.97(s,2H),6.72(bs,1H),6.55(d,J＝1.2Hz,1H),3.06-2.96(m,2H),2.39(m,2H)。LCMS[M+H]+＝321.2,[M-H]-＝319.1。
以下示出了D18的合成方案
Figure BDA0001960521980000771
步骤D18.01：3-(2-(6-氨基嘧啶-4-基)-5-(吡嗪-2-基)苯基)丙酰胺(D18)的合成。根据步骤D12.04使用2-氯吡嗪进行制备，得到标题化合物，为深色玻璃状物(0.066g，37％)。1H NMR(400MHz,DMSO-d6)δppm 9.29(s,1H),8.75(s,1H),8.64(d,J＝2.3Hz,1H),8.44(s,1H),8.11(s,1H),8.04(d,J＝8.0Hz,1H),7.45(d,J＝8.0Hz,1H),7.27(bs,1H),6.95(bs,2H),6.73(bs,1H),6.53(s,1H),3.00(t,J＝7.7Hz,2H),2.38(t,J＝7.8Hz,2H)。LCMS[M+H]+＝321.2,[M-H]-＝319.0。
以下示出了D17的合成方案
Figure BDA0001960521980000772
步骤D17.01：4-(吡嗪-2-基)苯酚的合成。在氮气气氛下在圆底烧瓶中装入4-羟基苯基硼酸(10.0g，0.045mol))、2-氯吡嗪(6.25g，0.0545mol)和碳酸铯(29.58g，0.0908mol)、1,4-二
Figure BDA0001960521980000781
烷(90mL)和水(10mL)。加入与二氯甲烷复合的[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)(1.85g，2.27mmol)并且将反应混合物在回流下加热2h。将混合物冷却，用乙酸乙酯(100mL)稀释，过滤并且转移至分液漏斗。将水相分离，用乙酸乙酯(100mL)和二氯甲烷(100mL)洗涤。将合并的有机萃取物干燥(硫酸镁)，过滤并且浓缩。将粗制物料通过急骤色谱(乙酸乙酯/二氯甲烷)纯化，得到标题化合物，为灰色粉末(7.1g，91％收率)。1HNMR(400MHz,DMSO-d6)δppm 9.91(s,1H),9.14(d,J＝1.5Hz,1H),8.63(dd,J＝1.6,2.4Hz,1H),8.49(d,J＝2.4Hz,1H),8.03-7.96(m,2H),6.94-6.87(m,2H)。LCMS[M+H]+＝173.1
步骤D17.02：2-羟基-5-(吡嗪-2-基)苯甲醛的合成。在圆底烧瓶中装入4-(吡嗪-2-基)苯酚(4.3g，25.0mmol)和三氟乙酸(50mL)。逐份加入六胺(5.26g，37.5mmol)并且将溶液在回流下加热6h。将混合物冷却，用水(200mL)稀释，搅拌30分钟标并且转移至分液漏斗。加入二氯甲烷(200mL)，将有机相分离，用水(100mL)和盐水(100mL)洗涤，干燥(硫酸镁)，过滤并且浓缩至干燥，得到标题化合物，为灰色粉末(2.11g，42％)。1H NMR(400MHz,CHLOROFORM-d)δppm 11.20(s,1H),10.04(d,J＝0.6Hz,1H),9.06-9.01(m,1H),8.65-8.60(m,1H),8.52(d,J＝2.3Hz,1H),8.33(d,J＝2.1Hz,1H),8.22(dd,J＝2.1,8.9Hz,1H),7.15(d,J＝8.7Hz,1H)。LCMS[M+H]+＝201.1。
步骤D17.03：三氟甲磺酸2-甲酰基-4-(吡嗪-2-基)苯酯的合成。在圆底烧瓶中装入2-羟基-5-(吡嗪-2-基)苯甲醛(3.5g，17.5mmol)、碳酸钾(4.84g，35.0mmol)和乙腈(100mL)。加入N-苯基双(三氟-甲磺酰亚胺)(6.87g，19.2mmol)并且将混合物在室温搅拌2h。加入乙酸乙酯(100mL)，将混合物过滤并且浓缩。通过急骤色谱(乙酸乙酯/己烷)纯化，得到标题化合物，为在静置时凝固的澄清油状物(4.6g，92％)。1H NMR(400MHz,CHLOROFORM-d)δppm 10.36(s,1H),9.12(d,J＝1.4Hz,1H),8.70(dd,J＝1.6,2.5Hz,1H),8.66(d,J＝2.2Hz,1H),8.63(d,J＝2.4Hz,1H),8.43(dd,J＝2.4,8.7Hz,1H),7.58(d,J＝8.6Hz,1H)。LCMS[M+H]+＝333.0。
步骤D17.04：三氟甲磺酸2-(羟甲基)-4-(吡嗪-2-基)苯酯的合成。根据步骤D6.02进行制备，得到标题化合物，为黄色固体(1.79g，51％)。LCMS[M+H]+＝335.0。
步骤D17.05：三氟甲磺酸2-(溴甲基)-4-(吡嗪-2-基)苯酯的合成。在氮气气氛下在匹配的圆底烧瓶中装入三苯基膦(2.26g，8.62mmol)和二氯甲烷(80mL)。将反应混合物在冰浴中搅拌并且冷却20分钟，然后缓慢加入三氟甲磺酸2-(羟甲基)-4-(吡嗪-2-基)苯酯(1.44g，4.31mmol)。将反应混合物在冰浴中搅拌并且冷却20分钟，然后使其温热至室温并且搅拌2h。将混合物浓缩并且通过急骤色谱(乙酸乙酯/己烷)纯化，得到标题化合物，为黄色油状物(1.53g，89％)。LCMS[M]+＝397.9,399.9。
步骤D17.06：2-[(((2-三氟甲基)磺酰基)氧代)-5-(吡嗪-2-基)-苄基]丙二酸1,3-二乙酯的合成。在氮气气氛下在装有回流器的圆底烧瓶中装入丙二酸二乙酯(0.726g，4.54mmol)和四氢呋喃(80mL)。在伴随剧烈气体释放的情况下将氢化钠(0.099g的在油中的60％分散液，4.16mmol)逐份加入至搅拌溶液中。将反应混合物搅拌10分钟，然后缓慢加入三氟甲磺酸2-(溴甲基)-4-(吡嗪-2-基)苯酯(0.75g，1.89mmol)在四氢呋喃(20mL)中的溶液。将反应在室温搅拌1h，然后浓缩。通过急骤色谱(乙酸乙酯/二氯甲烷)纯化，得到标题化合物，为浅黄色油状物(1.05g)。LCMS[M+H]+＝477.1,[M+Na]+＝499.0。
步骤D17.07：3-[5-(吡嗪-2-基)-2-((三氟甲磺酰基)苯基]丙酸甲酯的合成在圆底烧瓶中装入2-[(((2-三氟甲基)磺酰基)氧代)-5-(吡嗪-2-基)-苄基]丙二酸1,3-二乙酯(7.0g，14.7mmol)和硫酸水溶液(2M，15mL)。将混合物在回流下加热24h，冷却并且加入甲醇(50mL)。将混合物浓缩至干燥，得到标题化合物，为橙色油状物(1.72g，45％)。1H NMR(400MHz,CHLOROFORM-d)δppm 8.95(d，J＝1.5Hz,1H),8.58(dd,J＝1.6,2.4Hz,1H),8.50(d,J＝2.4Hz,1H),7.99(d,J＝2.2Hz,1H),7.88(dd,J＝2.3,8.6Hz,1H),7.36(d,J＝8.6Hz,1H),3.62(s,3H),3.08(t,J＝7.7Hz,2H),2.68(t,J＝7.7Hz,2H)。LCMS[M+H]+＝391.1,[M+Na]+＝413.1。
步骤D17.08：3-[2-羟基-5-(吡嗪-2-基)苯基]丙烯酰胺的合成。在微波瓶中装入3-[5-(吡嗪-2-基)-2-((三氟甲磺酰基)苯基]丙酸甲酯(1.19g，3.07mmol)和甲醇氨的溶液(7N，15mL)。将反应容器盖上并且将混合物在回流下加热48h。在冷却时，将混合物浓缩并且通过急骤色谱(甲醇/二氯甲烷)纯化，得到标题化合物，为浅黄色油状物(0.41g，55％)。LCMS[M+H]+＝244.2,[M+Na]+＝266.0。
步骤D17.09：三氟甲磺酸2-((3-氨基-3-氧代丙基)-4-(吡嗪-2-基)苯基)酯的合成。根据步骤D17.03进行制备，得到标题化合物，为在静置时凝固的澄清油状物(0.360g，58％)。1H NMR(400MHz,CHLOROFORM-d)δppm 8.96(d,J＝1.4Hz,1H),8.58(dd,J＝1.6,2.4Hz,1H),8.50(d,J＝2.4Hz,1H),8.03(d,J＝2.2Hz,1H),7.89(dd,J＝2.3,8.6Hz,1H),7.35(d,J＝8.6Hz,1H),5.37(br.s.,1H),5.24(br.s.,1H),3.14-3.08(m,2H),2.60-2.52(m,2H)。LCMS[M+H]+＝376.1,[M+Na]+＝398.0。
步骤D17.10：3-[2-(2-[(甲磺酰基)氨基]吡啶-4-基)-5-(吡嗪-2-基)苯基]丙酰胺的合成。根据步骤D11.06进行制备，得到标题化合物，为灰白色粉末(0.15g，70％)。1HNMR(400MHz,DMSO-d6)δppm 9.30(d,J＝1.4Hz,1H),8.75(dd,J＝1.5,2.5Hz,1H),8.65(d,J＝2.4Hz,1H),8.31(br.s.,1H),8.15(d,J＝1.8Hz,1H),8.06(dd,J＝1.9,8.0Hz,1H),7.36(d,J＝8.0Hz,1H),7.28(br.s.,1H),7.05(br.s.,1H),6.95(br.s.,1H),6.76(br.s.,1H),2.85(dd,J＝6.6,9.3Hz,2H),2.36(dd,J＝6.8,8.9Hz,2H),2.30(s,4H)。LCMS[M+H]+＝398.1,[M+Na]+＝420.0。
以下示出了D28的合成方案
Figure BDA0001960521980000801
步骤：D28.01.(2E)-3-(2-溴-5-羟基苯基)丙-2-烯酸的合成。在装有回流冷凝器的圆底烧瓶中装入4-溴-3-甲酰基苯酚(25.3g，0.126mol)、吡啶(150mL)、丙二酸(15.7g，0.151mol)和哌啶(1.50mL)。将反应混合物在回流下搅拌6.5h，然后使其冷却。将2M盐酸溶液(500mL)加入至反应混合物中并且用浓盐酸溶液将pH调节至<2。将混合物剧烈搅拌并且在冰浴中冷却至<10℃。将所得固体收集在Buchner漏斗上并且用2M盐酸溶液(200mL)和水(50mL)洗涤。将固体在乙酸乙酯(1.2L)和2M盐酸溶液(200mL)之间分配。将水层移除，并且将有机物用盐水(200mL)洗涤，用硫酸镁干燥，过滤并且浓缩，得到标题化合物，为浅紫色粉末(24.8g，81％)。1H NMR(400MHz,DMSO-d6)δppm 12.53(bs,1H),9.90(s,1H),7.75(d,J＝15.8Hz,1H),7.47(d,J＝8.6Hz,1H),7.19(d,J＝2.9Hz,1H),6.80(dd,J＝8.7,2.8Hz,1H),6.40(d,J＝15.8,2.8Hz,1H)。LCMS[M]+＝242.9,244.9。
步骤D28.02：(2E)-3-(2-溴-5-羟基苯基)丙-2-烯酰胺的合成。在装有回流冷凝器的圆底烧瓶中装入(2E)-3-(2-溴-5-羟基苯基)丙-2-烯酸(10.0g，0.041mol)、二氯甲烷(100mL)和N,N-二甲基甲酰胺(0.20mL)。在剧烈搅拌的情况下，在伴随剧烈气体释放的情况下，缓慢加入草酰氯(8.70mL)。当加入完成时，将反应混合物在回流下搅拌4h。将反应混合物冷却至室温并且浓缩至接近干燥。将残余物从二氯甲烷(50mL)中再次浓缩并且溶解在1,4-二
Figure BDA0001960521980000811
烷(100mL)中。将溶液缓慢倾倒至25％氨水溶液(30mL)在1,4-二/>
Figure BDA0001960521980000812
烷(50mL)中的搅拌混合物中。将反应混合物在室温搅拌2h并且浓缩至接近干燥。将残余物在乙酸乙酯(250mL)和水(150mL)之间分配，导致形成不溶性沉淀。将混合物过滤并且将滤液合并至分液漏斗中。将水层移除，并且将有机物用盐水(25mL)洗涤，用硫酸镁干燥，过滤并且浓缩，得到标题化合物，为深红色固体(8.88g，89％)。1H NMR(400MHz,DMSO-d6)δppm 9.89(bs,1H),7.62(bs,1H),7.59(d,J＝15.6,1H),7.45(d,J＝8.7Hz,1H),7.21(bs,1H),7.05(d,J＝2.7Hz,1H),6.75(dd,J＝8.7,2.8Hz,1H),6.52(d,J＝15.6Hz,1H)。LCMS[M+H]+＝241.9,243.9,[M+Na]+＝264.0,266.0,[M-H]-＝240.0,242.0。
步骤D28.03：(2E)-3-(4-羟基-3’-硝基联苯-2-基)丙-2-烯酰胺的合成。在装有回流冷凝器并且在氮气气氛下的圆底烧瓶中装入(2E)-3-(2-溴-5-羟基苯基)丙-2-烯酰胺(2.00g，8.26mmol)、3-硝基苯基硼酸(2.76g，16.5mmol)、碳酸钾(3.43g，24.8mmol)、1,4-二
Figure BDA0001960521980000813
烷(35mL)和水(1.5mL)。通过使氮气鼓泡通过5分钟将反应混合物脱气，然后加入四(三苯基膦)钯(0)(0.95g，0.83mmol)。将反应混合物在85℃搅拌4h并且冷却至室温。将反应混合物浓缩至接近干燥并且将残余物用乙酸乙酯(100mL)和水(50mL)稀释。将混合物过滤并且将固体用2M盐酸溶液(10mL)洗涤。将滤液合并，用2M盐酸溶液将水层调节至pH 4并且将混合物转移至分液漏斗。将有机物分离并且将水层进一步用乙酸乙酯(50mL)萃取。将有机物合并，用盐水(25mL)洗涤，用硫酸镁干燥，过滤并且浓缩。将残余物通过急骤色谱(乙酸乙酯/二氯甲烷/甲醇)纯化，得到标题化合物，为黄色粉末(1.83g，78％)。1H NMR(400MHz,DMSO-d6)δppm 9.89(s,1H),8.20-8.27(m,1H),8.04(t,J＝1.8Hz,1H),7.67-7.78(m,2H),7.54(bs,1H),7.17-7.30(m,2H),7.10(d,J＝2.5Hz,2H),6.92(dd,J＝8.4,2.5Hz,1H),6.52(d,J＝15.6Hz,1H)。LCMS[M+H]+＝285.1,[M+Na]+＝307.0,[M-H]-＝283.1。
步骤D28.04：2-[(1E)(3-氨基-3-氧代丙-1-烯-1-基)-3’-硝基联苯-4-基三氟甲磺酸酯的合成。在圆底烧瓶中装入(2E)-3-(4-羟基-3’-硝基联苯-2-基)丙-2-烯酰胺(1.83g，6.43mmol)、乙腈(30mL)和碳酸钾(1.82g，13.2mmol)。将黄色悬浮液剧烈搅拌并且在冰浴中冷却15分钟。逐份加入N-苯基双(三氟-甲磺酰亚胺)(2.53g，7.07mmol)并且使反应在3h内温热至室温。将反应混合物浓缩并且将残余物通过急骤色谱(乙酸乙酯/己烷)纯化，得到标题化合物，为灰白色固体(2.77g，定量)。1H NMR(400MHz,DMSO-d6)δppm8.34(ddd,J＝5.9,3.5,2.3Hz,1H),8.16-8.20(m,1H),7.85(s,1H),7.80-7.84(m,2H),7.65(d,J＝1.4Hz,2H),7.57(bs,1H),7.20(d,J＝15.6Hz,2H),6.70(d,J＝15.6Hz,1H)。LCMS[M+H]+＝417.0,[M+Na]+＝439.0,[M+HCO2]-＝461.1。
步骤D28.05：3’-氨基-2-(3-氨基-3-氧代丙基)联苯-4-基三氟甲磺酸酯的合成。在圆底烧瓶中装入2-[(1E)-2-(3-氨基-3-氧代丙-1-烯-1-基)-3’-硝基联苯-4-基三氟甲磺酸酯(0.500g，1.20mmol)和乙醇(25mL)。将混合物搅拌并且通过使氮气鼓泡通过5分钟进行脱气。将10％钯碳(0.050g)加入至反应混合物中，将其用氢气冲洗并且在氢气气氛下搅拌20h。将反应混合物通过硅藻土床过滤并且将硅藻土用乙醇(3x 15mL)洗涤。将乙醇滤液合并并且浓缩，并且将残余物通过急骤色谱(乙酸乙酯/己烷)纯化，得到标题化合物，为浅黄色晶体固体(0.108g，23％)。1H NMR(400MHz,CDCl3)δppm 7.28(m,1H),7.18-7.23(m,2H),7.11-7.17(dd,1H),6.70(ddd,J＝8.0,2.3,1.0Hz,1H),6.65(dt,J＝7.4,1.3Hz,1H),6.57-6.60(m,1H),5.17(brs,2H),2.94-3.04(m,2H),2.27-2.35(m,2H)。LCMS[M+H]+＝389.1,[M+Na]+＝411.1,[M+HCO2]-＝433.1。
步骤D28.06：3-(3’-氨基-4-(吡啶-3-基)联苯-2-基)丙烯酰胺的合成。在装有回流冷凝器并且在氮气气氛下的圆底烧瓶中装入3’-氨基-2-(3-氨基-3-氧代丙基)联苯-4-基三氟甲磺酸酯(0.786g，2.02mmol)、吡啶-3-硼酸(0.323g，2.63mmol)、碳酸钾(0.839g，6.07mmol)、水(11.5mL)、乙醇(20.5mL)和1,4-二
Figure BDA0001960521980000831
烷(32.0mL)。将混合物搅拌并且通过使氮气鼓泡通过5分钟进行脱气。加入四(三苯基膦)钯(0)(0.234g，0.20mmol)并且将反应在85℃搅拌3h。将反应混合物冷却至室温并且用水(75mL)和乙酸乙酯(150mL)稀释。将混合物过滤，转移至分液漏斗并且收集有机相。将水层进一步用乙酸乙酯(50mL)萃取并且将有机物合并，用盐水(25mL)洗涤，用硫酸镁干燥，过滤并且浓缩。将残余物通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为浅黄色胶状物(0.382g，60％)。1H NMR(400MHz,DMSO-d6)δppm 8.92(d,J＝1.6Hz,1H),8.58(dd,J＝4.8,1.7Hz,1H),8.06-8.12(m,1H),7.65(d,J＝1.7Hz,1H),7.57(dd,J＝7.8,2.0Hz,1H),7.46-7.53(m,1H),7.23(d,J＝8.0Hz,2H),7.08(t,J＝7.8Hz,1H),6.74(s,1H),6.57(dd,J＝8.0,1.4Hz,1H),6.52(t,J＝1.9Hz,1H),6.46(d,J＝7.4Hz,1H),5.14(s,2H),2.80-2.88(m,2H),2.28-2.36(m,2H)。LCMS[M+H]+＝318.2,[M+Na]+＝340.2,[M-H]-＝316.2。
步骤D28.07：3-(3’-((甲磺酰基)氨基)-4-(吡啶-3-基)联苯-2-基)丙酰胺(D28)的合成。在氮气气氛下在圆底烧瓶中装入3-(3’-氨基-4-(吡啶-3-基)联苯-2-基)丙酰胺(0.281g，0.885mmol)、二氯甲烷(15mL)和三乙胺(0.617mL，4.43mmol)。将反应混合物在冰浴中冷却15分钟，然后加入甲磺酰氯(0.069mL，0.885mmol)。将反应混合物在冰浴中搅拌3h并且然后使其温热至室温并且搅拌过夜。将反应混合物直接加载至二氧化硅上并且通过急骤色谱(二氯甲烷/甲醇)纯化，得到部分纯化的物料，为灰白色固体。将粗产物在二氯甲烷/己烷(1:1)(25mL)中搅拌数小时并且将所得固体通过过滤收集，用二氯甲烷/己烷(1:1)(2x10mL)洗涤并且在高真空中干燥，得到含有5摩尔％的来自之前步骤的烯烃杂质的标题化合物。用在乙醇中的10％钯碳对化合物进行氢化程序。在以通常的方式完成之后，得到标题化合物，为灰白色粉末(0.029g，47％)。1H NMR(400MHz,DMSO-d6)δppm8.94(br.s.,1H),8.52-8.67(m,1H),8.11(d,J＝7.23Hz,1H),7.70(br.s.,1H),7.62(d,J＝7.42Hz,1H),7.47-7.57(m,1H),7.43(t,J＝7.52Hz,1H),7.15-7.36(m,5H),7.10(d,J＝7.03Hz,1H),6.75(br.s.,1H),3.04(s,3H),2.84(t,J＝7.23Hz,2H),2.33(t,J＝7.23Hz,2H)。LCMS[M+H]+＝396.1。
以下示出了D29的合成方案
Figure BDA0001960521980000841
步骤D29.01：3-(3’-((甲基氨基甲酰基)氨基)-4-(吡啶-3-基)联苯-2-基)丙酰胺(D29)的合成。在氮气气氛下在圆底烧瓶中装入羰基二咪唑(0.403g，2.48mmol)和乙腈(30mL)并且在40℃搅拌。通过均压滴液漏斗将3-(3’-氨基-4-(吡啶-3-基)联苯-2-基)丙酰胺(0.394g，1.24mmol)在乙腈(30mL)中的溶液逐滴加入至反应混合物中并且将反应混合物在40℃搅拌2h。加入额外试样量的羰基二咪唑(0.403g，2.48mmol)并且将混合物在40℃搅拌过夜。在冷却至室温时，加入甲胺(4.5mL的在四氢呋喃中的2M溶液)并且将反应混合物在室温搅拌1h，然后直接加载至二氧化硅上并且通过急骤色谱(二氯甲烷/甲醇)纯化，得到部分纯化的物料，将其重新层析(二氯甲烷/甲醇)，得到标题化合物，为灰白色玻璃状物(0.102g，22％)。1H NMR(400MHz,DMSO-d6)δppm 8.93(dd,J＝2.4,0.7Hz,1H),8.61(s,1H),8.58(dd,J＝4.7,1.6Hz,1H),8.07-8.14(m,1H),7.68(d,J＝1.8Hz,1H),7.60(dd,J＝7.8,2.0Hz,1H),7.51(ddd,J＝8.0,4.8,0.9Hz,1H),7.47(t,J＝1.7Hz,1H),7.25-7.38(m,3H),7.23(br.s.,1H),6.88(dt,J＝7.4,1.4Hz,1H),6.73(br.s.,1H),6.07(q,J＝4.4Hz,1H),2.78-2.90(m,2H),2.60-2.69(m,3H),2.27-2.37(m,2H)。LCMS[M+H]+＝375.2,[M-H]-＝373.2。
以下示出了D31的合成方案
Figure BDA0001960521980000851
步骤D31.01：3-(3’-((甲基氨磺酰基)氨基)-4-(吡啶-3-基)联苯-2-基)丙酰胺(D31)的合成。在氮气气氛下在圆底烧瓶中装入3-(3’-氨基-4-(吡啶-3-基)联苯-2-基)丙酰胺(0.250g，0.788mmol)、二氯甲烷(10mL)和三乙胺(0.440mL，3.15mmol)。将反应混合物在室温搅拌并且以2mL每份加入甲基磺酸氯(methylsulfanic acid chloride)(0.256g，1.97mmol)在二氯甲烷(10mL)中的溶液。将反应混合物在室温搅拌48h，浓缩并且将残余物在具有少量甲醇以帮助溶解的水(30mL)和乙酸乙酯(30mL)中搅拌。将有机物分离并且将水层(pH～8)进一步用乙酸乙酯(20mL)萃取。将有机物合并，用水(25mL)、盐水(25mL)洗涤，用硫酸镁干燥，过滤并且浓缩。将残余物通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为灰白色粉末(0.063g，20％)。1H NMR(400MHz,DMSO-d6)δppm 9.79(s,1H),8.93(dd,J＝0.6,2.3Hz,1H),8.59(dd,J＝1.6,4.7Hz,1H),8.14-8.06(m,1H),7.69(d,J＝1.8Hz,1H),7.61(dd,J＝2.0,7.8Hz,1H),7.51(ddd,J＝0.8,4.7,8.0Hz,1H),7.42-7.33(m,2H),7.29(d,J＝8.0Hz,1H),7.25(br.s.,1H),7.21-7.14(m,2H),7.03-6.97(m,1H),6.79(br.s.,1H),2.87-2.79(m,2H),2.48(s,3H),2.34(dd,J＝7.0,9.0Hz,2H)。LCMS[M+H]+＝411.1,[M-H]-＝409.2。
以下示出了D30的合成方案
Figure BDA0001960521980000852
步骤D30.01：2-(2-(苯基甲氧基)-5-(吡啶-3-基)苄基)丙二酸1,3-二乙酯的合成。根据步骤D6.05使用3-吡啶基硼酸进行制备，得到标题化合物，为黄色油状物(1.57g，79％)。1H NMR(400MHz,CHLOROFORM-d)δppm8.77(dd,J＝0.8,2.3Hz,1H),8.54(dd,J＝1.6,4.7Hz,1H),7.82-7.76(m,1H),7.49-7.44(m,2H),7.44-7.37(m,4H),7.36-7.29(m,2H),7.01-6.96(m,1H),5.18(s,2H),4.18-4.07(m,4H),3.93(t,J＝7.8Hz,1H),3.34(d,J＝7.6Hz,2H),1.29-1.22(m,6H)。LCMS[M+H]+＝434.2。
步骤D30.02：2-(2-羟基-5-(吡啶-3-基)苄基)丙二酸1,3-二乙酯的合成。根据步骤D6.06进行制备，得到标题化合物，为浅黄色油状物(0.847g，68％)。1H NMR(400MHz,CHLOROFORM-d)δ8.75-8.81(m,1H),8.54(dd,J＝4.79,1.66Hz,1H),7.80(dt,J＝7.86,2.03Hz,1H),7.30-7.40(m,3H),6.99(d,J＝8.21Hz,1H),4.15-4.29(m,4H),3.79(t,J＝7.13Hz,1H),3.24(d,J＝7.03Hz,2H),2.04(s,1H),1.19-1.30(m,6H)。LCMS[M+H]+＝344.2。
步骤D30.03：2-[(((2-三氟甲基)磺酰基)氧代)-5-(吡啶-3-基)-苄基]丙二酸1,3-二乙酯的合成。根据步骤D6.07进行制备，得到标题化合物，为粗制黄色油状物(1.23g)。LCMS[M+H]+＝476.44。
步骤D30.04：2-(2-(8-氧代-7,9-二氮杂-双环[4.3.0]壬-1,3,5-三烯-3-基)-5-(吡啶-3-基)-苄基)丙二酸1,3-二乙酯的合成。将2-[(((2-三氟甲基)磺酰基)氧代)-5-(吡啶-3-基)-苄基]丙二酸1,3-二乙酯(1当量)、芳族硼酸或杂环硼酸频哪醇酯(1.1当量)和碳酸钾(2-3当量)的混合物溶解在1,4-二
Figure BDA0001960521980000861
烷(3.1mL/mmol)、乙醇(0.65mL/mmol)和水(0.65mL/mmol)的混合物中。使氮气鼓泡通过混合物10分钟。加入四(三苯基膦)钯(0)(0.1当量)并且将混合物在85℃在氮气下加热20h。将混合物在乙酸乙酯和水之间分配。将水相用乙酸乙酯萃取。将合并的乙酸乙酯萃取物用水和盐水洗涤，用无水硫酸钠干燥，并且过滤。将滤液蒸发至干燥并且通过急骤色谱(甲醇/二氯甲烷)纯化。将产物悬浮在1:1二氯甲烷/己烷中并且通过过滤分离。灰白色粉末(0.422g，58％)。1H NMR(400MHz,DMSO-d6)δppm10.69(s,1H),10.66(s,1H),8.92(s,1H),8.58(d,J＝3.5Hz,1H),8.04-8.14(m,1H),7.70(d,J＝1.6Hz,1H),7.63(dd,J＝7.91,1.7Hz,1H),7.51(dd,J＝7.81,4.9Hz,1H),7.29(d,J＝8.0Hz,1H),7.01(d,J＝8.0Hz,1H),6.82-6.95(m,2H),3.89-4.03(m,4H),3.72(t,J＝7.9Hz,1H),3.22(d,J＝8.0Hz,2H),0.99(t,J＝7.0Hz,6H)。LCMS[M+H]+＝460.1,[M-H]-＝458.2。
步骤D30.05：3-(2-(2-氧代-2,3-二氢-1H-苯并咪唑-5-基)-5-(吡啶
Figure BDA0001960521980000871
-3-基)苯基)丙酸硫酸氢盐的合成。在装有回流冷凝器的圆底烧瓶中装入2-(2-(8-氧代-7,9-二氮杂-双环[4.3.0]壬-1,3,5-三烯-3-基)-5-(吡啶-3-基)-苄基)-丙二酸1,3-二乙酯(0.422g，0.918mmol)和硫酸(5mL的在水中的2M溶液)。将反应混合物在回流下搅拌42h。将热溶液从不溶性物料中倾析并且放置以缓慢冷却。将所得固体通过真空过滤收集，用水(3x15mL)洗涤并且风干，得到标题化合物，为灰白色粉末(0.305g，73％)。1H NMR(400MHz,DMSO-d6)δppm 10.65(s,1H),10.69(s,1H),9.07(s,1H),8.70(d,J＝3.9Hz,1H),8.42(d,J＝7.4Hz,1H),7.79-7.70(m,2H),7.66(dd,J＝1.9,7.9Hz,1H),7.32(d,J＝8.0Hz,1H),7.01(d,J＝8.0Hz,1H),6.94-6.83(m,2H),2.93-2.85(m,2H),2.48-2.43(m,2H)。LCMS[M+H]+＝360.1,[M-H]-＝357.9。
步骤D30.06：3-(2-(2-氧代-2,3-二氢-1H-苯并咪唑-5-基)-5-(吡啶-3-基)苯基)丙酰胺(D30)的合成。在装有回流冷凝器并且在氮气气氛下的圆底烧瓶中装入3-(2-(2-氧代-2,3-二氢-1H-苯并咪唑-5-基)-5-(吡啶
Figure BDA0001960521980000872
-3-基)苯基)丙酸硫酸氢盐(0.150g，0.328mmol)和无水四氢呋喃(10mL)。加入羰基二咪唑(0.106g，0.656mmol)、三乙胺(0.046mL，0.328mmol)和二甲基乙酰胺(2mL)并且将反应混合物在室温搅拌过夜。根据LCMS分析，反应不完全，因此加入无水乙腈(20mL)并且将反应混合物在回流下搅拌1-2h。将反应冷却至室温并且加入氨(4mL的在二/>
Figure BDA0001960521980000873
烷中的0.5M溶液，2.00mmol)。将反应混合物在40-45℃搅拌并且在24h内再加入3次氨(1mL的在二/>
Figure BDA0001960521980000874
烷中的0.5M溶液，0.500mmol)。将反应混合物冷却至室温并且浓缩。将残余物用水(25mL)稀释并且用碳酸钠溶液将pH调节至～10。将混合物在冰浴中搅拌并且冷却15分钟并且将所得固体通过过滤收集并且风干。将固体通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为灰白色粉末(0.036 g，31％)。1H NMR(400MHz,DMSO-d6)δppm 10.64(s,2H),8.90-8.95(m,1H),8.58(dd,J＝4.7,1.6Hz,1H),8.05-8.13(m,1H),7.67(d,J＝2.0Hz,1H),7.58(dd,J＝7.8,2.0Hz,1H),7.50(ddd,J＝8.0,4.7,0.8Hz,1H),7.28(d,J＝7.8Hz,1H),7.22(bs,1H),6.99(d,J＝7.8Hz,1H),6.88-6.93(m,1H),6.87(s,1H),6.73(bs,1H),2.81-2.89(m,2H),2.27-2.34(m,2H)。LCMS[M+H]+＝359.2,[M-H]-＝357.1。/>
以下示出了D32的合成
Figure BDA0001960521980000881
步骤D32.01：(2E)-3-(2-(苄氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)丙-2-烯酰胺的合成。在装有回流冷凝器并且在氮气气氛下的圆底烧瓶中装入(2E)-3-[2-(苄氧基)-5-溴苯基]丙-2-烯酰胺(2.0g，6.0mmol)、双(频哪醇)二硼(1.168g，6.62mmol)、乙酸钾(2.36g，24.1mmol)和无水1,4-二
Figure BDA0001960521980000882
烷(60mL)。将混合物搅拌并且通过使氮气鼓泡通过5分钟进行脱气，然后加入与二氯甲烷复合的[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)(0.492g，0.603mmol)，并且将反应混合物在回流下搅拌3h并且然后在室温过夜。将混合物冷却至室温，用乙酸乙酯(200mL)和水(125mL)稀释，过滤并且转移至分液漏斗。将水层分离并且进一步用乙酸乙酯(50mL)萃取。将有机物合并，用盐水(25mL)洗涤，用硫酸镁干燥，过滤并且浓缩。将残余物通过急骤色谱(二氯甲烷/丙酮)纯化，得到标题化合物，为粗制深色油状物(3.33g)。LCMS[M+H]+＝380.26。
步骤D32.02：(2E)-3-(2-(苄氧基)-5-(2,4-二甲基-1,3-噻唑-5-基)苯基)丙-2-烯酰胺的合成。在装有回流冷凝器并且在氮气气氛下的圆底烧瓶中装入(2E)-3-(2-(苄氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)丙-2-烯酰胺(2.18g，5.73mmol)、5-溴-2,4-二甲基-1,3-噻唑(1.10g，5.73mmol)、碳酸铯(3.74g，11.5mmol)、1,4-二
Figure BDA0001960521980000883
烷(25mL)和水(2.5mL)。将混合物搅拌并且通过使氮气鼓泡通过5分钟进行脱气，然后加入与二氯甲烷复合的[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)(0.234g，0.287mmol)，并且将反应混合物在回流下搅拌2h。将混合物冷却至室温并且用乙酸乙酯(100mL)和水(50mL)稀释。将混合物过滤，转移至分液漏斗并且将水层分离并且进一步用乙酸乙酯(50mL)萃取。将有机物合并，用盐水(25mL)洗涤，用硫酸镁干燥，过滤并且浓缩。将残余物通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为含有未知杂质的棕色粉末(0.890g，43％)。1H NMR(400MHz,DMSO-d6)δppm 7.72(d,J＝16.02Hz,1H),7.56(d,J＝2.34Hz,1H),7.45-7.52(m,3H),7.32-7.45(m,4H),7.23(d,J＝8.60Hz,1H),7.10(bs,1H),6.68(d,J＝16.02Hz,1H),5.26(s,2H),2.61(s,3H),2.36(s,3H)。LCMS[M+H]+＝365.2,[M+Na]+＝387.1。
步骤D32.03：3-(5-(2,4-二甲基-1,3-噻唑-5-基)-2-羟基苯基)丙酰胺的合成。在高压反应器中装入(2E)-3-(2-(苄氧基)-5-(2,4-二甲基-1,3-噻唑-5-基)苯基)丙-2-烯酰胺(0.675g，2.44mmol)、甲醇(50mL)和氨溶液(5mL的25％水溶液)。将混合物搅拌并且通过使氮气鼓泡通过5分钟进行脱气。将10％钯碳(0.100g)加入至反应混合物中，将其用氢气冲洗并且在氢气气氛(20巴)下在室温搅拌4天。将混合物通过硅藻土塞过滤并且将硅藻土用热甲醇(3x 50mL)洗涤。将滤液合并并且浓缩。将残余物通过急骤色谱(二氯甲烷/甲醇)纯化，得到标题化合物，为浅棕色固体(0.211g，31％)。1H NMR(400MHz,DMSO-d6)δppm 9.68(s,1H),7.29(bs,1H),7.12(d,J＝2.34Hz,1H),7.07(dd,J＝8.30,2.44Hz,1H),6.84(d,J＝8.21Hz,1H),6.76(bs,1H),2.75(t,J＝7.62Hz,2H),2.58(s,3H),2.35(t,J＝7.62Hz,2H),2.32(s,3H)。LCMS[M+H]+＝277.2,[M+Na]+＝299.1,[M-H]-＝275.1。
步骤D32.04：三氟甲磺酸2-(3-氨基-3-氧代丙基)-4-(2,4-二甲基-1,3-噻唑-5-基)苯酯的合成。在氮气气氛下在圆底烧瓶中装入3-(5-(2,4-二甲基-1,3-噻唑-5-基)-2-羟基苯基)丙酰胺(0.211g，0.764mmol)、乙腈(10mL)和碳酸钾(0.317g，2.29mmol)。将反应混合物搅拌15分钟，然后加入N-苯基双(三氟甲磺酰亚胺)(0.286g，0.802mmol)并且在室温继续搅拌4.5h。将反应混合物浓缩并且将残余物在二氯甲烷/甲醇(9:1、50mL)之间分配并且用水(20mL)洗涤。将水相分离并且用二氯甲烷/甲醇(9:1，25mL)萃取。将有机物合并，用盐水(15mL)洗涤，用硫酸镁干燥，过滤并且浓缩，得到标题化合物，为灰白色固体(0.338g，定量)。1H NMR(400MHz,DMSO-d6)δppm 7.53(s,1H),7.44-7.48(m,2H),7.34(bs,1H),6.84(bs,1H),2.92(t,J＝7.42Hz,2H),2.63(s,3H),2.42-2.48(m,2H),2.39(s,3H)。LCMS[M+H]+＝409.0。
步骤D32.05：4-(2,4-二甲基-1,3-噻唑-5-基)-3-(3’-((甲磺酰基)氨基)联苯-2-基)丙酰胺(D32)的合成。在氮气气氛下在装有回流冷凝器的圆底烧瓶中装入三氟甲磺酸2-(3-氨基-3-氧代丙基)-4-(2,4-二甲基-1,3-噻唑-5-基)苯酯(0.145g，0.355mmol)、3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-N-苯甲磺酰胺(0.116g，0.390mmol)、碳酸钾(0.147g，1.06mmol)、1,4-二
Figure BDA0001960521980000902
烷(1.75mL)、乙醇(0.35mL)和水(0.35mL)。将反应混合物搅拌并且通过使氮气鼓泡通过5分钟进行脱气，然后加入四(三苯基膦)钯(0.021g，0.018mmol)。将反应混合物在85℃搅拌2h，冷却至室温并且用乙酸乙酯(20mL)稀释。加入水(5mL)并且用2M盐酸溶液将水相的pH调节至5-6。将两层充分混合并且将水层分离。将有机物用盐水(10mL)洗涤，用硫酸镁干燥，过滤并且浓缩。将残余物在乙酸乙酯/己烷(3:1，40mL)中搅拌并且轻轻地温热。在15分钟之后，将浆液在冰浴中冷却并且将固体通过过滤收集，用乙酸乙酯/己烷(1:1，2x 5mL)洗涤并且干燥，得到标题化合物，为棕色粉末(0.067g，32％)。1H NMR(400MHz,DMSO-d6)δppm 9.85(bs,1H),7.36-7.45(m,2H),7.30-7.36(m,1H),7.19-7.27(m,3H),7.17(s,1H),7.08(d,J＝7.81Hz,1H),6.73(bs,1H),3.02(s,3H),2.79(t,J＝7.72Hz,2H),2.63(s,3H),2.42(s,3H),2.27(t,J＝7.72Hz,2H)。LCMS[M+H]+＝430.1,[M-H]-＝428.2。
以下示出了D35的合成方案
Figure BDA0001960521980000901
步骤D35.01：3-(3-氨基-4”-氟-1,1’:4’:1”-三联苯基-2’-基)丙酰胺的合成。使用在步骤D28.06中描述的方法，用4-氟苯硼酸得到标题化合物，为灰白色粉末(0.064g，69％)。1H NMR(400MHz,CDCl3)δppm 7.53-7.61(m,2H),7.48(d,J＝1.8Hz,1H),7.43(dd,J＝8.0,2.0Hz,1H),7.28(d,J＝7.8Hz,1H),7.21(t,J＝7.7Hz,1H),7.09-7.17(m,2H),6.64-6.76(m,3H),5.15(bs,2H),3.00-3.10(m,2H),2.30-2.40(m,2H)。LCMS[M+H]+＝335.1,[M+Na]+＝357.1,[M+HCO2]-＝379.1。
步骤D35.02：3-(4”-氟-3-((甲磺酰基)氨基)-1,1’:4’,1”-三联苯基-2’-基)丙酰胺(D35)的合成。在氮气气氛下在圆底烧瓶中装入3-(3-氨基-4”-氟-1,1’:4’:1”-三联苯基-2’-基)丙酰胺(0.064g，0.191mmol)、二氯甲烷(5mL)和三乙胺(0.106mL，0.766mmol)。将反应混合物在冰浴中冷却15分钟，然后加入甲磺酰氯(0.045mL，0.573mmol)。将反应混合物在冰浴中搅拌3h，然后使其温热至室温并且搅拌48h。将反应混合物直接加载至二氧化硅上并且通过急骤色谱(二氯甲烷/甲醇)纯化，得到为胶状物的部分纯化的物料。将粗产物在二氯甲烷/己烷(1:1)(25mL)中搅拌数小时并且将所得固体通过过滤收集，用二氯甲烷/己烷(1:1)(2x 10mL)洗涤并且在高真空中干燥，得到标题化合物，为灰白色粉末(0.036g，46％)。1H NMR(400MHz,DMSO-d6)δppm 9.84(s,1H),7.70-7.78(m,2H),7.61(d,J＝1.8Hz,1H),7.53(dd,J＝7.8,2.0Hz,1H),7.39-7.46(m,1H),7.28-7.36(m,2H),7.15-7.28(m,4H),7.09(d,J＝7.6Hz,1H),6.73(bs,1H),3.03(s,3H),2.78-2.85(m,2H),2.31(dd,J＝9.0,7.0Hz,2H)。LCMS[M+H]+＝413.2,[M+Na]+＝435.1,[M-H]-＝411.2。
以下示出了D167的结构
Figure BDA0001960521980000911
3-(2-(3-((3-(2-(2-氨基甲酰基乙基)-4-(吡啶-3-基)苯基苯基氨基)甲酰基氨基)苯基)-5-(吡啶-3-基)-苯基)丙烯酰胺(D167)的合成。在通过急骤色谱纯化之后从D29的合成分离作为较慢洗脱的化合物。得到标题化合物，为白色粉末(0.046g，11％)。1H NMR(400MHz,DMSO-d6)δppm 9.00(s,2H),8.93(dd,J＝2.34,0.78Hz,2H),8.59(dd,J＝4.79,1.66Hz,2H),8.07-8.13(m,2H),7.69(d,J＝1.95Hz,2H),7.61(dd,J＝7.81,1.95Hz,2H),7.48-7.55(m,4H),7.33-7.40(m,2H)7.45(d,J＝9.18Hz,2H),7.30(d,J＝7.82Hz,2H),7.24(br.s.,2H),6.97(d,J＝7.62Hz,2H),6.74(br.s.,2H),2.81-2.90(m,4H),2.29-2.38(m,4H)。LCMS[M+H]+＝661.3。
以下示出了D171的合成方案
Figure BDA0001960521980000921
步骤D171.01：2-(2-(2-((1,1-二甲基乙氧基)甲酰基氨基)吡啶-4-基)-5-(嘧啶-5-基)苄基)丙二酸1,3-二乙酯的合成。在装有回流冷凝器并且在氮气气氛下的圆底烧瓶中装入2-(((2-三氟甲基)磺酰基)氧代)-5-(嘧啶-5-基)苄基)丙二酸1,3-二乙酯(0.400g，0.840mmol)、(1,1-二甲基乙氧基)(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-2-基氨基)甲酮(0.296g，0.924mmol)、碳酸钾(0.232g 1.68mmol)、1,4-二
Figure BDA0001960521980000922
烷(3.2mL)、乙醇(0.8mL)和水(0.8mL)。通过使氮气鼓泡通过2分钟将反应混合物脱气，然后加入四(三苯基膦)钯(0.097g，0.084mmol)并且将反应混合物在85℃搅拌2h。将反应混合物冷却至室温，用乙酸乙酯(25mL)和水(15mL)稀释。将混合物转移至分液漏斗，将水相分离并且进一步用乙酸乙酯(25mL)萃取。将有机物合并，用盐水(10mL)洗涤，干燥(硫酸镁)，过滤并且浓缩。通过急骤色谱(乙酸乙酯/己烷)纯化，得到标题化合物，为黄色固体(0.316g，72％)。LCMS[M+H]+＝521.3。
步骤D171.02：3-(2-(2-氨基吡啶-4-基)-5-(嘧啶-5-基)苯基)丙酸硫酸氢盐的合成。在装有回流冷凝器的圆底烧瓶中装入2-(2-(2-((1,1-二甲基乙氧基)甲酰基氨基)吡啶-4-基)-5-(嘧啶-5-基)苄基)丙二酸1,3-二乙酯(0.406g，0.780mmol)和硫酸(5mL的2M水溶液)。将反应混合物在回流下搅拌24h，然后冷却并且浓缩。通过加入碳酸钠溶液将pH调节至4-5并且将混合物搅拌2h。将所得黄色沉淀通过过滤收集，用水(3x 10mL)洗涤并且风干，得到标题化合物，为黄色固体(0.145g，44％)。1H NMR(400MHz,DMSO-d6)δppm 9.21(s,1H),9.20(s,2H),7.99(d,J＝5.67Hz,1H),7.85(d,J＝1.76Hz,1H),7.75(dd,J＝8.01,1.95Hz,1H),7.34(d,J＝8.01Hz,1H),6.66(d,J＝4.88Hz,1H),6.59(s,1H),2.84-2.92(m,2H),2.52-2.58(m,2H)。LCMS[M]+＝320.0。
步骤D171.03：3-(2-(2-氨基吡啶-4-基)-5-(嘧啶-5-基)苯基)丙酸甲酯的合成。在装有回流冷凝器的圆底烧瓶中装入3-(2-(2-氨基吡啶-4-基)-5-(嘧啶-5-基)苯基)丙酸硫酸氢盐(0.145mg，0.400mmol)、甲醇(75mL)和盐酸(1mL的2M水溶液)并且在回流下加热3h。将反应混合物热过滤，将残余物用甲醇(2x 15mL)洗涤并且将滤液合并并且浓缩。将残余物在乙酸乙酯(50mL)和碳酸钠溶液(50mL)之间分配。将水相分离并且进一步用乙酸乙酯(50mL)萃取。将有机物合并，用盐水(20mL)洗涤，用硫酸镁干燥并且浓缩至干燥，得到标题化合物，为黄色固体(0.048g，36％)。1H NMR(400MHz,DMSO-d6)δppm 9.20(s,1H),9.19(s,2H),7.97(d,J＝5.08Hz,1H),7.82(d,J＝1.76Hz,1H),7.72(dd,J＝7.81,1.95Hz,1H),7.30(d,J＝8.01Hz,1H),6.47(dd,J＝5.18,1.47Hz,1H),6.38(s,1H),6.02(s,2H),3.55(s,3H),2.87-2.94(m,2H),2.58-2.65(m,2H)。LCMS[M+H]+＝335.2。
步骤D171.04：3-[2-(2-氨基吡啶-4-基)-5-(嘧啶-5-基)苯基]丙烯酰胺(D171)的合成。根据步骤D6.11进行制备，得到标题化合物，为灰白色粉末(0.045g，41％)。1H NMR(400MHz,DMSO-d6)δppm 9.21(s,1H),9.18(s,2H),7.96(d,J＝5.08Hz,1H),7.77(d,J＝1.76Hz,1H),7.70(dd,J＝7.91,1.86Hz,1H),7.29(d,J＝7.82Hz,1H),7.25(br.s.,1H),6.76(br.s.,1H),6.48(dd,J＝5.18,1.47Hz,1H),6.39(s,1H),6.00(s,2H),2.81-2.89(m,2H),2.36(dd,J＝8.89,6.94Hz,2H)。LCMS[M+H]+＝320.2。
以下示出了D172的合成方案
Figure BDA0001960521980000931
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步骤D172.01：2-(2-(3,5-二氨基苯基)-5-(嘧啶-5-基)苄基)丙二酸1,3-二乙酯的合成。在装有回流冷凝器并且在氮气气氛下的圆底烧瓶中装入2-(((2-三氟甲基)磺酰基)氧代)-5-(嘧啶-5-基)苄基)丙二酸1,3-二乙酯(0.157g，0.329mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯-1,3-二胺(0.077g，0.329mmol)、碳酸钾(0.091g0.658mmol)、1,4-二
Figure BDA0001960521980000932
烷(2mL)、乙醇(0.5mL)和水(0.5mL)。通过使氮气鼓泡通过2分钟将反应混合物脱气，然后加入四(三苯基膦)钯(0.038g，0.033mmol)并且将反应混合物在85℃搅拌3h。将反应混合物冷却至室温，用乙酸乙酯(50mL)和水(25mL)稀释，并且用碳酸钠碱化至pH>10。将混合物转移至分液漏斗，将有机相分离并且用盐水(10mL)洗涤，干燥(硫酸镁)，过滤并且浓缩。通过急骤色谱(乙酸乙酯/己烷)纯化，得到标题化合物，为黄色固体(0.118g，82％)。1HNMR(400MHz,CHLOROFORM-d)δppm9.21(s，0.5H)，8.95(s，1.5H)，7.63-7.71(m,0.5H),7.54(d,J＝4.88Hz,0.5H),7.42-7.50(m,2.5H),7.34(d,J＝8.40Hz,1H),6.02-6.10(m,2.5H),4.09(q,J＝6.32Hz,4H),3.64(br.s.,3H),3.54(t,J＝7.91Hz,1H),3.36(d,J＝7.62Hz,2H),1.26(t,J＝7.03Hz,1H),1.15(t,J＝7.13Hz,6H)。LCMS[M+H]+＝435.2。
步骤D172.02：3-(2-(3,5-二氨基-苯基)-5-(嘧啶-5-基)苯基)丙酸甲酯的合成。根据步骤D6.10进行制备，得到标题化合物，为琥珀色胶状物(0.105g，90％)。1H NMR(400MHz,DMSO-d6)δppm 9.18(s,1H),9.17(s,2H),7.72(d,J＝1.76Hz,1H),7.51-7.58(m,1H),7.22(d,J＝7.82Hz,1H),5.83(t,J＝1.95Hz,1H),5.73(d,J＝1.95Hz,2H),4.81(s,4H),3.56(s,3H),2.89-2.97(m,2H),2.54-2.61(m,2H)。LCMS[M+H]+＝349.2。
步骤D172.03：3-(2-(3,5-二氨基苯基)-5-(嘧啶-5-基)苯基)丙烯酰胺(D172)的合成。根据步骤D6.11进行制备，得到标题化合物，为米黄色粉末(0.038g，38％)。1H NMR(400MHz,DMSO-d6)δppm 9.18(s,1H),9.15(s,2H),7.70(d,J＝1.76Hz,1H),7.62(dd,J＝7.81,1.95Hz,1H),7.22(d,J＝8.01Hz,2H),6.75(br.s.,1H),5.84(t,J＝1.86Hz,1H),5.74(d,J＝1.95Hz,2H),4.79(s,4H),2.82-2.92(m,2H),2.28-2.39(m,2H)。LCMS[M+H]+＝334.2。
实验例2：化合物的体内筛选
使用3％异氟烷将十四周龄的自发性高血压大鼠(SHR)麻醉，在将鼻子轻轻地封闭的同时将舌头轻轻地向前拉出并且使用微量移液器将在200μL的生理盐水中的博来霉素(bleomycin)10U/100g体重放在远端口咽部中。然后将大鼠静置以从麻醉中恢复。在16周龄时，将SHR随机分为对照组(16周或20周)或治疗组。将16周对照麻醉并且对血液取样并且获取组织。20周对照仅接受饮用溶液(5％乙醇)，而治疗组接受溶解在饮用水中的试验化合物，并且每周两次调节浓度以在4周内维持500pmol/kg/min的剂量。在20周龄时，将大鼠麻醉并且对血液取样并且获取组织。
为了进行组织学检查，将肺固定在福尔马林中并且使用马森三色染色(MassonTrichrome)将来自两个水平中的每一个的切片染色。由对实验组盲探的观察者通过组织形态测量(histomorphometry)对纤维化进行定量。
与20周对照相比，在使用500pmol/kg/min的A32、A79、A6、VB0004、P13、D30、D6和A81的4周治疗之后的肺中的纤维化减小(图1和2)，证明这些化合物预防了肺纤维化的发展。
与16周对照相比，在使用500pmol/kg/min的A32、A79、A6、VB0004、D30、D6和A81的4周治疗之后的肺中的纤维化减小(图1和2)，证明这些化合物使已经形成的肺纤维化逆转。
实验例3：化合物的体外筛选
在使用试验化合物处理人小气道上皮细胞(ATCC)之后，使用xCELLigence SP系统(Roche)测量细胞阻抗(细胞指数)的变化。在这个基于体外细胞的实验系统中，发现负阻抗曲线与减轻的肺纤维化相关(图3和4)。
简而言之，将50μl的细胞培养基(在37℃的DMEM低葡萄糖，补充有15％胎牛血清)加入至E-Plate 96(Roche)的每个孔中，并且测量每个孔中的本底阻抗。然后将50μl的人小气道上皮细胞悬浮液(10,000个细胞/孔)加入至E-Plate 96的适当的孔中。在细胞培养温育器中，对在RTCA SPStation中的E-Plate 96的每个孔监测细胞指数。在5％CO2和95％湿度下过夜温育16-20小时之后，将100μl的试验化合物溶液(试验化合物在DMSO中制备并且用细胞培养基稀释至10μM、20μM或30μM的试验化合物浓度，并且最终DMSO浓度为0.25％)加入至E-Plate 96的适当的孔中并且在化合物处理之后每20秒立即测量细胞指数值，持续3小时。通过减去赋形剂处理的细胞的细胞指数以将细胞指数值基线校正，并且通过除以即将加入化合物的时间点时的细胞指数将细胞指数值归一化。使用Roche RTCA软件绘制基线归一化细胞指数相对于时间的函数。
对于A6、A26、A27、A30、A32、A35、A56、A79、A81、D4、D5、D6、D10、D11、D12、D16、D17、D18、D28、D30、D31、D32、D35、D167、D171、D172、P13、P14、P25、P42、P43、P44和VB0004，观察到在人小气道上皮细胞中的负阻抗反应(图5)，表明这些化合物减轻了肺纤维化。

Claims (11)

1.一种下式的化合物：
Figure FDF0000023724600000011
或其药理学上可接受的盐，
其中：
B选自由下列各项组成的组：
Figure FDF0000023724600000012
Q独立地选自氨基或式-NHW，其中：W选自-SO2(X1)aY或-CO(X1)aY，a是0或1，
X1选自-NH-，并且Y选自-H、-CH3、或-CH2CH3；
n是1或2；
D选自由以下组成的组：
Figure FDF0000023724600000021
T独立地选自C1-6烷基或卤素；并且
m是0、1或2，
其中D不能是未取代的苯基，且当D为苯环时，T是卤素且m是1。
2.根据权利要求1所述的化合物，其中所述化合物选自由下列各项组成的组：
Figure FDF0000023724600000022
/>
Figure FDF0000023724600000031
/>
Figure FDF0000023724600000041
或其药理学上可接受的盐。
3.根据权利要求1至2中任一项所述的化合物在制备预防性地或治疗性地治疗肺纤维化或者在患有肺纤维化或处于发展肺纤维化的风险下的受试者中的相关病况的药物中的用途。
4.根据权利要求3所述的用途，其中处于发展肺纤维化的风险下的所述受试者已经暴露于气体、烟、化学品、石棉纤维或灰尘。
5.根据权利要求3所述的用途，其中处于发展肺纤维化的风险下的所述受试者患有肺的自身免疫病症、病毒感染或细菌感染。
6.根据权利要求3所述的用途，其中处于发展肺纤维化的风险下的所述受试者已经接受了针对肺癌或乳腺癌的放射疗法。
7.根据权利要求3所述的用途，其中处于发展肺纤维化的风险下的所述受试者具有遗传倾向性。
8.根据权利要求3所述的用途，其中处于发展肺纤维化的风险下的所述受试者是吸烟者。
9.根据权利要求3至8中任一项所述的用途，其中所述相关病况选自肺动脉高压、右侧心力衰竭、呼吸衰竭、缺氧、咳嗽、血栓形成、肺炎和肺癌。
10.根据权利要求3至8中任一项所述的用途，其中所述药物预防、减轻或延缓肺纤维化的发展。
11.根据权利要求3至8中任一项所述的用途，其中所述药物减轻已经形成的肺纤维化。
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