CN109748873B - 化合物及其治疗癌症的用途 - Google Patents

化合物及其治疗癌症的用途 Download PDF

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CN109748873B
CN109748873B CN201711091268.0A CN201711091268A CN109748873B CN 109748873 B CN109748873 B CN 109748873B CN 201711091268 A CN201711091268 A CN 201711091268A CN 109748873 B CN109748873 B CN 109748873B
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brm2
alkyl
cancer
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compound
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CN109748873A (zh
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何伟
侯晓清
梁锷
李宏博
李彬
郭乐
杨爽
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BEIJING JIALIN PHARMACEUTICAL CO LTD
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BEIJING JIALIN PHARMACEUTICAL CO LTD
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Priority to CN202011437196.2A priority Critical patent/CN112480005B/zh
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Priority to CN202011433438.0A priority patent/CN112457255B/zh
Priority to CN202011433095.8A priority patent/CN112480079B/zh
Priority to CN201711091268.0A priority patent/CN109748873B/zh
Priority to EP18877108.3A priority patent/EP3705476A1/en
Priority to US16/761,091 priority patent/US11332461B2/en
Priority to PCT/CN2018/111154 priority patent/WO2019091277A1/zh
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Abstract

本发明提供了式(I)的化合物或其药学上可接受的盐、立体异构体、醚、酯、前药和溶剂化物，所述的化合物能够用于预防和/或治疗癌症，

Description

化合物及其治疗癌症的用途
技术领域
本发明属于医药领域，涉及一种预防和/或治疗癌症的化合物及其制备方法。
背景技术
BRG1和BRM是哺乳动物染色质重构复合物SWI/SNF的核心ATP酶亚单位，两者结构相似、功能互补。BRG1的ATP水解酶结构域可以结合并水解ATP提供能量，使染色质重构复合物结合到染色质上介导DNA从核小体上解离从而调节基因的转录。BRG1的C-末端是一个组蛋白密码的reader结构域，它可以特异性的识别乙酰化修饰的赖氨酸，该过程对于染色质重构复合物结合到正确的染色质位点至关重要。
已有研究认为，BRG1参与调控一些和肿瘤发生发展转录突变，如CD44、c-fos等，而且在肺癌、膀胱癌、乳腺癌、***癌、胃癌等癌症中，BRG1是发病重要的抑癌基因。另外，Takahiro Oike等人也报道BRM蛋白可以作为BRG1缺乏型肺癌治疗的候选靶点。通过免疫组化分析方法显示，约10％的非小细胞肺癌(NSCLCs)患者中存在BRG1-缺乏和BRM过表达的现象，因此证明针对BRM靶点的疗法具有可行性，并且BRG1的缺失也发生在其他癌症中，包括胰腺，皮肤和脑癌，例如BRG1最近被确定为在成神经管细胞瘤中经常突变的基因，由此针对BRM蛋白的靶向治疗可适用于治疗各种癌症。
CN105523955A公开了一系列用于癌症治疗的化合物，特别是对于BRG1基因缺失的非小细胞肺癌具有治疗作用，然而其中披露的化合物仍然存在活性不足以及成药性差的缺陷，特别是对于2-(1H-吡唑-3-基)苯酚类型的化合物而言，吡唑环上的取代基仅能够适用于烷基取代基团，极大的限制了应用范围。
发明内容
本发明的一个方面提供式(I)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药和溶剂化物，
Figure BDA0001461263200000011
其中，
R1选自H、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基时，R2选自C2-10烯基、C2-10炔基，其中所述烷基、烯基或炔基上的任意碳原子可被一个或两个以上的以下基团取代：卤素、-CN、-OC0-10烷基、-S(O)mC0-10烷基、-SO2N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)C(＝O)(C0-10烷基)、-N(C0-10烷基)C(＝O)O(C0-10烷基)、-N(C0-10烷基)C(＝O)N(C0-10烷基)、-C(＝O)C0-10烷基、-C(＝O)OC0-10烷基、-C(＝O)N(C0-10烷基)(C0-10烷基)、-杂环烷基、-N(C0-10烷基)杂环烷基、-N(C0-10烷基)芳香基、-N(C0-10烷基)杂环芳香基、芳基、-N杂环芳香基、-S杂环芳香基或-O杂环芳香基，m为0、1或2，
优选的，R1选自H、C1-6烷基时，R2选自C2-6烯基、C2-6炔基，其中所述烯基或炔基上的任意碳原子可被一个或两个以上的以下基团取代：卤素、苯基，
更优选的，R1选自H、C1-3烷基时，R2选自C2-6烯基，其中所述烯基或炔基上的一个碳原子可被以下基团取代：卤素、苯基，
最优选的，R1选自甲基、乙基或丙基时，R2选自-CH＝CH2、-CH＝CHCH2CH2CH3、
Figure BDA0001461263200000012
或者，
R1选自
Figure BDA0001461263200000013
时，R2选自H、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基，其中所述烷基、烯基或炔基上的任意碳原子可被一个或两个以上的以下基团取代：卤素、-CN、-OC0-10烷基、-S(O)mC0-10烷基、-SO2N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)C(＝O)(C0-10烷基)、-N(C0-10烷基)C(＝O)O(C0-10烷基)、-N(C0-10烷基)C(＝O)N(C0-10烷基)、-C(＝O)C0-10烷基、-C(＝O)OC0-10烷基、-C(＝O)N(C0-10烷基)(C0-10烷基)、-杂环烷基、-N(C0-10烷基)杂环烷基、-N(C0-10烷基)芳香基、-N(C0-10烷基)杂环芳香基、芳基、-N杂环芳香基、-S杂环芳香基或-O杂环芳香基，m为0、1或2，
优选的，R1选自
Figure BDA0001461263200000021
时，R2选自H、C1-6烷基、C2-6烯基，其中所述烷基或烯基或炔基上的任意碳原子可被一个或两个以上的以下基团取代：卤素、-OC0-6烷基、-S(O)mC0-6烷基、苯基，m为0、1或2，
其中，R8选自单键、C1-10亚烷基、C1-10亚烷基芳基、C(＝O)N(C0-10烷基)(C1-10亚烷基)、-C(＝O)N(C0-10烷基)(芳基)-、-芳基C(＝O)N(C0-10烷基)-、-C1-10亚烷基C(＝O)N(C0-10烷基)-，其中所述亚烷基、烷基、芳基上的任意碳原子可被一个或两个以上的以下基团取代：卤素、-CN、-OC0-10烷基、-S(O)mC0-10烷基、-SO2N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)C(＝O)(C0-10烷基)、-N(C0-10烷基)C(＝O)O(C0-10烷基)、-N(C0-10烷基)C(＝O)N(C0-10烷基)、-C(＝O)C0-10烷基、-C(＝O)OC0-10烷基、-C(＝O)N(C0-10烷基)(C0-10烷基)、-杂环烷基、-N(C0-10烷基)杂环烷基、-N(C0-10烷基)芳香基、-N(C0-10烷基)杂环芳香基、芳基、-C1-10烷基芳基、-C1-10烷基杂环芳香基、-N杂环芳香基、-S杂环芳香基或-O杂环芳香基，m为0、1或2，
优选的，R8选自单键、C1-6亚烷基、
Figure BDA0001461263200000022
-N(C0-6烷基)C(＝O)-、-N(C0-6烷基)C(＝O)(C1-6亚烷基)、
Figure BDA0001461263200000023
-N(C0-6烷基)C(＝O)-、C1-6亚烷基N(C0-6烷基)C(＝O)-、
Figure BDA0001461263200000024
其中所述亚烷基、烷基、苯基上的任意碳原子可被一个或两个以上的以下基团取代：卤素、-OC0-6烷基，
更优选的，R8选自单键、-CH2、-CH2CH2-、
Figure BDA0001461263200000025
-NHC(＝O)-、
Figure BDA0001461263200000026
R16、R17、R18、R19和R20独立的选自H、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基，卤素、-CN、-OC0-10烷基、-S(O)mC0-10烷基、-SO2N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)C(＝O)R21、-N(C0-10烷基)C(＝O)O(C0-10烷基)、-N(C0-10烷基)C(＝O)N(C0-10烷基)、-C(＝O)C0-10烷基、-C(＝O)OC0-10烷基、-C(＝O)N(C0-10烷基)(C0-10烷基)、-杂环烷基、-N(C0-10烷基)杂环烷基、-N(C0-10烷基)杂环芳香基、-N(C0-10烷基)芳香基、杂环烷基、芳香基、-N杂环芳香基、-S杂环芳香基或-O杂环芳香基、硅烷基，其中所述烷基、芳基、杂环烷基、杂环芳香基、烯基或炔基上的任意碳原子可被一个或两个以上的以下基团任意取代：卤素、-CN、-OC0-10烷基、-S(O)mC0-10烷基、-SO2N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)C(＝O)(C0-10烷基)、-N(C0-10烷基)C(＝O)O(C0-10烷基)、-N(C0-10烷基)C(＝O)N(C0-10烷基)、-C(＝O)C0-10烷基、-C(＝O)OC0-10烷基、-C(＝O)N(C0-10烷基)(C0-10烷基)、-杂环烷基、-N(C0-10烷基)杂环烷基、-N(C0-10烷基)杂环芳香基、杂环烷基、芳基、-C1-10烷基芳基、-C1-10烷基杂环芳香基、-N杂环芳香基、-S杂环芳香基或-O杂环芳香基，m为0、1或2，
其中，R21选自H、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基，卤素、-CN、-OC0-10烷基、-S(O)mC0-10烷基、-SO2N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)C(＝O)O(C0-10烷基)、-N(C0-10烷基)C(＝O)N(C0-10烷基)、-C(＝O)C0-10烷基、-C(＝O)OC0-10烷基、-C(＝O)N(C0-10烷基)(C0-10烷基)、-杂环烷基、-N(C0-10烷基)杂环烷基、-N(C0-10烷基)杂环芳香基、-N(C0-10烷基)芳香基、杂环烷基、芳香基、-N杂环芳香基、-S杂环芳香基或-O杂环芳香基、硅烷基，其中所述烷基、芳基、杂环烷基、杂环芳香基、烯基或炔基上的任意碳原子可被一个或两个以上的以下基团任意取代：卤素、-CN、-OC0-10烷基、-S(O)mC0-10烷基、-SO2N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)C(＝O)(C0-10烷基)、-N(C0-10烷基)C(＝O)O(C0-10烷基)、-N(C0-10烷基)C(＝O)N(C0-10烷基)、-C(＝O)C0-10烷基、-C(＝O)OC0-10烷基、-C(＝O)N(C0-10烷基)(C0-10烷基)、-杂环烷基、-N(C0-10烷基)杂环烷基、-N(C0-10烷基)杂环芳香基、杂环烷基、芳基、-C1-10烷基芳基、-C1-10烷基杂环芳香基、-N杂环芳香基、-S杂环芳香基或-O杂环芳香基，m为0、1或2，
优选的，R16、R17、R18、R19和R20独立的选自H、C1-6烷基、卤素、苯基、-CN、-OH、-S(O)2C0-3烷基、-C(＝O)C0-3烷基、-N(C0-3烷基)C(＝O)(C0-3烷基)、三甲基硅烷、三乙基硅烷、N杂环丁烷基、吡啶基、吡唑基、吡咯烷基、吡喃基、四氢吡喃基、噻吩、四氢呋喃基、吡嗪基、咪唑基、哌啶基、哌嗪基、吲哚基、吗啉基、高哌嗪基、噻吩基、呋喃基、噁唑基、-NHC(＝O)R21，其中N原子上的H可任选的被C1-10烷基、C3-10环烷基、-CF3、叔丁氧羰基取代，
更优选的，R21选自C1-6直链或支链烷基、C3-10环烷基，卤素、-OC0-6烷基、苯基、N杂环丁烷基、吡啶基、吡唑基、吡咯烷基、吡喃基、四氢吡喃基、噻吩、四氢呋喃基、吡嗪基、咪唑基、哌啶基，哌嗪基，吲哚基、吗啉基、高哌嗪基、噻吩基、呋喃基、噁唑基，其中N原子上的H可任选的被C1-10烷基、C3-10环烷基、-CF3、叔丁氧羰基取代，
最优选的，R21选自卤代苯基、苄基、
Figure BDA0001461263200000031
Figure BDA0001461263200000032
Figure BDA0001461263200000033
异丁基、丙基，
特别优选的，R16、R17、R18、R19和R20选自H、甲基、乙基、丙基、异丙基、卤素、-OH、
Figure BDA0001461263200000034
Figure BDA0001461263200000035
R10选自H、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、杂环烷基、芳香基、-N杂环芳香基、-S杂环芳香基或-O杂环芳香基，其中所述烷基、芳基、杂环烷基、杂环芳香基、烯基或炔基上的任意碳原子可被一个或两个以上的以下基团任意取代：卤素、-CN、-OC0-10烷基、-S(O)mC0-10烷基、-SO2N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)C(＝O)(C0-10烷基)、-N(C0-10烷基)C(＝O)O(C0-10烷基)、-N(C0-10烷基)C(＝O)N(C0-10烷基)、-C(＝O)C0-10烷基、-C(＝O)OC0-10烷基、-C(＝O)N(C0-10烷基)(C0-10烷基)、-杂环烷基、-N(C0-10烷基)杂环烷基、-N(C0-10烷基)杂环芳香基、杂环烷基、芳基、-C1-10烷基芳基、-C1-10烷基杂环芳香基、-N杂环芳香基、-S杂环芳香基或-O杂环芳香基，m为0、1或2，
优选的，R10选自H、C1-6直链或支链烷基、苯基、吡啶基，
R11和R12独立的选自H、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、杂环烷基、-N(C0-10烷基)杂环烷基、-N(C0-10烷基)杂环芳香基、杂环烷基、芳香基、-N杂环芳香基、-S杂环芳香基或-O杂环芳香基，其中所述烷基、芳基、杂环烷基、杂环芳香基、烯基或炔基上的任意碳原子可被一个或两个以上的以下基团任意取代：卤素、-CN、-OC0-10烷基、-S(O)mC0-10烷基、-SO2N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)C(＝O)(C0-10烷基)、-N(C0-10烷基)C(＝O)O(C0-10烷基)、-N(C0-10烷基)C(＝O)N(C0-10烷基)、-C(＝O)C0-10烷基、-C(＝O)杂环烷基、-C(＝O)OC0-10烷基、-C(＝O)N(C0-10烷基)(C0-10烷基)、-杂环烷基、-N(C0-10烷基)杂环烷基、-N(C0-10烷基)杂环芳香基、杂环烷基、芳基、-C1-10烷基芳基、-C1-10烷基杂环芳香基、-N杂环芳香基、-S杂环芳香基或-O杂环芳香基，m为0、1或2，
优选的，R11和R12独立的选自H、C1-6烷基、C3-10环烷基、苯基、N杂环丁烷基，吡啶基、吡唑基、吡咯烷基、吡喃基、四氢吡喃基、噻吩、四氢呋喃基、吡嗪基、咪唑基、哌啶基，哌嗪基，吲哚基、吗啉基、高哌嗪基、噻吩基、呋喃基、噁唑基，其中N原子上的H可任选的被C1-6烷基、C3-10环烷基、-CF3，叔丁氧羰基取代，优选的，所述的烷基被上的任意碳原子可被一个或两个以上的以下基团任意取代：卤素、-OC0-6烷基、-S(O)mC0-6烷基、苯基、卤代苯基、苄基、对羟基苯基、吲哚基、-C(＝O)OC0-6烷基、对甲酰胺基苯基、-C(＝O)四氢吡咯、-C(＝O)吗啉，m为0、1或2，
更优选的，R11和R12独立的选自甲基、乙基、
Figure BDA0001461263200000041
Figure BDA0001461263200000042
R13选自H、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基、杂环烷基、芳香基、-N杂环芳香基、-S杂环芳香基或-O杂环芳香基，其中所述烷基、芳基、杂环烷基、杂环芳香基、烯基或炔基上的任意碳原子可被一个或两个以上的以下基团任意取代：卤素、-CN、-OC0-10烷基、-S(O)mC0-10烷基、-SO2N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)C(＝O)(C0-10烷基)、-N(C0-10烷基)C(＝O)O(C0-10烷基)、-N(C0-10烷基)C(＝O)N(C0-10烷基)、-C(＝O)C0-10烷基、-C(＝O)OC0-10烷基、-C(＝O)N(C0-10烷基)(C0-10烷基)、-杂环烷基、-N(C0-10烷基)杂环烷基、-N(C0-10烷基)杂环芳香基、杂环烷基、芳基、-C1-10烷基芳基、-C1-10烷基杂环芳香基、-N杂环芳香基、-S杂环芳香基或-O杂环芳香基，m为0、1或2，
优选的，R13选自H、C1-6烷基、吡啶基、苯基、叔丁氧羰基，-C(＝O)OC0-6烷基，
Y1和Y2选自N或C，
n选自1、2或3，
R14和R15独立的选自H、C1-10直链或支链烷基、C2-10直链或支链烯基、C2-10直链或支链炔基、C3-10环烷基、杂环烷基、-C(＝O)C0-10烷基、-C(＝O)杂环芳香基、-C(＝O)芳香基、杂环芳香基、杂环烷基、芳香基、-N杂环芳香基、-S杂环芳香基或-O杂环芳香基，其中所述烷基、芳基、杂环烷基、杂环芳香基、烯基或炔基上的任意碳原子可被一个或两个以上的以下基团任意取代：卤素、-CN、-OC0-10烷基、-S(O)mC0-10烷基、-SO2N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)C(＝O)(C0-10烷基)、-N(C0-10烷基)C(＝O)O(C0-10烷基)、-N(C0-10烷基)C(＝O)N(C0-10烷基)、-C(＝O)C0-10烷基、-C(＝O)杂环烷基、-C(＝O)OC0-10烷基、-C(＝O)N(C0-10烷基)(C0-10烷基)、-杂环烷基、-N(C0-10烷基)杂环烷基、-N(C0-10烷基)杂环芳香基、杂环烷基、芳基、-C1-10烷基芳基、-C1-10烷基杂环芳香基、-N杂环芳香基、-S杂环芳香基或-O杂环芳香基，m为0、1或2，
优选的，R14和R15独立的选自H、C1-6烷基、-C(＝O)C0-6烷基、-C(＝O)C0-6亚烷基苯基、-C(＝O)吡啶基、-C(＝O)吡嗪基、-C(＝O)咪唑基、-C(＝O)吡唑基、-C(＝O)苯基，其中所述烷基、苯基、杂环芳香基上的任意碳原子可被一个或两个以上的以下基团任意取代：卤素、-OC0-6烷基、CF3，
优选的，R14和R15独立的选自
Figure BDA0001461263200000043
Figure BDA0001461263200000044
Figure BDA0001461263200000051
R3、R4、R5和R6独立的选自H、C1-10烷基、C2-10烯基、C2-10炔基、C3-10环烷基，卤素、-CN、-OC0-10烷基、-S(O)mC0-10烷基、-SO2N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)C(＝O)R21、-N(C0-10烷基)C(＝O)O(C0-10烷基)、-N(C0-10烷基)C(＝O)N(C0-10烷基)、-C(＝O)C0-10烷基、-C(＝O)OC0-10烷基、-C(＝O)N(C0-10烷基)(C0-10烷基)、-杂环烷基、-N(C0-10烷基)杂环烷基、-N(C0-10烷基)杂环芳香基、-N(C0-10烷基)芳香基、杂环烷基、芳香基、-N杂环芳香基、-S杂环芳香基或-O杂环芳香基、硅烷基，其中所述烷基、芳基、杂环烷基、杂环芳香基、烯基或炔基上的任意碳原子可被一个或两个以上的以下基团任意取代：卤素、-CN、-OC0-10烷基、-S(O)mC0-10烷基、-SO2N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)C(＝O)(C0-10烷基)、-N(C0-10烷基)C(＝O)O(C0-10烷基)、-N(C0-10烷基)C(＝O)N(C0-10烷基)、-C(＝O)C0-10烷基、-C(＝O)OC0-10烷基、-C(＝O)N(C0-10烷基)(C0-10烷基)、-杂环烷基、-N(C0-10烷基)杂环烷基、-N(C0-10烷基)杂环芳香基、杂环烷基、芳基、-C1-10烷基芳基、-C1-10烷基杂环芳香基、-N杂环芳香基、-S杂环芳香基或-O杂环芳香基，m为0、1或2，
优选的，R3、R4、R5和R6独立的选自H、C1-6烷基、C3-10环烷基，卤素、-OC0-6烷基、-N(C0-6烷基)(C0-6烷基)、-N(C0-6烷基)C(＝O)(C0-6烷基)、-N(C0-6烷基)C(＝O)O(C0-6烷基)、-N(C0-6烷基)C(＝O)N(C0-6烷基)、-C(＝O)C0-6烷基、-C(＝O)OC0-6烷基、-C(＝O)N(C0-6烷基)(C0-6烷基)、苯基，
更优选的，R3选自-NH2，
更优选的，R4选自卤素，
更优选的，R5和R6独立的选自H、C1-6烷基，
R7选自H、C1-10烷基、C3-10环烷基、-OC0-10烷基、C(＝O)C0-10烷基，其中所述烷基上的任意碳原子可被一个或两个以上的以下基团任意取代：卤素、-CN、-OC0-10烷基、-S(O)mC0-10烷基、-SO2N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)C(＝O)(C0-10烷基)、-N(C0-10烷基)C(＝O)O(C0-10烷基)、-N(C0-10烷基)C(＝O)N(C0-10烷基)、-C(＝O)C0-10烷基、-C(＝O)OC0-10烷基、-C(＝O)N(C0-10烷基)(C0-10烷基)、-杂环烷基、-N(C0-10烷基)杂环烷基、-N(C0-10烷基)杂环芳香基、杂环烷基、芳基、-C1-10烷基芳基、-C1-10烷基杂环芳香基、-N杂环芳香基、-S杂环芳香基或-O杂环芳香基，m为0、1或2，
优选的，R7选自H、C1-6烷基，
更优选的，R7选自H。
在本发明的具体实施方式中提供式(Ⅱ)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药和溶剂化物，
Figure BDA0001461263200000052
优选的，在本发明的具体实施方式中提供式(Ⅱ-1)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药和溶剂化物，
Figure BDA0001461263200000053
优选的，在本发明的具体实施方式中提供式(Ⅱ-2)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药和溶剂化物，
Figure BDA0001461263200000061
在本发明的具体实施方式中提供式(Ⅲ)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药和溶剂化物，
Figure BDA0001461263200000062
优选的，在本发明的具体实施方式中提供式(Ⅲ-1)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药和溶剂化物，
Figure BDA0001461263200000063
优选的，在本发明的具体实施方式中提供式(Ⅲ-2)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药和溶剂化物，
Figure BDA0001461263200000064
优选的，在本发明的具体实施方式中提供式(Ⅲ-3)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药和溶剂化物，
Figure BDA0001461263200000065
在本发明的具体实施方式中提供式(Ⅳ)的化合物，及其药学上可接受的盐、立体异构体、酯、前药和溶剂化物，
Figure BDA0001461263200000071
优选的，在本发明的具体实施方式中提供式(Ⅳ-1)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药和溶剂化物，
Figure BDA0001461263200000072
其中，R22、R23、R24、R25和R26独立的选自卤素、-NH2、-OH、C1-10烷基、-CF3，m为0、1、2。
在本发明的具体实施方式中提供式(Ⅴ)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药和溶剂化物，
Figure BDA0001461263200000073
优选的，在本发明的具体实施方式中提供式(Ⅴ-1)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药和溶剂化物，
Figure BDA0001461263200000074
优选的，在本发明的具体实施方式中提供式(Ⅴ-2)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药和溶剂化物，
Figure BDA0001461263200000075
优选的，在本发明的具体实施方式中提供式(Ⅴ-3)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药和溶剂化物，
Figure BDA0001461263200000081
在本发明的具体实施方式中提供式(Ⅵ)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药和溶剂化物，
Figure BDA0001461263200000082
优选的，在本发明的具体实施方式中提供式(Ⅵ-1)的化合物，及其药学上可接受的盐、立体异构体、醚、酯、前药和溶剂化物，
Figure BDA0001461263200000083
其中，R22、R23、R24、R25和R26独立的选自卤素、-NH2、-OH、C1-10烷基、-CF3，m为0、1、2。
在本发明更具体实施方式中，提供如下的具体化合物：
BRM2-1
Figure BDA0001461263200000084
BRM2-2
Figure BDA0001461263200000085
BRM2-3
Figure BDA0001461263200000086
BRM2-4
Figure BDA0001461263200000087
BRM2-5
Figure BDA0001461263200000091
BRM2-6
Figure BDA0001461263200000092
BRM2-7
Figure BDA0001461263200000093
BRM2-8
Figure BDA0001461263200000094
BRM2-9
Figure BDA0001461263200000095
BRM2-10
Figure BDA0001461263200000096
BRM2-11
Figure BDA0001461263200000097
BRM2-12
Figure BDA0001461263200000098
BRM2-13
Figure BDA0001461263200000099
BRM2-14
Figure BDA0001461263200000101
BRM2-15
Figure BDA0001461263200000102
BRM2-16
Figure BDA0001461263200000103
BRM2-17
Figure BDA0001461263200000104
BRM2-18
Figure BDA0001461263200000105
BRM2-19
Figure BDA0001461263200000106
BRM2-20
Figure BDA0001461263200000107
BRM2-21
Figure BDA0001461263200000108
BRM2-22
Figure BDA0001461263200000109
BRM2-23
Figure BDA0001461263200000111
BRM2-24
Figure BDA0001461263200000112
BRM2-25
Figure BDA0001461263200000113
BRM2-26
Figure BDA0001461263200000114
BRM2-27
Figure BDA0001461263200000115
BRM2-28
Figure BDA0001461263200000116
BRM2-29
Figure BDA0001461263200000117
BRM2-30
Figure BDA0001461263200000118
BRM2-31
Figure BDA0001461263200000119
BRM2-32
Figure BDA00014612632000001110
BRM2-33
Figure BDA00014612632000001111
BRM2-34
Figure BDA0001461263200000121
BRM2-35
Figure BDA0001461263200000122
BRM2-36
Figure BDA0001461263200000123
BRM2-37
Figure BDA0001461263200000124
BRM2-38
Figure BDA0001461263200000125
BRM2-39
Figure BDA0001461263200000126
BRM2-40
Figure BDA0001461263200000127
BRM2-41
Figure BDA0001461263200000128
BRM2-42
Figure BDA0001461263200000129
BRM2-96
Figure BDA0001461263200000131
BRM2-97
Figure BDA0001461263200000132
BRM2-98
Figure BDA0001461263200000133
BRM2-99
Figure BDA0001461263200000134
BRM2-100
Figure BDA0001461263200000135
BRM2-101
Figure BDA0001461263200000136
BRM2-102
Figure BDA0001461263200000137
BRM2-103
Figure BDA0001461263200000138
BRM2-104
Figure BDA0001461263200000139
BRM2-105
Figure BDA0001461263200000141
BRM2-106
Figure BDA0001461263200000142
BRM2-107
Figure BDA0001461263200000143
BRM2-108
Figure BDA0001461263200000144
BRM2-109
Figure BDA0001461263200000145
BRM2-110
Figure BDA0001461263200000146
BRM2-111
Figure BDA0001461263200000147
BRM2-112
Figure BDA0001461263200000148
BRM2-113
Figure BDA0001461263200000149
BRM2-114
Figure BDA0001461263200000151
BRM2-115
Figure BDA0001461263200000152
BRM2-116
Figure BDA0001461263200000153
BRM2-117
Figure BDA0001461263200000154
BRM2-118
Figure BDA0001461263200000155
BRM2-119
Figure BDA0001461263200000156
BRM2-120
Figure BDA0001461263200000157
BRM2-121
Figure BDA0001461263200000158
BRM2-122
Figure BDA0001461263200000159
BRM2-123
Figure BDA00014612632000001510
BRM2-124
Figure BDA0001461263200000161
BRM2-125
Figure BDA0001461263200000162
BRM2-126
Figure BDA0001461263200000163
BRM2-127
Figure BDA0001461263200000164
BRM2-128
Figure BDA0001461263200000165
BRM2-129
Figure BDA0001461263200000166
BRM2-130
Figure BDA0001461263200000167
BRM2-131
Figure BDA0001461263200000168
BRM2-132
Figure BDA0001461263200000169
BRM2-133
Figure BDA0001461263200000171
BRM2-134
Figure BDA0001461263200000172
BRM2-135
Figure BDA0001461263200000173
BRM2-136
Figure BDA0001461263200000174
BRM2-137
Figure BDA0001461263200000175
BRM2-138
Figure BDA0001461263200000176
BRM2-139
Figure BDA0001461263200000177
BRM2-140
Figure BDA0001461263200000178
BRM2-141
Figure BDA0001461263200000179
BRM2-142
Figure BDA00014612632000001710
BRM2-143
Figure BDA00014612632000001711
BRM2-144
Figure BDA0001461263200000181
BRM2-145
Figure BDA0001461263200000182
BRM2-146
Figure BDA0001461263200000183
BRM2-147
Figure BDA0001461263200000184
BRM2-148
Figure BDA0001461263200000185
BRM2-149
Figure BDA0001461263200000186
BRM2-150
Figure BDA0001461263200000187
BRM2-151
Figure BDA0001461263200000188
BRM2-152
Figure BDA0001461263200000189
BRM2-153
Figure BDA0001461263200000191
BRM2-154
Figure BDA0001461263200000192
BRM2-155
Figure BDA0001461263200000193
BRM2-156
Figure BDA0001461263200000194
BRM2-157
Figure BDA0001461263200000195
BRM2-158
Figure BDA0001461263200000196
BRM2-159
Figure BDA0001461263200000197
BRM2-160
Figure BDA0001461263200000198
BRM2-161
Figure BDA0001461263200000201
BRM2-162
Figure BDA0001461263200000202
BRM2-163
Figure BDA0001461263200000203
BRM2-164
Figure BDA0001461263200000204
BRM2-165
Figure BDA0001461263200000205
BRM2-166
Figure BDA0001461263200000206
BRM2-167
Figure BDA0001461263200000207
BRM2-168
Figure BDA0001461263200000208
BRM2-169
Figure BDA0001461263200000209
BRM2-170
Figure BDA0001461263200000211
BRM2-171
Figure BDA0001461263200000212
BRM2-172
Figure BDA0001461263200000213
BRM2-173
Figure BDA0001461263200000214
BRM2-174
Figure BDA0001461263200000215
Figure BDA0001461263200000216
本发明所述的式(I)的化合物可以采用如下的反应路线进行：
(路线1)4-取代吡唑类化合物的合成：
Figure BDA0001461263200000221
化合物1(1eq.)加入反应溶剂二氯甲烷中，化合物2(1.2eq.)分批加至溶液中。所得反应液在r.t.下反应8h后，二氯甲烷DCM萃取后使用硅胶柱层析分离，得到中间体3。中间体3(1eq.)，对甲苯磺酰肼(TsNHNH2，2eq.)和四丁基溴化铵(TBAB,1eq.)分批缓慢加入NaOH(3eq.)的水溶液中，边加边搅拌。所得的混合液在95℃下搅拌12h。反应液降至室温，并使用2N的盐酸调pH至4～5。所得混合液使用等体积乙酸乙酯萃取三次。有机相使用水和盐水洗之后，使用无水硫酸钠进行干燥。过滤出去硫酸钠后，有机相使用旋转蒸发仪去除。所得粗品使用硅胶柱层析的方法进行分离纯化，得到中间体4。中间体4(1eq.)，N-碘代丁二酰亚胺NIS(1.1eq.)溶解于二氯甲烷在r.t.下反应12h，得到中间体5。中间体5(1.0eq.)，邻苯二甲酸二庚酯DHP(2.0eq.)及PPST(0.2eq.)溶解于二氯甲烷，在r.t.下反应12h后，中性氧化铝层析柱分离得到中间体6。中间体6(1.0eq.),烯基频那硼酸酯(1.2eq.)，Pd(PPh3)4(0.05eq.)以及K2CO3(2.0eq.)溶解于二甲醚DME和水的混合溶剂，在100℃反应12h后，中性氧化铝层析柱分离得到中间体7。中间体7溶解于乙醇，并加入2N HCl的乙醇溶液，乙酸乙酯萃取并加入饱和碳酸氢钠，有机相旋干得到中间体8直接用于下一步的反应。中间体8溶解于二氯甲烷，-78℃加入BBr3(10eq.)，然后将反应升温至室温，反应24h，反应结束后，减压旋走溶剂，粗品用乙酸乙酯溶解后，水洗一次，盐水洗一次，有机相干燥后硅胶柱层析纯化得到中间体9。中间体9溶解于乙醇，并加入还原Fe粉以及氯化铵的水溶液，在r.t.下反应12h后硅胶柱层析分离得到取代吡唑类化合物。
(路线2)5-取代吡唑类化合物的合成：
Figure BDA0001461263200000231
中间体10使用干燥的四氢呋喃THF溶解，然后在冰浴下滴入酮(1.1eq.)和LiHMDS(1.5eq.)的反应溶液中。所得反应液在r.t.下搅拌1h后，加水淬灭。使用二氯甲烷萃取，有机相使用无水硫酸镁干燥。干燥剂被过滤后，有机相拌硅胶，使用硅胶层析柱分离纯化，得到中间体11。中间体11溶解于甲醇，NH2NH2.H2O(3.0eq.)滴加到反应液中，在r.t.下反应12h后，旋干得到粗产品中间体12直接用于下一步反应。中间体12溶解于二氯甲烷，-78℃加入BBr3(10eq.)，然后将反应升温至室温，反应24h，反应结束后，旋干得到粗产品用乙酸乙酯溶解后，水洗一次，盐水洗一次，有机相干燥后硅胶柱层析纯化得到中间体13。中间体13溶解于乙醇，并加入还原Fe粉以及氯化铵的水溶液，在r.t.下反应12h后硅胶柱层析分离得到5-取代吡唑类化合物。
(路线3)5-芳基取代吡唑类化合物衍生物的合成：
Figure BDA0001461263200000241
将中间体12(1eq)，4-甲基苯磺酸吡啶(PPTS,0.1eq)溶于二氯甲烷，再加入3，4-二氢-2H-吡喃(DHP,3eq)，室温反应24h，反应结束后减压旋走有机相，粗产物用中性三氧化二铝进行柱层析分离得到中间体15。
将中间体15(1eq)溶于乙二醇二甲醚和水的混合液(DME：H2O＝4:1)中，加入K2CO3(2.5eq)，Pd(PPh3)4(0.1eq)，芳基硼酸化合物(1.2eq)。氮气保护后加热至100℃反应24h，反应结束后减压旋走有机溶剂，然后用乙酸乙酯萃取两次，有机相干燥后用硅胶柱层析纯化得到中间体16。将中间体16溶解于二氯甲烷，-78℃加入BBr3(10eq.)，然后将反应升温至室温，反应24h，反应结束后，旋干有机相，粗产品用乙酸乙酯溶解后，水洗一次，盐水洗一次，有机相干燥后硅胶柱层析纯化得到吡唑环类化合物的芳香环衍生物。
将中间体15(1eq)，胺基化合物(2eq)溶于甲苯，再加入Pd2(dba)3(0.05eq)，1，1'-联萘-2,2'-双二苯膦(BINAP，0.1eq)，NaOtBu(2.5eq)。反应瓶用氮气置换保护后，加热至105℃反应24h。反应结束后用乙酸乙酯萃取，有机相分别用水和盐水洗一次，干燥后用硅胶柱层析纯化得到中间体17。将中间体17溶解于二氯甲烷，-78℃加入BBr3(10eq.)，然后将反应升温至室温，反应24h，反应结束后，旋干有机相，粗产品用乙酸乙酯溶解后，水洗一次，盐水洗一次，有机相干燥后硅胶柱层析纯化得到吡唑环类化合物的胺基衍生物。
(路线4)双N杂环取代吡唑类化合物的合成：
Figure BDA0001461263200000251
将化合物18(1eq)溶于无水甲苯，加入二硫化碳(1.6eq)，碘甲烷(3.5eq)，将反应器冰浴，慢慢加入NaH(2.2eq)，加完后再慢慢滴入N,N-二甲基乙酰胺(2.2eq)，加完后将反应器提升至室温反应两天，反应结束后，加水淬灭反应，有机相分别用水和盐水各洗一次，干燥后硅胶柱层析纯化得到化合物19。将化合物19溶于乙醇，加入胺类化合物R1(2.2eq)，搅拌下加热回流24h，反应结束后，直接用硅胶柱层析纯化得到化合物20。将化合物20溶解于无水乙醇中，加入98％水合肼(2eq)，加热回流12h，反应结束后，直接用硅胶柱层析纯化得到胺基取代吡唑类化合物。
(路线5)对酰胺芳基取代吡唑骨架类化合物的合成：
Figure BDA0001461263200000252
中间体40(1.0eq.)，DHP(3.0eq.)及PPST(0.2eq.)溶解于二氯甲烷，在r.t.下反应12h后，中性氧化铝层析柱分离得到中间体41。中间体41(1.0eq.),酰胺(1.2eq.)，Pd(OAc)2(0.02eq),Xantphos(0.03eq.)以及Cs2CO3(1.4eq.)溶解于1，4-二氧六环，在100℃反应12h后，中性氧化铝层析柱分离得到中间体42。中间体42溶解于乙醇，并加入2N HCl的乙醇溶液，乙酸乙酯萃取并加入饱和碳酸氢钠，粗品干燥后，硅胶柱层析纯化得到对酰胺芳基取代吡唑骨架类化合物。
(路线6)吡唑酰胺类化合物的合成：
Figure BDA0001461263200000261
将化合物43(1eq)滴加到EtONa(2.3eq)室温搅拌1h，然后慢慢滴入草酸二乙酯，加热回流4h，反应结束后冷却到室温，然后加入冰醋酸(4eq)，产生大量白色固体，将产物过滤，然后分别用少量水，乙醇，***冲洗得到产物44。将中间体44溶解到到乙酸中，然后冰浴下慢慢滴入水合肼(1.2eq)，室温下反应过夜，反应结束后将产物过滤，将反应产物在乙醇里进行重结晶，得到中间体45。将中间体45溶解于无水二氯甲烷中，-78℃加入BBr3(6eq)，1h后将反应升至室温，反应过夜，反应结束后，慢慢加水淬灭反应，有机相用旋转蒸发仪除去，将反应液pH值调至5，用乙酸乙酯将产物萃取出来，干燥后减压旋走有机溶剂即得到中间体46。将中间体46，EDCI(1.2eq)，HOBt(1.2eq)加入到无水DMF中，搅拌半小时后再加入相应的胺类化合物R，反应12h，反应结束后加入乙酸乙酯，有机相用饱和氯化铵溶液洗三次，饱和氯化钠溶液洗一次，无水硫酸镁干燥后用硅胶柱层析春华，的到最后产物吡唑酰胺类化合物。
(路线7)5-取代氨基吡唑类化合物的合成：
Figure BDA0001461263200000262
将化合物47(1.0eq.)，碘甲烷(3.0eq.)，碳酸钾(3.0eq.)溶于一定量丙酮溶液，40℃下搅拌反应12h，旋干溶剂，乙酸乙酯萃取并加入饱和碳酸氢钠，粗品干燥后，硅胶柱层析纯化得到中间体48。48(1.0eq.)溶于超干甲苯中，加入乙腈(3.0eq.)，然后加入氢化钠(3.0eq.)，加缓冲气球，加热到90℃反应3h。旋干溶剂，乙酸乙酯萃取并加入饱和碳酸氢钠，粗品干燥后，硅胶柱层析纯化得到中间体49。49(1.0eq.)和一水合肼(1.2eq.)一起溶于乙醇，再加入冰醋酸(6.0eq.),50℃加热反应3h时后，旋干溶剂，乙酸乙酯萃取并加入饱和碳酸氢钠，粗品干燥后，硅胶柱层析纯化得到中间体50。50与不同类型羧酸按照一比一当量加入DMF溶剂，加入HATU(1.5eq.)和DIPEA(1.5eq.),70℃下反应12h，乙酸乙酯萃取粗品干燥后，硅胶柱层析纯化得到中间体51。51或50(1eq.)溶于超干DCM中，0℃下加入三溴化硼(8eq.)，常温下搅拌反应12h，旋干溶剂，乙酸乙酯萃取并加入饱和碳酸氢钠，粗品干燥后，硅胶柱层析纯化得到终产物5-取代氨基吡唑类化合物。
本发明所述的药学上可接受的盐中包括酸加成盐和碱加成盐。
所述的酸加成盐包括但是不限于来自无机酸诸如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸和膦酸的盐，以及来自有机酸如脂肪族单羧酸和二羧酸、苯基取代的链烷酸、羟基链烷酸、链烷二酸、芳香酸和脂肪族和芳香族磺酸的盐。因此，这些盐包括但是不限于硫酸盐，焦硫酸盐，硫酸氢盐，亚硫酸盐，亚硫酸氢盐，硝酸盐，磷酸，磷酸一氢盐，磷酸二氢盐，偏磷酸盐，焦磷酸盐，盐酸盐，氢溴酸盐，碘酸盐，乙酸盐，丙酸盐，辛酸盐，异丁酸盐，乙二酸盐，丙二酸盐，琥珀酸盐，辛二酸，癸二酸盐，富马酸盐，马来酸盐，苦杏仁酸盐，苯甲酸盐，氯代苯甲酸盐，甲基苯甲酸盐，二硝基苯甲酸盐，酞酸盐，苯磺酸盐，甲苯磺酸盐，苯基乙酸盐，柠檬酸盐，乳酸盐，马来酸盐，酒石酸和甲磺酸盐，还包含氨基酸的盐如精氨酸盐，葡糖酸盐，半乳糖醛酸盐等。酸加成盐可以通过以常规方式使游离碱与足够量的所需酸接触形成盐的方式制备。可通过使盐与碱接触重新生成游离碱形式，并且以常规方式分离该游离碱。
所述的碱加成盐与金属或者胺形成，诸如碱金属和碱土金属的氢氧化物，或者与有机胺形成。用作阳离子的金属的例子包括但是不限于钠、钾、镁、和钙。适当的胺的例子包括但是不限于N，N′-二苄基乙二胺，氯普鲁卡因，胆碱，二乙醇胺，乙二胺(乙烷-1，2-二胺)，N-甲基葡糖胺和普鲁卡因。碱加成盐可通过以常规方式使游离酸与足够量的所需碱接触形成盐的方式制备。可通过使盐与酸接触重新生成游离酸形式，并且以常规方式分离游离酸。
本发明所述的立体异构体包括对映体、非对映体和几何异构体的形式存在。本发明的一些化合物具有环烷基，其可在超过一个碳原子上被取代，在这种情况下，其所有的几何形式，包括顺式和反式，及其混合物，都处在本发明的范围内。
本发明所述的溶剂化物是指本发明的化合物与一种或多种溶剂分子的物理结合。该物理结合包括各种程度的离子和共价键合，包括氢键合。在某些情况下，溶剂化物可被分离出来，例如当一个或多个溶剂分子掺入到结晶固体的晶格中。“溶剂化物”包括溶液相的和可分离的溶剂化物。代表性的溶剂化物包括乙醇化物、甲醇化物等。“水合物”是其中一个或多个溶剂分子为H2O的溶剂化物。
本发明所述的前药指适于对患者给药的无过分毒性、刺激性和***反应等的并且对其应用目的有效的式Ⅰ化合物形式，包括缩醛、酯和两性离子形式。前药在体内转化(例如通过在血液中水解)得到上式的母体化合物。
本发明另外提供了药物组合物，其包含本发明的化合物(例如式I化合物及其药学上可接受的盐、立体异构体、酯、前药和溶剂化物)，以及可药用的载体、稀释剂或赋形剂。优选地，药物组合物包含治疗有效量的本发明的化合物。
本发明的化合物可以配制为以下形式的药物组合物：糖浆剂，酏剂，悬浮剂，粉剂，颗粒剂，片剂，胶囊，锭剂，水溶液，霜剂，膏剂，洗液剂，凝胶剂，乳剂等。
药物制剂优选为单位剂型。在这种形式中，该制剂被再分成包含适当的量的活性组分的单位剂量。单位剂型可以是包装好的制剂，该包装含有离散的量的制剂，诸如包装在小瓶或者安瓿中的片剂、胶囊和粉剂。另外，单位剂型可以是胶囊，片剂或者其可以是在包装形式中的适当数目的任何这些剂型。
单位剂量制剂中活性组分的量可从0.001毫克到1000毫克之间改变或调整，根据活性组分的具体应用和效力而定。如果需要，组合物还可包含其它适合的治疗剂。
可药用载体部分地根据给用的具体组合物而定，并根据组合物的具体给药方法而定。因此，本发明的药物组合物存在各种适当的制剂。
本发明的化合物，单独或与其它适当的组分结合，被制成气雾剂(即，它们可被“雾化”)以经由吸入被给药。气雾剂可被置于可接受的被加压的发射剂诸如二氯二氟己烷、丙烷、氮气等中。
适于非肠胃给药诸如例如通过静脉内、肌内、皮内和皮下途径给药的制剂包括含水和非水的等渗无菌注射液，其可包含抗氧化剂，缓冲剂，抑菌剂，和使制剂与接受者的血液等渗的溶质，以及含水和非水的无菌悬浮剂，其可包含助悬剂，增溶剂，增稠剂，稳定剂和防腐剂。在本发明的实践中，组合物可通过例如静脉内输注，经口，局部，腹膜内，膀胱内和鞘内给药。化合物的制剂可存在于单位剂量或者多剂量密封容器诸如安瓿和小瓶中。注射用溶液液和悬浮液可从先前所述类型的无菌粉剂、颗粒和片剂制备。
在本发明的环境下，对对象剂量给用应当足够随着时间在对象体内产生有益的治疗学应答。剂量通过所用的具体化合物的效力和对象的病况、以及待治疗对象的体重或者体表面积而定。剂量的大小将根据在具体对象中伴随具体化合物给药产生的任何不利副作用的存在、性质和程度而定。在正被治疗的病症的治疗或者预防中确定待给药的化合物的有效量中，医师可以评价诸如化合物的循环血浆水平、化合物毒性和/或疾病进程等因素而定。
本发明还提供了式(I)的化合物及其药学上可接受的盐、立体异构体、酯、前药和溶剂化物在预防和/或治疗癌症中的应用。
本发明还提供了式(I)的化合物及其药学上可接受的盐、立体异构体、酯、前药和溶剂化物在癌症免疫疗法中的应用。
本发明还提供了式(I)的化合物及其药学上可接受的盐、立体异构体、酯、前药和溶剂化物在制备预防和/或治疗癌症的药物中的应用。
本发明所述的癌症包括淋巴瘤，母细胞瘤，髓母细胞瘤，视网膜母细胞瘤，肉瘤，脂肪肉瘤，滑膜细胞肉瘤，神经内分泌肿瘤，类癌肿瘤，胃泌素瘤，胰岛细胞癌，间皮瘤，神经鞘瘤，听神经瘤，脑膜瘤，腺癌，黑素瘤，白血病或淋巴样恶性肿瘤，鳞状细胞癌，上皮鳞状细胞癌，肺癌，小细胞肺癌，非小细胞肺癌，腺癌肺癌，肺鳞癌，腹膜癌，肝细胞癌，胃癌，肠癌，胰腺癌，成胶质细胞瘤，子***，卵巢癌，肝癌，膀胱癌，肝癌，乳腺癌，转移性乳腺癌，结肠癌，直肠癌，结肠直肠癌，子宫癌，唾液腺癌，肾癌，***癌，外阴癌，甲状腺癌，肝癌，***癌，***癌，梅克尔细胞癌，食管癌，胆道肿瘤，头颈部癌和血液恶性肿瘤。
本发明中所述的术语C0-10烷基，C0烷基是指H，因此，C0-10烷基包括H、C1烷基、C2烷基、C3烷基、C4烷基、C5烷基、C6烷基、C7烷基、C8烷基、C9烷基、C10烷基。
本发明中所述的术语C1-10亚烷基，包括C1亚烷基、C2亚烷基、C3亚烷基、C4亚烷基、C5亚烷基、C6亚烷基、C7亚烷基、C8亚烷基、C9亚烷基、C10亚烷基。
本发明中所述的术语C3-10环烷基，包括C3环烷基、C4环烷基、C5环烷基、C6环烷基、C7环烷基、C8环烷基、C9环烷基、C10环烷基。
本发明中所述的术语C1-6烷基，包括HC1烷基、C2烷基、C3烷基、C4烷基、C5烷基、C6烷基。
本发明中所述的术语C1-6直链烷基，包括甲基、乙基、C3直链烷基、C4直链烷基、C5直链烷基、C6直链烷基。
本发明中所述的术语C3-6环烷基，包括C3环烷基、C4环烷基、C5环烷基、C6环烷基。
本发明所述的术语卤素，包括氟、氯、溴、碘。
本发明所述的术语杂环烷基是指含3-10个环原子，优选5-10个环原子的非芳香的饱和单环或多环环系，其中的一个或多个环原子不是碳原子，而是例如氮、氧或硫原子。优选的杂环烷基含有5-6个环原子。杂环烷基前的前缀氮杂、氧杂或硫杂分别是指至少有一个氮、氧或硫原子作为环原子。代表性的单环杂环烷基包括哌啶基、吡咯烷基、哌嗪基、吗啉基、硫代吗啉基、噻唑烷基、1,3-二氧戊环基、1,4-二氧杂环己烷基、四氢呋喃基、四氢噻吩基、四氢噻喃基等。
本发明所述的术语杂环芳香基是指含5-14个环原子，优选5-10个环原子的芳香单环或多环环系，其中的一个或多个环原子不是碳原子，而是例如氮、氧或硫原子。优选的杂环芳香基含有5-6个环原子。代表性的杂环芳香基包括吡嗪基、呋喃基、噻吩基、吡啶基、嘧啶基、异噁唑基、异噻唑基、噁唑基、噻唑基、吡唑基、呋咱基、吡咯基、吡唑基、***基、1,2,4-硫杂二唑基、吡嗪基、哒嗪基、喹喔啉基、2,3-二氮杂萘基、咪唑并[1,2-a]吡啶、咪唑并[2,1-b]噻唑基、苯并呋咱基、吲哚基、氮杂吲哚基、苯并咪唑基、苯并噻吩基、喹啉基、咪唑基、噻吩并吡啶基、喹唑啉基、噻吩并嘧啶基、吡咯并吡啶基、咪唑并吡啶基、异喹啉基、苯并氮杂吲哚基、1,2,4-三嗪基、苯并噻唑基等。
本发明所述的术语Me代表甲基的缩写。
本发明所述的术语Ph代表苯基的缩写。
本发明所述的术语Boc代表叔丁氧羰基的缩写。
本发明所述的术语“单位剂型”指适合作为人受试者和其它哺乳动物的单一剂量的物理上离散的单位，每个单位包含与需要的药物载体结合的经计算可在治疗期间的过程中产生期望的预防或治疗效果的预定量的活性物质。
本发明所述的术语“辅料”含义是该成分没有生物活性或其他不良活性的杂质，例如该成分可以纳入公开的药物制剂并给与患者，但不引起显著的不良生物效果或以有害的方式和该制剂中包含的其他成分产生相互作用。
本发明所述的术语“治疗”包括抑制、延迟、缓和、减弱、限制、减轻或消退疾病、障碍、病症或状态，其发生和/或进程，和/或其症状。
本发明所述的术语“预防”包括减小以下风险：患有、感染或经历疾病、障碍、病症或状态，其发生和/或进程，和/或其症状。
本发明所述的术语“包含”表示“开放”或“包含性”用语，使得它们包括列举的要素，而且还允许包括额外的、未提及的要素。
本发明所述的术语“约”通常意指所述值的+/-5％，更通常指所述值的+/-4％，更通常指所述值的+/-3％，更通常指所述值的+/-2％，更通常指所述值的+/-1％，更通常指所述值的+/-0.5％。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1 4-取代吡唑类化合物(BRM2-1～3)的合成：
Figure BDA0001461263200000291
化合物1(1eq.)加入反应溶剂二氯甲烷中，化合物2(1.2eq.)分批加至溶液中。所得反应液在r.t.下反应8h后，二氯甲烷萃取后使用硅胶柱层析分离，得到中间体3。中间体3(1eq.)，对甲苯磺酰肼(2eq.)和四丁基溴化铵(TBAB,1eq.)分批缓慢加入NaOH(3eq.)的水溶液中，边加边搅拌。所得的混合液在95℃下搅拌12h。反应液降至室温，并使用2N的盐酸调pH至4～5。所得混合液使用等体积乙酸乙酯萃取三次。有机相使用水和盐水洗之后，使用无水硫酸钠进行干燥。过滤出去硫酸钠后，有机相使用旋转蒸发仪去除。所得粗品使用硅胶柱层析的方法进行分离纯化，得到中间体4。中间体4(1eq.)，NIS(1.1eq.)溶解于二氯甲烷在r.t.下反应12h，得到中间体5。中间体5(1.0eq.)，DHP(2.0eq.)及PPST(0.2eq.)溶解于二氯甲烷，在r.t.下反应12h后，中性氧化铝层析柱分离得到中间体6。中间体6(1.0eq.),烯基频那硼酸酯(1.2eq.)，Pd(PPh3)4(0.05eq.)以及K2CO3(2.0eq.)溶解于DME和水的混合溶剂，在100℃反应12h后，中性氧化铝层析柱分离得到中间体7。中间体7溶解于乙醇，并加入2N HCl的乙醇溶液，乙酸乙酯萃取并加入饱和碳酸氢钠，有机相旋干得到中间体8直接用于下一步的反应。中间体8溶解于二氯甲烷，-78℃加入BBr3(10eq.)，然后将反应升温至室温，反应24h，反应结束后，减压旋走溶剂，粗品用乙酸乙酯溶解后，水洗一次，盐水洗一次，有机相干燥后硅胶柱层析纯化得到中间体9。中间体9溶解于乙醇，并加入还原Fe粉以及氯化铵的水溶液，在r.t.下反应12h后硅胶柱层析分离得到取代吡唑类化合物BRM2-1～3。
实施例2 5-取代吡唑类化合物(BRM2-4～20)的合成：
Figure BDA0001461263200000301
中间体10使用干燥的四氢呋喃溶解，然后在冰浴下滴入酮(1.1eq.)和LiHMDS(1.5eq.)的反应溶液中。所得反应液在r.t.下搅拌1h后，加水淬灭。使用二氯甲烷萃取，有机相使用无水硫酸镁干燥。干燥剂被过滤后，有机相拌硅胶，使用硅胶层析柱分离纯化，得到中间体11。中间体11溶解于甲醇，NH2NH2.H2O(3.0eq.)滴加到反应液中，在r.t.下反应12h后，旋干得到粗产品中间体12直接用于下一步反应。中间体12溶解于二氯甲烷，-78℃加入BBr3(10eq.)，然后将反应升温至室温，反应24h，反应结束后，旋干得到粗产品用乙酸乙酯溶解后，水洗一次，盐水洗一次，有机相干燥后硅胶柱层析纯化得到中间体13。中间体13溶解于乙醇，并加入还原Fe粉以及氯化铵的水溶液，在r.t.下反应12h后硅胶柱层析分离得到化合物BRM2-4～20。
实施例3 5-芳基取代吡唑类化合物衍生物(BRM2-21～39)的合成：
Figure BDA0001461263200000311
将中间体12(1eq)，4-甲基苯磺酸吡啶(PPTS,0.1eq)溶于二氯甲烷，再加入3,4-二氢-2H-吡喃(DHP,3eq)，室温反应24h，反应结束后减压旋走有机相，粗产物用中性三氧化二铝进行柱层析分离得到中间体15。
吡唑环类化合物的芳香环衍生物合成方法：将中间体15(1eq)溶于乙二醇二甲醚和水的混合液(DME：H2O＝4:1)中，加入K2CO3(2.5eq)，Pd(PPh3)4(0.1eq)，芳基硼酸化合物(1.2eq)。氮气保护后加热至100℃反应24h，反应结束后减压旋走有机溶剂，然后用乙酸乙酯萃取两次，有机相干燥后用硅胶柱层析纯化得到中间体16。将中间体16溶解于二氯甲烷，-78℃加入BBr3(10eq.)，然后将反应升温至室温，反应24h，反应结束后，旋干有机相，粗产品用乙酸乙酯溶解后，水洗一次，盐水洗一次，有机相干燥后硅胶柱层析纯化得到化合物BRM2-21～30，35，37。
吡唑环类化合物的胺基衍生物合成方法：将中间体15(1eq)，胺基化合物(2eq)溶于甲苯，再加入Pd2(dba)3(0.05eq)，1,1'-联萘-2,2'-双二苯膦(BINAP，0.1eq)，NaOtBu(2.5eq)。反应瓶用氮气置换保护后，加热至105℃反应24h。反应结束后用乙酸乙酯萃取，有机相分别用水和盐水洗一次，干燥后用硅胶柱层析纯化得到中间体17。将中间体17溶解于二氯甲烷，-78℃加入BBr3(10eq.)，然后将反应升温至室温，反应24h，反应结束后，旋干有机相，粗产品用乙酸乙酯溶解后，水洗一次，盐水洗一次，有机相干燥后硅胶柱层析纯化得到化合物BRM2-31～34，36，38～39。
实施例4双N杂环取代吡唑类化合物(BRM2-40～42)的合成：
Figure BDA0001461263200000321
将化合物18(1eq)溶于无水甲苯，加入二硫化碳(1.6eq)，碘甲烷(3.5eq)，将反应器冰浴，慢慢加入NaH(2.2eq)，加完后再慢慢滴入N,N-二甲基乙酰胺(2.2eq)，加完后将反应器提升至室温反应两天，反应结束后，加水淬灭反应，有机相分别用水和盐水各洗一次，干燥后硅胶柱层析纯化得到化合物19。将化合物19溶于乙醇，加入胺类化合物R1(2.2eq)，搅拌下加热回流24h，反应结束后，直接用硅胶柱层析纯化得到化合物20。将化合物20溶解于无水乙醇中，加入98％水合肼(2eq)，加热回流12h，反应结束后，直接用硅胶柱层析纯化得到胺基取代吡唑类化合物BRM2-40～42。
实施例5对酰胺芳基取代吡唑骨架类化合物(BRM2-96～128)的合成：
Figure BDA0001461263200000322
中间体40(1.0eq.)，DHP(3.0eq.)及PPST(0.2eq.)溶解于二氯甲烷，在r.t.下反应12h后，中性氧化铝层析柱分离得到中间体41。中间体41(1.0eq.),酰胺(1.2eq.)，Pd(OAc)2(0.02eq),Xantphos(0.03eq.)以及Cs2CO3(1.4eq.)溶解于1,4-二氧六环，在100℃反应12h后，中性氧化铝层析柱分离得到中间体42。中间体42溶解于乙醇，并加入2N HCl的乙醇溶液，乙酸乙酯萃取并加入饱和碳酸氢钠，粗品干燥后，硅胶柱层析纯化得到化合物BRM2-96～128。
实施例6吡唑酰胺类化合物(BRM2-129～159)的合成：
Figure BDA0001461263200000331
将化合物43(1eq)滴加到EtONa(2.3eq)室温搅拌1h，然后慢慢滴入草酸二乙酯，加热回流4h，反应结束后冷却到室温，然后加入冰醋酸(4eq)，产生大量白色固体，将产物过滤，然后分别用少量水，乙醇，***冲洗得到产物44。将中间体44溶解到到乙酸中，然后冰浴下慢慢滴入水合肼(1.2eq)，室温下反应过夜，反应结束后将产物过滤，将反应产物在乙醇里进行重结晶，得到中间体45。将中间体45溶解于无水二氯甲烷中，-78℃加入BBr3(6eq)，1h后将反应升至室温，反应过夜，反应结束后，慢慢加水淬灭反应，有机相用旋转蒸发仪除去，将反应液pH值调至5，用乙酸乙酯将产物萃取出来，干燥后减压旋走有机溶剂即得到中间体46。将中间体46，EDCI(1.2eq)，HOBt(1.2eq)加入到无水DMF中，搅拌半小时后再加入相应的胺类化合物R，反应12h，反应结束后加入乙酸乙酯，有机相用饱和氯化铵溶液洗三次，饱和氯化钠溶液洗一次，无水硫酸镁干燥后用硅胶柱层析春华，的到最后产物BRM2-129～159。
实施例7 5-取代氨基吡唑类化合物(BRM2-160～174)的合成：
Figure BDA0001461263200000332
将化合物47(1.0eq.)，碘甲烷(3.0eq.)，碳酸钾(3.0eq.)溶于一定量丙酮溶液，40℃下搅拌反应12h，旋干溶剂，乙酸乙酯萃取并加入饱和碳酸氢钠，粗品干燥后，硅胶柱层析纯化得到中间体48。48(1.0eq.)溶于超干甲苯中，加入乙腈(3.0eq.)，然后加入氢化钠(3.0eq.)，加缓冲气球，加热到90℃反应3h。旋干溶剂，乙酸乙酯萃取并加入饱和碳酸氢钠，粗品干燥后，硅胶柱层析纯化得到中间体49。49(1.0eq.)和一水合肼(1.2eq.)一起溶于乙醇，再加入冰醋酸(6.0eq.),50℃加热反应3h时后，旋干溶剂，乙酸乙酯萃取并加入饱和碳酸氢钠，粗品干燥后，硅胶柱层析纯化得到中间体50。50与不同类型羧酸按照一比一当量加入DMF溶剂，加入HATU(1.5eq.)和DIPEA(1.5eq.)，70℃下反应12h，乙酸乙酯萃取粗品干燥后，硅胶柱层析纯化得到中间体51。51或50(1eq.)溶于超干DCM中，0℃下加入三溴化硼(8eq.)，常温下搅拌反应12h，旋干溶剂，乙酸乙酯萃取并加入饱和碳酸氢钠，粗品干燥后，硅胶柱层析纯化得到终产物BRM2-160-174。
实施例8实施例1-7制备得到化合物的谱图数据：
在本实施例中，按照前面所描述的一般合成方法制备得到的化合物，相应的合成鉴定谱图数据如下：
BRM2-1:1H NMR(400MHz,CDCl3)δ6.97–6.82(m,1H),6.48(dd,J＝17.9,11.6Hz,1H),6.31(dd,J＝8.6,4.0Hz,1H),5.22(dd,J＝38.2,14.7Hz,2H),2.74(t,J＝7.6Hz,2H),1.73(dd,J＝15.1,7.5Hz,2H),1.03(t,J＝7.3Hz,3H).质谱(ESI,m/z):C14H16FN3O,[M+H]+:262.13.
BRM2-2:1H NMR(400MHz,CDCl3)δ7.34(dt,J＝15.2,7.6Hz,4H),7.25(t,J＝6.8Hz,1H),6.96(t,J＝9.7Hz,1H),6.86(d,J＝16.6Hz,1H),6.65(d,J＝16.6Hz,1H),6.34(d,J＝5.2Hz,1H),2.88(t,J＝7.6Hz,2H),1.88-1.80(m,2H),1.08(t,J＝7.3Hz,3H).质谱(ESI,m/z):C20H20FN3O,[M+H]+:338.16.
BRM2-3:1H NMR(400MHz,CDCl3)δ6.97–6.82(m,1H),6.27(dd,J＝8.8,4.1Hz,1H),6.07(d,J＝16.1Hz,1H),5.78–5.62(m,1H),2.68–2.48(m,2H),2.06(q,J＝7.1Hz,2H),1.70–1.51(m,2H),1.37(dd,J＝14.6,7.3Hz,2H),0.93(t,J＝7.3Hz,3H),0.87(t,J＝7.3Hz,4H).质谱(ESI,m/z):C17H20FN3O,[M+H]+:304.17.
BRM2-4:1H NMR(400MHz,MeOD)δ7.71(d,J＝6.8Hz,2H),7.59(d,J＝6.8Hz,2H),7.01(s,1H),6.82(t,J＝8.9Hz,1H),6.20(s,1H).质谱(ESI,m/z):C15H10BrFN2O,[M+H]+:333.00.
BRM2-5:1H NMR(400MHz,MeOD)δ7.69(d,J＝8.2Hz,2H),7.56–7.41(m,3H),7.05(s,1H),6.97–6.85(m,2H),1.35(s,9H).质谱(ESI,m/z):C19H19FN2O,[M+H]+:311.15.
BRM2-6:1H NMR(400MHz,MeOD)δ7.67(d,J＝7.9Hz,2H),7.50–7.39(m,1H),7.28(d,J＝8.0Hz,2H),7.02(s,1H),7.00–6.77(m,2H),2.67(q,J＝7.6Hz,2H),1.25(t,J＝7.6Hz,3H).质谱(ESI,m/z):C17H15FN2O,[M+H]+:283.12.
BRM2-7:1H NMR(400MHz,MeOD)δ7.43(d,J＝8.3Hz,2H),7.30(s,3H),6.90(d,J＝5.7Hz,2H),6.83(s,1H),2.42(s,3H).质谱(ESI,m/z):C16H13FN2O,[M+H]+:269.10.
BRM2-8:1H NMR(400MHz,MeOD)δ7.66–7.48(m,2H),7.48–7.38(m,1H),7.32(t,J＝7.6Hz,1H),7.18(d,J＝7.5Hz,1H),7.04(s,1H),6.89(d,J＝5.5Hz,2H),2.39(s,3H).质谱(ESI,m/z):C16H12FN2O,[M+H]+:269.10.
BRM2-9:1H NMR(400MHz,MeOD)δ7.42(d,J＝10.3Hz,1H),7.26(s,1H),7.15(dd,J＝26.4,7.6Hz,2H),6.90(d,J＝5.3Hz,2H),6.82(s,1H),2.35(d,J＝14.3Hz,6H).质谱(ESI,m/z):C17H15FN2O,[M+H]+:283.12.
BRM2-10:1H NMR(400MHz,MeOD)δ7.44(d,J＝9.7Hz,1H),7.38(s,2H),7.03(d,J＝4.8Hz,2H),6.89(d,J＝4.1Hz,2H),2.36(s,6H).质谱(ESI,m/z):C17H15FN2O,[M+H]+:283.12.
BRM2-11:1H NMR(400MHz,CDCl3)δ7.35–7.30(m,1H),7.26(s,2H),7.10(s,1H),7.05–6.93(m,2H),6.87(s,1H),2.42(s,6H).质谱(ESI,m/z):C17H15FN2O,[M+H]+:283.12.
BRM2-12:1H NMR(400MHz,DMSO)δ13.44(d,J＝188.0Hz,1H),10.52(s,1H),7.93(s,1H),7.64(s,1H),7.38(d,J＝36.3Hz,4H),7.04(t,J＝8.3Hz,1H),6.97(d,J＝4.8Hz,1H).质谱(ESI,m/z):C15H10F2N2O,[M+H]+:273.08.
BRM2-13:1H NMR(400MHz,CDCl3)δ7.46(d,J＝7.8Hz,2H),7.07(d,J＝7.9Hz,2H),6.93–6.85(m,1H),6.61(s,1H),6.37(d,J＝4.5Hz,1H),3.12-3.04(m,2H),3.02-2.94(m,2H).质谱(ESI,m/z):C15H10ClFN2O,[M+H]+:289.05.
BRM2-14:1H NMR(400MHz,MeOD)δ12.62(s,1H),7.68-7.66(m,2H),7.45(m,1H),7.35-7.30(m,2H),7.05-6.95(m,2H),6.81(m,1H).质谱(ESI,m/z):C15H10BrFN2O,[M+H]+:333.00.
BRM2-15：1H NMR(400MHz,MeOD)δ7.47(d,J＝6.6Hz,1H),7.35–7.19(m,3H),6.90–6.74(m,2H),6.24(dd,J＝8.8,4.2Hz,1H),2.44(s,3H).质谱(ESI,m/z):C15H11BrFN3O,[M+H]+:348.01.
BRM2-16:1H NMR(400MHz,MeOD)δ7.42(d,J＝7.5Hz,1H),7.34(d,J＝4.0Hz,2H),7.29–7.19(m,1H),6.95-6.81(m,2H),6.22(dd,J＝8.8,4.2Hz,1H),2.80(q,J＝7.6Hz,2H),1.17(t,J＝7.5Hz,3H).质谱(ESI,m/z):C16H13BrFN3O,[M+H]+:362.02.
BRM2-17：1H NMR(400MHz,CDCl3)δ7.50-7.42(m,2H),7.35–7.24(m,2H),6.93-6.86(m,2H),6.36(s,1H),3.32–3.02(m,1H),1.23(d,J＝6.5Hz,6H).质谱(ESI,m/z):C15H12BrN3O,[M+H]+:330.02.
BRM2-18:1H NMR(400MHz,DMSO)δ13.44(d,J＝188.0Hz,1H),10.52(s,1H),7.93(s,1H),7.64(s,1H),7.38(d,J＝36.3Hz,4H),7.04(t,J＝8.3Hz,1H),6.97(d,J＝4.8Hz,1H).质谱(ESI,m/z):C16H14FN3O,[M+H]+:284.11.
BRM2-19:1H NMR(400MHz,Acetone)δ12.90(s,1H),10.72(s,1H),7.78(dd,J＝5.9,3.4Hz,1H),7.62(ddd,J＝12.6,7.4,2.8Hz,2H),7.55–7.47(m,2H),7.32(s,1H),7.06–6.93(m,2H).质谱(ESI,m/z):C17H16FN3O,[M+H]+:298.13.
BRM2-20:1H NMR(400MHz,CDCl3)δ7.85(s,1H),7.61(d,J＝7.7Hz,1H),7.48(d,J＝7.9Hz,1H),7.29(dd,J＝13.4,6.5Hz,2H),6.90(d,J＝5.6Hz,2H),6.83(s,1H).质谱(ESI,m/z):C18H18FN3O,[M+H]+:312.14.
BRM2-21:1H NMR(400MHz,MeOD)δ7.86(d,J＝7.0Hz,2H),7.68(dd,J＝19.1,7.3Hz,4H),7.45(t,J＝6.8Hz,2H),7.35(d,J＝6.8Hz,1H),7.07(s,1H),6.82(t,J＝9.5Hz,1H),6.22(d,J＝4.9Hz,1H).质谱(ESI,m/z):C21H16FN3O,[M+H]+:346.13.
BRM2-22:1H NMR(400MHz,MeOD)δ7.85(d,J＝8.0Hz,2H),7.67(dd,J＝7.9,4.4Hz,4H),7.18(t,J＝8.6Hz,2H),7.06(s,1H),6.93–6.70(m,1H),6.21(dd,J＝8.8,4.1Hz,1H).质谱(ESI,m/z):C21H15F2N3O,[M+H]+:364.12.
BRM2-23:1H NMR(400MHz,CDCl3)δ12.62(s,1H),10.10(br,1H),8.30(dd,2H),7.85-7,70(m,5H),7.35-7.27(m,2H),7.03-6.99(m,2H),6.45(d,1H).质谱(ESI,m/z):C23H16FN3O,[M+H]+:370.13.
BRM2-24:1H NMR(400MHz,CDCl3)δ7.82–7.46(m,7H),7.40-7.20(m,2H),6.97-6.84(m,3H).质谱(ESI,m/z):C21H14BrFN2O,[M+H]+:409.03.
BRM2-25:1H NMR(400MHz,MeOD)δ7.87(d,J＝7.9Hz,2H),7.73(d,J＝8.0Hz,2H),7.67(d,J＝8.2Hz,2H),7.47(d,J＝8.2Hz,3H),7.16(s,1H),6.93(d,J＝4.2Hz,2H).质谱(ESI,m/z):C21H14ClFN2O,[M+H]+:365.08.
BRM2-26:1H NMR(400MHz,DMSO)δ13.81(s,1H),10.68(s,1H),8.98(s,1H),8.59(s,1H),8.15(d,J＝6.4Hz,1H),7.95(t,J＝15.6Hz,4H),7.64(s,1H),7.60–7.36(m,2H),7.10–6.88(m,2H).质谱(ESI,m/z):C20H14FN3O,[M+H]+:332.11.
BRM2-27:1H NMR(400MHz,MeOD)δ7.84(d,J＝7.8Hz,2H),7.47(d,J＝9.9Hz,1H),7.20(d,J＝7.8Hz,2H),7.15–7.04(m,4H),6.92(d,J＝5.7Hz,2H),2.02(s,6H).质谱(ESI,m/z):C23H19FN2O,[M+H]+:359.15.
BRM2-28:1H NMR(400MHz,MeOD)δ7.81(d,J＝7.5Hz,2H),7.66(d,J＝7.8Hz,2H),7.46(d,J＝9.0Hz,1H),7.24(s,2H),7.09(s,1H),7.00(s,1H),6.92(d,J＝5.2Hz,2H),2.36(s,6H).质谱(ESI,m/z):C23H19FN2O,[M+H]+:359.15.
BRM2-29:1H NMR(400MHz,MeOD)δ7.80(d,J＝8.0Hz,2H),7.64(d,J＝8.1Hz,2H),7.52–7.42(m,1H),7.16–7.07(m,2H),7.04(dd,J＝8.2,2.0Hz,1H),6.96–6.90(m,2H),6.88(d,J＝8.2Hz,1H).质谱(ESI,m/z):C21H15FN2O3,[M+H]+:363.11.
BRM2-30:1H NMR(400MHz,DMSO)δ8.10–7.95(m,6H),7.90(d,J＝8.1Hz,2H),7.61(dd,J＝9.8,2.5Hz,1H),7.41(s,1H),7.02(td,J＝8.5,2.6Hz,1H),6.95(dd,J＝8.8,5.0Hz,1H),3.28(s,3H).质谱(ESI,m/z):C22H17FN2O3S,[M+H]+:409.09.
BRM2-31:1H NMR(400MHz,Acetone)δ13.08(s,1H),10.80(s,1H),8.21(s,1H),7.89(d,J＝7.4Hz,1H),7.75(dd,J＝19.1,7.7Hz,3H),7.61(t,J＝8.4Hz,2H),7.55–7.36(m,4H),7.00(dd,J＝13.2,4.0Hz,2H).质谱(ESI,m/z):C21H15FN2O,[M+H]+:331.12
BRM2-32:1H NMR(400MHz,Acetone)δ13.05(s,1H),10.80(s,1H),8.21(s,1H),7.90(d,J＝7.7Hz,1H),7.77(dd,J＝15.3,7.6Hz,3H),7.67–7.56(m,2H),7.53(t,J＝7.6Hz,2H),7.48(s,1H),7.43(t,J＝7.3Hz,1H),7.05–6.91(m,2H).质谱(ESI,m/z):C21H15FN2O,[M+H]+:331.12.
BRM2-33:1H NMR(400MHz,Acetone)δ12.91(s,1H),10.84(s,1H),7.57(d,J＝9.5Hz,1H),7.47(s,1H),7.33(d,J＝8.0Hz,2H),7.27(d,J＝7.3Hz,1H),7.07–6.87(m,3H),3.26(d,J＝4.7Hz,4H),1.65(dd,J＝34.6,4.1Hz,6H).质谱(ESI,m/z):C20H20FN3O,[M+H]+:338.16.
BRM2-34:1H NMR(400MHz,MeOD)δ7.50–7.43(m,1H),7.36(s,1H),7.31(t,J＝7.8Hz,1H),7.26(d,J＝7.6Hz,1H),7.09(d,J＝5.1Hz,1H),6.98–6.89(m,3H),3.33–3.25(m,4H),2.81–2.70(m,4H),2.45(s,3H).质谱(ESI,m/z):C20H21FN4O,[M+H]+:353.17.
BRM2-35:1H NMR(400MHz,Acetone)δ12.91(s,1H),10.86(s,1H),7.57(dd,J＝9.6,2.9Hz,1H),7.49–7.44(m,1H),7.36–7.29(m,2H),7.28–7.23(m,1H),7.04–6.92(m,3H),3.31–3.21(m,4H),1.75–1.64(m,4H),1.60(ddd,J＝11.5,4.7,2.2Hz,2H).质谱(ESI,m/z):C20H20FN3O,[M+H]+:338.16.
BRM2-36:1H NMR(400MHz,MeOD)δ7.51–7.45(m,1H),7.36(dd,J＝15.8,7.9Hz,2H),7.27(d,J＝7.7Hz,1H),7.11(s,1H),7.01(dd,J＝8.2,1.7Hz,1H),6.95–6.90(m,2H),3.32–3.26(m,4H),2.72–2.64(m,4H),2.39(s,3H).质谱(ESI,m/z):C20H21FN4O,[M+H]+:353.17.
BRM2-37:1H NMR(400MHz,MeOD)δ7.60(d,J＝8.4Hz,2H),7.49–7.38(m,1H),6.91(t,J＝5.0Hz,3H),6.81(d,J＝8.5Hz,2H),3.70–3.58(m,2H),3.53(t,J＝6.2Hz,2H),2.99–2.86(m,2H),2.84–2.73(m,2H),2.51(s,3H),2.15–2.01(m,2H).质谱(ESI,m/z):C21H23FN4O,[M+H]+:367.19.
BRM2-38:1H NMR(400MHz,Acetone)δ12.76(s,1H),10.92(s,1H),7.74(d,J＝8.2Hz,2H),7.54(d,J＝9.6Hz,1H),7.19(s,1H),7.08(d,J＝8.2Hz,2H),6.96(dt,J＝13.5,8.5Hz,2H),3.31(s,4H),2.56(s,4H),2.31(s,3H).质谱(ESI,m/z):C20H21FN4O,[M+H]+:353.17.
BRM2-39:1H NMR(400MHz,Acetone)δ12.72(s,1H),10.93(s,1H),7.72(d,J＝8.6Hz,2H),7.54(dd,J＝9.6,2.7Hz,1H),7.17(s,1H),7.07(d,J＝8.2Hz,2H),7.02–6.89(m,2H),3.39–3.21(m,4H),1.66(dd,J＝25.3,4.2Hz,6H).质谱(ESI,m/z):C20H20FN3O,[M+H]+:338.16.
BRM2-40:1H NMR(400MHz,DMSO)δ12.25(s,1H),11.30(s,1H),8.06(d,J＝3.5Hz,1H),7.55–7.35(m,2H),6.96(td,J＝8.5,3.0Hz,1H),6.90-6.83(m,1H),6.66(d,J＝8.6Hz,1H),6.57–6.43(m,1H),6.09(s,1H),3.86-3.80(m,2H),3.55(d,J＝4.8Hz,4H),3.38–3.32(m,2H),2.06–1.88(m,2H).质谱(ESI,m/z):C19H20FN5O,[M+H]+:353.17.
BRM2-41:1H NMR(400MHz,Acetone)δ11.62(s,1H),11.10(s,1H),8.06(d,J＝4.0Hz,1H),7.55–7.38(m,1H),7.34(dd,J＝9.7,3.0Hz,1H),6.99–6.78(m,2H),6.54(dd,J＝6.8,5.2Hz,1H),6.46(d,J＝8.5Hz,1H),6.01(s,1H),4.98(s,1H),4.58(s,1H),3.70(dd,J＝8.7,1.6Hz,1H),3.63–3.48(m,2H),3.31(d,J＝8.7Hz,1H),2.13(q,J＝9.6Hz,2H).质谱(ESI,m/z):C19H18FN5O,[M+H]+:352.15.
BRM2-42:1H NMR(400MHz,Acetone)δ11.89(s,1H),11.07(s,1H),7.41(dd,J＝9.7,3.0Hz,1H),7.32–7.21(m,2H),7.05(d,J＝8.0Hz,2H),6.99–6.80(m,3H),6.27(s,1H),3.50–3.40(m,4H),3.40–3.30(m,4H).质谱(ESI,m/z):C19H19FN4O,[M+H]+:339.15.
BRM2-96:1H NMR(400MHz,CDCl3)δ8.97(s,1H),7.91–7.76(m,4H),7.76–7.45(m,3H),7.46–7.30(m,2H),7.21–7.06(m,2H),6.95(dd,J＝15.0,10.1Hz,1H),4.94(s,1H).质谱(ESI,m/z):C22H15F2N3O2,[M+H]+:392.11。
BRM2-97:1H NMR(400MHz,CDCl3)δ9.04(s,1H),8.28–8.02(m,1H),8.00–7.70(m,4H),7.51(tdd,J＝14.9,10.0,3.1Hz,1H),7.42–7.25(m,2H),7.21–6.99(m,3H),6.95(dd,J＝15.0,10.1Hz,1H),4.89(s,1H).质谱(ESI,m/z):C22H15F2N3O2,[M+H]+:392.11。
BRM2-98:1H NMR(400MHz,CDCl3)δ9.17(s,1H),8.01–7.76(m,6H),7.76–7.53(m,2H),7.35(dd,J＝16.0,3.0Hz,1H),7.31–7.04(m,2H),6.95(dd,J＝15.0,10.0Hz,1H),4.97(s,1H).质谱(ESI,m/z):C22H15BrFN3O2,[M+H]+:452.03。
BRM2-99:1H NMR(400MHz,CDCl3)δ9.19(s,1H),8.25–8.04(m,2H),7.98–7.66(m,4H),7.52–7.27(m,3H),7.22–7.06(m,2H),6.95(dd,J＝15.0,10.0Hz,1H),4.97(s,1H).质谱(ESI,m/z):C22H15F2N3O2,[M+H]+:392.11。
BRM2-100:1H NMR(400MHz,CDCl3)δ8.95(s,1H),8.02–7.73(m,6H),7.76–7.52(m,2H),7.35(dd,J＝16.0,2.9Hz,1H),7.24–7.07(m,2H),6.95(dd,J＝15.0,10.1Hz,1H),4.92(s,1H).质谱(ESI,m/z):C22H15FClN3O2,[M+H]+:408.08。
BRM2-101:1H NMR(400MHz,CDCl3)δ9.17(s,1H),8.01–7.59(m,4H),7.43(s,4H),7.35(dd,J＝16.0,2.9Hz,1H),7.25–7.04(m,2H),6.95(dd,J＝15.0,10.1Hz,1H),4.93(s,1H).质谱(ESI,m/z):C22H15FClN3O2,[M+H]+:408.08。
BRM2-102:1H NMR(400MHz,CDCl3)δ8.95(s,1H),8.01–7.59(m,6H),7.50–7.21(m,3H),7.22–7.03(m,2H),6.95(dd,J＝15.0,10.1Hz,1H),4.94(s,1H),2.42(s,3H).质谱(ESI,m/z):C23H18FN3O2,[M+H]+:388.14。
BRM2-103:1H NMR(400MHz,CDCl3)δ9.20(s,1H),8.04–7.61(m,6H),7.48–7.22(m,3H),7.24–7.03(m,2H),6.95(dd,J＝15.0,10.0Hz,1H),4.98(s,1H),2.41(s,3H).质谱(ESI,m/z):C23H18FN3O2,[M+H]+:388.14。
BRM2-104:1H NMR(400MHz,CDCl3)δ9.10(s,1H),7.98–7.58(m,6H),7.55–7.26(m,2H),7.31–7.02(m,3H),6.95(dd,J＝15.0,10.0Hz,1H),4.96(s,1H).质谱(ESI,m/z):C23H15F4N3O2,[M+H]+:442.12。
BRM2-105:1H NMR(400MHz,CDCl3)δ9.58(s,1H),8.07–7.67(m,4H),7.59–7.41(m,1H),7.38–7.22(m,2H),7.18–7.04(m,3H),6.95(dd,J＝15.0,10.1Hz,1H).质谱(ESI,m/z):C22H14F3N3O2,[M+H]+:410.10。
BRM2-106:1H NMR(400MHz,CDCl3)δ9.00(s,1H),8.10–7.58(m,4H),7.35(dd,J＝16.0,2.9Hz,1H),7.20–7.00(m,2H),6.95(dd,J＝15.0,10.1Hz,1H),4.43(s,1H),2.10–1.96(m,3H),1.97–1.78(m,6H),1.81–1.52(m,6H).质谱(ESI,m/z):C26H26FN3O2,[M+H]+:432.20。
BRM2-107:1H NMR(400MHz,CDCl3)δ8.93(s,1H),8.08–7.65(m,6H),7.35(dd,J＝16.0,2.9Hz,1H),7.25–7.04(m,4H),6.95(dd,J＝15.0,10.1Hz,1H),4.94(s,1H),3.79(s,3H).质谱(ESI,m/z):C23H18FN3O2,[M+H]+:404.13。
BRM2-108:1H NMR(400MHz,CDCl3)δ8.94(s,1H),8.08–7.59(m,4H),7.35(dd,J＝16.0,2.9Hz,1H),7.25–7.03(m,2H),6.95(dd,J＝15.0,10.1Hz,1H),4.95(s,1H),4.54–3.86(m,2H),2.96–2.59(m,2H),2.37(p,J＝15.6Hz,1H),1.90–1.69(m,2H),1.67–1.40(m,1H),1.37–0.89(m,3H).质谱(ESI,m/z):C22H22FN3O2,[M+H]+:380.17。
BRM2-109:1H NMR(400MHz,CDCl3)δ8.92(s,1H),8.82(d,J＝15.0Hz,2H),8.07–7.62(m,6H),7.35(dd,J＝16.0,2.9Hz,1H),7.35(dd,J＝16.0,2.9Hz,1H),7.17–7.00(m,2H),6.95(dd,J＝15.0,10.1Hz,1H),4.57(s,1H).质谱(ESI,m/z):C21H15FN4O2,[M+H]+:375.12。
BRM2-110:1H NMR(400MHz,CDCl3)δ8.93(s,1H),8.03–7.72(m,6H),7.68–7.46(m,3H),7.35(dd,J＝16.0,2.9Hz,1H),7.27(s,1H),7.22–7.05(m,1H),6.95(dd,J＝15.0,10.1Hz,1H).质谱(ESI,m/z):C22H16FN3O2,[M+H]+:374.12。
BRM2-111:1H NMR(400MHz,CDCl3)δ9.15–8.80(m,2H),8.09(dd,J＝15.0,3.0Hz,1H),7.97–7.65(m,4H),7.55–7.27(m,2H),7.28–7.06(m,2H),6.95(dd,J＝15.0,10.1Hz,1H),4.94(s,1H),2.55(s,3H)质谱(ESI,m/z):C22H17FN4O2,[M+H]+:389.13。
BRM2-112:1H NMR(400MHz,CDCl3)δ8.97–8.61(m,2H),8.53–8.28(m,1H),8.14–7.66(m,6H),7.35(dd,J＝16.0,2.9Hz,1H),7.22–7.04(m,2H),6.95(dd,J＝15.0,10.1Hz,1H),4.92(s,1H).质谱(ESI,m/z):C21H15FN4O2,[M+H]+:375.12。
BRM2-113:1H NMR(400MHz,CDCl3)δ9.79(s,1H),7.79(ddd,J＝18.3,9.0,4.5Hz,5H),7.50–7.27(m,2H),7.25–7.01(m,3H),6.95(dd,J＝7.4,5.0Hz,1H),4.96(s,1H),3.87(d,J＝16.0Hz,6H).质谱(ESI,m/z):C24H20FN3O4,[M+H]+:434.14。
BRM2-114:1H NMR(400MHz,CDCl3)δ9.00(s,1H),8.00–7.62(m,5H),7.49–7.20(m,3H),7.17–7.04(m,2H),6.95(dd,J＝15.0,10.1Hz,1H),4.93(s,1H).质谱(ESI,m/z):C22H14F3N3O2,[M+H]+:410.10。
BRM2-115:1H NMR(400MHz,CDCl3)δ8.31(s,1H),7.98–7.59(m,4H),7.35(dd,J＝16.0,2.9Hz,1H),7.27–7.07(m,2H),6.95(dd,J＝15.0,10.1Hz,1H),4.98(s,1H),3.98–3.38(m,4H),3.00(tt,J＝17.7,15.8Hz,1H),2.30–1.65(m,4H).质谱(ESI,m/z):C21H20FN3O3,[M+H]+:382.15。
BRM2-116:1H NMR(400MHz,CDCl3)δ8.79(s,1H),8.24–7.65(m,4H),7.49–7.21(m,2H),7.20–7.07(m,1H),6.95(dd,J＝15.0,10.1Hz,1H),2.48–1.88(m,1H),1.21–0.30(m,4H).质谱(ESI,m/z):C19H16FN3O2,[M+H]+:338.12。
BRM2-117:1H NMR(400MHz,CDCl3)δ8.67(s,1H),8.15–7.69(m,5H),7.55–7.22(m,2H),7.21–7.01(m,2H),6.95(dd,J＝15.0,10.1Hz,1H),6.71(t,J＝15.0Hz,1H),4.99(s,1H).质谱(ESI,m/z):C20H14FN3O3,[M+H]+:364.10。
BRM2-118:1H NMR(400MHz,CDCl3)δ8.98(s,1H),8.02–7.74(m,5H),7.67–7.44(m,1H),7.35(dd,J＝16.0,2.9Hz,1H),7.33(d,J＝2.9Hz,1H),7.24–6.69(m,5H),4.94(s,1H),4.05(q,J＝11.8Hz,2H),1.34(t,J＝11.8Hz,3H).质谱(ESI,m/z):C24H20FN3O3,[M+H]+:418.15。
BRM2-119:1H NMR(400MHz,CDCl3)δ8.82(s,1H),8.30(dd,J＝15.0,3.0Hz,1H),8.08–7.65(m,5H),7.35(dd,J＝16.0,2.9Hz,1H),7.27–7.07(m,3H),6.95(dd,J＝15.0,10.1Hz,1H),4.95(s,1H).质谱(ESI,m/z):C20H14FN3O2S,[M+H]+:380.08。
BRM2-120:1H NMR(400MHz,CDCl3)δ7.95–7.48(m,4H),7.34(dd,J＝16.0,2.9Hz,1H),7.20–7.00(m,1H),7.07–6.73(m,1H),2.68–2.13(m,4H),2.10–1.67(m,3H).质谱(ESI,m/z):C20H18FN3O2,[M+H]+:352.14。
BRM2-121:1H NMR(400MHz,CDCl3)δ9.14(dd,J＝3.0,0.5Hz,1H),8.93(s,1H),8.85–8.61(m,1H),8.21(dt,J＝15.0,3.0Hz,1H),8.02–7.63(m,4H),7.58–7.30(m,2H),7.22–7.09(m,2H),6.95(dd,J＝15.0,10.1Hz,1H),4.93(s,1H).质谱(ESI,m/z):C21H15FN4O2,[M+H]+:375.12。
BRM2-122:1H NMR(400MHz,CDCl3)δ8.78(s,1H),8.05(s,1H),7.93–7.65(m,4H),7.35(dd,J＝16.0,2.9Hz,1H),7.28–7.01(m,2H),6.95(dd,J＝15.0,10.1Hz,1H),4.94(s,1H),2.43(s,3H).质谱(ESI,m/z):C20H15FN4O3,[M+H]+:379.11。
BRM2-123:1H NMR(400MHz,CDCl3)δ8.95(s,1H),8.43(d,J＝15.0Hz,1H),8.08–7.72(m,5H),7.62(d,J＝2.9Hz,1H),7.35(dd,J＝16.0,2.9Hz,1H),7.27–7.03(m,2H),6.95(dd,J＝15.0,10.1Hz,1H),4.93(s,1H).质谱(ESI,m/z):C21H20ClFN4O2,[M+H]+:409.08。
BRM2-124:1H NMR(400MHz,CDCl3)δ9.96(s,1H),9.10(d,J＝15.0Hz,1H),8.89(d,J＝15.0Hz,1H),8.78(s,1H),8.07–7.58(m,4H),7.35(dd,J＝16.0,2.9Hz,1H),7.22–7.06(m,2H),6.97–6.69(m,1H),4.90(s,1H).质谱(ESI,m/z):C20H14FN5O2,[M+H]+:376.11。
BRM2-125:1H NMR(400MHz,CDCl3)δ8.96(s,1H),7.97–7.66(m,4H),7.35(dd,J＝16.0,2.9Hz,1H),7.20–7.01(m,2H),6.95(dd,J＝15.0,10.1Hz,1H),6.46(dt,J＝6.9,2.5Hz,3H),4.93(s,1H),3.77(s,6H).质谱(ESI,m/z):C24H20FN3O4,[M+H]+:434.14。
BRM2-126:1H NMR(400MHz,CDCl3)δ8.23(s,1H),8.05–7.58(m,4H),7.44–7.15(m,1H),7.31–6.82(m,3H),4.31(s,1H),2.32(td,J＝15.0,0.8Hz,2H),2.00–1.50(m,2H),0.98(t,J＝13.1Hz,3H).质谱(ESI,m/z):C19H18FN3O2,[M+H]+:340.14。
BRM2-127:1H NMR(400MHz,CDCl3)δ8.19(s,1H),7.93–7.59(m,4H),7.35(dd,J＝16.0,2.9Hz,1H),7.18–7.06(m,2H),6.95(dd,J＝15.0,10.1Hz,1H),4.93(s,1H),1.23(s,9H).质谱(ESI,m/z):C20H20FN3O2,[M+H]+:354.15。
BRM2-128:1H NMR(400MHz,CDCl3)δ8.99(s,1H),8.07–7.69(m,4H),7.46–7.03(m,8H),6.95(dd,J＝15.0,10.1Hz,1H),4.95(s,1H),3.23–2.68(m,4H).质谱(ESI,m/z):C24H20FN3O2,[M+H]+:402.15。
BRM2-129:1H NMR(400MHz,CDCl3)δ7.32(dd,J＝16.0,2.9Hz,1H),7.21–7.01(m,2H),6.92(dd,J＝14.9,10.0Hz,1H),5.93(s,1H),4.88(s,1H),3.55(p,J＝15.2Hz,1H),2.80–2.24(m,4H),2.17(s,3H),1.83(dddt,J＝62.2,24.8,15.3,11.1Hz,4H).质谱(ESI,m/z):C16H19FN4O2,[M+H]+:319.15。
BRM2-130:1H NMR(400MHz,CDCl3)δ9.09(s,1H),7.61–7.03(m,4H),7.03–6.58(m,4H),4.91(s,1H),3.44(t,J＝10.3Hz,4H),2.35(t,J＝10.3Hz,4H),2.21(s,3H).质谱(ESI,m/z):C21H22FN5O2,[M+H]+:396.18。
BRM2-131:1H NMR(400MHz,CDCl3)δ7.80(d,J＝15.0Hz,1H),7.35(dd,J＝16.0,2.9Hz,1H),7.25–6.99(m,2H),7.04–6.72(m,2H),4.45(s,1H),3.94(s,3H).质谱(ESI,m/z):C14H12FN5O2,[M+H]+:302.10。
BRM2-132:1H NMR(400MHz,CDCl3)δ8.04(dd,J＝15.0,2.9Hz,1H),7.55(td,J＝15.0,3.0Hz,1H),7.35(dd,J＝16.0,2.9Hz,1H),7.27–6.87(m,4H),6.73(td,J＝15.0,3.0Hz,1H),4.87(s,1H),3.99(t,J＝10.0Hz,4H),3.36(t,J＝10.0Hz,4H).质谱(ESI,m/z):C19H18FN5O2,[M+H]+:368.14。
BRM2-133:1H NMR(400MHz,CDCl3)δ7.33(dd,J＝16.0,2.9Hz,1H),7.22–7.00(m,2H),6.93(dd,J＝15.0,10.1Hz,1H),4.87(s,1H),3.42–2.96(m,6H),2.81(t,J＝10.1Hz,2H),2.17(s,3H),2.02–1.55(m,2H).质谱(ESI,m/z):C16H19FN4O2,[M+H]+:319.15。
BRM2-134:1H NMR(400MHz,CDCl3)δ7.35(dd,J＝16.0,3.0Hz,1H),7.15–7.04(m,2H),6.94(dd,J＝15.0,10.1Hz,1H),4.91(s,1H),3.52–2.97(m,8H),1.42(s,9H).质谱(ESI,m/z):C19H23FN4O4,[M+H]+:391.17。
BRM2-135:1H NMR(400MHz,CDCl3)δ7.35(dd,J＝16.0,2.9Hz,1H),7.24–7.02(m,2H),6.95(dd,J＝15.0,10.1Hz,1H),6.29(s,1H),4.92(s,1H),3.75–3.32(m,4H),3.11–2.88(m,2H),2.21–1.78(m,3H),1.55(ddt,J＝24.8,15.3,11.1Hz,2H),1.42(s,9H).质谱(ESI,m/z):C21H27FN4O4,[M+H]+:419.20。
BRM2-136:1H NMR(400MHz,CDCl3)δ7.53–7.20(m,3H),7.27–6.89(m,5H),6.82(s,1H),4.83(s,1H),4.11(s,2H).质谱(ESI,m/z):C17H13F2N3O2,[M+H]+:330.10。
BRM2-137:1H NMR(400MHz,CDCl3)δ7.35(dd,J＝16.0,2.9Hz,1H),7.21–6.82(m,5H),6.78–6.55(m,2H),6.35(s,1H),4.65(d,J＝50.8Hz,2H),3.37(td,J＝15.4,0.8Hz,2H),2.79(td,J＝15.4,0.8Hz,2H)质谱(ESI,m/z):C18H16FN3O3,[M+H]+:342.12。
BRM2-138:1H NMR(400MHz,CDCl3)δ7.35(dd,J＝16.0,2.9Hz,1H),7.24(s,1H),7.14(dd,J＝15.1,2.9Hz,1H),7.10–7.02(m,1H),6.99–6.89(m,3H),6.82–6.66(m,2H),4.64(s,1H),4.11(s,2H).质谱(ESI,m/z):C17H14FN3O3,[M+H]+:328.10。
BRM2-139:1H NMR(400MHz,6d-DMSO)δ8.98(s,1H),7.62–7.22(m,3H),7.27–6.80(m,7H),3.31(t,J＝10.4Hz,2H),2.90(t,J＝10.4Hz,2H).质谱(ESI,m/z):C20H17FN4O2,[M+H]+:365.13。
BRM2-140:1H NMR(400MHz,6d-DMSO)δ8.98(s,1H),7.46–7.27(m,3H),7.18–6.83(m,6H),3.37(td,J＝15.4,0.8Hz,2H),2.79(td,J＝15.4,0.8Hz,2H).质谱(ESI,m/z):C18H15ClFN3O2,[M+H]+:360.08。
BRM2-141:1H NMR(400MHz,6d-DMSO)δ8.98(s,1H),7.35(dd,J＝16.0,2.9Hz,1H),7.31–7.07(m,6H),7.03(t,J＝8.2Hz,2H),6.98(dd,J＝15.0,10.1Hz,1H),3.37(td,J＝15.4,0.8Hz,2H),2.79(td,J＝15.4,0.8Hz,2H).质谱(ESI,m/z):C18H16FN3O2,[M+H]+:326.12。
BRM2-142:1H NMR(400MHz,6d-DMSO)δ8.98(s,1H),7.48–7.14(m,1H),7.25–6.65(m,4H),3.25(t,J＝15.2Hz,2H),1.75–1.20(m,2H),0.88(t,J＝13.2Hz,3H).质谱(ESI,m/z):C13H14FN3O3,[M+H]+:264.11。
BRM2-143:1H NMR(400MHz,6d-DMSO)δ7.37–7.12(m,3H),7.10–6.78(m,6H),4.61(s,3H),3.19(s,3H).质谱(ESI,m/z):C18H16FN3O2,[M+H]+:326.12。
BRM2-144:1H NMR(400MHz,6d-DMSO)δ7.45–7.22(m,3H),7.20–6.91(m,6H),4.67(s,3H),3.07(q,J＝12.6Hz,2H),1.17(t,J＝12.6Hz,3H).质谱(ESI,m/z):C19H18FN3O3,[M+H]+:340.14。
BRM2-145:1H NMR(400MHz,6d-DMSO)δ7.43–7.25(m,6H),7.19–7.03(m,3H),6.98(dd,J＝15.0,10.1Hz,1H),4.67(s,2H),3.77(hept,J＝12.0Hz,1H),1.26(d,J＝12.0Hz,6H).质谱(ESI,m/z):C20H20FN3O3,[M+H]+:354.15。
BRM2-146:1H NMR(400MHz,6d-DMSO)δ7.43(d,J＝8.9Hz,1H),7.41–7.20(m,11H),7.18–6.87(m,3H),4.67(s,4H).质谱(ESI,m/z):C24H20FN3O3,[M+H]+:402.15。
BRM2-147:1H NMR(400MHz,6d-DMSO)δ9.38(s,1H),7.33(dt,J＝25.8,12.9Hz,1H),7.28–6.70(m,9H),4.81(t,J＝14.2Hz,1H),3.66(s,3H),3.10(ddd,J＝103.0,24.8,14.2Hz,2H).质谱(ESI,m/z):C20H18FN3O4,[M+H]+:384.13。
BRM2-148:1H NMR(400MHz,6d-DMSO)δ9.38(s,1H),7.35(dd,J＝16.0,2.9Hz,1H),7.22–6.76(m,4H),4.51(t,J＝12.9Hz,1H),3.66(s,3H),2.60(td,J＝16.0,1.3Hz,2H),2.38–1.88(m,5H).质谱(ESI,m/z):C16H18FN3O4S,[M+H]+:368.10。
BRM2-149:1H NMR(400MHz,6d-DMSO)δ9.38(s,1H),7.56–7.30(m,2H),7.27–6.78(m,3H),4.51(t,J＝6.6Hz,1H),3.66(s,3H),2.89(dd,J＝17.4,6.1Hz,2H),2.80(s,3H),2.56–2.42(m,2H).质谱(ESI,m/z):C16H18FN3O6S,[M+H]+:400.09。
BRM2-150:1H NMR(400MHz,6d-DMSO)δ7.35(dd,J＝16.0,2.9Hz,1H),7.22–6.87(m,4H),4.43–4.08(m,1H),4.01–3.17(m,5H),2.40–1.86(m,2H),1.83–1.43(m,2H).质谱(ESI,m/z):C16H16FN3O4,[M+H]+:334.11。
BRM2-151:1H NMR(400MHz,6d-DMSO)δ9.38(s,1H),9.05(s,1H),7.35(dd,J＝16.0,2.9Hz,1H),7.28–6.85(m,6H),6.75–6.50(m,2H),4.81(t,J＝6.9Hz,1H),3.11(ddd,J＝103.0,24.8,6.8Hz,2H).质谱(ESI,m/z):C20H18FN3O5,[M+H]+:400.12。
BRM2-152:1H NMR(400MHz,6d-DMSO)δ9.38(s,1H),8.47(d,J＝0.5Hz,1H),7.35(dd,J＝16.0,1.6Hz,2H),7.21–6.78(m,4H),4.68(t,J＝7.8Hz,1H),3.66(s,3H),3.10(dd,J＝24.8,7.8Hz,1H),2.44(dd,J＝24.8,7.8Hz,1H).质谱(ESI,m/z):C17H16FN5O4,[M+H]+:374.12。
BRM2-153:1H NMR(400MHz,6d-DMSO)δ9.34(s,1H),7.32(dd,J＝16.0,2.9Hz,1H),7.17–6.80(m,4H),4.19(d,J＝4.8Hz,1H),3.64(s,3H),2.80(tqd,J＝15.5,13.0,4.8Hz,1H),1.78–1.37(m,2H),1.21–0.75(m,6H).质谱(ESI,m/z):C17H20FN3O4,[M+H]+:350.14。
BRM2-154:1H NMR(400MHz,6d-DMSO)δ9.38(s,1H),7.46–7.24(m,1H),7.28–6.76(m,9H),5.11(t,J＝12.2Hz,1H),3.98–3.42(m,4H),3.39–2.83(m,2H),2.14–1.67(m,4H).质谱(ESI,m/z):C23H23FN4O3,[M+H]+:423.18。
BRM2-155:1H NMR(400MHz,6d-DMSO)δ9.38(s,1H),7.35(dd,J＝16.0,2.9Hz,1H),7.32–7.21(m,1H),7.15–6.92(m,7H),4.81(t,J＝11.7Hz,1H),3.64(tdd,J＝10.2,8.3,3.9Hz,6H),3.51–3.12(m,3H),3.04(dd,J＝24.8,11.7Hz,1H).质谱(ESI,m/z):C23H23FN4O4,[M+H]+:439.17。
BRM2-156:1H NMR(400MHz,6d-DMSO)δ9.33(s,1H),7.31(dd,J＝16.0,2.9Hz,1H),7.17–6.62(m,4H),6.11(s,2H),4.67–4.26(m,1H),3.75(dd,J＝9.9,8.6Hz,2H),3.59(dd,J＝9.8,8.8Hz,4H),3.39(dd,J＝9.7,8.8Hz,2H),2.40–1.76(m,4H).质谱(ESI,m/z):C19H22FN5O5,[M+H]+:420.16。
BRM2-157:1H NMR(400MHz,6d-DMSO)δ8.98(s,1H),7.35(dd,J＝16.0,2.9Hz,1H),7.28–6.75(m,8H),3.37(td,J＝15.4,0.8Hz,2H),2.79(td,J＝15.4,0.8Hz,2H).质谱(ESI,m/z):C18H15F2N3O2,[M+H]+:344.11。
BRM2-158:1H NMR(400MHz,6d-DMSO)δ8.98(s,1H),7.35(dd,J＝16.0,2.9Hz,1H),7.22–6.75(m,3H),4.26(dd,J＝103.0,24.8Hz,4H),0.92(s,3H).质谱(ESI,m/z):C15H16FN3O3,[M+H]+:306.12。
BRM2-159:1H NMR(400MHz,6d-DMSO)δ8.98(s,1H),8.21–7.73(m,2H),7.35(dd,J＝16.0,2.9Hz,1H),7.21–6.85(m,6H),6.08(s,2H),3.37(t,J＝10.2Hz,2H),2.79(t,J＝10.2Hz,2H).质谱(ESI,m/z):C19H17FN4O3,[M+H]+:369.13。
BRM2-160:1H NMR(400MHz,6d-DMSO)δ7.35(dd,J＝7.9,1.4Hz,1H),7.12(td,J＝7.8,1.4Hz,1H),7.05(s,1H),6.98(dd,J＝7.4,5.0Hz,1H),5.99(s,2H),5.57(s,1H).质谱(ESI,m/z):C9H8FN3O,[M+H]+:194.07。
BRM2-161:1H NMR(400MHz,6d-DMSO)δ7.35(dd,J＝16.0,2.9Hz,1H),7.23–6.84(m,3H),5.74(s,1H),2.36(td,J＝16.1,0.7Hz,2H),1.89–1.38(m,2H),0.98(t,J＝13.1Hz,3H).质谱(ESI,m/z):C13H14FN3O2,[M+H]+:264.11。
BRM2-162:1H NMR(400MHz,6d-DMSO)δ8.03–7.80(m,1H),7.73–7.45(m,2H),7.45–7.25(m,1H),7.24–6.85(m,2H),5.99(s,1H).质谱(ESI,m/z):C16H12FN3O2,[M+H]+:298.09。
BRM2-163:1H NMR(400MHz,6d-DMSO)δ9.68(s,1H),7.92–7.58(m,2H),7.35(dd,J＝16.0,2.9Hz,1H),7.24–6.72(m,5H),5.98(s,1H).质谱(ESI,m/z):C16H12FN3O3,[M+H]+:314.09。
BRM2-164:1H NMR(400MHz,6d-DMSO)δ9.05(s,1H),7.35(dd,J＝16.0,2.9Hz,1H),7.26–6.78(m,5H),6.78–6.56(m,2H),5.83(s,1H),3.80(s,2H).质谱(ESI,m/z):C17H14FN3O3,[M+H]+:328.10。
BRM2-165:1H NMR(400MHz,6d-DMSO)δ9.14(dd,J＝3.0,0.5Hz,1H),8.92–8.60(m,1H),8.30(dt,J＝15.0,3.0Hz,1H),7.59(t,J＝15.0Hz,1H),7.50–7.30(m,1H),7.25–6.80(m,3H),5.37(s,1H).质谱(ESI,m/z):C15H11FN4O2,[M+H]+:299.09。
BRM2-166:1H NMR(400MHz,6d-DMSO)δ9.96(s,1H),9.10(d,J＝15.0Hz,1H),8.89(d,J＝15.0Hz,1H),7.32(dt,J＝46.6,23.3Hz,1H),7.27–6.55(m,3H),5.80(s,1H).质谱(ESI,m/z):C14H10FN5O2,[M+H]+:300.08。
BRM2-167:1H NMR(400MHz,6d-DMSO)δ9.05(s,1H),7.35(dd,J＝16.0,2.9Hz,1H),7.20–6.86(m,5H),6.76–6.54(m,2H),5.65(s,1H),3.25–2.49(m,4H).质谱(ESI,m/z):C18H16FN3O3,[M+H]+:342.12。
BRM2-168:1H NMR(400MHz,6d-DMSO)δ7.50–7.21(m,2H),7.27–6.85(m,4H),5.85(s,2H),3.80(s,2H).质谱(ESI,m/z):C17H13F2N3O2,[M+H]+:330.10。
BRM2-169:1H NMR(400MHz,6d-DMSO)δ8.11–7.70(m,1H),7.55–7.24(m,2H),7.30–6.50(m,5H),5.99(s,1H).质谱(ESI,m/z):C16H12FN3O3,[M+H]+:314.09。
BRM2-170:1H NMR(400MHz,6d-DMSO)δ7.91–7.72(m,1H),7.72–7.49(m,1H),7.35(dd,J＝16.0,2.9Hz,1H),7.15–6.68(m,1H),5.69(s,1H).质谱(ESI,m/z):C17H11F4N3O2,[M+H]+:366.08。
BRM2-171:1H NMR(400MHz,6d-DMSO)δ8.19–7.86(m,1H),7.77–7.49(m,1H),7.35(dd,J＝16.0,2.9Hz,1H),7.17–6.65(m,1H),5.98(s,1H).质谱(ESI,m/z):C16H11BrFN3O3,[M+H]+:376.00。
BRM2-172:1H NMR(400MHz,6d-DMSO)δ7.42(d,J＝15.0Hz,1H),7.35(dd,J＝16.0,2.9Hz,1H),7.21–7.07(m,1H),7.06–6.91(m,2H),6.70(d,J＝15.0Hz,1H),6.00(s,1H).质谱(ESI,m/z):C13H10FN5O2,[M+H]+:288.08。
BRM2-173:1H NMR(400MHz,6d-DMSO)δ7.44(dd,J＝7.9,1.4Hz,1H),7.35(dd,J＝7.9,1.4Hz,1H),7.27(td,J＝7.8,1.4Hz,1H),7.12(td,J＝7.8,1.4Hz,1H),7.05(s,1H),6.97(ddd,J＝7.6,4.9,3.9Hz,2H),6.00(s,1H).质谱(ESI,m/z):C16H11F2N3O2,[M+H]+:332.08。
BRM2-174:1H NMR(400MHz,6d-DMSO)δ7.35(dd,J＝16.0,2.9Hz,1H),7.22–7.07(m,1H),7.05(s,1H),6.98(dd,J＝15.0,10.1Hz,1H),5.73(s,1H).质谱(ESI,m/z):C16H12FN3O3,[M+H]+:314.09。质谱(ESI,m/z):C18H13F2N5O2,[M+H]+:370.10。
实施例9细胞活力实验方法测定本发明所述化合物的药效活性：
使用四唑盐(MTT)的方法测定本发明所述化合物的药效活性，使用的细胞系为H1299细胞，该细胞系BRG1基因缺失(BRG1-)，而BRM基因非缺失(BRM+)，即该细胞系的细胞内不能表达BRG1蛋白，但可正常表达BRM蛋白。能在细胞内阻止BRM蛋白与染色体相互作用的小分子，即可阻止BRM蛋白行使细胞内的功能。根据协同致死规律，在BRGI基因缺失的细胞里，阻止BRM蛋白的功能，则会导致细胞死亡，实现小分予杀死癌细胞的作用。
实验具体操作步骤如下：
(1)将不同的实验细胞系传代分板到96孔板中。为了防止边际效应96孔板的四周加入100μL的PBS作空白，其中使用的细胞系为H1299细胞(BRG1-/BRM+细胞系)。
(2)细胞贴壁生长40-50％时，加入不同浓度的药物分子和DMSO作为对照。小分子处理过的细胞继续培养3-4天。中途换一次加小分子的培养基。
(3)对照组DMSO处理过的96孔板细胞长满后，每孔中加入20μL的MTT母液(5mg/mL)。
(4)将细胞板继续放回37℃的C2O培养箱中孵育4小时。
(5)吸去MTT液，每孔中加入150μLDMSO。
(6)室温下将96孔板避光放入震荡摇床中，15min直到将紫色结晶全部溶解。
(7)利用SpectraMax M5多孔读板仪(Molecular Devices,美国)在490nm波长下，测定每孔的吸光值(OD)。
按照常规检测方法，确定了各化合物(小分子)的EC50值，结果总结在表l中。
表1
Figure BDA0001461263200000401
Figure BDA0001461263200000411
Figure BDA0001461263200000421
Figure BDA0001461263200000431
Figure BDA0001461263200000441

Claims (8)

1.一种式(Ⅱ)的化合物或其药学上可接受的盐，其特征在于，所述的化合物具有如下结构：
Figure FDA0002823013230000011
其中，
当R8为单键时，所述的式(Ⅱ)的化合物具有如下结构
Figure FDA0002823013230000012
R21选自C3-10环烷基、苯基、N杂环丁烷基，吡啶基、吡唑基、吡咯烷基、吡喃基、四氢吡喃基、噻吩、四氢呋喃基、吡嗪基、咪唑基、哌啶基，哌嗪基，吲哚基、吗啉基、高哌嗪基、噻吩基、呋喃基、噁唑基，其中N原子上的H可任选的被C1-10烷基、C3-10环烷基、-CF3、叔丁氧羰基取代，
R2选自H、C1-10烷基、C3-10环烷基，
R3、R4、R5和R6独立的选自H、C1-10烷基、C3-10环烷基，卤素、-CN、-OC1-10烷基、-N(C1-10烷基)(C1-10烷基)，
R7选自H、C1-10烷基、C3-10环烷基；
R8选自
Figure FDA0002823013230000013
-NHC(＝O)-，
Figure FDA0002823013230000014
R16、R17、R18、R19和R20独立的选自H、C1-6烷基、卤素、苯基、-CN、-OH、-S(O)2C1-3烷基、-C(＝O)C1-3烷基、-N(C1-3烷基)C(＝O)(C1-3烷基)、三甲基硅烷、三乙基硅烷、N杂环丁烷基，吡啶基、吡唑基、吡咯烷基、吡喃基、四氢吡喃基、噻吩、四氢呋喃基、吡嗪基、咪唑基、哌啶基，哌嗪基，吲哚基、吗啉基、高哌嗪基、噻吩基、呋喃基、噁唑基、-NHC(＝O)R21，其中N原子上的H可任选的被C1-10烷基、C3-10环烷基、-CF3、叔丁氧羰基取代，
R2选自H、C1-10烷基、C3-10环烷基，
R3、R4、R5和R6独立的选自H、C1-10烷基、C3-10环烷基，卤素、-CN、-OC1-10烷基、-N(C1-10烷基)(C1-10烷基)，
R7选自H、C1-10烷基、C3-10环烷基。
2.根据权利要求1所述的式(Ⅱ)的化合物或其药学上可接受的盐，其特征在于，R2选自H、C1-6烷基。
3.根据权利要求1所述的式(Ⅱ)的化合物或其药学上可接受的盐，其特征在于，R16、R17、R18、R19和R20独立的选自H、甲基、乙基、丙基、异丙基、卤素、-OH、
Figure FDA0002823013230000021
4.根据权利要求1所述的式(Ⅱ)的化合物或其药学上可接受的盐，其特征在于，R21选自卤代苯基、苄基、
Figure FDA0002823013230000022
Figure FDA0002823013230000023
5.化合物或其药学上可接受的盐，所述的化合物为如下结构：
BRM2-21
Figure FDA0002823013230000024
BRM2-22
Figure FDA0002823013230000025
BRM2-24
Figure FDA0002823013230000031
BRM2-25
Figure FDA0002823013230000032
BRM2-27
Figure FDA0002823013230000033
BRM2-28
Figure FDA0002823013230000034
BRM2-29
Figure FDA0002823013230000035
BRM2-30
Figure FDA0002823013230000036
BRM2-96
Figure FDA0002823013230000037
BRM2-97
Figure FDA0002823013230000038
BRM2-98
Figure FDA0002823013230000039
BRM2-99
Figure FDA00028230132300000310
BRM2-100
Figure FDA0002823013230000041
BRM2-101
Figure FDA0002823013230000042
BRM2-102
Figure FDA0002823013230000043
BRM2-103
Figure FDA0002823013230000044
BRM2-104
Figure FDA0002823013230000045
BRM2-105
Figure FDA0002823013230000046
BRM2-106
Figure FDA0002823013230000047
BRM2-107
Figure FDA0002823013230000048
BRM2-108
Figure FDA0002823013230000049
BRM2-109
Figure FDA0002823013230000051
BRM2-110
Figure FDA0002823013230000052
BRM2-111
Figure FDA0002823013230000053
BRM2-112
Figure FDA0002823013230000054
BRM2-113
Figure FDA0002823013230000055
BRM2-114
Figure FDA0002823013230000056
BRM2-115
Figure FDA0002823013230000057
BRM2-116
Figure FDA0002823013230000058
BRM2-117
Figure FDA0002823013230000059
BRM2-118
Figure FDA0002823013230000061
BRM2-119
Figure FDA0002823013230000062
BRM2-120
Figure FDA0002823013230000063
BRM2-121
Figure FDA0002823013230000064
BRM2-122
Figure FDA0002823013230000065
BRM2-123
Figure FDA0002823013230000066
BRM2-124
Figure FDA0002823013230000067
BRM2-125
Figure FDA0002823013230000068
BRM2-128
Figure FDA0002823013230000069
BRM2-136
Figure FDA0002823013230000071
BRM2-137
Figure FDA0002823013230000072
BRM2-138
Figure FDA0002823013230000073
BRM2-141
Figure FDA0002823013230000074
BRM2-143
Figure FDA0002823013230000075
BRM2-144
Figure FDA0002823013230000076
BRM2-145
Figure FDA0002823013230000077
BRM2-146
Figure FDA0002823013230000078
BRM2-147
Figure FDA0002823013230000079
BRM2-151
Figure FDA00028230132300000710
BRM2-154
Figure FDA0002823013230000081
BRM2-155
Figure FDA0002823013230000082
BRM2-157
Figure FDA0002823013230000083
BRM2-158
Figure FDA0002823013230000084
BRM2-159
Figure FDA0002823013230000085
BRM2-162
Figure FDA0002823013230000086
BRM2-163
Figure FDA0002823013230000087
BRM2-164
Figure FDA0002823013230000088
BRM2-167
Figure FDA0002823013230000091
BRM2-168
Figure FDA0002823013230000092
BRM2-169
Figure FDA0002823013230000093
BRM2-170
Figure FDA0002823013230000094
BRM2-171
Figure FDA0002823013230000095
BRM2-173
Figure FDA0002823013230000096
6.一种药物组合物，包括权利要求1-4任意一项所述的式(II)的化合物或其药学上可接受的盐以及药学上可接受的辅料。
7.权利要求1-4任意一项所述的式(II)的化合物或其药学上可接受的盐在制备预防和/或治疗癌症药物中的应用。
8.权利要求7所述的应用，所述的癌症包括淋巴瘤，母细胞瘤，肉瘤，神经内分泌肿瘤，类癌肿瘤，胃泌素瘤，胰岛细胞癌，间皮瘤，神经鞘瘤，听神经瘤，脑膜瘤，黑素瘤，鳞状细胞癌，肺癌，腹膜癌，胃癌，肠癌，胰腺癌，卵巢癌，肝癌，膀胱癌，乳腺癌，子宫癌，唾液腺癌，肾癌，***癌，外阴癌，甲状腺癌，***癌，***癌，食管癌和胆道肿瘤。
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