CN115594607A - 一类苯并七元环类化合物及其应用 - Google Patents

一类苯并七元环类化合物及其应用 Download PDF

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CN115594607A
CN115594607A CN202210798511.7A CN202210798511A CN115594607A CN 115594607 A CN115594607 A CN 115594607A CN 202210798511 A CN202210798511 A CN 202210798511A CN 115594607 A CN115594607 A CN 115594607A
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cycloalkyl
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王奎锋
李家鹏
张涛
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Suzhou Genhouse Pharmaceutical Co ltd
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Suzhou Genhouse Pharmaceutical Co ltd
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    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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Abstract

本发明涉及一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，所述式(Ⅰ)化合物的结构为：

Description

一类苯并七元环类化合物及其应用
技术领域
本发明属于医药领域，涉及一种苯并七元环类化合物及其制备方法和应用，本发明公开了其作为雌激素失败后调节剂预防和/或治疗雌激素受体介导的或依赖性的疾病和病症的用途。
背景技术
在新诊断的女性癌症中，乳腺癌是发病率最高的癌种。而在所有新诊断的乳腺癌中，雌激素受体阳性(ER+)分群病人占75％左右。由于雌激素受体在这部分病人肿瘤中的重要作用，目前主要的治疗都是针对这条信号通路进行，包括使用芳香酶抑制剂如依西美坦、来曲唑、阿那曲唑抑制雌激素合成，使用雌激素受体调节剂(SERM)如他莫西芬或降解剂(SERD)氟维司群直接抑制雌激素受体功能。
在临床上这些疗法的耐药仍然是一个主要的问题。目前的研究发现了很多耐药机制，包括：其他激酶及相关信号通路的激活，尤其是HER2；细胞周期相关信号通路的失调；ER共激活因子异常表达；以及ER蛋白自身的突变。在大约30％对内分泌疗法耐药的病人中都发现了ER的热点突变。这些突变会导致不依赖于配体的受体持续激活，导致对现有疗法的耐药。
带有ER热点突变的病人预后明显差于野生型ER。然而，即使是在针对雌激素受体的多线标准疗法失败耐药后，这部分肿瘤仍然依赖于雌激素受体的功能。所以，开发基于新作用机制的雌激素受体相关信号通路疗法仍然很有必要。
在小分子靶向抗肿瘤药物开发的过程中，非可逆抑制剂是解决耐药的一种重要思路。一个比较经典的例子是EGFR受体不可逆抑制剂阿法替尼的开发(2013年上市)，其结构中的亲电活性基团丙烯酰胺与EGFR受体活性位点中的半胱氨酸残基(巯基)形成共价键，克服了第一代EGFR(吉非替尼、厄洛替尼等)受体抑制剂出现的耐药性问题，同时对非耐药性EGFR受体也表现出良好的活性。非可逆抑制思路同样有希望用于耐药ER+病人的药物开发。
发明内容
发明要解决的问题
为了解决上述问题，本发明提供了一类能够预防和/或治疗雌激素受体介导的或依赖性的疾病和病症的苯并七元环类化合物。
用于解决问题的方案
为了解决上述技术问题，本发明提供了一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，所述式(Ⅰ)化合物的结构为：
Figure BDA0003736588930000021
其中，
每一个R1独立地选自-H,D,-OH,-NH2,-COOH,-CH2NH2和-CH2OH；
R2选自取代或未取代的芳基、杂环基和杂芳基；
R3选自-(CH2)pCH＝CHCONR4R5和-COCH＝CR6R7，其中，
R4，R5，R6，R7分别独立地选自-H、D、烷基、环烷基和杂环基；
或R4与R5以及相连的氮原子形成3-7元杂环基，或R6和R7以及相连的碳原子形成C3-6环烷基或3-7元杂环基；
p选自0,1,2和3；
Z选自O、S，CHR11和NH，R11可以为H，OH，D,NH2和C1-3烷基；
Y选自-R8NH-、-(CR9R10)q NH-和3-7元含氮杂环基，其中，
R8为C3-6环烷基或3-7元杂环基；
每一个R9和R10分别独立地选自-H、卤素原子、取代或未取代的C1-6烷基和C3-6环烷基；或R9和R10以及与其相连的碳原子形成取代或未取代的C3-6环烷基或3-7元杂环基；或R9或R10、与R9或R10的碳原子以及与所述碳原子相邻的碳原子形成C3-6环烷基；
q选自1,2,3,4和5；
Figure BDA0003736588930000022
选自取代或未取代的芳基和杂芳基；
m选自1,2,3和4。
优选的，R2选自取代或未取代的苯基、3-9元杂环基和5-10元杂芳基，所述取代是被选自C1-6烷基、卤素原子、-NH2、-CN、-COOH、-CHO、-OH、-NO2、C1-6烷氧基、C1-6烷氨基、C3-6环烷基、C6-10芳基、5-10元杂芳基或3-7元杂环基中的一个或多个取代基所取代，上述取代基任选被1-3个选自C1-6烷基、卤素原子、-NH2、-CN、-COOH、-CHO、-OH、-NO2、C1-6烷氧基、C1-6烷氨基、C3-6环烷基所取代。更优选的，所述3-9元杂环基选自氮丙啶基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、四氢噻吩基、哌啶基、吗啉基、哌嗪基、硫代吗啉基、四氢吡喃基、1,1-二氧硫代吗啉基、丁内酰胺基、戊内酰胺基、己内酰胺基、丁内酯基、戊内酯基、己内酯基、2,3-二氢-1H-吲哚基和苯并二氧戊环基中的任一种；
所述5-10元杂芳基含有1-3个任选自N、NH、O、S的杂原子；优选的，所述5-10元杂芳环选自噻吩基、吡啶基、嘧啶基、吡嗪基、哒嗪基、吡咯基、吡唑基、噻唑基、1，2，3-三唑基、1，2，4-三唑基、咪唑基、四氮唑基、异噻唑基、噁唑基、异噁唑基、噻二唑基、噁二唑基、苯并噻吩基、吲哚基、苯并咪唑基、苯并噻唑基、苯并吡唑、苯并呋喃基、苯并恶唑基、苯并异噁唑基、喹啉基、异喹啉基、喹唑啉基、吲唑基或吲哚[1,2-a]吡嗪基中的任一种。
优选的，R3选自-(CH2)pCH＝CHCONR4R5和-COCH＝CR6R7，其中，
R4，R5，R6，R7分别独立地选自-H、D、C1-3烷基、C3-6环烷基和5-6元杂环基；
或R4与R5以及相连的氮原子形成5-6元杂环基；
p为1。
优选的，Y选自-R8NH-、-(CR9R10)q NH-和4-6元含氮杂环基，其中，
R8为C3-6环烷基或4-6元杂环基；
每一个R9和R10分别独立地选自-H、卤素原子、取代或未取代的C1-6烷基和C3-6环烷基；或R9和R10以及与其相连的碳原子形成C3-6环烷基或3-7元杂环基；或R9或R10、与R9或R10的碳原子以及与所述碳原子相邻的碳原子形成C3-6环烷基；所述取代的C1-6烷基和C3-6环烷基是被选自卤素原子、-NH2、-CN、-COOH、-CHO、-OH、-NO2、C1-6烷氧基和C1-6烷氨基的取代基所取代；
q选自1,2和3，优选为2。
优选的，
Figure BDA0003736588930000031
选自取代或未取代的C6-10芳基和5-10元杂芳基，所述取代是被选自C1-6烷基、卤素原子、-NH2、-CN、-COOH、-CHO、-OH、-NO2、C1-6烷氧基、C1-6烷氨基、C3-6环烷基、C6-10芳基、5-10元杂芳基或3-7元杂环基中的一个或多个取代基所取代，上述取代基任选被1-3个选自C1-6烷基、卤素原子、-NH2、-CN、-COOH、-CHO、-OH、-NO2、C1-6烷氧基、C1-6烷氨基、C3-6环烷基所取代。更优选的，上述
Figure BDA0003736588930000032
选自取代或未取代的苯基和吡啶基，所述取代是被选自C1-6烷基、卤素原子、-NH2、-CN、-COOH、-CHO、-OH、-NO2、C1-6烷氧基、C1-6烷氨基、C3-6环烷基、C6-10芳基、5-10元杂芳基或3-7元杂环基中的一个或多个取代基所取代，上述取代基任选被1-3个选自C1-6烷基、卤素原子、-NH2、-CN、-COOH、-CHO、-OH、-NO2、C1-6烷氧基、C1-6烷氨基、C3-6环烷基所取代。
优选的，所述化合物的结构如式Ⅱ所示：
Figure BDA0003736588930000041
R1独立地选自-H,-OH和-NH2；
R2选自取代或未取代的苯基、C5-10杂芳基；所述取代是被选自卤素、氰基、C1-3烷氧基、卤素取代的C1-3烷氧基的取代基所取代；
R3选自-CH2CH＝CHCONR4R5，其中，
R4，R5分别独立地选自-H和C1-3烷基；或R4与R5以及相连的氮原子形成吡咯烷基或哌啶基；
Z选自O、S和NH；
Y选自-R8NH-、-(CR9R10)q NH-和3-7元含氮杂环基，其中，
R8为C3-6环烷基；
每一个R9和R10分别独立地选自-H、卤素原子、C1-3烷基；或R9和R10以及与其相连的碳原子形成C3-6环烷基；
q为2；
Figure BDA0003736588930000042
选自取代或未取代的苯基和吡啶基，所述取代是被选自-H、卤素原子和C1-3烷氧基的取代基所取代。
本发明还提供了一种化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，其特征在于，所述化合物选自：
Figure BDA0003736588930000051
Figure BDA0003736588930000061
Figure BDA0003736588930000071
Figure BDA0003736588930000081
本发明还提供了一种药物组合物，其包含上述任一所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物。
本发明还提供了上述任一所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，或者所述的药物组合物，其用作预防和/或治疗雌激素受体介导的或依赖性的疾病和病症。
本发明还提供了上述任一所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，或者所述的药物组合物用作预防和/或治疗雌激素受体介导的或依赖性的疾病和病症的用途。
本发明还提供了上述任一所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，或者所述的药物组合物在制备预防和/或治疗雌激素受体介导的或依赖性的疾病和病症的药物中的应用，优选的，所述疾病为乳腺癌。
本发明还提供了一种预防和/或治疗雌激素受体介导的或依赖性的疾病和病症的方法，其包括下列步骤：将治疗有效量的根据上述任一所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，或者所述的药物组合物施用于对其有需求的患者。
本发明还提供了一种药物联合形式，其包含上述任一所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，或者所述的药物组合物，以及至少一种额外的治疗剂。
发明的效果
本发明所提供的一类苯并七元环类化合物具有很好的选择性抑制雌激素受体活性的抑制能力和对雌激素受体野生型、Y537S及D538G突变体的人乳腺癌细胞株MCF-7细胞株的抗增殖活性，本发明所提供的化合物能够用于预防和/或治疗雌激素受体介导的或依赖性的疾病和病症。
具体实施方式
为使本发明的技术方案和有益效果能够更加明显易懂，下面通过列举具体实施例的方式进行详细说明。
首先，本发明提供了一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，所述式(Ⅰ)化合物的结构为：
Figure BDA0003736588930000091
其中，
每一个R1独立地选自-H,D,-OH,-NH2,-COOH,-CH2NH2和-CH2OH；
R2选自取代或未取代的芳基、杂环基和杂芳基；
R3选自-(CH2)pCH＝CHCONR4R5和-COCH＝CR6R7，其中，
R4，R5，R6，R7分别独立地选自-H、D、烷基、环烷基和杂环基；
或R4与R5以及相连的氮原子形成3-7元杂环基，或R6和R7以及相连的碳原子形成C3-6环烷基或3-7元杂环基；
p选自0,1,2和3；
Z选自O、S，CHR11和NH，R11可以为H，OH，D,NH2和C1-3烷基；
Y选自-R8NH-、-(CR9R10)q NH-和3-7元含氮杂环基，其中，
R8为C3-6环烷基或3-7元杂环基；
每一个R9和R10分别独立地选自-H、卤素原子、取代或未取代的C1-6烷基和C3-6环烷基；或R9和R10以及与其相连的碳原子形成取代或未取代的C3-6环烷基或3-7元杂环基；或R9或R10、与R9或R10的碳原子以及与所述碳原子相邻的碳原子形成C3-6环烷基；
q选自1,2,3,4和5；
Figure BDA0003736588930000092
选自取代或未取代的芳基和杂芳基；
m选自1,2,3和4。
在一项优选的实施方式中，R2选自取代或未取代的苯基、3-9元杂环基和5-10元杂芳基，所述取代是被选自C1-6烷基、卤素原子、-NH2、-CN、-COOH、-CHO、-OH、-NO2、C1-6烷氧基、C1-6烷氨基、C3-6环烷基、C6-10芳基、5-10元杂芳基或3-7元杂环基中的一个或多个取代基所取代，上述取代基任选被1-3个选自C1-6烷基、卤素原子、-NH2、-CN、-COOH、-CHO、-OH、-NO2、C1-6烷氧基、C1-6烷氨基、C3-6环烷基所取代。
在一项更优选的实施方式中，所述3-9元杂环基选自氮丙啶基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、四氢噻吩基、哌啶基、吗啉基、哌嗪基、硫代吗啉基、四氢吡喃基、1,1-二氧硫代吗啉基、丁内酰胺基、戊内酰胺基、己内酰胺基、丁内酯基、戊内酯基、己内酯基、2,3-二氢-1H-吲哚基和苯并二氧戊环基中的任一种；
所述5-10元杂芳基含有1-3个任选自N、NH、O、S的杂原子；优选的，所述5-10元杂芳环选自噻吩基、吡啶基、嘧啶基、吡嗪基、哒嗪基、吡咯基、吡唑基、噻唑基、1，2，3-三唑基、1，2，4-三唑基、咪唑基、四氮唑基、异噻唑基、噁唑基、异噁唑基、噻二唑基、噁二唑基、苯并噻吩基、吲哚基、苯并咪唑基、苯并噻唑基、苯并吡唑、苯并呋喃基、苯并恶唑基、苯并异噁唑基、喹啉基、异喹啉基、喹唑啉基、吲唑基或吲哚[1,2-a]吡嗪基中的任一种。
在一项优选的实施方式中，R3选自-(CH2)pCH＝CHCONR4R5和-COCH＝CR6R7，其中，
R4，R5，R6，R7分别独立地选自-H、D、C1-3烷基、C3-6环烷基和5-6元杂环基；
或R4与R5以及相连的氮原子形成5-6元杂环基；
p为1。
在一项优选的实施方式中，Y选自-R8NH-、-(CR9R10)q NH-和4-6元含氮杂环基，其中，R8为C3-6环烷基或4-6元杂环基；
每一个R9和R10分别独立地选自-H、卤素原子、取代或未取代的C1-6烷基和C3-6环烷基；或R9和R10以及与其相连的碳原子形成C3-6环烷基或3-7元杂环基；或R9或R10、与R9或R10的碳原子以及与所述碳原子相邻的碳原子形成C3-6环烷基；所述取代的C1-6烷基和C3-6环烷基是被选自卤素原子、-NH2、-CN、-COOH、-CHO、-OH、-NO2、C1-6烷氧基和C1-6烷氨基的取代基所取代；
q选自1,2和3，优选为2。
在一项优选的实施方式中，
Figure BDA0003736588930000101
选自取代或未取代的C6-10芳基和5-10元杂芳基，所述取代是被选自C1-6烷基、卤素原子、-NH2、-CN、-COOH、-CHO、-OH、-NO2、C1-6烷氧基、C1-6烷氨基、C3-6环烷基、C6-10芳基、5-10元杂芳基或3-7元杂环基中的一个或多个取代基所取代，上述取代基任选被1-3个选自C1-6烷基、卤素原子、-NH2、-CN、-COOH、-CHO、-OH、-NO2、C1-6烷氧基、C1-6烷氨基、C3-6环烷基所取代。
在一项更优选的实施方式中，上述
Figure BDA0003736588930000111
选自取代或未取代的苯基和吡啶基，所述取代是被选自C1-6烷基、卤素原子、-NH2、-CN、-COOH、-CHO、-OH、-NO2、C1-6烷氧基、C1-6烷氨基、C3-6环烷基、C6-10芳基、5-10元杂芳基或3-7元杂环基中的一个或多个取代基所取代，上述取代基任选被1-3个选自C1-6烷基、卤素原子、-NH2、-CN、-COOH、-CHO、-OH、-NO2、C1-6烷氧基、C1-6烷氨基、C3-6环烷基所取代。
在一项优选的实施方式中，所述化合物的结构如式Ⅱ所示：
Figure BDA0003736588930000112
R1独立地选自-H,-OH和-NH2；
R2选自取代或未取代的苯基、C5-10杂芳基；所述取代是被选自卤素、氰基、C1-3烷氧基、卤素取代的C1-3烷氧基的取代基所取代；
R3选自-CH2CH＝CHCONR4R5，其中，
R4，R5分别独立地选自-H和C1-3烷基；或R4与R5以及相连的氮原子形成吡咯烷基或哌啶基；
Z选自O、S和NH；
Y选自-R8NH-、-(CR9R10)q NH-和3-7元含氮杂环基，其中，
R8为C3-6环烷基；
每一个R9和R10分别独立地选自-H、卤素原子、C1-3烷基；或R9和R10以及与其相连的碳原子形成C3-6环烷基；
q为2；
Figure BDA0003736588930000113
选自取代或未取代的苯基和吡啶基，所述取代是被选自-H、卤素原子和C1-3烷氧基的取代基所取代。
本发明还提供了一种化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，其特征在于，所述化合物选自：
Figure BDA0003736588930000121
Figure BDA0003736588930000131
Figure BDA0003736588930000141
Figure BDA0003736588930000151
本发明还提供了一种药物组合物，其包含上述任一所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物。
本发明还提供了上述任一所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，或者所述的药物组合物，其用作预防和/或治疗雌激素受体介导的或依赖性的疾病和病症。
本发明还提供了上述任一所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，或者所述的药物组合物用作预防和/或治疗雌激素受体介导的或依赖性的疾病和病症的用途。
本发明还提供了上述任一所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，或者所述的药物组合物在制备预防和/或治疗雌激素受体介导的或依赖性的疾病和病症的药物中的应用。
本发明还提供了一种预防和/或治疗雌激素受体介导的或依赖性的疾病和病症的方法，其包括下列步骤：将治疗有效量的根据上述任一所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，或者所述的药物组合物施用于对其有需求的患者。
最后，本发明还提供了一种药物联合形式，其包含上述任一所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，或者所述的药物组合物，以及至少一种额外的治疗剂。
为了更为清晰地描述本发明的内容，现将所涉及的全部术语定义如下：
术语“卤素原子”指单独或者以组合方式表示氟、氯、溴或碘，特别的是氟、氯或溴。
术语“C1-6烷基”单独或者以组合方式表示包含1-6个碳原子的饱和直链或支链的烷基，包括甲基、乙基、丙基、异丙基、丁基、仲丁基、异丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、正己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3,-二甲基-2-丁基等。优选地，“C1-6烷基”是甲基、乙基、正丙基、异丙基、叔丁基中的任一种。类似的，术语“C1-3烷基”单独或者以组合方式表示包含1-3个碳原子的饱和直链或支链的烷基，包括甲基、乙基、正丙基、异丙基等。
术语“C1-6烷氧基”单独或者以组合方式表示基团C1-6烷基-O-，其中“C1-6烷基”表示如以上所定义，其包括(但不限于)甲氧基(-OCH3)、乙氧基(-OCH2CH3)、正丙氧基(-OCH2CH2CH3)、异丙氧基(-OCH(CH3)2)、正丁氧基(-OCH2CH2CH2CH3)、仲丁氧基(-OCH(CH3)CH2CH3)、异丁氧基(-OCH2CH(CH3)2)、叔丁氧基(-OC(CH3)3)、正戊氧基(-OCH2CH2CH2CH2CH3)、新戊氧基(-OCH2C(CH3)3)等。
术语“C3-6环烷基”指单独或者以组合方式表示具有3到6个碳原子的饱和或者部分不饱和单环或多环环烷基，包括环丙基、环丁基、环戊基、环己基、环庚基等。
术语“杂环基”表示环上的碳原子被至少一个选自硫、氧或氮的杂原子置换形成的饱和或部分不饱和单环或多环杂环基，术语“3-9元杂环基”是指包含3-9个，特别是3-7个碳原子和杂原子或杂原子基团的饱和或部分不饱和单环或多环杂环基，所述杂原子或杂原子基团选自N、NH、O、C(O)、S(O)m(其中m是0、1或2)；所述3-9元杂环基包括氮丙啶基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、四氢噻吩基、哌啶基、吗啉基、哌嗪基、硫代吗啉基、四氢吡喃基、1,1-二氧硫代吗啉基、丁内酰胺基、戊内酰胺基、己内酰胺基、丁内酯基、戊内酯基、己内酯基或2,3-二氢-1H-吲哚基和苯并二氧戊环基等中的任一种。术语“3-9元杂环基”和术语“3-9元杂环基”的定义类似，是指包含5-6个碳原子和杂原子或杂原子基团的饱和或部分不饱和单环或多环杂环基
术语“芳基”表示任何稳定的6-10元单环或双环芳香族基团，包括苯基、萘基、四氢萘基、2,3-二氢化茚基或联苯基等。“芳基”上的氢原子独立任选地被一个或多个本发明所描述的取代基所取代。
术语“杂芳基”表示环上的碳原子被至少一个选自硫、氧或氮的杂原子置换形成的芳香环基团，此芳香环基团可以是5-7元单环或7-12双环基团。在本发明中，杂芳基中杂原子个数优选1、2、3或4，例如所述5-10元杂芳环选自噻吩基、吡啶基、嘧啶基、吡嗪基、哒嗪基、吡咯基、吡唑基、噻唑基、1，2，3-三唑基、1，2，4-三唑基、咪唑基、四氮唑基、异噻唑基、噁唑基、异噁唑基、噻二唑基、噁二唑基、苯并噻吩基、苯并吡唑、吲哚基、苯并咪唑基、苯并噻唑基、苯并呋喃基、苯并噁唑基、苯并异噁唑基、喹啉基、异喹啉基、喹唑啉基、吲唑基或吲哚[1,2-a]吡嗪基等中的任一种。“杂芳基”上的氢原子独立任选地被一个或多个本发明所描述的取代基所取代。
术语“C6-10芳基”表示具有6-10个碳原子的芳基，其中芳基表示如以上所定义。
术语“5-10元杂芳基”表述具有5-10个碳原子和杂原子的杂芳环，其中杂芳环表示如以上所定义。
术语“氨基”单独或者以组合方式表示伯氨基(-NH2)，仲氨基(-NH-)或叔氨基
Figure BDA0003736588930000171
术语“C1-6烷氨基”单独或者以组合方式表示如上所定义的氨基基团，其中氨基基团的氢原子被至少一个C1-6烷基所取代，其中“C1-6烷基”表示如以上所定义，相应地，“C1-6烷氨基”包括甲基氨基、乙基胺基、丙基氨基、异丙基氨基、正丁基胺基、异丁基氨基、2-丁基氨基、叔丁基氨基、正戊基氨基、2-戊基氨基、3-戊基氨基、2-甲基-2-丁基氨基、3-甲基-2-丁基氨基、3-甲基-1-丁基氨基、2-甲基-1-丁基氨基、正己基氨基、2-己基氨基、3-己基氨基、2-甲基-2-戊基氨基、3-甲基-2-戊基氨基、4-甲基-2-戊基氨基、3-甲基-3-戊基氨基、2-甲基-3-戊基氨基、2,3-二甲基-2-丁基氨基、3,3-二甲基-2-丁基氨基等。特别的“C1-C10烷氨基”是甲基氨基、乙基氨基、异丙基氨基、叔丁基氨基等。
术语“异构体”包含所有的同分异构形式包括对映异构体、非对映异构体、互变异构体和几何异构体(包括顺反异构体)。因此，本发明中所设计的化合物的单个立体化学异构体或其对映异构体、非对映异构体、互变异构体或几何异构体(或顺反异构体)的混合物都属于本发明的范围。
术语“药学上可接受的盐”表示本发明的化合物以它们的药用盐的形式存在，包括酸加成盐和碱加成盐。药学上可接受的盐在S.M.Berge在J.Pharmaceutical Sciences(66卷:1-19页,1977年)中描述的pharmaceutically salts中有所描述。在本发明中，药学上可接受的无毒的酸加成盐表示本发明中的化合物与有机或无机酸形成的盐，有机或无机酸包括但不限于盐酸、硫酸、氢溴酸、氢碘酸、磷酸、硝酸、高氯酸、乙酸、草酸、马来酸、富马酸、酒石酸、苯磺酸、甲磺酸、水杨酸、琥珀酸、柠檬酸、乳酸、丙酸、苯甲酸、对甲苯磺酸、苹果酸等。药学上可接受的无毒的碱加成盐表示本发明中的化合物与有机或无机碱所形成的盐，包括但不限于碱金属盐，例如锂、钠或钾盐；碱土金属盐，例如钙或镁盐；有机碱盐，例如通过与含N基团的有机碱形成的铵盐或N+(C1-6烷基)4盐，优选为氢氧化锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、碳酸镁、碳酸钙、氨水、三乙胺、四丁基氢氧化铵等。
术语“溶剂化物”表示一个或多个溶剂分子与本发明中的化合物所形成的缔合物。形成溶剂化物的溶剂包括但不限于水、甲醇、乙醇、异丙醇、乙酸乙酯、四氢呋喃、N,N-二甲基甲酰胺、二甲亚砜等。“药学上可接受的盐”可通过一般的化学方法合成。
术语“酯”用于表示有机酯，包括单酯、二酯、三酯、和更通常地多酯。
术语“前药”表示作为本发明的化合物的化学衍生物，该衍生物在体内通过发生化学反应转换成通式I所表示的化合物。
术语“同位素衍生物”表示通式(I)中的氢原子被1-6个氘原子(D)所取代得到的同位素衍生物、通式(I)中的碳原子被1-3个碳14原子(14C)所取代得到的同位素衍生物。
以上对本发明的涉及的术语进行了定义，本领域技术人员还可以结合现有技术对以上术语进行理解，以下基于本发明的内容以及对术语的定义进一步进行描述。
下面的实施例可以对本发明做进一步的描述，然而，这些实施例不应作为对本发明的范围的限制。
实施例1化合物001的制备
Figure BDA0003736588930000181
化合物001的制备路线如下：
Figure BDA0003736588930000182
Figure BDA0003736588930000191
向化合物001-1(15.0g,68.2mmol,1.0eq.)的CH3CN(150mL)溶液中一次加入Cs2CO3(44.4g,136.3mmol,2.0eq.)和化合物001-2(21.4g,95.4mmol,1.4eq.)，该反应混合物在110℃下反应16小时。待反应完成后，将反应混合物倒入300mL水中，乙酸乙酯萃取三次(450mL)，合并有机相，硫酸镁干燥，浓缩、柱层析得到黄色油状化合物001-3(21.8g,49.8mmol,73.1％)。1H NMR:(400MHz,DMSO-d6)δ7.60(d,J＝8.6Hz,2H),7.51(d,J＝8.4Hz,1H),6.92(d,J＝8.5Hz,2H),3.98(t,J＝5.8Hz,2H),3.32-3.24(m,2H),1.40-1.37(m,9H),1.30-1.26(m,12H)。
Figure BDA0003736588930000192
在氮气保护的条件下，向冷却至0℃的001-4(5.0g,30.3mmol,1.0eq.)的无水四氢呋喃(100mL)溶液中加入SOCl2(14.4g,121.2mmol,8.79mL,4.0eq.)，反应混合物移至室温继续反应12小时，浓缩得到棕色油状化合物，直接用于后续反应。将上述棕色油状化合物溶解于50mL无水二氯甲烷中，在氮气保护条件下一次加入二甲胺盐酸盐hydrochloride(2.45g,30.0mmol,1.1eq.)，三乙胺的二氯甲烷溶液(8.27g溶解于100mL二氯甲烷,3.0eq.)。室温反应完成后，向反应混合物中加入100mL水，分液得到有机相，水相再以二氯甲烷萃取两次，合并有机相并以硫酸镁干燥，浓缩得到棕色油状物，直接用于下一步反应。
1H NMR:(400MHz,DMSO-d6)δ6.93-6.77(m,1H),6.55-6.37(m,1H),4.16-3.95(m,2H),3.04-2.93(m,6H)。(ESI+)m/z 192.0(M+H)+。
Figure BDA0003736588930000193
向化合物001-6(45.0g,236.6mmol,1.0eq.)的无水甲苯(500mL)溶液中缓慢加入AlCl3(75.7g,567.7mmol,31.0mL,2.4eq.)，反应混合物在90℃下反应一小时。反应化合物倒入1500mL的冰水混合物中，悬浊液搅拌20分钟，过滤得到固体物质，并用500mL水洗滤饼，减压浓缩得到黄色固体物质001-7(41.0g,232.7mmol,98.4％)。
1H NMR:(400MHz,DMSO-d6)δ10.13(s,1H),7.55(d,J＝8.5Hz,1H),6.70(dd,J＝2.4,8.4Hz,1H),6.65(d,J＝2.3Hz,1H),2.89-2.79(m,2H),2.65-2.57(m,2H),1.80-1.71(m,2H),1.71-1.62(m,2H)。
Figure BDA0003736588930000201
向化合物001-7(41.0g,232.7mmol,1.0eq.)的丙酮(500mL)溶液中一次加入碳酸钾(32.2g,232.7mmol,1.0eq.),2,2-二甲基丙酸酰氯(32.3g,267.6mmol,32.9mL,1.15eq.)，室温反应16小时。将反应混合物减压浓缩，并向其中加入500mL水和500mL乙酸乙酯，饱和食盐水洗有机相，并以硫酸镁干燥有机相，浓缩得到的粗产物进行柱层析得到黄色固体化合物001-8(52.0g,199.8mmol,85.9％)。
1H NMR:(400MHz,DMSO-d6)7.68-7.75(m,1H),7.27-6.88(m,2H),2.95(t,J＝6.4Hz,2H),2.69(t,J＝6.4Hz,2H),1.83-1.76(m,2H),1.75-1.66(m,2H),1.31(s,9H).
Figure BDA0003736588930000202
在室温下，向化合物001-8(22.5g,86.4mmol,1.0eq.)和吡啶(10.3g,129.6mmol,10.5mL,1.5eq.)的二氯甲烷溶液中(500mL)滴加三氟甲磺酸酐(48.8g,172.9mmol,28.5mL,2.0eq.)反应混合物继续在室温反应2个小时。向反应混合物中缓慢滴加250mL水，分离有机相。以饱和食盐水洗有机相一次，并用硫酸镁干燥。浓缩得到的粗产物进行柱层析分离，得到白色固体化合物001-9(31.5g,80.3mmol,92.9％)
1H NMR:(400MHz,DMSO-d6)δ7.50(d,J＝9.3Hz,1H),7.13(dd,J＝2.3,4.5Hz,2H),6.40(t,J＝6.1Hz,1H),2.85-2.62(m,2H),2.33-2.17(m,2H),2.08-1.86(m,2H),1.31(s,9H)。
Figure BDA0003736588930000203
将化合物001-9(13.0g,33.1mmol,1.0eq.)和001-3(12.6g,34.8mmol,1.05eq.)溶解于二氧六环(130mL)和水(25mL)中，并向该溶液中一次加入Pd(dppf)Cl2(1.21g,1.66mmol,0.05eq.)和碳酸铯(21.6g,66.3mmol,2.0eq.)，该反应混合物在室温反应一小时。缓慢地向反应混合物中加入饱和食盐水(100mL)和二氯甲烷(100mL)，分离有机相，并以硫酸镁干燥。浓缩得到的粗产物经过柱层析纯化得到白色固体产物001-10(14.8g,30.9mmol,93.1％)。
1H NMR:(400MHz,DMSO-d6)7.13(d,J＝8.8Hz,2H),7.09-7.06(m,1H),7.03-6.98(m,1H),6.95-6.88(m,4H),6.38(t,J＝7.3Hz,1H),3.96(brt,J＝5.8Hz,2H),3.31-3.26(m,2H),2.62-2.56(m,2H),2.17-2.08(m,2H),1.88(q,J＝7.4Hz,2H),1.39(s,9H),1.32(s,9H).
Figure BDA0003736588930000211
在室温条件下，向化合物001-10(14.8g,30.9mmol,1.0eq.)的四氢呋喃(200mL)溶液中加入三溴吡啶盐(10.4g,32.4mmol,1.05eq.)，该反应混合液在室温下继续反应一小时。将反应混合物加入到饱和碳酸氢钠(100mL)溶液中，以二氯甲烷(100mL*2)萃取上述混合物，合并有机相，并以饱和食盐水洗涤有机相，硫酸镁干燥有机相。浓缩得到的粗产物经过柱层析得到白色固体产物001-11(11.5g,20.6mmol,66.7％)。
1H NMR:(400MHz,DMSO-d6)δ7.14(d,J＝8.8Hz,2H),7.11-7.08(m,1H),7.07-7.01(m,1H),6.98-6.91(m,3H),6.83-6.76(m,2H),4.00(br t,J＝5.8Hz,2H),3.66-3.61(m,1H),2.81-2.73(m,2H),2.28(br t,J＝6.9Hz,2H),1.80(td,J＝3.2,6.7Hz,1H),1.42(s,9H),1.33(s,10H).
Figure BDA0003736588930000212
将化合物001-11(198.5mg,1.29mmol,1.2eq.)、(0.6g,1.07mmol,1.0eq.)和Cs2CO3(700.0mg,2.15mmol,2.0eq.)溶于二氧六环(5mL)和水(1mL)中，反应混合脱气并以氮气保护，向上述反应混合物中加入Pd(dppf)Cl2(39.3mg,53.7umol,0.05eq.)，该反应混合物继续在90℃下反应一小时。反应混合物以H2O(100mL)稀释，并用乙酸乙酯萃取两次(100mL*2)。饱和食盐水洗涤有机相、硫酸镁干燥，浓缩得到的粗产物经过柱色谱纯化得到黄色油状物001-12(750mg,1.02mmol,95.0％)
1H NMR:(400MHz,CDCl3)δ6.96-6.85(m,2H),6.80-6.69(m,6H),6.57-6.44(m,2H),4.97-4.78(m,1H),3.85(t,J＝5.0Hz,2H),3.40(d,J＝5.0Hz,2H),2.73(t,J＝6.9Hz,2H),2.26-2.22(m,1H),2.30-2.18(m,4H),2.09(q,J＝6.8Hz,2H),1.37(s,9H),1.29(s,9H)。
Figure BDA0003736588930000221
向化合物001-12(500mg,850.8umol,1.0eq.)的二氯甲烷(5mL)溶液中加入三氟乙酸(1.54g,13.5mmol,1.0mL,15.9eq.)，反应化合物在室温下反应两小时。反应也浓缩后得到黄色固体产物001-13(500mg,831.1μmol,97.7％)，直接用于下一步反应。
(ESI+)m/z 488.2(M+H)+。
Figure BDA0003736588930000222
向化合物001-13(450mg,922.9μmol,1.0eq.)的N，N-二甲酰胺(20mL)的溶液中以此加入化合物001-05(141.8mg,738.3μmol,0.8eq.),碘化钾(153.2mg,922.9μmol,1.0eq.)和碳酸钾(255.1mg,1.85mmol,2.0eq.)。该反应混合物在室温下反应十六小时。反应混合物用50mL水稀释，乙酸乙酯萃取稀释后的溶液三次(50mL*3)。合并有机相，用硫酸镁干燥，浓缩得到粗产物，柱层析得到黄色油状化合物001-14(76mg,124.4μmol,13.5％)。
(ESI+)m/z 599.5(M+H)+。
Figure BDA0003736588930000231
向化合物001-14(76mg,126.9umol,1.0eq.)的甲醇溶液中(1mL)加入氢氧化钠(10.2mg,253.9umol,2.0eq.)，反应混合物反应一小时。以3mol/L盐酸调节反应混合物的pH到6，粗品经过制备液相色谱纯化得到白色固体化合物001(43.74mg,62.6％)。制备液相条件：柱子:Phenomenex Luna C18 100*30mm*3um；流动相:A水(0.225％甲酸)，B乙腈，B％:25％-45％,8分钟。
1H NMR:(400MHz,DMSO-d6)δ8.19(s,1H),7.01(t,J＝7.9Hz,1H),6.91-6.80(m,2H),6.73(t,J＝9.3Hz,3H),6.69-6.64(m,2H),6.64-6.58(m,1H),6.58-6.50(m,3H),3.93(t,J＝5.5Hz,2H),3.27-3.18(m,2H),3.02(s,3H),2.86(s,3H),2.85-2.81(m,2H),2.72-2.67(m,2H),2.24(s,3H),2.20-2.14(m,2H),2.09-2.02(m,2H)；(ESI+)m/z 515.3(M+H)+。
LCMS条件:流动相:0.02％氨水(流动相A)，乙腈(流动相B),经过三分钟流动相B从10％到80％，保持80％的流动相B0.5分钟，流速：1.0ml/min；色谱柱:Xbrige Shield RP-18,5um,2.1*50mm；检测波长:UV 220nm和254nm；柱温:50℃。
实施例2化合物002的制备
Figure BDA0003736588930000232
参照实施例1合成路线合成得到黄色固体化合物002。
1H NMR:(400MHz,DMSO-d6)δ9.50(s,1H),9.07-8.81(m,2H),7.57(d,J＝2.1Hz,1H),7.26(dd,J＝2.1,8.3Hz,1H),7.20-7.13(m,1H),6.86-6.73(m,6H),6.63-6.53(m,3H),4.13(br t,J＝4.9Hz,2H),3.83(br d,J＝3.0Hz,2H),3.05(s,4H),2.89(s,4H),2.82-2.72(m,2H),2.23-2.14(m,2H),2.13-2.04(m,2H)；(ESI+)m/z 551.0(M+H)+。
液相质谱联用(LC-MS)条件:0.037％三氟乙酸水溶液(流动相A)，0.018％三氟乙酸乙腈溶液(流动相B),流动相B经过3分钟从5％-80％，保持80％流动相B0.5分钟；流速：1mL/min；柱子:
Figure BDA0003736588930000242
C18 2.1*30mm,3um；检测波长:UV 220nm和254nm；柱温:50℃；质谱离子源:ESI。
实施例3化合物003的制备
Figure BDA0003736588930000241
参照实施例1合成得到白色固体化合物003。
1H NMR:(400MHz,DMSO-d6)δ10.41-8.77(m,1H),8.20(s,1H),7.38(dd,J＝2.5,8.9Hz,1H),7.17(dd,J＝6.4,8.4Hz,1H),7.04(dt,J＝2.6,8.5Hz,1H),6.78-6.59(m,6H),6.58-6.49(m,3H),3.92(br t,J＝5.5Hz,2H),3.36(br d,J＝4.9Hz,2H),3.02(s,3H),2.90-2.73(m,7H),2.24-2.15(m,2H),2.09(br s,2H)；19FNMR:(400MHz,DMSO-d6)δ-114.18(s,1F)；(ESI+)m/z 535.1(M+H)+。
液相质谱联用(LC-MS)条件:0.037％三氟乙酸水溶液(流动相A)，0.018％三氟乙酸乙腈溶液(流动相B),流动相B经过3分钟从5％-80％，保持80％流动相B0.5分钟；流速：1mL/min；柱子:
Figure BDA0003736588930000243
C18 2.1*30mm,3um；检测波长:UV 220nm和254nm；柱温:50℃；质谱离子源:ESI。
实施例4化合物004的制备
Figure BDA0003736588930000251
参照实施例1合成得到白色固体化合物004。
1H NMR:(400MHz,DMSO-d6)δ9.40(s,1H),7.18(d,J＝1.8Hz,1H),7.13-6.98(m,2H),6.71(s,1H),6.70-6.63(m,4H),6.63-6.59(m,1H),6.58-6.49(m,3H),3.91(t,J＝5.5Hz,2H),3.30(s,1H),3.01(s,3H),2.86(s,3H),2.80(br t,J＝5.5Hz,2H),2.77-2.66(m,3H),2.14(s,5H),2.07(br dd,J＝5.6,11.9Hz,2H)；(ESI+)m/z 531.3(M+H)+。
LCMS条件:流动相:0.02％氨水(流动相A)，乙腈(流动相B),经过六分钟流动相B从10％到80％，保持80％的流动相B一分钟，流速：1.0ml/min；色谱柱:Xbrige Shield RP-18,5um,2.1*50mm；检测波长:220nm和254nm；柱温:45℃。
实施例5化合物005的制备
Figure BDA0003736588930000252
参照实施例1合成得到白色固体化合物005。
1H NMR:(400MHz,DMSO-d6)δ9.38(s,1H),6.98-6.91(m,1H),6.88(t,J＝7.4Hz,1H),6.82-6.77(m,1H),6.73-6.66(m,3H),6.64-6.58(m,3H),6.58-6.51(m,3H),3.91(brt,J＝5.4Hz,2H),3.33(br s,2H),3.01(s,3H),2.86(s,3H),2.85-2.81(m,2H),2.81-2.72(m,1H),2.72-2.66(m,1H),2.49-2.40(m,1H),2.19(s,3H),2.15(br d,J＝6.6Hz,1H),2.12(s,3H),2.09-1.98(m,3H)；(ESI+)m/z 511.1(M+H)+。
液相质谱联用(LC-MS)条件:0.037％三氟乙酸水溶液(流动相A)，0.018％三氟乙酸乙腈溶液(流动相B),流动相B经过3分钟从5％-80％，保持80％流动相B0.5分钟；流速：1mL/min；柱子:
Figure BDA0003736588930000262
C18 2.1*30mm,3um；检测波长:UV 220nm和254nm；柱温:50℃；质谱离子源:ESI。
实施例6化合物006的制备
Figure BDA0003736588930000261
参照实施例1合成得到白色固体化合物006。
1H NMR:(400MHz,DMSO-d6)δ9.38(s,1H),6.98-6.91(m,1H),6.88(t,J＝7.4Hz,1H),6.82-6.77(m,1H),6.73-6.66(m,3H),6.64-6.58(m,3H),6.58-6.51(m,3H),3.91(brt,J＝5.6Hz,2H),3.92(t,J＝5.6Hz,2H),3.01(s,3H),2.86(s,3H),2.76-2.65(m,4H),2.09-2.07(m,2H),2.06-2.04(m,4H),1.29(t,J＝7.2Hz,3H)；(ESI+)m/z 561.1(M+H)+。
液相质谱联用(LC-MS)条件:0.037％三氟乙酸水溶液(流动相A)，0.018％三氟乙酸乙腈溶液(流动相B),流动相B经过3分钟从5％-80％，保持80％流动相B0.5分钟；流速：1mL/min；柱子:
Figure BDA0003736588930000263
C18 2.1*30mm,3um；检测波长:UV 220nm和254nm；柱温:50℃；质谱离子源:ESI。
实施例7化合物007的制备
Figure BDA0003736588930000271
参照实施例1合成得到白色固体化合物007。
1H NMR:(400MHz,DMSO-d6)δ9.85-9.68(m,1H),7.24-7.15(m,3H),7.06-7.00(m,2H),6.74-6.65(m,7H),6.55-6.50(m,1H),3.95-3.91(m,2H),3.06-2.97(m,4H),2.90-2.79(m,6H),2.69-2.52(m,5H)；19F NMR:(400MHz,DMSO-d6)δ-82.23(d,J＝3.5Hz,2F),-131.66-131.71(s,1F)；(ESI+)m/z 567.1(M+H)+。
液相质谱联用(LC-MS)条件:0.037％三氟乙酸水溶液(流动相A)，0.018％三氟乙酸乙腈溶液(流动相B),流动相B经过3分钟从5％-80％，保持80％流动相B0.5分钟；流速：1mL/min；柱子:
Figure BDA0003736588930000273
C18 2.1*30mm,3um；检测波长:UV 220nm和254nm；柱温:50℃；质谱离子源:ESI。
实施例8化合物008的制备
Figure BDA0003736588930000272
参照实施例1合成得到白色固体化合物008。
1H NMR:(400MHz,DMSO-d6)δ9.82-9.65(m,1H),7.07-6.98(m,2H),6.92-6.86(m,1H),6.74-6.59(m,8H),6.56-6.49(m,1H),3.96-3.83(m,4H),3.05-2.98(m,3H),2.88-2.79(m,5H),2.70-2.54(m,3H),2.49-2.31(m,4H),1.23-1.18(m,3H)；19F NMR:(400MHz,DMSO-d6)δ-137.38(s,1F)；(ESI+)m/z 545.2(M+H)+。
液相质谱联用(LC-MS)条件:0.037％三氟乙酸水溶液(流动相A)，0.018％三氟乙酸乙腈溶液(流动相B),流动相B经过3分钟从5％-80％，保持80％流动相B0.5分钟；流速：1mL/min；柱子:
Figure BDA0003736588930000282
C18 2.1*30mm,3um；检测波长:UV 220nm和254nm；柱温:50℃；质谱离子源:ESI。
实施例9化合物009的制备
Figure BDA0003736588930000281
参照实施例1合成得到白色固体化合物009。
1H NMR:(400MHz,DMSO-d6)δ8.19(s,1H),6.97-6.89(m,2H),6.89-6.82(m,1H),6.79-6.74(m,2H),6.71(br d,J＝9.0Hz,3H),6.66-6.59(m,1H),6.58-6.42(m,3H),4.03(q,J＝7.0Hz,2H),3.95(br t,J＝5.5Hz,2H),3.37(br s,2H),3.02(s,3H),2.86(s,3H),2.84(br s,2H),2.67(br d,J＝6.3Hz,2H),2.23(br t,J＝6.5Hz,2H),2.09-1.99(m,2H),1.31(t,J＝6.8Hz,3H).；19F NMR:(400MHz,DMSO-d6)δ-135.44(s,1F)；(ESI+)m/z 545.2(M+H)+；
液相质谱联用(LC-MS)条件:0.037％三氟乙酸水溶液(流动相A)，0.018％三氟乙酸乙腈溶液(流动相B),流动相B经过3分钟从5％-80％，保持80％流动相B0.5分钟；流速：1mL/min；柱子:
Figure BDA0003736588930000283
C18 2.1*30mm,3um；检测波长:UV 220nm和254nm；柱温:50℃；质谱离子源:ESI。
实施例10化合物010的制备
Figure BDA0003736588930000291
参照实施例1合成得到白色固体化合物010。
1H NMR:(400MHz,DMSO-d6)δ10.10-8.93(m,1H),8.43(d,J＝1.5Hz,1H),8.18(s,1H),7.88-7.82(m,1H),7.74(d,J＝8.1Hz,1H),6.76(br d,J＝13.4Hz,5H),6.58(s,4H),3.99-3.93(m,2H),3.18-3.13(m,2H),3.10-2.98(m,3H),2.89-2.82(m,5H),2.76-2.70(m,2H),2.40-2.29(m,2H),2.13-2.04(m,2H)；19FNMR:δ-66.11(s,1F)；(ESI+)m/z 552.1(M+H)+；
液相质谱联用(LC-MS)条件:0.037％三氟乙酸水溶液(流动相A)，0.018％三氟乙酸乙腈溶液(流动相B),流动相B经过3分钟从5％-80％，保持80％流动相B0.5分钟；流速：1mL/min；柱子:
Figure BDA0003736588930000293
C18 2.1*30mm,3um；检测波长:UV 220nm和254nm；柱温:50℃；质谱离子源:ESI。
实施例11化合物011的制备
Figure BDA0003736588930000292
在0摄氏度条件下，缓慢地向化合物011-1(0.8g,4.27mmol,1.0eq.)和三乙胺(864.7mg,8.55mmol,1.19mL,2.0eq.)的二氯甲烷溶液中(30mL)加入甲烷磺酰氯(0.62g,5.41mmol,418.9uL,1.27eq.)，加毕，反应混合液在室温下反应2小时。100mL冰水淬灭反应，分液得到有机相，二氯甲烷萃取水相两次(100mL*2)。合并有机相，并用饱和食盐水洗涤一次，硫酸镁干燥，浓缩得到的粗产物经过柱层析得到白色固体化合物011-2(1.1g,3.32mmol,77.6％)。
1H NMR:(400MHz,CDCl3)δ4.77-4.70(m,2H),3.84(br s,1H),3.01(s,3H),2.96-2.90(m,2H),2.24-2.18(m,2H),1.46(s,9H)。
Figure BDA0003736588930000301
将化合物011-2(2.65g,9.99mmol,1.0eq.)和化合物011-3(2.20g,9.99mmol,1.0eq溶解于N，N-二甲基甲酰胺(80mL)中，向其中加入碳酸钾(2.76g,19.9mmol,2.0eq.)，该反应混合物在90℃反应12小时。加入300mL水稀释反应混合物，并用乙酸乙酯萃取三次(20mL*3)。合并有机相，并以饱和食盐水洗(100mL*2，硫酸镁干燥有机相，浓缩得到的粗产物经过柱层析得到黄色油状化合物011-4(1.9g,4.88mmol,48.9％)。
1H NMR:(400MHz,CDCl3)δ7.71-7.62(m,2H),6.80-6.65(m,2H),4.80-4.57(m,1H),4.38-4.14(m,1H),2.88(br s,1H),2.53-2.27(m,2H),1.96-1.88(m,2H),1.60-1.32(m,9H),1.26(s,12H)；。
Figure BDA0003736588930000302
参照实施例1合成得到白色固体化合物011。
1H NMR:(400MHz,DMSO-d6)δ9.79-9.17(m,1H),8.17(s,1H),7.55(d,J＝2.1Hz,1H),7.24(dd,J＝2.1,8.3Hz,1H),7.14(d,J＝8.3Hz,1H),6.76-6.69(m,3H),6.67-6.47(m,6H),4.72-4.67(m,1H),4.30-4.25(m,1H),3.40-3.26(m,2H),3.01(s,3H),2.86(s,3H),2.72-2.64(m,2H),2.25-2.01(m,8H).；LCMS：(ESI+)m/z 577.1(M+H)+。
液相质谱联用(LC-MS)条件:0.037％三氟乙酸水溶液(流动相A)，0.018％三氟乙酸乙腈溶液(流动相B),流动相B经过3分钟从5％-80％，保持80％流动相B0.5分钟；流速：1mL/min；柱子:
Figure BDA0003736588930000303
C18 2.1*30mm,3um；检测波长:UV 220nm和254nm；柱温:50℃；质谱离子源:ESI。
实施例12化合物012的制备
Figure BDA0003736588930000311
参照实施例1合成得到白色固体化合物012。
1H NMR:(400MHz,DMSO-d6)δ9.81-8.86(m,1H),8.24(s,1H),7.04(dd,J＝6.3,8.3Hz,1H),6.95(dd,J＝2.4,10.4Hz,1H),6.86(dt,J＝2.8,8.4Hz,1H),6.74-6.59(m,5H),6.58-6.47(m,3H),3.91(t,J＝5.6Hz,2H),3.35-3.34(m,2H),3.01(s,3H),2.86(s,3H),2.82-2.72(m,4H),2.15(s,3H),2.13-2.07(m,4H)；LCMS:(ESI+)m/z 515.3(M+H)+。
LCMS条件:流动相:0.02％氨水(流动相A)，乙腈(流动相B),经过三分钟流动相B从10％到80％，保持80％的流动相B0.5分钟，流速：1.0ml/min；色谱柱:Xbrige Shield RP-18,5um,2.1*50mm；检测波长:UV 220nm和254nm；柱温:50℃。
实施例13化合物013的制备
Figure BDA0003736588930000312
参照实施例1合成得到白色固体化合物013。
1H NMR:(400MHz,DMSO-d6)δ9.44(s,1H),7.97(d,J＝2.1Hz,1H),7.64(s,2H),6.93(d,J＝8.5Hz,1H),6.81-6.70(m,5H),6.56(s,4H),3.95(t,J＝5.5Hz,2H),3.37-3.34(m,2H),3.02(s,3H),2.86(s,5H),2.72-2.67(m,2H),2.36-2.24(m,3H),2.12-2.05(m,2H)；19FNMR:δ-87.09(s,1F)；LCMS:(ESI+)m/z 550.1(M+H)+。
液相质谱联用(LC-MS)条件:0.037％三氟乙酸水溶液(流动相A)，0.018％三氟乙酸乙腈溶液(流动相B),流动相B经过3分钟从5％-80％，保持80％流动相B0.5分钟；流速：1mL/min；柱子:
Figure BDA0003736588930000322
C18 2.1*30mm,3um；检测波长:UV 220nm和254nm；柱温:50℃；质谱离子源:ESI。
实施例14化合物014的制备
Figure BDA0003736588930000321
参照实施例11合成得到白色固体化合物014。
1H NMR:(400MHz,DMSO-d6)δ8.19(s,1H),7.55(d,J＝2.0Hz,1H),7.28-7.20(m,1H),7.14(d,J＝8.4Hz,1H),6.76-6.69(m,3H),6.62(d,J＝8.8Hz,2H),6.60-6.46(m,4H),4.75(t,J＝6.4Hz,1H),3.20(br d,J＝5.0Hz,2H),3.00(s,3H),2.86(s,3H),2.80-2.62(m,4H),2.56(br d,J＝10.4Hz,1H),2.41(br d,J＝7.1Hz,1H),2.22(br s,1H),2.18-2.12(m,2H),2.08(br s,2H),1.71(br dd,J＝5.5,7.9Hz,1H).；(ESI+)m/z 577.2(M+H)+。
液相质谱联用(LC-MS)条件:0.037％三氟乙酸水溶液(流动相A)，0.018％三氟乙酸乙腈溶液(流动相B),流动相B经过3分钟从5％-80％，保持80％流动相B0.5分钟；流速：1mL/min；柱子:
Figure BDA0003736588930000323
C18 2.1*30mm,3um；检测波长:UV 220nm和254nm；柱温:50℃；质谱离子源:ESI。
实施例15化合物015的制备
Figure BDA0003736588930000331
参照实施例11合成得到白色固体化合物015。
1H NMR:(400MHz,DMSO-d6)δ8.20(s,1H),7.55(d,J＝2.1Hz,1H),7.30-7.21(m,1H),7.19-7.10(m,1H),6.76-6.66(m,5H),6.66-6.59(m,1H),6.58-6.53(m,2H),6.52-6.45(m,1H),3.82(s,2H),3.42(br s,2H),2.99-2.95(m,3H),2.84(s,3H),2.80-2.70(m,2H),2.22-2.12(m,2H),2.12-1.98(m,2H),0.66-0.57(m,2H),0.57-0.47(m,2H)；LCMS:(ESI+)m/z 577.0(M+H)+。
液相质谱联用(LC-MS)条件:0.037％三氟乙酸水溶液(流动相A)，0.018％三氟乙酸乙腈溶液(流动相B),流动相B经过3分钟从5％-80％，保持80％流动相B0.5分钟；流速：1mL/min；柱子:
Figure BDA0003736588930000333
C18 2.1*30mm,3um；检测波长:UV 220nm和254nm；柱温:50℃；质谱离子源:ESI。
实施例16化合物016的制备
Figure BDA0003736588930000332
参照实施例11合成得到白色固体化合物016。
1H NMR:(400MHz,DMSO-d6)δ11.36-11.07(m,1H),9.53(br s,1H),7.57(d,J＝2.1Hz,1H),7.29-7.21(m,1H),7.16(d,J＝8.3Hz,1H),6.96-6.84(m,1H),6.79(d,J＝8.6Hz,2H),6.74(d,J＝2.3Hz,1H),6.67-6.61(m,2H),6.60-6.55(m,1H),6.52-6.43(m,1H),6.52-6.42(m,1H),5.12-4.76(m,1H),4.62(br s,1H),4.39(br s,1H),4.24-3.87(m,4H),3.06(br s,3H),2.88(s,3H),2.82-2.70(m,2H),2.22-2.14(m,2H),2.12-2.02(m,2H)；LCMS：(ESI+)m/z 563.1(M+H)+。
液相质谱联用(LC-MS)条件:0.037％三氟乙酸水溶液(流动相A)，0.018％三氟乙酸乙腈溶液(流动相B),流动相B经过3分钟从5％-80％，保持80％流动相B0.5分钟；流速：1mL/min；柱子:
Figure BDA0003736588930000342
C18 2.1*30mm,3um；检测波长:UV 220nm和254nm；柱温:50℃；质谱离子源:ESI。
实施例17化合物017的制备
Figure BDA0003736588930000341
参照实施例11合成得到白色固体化合物017。
1H NMR:(400MHz,DMSO-d6)δ9.52(s,1H),7.55(d,J＝2.0Hz,1H),7.29-7.22(m,1H),7.21-7.15(m,1H),6.82-6.71(m,6H),6.67-6.61(m,2H),6.59-6.49(m,2H),4.10(s,2H),3.93(br d,J＝3.0Hz,2H),3.57-3.47(m,2H),3.35-3.24(m,2H),2.84-2.71(m,2H),2.22-2.14(m,2H),2.13-2.03(m,2H),1.87(q,J＝6.5Hz,2H),1.80(q,J＝6.5Hz,2H),1.28-1.19(m,2H),1.00-0.91(m,2H).；LCMS：(ESI+)m/z 603.1(M+H)+。
液相质谱联用(LC-MS)条件:0.037％三氟乙酸水溶液(流动相A)，0.018％三氟乙酸乙腈溶液(流动相B),流动相B经过3分钟从5％-80％，保持80％流动相B0.5分钟；流速：1mL/min；柱子:
Figure BDA0003736588930000343
C18 2.1*30mm,3um；检测波长:UV 220nm和254nm；柱温:50℃；质谱离子源:ESI。
实施例18化合物018的制备
Figure BDA0003736588930000351
参照实施例1合成得到白色固体化合物018。
1H NMR:(400MHz,DMSO-d6)δ9.72-9.44(m,1H),9.35(br s,2H),7.56(d,J＝2.0Hz,1H),7.26(dd,J＝1.9,8.3Hz,1H),7.17(d,J＝8.3Hz,1H),6.86-6.70(m,5H),6.69-6.61(m,2H),6.60-6.52(m,2H),4.18(br t,J＝4.4Hz,2H),3.82(br s,2H),3.51(br t,J＝6.8Hz,2H),3.33(br s,2H),3.28(br s,2H),2.84-2.71(m,2H),2.18(br d,J＝6.4Hz,2H),2.08(br d,J＝5.0Hz,2H),1.94-1.85(m,2H),1.79(td,J＝6.4,13.3Hz,2H)；LCMS：(ESI+)m/z577.1(M+H)+。
液相质谱联用(LC-MS)条件:0.037％三氟乙酸水溶液(流动相A)，0.018％三氟乙酸乙腈溶液(流动相B),流动相B经过3分钟从5％-80％，保持80％流动相B0.5分钟；流速：1mL/min；柱子:
Figure BDA0003736588930000353
C18 2.1*30mm,3um；检测波长:UV 220nm和254nm；柱温:50℃；质谱离子源:ESI。
实施例19化合物030的制备
Figure BDA0003736588930000352
参照实施例1合成得到白色固体化合物030。
1H NMR:(400MHz,DMSO-d6)δ9.40(s,1H),8.65(s,1H),7.55(dd,J＝3.4,4.7Hz,2H),7.19(dd,J＝1.3,8.6Hz,1H),6.77-6.69(m,3H),6.67-6.62(m,2H),6.60(s,1H),6.56(d,J＝1.0Hz,2H),6.53-6.47(m,1H),3.89(t,J＝5.5Hz,2H),3.36-3.34(m,2H),3.00(s,3H),2.85(s,3H),2.78(br t,J＝5.0Hz,2H),2.72(brs,2H),2.32(br d,J＝1.8Hz,2H),2.14-1.99(m,3H)；LCMS：(ESI+)m/z 524.6(M+H)+。
实施例20化合物031的制备
Figure BDA0003736588930000361
参照实施例1合成得到白色固体化合物031。
1H NMR:(400MHz,DMSO-d6)δ13.13-12.67(m,1H),9.73-9.07(m,1H),7.93(s,1H),7.53(s,1H),7.34-7.26(m,1H),7.14-7.04(m,1H),6.78-6.68(m,3H),6.66-6.47(m,6H),3.94-3.82(m,2H),3.31-3.28(m,2H),2.93(s,3H),2.78(br t,J＝5.3Hz,5H),2.74-2.68(m,2H),2.34-2.28(m,2H),2.12-1.96(m,3H)；LCMS:(ESI+)m/z 523.4(M+H)+。
实施例21化合物032的制备
Figure BDA0003736588930000362
参照实施例1合成得到白色固体化合物032。
1H NMR:(400MHz,DMSO-d6)δ9.63-9.17(m,1H),7.46-7.40(m,1H),7.40-7.37(m,1H),7.12-7.07(m,1H),6.77-6.69(m,3H),6.67-6.58(m,3H),6.57-6.48(m,3H),3.93-3.85(m,2H),3.32-3.28(m,2H),3.05-2.97(m,3H),2.88-2.83(m,3H),2.81-2.75(m,2H),2.74-2.69(m,2H),2.57-2.54(m,3H),2.33-2.26(m,2H),1.99(br s,3H)；LCMS:(ESI+)m/z 538.4(M+H)+。
实施例22化合物033的制备
Figure BDA0003736588930000371
参照实施例1合成得到白色固体化合物033。
1H NMR:(400MHz,DMSO-d6)δ9.50(s,1H),8.32(d,J＝6.0Hz,2H),7.09(d,J＝6.0Hz,2H),6.79-6.73(m,2H),6.72-6.67(m,3H),6.66-6.58(m,1H),6.56(s,2H),6.54-6.48(m,1H),3.93(t,J＝5.5Hz,2H),3.01(s,3H),2.85(s,3H),2.81(br t,J＝5.5Hz,2H),2.67(br t,J＝6.0Hz,2H),2.53-2.52(m,2H),2.27(br t,J＝6.8Hz,2H),2.04(br t,J＝6.8Hz,2H)；LCMS：(ESI+)m/z 484.3(M+H)+。
实施例23化合物034的制备
Figure BDA0003736588930000372
参照实施例1合成得到白色固体化合物034。
1H NMR:(400MHz,DMSO-d6)δ8.61-8.51(m,2H),8.43(d,J＝8.3Hz,1H),7.88(dd,J＝5.9,8.1Hz,1H),6.96-6.86(m,5H),6.78(d,J＝2.3Hz,1H),6.69(td,J＝6.8,15.1Hz,1H),6.66-6.62(m,1H),6.62-6.57(m,1H),4.32-4.19(m,2H),3.94(d,J＝6.6Hz,2H),3.47(t,J＝4.7Hz,2H),3.16(s,3H),3.01(s,3H),2.82(br t,J＝7.0Hz,2H),2.50(t,J＝6.9Hz,2H),2.23(br t,J＝6.9Hz,2H)；LCMS：(ESI+)m/z 484.2(M+H)+。
实施例24化合物035的制备
Figure BDA0003736588930000381
参照实施例1合成得到白色固体化合物035。
1H NMR:(400MHz,DMSO-d6)δ9.43(s,1H),9.14-9.02(m,2H),7.06-7.00(m,1H),6.97-6.92(m,1H),6.89-6.82(m,1H),6.78-6.68(m,6H),6.66-6.59(m,1H),6.56(s,2H),4.17-4.09(m,2H),3.86-3.77(m,2H),3.41-3.36(m,2H),3.31-3.26(m,3H),2.80-2.67(m,2H),2.19-2.11(m,5H),2.10-2.01(m,2H),1.14-1.08(m,3H),1.06-0.99(m,3H)；LCMS：(ESI+)m/z 543.5(M+H)+。
实施例25化合物036的制备
Figure BDA0003736588930000382
参照实施例1合成得到白色固体化合物036。
1H NMR:(400MHz,DMSO-d6)δ9.43(s,1H),9.10(br s,2H),7.07-7.01(m,1H),6.98-6.93(m,1H),6.89-6.84(m,1H),6.74-6.69(m,4H),6.65-6.61(m,2H),6.59-6.54(m,2H),4.18-4.10(m,2H),3.87-3.79(m,2H),3.54-3.48(m,2H),3.29(brs,3H),2.70(brs,2H),2.20-2.03(m,8H),1.94-1.87(m,2H),1.83-1.75(m,2H)；LCMS：(ESI+)m/z 541.5(M+H)+。
实施例26化合物037的制备
Figure BDA0003736588930000383
参照实施例1合成得到白色固体化合物037。
1H NMR:(400MHz,DMSO-d6)δ9.47(br s,1H),7.37(dd,J＝2.6,8.9Hz,1H),7.16(dd,J＝6.4,8.4Hz,1H),7.09-6.97(m,1H),6.74(s,1H),6.71(s,2H),6.67(s,2H),6.65-6.61(m,1H),6.55(d,J＝1.0Hz,2H),6.44(d,J＝15.1Hz,1H),3.90(br t,J＝5.6Hz,2H),3.33(br d,J＝4.1Hz,2H),3.31-3.27(m,2H),2.84-2.78(m,2H),2.78-2.68(m,2H),2.52(br s,2H),2.21-2.13(m,2H),2.07(br d,J＝2.9Hz,3H),1.07(br t,J＝7.0Hz,3H),1.02(br t,J＝7.0Hz,3H)；LCMS：(ESI+)m/z 563.5(M+H)+。
实施例27化合物038的制备
Figure BDA0003736588930000391
参照实施例1合成得到白色固体化合物038。
1H NMR:(400MHz,DMSO-d6)δ9.58-9.49(m,1H),7.73-7.64(m,1H),7.35-7.25(m,1H),7.16-7.06(m,1H),6.79-6.71(m,5H),6.67-6.60(m,1H),6.59-6.50(m,3H),4.00-3.91(m,2H),3.05-2.98(m,3H),2.92-2.78(m,6H),2.71-2.65(m,3H),2.32-2.24(m,2H),2.15-2.00(m,3H)；LCMS：(ESI+)m/z 526.5(M+H)+。
实施例28化合物039的制备
Figure BDA0003736588930000392
参照实施例1合成得到白色固体化合物039。
1H NMR:(400MHz,DMSO-d6)δ9.76-9.12(m,2H),7.28-7.21(m,2H),7.19-7.13(m,2H),6.89-6.69(m,6H),6.65-6.50(m,3H),4.24-4.12(m,2H),3.87-3.76(m,2H),3.31-3.22(m,2H),3.10-3.00(m,3H),2.91-2.84(m,3H),2.72-2.64(m,2H),2.31-2.22(m,2H),2.11-2.00(m,2H)；LCMS：(ESI+)m/z 567.5(M+H)+。
实施例29化合物040的制备
Figure BDA0003736588930000401
参照实施例1合成得到化合物040。
1H NMR:(400MHz,MeOH-d4)δ7.65(d,J＝2.3Hz,1H),7.42(dd,J＝2.4,8.8Hz,1H),7.05(dd,J＝6.0,8.4Hz,1H),6.93-6.85(m,3H),6.81-6.75(m,2H),6.72-6.60(m,3H),4.61-4.53(m,2H),3.92(dd,J＝0.8,6.6Hz,2H),3.52-3.44(m,2H),3.15(s,3H),3.01(s,3H),2.92-2.75(m,2H),2.32-2.17(m,7H)；LCMS：(ESI+)m/z 516.4(M+H)+。
实施例30化合物041的制备
Figure BDA0003736588930000402
参照实施例1合成得到化合物041。
1H NMR:(400MHz,DMSO-d6)δ9.70-9.10(m,1H),7.07(dd,J＝6.3,8.3Hz,1H),7.00-6.85(m,2H),6.77-6.68(m,2H),6.67-6.55(m,3H),6.55-6.48(m,1H),6.33-6.24(m,2H),3.95-3.86(m,2H),3.07-2.98(m,3H),2.89-2.84(m,3H),2.83-2.75(m,4H),2.72(br s,2H),2.58-2.57(m,3H),2.20-2.15(m,1H),2.15-2.13(m,3H),2.12-1.91(m,3H)；LCMS：(ESI+)m/z 545.5(M+H)+。
实施例31化合物042的制备
Figure BDA0003736588930000411
参照实施例1合成得到化合物042。
1H NMR:(400MHz,DMSO-d6)δ11.02-10.87(m,1H),9.16-8.99(m,2H),7.36-7.31(m,1H),7.27-7.22(m,1H),7.18-7.12(m,1H),6.91-6.73(m,5H),6.72-6.65(m,3H),6.62-6.53(m,3H),6.32-6.22(m,1H),4.16-4.08(m,2H),3.85-3.79(m,2H),3.28-3.23(m,2H),3.06-3.02(m,3H),2.90-2.86(m,3H),2.72(br d,J＝6.3Hz,2H),2.34-2.31(m,2H),2.11-2.02(m,2H)；LCMS：(ESI+)m/z 522.2(M+H)+。
实施例32化合物043的制备
Figure BDA0003736588930000412
参照实施例1合成得到化合物043。
1H NMR:(400MHz,DMSO-d6)δ9.46-9.36(m,1H),7.30(d,J＝2.1Hz,1H),7.22-7.15(m,1H),6.77-6.61(s,8H),6.56-6.50(m,3H),3.98-3.90(m,2H),3.48-3.42(m,2H),3.04-2.99(m,3H),2.88-2.80(m,5H),2.69-2.64(m,2H),2.23-2.16(m,2H),2.08-2.01(m,2H)；LCMS：(ESI+)m/z 524.5(M+H)+。
实施例33化合物044的制备
Figure BDA0003736588930000413
参照实施例1合成得到化合物044。
1H NMR:(400MHz,DMSO-d6)δ9.49-9.40(m,2H),9.31(d,J＝1.1Hz,1H),8.51-8.46(m,1H),8.34-8.27(m,1H),7.97-7.90(m,2H),7.86-7.82(m,1H),7.30-7.20(m,1H),6.81-6.75(m,2H),6.73-6.70(m,1H),6.67-6.62(m,2H),6.59-6.56(m,2H),6.55-6.46(m,1H),3.98(br s,2H),2.96(s,3H),2.90-2.82(m,3H),2.81-2.75(m,2H),2.74-2.67(m,2H),2.36-2.33(m,2H),2.10-2.04(m,2H)；LCMS：(ESI+)m/z 540.5(M+H)+。
实施例34化合物045的制备
Figure BDA0003736588930000421
参照实施例1合成得到化合物045。
1H NMR:(400MHz,DMSO-d6)δ9.55(s,1H),9.28(br s,2H),7.73(d,J＝7.0Hz,1H),7.30(d,J＝9.6Hz,1H),6.86-6.72(m,6H),6.64-6.52(m,3H),4.17(br t,J＝4.6Hz,2H),3.81(br d,J＝5.5Hz,2H),3.28(br s,2H),3.05(s,3H),2.88(s,3H),2.84-2.71(m,2H),2.17(br d,J＝6.3Hz,2H),2.13-2.04(m,2H))；LCMS：(ESI+)m/z 569.4(M+H)+。
实施例35化合物046的制备
Figure BDA0003736588930000422
参照实施例1合成得到化合物046。
1H NMR:(400MHz,DMSO-d6)δ9.56-9.27(m,1H),7.27-7.09(m,2H),6.97-6.87(m,1H),6.79-6.49(m,9H),4.02-3.85(m,2H),3.31-3.13(m,2H),3.06-2.96(m,3H),2.90-2.77(m,5H),2.72-2.63(m,2H),2.29-2.20(m,2H),2.10-1.99(m,2H)；LCMS:(ESI+)m/z 563.5(M+H)+。
实施例36化合物047的制备
Figure BDA0003736588930000431
参照实施例1合成得到化合物047。
1H NMR:(400MHz,DMSO-d6)δ9.53-9.02(m,3H),7.64(d,J＝2.3Hz,1H),7.37(d,J＝1.4Hz,1H),6.89-6.75(m,5H),6.71-6.68(m,1H),6.62-6.50(m,3H),4.20-4.13(m,2H),3.84-3.79(m,3H),3.77(s,2H),3.34-3.27(m,2H),3.06-3.03(m,3H),2.88-2.85(m,3H),2.67-2.63(m,2H),2.26-2.18(m,2H),2.07-1.98(m,5H)；LCMS:(ESI+)m/z 528.5(M+H)+。
实施例37化合物048的制备
Figure BDA0003736588930000432
参照实施例1合成得到化合物048。
1H NMR:(400MHz,DMSO-d6)δ9.61-9.39(m,1H),9.29-9.09(m,2H),7.74-7.65(m,1H),7.51-7.41(m,1H),6.98-6.75(m,5H),6.74-6.70(m,1H),6.66-6.52(m,3H),4.24-4.16(m,2H),3.89-3.79(m,5H),3.33-3.27(m,2H),3.08-3.03(m,3H),2.91-2.87(m,3H),2.64(br s,2H),2.29-2.21(m,2H),2.13-2.05(m,2H)；LCMS:(ESI+)m/z 532.3(M+H)+。
实施例38化合物049的制备
Figure BDA0003736588930000433
参照实施例1合成得到化合物049。
1H NMR:(400MHz,DMSO-d6)δ9.59-9.40(m,1H),8.31(d,J＝1.9Hz,1H),8.16(d,J＝1.3Hz,1H),7.74(s,1H),6.83-6.69(m,5H),6.51(s,5H),4.00-3.88(m,2H),3.38-3.35(m,2H),3.05-2.99(m,3H),2.88-2.80(m,5H),2.70-2.66(m,2H),2.29-2.24(m,2H),2.10-2.05(m,2H)；LCMS:(ESI+)m/z 518.4(M+H)+。
实施例39化合物050的制备
Figure BDA0003736588930000441
参照实施例1合成得到化合物050。
1H NMR:(400MHz,DMSO-d6)δ9.52(br s,1H),8.36(d,J＝1.5Hz,1H),8.24(d,J＝4.6Hz,1H),7.25(dd,J＝5.2,6.2Hz,1H),6.77-6.72(m,3H),6.71-6.66(m,2H),6.60(s,1H),6.58(s,2H),6.54-6.48(m,1H),3.92(t,J＝5.6Hz,2H),3.01(s,3H),2.85(s,3H),2.80(t,J＝5.6Hz,2H),2.70(br t,J＝6.9Hz,2H),2.52(br s,2H),2.25-2.18(m,2H),2.15-1.90(m,3H)；LCMS:(ESI+)m/z 502.4(M+H)+。
实施例40化合物052的制备
Figure BDA0003736588930000442
参照实施例1合成得到化合物052。
1H NMR:(400MHz,DMSO-d6)δ9.46(s,1H),9.26-8.94(m,2H),7.05(dd,J＝6.3,8.4Hz,1H),6.98(dd,J＝2.5,10.1Hz,1H),6.92(d,J＝8.8Hz,1H),6.91-6.85(m,1H),6.84-6.77(m,2H),6.75-6.68(m,2H),6.64-6.54(m,3H),4.24(br d,J＝3.9Hz,2H),3.88(br d,J＝5.1Hz,2H),3.04(s,3H),2.88(s,3H),2.83-2.69(m,2H),2.52-2.52(m,2H),2.17(s,3H),2.14(br s,2H),2.12-2.06(m,2H)；LCMS:(ESI+)m/z 549.5(M+H)+。
实施例41化合物053的制备
Figure BDA0003736588930000451
参照实施例1合成得到化合物053。
1H NMR:(400MHz,DMSO-d6)δ9.46(s,1H),9.23-8.89(m,2H),7.06(dd,J＝6.2,8.4Hz,1H),7.02-6.93(m,2H),6.89(dt,J＝2.8,8.5Hz,1H),6.81(br d,J＝15.3Hz,1H),6.74(s,1H),6.62-6.54(m,5H),4.23(br s,2H),3.83(br d,J＝5.5Hz,2H),3.05(s,3H),2.89(s,3H),2.82-2.69(m,2H),2.53(br s,2H),2.18(s,3H),2.14(br d,J＝4.6Hz,2H),2.13-2.07(m,2H)；LCMS:(ESI+)m/z 533.4(M+H)+。
实施例42化合物054的制备
Figure BDA0003736588930000452
参照实施例1合成得到化合物054。
1H NMR:(400MHz,DMSO-d6)δ9.40(s,1H),9.06(br d,J＝1.3Hz,2H),7.07-6.90(m,2H),6.89-6.77(m,3H),6.71(s,1H),6.65(dd,J＝2.3,11.7Hz,1H),6.62-6.55(m,2H),6.54(s,2H),4.15(br d,J＝4.3Hz,2H),3.81(br d,J＝5.8Hz,2H),3.28(br s,2H),3.05(s,3H),2.88(s,3H),2.86-2.68(m,2H),2.21(br s,3H),2.19-2.09(m,4H)；LCMS:(ESI+)m/z533.3(M+H)+。
实施例43化合物055的制备
Figure BDA0003736588930000461
参照实施例1合成得到化合物055。
1H NMR:(400MHz,DMSO-d6)δ9.45(br s,3H),7.05-6.82(m,3H),6.82-6.67(m,3H),6.66-6.57(m,1H),6.57-6.42(m,2H),6.41-6.21(m,2H),4.17(br t,J＝4.6Hz,2H),3.80(br d,J＝5.1Hz,2H),3.56-3.43(m,3H),3.25(br s,2H),3.05(s,3H),3.02-2.78(m,4H),2.76-2.55(m,1H),2.26-2.17(m,3H),2.17-1.91(m,4H)；LCMS:(ESI+)m/z 545.5(M+H)+。
实施例44化合物056的制备
Figure BDA0003736588930000462
参照实施例1合成得到化合物056。
1H NMR:(400MHz,DMSO-d6)δ9.50(s,1H),7.07-6.97(m,2H),6.92-6.85(m,1H),6.74-6.70(m,1H),6.64-6.56(m,3H),6.47(s,1H),6.46-6.38(m,2H),4.08-4.01(m,2H),3.31-3.27(m,2H),3.03-2.96(m,3H),2.88-2.82(m,3H),2.79-2.63(m,4H),2.18-2.05(m,7H)；LCMS:(ESI+)m/z 551.5(M+H)+。
实施例45化合物057的制备
Figure BDA0003736588930000463
参照实施例1合成得到化合物057。
1H NMR:(400MHz,DMSO-d6)δ9.45(s,1H),7.07-6.92(m,2H),6.82-6.71(m,4H),6.69(d,J＝1.6Hz,1H),6.67-6.58(m,1H),6.58-6.48(m,3H),4.05(q,J＝7.0Hz,2H),3.95(t,J＝5.6Hz,2H),3.01(s,3H),2.85(s,3H),2.82(br t,J＝5.6Hz,2H),2.70-2.64(m,2H),2.52(br d,J＝1.9Hz,2H),2.27-2.20(m,2H),2.10-2.01(m,2H),1.27(t,J＝7.0Hz,3H)；LCMS:(ESI+)m/z 579.4(M+H)+。
实施例46化合物059的制备
Figure BDA0003736588930000471
参照实施例1合成得到化合物059。
1H NMR:(400MHz,DMSO-d6)δ9.54-9.44(m,1H),7.72-7.62(m,1H),6.85(br t,J＝7.6Hz,3H),6.74-6.70(m,1H),6.65-6.47(m,5H),4.22-4.13(m,2H),3.32(br d,J＝5.0Hz,3H),3.03-2.97(m,3H),2.72(br d,J＝5.8Hz,7H),2.26-2.09(m,6H)；LCMS:(ESI+)m/z534.5(M+H)+。
实施例47化合物060的制备
Figure BDA0003736588930000472
参照实施例1合成得到化合物060。
1H NMR:(400MHz,DMSO-d6)δ9.52-9.39(m,1H),7.78-7.67(m,1H),7.28-7.00(m,1H),6.79(dt,J＝2.4,8.5Hz,3H),6.73-6.70(m,1H),6.65-6.57(m,1H),6.56-6.47(m,3H),4.24-4.12(m,2H),3.31(br s,3H),2.95(br s,4H),2.89(br s,3H),2.81-2.74(m,2H),2.68-2.57(m,1H),2.35-2.24(m,3H),2.21-2.06(m,4H)；LCMS:(ESI+)m/z 550.4(M+H)+。
实施例48化合物062的制备
Figure BDA0003736588930000481
参照实施例1合成得到化合物062。
1H NMR:(400MHz,DMSO-d6)δ7.01(dd,J＝6.1,8.3Hz,1H),6.91(d,J＝8.5Hz,1H),6.88-6.49(m,9H),4.01(br t,J＝4.8Hz,2H),3.47(d,J＝5.6Hz,2H),3.29-3.14(m,1H),3.12(s,3H),3.06-2.94(m,5H),2.78-2.57(m,1H),2.42-2.10(m,7H)；LCMS:(ESI+)m/z549.2(M+H)+。
实施例49化合物063的制备
Figure BDA0003736588930000482
参照实施例1合成得到化合物063。
1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),7.50(s,1H),7.44–7.39(m,1H),7.27(d,J＝7.9Hz,1H),6.75(t,J＝1.4Hz,1H),6.73–6.65(m,4H),6.65–6.51(m,4H),3.93(t,J＝5.6Hz,2H),3.03(s,3H),2.88(s,3H),2.82(t,J＝5.5Hz,2H),2.80–2.71(m,2H),2.26(s,3H),2.19(t,J＝5.9Hz,2H),2.11(d,J＝6.7Hz,2H),1.27(s,2H).LCMS:(ESI+)m/z 565.5(M+H)+。
实施例50化合物064的制备
Figure BDA0003736588930000483
参照实施例1合成得到化合物064。
1H NMR(400MHz,Methanol-d4)δ8.51(s,1H),7.95(d,J＝5.3Hz,1H),7.09(d,J＝5.4Hz,1H),6.91(d,J＝8.1Hz,2H),6.88–6.80(m,4H),6.78(d,J＝3.3Hz,2H),6.67(d,J＝8.3Hz,1H),6.65–6.60(m,1H),4.19(t,J＝5.0Hz,2H),3.74(t,J＝2.3Hz,2H),3.26(t,J＝5.1Hz,2H),3.18(s,3H),3.04(s,3H),2.79(t,J＝7.1Hz,2H),2.44(t,J＝7.0Hz,2H),2.20(d,J＝8.0Hz,2H).LCMS:(ESI+)m/z 502.5(M+H)+。
实施例51化合物065的制备
Figure BDA0003736588930000491
参照实施例1合成得到化合物065。
1H NMR(400MHz,Methanol-d4)δ8.56(s,1H),8.31–8.15(m,2H),7.17(d,J＝5.1Hz,1H),6.85–6.60(m,9H),4.11(t,J＝5.1Hz,2H),3.65(d,J＝5.5Hz,2H),3.16(d,J＝4.1Hz,5H),3.03(s,3H),2.86(t,J＝7.1Hz,2H),2.32(d,J＝7.1Hz,2H),2.19(s,5H).LCMS:(ESI+)m/z 498.6(M+H)+。
实施例52化合物066的制备
Figure BDA0003736588930000492
参照实施例1合成得到化合物066。
1H NMR(400MHz,Methanol-d4)δ7.41(dd,J＝9.4,2.8Hz,1H),7.15(dt,J＝19.5,5.2Hz,2H),6.95–6.47(m,9H),4.03(t,J＝5.0Hz,2H),3.50(d,J＝5.7Hz,2H),3.14(s,3H),3.01(s,3H),2.98(d,J＝5.5Hz,2H),2.72(d,J＝12.6Hz,2H),2.36–2.12(m,4H).LCMS:(ESI+)m/z 569.5(M+H)+。
实施例53化合物067的制备
Figure BDA0003736588930000501
参照实施例1合成得到化合物067。
1H NMR(400MHz,DMSO-d6)δ8.22(s,1H),7.73(d,J＝10.6Hz,1H),7.39–7.01(m,3H),6.97(dd,J＝8.5,1.9Hz,1H),6.72(d,J＝2.2Hz,1H),6.65–6.55(m,4H),6.51(d,J＝15.2Hz,1H),4.23(t,J＝5.7Hz,2H),3.40-3.30(m,3H),3.01(s,3H),2.85(s,3H),2.81(t,J＝5.8Hz,2H),2.71(t,J＝7.0Hz,2H),2.30(t,J＝7.0Hz,2H),2.17–2.08(m,2H).LCMS:(ESI+)m/z 586.5(M+H)+。
实施例54化合物068的制备
Figure BDA0003736588930000502
参照实施例1合成得到化合物068。
1H NMR(400MHz,DMSO-d6)δ8.21(s,1H),7.68(d,J＝10.7Hz,1H),7.51(s,1H),7.39(d,J＝7.9Hz,1H),7.23(s,1H),6.74(d,J＝2.4Hz,1H),6.64–6.53(m,4H),6.50(d,J＝15.2Hz,1H),4.18(t,J＝5.7Hz,2H),3.31(s,2H),3.30(s,2H),3.00(s,3H),2.85(s,3H),2.78(t,J＝5.7Hz,2H),2.30(s,3H),2.22(t,J＝5.6Hz,2H),2.14(t,J＝6.3Hz,2H).LCMS:(ESI+)m/z 584.5(M+H)+。
实施例55化合物069的制备
Figure BDA0003736588930000511
参照实施例1合成得到化合物069。
1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),7.72(d,J＝10.6Hz,1H),7.27(d,J＝1.7Hz,1H),7.21(d,J＝8.3Hz,1H),6.91(dd,J＝8.3,1.7Hz,1H),6.71(d,J＝2.2Hz,1H),6.62–6.55(m,4H),6.54–66.48(m,1H),4.22(t,J＝5.7Hz,2H),3.28(s,2H),3.01(s,3H),2.85(s,3H),2.80(t,J＝5.7Hz,2H),2.72(t,J＝7.0Hz,2H),2.33–2.26(m,2H),2.12(t,J＝7.0Hz,2H).LCMS:(ESI+)m/z 582.5(M+H)+。
实施例56化合物070的制备
Figure BDA0003736588930000512
参照实施例1合成得到化合物070。
1H NMR(400MHz,DMSO-d6)8.23(s,1H),7.68(d,J＝10.6Hz,1H),7.59(dd,J＝9.3,2.7Hz,1H),7.40(td,J＝8.3,2.7Hz,1H),7.34(d,J＝6.8Hz,1H),6.72(d,J＝2.4Hz,1H),6.65–6.48(m,5H),4.19(t,J＝5.8Hz,2H),3.32(d,J＝1.5Hz,3H),3.00(s,3H),2.85(s,3H),2.79(t,J＝5.7Hz,2H),2.70(dt,J＝12.0,5.0Hz,1H),2.30–2.11(m,4H).LCMS:(ESI+)m/z 588.5(M+H)+。
实施例57化合物071的制备
Figure BDA0003736588930000521
参照实施例1合成得到化合物071。
1H NMR(400MHz,DMSO-d6)δ9.58(s,1H),8.50(d,J＝2.1Hz,1H),8.25(s,1H),7.87(dd,J＝8.1,2.1Hz,1H),7.81–7.72(m,2H),6.75(d,J＝2.3Hz,1H),6.66–6.57(m,4H),6.51(dt,J＝15.1,1.5Hz,1H),4.22(t,J＝5.7Hz,2H),3.25-3.10(m,2H),3.01(s,3H),2.85(s,3H),2.81(t,J＝5.8Hz,2H),2.75(t,J＝7.0Hz,2H),2.37(t,J＝7.0Hz,2H),2.15(t,J＝7.0Hz,2H).LCMS:(ESI+)m/z 571.4(M+H)+。
实施例58化合物072的制备
Figure BDA0003736588930000522
参照实施例1合成得到化合物072。
1H NMR(400MHz,Methanol-d4)δ7.41(d,J＝2.0Hz,1H),7.13–7.03(m,1H),6.93(dd,J＝11.6,2.1Hz,2H),6.87–6.74(m,3H),6.74–6.61(m,3H),4.47(t,J＝5.4Hz,2H),3.66–3.55(m,2H),3.14(d,J＝13.8Hz,5H),3.03(s,3H),2.93–2.77(m,2H),2.37–2.27(m,5H),2.22(t,J＝6.8Hz,2H).LCMS:(ESI+)m/z 534.5(M+H)+。
实施例59化合物073的制备
Figure BDA0003736588930000523
参照实施例1合成得到化合物073。
1H NMR(400MHz,Methanol-d4)δ7.48(d,J＝1.8Hz,1H),7.01(m,2H),6.99(s,1H),6.97(m,1H),6.73(m,1H),6.66(s,1H),6.64(m,1H),6.58(m,1H),6.35(m,1H),3.69(m,3H),3.68–3.63(m,2H),3.59(s,3H),3.52(m,1H),3.16(m,3H),3.09(m,2H),3.03m,3H),2.46–2.35(m,2H),2.22(m,2H).LCMS:(ESI+)m/z 594.2(M+H)+。
生物活性评价
本发明的化合物选择性抑制雌激素受体活性的抑制能力和对雌激素受体野生型、Y537S及D538G突变体的人乳腺癌细胞株MCF-7细胞株的抗增殖活性，本文所述的生物活性评价可通过如下实验中的测试来证明。
本实验基于核受体(NR)激动剂依赖的共激活肽募集反应原理：通过抗原-抗体反应将Tb标记于NR，Agonist与NR的结合导致其构象的改变，进而导致NR与共激活肽亲和力的增加。共激活肽(FITC)与NR(Tb)两者靠近则产生FRET信号。基于以上反应来评价本申请中化合物对ERα蛋白的抑制活性。
将5μL测试化合物与10nM的ERα蛋白(5μL)分别加入到384孔板中，化合物10μM起始，5倍稀释，9个浓度点，三复孔，并设置对照孔和空白孔。对照孔不加化合物，空白孔不加蛋白，DMSO的终浓度为1％。室温反应15min后，分别加入1test Tb抗体和500nM多肽，两者各5μL。体系混匀后，室温反应24h，读取TR-FRET值。334nm激发，492nm发射；334nm激发，520nm发射；延迟200μs、积分100μs。进而计算各浓度下的抑制率，IC50由GraphPadPrism 7.0软件拟合得到。
表1测试化合物对ERα蛋白抑制活性(IC50)
Figure BDA0003736588930000531
Figure BDA0003736588930000541
上述列表中活性小于***表示为<10nM；**表示为大于>10nM，<100nM；*表示为>100nM。
采用CCK8评价测试化合物对人乳腺癌细胞株MCF-7-ERα(WT、Y537S、D538G)点突变稳转单克隆细胞株的抗增殖活性。取上述生长正常的细胞，用胰酶细胞消化液进行消化，离心，计数，以5000个/孔的细胞密度铺到96孔板中，每孔100μL。细胞铺板后第二天进行给药，每孔加不同浓度梯度的化合物，每个浓度点设三个复孔，另外设置相应的DMSO阴性处理对照组。药物处理72h后，每孔加入CCK8溶液，37℃孵育一段时间后(Vehicle组OD450达到1.0以上)，读取酶标仪450nm处的吸收，计算抑制率，IC50值由GraphPad Prism 7.0软件拟合得到。
表2测试化合物对MCF-7-ERα/WT细胞株增殖抑制活性(IC50)
Figure BDA0003736588930000542
Figure BDA0003736588930000551
上述列表中ND表示未测试；活性小于***表示为<10nM；**表示为大于>10nM，<100nM；*表示为>100nM。
应当理解，以上实施例均为示例性的，不用于包含权利要求所包含的所有可能的实施方式。在不脱离本公开的范围的情况下，还可以在以上实施例的基础上做出各种变形和改变。同样的，也可以对以上实施例的各个技术特征进行任意组合，以形成可能没有被明确描述的本发明的另外的实施例。因此，上述实施例仅表达了本发明的几种实施方式，不对本发明专利的保护范围进行限制。

Claims (15)

1.一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，所述式(Ⅰ)化合物的结构为：
Figure FDA0003736588920000011
其中，
每一个R1独立地选自-H,D,-OH,-NH2,-COOH,-CH2NH2和-CH2OH；
R2选自取代或未取代的芳基、杂环基和杂芳基；
R3选自-(CH2)pCH＝CHCONR4R5和-COCH＝CR6R7，其中，
R4，R5，R6，R7分别独立地选自-H、D、烷基、环烷基和杂环基；
或R4与R5以及相连的氮原子形成3-7元杂环基，或R6和R7以及相连的碳原子形成C3-6环烷基或3-7元杂环基；
p选自0,1,2和3；
Z选自O、S、CHR11和NH，R11可以为H,OH,D,NH2和C1-3烷基；
Y选自-R8NH-、-(CR9R10)q NH-和3-7元含氮杂环基，其中，
R8为C3-6环烷基或3-7元杂环基；
每一个R9和R10分别独立地选自-H、卤素原子、取代或未取代的C1-6烷基和C3-6环烷基；或R9和R10以及与其相连的碳原子形成取代或未取代的C3-6环烷基或3-7元杂环基；或R9或R10、与R9或R10的碳原子以及与所述碳原子相邻的碳原子形成C3-6环烷基；
q选自1,2,3,4和5；
Figure FDA0003736588920000012
选自取代或未取代的芳基和杂芳基；
m选自1,2,3和4。
2.根据权利要求1所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，其特征在于，
R2选自取代或未取代的苯基、3-9元杂环基和5-10元杂芳基，所述取代是被选自C1-6烷基、卤素原子、-NH2、-CN、-COOH、-CHO、-OH、-NO2、C1-6烷氧基、C1-6烷氨基、C3-6环烷基、C6-10芳基、5-10元杂芳基或3-7元杂环基中的一个或多个取代基所取代，上述取代基任选被1-3个选自C1-6烷基、卤素原子、-NH2、-CN、-COOH、-CHO、-OH、-NO2、C1-6烷氧基、C1-6烷氨基、C3-6环烷基所取代。
3.根据权利要求2所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，其特征在于，
所述3-9元杂环基选自氮丙啶基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、四氢噻吩基、哌啶基、吗啉基、哌嗪基、硫代吗啉基、四氢吡喃基、1,1-二氧硫代吗啉基、丁内酰胺基、戊内酰胺基、己内酰胺基、丁内酯基、戊内酯基、己内酯基、2,3-二氢-1H-吲哚基和苯并二氧戊环基中的任一种；
所述5-10元杂芳基含有1-3个任选自N、NH、O、S的杂原子；优选的，所述5-10元杂芳环选自噻吩基、吡啶基、嘧啶基、吡嗪基、哒嗪基、吡咯基、吡唑基、噻唑基、1，2，3-三唑基、1，2，4-三唑基、咪唑基、四氮唑基、异噻唑基、噁唑基、异噁唑基、噻二唑基、噁二唑基、苯并噻吩基、吲哚基、苯并咪唑基、苯并噻唑基、苯并吡唑、苯并呋喃基、苯并噁唑基、苯并异噁唑基、喹啉基、异喹啉基、喹唑啉基、吲唑基或吲哚[1,2-a]吡嗪基中的任一种。
4.根据权利要求1所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，其特征在于，
R3选自-(CH2)pCH＝CHCONR4R5和-COCH＝CR6R7，其中，
R4，R5，R6，R7分别独立地选自-H、D、C1-3烷基、C3-6环烷基和5-6元杂环基；
或R4与R5以及相连的氮原子形成5-6元杂环基；
p为1。
5.根据权利要求1所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，其特征在于，
Y选自-R8NH-、-(CR9R10)q NH-和4-6元含氮杂环基，其中，
R8为C3-6环烷基或4-6元杂环基；
每一个R9和R10分别独立地选自-H、卤素原子、取代或未取代的C1-6烷基和C3-6环烷基；或R9和R10以及与其相连的碳原子形成C3-6环烷基或3-7元杂环基；或R9或R10、与R9或R10的碳原子以及与所述碳原子相邻的碳原子形成C3-6环烷基；所述取代的C1-6烷基和C3-6环烷基是被选自卤素原子、-NH2、-CN、-COOH、-CHO、-OH、-NO2、C1-6烷氧基和C1-6烷氨基的取代基所取代；
q选自1,2和3，优选为2。
6.根据权利要求1所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，其特征在于，
Figure FDA0003736588920000031
选自取代或未取代的C6-10芳基和5-10元杂芳基，所述取代是被选自C1-6烷基、卤素原子、-NH2、-CN、-COOH、-CHO、-OH、-NO2、C1-6烷氧基、C1-6烷氨基、C3-6环烷基、C6-10芳基、5-10元杂芳基或3-7元杂环基中的一个或多个取代基所取代，上述取代基任选被1-3个选自C1-6烷基、卤素原子、-NH2、-CN、-COOH、-CHO、-OH、-NO2、C1-6烷氧基、C1-6烷氨基、C3-6环烷基所取代。
7.根据权利要求6所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，其特征在于，
Figure FDA0003736588920000032
选自取代或未取代的苯基和吡啶基，所述取代是被选自C1-6烷基、卤素原子、-NH2、-CN、-COOH、-CHO、-OH、-NO2、C1-6烷氧基、C1-6烷氨基、C3-6环烷基、C6-10芳基、5-10元杂芳基或3-7元杂环基中的一个或多个取代基所取代，上述取代基任选被1-3个选自C1-6烷基、卤素原子、-NH2、-CN、-COOH、-CHO、-OH、-NO2、C1-6烷氧基、C1-6烷氨基、C3-6环烷基所取代。
8.根据权利要求1所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，其特征在于，所述化合物的结构如式Ⅱ所示：
Figure FDA0003736588920000033
其中，
R1独立地选自-H,-OH和-NH2；
R2选自取代或未取代的苯基、C5-10杂芳基；所述取代是被选自卤素、氰基、C1-3烷氧基、卤素取代的C1-3烷氧基的取代基所取代；
R3选自-CH2CH＝CHCONR4R5，其中，
R4，R5分别独立地选自-H和C1-3烷基；或R4与R5以及相连的氮原子形成吡咯烷基或哌啶基；
Z选自O、S和NH；
Y选自-R8NH-、-(CR9R10)q NH-和3-7元含氮杂环基，其中，
R8为C3-6环烷基；
每一个R9和R10分别独立地选自-H、卤素原子、C1-3烷基；或R9和R10以及与其相连的碳原子形成C3-6环烷基；
q为2；
Figure FDA0003736588920000041
选自取代或未取代的苯基和吡啶基，所述取代是被选自-H、卤素原子和C1-3烷氧基的取代基所取代。
9.一种化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，其特征在于，所述化合物选自：
Figure FDA0003736588920000042
Figure FDA0003736588920000051
Figure FDA0003736588920000061
Figure FDA0003736588920000071
10.一种药物组合物，其包含权利要求1-9任一项所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物。
11.权利要求1至9中任一项所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，或者权利要求10所述的药物组合物，其用作预防和/或治疗雌激素受体介导的或依赖性的疾病和病症。
12.权利要求1至9中任一项所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，或者权利要求10所述的药物组合物用作预防和/或治疗雌激素受体介导的或依赖性的疾病和病症的用途。
13.权利要求1至9中任一项所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，或者权利要求10所述的药物组合物在制备预防和/或治疗雌激素受体介导的或依赖性的疾病和病症的药物中的应用。
14.一种预防和/或治疗雌激素受体介导的或依赖性的疾病和病症的方法，其包括下列步骤：将治疗有效量的根据权利要求1至9中任一项所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，或者权利要求10所述的药物组合物施用于对其有需求的患者。
15.一种药物联合形式，其包含权利要求1至9中任一项所述的一种式(Ⅰ)化合物或其药学上可接受的盐、酯、异构体、溶剂化物、前药或同位素标记物，或者权利要求10所述的药物组合物，以及至少一种额外的治疗剂。
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