CN113387930A - 一种双官能化合物及其制备方法和用途 - Google Patents
一种双官能化合物及其制备方法和用途 Download PDFInfo
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- CN113387930A CN113387930A CN202110246427.XA CN202110246427A CN113387930A CN 113387930 A CN113387930 A CN 113387930A CN 202110246427 A CN202110246427 A CN 202110246427A CN 113387930 A CN113387930 A CN 113387930A
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Abstract
本发明涉及一种双官能化合物及其制备方法和用途，其中双官能化合物包含结合到E3泛素连接酶结合部分；结合到雄激素受体的靶蛋白结合部分；和将E3泛素连接酶结合部分和靶蛋白结合部分连接的连接部分。本申请双官能化合物使雄激素受体邻近泛素连接酶定位，以实现雄激素受体的降解或抑制。
Description
技术领域
本发明属于药物领域，具体涉及一种双官能化合物及其制备方法和用途，其中双官能化合物包含结合到E3泛素连接酶结合部分；结合到雄激素受体的靶蛋白结合部分；和将E3泛素连接酶结合部分和靶蛋白结合部分连接的连接部分。本申请双官能化合物使雄激素受体邻近泛素连接酶定位，以实现雄激素受体的降解或抑制。
背景技术
雄激素受体(AR)属于被雄激素活化的细胞核激素受体家族。在没有雄激素存在下，AR被胞质溶胶中的热休克蛋白90(Hsp90)结合。当雄激素结合AR时，它的构象变成从Hsp90释放AR并暴露核定位信号(NLS)。后者能使AR转移进细胞核中，AR作为转录因子起作用以促进负责雄性性别特征的基因表达。AR缺乏会导致雄激素不敏感综合征。
尽管AR负责雄性性别特征的发育，它也是某些形式的癌症中充分记载的癌基因，例如前列腺癌。AR活性的一种通常测量的靶基因是分泌的前列腺特异性抗原(PSA)蛋白。前列腺癌的当前治疗方案包括两种方案。第一个方案依赖于雄激素的减少，而第二个策略目标在于抑制AR功能。尽管开发了有效的靶向疗法，大多数患者发生抗药性，且疾病持续进展。用于治疗前列腺癌的一个替代方案包括消除AR蛋白。因为AR是许多形式的前列腺癌中的肿瘤发生的关键驱动器，它的消除将会导致治疗上有益的应答。
本领域中继续需要与异常AR调节或活性有关的疾病和病症(例如，癌症、前列腺癌和肯尼迪氏病的有效治疗。
发明内容
本发明提供一种双官能化合物，其作用是将内源蛋白质募集到E3泛素连接酶进行降解。具体地，本发明提供了双功能化合物或蛋白酶解靶向嵌合(PROTAC)化合物，其用作雄激素受体(AR)的靶向泛素化和降解的调节剂。另外，本发明提供了使用有效量的如本文中所述的化合物用于治疗或改善疾病状况(包括癌症，例如，前列腺癌和肯尼迪氏病)的方法。
在一个方面，本发明提供了起将内源性蛋白(例如，AR蛋白)募集至E3泛素连接酶用于泛素化和降解的作用的化合物。
在某些实施方案中，式(I)所示的双官能化合物或其药学上可用的盐、溶剂化物、立体异构体和前药：
ABM-L-ULM(I)，
其中ABM具有式(IV)结构，其中
表示连接部分的连接点：
Z1选自：氢、卤素、氰基、任选地被一个或更多个卤素所取代的C1-4烷基和任选地被一个或更多个卤素所取代的C1-4烷氧基；
X选自：卤素、羟基、氰基和任选地被一个或更多个卤素所取代的C1-4烷氧基；
Y1、Y2各自独立地选自：O、S；
R1、R2各自独立地选自：H、卤素、任选被卤素、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，或R1、R2连同它们所连接的原子一起形成含有0到2个杂原子的3到8元环；
W1选自：化学键，C6-10芳基，5-10元杂芳基、联C6-10芳基或联5-10元杂芳基，各自任选地被1-10个RW1取代；
每个RW1独立地选自：H、卤基、氰基、羟基、胺基、-COORW11、-CONRW11RW12、任选被卤素、羟基、氰基、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，C3-6环烷基、C4-6环杂烷基、C6-10芳基或5-10元杂芳基；RW11和RW12各自独立地选自：氢、任选被卤素取代的C1-6烷基或C3-6环烷基；
L是连接ABM和ULM的化学连接部分；
ULM是羟脑苷脂E3泛素连接酶结合部分(CLM)或VHLE3连接酶结合部分(VLM)。
在某些实施方案中，双官能化合物为下述式I结构的双官能化合物，及其盐、多晶型物和前药：
ABM-L-ULM(I)，
其中ABM是雄激素受体(AR)结合部分，L是连接ABM和ULM的化学连接部分，ULM是E3连接酶结合部分，例如，羟脑苷脂E3泛素连接酶结合部分(CLM)或VHLE3连接酶结合部分(VLM)。
所述ABM具有式(IV)结构，其中
表示连接部分的连接点：
其中：
Z1选自：氢、卤素、氰基、任选地被一个或更多个卤素所取代的C1-4烷基和任选地被一个或更多个卤素所取代的C1-4烷氧基；
X选自：卤素、羟基、氰基和任选地被一个或更多个卤素所取代的C1-4烷氧基；
Y1、Y2各自独立地选自：O、S；
R1、R2各自独立地选自：氢、卤素、任选被卤素、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，或R1、R2连同它们所连接的原子一起形成含有0到2个杂原子的3到8元环；
W1选自：化学键，C6-10芳基，5-10元杂芳基、联C6-10芳基或联5-10元杂芳基，各自任选地被1-10个RW1取代；
每个RW1独立地选自：氢、卤基、氰基、羟基、胺基、任选被卤素、羟基、氰基、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，C3-6环烷基、C4-6环杂烷基、C6-10芳基或5-10元杂芳基。
在某些实施方案中，Z1选自卤素、氰基、甲基、CH2F、CHF2、CF3、甲氧基和CF3O；
X选自：卤素、羟基、氰基、C1-3烷氧基和CF3O；
Y1、Y2各自独立地选自：O、S；
R1、R2各自独立地选自：任选被卤素、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，或R1、R2连同它们所连接的原子一起形成C3-6环烷基；
W1选自：化学键，C6-10芳基，5-10元杂芳基、联C6-10芳基或联5-10元杂芳基，各自任选地被1、2或3个RW1取代；并且
每个RW1独立地选自：氢、卤基、氰基、任选被卤素、羟基、氰基取代的C1-6烷基或C1-6烷氧基。
在本发明的某些实施方案中，W1选自：化学键、苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基，各自任选地被1、2或3个RW1取代；并且
每个RW1独立地选自：氢、卤基、氰基、任选被卤素、羟基、氰基取代的C1-6烷基或C1-6烷氧基、-COORW11、-CONRW11RW12；RW11和RW12各自独立地选自：氢、任选被卤素取代的C1-6烷基。
在某些实施方案中，Z1选自卤素、氰基、甲基、CH2F、CHF2、CF3、甲氧基和CF3O；
X选自：卤素、羟基、氰基、C1-3烷氧基和CF3O；
Y1、Y2各自独立地选自：O、S；
R1、R2各自独立地选自：任选被卤素、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，或R1、R2连同它们所连接的原子一起形成C3-6环烷基；
W1选自：化学键，C6-10芳基，5-10元杂芳基、联C6-10芳基或联5-10元杂芳基，各自任选地被1、2或3个RW1取代；并且
每个RW1独立地选自：氢、卤基、氰基、任选被卤素、羟基、氰基取代的C1-6烷基或C1-6烷氧基、-COORW11、-CONRW11RW12；RW11和RW12各自独立地选自：氢、任选被卤素取代的C1-6烷基。
在某些实施方案中，Z1选自：卤素、氰基、甲基、CH2F、CHF2、CF3、甲氧基和CF3O；
X选自：卤素；
Y1、Y2各自独立地选自：O、S；
R1、R2各自独立地选自：甲基，或R1、R2连同它们所连接的原子一起形成C3-6环烷基；
W1选自：化学键，
其各自任选地被1、2或3个RW1取代；并且
每个RW1独立地选自：氢、卤基、氰基、任选被卤素取代的C1-3烷基或C1-3烷氧基。
在某些实施方案中，Z1选自：卤素、氰基、甲基、CH2F、CHF2、CF3、甲氧基和CF3O；
X选自：卤素；
Y1、Y2各自独立地选自：O、S；
R1、R2各自独立地选自：甲基，或R1、R2连同它们所连接的原子一起形成C3-6环烷基；
W1选自：化学键，
其各自任选地被1、2或3个RW1取代；并且
每个RW1独立地选自：氢、卤基、氰基、任选被卤素取代的C1-3烷基或C1-3烷氧基、-COORW11、-CONRW11RW12；RW11和RW12各自独立地选自：氢、任选被卤素取代的C1-6烷基。
在某些实施方案中，Z1选自：CF3；
X选自：F；
Y1、Y2各自独立地选自：O、S；
R1、R2各自独立地选自：甲基，或R1、R2连同它们所连接的原子一起形成C3-4环烷基；
W1选自：化学键，
其各自任选地被1、2或3个RW1取代；并且
每个RW1独立地选自：氢、卤基、氰基、任选被F取代的C1-3烷基或C1-3烷氧基。
在某些实施方案中，Z1选自：CF3；
X选自：F；
Y1、Y2各自独立地选自：O、S；
R1、R2各自独立地选自：甲基，或R1、R2连同它们所连接的原子一起形成C3-4环烷基；
W1选自：化学键，
其各自任选地被1、2或3个RW1取代；并且
每个RW1独立地选自：氢、卤基、氰基、任选被F取代的C1-3烷基或C1-3烷氧基、-CONH2、-COOC1-3烷基。
在某些实施方案中，ABM选自如下化合物片段，其中
表示连接部分的连接点：
在某些实施方案中，ABM选自如下化合物片段，其中
表示连接部分的连接点：
在第一种方案中，本发明提供一种具有式(II)结构的双官能化合物，及其盐、多晶型物和前药：
ABM-L-CLM(II)，
其中ABM是雄激素受体(AR)结合部分，L是连接ABM和CLM的化学连接部分，CLM是羟脑苷脂E3泛素连接酶结合部分。
其中，ABM定义如上。
在某些实施方案中，CLM包含衍生自酰亚胺、硫代酰亚胺、酰胺或硫代酰胺的化学基团，其结合到羟脑苷脂E3泛素连接酶。
在某些实施方案中，CLM是邻苯二酰亚胺基或其类似物。
在某些实施方案中，CLM为式(V)所示结构片段或其立体异构体，其中
表示连接部分的连接点：
其中
W选自：CH2、CHR11、C＝O、NH或-N-C1-6烷基；
每个T独立地选自：O或S；
G选自：氢、C1-6烷基或羟基；
Q1、Q2、Q3和Q4独立地选自：CR′或N；
A选自：氢、C1-6烷基、C3-6环烷基、或卤素；
R11选自：卤素、氰基、任选被卤素取代的C1-6烷基或C1-6烷氧基、C3-6环烷基、-CONR′R″、-OR′、或-NR′R″；
R′和R″各自独立地选自：氢、卤素、胺基、氰基、任选被卤素取代的C1-6烷基或C1-6烷氧基、C3-6环烷基。
在某些实施方案中，W选自：CH2、CHR11或C＝O；
每个T独立地选自：O或S；
G选自：氢、或C1-6烷基；
Q1、Q2、Q3和Q4独立地选自：CH；
A选自：氢、C1-6烷基或卤素；
R11选自：卤素、氰基、-CF3、OCF3、甲基、-CONR′R″、-OR′、或-NR′R″；
R′和R″各自独立地选自：氢、卤素、氰基、胺基、-CF3、OCF3或甲基。
在某些实施方案中，CLM为式(V)-1所示结构片段或其立体异构体，其中
表示连接部分的连接点：：
其中：
W选自：CH2或C＝O；
A选自：氢或C1-6烷基。
在某些实施方案中，CLM为式(V)-2或(V)-3所示结构片段或其立体异构体，其中
表示连接部分的连接点：
在某些实施方案中，CLM是沙立度胺、来那度胺、泊马度胺或其类似物的片段。
在本发明的方案中，连接基团(L)选自如下通式结构表示的基团：
-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-CO-(CH2)o-O-；
-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-；
-(CH2)m-CO-N(R31)-；
-O-(CH2)n-N(R31)-CO-(CH2)o-O-；
-Cy-CO-N(R31)-(CH2)n-N(R31)-CO-(CH2)o-O-；
-C≡C-Cy-(CH2)n-N(R31)-CO-(CH2)o-O-；
-O-(CH2)n-N(R31)-；
-C≡C-(Cy)p-CO-(CH2)o-O-；
-O-(Cy)p-CO-(CH2)o-O-；
-O-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-；
-(CH2)m-CO-Cy-CO-(CH2)o-O-；
-(Cy)q-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-CO-(CH2)o-O-；
-(Cy)q-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-；
-(Cy)q-(CH2)m-CO-N(R31)-；
-(Cy)q-O-(CH2)n-N(R31)-CO-(CH2)o-O-；
-(Cy)q-Cy-CO-N(R31)-(CH2)n-N(R31)-CO-(CH2)o-O-；
-(Cy)q-C≡C-Cy-(CH2)n-N(R31)-CO-(CH2)o-O-；
-(Cy)q-O-(CH2)n-N(R31)-；
-(Cy)q-(Cy)q-C≡C-(Cy)p-CO-(CH2)o-O-；
-(Cy)q-O-(Cy)p-CO-(CH2)o-O-；
-(Cy)q-O-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-；
-(Cy)q-(CH2)m-CO-Cy-CO-(CH2)o-O-；
-(CH2)m-O-(CH2)n-CO-N(R31)-(CH2)o-N(R31)-CO-(CH2)t-O-；
-CO-N(R31)-(CH2)m-N(R31)-(CH2)n-CO-N(R31)-；
-(Cy)q-O-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-CO-(CH2)t-O-；
其中m、n、o、p、q和t各自独立地选自：0、1、2、3、4、5、6，其条件是当所述数目是零时，不存在N-O或O-O键，各个R31独立地选自基团氢、甲基或乙基，Cy选自C6-10芳基,C3-6杂芳基，C3-6环烷基,C3-6杂环烷基，优选
其各自任选地被1、2或3个RCy取代；并且
每个RCy独立地选自：氢、卤基、氰基、任选被卤素取代的C1-3烷基或C1-3烷氧基。
在优选的本发明的方案中，连接基团(L)选自如下通式结构表示的基团：
-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-CO-(CH2)o-O-；
-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-；
-(CH2)m-CO-N(R31)-；
-O-(CH2)n-N(R31)-CO-(CH2)o-O-；
-Cy-CO-N(R31)-(CH2)n-N(R31)-CO-(CH2)o-O-；
-C≡C-Cy-(CH2)n-N(R31)-CO-(CH2)o-O-；
-O-(CH2)n-N(R31)-；
-C≡C-(Cy)p-CO-(CH2)o-O-；
-O-(Cy)p-CO-(CH2)o-O-；
-O-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-；
-(CH2)m-CO-Cy-CO-(CH2)o-O-；
-(Cy)q-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-CO-(CH2)o-O-；
-(Cy)q-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-；
-(Cy)q-(CH2)m-CO-N(R31)-；
-(Cy)q-O-(CH2)n-N(R31)-CO-(CH2)o-O-；
-(Cy)q-Cy-CO-N(R31)-(CH2)n-N(R31)-CO-(CH2)o-O-；
-(Cy)q-C≡C-Cy-(CH2)n-N(R31)-CO-(CH2)o-O-；
-(Cy)q-O-(CH2)n-N(R31)-；
-(Cy)q-(Cy)q-C≡C-(Cy)p-CO-(CH2)o-O-；
-(Cy)q-O-(Cy)p-CO-(CH2)o-O-；
-(Cy)q-O-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-；
-(Cy)q-(CH2)m-CO-Cy-CO-(CH2)o-O-；
其中m、n、o、p和q各自独立地选自：0、1、2、3、4、5、6，其条件是当所述数目是零时，不存在N-O或O-O键，各个R31独立地选自基团氢、甲基或乙基，Cy选自C3-6芳基,C3-6杂芳基，C3-6环烷基,C3-6杂环烷基，优选
其各自任选地被1、2或3个RCy取代；并且
每个RCy独立地选自：氢、卤基、氰基、任选被卤素取代的C1-3烷基或C1-3烷氧基。
在某些实施方案中，连接基团(L)选自基团：
在某些实施方案中，连接基团(L)选自基团：
在本发明第二种方案中，本发明提供了具有式(III)结构的化合物，及其盐、多晶型物和前药：
ABM-L-VLM(III)，
其中，ABM如定义如上；
VLM为式(VI)所示结构片段或其立体异构体：
Y3是NRY3RY4、ORY3、SRY3、
R21和R22独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基；
RY3和RY4独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基、任选地被卤素、羟基、氰基取代的C1-6烷基-CO-、任选地被卤素、羟基、氰基取代的C3-6环烷基-CO-；或RY3、R21和它们所连接的碳原子和氮原子一起形成任选地被取代的5-6元杂环烷基；
XY3是O或S；
R23、R24各自独立地选自：H、任选地被卤素、羟基、氰基取代的C1-6烷基；
W2是C6-10芳基或5-10元杂芳基；
R25是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C1-6烷基，任选地被卤素、羟基、氰基取代的C1-6烷氧基，NR25aR25b，CONR25aR25b，C6-10芳基，6-10元杂芳基，噻吩基，或
其中R25a、R25b各自独立地选自：H、任选地被卤素、羟基、氰基取代的C1-6烷基；R27是H、卤素、任选地被卤素、羟基、氰基取代的C1-6烷基，且Xa是S、O或NR28；R28是氢、任选地被卤素取代的C1-6烷基；所述C6-10芳基、6-10元杂芳基、噻吩基任选被一个或更多个选自氢、卤素、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基、-CONHC1-6烷基、-COOC1-6烷基的基团取代；
R26是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C1-6烷基，任选地被卤素、羟基、氰基取代的C1-6烷氧基；
在优选的本发明第二种方案中，本发明提供了具有式(III)结构的化合物，及其盐、多晶型物和前药：
ABM-L-VLM(III)，
其中ABM是AR结合部分，L是连接ABM和VLM化学连接部分，VLM是VHLE3连接酶结合部分。在某些实施方案中，所述VLM包含羟基脯氨酰基部分。
其中，ABM定义如上；
VLM为式(VI)所示结构片段或其立体异构体：
其中，
Y3是NRY3RY4、ORY3、SRY3；
R21和R22独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基；
RY3和RY4独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基、任选地被卤素、羟基、氰基取代的C1-6烷基-CO-、任选地被卤素、羟基、氰基取代的C3-6环烷基-CO-；或RY3、R21和它们所连接的碳原子和氮原子一起形成任选地被取代的5-6元杂环烷基；
R23、R24各自独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基；
W2是C6-10芳基或5-10元杂芳基；
R25是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C1-6烷基，任选地被卤素、羟基、氰基取代的C1-6烷氧基，NR25aR25b，CONR25aR25b，C6-10芳基，或
其中R25a、R25b各自独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基；R27是氢、卤素、任选地被卤素、羟基、氰基取代的C1-6烷基，且Xa是S或O；
R26是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C1-6烷基，任选地被卤素、羟基、氰基取代的C1-6烷氧基；
在某些实施方案中，Y3是NRY3RY4、ORY3；
R21和R22独立地选自：氢、C1-6烷基；
RY3和RY4独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基-CO-；或RY3、R21和它们所连接的碳原子和氮原子一起形成任选地被取代的5-6元杂环烷基；
R23、R24各自独立地选自：氢、C1-6烷基；
W2是苯基；
R25是氢，卤素，C1-6烷基，CONR25aR25b，或
其中R25a、R25b各自独立地选自：氢、C1-6烷基；R27是氢、C1-6烷基，且Xa是S；
R26是氢，C1-6烷基。
在某些实施方案中，Y3是NRY3RY4、ORY3；
R21和R22独立地选自：氢、C1-6烷基；
RY3和RY4独立地选自：氢、C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基-CO-；或RY3、R21和它们所连接的碳原子和氮原子一起形成任选地被取代的5元杂环烷基；
R23、R24各自独立地选自：氢、C1-6烷基；
W2是苯基；
R25是CONR25aR25b，或
其中R25a、R25b各自独立地选自：氢、C1-6烷基；R27是C1-6烷基，且Xa是S；
R26是氢。
在某些实施方案中，Y3是
RY3选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基；
XY3是O或S。
在某些实施方案中，其中Y3是
在某些实施方案中，所述VLM选自如下的结构片段或其立体异构体，其中
表示连接部分的连接点：
在某些实施方案中，VLM为式(VI)-1所示结构片段或其立体异构体：
其中，Y3，R21，R23，R25定义如上。
在某些实施方案中，VLM为式(VI)-2所示结构片段或其立体异构体：
其中，
Y5是NRY5、O；
R21和R22独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基；
RY5是氢、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基、任选地被卤素、羟基、氰基取代的C1-6烷基-CO-、任选地被卤素、羟基、氰基取代的C3-6环烷基-CO-；或RY5、R21和它们所连接的碳原子和氮原子一起形成任选地被取代的5-6元杂环烷基；
R23、R24各自独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基；
W2是C6-10芳基或5-10元杂芳基；
R25是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C1-6烷基，任选地被卤素、羟基、氰基取代的C1-6烷氧基，NR25aR25b，CONR25aR25b，C6-10芳基，或
其中R25a、R25b各自独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基；R27是氢、卤素、任选地被卤素、羟基、氰基取代的C1-6烷基，且Xa是S或O；
R26是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C1-6烷基，任选地被卤素、羟基、氰基取代的C1-6烷氧基。
在某些实施方案中，VLM为式(VI)-2所示结构片段或其立体异构体：
Y5是NRY5、O；
R21和R22独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基；
RY5是氢、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基、任选地被卤素、羟基、氰基取代的C1-6烷基-CO-、任选地被卤素、羟基、氰基取代的C3-6环烷基-CO-；或RY5、R21和它们所连接的碳原子和氮原子一起形成任选地被取代的5-6元杂环烷基；
R23、R24各自独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基；
W2是5-6元杂芳基；
R25是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C1-6烷基，任选地被卤素、羟基、氰基取代的C1-6烷氧基，NR25aR25b，CONR25aR25b，C6-10芳基，6-10元杂芳基，噻吩基，或
其中R25a、R25b各自独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基；R27是H、卤素、任选地被卤素、羟基、氰基取代的C1-6烷基，且Xa是S、O或NR28；R28是氢、任选地被卤素取代的C1-6烷基；所述C6-10芳基、6-10元杂芳基、噻吩基任选被一个或更多个选自氢、卤素、任选地被卤素取代的C1-6烷基、任选地被卤素取代的C3-6环烷基、-CONHC1-6烷基、-COOC1-6烷基的基团取代；
R26是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C1-6烷基，任选地被卤素、羟基、氰基取代的C1-6烷氧基。
在某些实施方案中，Y5是NRY5、O；
R21和R22独立地选自：氢、C1-6烷基；
RY5是氢、C1-6烷基；或RY5、R21和它们所连接的碳原子和氮原子一起形成任选地被取代的5元杂环烷基；
R23、R24各自独立地选自：氢、C1-6烷基；
W2是苯基；
R25是CONR25aR25b，或
其中R25a、R25b各自独立地选自：氢、C1-6烷基；R27是C1-6烷基，且Xa是S；
R26是氢。
在本发明的某些实施方案中，R21选自：甲基、乙基、正丙基、异丙基、正丁基、2-甲基丙基、仲丁基、叔丁基、正戊基、异戊基或新戊基。
在某些实施方案中，Y5是NRY5、O；
R21选自：甲基、乙基、正丙基、异丙基、正丁基、2-甲基丙基、仲丁基、叔丁基、正戊基、异戊基或新戊基；
R22选自：氢；
RY5是氢、C1-6烷基；
R23、R24各自独立地选自：氢、C1-6烷基；
W2是
R25是
其中R27是C1-3烷基，且Xa是S；
R26是氢。
在某些实施方案中，Y5是NRY5、O；
R21和R22独立地选自：氢、C1-6烷基；
RY5是氢、C1-6烷基；或RY5、R21和它们所连接的碳原子和氮原子一起形成任选地被取代的5元杂环烷基；
R23、R24各自独立地选自：氢、C1-6烷基；
W2是噁唑基或噻唑基；
R25是氢；
R26是氢。
在某些实施方案中，其中Y5是NRY5、O；
R21选自：甲基、乙基、正丙基、异丙基、正丁基、2-甲基丙基、仲丁基、叔丁基、正戊基、异戊基或新戊基；
R22选自：氢；
RY5是氢、C1-6烷基；
R23、R24各自独立地选自：氢、C1-6烷基；
W2是噁唑基或噻唑基；
R25是氢；
R26是氢。
在某些实施方案中，所述VLM选自如下的结构片段或其立体异构体，其中
表示连接部分的连接点：
在某些实施方案中，VLM为式(VI)-3所示结构片段或其立体异构体：
其中，Y5，R21，R23，R25定义如上。
在另一个实施方案中，VLM为式(VI)-4或(VI)-5所示结构片段或其立体异构体：
其中，R21，R22，Xa定义如上；R27a，R27b各自独立地选自：氢、C1-6烷基。
在某些实施方案中，所述VLM选自如下的结构片段或其立体异构体，其中
表示连接部分的连接点：
在某些实施方案中，VLM为式(VI)-5所示结构片段或其立体异构体：
R21和R22独立地选自：氢、C1-6烷基；
R27a，R27b各自独立地选自：H、5-6元杂芳基，优选H、噻唑基。
在某些实施方案中，所述VLM选自如下的结构片段或其立体异构体，其中
表示连接部分的连接点：
在某些实施方案中，VLM为式(VI)-61所示结构片段或其立体异构体：
R21和R22独立地选自：氢、C1-6烷基；
R29是任选地被卤素取代的C1-6烷基。
在某些实施方案中，所述VLM选自如下的结构片段或其立体异构体，其中
表示连接部分的连接点：
在某些实施方案中，VLM为式(VI)-71或式(VI)-81所示结构片段或其立体异构体：
R21和R22独立地选自：氢、C1-6烷基；
R25是苯基，吡啶基，嘧啶基，噻吩基，或
R27是C1-6烷基，且Xa是S、O或NR28；R28是C1-6烷基；所述苯基、吡啶基、嘧啶基、噻吩基任选被一个或更多个选自卤素、C1-6烷基、-CONHC1-6烷基的基团取代；
XV是S、O或NR29；R29是氢、C1-6烷基；W是CH。
在某些实施方案中，所述VLM选自如下的结构片段或其立体异构体，其中
表示连接部分的连接点：
在某些实施方案中，连接基团(L)选自如下通式结构表示的基团：
-(CH2)m-CO-N(R31)-(CH2)n-CO-；
-O-(CH2)m-O-(CH2)n-CO-；
-O-(CH2)m-CO-；
-C≡C-(Cy)p-(CH2)m-CO-；
-CO-N(R31)-(CH2)m-(Cy)p-(CH2)n-CO-；
-CO-(Cy)p-(CH2)n-CO-；
-O-(CH2)m-(Cy)p-(CH2)n-CO-；
-N(R31)-CO-(CH2)m-O-(CH2)n-CO-；
-N(R31)-(CH2)m-O-(CH2)n-CO-；
-(CH2)m-(Cy)p-(CH2)n-CO-；
-O-(CH2)m-O-(CH2)n-O-(CH2)o-CO-；
-(Cy)p-(CH2)n-O-(CH2)o-CO-；
-C≡C-(CH2)m-CO-；
-(CH2)m-CO-N(R31)-(CH2)n-(Cy)p-CO-；
-C≡C-(Cy)p-(CH2)m-N(R31)-CO-；
-(Cy)q-(CH2)m-CO-N(R31)-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-O-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-CO-；
-(Cy)q-C≡C-(Cy)p-(CH2)m-CO-；
-(Cy)q-CO-N(R31)-(CH2)m-(Cy)p-(CH2)n-CO-；
-(Cy)q-CO-(Cy)p-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-(Cy)p-(CH2)n-CO-；
-(Cy)q-N(R31)-CO-(CH2)m-O-(CH2)n-CO-；
-(Cy)q-N(R31)-(CH2)m-O-(CH2)n-CO-；
-(Cy)q-(CH2)m-(Cy)p-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-O-(CH2)n-O-(CH2)o-CO-；
-(Cy)q-(Cy)p-(CH2)n-O-(CH2)o-CO-；
-(Cy)q-C≡C-(CH2)m-CO-；
-(Cy)q-(CH2)m-CO-N(R31)-(CH2)n-(Cy)p-CO-；
-(Cy)q-C≡C-(Cy)p-(CH2)m-N(R31)-CO-；
-O-(CH2)m-O-(CH2)n-；
-CH＝CH-CO-N(R31)-(CH2)m-O-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-N(R31)-CO-；
-(Cy)q-O-(Cy)p-(CH2)m-N(R31)-CO-；
-(Cy)q-N(R31)-CO-(CH2)m-(Cy)p-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-(Cy)p-CO-；
-O-(CH2)m-O-(CH2)n-O-(CH2)o-O-(CH2)t-CO-；
-O-(Cy)q-CO-N(R31)-(CH2)m-O-(CH2)n-CO-；
-O-(Cy)q-O-(CH2)m-O-(CH2)n-CO-；
-O-(CH2)m-O-(CH2)n-O-(CH2)o-(Cy)q-CO-；
-O-(CH2)m-O-(CH2)n-(Cy)q-CO-；
其中m、n、o、p、q和t各自独立地选自：0、1、2、3、4、5、6，其条件是当所述数目是零时，不存在N-O或O-O键，各个-CH2-中的一个或两个氢原子可以被氟原子替代，各个R31独立地选自基团氢、甲基、乙基、或苄基，Cy选自C6-10芳基,C3-6杂芳基，C3-6环烷基,C3-6杂环烷基，优选
其各自任选地被1、2或3个RCy取代；并且
每个RCy独立地选自：氢、卤基、氰基、任选被卤素取代的C1-3烷基或C1-3烷氧基。
在某些实施方案中，连接基团(L)选自如下通式结构表示的基团：
-(CH2)m-CO-N(R31)-(CH2)n-CO-；
-O-(CH2)m-O-(CH2)n-CO-；
-O-(CH2)m-CO-；
-C≡C-(Cy)p-(CH2)m-CO-；
-CO-N(R31)-(CH2)m-(Cy)p-(CH2)n-CO-；
-CO-(Cy)p-(CH2)n-CO-；
-O-(CH2)m-(Cy)p-(CH2)n-CO-；
-N(R31)-CO-(CH2)m-O-(CH2)n-CO-；
-N(R31)-(CH2)m-O-(CH2)n-CO-；
-(CH2)m-(Cy)p-(CH2)n-CO-；
-O-(CH2)m-O-(CH2)n-O-(CH2)o-CO-；
-(Cy)p-(CH2)n-O-(CH2)o-CO-；
-C≡C-(CH2)m-CO-；
-(CH2)m-CO-N(R31)-(CH2)n-(Cy)p-CO-；
-C≡C-(Cy)p-(CH2)m-N(R31)-CO-；
-(Cy)q-(CH2)m-CO-N(R31)-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-O-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-CO-；
-(Cy)q-C≡C-(Cy)p-(CH2)m-CO-；
-(Cy)q-CO-N(R31)-(CH2)m-(Cy)p-(CH2)n-CO-；
-(Cy)q-CO-(Cy)p-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-(Cy)p-(CH2)n-CO-；
-(Cy)q-N(R31)-CO-(CH2)m-O-(CH2)n-CO-；
-(Cy)q-N(R31)-(CH2)m-O-(CH2)n-CO-；
-(Cy)q-(CH2)m-(Cy)p-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-O-(CH2)n-O-(CH2)o-CO-；
-(Cy)q-(Cy)p-(CH2)n-O-(CH2)o-CO-；
-(Cy)q-C≡C-(CH2)m-CO-；
-(Cy)q-(CH2)m-CO-N(R31)-(CH2)n-(Cy)p-CO-；
-(Cy)q-C≡C-(Cy)p-(CH2)m-N(R31)-CO-；
其中m、n、o、p和q各自独立地选自：0、1、2、3、4、5、6，其条件是当所述数目是零时，不存在N-O或O-O键，各个R31独立地选自基团氢、甲基、乙基、或苄基，Cy选自C3-6环烷基,C3-6杂环烷基，优选
其各自任选地被1、2或3个RCy取代；并且
每个RCy独立地选自：氢、卤基、氰基、任选被卤素取代的C1-3烷基或C1-3烷氧基。
在本发明的某些实施方案中，Cy选自C6-10芳基,C3-6杂芳基，C3-6环烷基,C3-6杂环烷基，优选苯基、吡啶基、三唑基、氮杂环丁基、四氢吡咯基、哌啶基、哌嗪基、氧代哌嗪基、四氢吡啶基、氧代二氢吡啶基，进一步优选
其各自任选地被1、2或3个RCy取代；并且
每个RCy独立地选自：氢、卤基、氰基、任选被卤素取代的C1-3烷基。
在某些实施方案中，连接基团(L)选自如下基团：
-O-(CH2)m-O-(CH2)n-CO-；
-O-(CH2)m-CO-；
-O-(CH2)m-O-(CH2)n-O-(CH2)o-CO-；
-(Cy)p-(CH2)n-O-(CH2)o-CO-；
-(Cy)q-O-(CH2)m-O-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-CO-；
-(Cy)q-O-(CH2)m-O-(CH2)n-O-(CH2)o-CO-；
-O-(Cy)q-O-(CH2)m-O-(CH2)n-CO-；
-O-(CH2)m-O-(CH2)n-O-(CH2)o-(Cy)q-CO-；
-O-(CH2)m-O-(CH2)n-(Cy)q-CO-；
其中m、n和o各自独立地选自：1、2、3、4、5、6，q选自：1，Cy选自C6-10芳基,C3-6杂芳基，C3-6环烷基,C3-6杂环烷基，优选苯基、吡啶基、三唑基、氮杂环丁基、四氢吡咯基、哌啶基、哌嗪基、氧代哌嗪基、四氢吡啶基、氧代二氢吡啶基，进一步优选
其各自任选地被1、2或3个RCy取代；并且
每个RCy独立地选自：氢、卤基、氰基、任选被卤素取代的C1-3烷基。
在某些实施方案中，连接基团(L)选自基团：
在某些实施方案中，连接基团(L)选自基团：
本发明具体化合物如下：
本发明的另一方面提供一种组合物，其包含有效量的本发明双官能化合物和药学上可接受的载体。
本发明的药学上可接受的载体包括离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白质、缓冲物质(例如磷酸盐、甘氨酸、山梨酸、山梨酸钾)、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质。
在一个实施方案中，使用保护化合物以免从身体快速排除的载体制备活性化合物，例如控释型配制物，包括植入物和微囊封递送系统。可以使用可生物降解的生物相容性聚合物，例如乙烯乙酸乙烯酯、聚酸酐、聚乙醇酸、胶原蛋白、聚原酸酯以及聚乳酸。用于制备此类配制物的方法对于所属领域的技术人员来说是显而易见的。
脂质体悬浮液也可以是药学上可接受的载体，脂质体配制物可以如下制备：将适当脂质(例如硬脂酰基磷脂酰基乙醇胺、硬脂酰基磷脂酰基胆碱、花生四烯酰基磷脂酰基胆碱和胆固醇)溶解于无机溶剂中，然后蒸发，在容器表面上留下干燥脂质的薄膜。然后将活性化合物的水溶液引入容器中。然后用手旋转容器以使脂质材料脱离容器的侧面，并且分散脂质聚集体，从而形成脂质体悬浮液。
在本发明的方案中，组合物进一步包含至少一种其它生物活性剂。
在本发明的方案中，生物活性剂是抗癌剂。
本发明的另一个方面提供一种治疗组合物，其包含有效量的至少两种不同的本发明所述的化合物。
本发明的另一个方面提供一种在需要其的受试者中将内源蛋白质募集到E3泛素连接酶进行降解的方法，所述方法包括给予本发明所述的化合物。
本发明的另一个方面提供一种在需要其的受试者中将雄激素受体降解或抑制的方法，所述方法包括给予本发明所述的化合物。
本发明的另一方面提供了一种治疗受试者的疾病或病症的方法，其包含以下步骤：向有需要的受试者施用组合物，所述组合物包含药学上可接受的载体和有效量的本发明所述的化合物。
在某些实施方案中，所述疾病或病症是痤疮、多毛症、皮脂腺增大、脱发、哮喘、多发性硬化症、癌症、肯尼亚病(Kenney′sdisease)、纤毛病、腭裂、糖尿病、心脏病、高血压、发炎性肠病、智力迟钝、情绪障碍、肥胖症、屈光不正、不育症、安格尔曼综合症(Angelmansyndrome)、卡纳万疾病(Canavandisease)、腹腔病、夏-马-图三氏病(Charcot-Marie-Toothdisease)、囊肿性纤维化、杜氏肌营养不良(Duchennemusculardystrophy)、血色病、血友病、克氏综合症(Klinefelter′ssyndrome)、神经纤维瘤、苯丙酮尿症、多囊性肾病(PKDl)或4(PKD2)、普拉德-威利综合症(Prader-Willisyndrome)、镰状细胞病、泰伊-萨克斯二氏病(Tay-Sachsdisease)、特纳综合症(Turnersyndrome)。其中所述癌症是鳞状细胞癌、基底细胞癌、腺癌、肝细胞癌和肾细胞癌瘤；膀胱、肠道、乳房、子宫颈、结肠、食道、头、肾脏、肝脏、肺、颈、卵巢、胰腺、前列腺和胃的癌症；白血病；良性和恶性淋巴瘤，尤其伯基特氏淋巴瘤(Burkitt′slymphoma)和非霍奇金淋巴瘤(Non-Hodgkin′slymphoma)；良性和恶性黑色素瘤；骨髓增生性疾病；肉瘤，包括尤文氏肉瘤(Ewing′ssarcoma)、血管内皮瘤、卡波西肉瘤(Kaposi′ssarcoma)、脂肪肉瘤、肌肉瘤、末梢神经上皮瘤、滑膜肉瘤、神经胶质瘤、星形细胞瘤、寡突神经胶质细胞瘤、室管膜瘤、神经胶母细胞瘤、神经母细胞瘤、神经节神经胶质瘤、髓母细胞瘤、松果体细胞肿瘤、脑膜瘤、脑膜肉瘤、神经纤维瘤和许旺细胞瘤(Schwannomas)；肠道癌、乳癌、前列腺癌、子宫颈癌、子宫癌、肺癌、卵巢癌、睾丸癌、甲状腺癌、星形细胞瘤、食道癌、胰脏癌、胃癌、肝癌、结肠癌、黑色素瘤；癌肉瘤、霍奇金氏疾病、维尔姆斯瘤或畸胎癌。
在本发明的方案中，所述疾病或病症是癌症、痤疮、多毛症、皮脂腺增大、脱发、或肯尼迪病。
在本发明的方案中，所述疾病或病症是前列腺癌、痤疮或脱发。
在另一方面，说明书提供了治疗组合物，其包含有效量的如本发明所述化合物或其盐形式和药学上可接受的载体。治疗组合物调节患者或受试者中的蛋白质降解，并且能够用于治疗或改善通过降解的蛋白质调节的疾病状态或病状。在某些实施方案中，如本发明所述的治疗组合物能够用于实现所关注蛋白质的降解和/或抑制，以便治疗或改善疾病，例如癌症。
定义
除非另外定义，否则本文所用的术语具有与本领域所属领域的普通技术人员通常所理解相同的含义。说明书中所用的术语仅用于描述特定实施方案并且不希望限制本发明。
术语“烃基”应指含有碳和氢并且可以是完全饱和、部分不饱和或芳香族并且包括芳基、烷基、烯基和炔基的化合物。
术语“烷基”在其上下文内应该指可以任选地被取代的直链、支链链或环状完全饱和烃基或烷基，优选C1-C10，更优选C1-C6，或者C1-C3烷基。烷基实例是甲基、乙基、正丁基、仲丁基、正己基、正庚基、正辛基、正壬基、正癸基、异丙基、2-甲基丙基、环丙基、环丙基甲基、环丁基、环戊基、环戊基乙基、环己基乙基和环己基等等。
术语“烯基”是指含有至少一个C＝C键的直链、支链链或环状C2-C10(优选C2-C6)烃基。
术语“炔基”是指含有至少一个C≡C键的直链、支链链或环状C2-C10(优选C2-C6)烃基。
术语“亚烷基”在使用时是指可以任选地被取代的-(CH2)n-基团(n一般是整数0-6)。被取代时，亚烷基优选地在一个或多个亚甲基上被C1-C6烷基(包括环丙基或叔丁基)取代，而且可以被一个或多个卤基(优选1到3个卤基)或一个或两个羟基或C1-6烷基氧基。
术语“未被取代”应该指仅被氢原子取代。
术语“被取代”或“任选地被取代”指分子任一处的碳(或氮)位置处独立地存在一个或多个取代基，优选1-5个取代基，最优选1-3个取代基，取代基可以为：羟基、硫醇、羧基、氰基、硝基、卤素(优选地，1、2或3个卤素，尤其在烷基上，尤其甲基，例如三氟甲基)、烷基(优选C1-C10，更优选地，C1-C6)、卤代烷基、芳基(尤其苯基和被取代的苯基，例如苯甲基或苯甲酰基)、烷氧基(优选C1-C6烷基或芳基，包括苯基和被取代的苯基)、硫醚(C1-C6烷基或芳基)、酰基(优选C1-C6酰基)、C1-C6烷基胺、C1-C6二烷基胺，被一或两个C1-C6烷基取代的酰胺基(包括任选地被一个或两个C1-C6烷基取代的甲酰胺)、羧基、C1-C6酯等。
术语“芳基”是指具有单环(例如苯基)或稠环(例如萘基、蒽基、菲基等)的被取代或未被取代的C6-C16芳香族基团，优选C6-C10芳香族基团。
术语“杂芳基”是指含有至少一个杂原子(例如N、O或S)的5-16元芳香族基团，优选5-10元芳香族基团，可以指任选地被取代的喹啉、任选地被取代的吲哚、任选地被取代的吲哚嗪、任选地被取代的氮杂吲哚嗪、任选地被取代的苯并咪唑、苯并二唑、苯并呋喃、任选地被取代的咪唑、任选地被取代的异噁唑、任选地被取代的噁唑(优选被甲基取代)、任选地被取代的二唑、任选地被取代的三唑、四唑、任选地被取代的苯并呋喃、任选地被取代的噻吩、任选地被取代的噻唑(优选被甲基和/或硫醇取代)、任选地被取代的异噻唑、任选地被取代的三唑、任选地被取代的吡啶(2-吡啶、3-吡啶或4-吡啶)。
术语“芳烷基”和“杂芳基烷基”是指分别包含芳基或杂芳基的基团，以及符合上述定义的烷基和/或杂烷基和/或碳环和/或杂环烷基环系统。
术语“杂环基”是指含有至少一个杂原子(例如N、O或S)的3-10元环基，优选3-6元环基，且可以是芳香族(杂芳基)或非芳香族。其包括：氮杂环丁烷基、苯并咪唑基、1，4-苯并二噁烷基、1，3-苯并间二氧杂环戊烯基、苯并噁唑基、苯并噻唑基、苯并噻吩基、二氢咪唑基、二氢吡喃基、二氢呋喃基、二噁烷基、二氧杂环戊烷基、亚乙基脲、1，3-二氧杂环戊烷、1，3-二噁烷、1，4-二噁烷、呋喃基、高哌啶基、咪唑基、咪唑啉基、咪唑啶基、吲哚啉基、吲哚基、异喹啉基、异噻唑啶基、异噻唑基、异噁唑啶基、异噁唑基、吗啉基、萘啶基、噁唑啶基、噁唑基、吡啶酮、2-吡咯烷酮、吡啶、哌嗪基、N-甲基哌嗪基、哌啶基、邻苯二甲酰亚胺、丁二酰亚胺、吡嗪基、吡唑啉基、吡啶基、嘧啶基、吡咯啶基、吡咯啉基、吡咯基、喹啉基、四氢呋喃基、四氢吡喃基、四氢喹啉、噻唑啶基、噻唑基、噻吩基、四氢噻吩、噁烷、氧杂环丁烷基、氧硫杂环戊烷基、噻烷等等。
术语“环烷基”是指C3-C20的单环或多环烷基，优选C3-C15的单环或多环烷基，最优选C3-C10的单环或多环烷基，包括环丙基、环丁基、环戊基、环己基、环庚基等。
“杂环烷基”是指3-20元的单环或多环烷基，优选3-15元的单环或多环烷基，最优选3-10元的单环或多环烷基，，其中其环状结构中的至少一个环碳原子被选自由N、O、S或P组成的组的杂原子置换。
“卤素”是指F、Cl、Br、I。
术语“药学上可接受的盐”用于描述本文所述的一种或多种化合物的盐形式，提供其是为了增加化合物在患者胃肠道的胃汁液中的溶解度以便促进化合物的溶解和生物利用度。药学上可接受的盐在适用时包括衍生自药学上可接受的无机或有机碱和酸的盐。适合的盐包括衍生自碱金属(例如钾和钠)、碱土金属(例如钙、镁和铵盐)以及药学领域中众所周知的许多其它酸和碱的盐。
制备适用于本发明的药学上可接受的酸加成盐所用的酸是形成无毒酸加成盐的酸，即，含有药理学上可接受的阴离子的盐，例如盐酸盐、氢溴酸盐、氢碘化物、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、乙酸盐、乳酸盐、柠檬酸盐、酸式柠檬酸盐、酒石酸盐、酒石酸盐、酒石酸氢盐、丁二酸盐、顺丁烯二酸盐、反丁烯二酸盐、葡糖酸盐、葡糖二酸盐、苯甲酸盐、甲烷磺酸盐、乙烷磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐盐，以及多种其它盐。
术语“有效”可以意指但不限于活性医药成分的量/剂量，当在其预定用途的背景下使用时，其在需要此类治疗或接受此类治疗的受试者中实现或足以预防病状、病症或疾病状态，抑制其发生，改善、延迟或治疗其症状(在一定程度上，优选完全缓解症状)。
术语“药学上可接受的载体”可以意指与药物施用兼容的任何和所有溶剂、分散介质、包衣、抗细菌和抗等。
除非另外指明，术语“化合物”是指本文公开的任何特定化合物并且包括互变异构体、区位异构体、几何异构体，以及适用时，立体异构体，包括光学异构体(对映异构体)和其它立体异构体(非对映异构体)，以及其药学上可接受的盐和衍生物(包括前药形式)。其在上下文中使用时，术语化合物通常不仅指单一化合物，而且可以包括其它化合物，例如立体异构体、区位异构体和/或光学异构体(包括外消旋混合物)，以及所公开化合物的特定对映异构体或对映异构体增浓混合物。所述术语在上下文中还指化合物的前药形式，其已经修饰以促进化合物施用和递送到活性部位。
附图说明
本发明附图示出了本发明的若干实施方案，且与说明书一起用于解释本发明的原理。附图仅出于图示本发明的实施方案的目的并且不被解释为限制本发明。结合展示本发明的说明性实施方案的附图，从以下详细描述中将显而易知本发明的其它目标、特点和优点，其中：
图1为本发明化合物对LNCaP细胞AR蛋白的降解实验结果；
图2为本发明化合物对LNCaP小鼠移植瘤的PK/PD实验结果；
图3为本发明化合物对雌性金黄地鼠皮脂腺斑生长的抑制结果；
图4为本发明化合物及其对照药给药后第21天对金黄地鼠体重的影响作用；
图5为本发明化合物及其对照药给药后对C57BL/6小鼠体重的影响图；
图6为本发明化合物A279与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图7为本发明化合物A283-A286与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图8为本发明化合物A288与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图9为本发明化合物A307与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图10为本发明化合物A308与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图11为本发明化合物A309-A313与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图12为本发明化合物A314、A315、A317和A318与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图13为本发明化合物A320-A324和A318与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图14为本发明化合物A340和A318与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图15为本发明化合物A347-A351和A318与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图16为本发明化合物A352-A354和A318与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比；
图17为本发明化合物A357-A358和A318与阳性化合物ARD-69对LNCaP细胞AR蛋白的降解实验结果对比。
具体实施方式
下面将结合附图以及进一步的详细说明来举例说明本发明。需要指出的是，以下说明仅仅是对本发明要求保护的技术方案的举例说明，并非对这些技术方案的任何限制。本发明的保护范围以所附权利要求书记载的内容为准。
一、制备实施例
ABM-L-CLM的合成
实施例A1
将1-1(2g,10mmol)，TMSCN(3g,30mmol)，ZnCl2(136mg,1mmol)依次加入到50ml丙酮中，室温反应1h，反应结束后，100ml水洗，100mlEA萃取，50ml饱和食盐水洗涤，无水硫酸钠干燥，旋干得2.3g产物1-2，产率88％，产品不经纯化直接用于下一步。
将1-2(2.3g,8.8mmol)，1-3(4.3g,17.6mmol)依次加入到10mlDMF中，室温反应过夜，反应结束后，加入20ml甲醇，20ml6NHCl，90℃反应1h，反应结束用50ml水洗，50mlEA萃取，20ml饱和食盐水洗涤，无水硫酸钠干燥，旋干上层析柱PE:EA＝5:1-2:1得到400mg产物1-4，产率9.2％。
将1-4(300mg,0.6mmol)，1-5(112mg,0.6mmol)，HATU(456mg,1.2mmol)，三乙胺(0.2ml,1.2mmol)依次加入到10mlDCM中，室温搅拌一小时，反应结束后，用50ml水洗涤，50mlDCM萃取，20ml饱和食盐水洗涤，无水硫酸钠干燥，旋蒸，上厚制备板DCM:MeOH＝15:1，得到150mg产物1-6，产率37％。
将1-6(150mg)加入大2mlTHF中，冷却至0℃，通入HCl气体，0℃反应2h，反应结束后，用饱和碳酸氢钠溶液调节pH＝8，20mlEA萃取，10ml饱和食盐水洗涤，无水硫酸钠干燥，旋干得到80mg产物1-7，产率63％。
将1-7(80mg，0.14mmol)，2(46mg，0.14mmol)，HATU(106mg，0.28mmol)，三乙胺(28mg，0.28mmol)依次加入到5mlDMF中，室温搅拌一小时，反应结束后，用20ml水洗涤，20mlEA萃取，20ml饱和食盐水洗涤，无水硫酸钠干燥，旋蒸，上后制备板DCM:MeOH＝10:1,得到50mg，再HPLC制备得25mg白色固体A1，纯度97.5％，收率20％。
LCMS([M+H]+):878.2
1HNMR(400MHz,DMSO-d6)δ11.13(s,1H),8.39–8.21(m,2H),7.99(t,J＝5.7Hz,1H),7.82(dd,J＝13.9,6.6Hz,2H),7.50(d,J＝7.2Hz,1H),7.37(s,3H),7.32(d,J＝8.4Hz,2H),5.13(dd,J＝12.9,5.4Hz,1H),4.77(s,2H),3.15(d,J＝5.9Hz,2H),3.05(d,J＝5.9Hz,2H),3.01–2.83(m,1H),2.62(dd,J＝18.9,11.2Hz,3H),2.13(t,J＝7.4Hz,2H),2.03(dd,J＝25.3,10.3Hz,2H),1.85(dd,J＝15.2,7.4Hz,2H),1.50(d,J＝4.2Hz,6H),1.43(s,4H).
实施例A2-A45采用与实施例A1相似的操作，用与之相对应的试剂合成。
实施例A2
LCMS([M+H]+):820.2
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.53(d,J＝2.4Hz,1H),8.33–8.23(m,2H),7.87(t,J＝5.6Hz,1H),7.82(dd,J＝8.3,2.5Hz,1H),7.59–7.52(m,1H),7.45(t,J＝9.8Hz,1H),7.11(d,J＝8.6Hz,1H),7.01(d,J＝7.0Hz,1H),6.58(t,J＝5.9Hz,1H),5.05(dd,J＝12.8,5.4Hz,1H),3.31(s,2H),3.09(dd,J＝12.4,6.3Hz,2H),2.96–2.70(m,4H),2.62–2.53(m,2H),2.15(t,J＝7.4Hz,2H),2.10–1.90(m,4H),1.53(s,6H),1.47(d,J＝7.3Hz,2H).
实施例A3
LCMS([M+H]+):854.2
1HNMR(400MHz,DMSO-d6)δ11.13(s,1H),8.54(t,J＝5.4Hz,1H),8.30–8.22(m,2H),8.02(t,J＝5.7Hz,1H),7.81(dd,J＝8.4,7.4Hz,1H),7.75(t,J＝8.0Hz,1H),7.52(dd,J＝10.6,1.8Hz,1H),7.49(d,J＝7.2Hz,1H),7.37(m,2H),5.12(dd,J＝12.9,5.4Hz,1H),4.78(s,2H),3.27(d,J＝5.5Hz,2H),3.19(d,J＝5.7Hz,2H),2.95–2.83(m,1H),2.63–2.51(m,2H),2.06–1.96(m,1H),1.55(d,J＝1.7Hz,6H),1.52(m,4H).
实施例A4
LCMS([M+H]+):750.3
1HNMR(400MHz,DMSO-d6)δ11.18(s,1H),9.80(s,1H),8.54(d,J＝2.4Hz,1H),8.45(d,J＝8.4Hz,1H),8.32–8.25(m,2H),7.83(m,2H),7.63(d,J＝7.3Hz,1H),7.52(d,J＝8.2Hz,1H),5.15(dd,J＝12.8,5.3Hz,1H),2.97–2.81(m,4H),2.58(m,4H),2.08(m,2H),1.52(s,6H).
实施例A5
LCMS([M+H]+):835.3
1HNMR(400MHz,DMSOd6)δ11.12(s,1H),8.63(t,J＝5.6Hz,1H),8.26(s,2H),8.02(d,J＝5.8Hz,1H),7.98(d,J＝8.4Hz,2H),7.79(t,J＝7.9Hz,1H),7.52(d,J＝8.2Hz,2H),7.46(d,J＝7.2Hz,1H),7.36(d,J＝8.5Hz,1H),5.14–5.07(m,1H),4.76(s,2H),3.27(d,J＝6.0Hz,2H),3.17(t,J＝6.4Hz,2H),2.89–2.81(m,1H),2.62–2.49(m,2H),1.99(t,J＝7.6Hz,1H),1.51(d,J＝2.3Hz,10H).
实施例A6
LCMS([M+H]+):851.2
1HNMR(400MHz,DMSO-d6)δ11.13(s,1H),8.52(d,J＝2.4Hz,1H),8.33–8.23(m,2H),8.07(t,J＝5.6Hz,1H),7.92(t,J＝5.4Hz,1H),7.85–7.75(m,2H),7.47(dd,J＝11.8,7.8Hz,2H),7.39(d,J＝8.5Hz,1H),5.12(dd,J＝12.9,5.3Hz,1H),4.77(s,2H),3.24–3.17(m,2H),3.17–3.11(m,2H),2.81–2.74(m,2H),2.13(t,J＝7.4Hz,2H),2.06–1.86(m,6H),1.52(s,6H).
实施例A7
LCMS([M+H]+):605.2
1HNMR(400MHz,DMSO-d6)δ10.81(s,1H),8.53(d,J＝2.4Hz,1H),8.32–8.20(m,3H),7.82(dd,J＝8.3,2.5Hz,1H),7.49(d,J＝8.3Hz,1H),4.56(dd,J＝18.0,7.9Hz,1H),2.88–2.80(m,2H),2.77–2.68(m,1H),2.47(d,J＝3.3Hz,1H),2.23(t,J＝7.4Hz,2H),2.00–1.89(m,4H),1.53(s,6H).
实施例A8
LCMS([M+H]+):799.2
1HNMR(400MHz,DMSO-d6)δ11.14(s,1H),8.33(t,J＝5.7Hz,1H),8.29–8.22(m,2H),7.74(dd,J＝8.4,7.4Hz,1H),7.47(d,J＝7.2Hz,1H),7.42(dd,J＝11.7,2.0Hz,1H),7.39–7.32(m,2H),7.21(d,J＝8.8Hz,1H),5.12(dd,J＝12.8,5.4Hz,1H),4.84(s,2H),4.20(t,J＝5.4Hz,2H),3.60(d,J＝3.2Hz,2H),2.95–2.84(m,1H),2.60(d,J＝18.0Hz,1H),2.08–1.92(m,2H),1.52(s,6H).
实施例A9
LCMS([M+H]+):808.3
1HNMR(400MHz,DMSOd6)δ11.14(s,1H),8.68(t,J＝5.3Hz,1H),8.29(d,J＝5.2Hz,2H),8.20(t,J＝5.6Hz,1H),8.00–7.95(m,2H),7.77–7.72(m,1H),7.56–7.51(m,2H),7.45(dd,J＝7.2,2.7Hz,1H),7.37(d,J＝8.6Hz,1H),5.18–5.07(m,2H),4.80(s,2H),3.39(d,J＝7.8Hz,2H),2.87(d,J＝17.1Hz,2H),2.64–2.52(m,2H),2.06–1.98(m,1H),1.54(d,J＝2.0Hz,6H).
实施例A10
LCMS([M+H]+):879.3
1HNMR(400MHz,DMSO-d6)δ11.12(s,1H),8.51(d,J＝2.3Hz,1H),8.25(s,2H),7.97(t,J＝5.6Hz,1H),7.86–7.75(m,3H),7.46(t,J＝7.7Hz,2H),7.36(d,J＝8.5Hz,1H),5.10(dd,J＝12.9,5.4Hz,1H),4.75(s,2H),3.18–3.09(m,2H),3.06–2.98(m,2H),2.93–2.82(m,1H),2.78(s,2H),2.56(t,J＝13.3Hz,1H),2.13(s,2H),2.06(s,1H),2.04–1.98(m,1H),1.92(dt,J＝14.7,7.5Hz,2H),1.51(s,6H),1.40(s,4H).
实施例A11
LCMS([M+H]+):793.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.52(d,J＝2.3Hz,1H),8.33–8.24(m,2H),8.13(t,J＝5.4Hz,1H),7.80(dd,J＝8.2,2.4Hz,1H),7.61–7.53(m,1H),7.44(d,J＝8.3Hz,1H),7.19(d,J＝8.7Hz,1H),7.02(d,J＝7.0Hz,1H),6.75(t,J＝6.0Hz,1H),5.05(dd,J＝12.8,5.3Hz,1H),3.40-3.38(m,2H),3.26-3.25(m,2H),2.92–2.74(m,3H),2.59-2.55(m,2H),2.15(t,J＝7.3Hz,2H),2.01–1.88(m,3H),1.53(s,6H).
实施例A12
LCMS([M+H]+):852.2
1HNMR(400MHz,DMSO-d6)11.17–11.10(m,1H),8.36–8.23(m,2H),8.17–8.05(m,1H),8.05–7.90(m,1H),7.86–7.75(m,1H),7.64–7.54(m,2H),7.53–7.47(m,1H),7.41(q,J＝8.3Hz,3H),5.20–5.05(m,1H),4.86–4.69(m,2H),4.65–4.50(m,2H),4.04–3.90(m,2H),3.30–3.17(m,4H),2.59(ddd,J＝23.2,12.6,4.2Hz,2H),2.06–1.94(m,2H),1.57–1.47(m,6H).
实施例A13
LCMS([M+H]+):820.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.33–8.22(m,2H),7.86(d,J＝5.4Hz,1H),7.55(t,J＝7.8Hz,1H),7.34(dd,J＝21.9,8.2Hz,4H),7.10(d,J＝8.6Hz,1H),7.00(d,J＝7.0Hz,1H),6.56(d,J＝6.0Hz,1H),5.04(dd,J＝12.6,5.2Hz,1H),3.30(s,2H),3.09(d,J＝5.8Hz,2H),2.93–2.80(m,1H),2.60(dd,J＝20.9,12.9Hz,3H),2.12(t,J＝7.2Hz,2H),2.08–1.94(m,2H),1.91–1.76(m,2H),1.53(dd,J＝24.3,5.8Hz,10H).
实施例A14
LCMS([M+H]+):896.2
1HNMR(400MHz,DMSO-d6)δ11.15(s,1H),8.27(s,2H),8.00(t,J＝5.6Hz,1H),7.86(t,J＝5.3Hz,1H),7.81(t,J＝7.9Hz,1H),7.50–7.46(m,2H),7.40–7.30(m,2H),7.21(d,J＝7.8Hz,1H),5.12(dd,J＝12.9,5.3Hz,1H),4.77(s,2H),3.14(d,J＝5.7Hz,2H),3.03(d,J＝5.6Hz,2H),2.92–2.86(m,1H),2.68–2.55(m,3H),2.13(t,J＝7.3Hz,2H),2.07–1.93(m,2H),1.87–1.76(m,2H),1.52(s,6H),1.41(m,4H).
实施例A15
LCMS([M+H]+):865.2
1HNMR(400MHz,DMSO-d6)δ11.13(s,1H),8.53(d,J＝2.4Hz,1H),8.36–8.20(m,2H),8.11–7.96(m,1H),7.91–7.74(m,3H),7.49(t,J＝7.8Hz,2H),7.40(d,J＝8.5Hz,1H),5.12(dd,J＝12.9,5.4Hz,1H),4.79(s,2H),3.16(dd,J＝12.9,6.6Hz,2H),3.07(dd,J＝12.2,6.1Hz,2H),2.96–2.73(m,4H),2.66–2.52(m,2H),2.15(t,J＝7.3Hz,2H),2.10–1.90(m,4H),1.67–1.44(m,6H).
实施例A16
LCMS([M+H]+):835.2
1HNMR(400MHz,DMSO-d6)δ11.15(s,1H),8.81(d,J＝8.4Hz,1H),8.61(t,J＝5.6Hz,1H),8.28(s,2H),7.99–7.94(m,2H),7.85(dd,J＝8.5,7.3Hz,1H),7.60(d,J＝7.2Hz,1H),7.55–7.50(m,2H),5.16(dd,J＝13.0,5.4Hz,1H),3.41–3.36(m,2H),3.28(s,2H),2.89(td,J＝17.3,16.0,5.4Hz,1H),2.67–2.53(m,4H),2.10–1.95(m,2H),1.59(s,4H),1.54(d,J＝2.1Hz,6H).
实施例A17
LCMS([M+H]+):851.2
1HNMR(400MHz,)δ11.13(s,1H),8.52(d,J＝2.4Hz,1H),8.28(s,3H),8.10–7.71(m,3H),7.43(ddd,J＝10.6,7.1,3.0Hz,3H),5.13(dd,J＝12.9,5.3Hz,1H),4.72(s,2H),3.19(dt,J＝11.2,5.7Hz,4H),2.96–2.72(m,4H),2.70–2.53(m,2H),2.16(t,J＝7.4Hz,2H),2.08(s,4H),1.53(s,6H).
实施例A18
LCMS([M+H]+):877.2
1HNMR(400MHz,DMSO-d6)δ11.12(s,1H),8.55(s,1H),8.28(d,J＝5.1Hz,2H),7.86–7.74(m,2H),7.48(dd,J＝16.4,7.7Hz,2H),7.36(d,J＝8.5Hz,1H),5.21(s,2H),5.15–5.07(m,1H),3.58(s,2H),3.46(d,J＝12.7Hz,6H),2.93–2.83(m,3H),2.60(d,J＝17.2Hz,2H),2.45(s,2H),2.05–1.93(m,3H),1.55(s,6H).
实施例A19
LCMS([M+H]+):851.2
1HNMR(400MHz,DMSO-d6)δ11.13(s,1H),8.52(d,J＝2.4Hz,1H),8.31–8.23(m,2H),7.97(t,J＝5.7Hz,1H),7.88(t,J＝5.6Hz,1H),7.83–7.79(m,2H),7.48(t,J＝8.1Hz,2H),7.38(d,J＝8.5Hz,1H),5.12(dd,J＝12.9,5.3Hz,1H),4.77(s,2H),3.14(dd,J＝12.1,6.1Hz,2H),3.04(dd,J＝10.2,4.9Hz,4H),2.96–2.80(m,2H),2.56–2.54(m,2H),2.04–1.99(m,2H),1.52(s,6H),1.40–1.39(m,2H).
实施例A20
LCMS([M+H]+):837.2
1HNMR(400MHz,DMSO-d6)δ11.12(s,1H),8.52(d,J＝2.4Hz,1H),8.31–8.24(m,2H),8.06(t,J＝5.4Hz,1H),7.98(t,J＝5.4Hz,1H),7.84–7.76(m,2H),7.51–7.43(m,2H),7.39(d,J＝8.5Hz,1H),5.12(dd,J＝12.9,5.4Hz,1H),4.77(s,2H),3.22–3.10(m,4H),3.06–2.99(m,2H),2.94–2.81(m,2H),2.56–2.54(m,3H),2.03–1.99(m,3H),1.52(s,6H).
实施例A21
LCMS([M+H]+):915.2
1HNMR(400MHz,DMSO-d6)δ11.12(s,1H),8.66(d,J＝2.4Hz,1H),8.33–8.21(m,3H),8.12(d,J＝8.8Hz,4H),7.95(dd,J＝8.5,2.5Hz,1H),7.78(dd,J＝8.4,7.4Hz,1H),7.47(d,J＝7.2Hz,1H),7.38(d,J＝8.5Hz,1H),7.09(d,J＝8.9Hz,2H),5.10(dd,J＝12.9,5.4Hz,1H),4.77(s,2H),4.54(s,2H),3.27(m,4H),2.92–2.83(m,1H),2.62–2.51(m,2H),2.06–1.96(m,1H),1.58(s,6H).
实施例A22
LCMS([M+H]+):857.3
1HNMR(400MHz,DMSO-d6)δ11.15(s,1H),8.33–8.19(m,3H),7.84–7.74(m,3H),7.69(d,J＝8.8Hz,2H),7.51–7.44(m,3H),7.41(d,J＝8.5Hz,1H),7.07(d,J＝8.8Hz,2H),5.12(dd,J＝12.8,5.5Hz,1H),4.83(s,2H),4.11(t,J＝5.4Hz,2H),3.60–3.58(m,2H),2.95–287(m,1H),2.62–2.54(m,2H),2.10–1.94(m,2H),1.56(d,J＝2.8Hz,6H).
实施例A23
LCMS([M+H]+):858.3
1HNMR(400MHz,DMSO-d6)δ11.14(s,1H),8.66(d,J＝2.4Hz,1H),8.34–8.20(m,3H),8.14–8.07(m,3H),7.95(dd,J＝8.5,2.5Hz,1H),7.77(dd,J＝8.3,7.4Hz,1H),7.47(d,J＝7.2Hz,1H),7.41(d,J＝8.5Hz,1H),7.09(d,J＝8.9Hz,2H),5.11(dd,J＝12.8,5.4Hz,1H),4.83(s,2H),4.14(t,J＝5.4Hz,2H),3.64–3.55(m,2H),2.90(ddd,J＝16.3,13.8,5.1Hz,1H),2.66–2.51(m,2H),2.03(dd,J＝10.2,5.2Hz,1H),1.59(s,6H).
实施例A24
LCMS([M+H]+):849.3
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.43(d,J＝2.4Hz,1H),8.31–8.24(m,2H),8.12(m,1H),7.99(m,1H),7.80–7.70(m,2H),7.48(d,J＝7.3Hz,1H),7.43(d,J＝8.4Hz,1H),7.35(d,J＝8.6Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.74(s,2H),3.02–2.90(m,4H),2.90–2.83(m,1H),2.63–2.55(m,2H),2.14–2.06(m,1H),2.03–1.99(m,1H),1.69–1.64(m,1H),1.47(s,6H),1.33–1.24(m,2H).
实施例A25
LCMS([M+H]+):862.3
1HNMR(400MHz,DMSO-d6)δ11.12(s,1H),8.43(s,1H),8.30–8.22(m,2H),8.04(t,J＝5.8Hz,1H),7.87(m,1H),7.81–7.75(m,1H),7.72(dt,J＝8.4,2.7Hz,1H),7.49(d,J＝7.2Hz,1H),7.41(d,J＝8.4Hz,1H),7.36(d,J＝8.5Hz,1H),5.11(dd,J＝12.9,5.3Hz,1H),4.74(s,2H),3.06–2.82(m,5H),2.58(dd,J＝16.6,8.4Hz,3H),2.13(dd,J＝15.3,8.0Hz,1H),2.03–1.99(m,1H),1.67(m,1H),1.47(s,6H),1.39–1.27(m,3H).
实施例A26
LCMS([M+H]+):877.3
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.43(d,J＝2.3Hz,1H),8.30–8.22(m,2H),8.02(t,J＝5.7Hz,1H),7.92(t,J＝5.6Hz,1H),7.82–7.76(m,1H),7.76–7.71(m,1H),7.48(d,J＝7.2Hz,1H),7.42(d,J＝8.4Hz,1H),7.37(d,J＝8.5Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.75(s,2H),3.06(dd,J＝12.5,6.3Hz,2H),2.95–2.85(m,3H),2.63–2.52(m,3H),2.12(dd,J＝15.4,8.1Hz,1H),2.05–1.98(m,1H),1.69–1.65(m,1H),1.49(s,6H),1.32–1.27(m,3H),1.23–1.22(m,2H).
实施例A27
LCMS([M+H]+):872.3
1HNMR(400MHz,DMSO-d6)δ11.12(s,1H),8.27(d,J＝4.6Hz,2H),7.83(q,J＝8.1,7.4Hz,2H),7.57(d,J＝8.0Hz,2H),7.51(d,J＝7.3Hz,1H),7.42(t,J＝7.1Hz,3H),5.11(dd,J＝12.6,5.4Hz,1H),4.78(s,2H),3.28(d,J＝6.4Hz,3H),2.87(t,J＝14.3Hz,1H),2.74–2.62(m,3H),2.40(t,J＝6.3Hz,2H),2.24(s,2H),2.09–2.00(m,1H),1.92–1.80(m,2H),1.60(d,J＝12.1Hz,2H),1.52(s,6H).
实施例A28
LCMS([M+H]+):877.2
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.47(s,1H),8.31–8.24(m,2H),8.20(t,J＝5.1Hz,1H),7.98(t,J＝5.7Hz,1H),7.82–7.77(m,2H),7.63(d,J＝8.3Hz,1H),7.49(d,J＝7.2Hz,1H),7.38(d,J＝8.5Hz,1H),5.11(dd,J＝12.9,5.3Hz,1H),4.77(s,2H),3.18–3.11(m,2H),3.08(d,J＝5.8Hz,2H),2.93–2.83(m,1H),2.62–2.51(m,3H),2.23–2.17(m,1H),2.06–1.99(m,1H),1.52(s,6H),1.47–1.36(m,6H).
实施例A29
LCMS([M+H]+):849.2
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.47(s,1H),8.33–8.24(m,3H),8.12(m,1H),7.82–7.76(m,2H),7.63(d,J＝8.3Hz,1H),7.48(d,J＝7.2Hz,1H),7.38(d,J＝8.5Hz,1H),5.11(dd,J＝12.9,5.5Hz,1H),4.77(s,2H),3.20(s,4H),2.95–2.84(m,1H),2.61–2.54(m,3H),2.22–2.15(m,1H),2.06–1.98(m,1H),1.52(s,6H),1.40–1.38(m,2H).
实施例A30
LCMS([M+H]+):863.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.47(d,J＝2.3Hz,1H),8.31–8.25(m,2H),8.27–8.23(m,1H),8.01(t,J＝5.6Hz,1H),7.84–7.76(m,2H),7.63(d,J＝8.4Hz,1H),7.49(d,J＝7.2Hz,1H),7.39(d,J＝8.5Hz,1H),5.12(dd,J＝12.9,5.4Hz,1H),4.77(s,2H),3.20–3.06(m,4H),2.94–2.82(m,1H),2.63–2.52(m,3H),2.23–2.16(m,1H),2.05–1.99(m,1H),1.62–1.55(m,2H),1.52(s,6H),1.43–1.38(m,2H).
实施例A31
LCMS([M+H]+):814.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.65(d,J＝2.5Hz,1H),8.29(q,J＝8.4Hz,2H),8.12(d,J＝8.8Hz,3H),7.95(dd,J＝8.5,2.5Hz,1H),7.60–7.54(m,1H),7.14(dd,J＝13.8,8.8Hz,3H),7.03(d,J＝7.0Hz,1H),6.78(t,J＝5.8Hz,1H),5.06(dd,J＝12.9,5.5Hz,1H),4.17(t,J＝5.8Hz,2H),3.53(d,J＝6.0Hz,2H),2.88(dd,J＝22.5,8.8Hz,1H),2.63–2.52(m,3H),2.13–2.05(m,2H),1.58(s,6H).
实施例A32
LCMS([M+H]+):842.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.66(d,J＝2.4Hz,1H),8.30(q,J＝8.5Hz,2H),8.12(dd,J＝8.8,2.4Hz,3H),7.95(dd,J＝8.5,2.5Hz,1H),7.62–7.56(m,1H),7.15–7.00(m,4H),6.59(t,J＝5.8Hz,1H),5.06(dd,J＝12.8,5.3Hz,1H),4.08(t,J＝6.3Hz,2H),2.95–2.83(m,1H),2.64–2.51(m,3H),2.21–1.95(m,2H),1.86–1.76(m,2H),1.67(dd,J＝14.4,7.0Hz,2H),1.59(s,6H),1.54(d,J＝6.9Hz,2H).
实施例A33
LCMS([M+H]+):912.3
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.27(d,J＝4.2Hz,2H),7.77(dd,J＝8.5,7.3Hz,1H),7.57(d,J＝8.0Hz,2H),7.47–7.39(m,3H),7.32(d,J＝8.6Hz,1H),5.21–5.06(m,3H),4.34(d,J＝12.1Hz,1H),3.84(s,1H),3.04(t,J＝12.7Hz,2H),2.96–2.82(m,2H),2.78(s,1H),2.68–2.52(m,4H),2.39(s,1H),2.14–1.56(m,9H),1.51(d,J＝1.9Hz,7H).
实施例A34
LCMS([M+H]+):885.3
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.77(d,J＝2.0Hz,1H),8.65(m,1H),8.27(m,6H),8.07(dd,J＝8.5,2.4Hz,1H),7.96(d,J＝8.4Hz,2H),7.81–7.74(m,1H),7.43(dd,J＝22.6,7.9Hz,2H),7.29–7.02(m,1H),5.09(m,1H),4.81(m,2H),3.39(m,4H),2.95–2.82(m,2H),2.08–1.93(m,2H),1.61(s,6H).
实施例A35
LCMS([M+H]+):876.3
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.67(d,J＝2.5Hz,1H),8.34–8.23(m,3H),8.17(d,J＝8.5Hz,1H),8.06–7.92(m,3H),7.75(dd,J＝8.5,7.3Hz,1H),7.47(d,J＝7.2Hz,1H),7.39(d,J＝8.5Hz,1H),7.33(t,J＝8.8Hz,1H),5.09(dd,J＝12.9,5.4Hz,1H),4.83(s,2H),4.22(t,J＝5.5Hz,2H),3.61(t,J＝5.7Hz,2H),2.88(ddd,J＝17.4,14.0,5.3Hz,1H),2.57(td,J＝13.9,3.9Hz,2H),2.01(ddd,J＝14.8,6.5,2.3Hz,1H),1.59(s,6H).
实施例A36
LCMS([M+H]+):883.3
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.71(d,J＝2.4Hz,1H),8.51(d,J＝2.3Hz,1H),8.45(dd,J＝8.9,2.4Hz,1H),8.32–8.23(m,4H),8.03(dd,J＝8.5,2.5Hz,1H),7.76(dd,J＝8.5,7.3Hz,1H),7.48–7.38(m,3H),5.08(dd,J＝12.9,5.4Hz,1H),4.83(s,2H),4.33(t,J＝5.5Hz,2H),3.63(q,J＝5.6Hz,2H),2.87(ddd,J＝17.3,14.0,5.5Hz,1H),2.63–2.51(m,2H),1.59(s,6H).
实施例A37
LCMS([M+H]+):898.3
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.67(m,1H),8.29(m,2H),8.13(d,J＝8.1Hz,3H),7.96(d,J＝7.9Hz,1H),7.79(t,J＝7.6Hz,1H),7.47(d,J＝6.6Hz,1H),7.37(d,J＝8.4Hz,1H),7.16(d,J＝7.9Hz,2H),5.23(m,2H),5.11(m,1H),4.79(m,1H),3.79(m,3H),2.88(m,1H),2.66–2.51(m,4H),2.05(m,3H),1.78(m,1H),1.59(s,6H).
实施例A38
LCMS([M+H]+):858.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.65(d,J＝2.5Hz,1H),8.48(t,J＝5.6Hz,1H),8.29(q,J＝8.5Hz,2H),8.11(d,J＝8.9Hz,3H),7.95(dd,J＝8.5,2.5Hz,1H),7.84(d,J＝8.3Hz,1H),7.46(d,J＝2.2Hz,1H),7.39(dd,J＝8.3,2.3Hz,1H),7.07(d,J＝8.9Hz,2H),5.11(dd,J＝12.8,5.4Hz,1H),4.78(s,2H),4.13(t,J＝5.5Hz,2H),3.61–3.52(m,2H),2.93–2.80(m,1H),2.57(dd,J＝21.7,6.7Hz,2H),2.08–1.97(m,1H),1.58(s,6H).
实施例A39
LCMS([M+H]+):894.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.63(s,1H),8.32–8.25(m,3H),8.16(dd,J＝11.9,1.9Hz,1H),7.84(m,2H),7.75(m,1H),7.47(d,J＝7.2Hz,1H),7.38(dd,J＝16.1,8.8Hz,2H),5.08(m,1H),4.83(s,2H),4.24(m,2H),3.62(m,2H),2.88(m,1H),2.62–2.51(m,2H),2.03(m,1H),1.61(brs,6H).
实施例A40
LCMS([M+H]+):894.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.63(s,1H),8.51(t,J＝5.7Hz,1H),8.32–8.24(m,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.89–7.80(m,3H),7.45(d,J＝2.2Hz,1H),7.42–7.32(m,2H),5.10(m,J＝12.9,5.4Hz,1H),4.78(s,2H),4.23(m,2H),3.59(m,2H),2.88(m,1H),2.63–2.51(m,2H),2.06–1.97(m,1H),1.61(s,6H).
实施例A41
LCMS([M+H]+):893.2
1HNMR(400MHz,DMSO-d6)δ11.09(s,1H),8.63(s,1H),8.38(t,J＝5.8Hz,1H),8.29(s,2H),8.17(d,J＝11.9Hz,1H),7.87(d,J＝13.8Hz,1H),7.76(d,J＝8.0Hz,1H),7.61–7.56(m,1H),7.24–7.17(m,2H),7.02(d,J＝6.9Hz,1H),6.75(s,1H),5.05(dd,J＝13.0,5.4Hz,1H),4.70(s,2H),3.43(s,2H),3.39(d,J＝4.8Hz,2H),2.88(s,1H),2.00(d,J＝7.6Hz,3H),1.62(s,6H).
实施例A42
LCMS([M+H]+):934.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.64(s,1H),8.28(d,J＝3.3Hz,2H),8.17(dd,J＝11.8,1.9Hz,1H),7.86(dd,J＝12.4,9.9Hz,3H),7.48(dd,J＝16.3,5.5Hz,2H),7.36(dd,J＝8.3,2.3Hz,1H),5.18(s,2H),5.12(dd,J＝12.9,5.4Hz,1H),4.83(s,1H),3.78(d,J＝54.3Hz,2H),3.41(s,2H),2.87(d,J＝11.5Hz,1H),2.61(dd,J＝31.3,14.5Hz,2H),2.12–1.94(m,4H),1.81(s,1H),1.61(s,6H).
实施例A43
LCMS([M+H]+):934.3
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.64(s,1H),8.28(s,2H),8.17(dd,J＝11.8,1.9Hz,1H),7.86(t,J＝9.8Hz,2H),7.82–7.76(m,1H),7.48(dd,J＝17.1,8.1Hz,2H),7.37(d,J＝8.7Hz,1H),5.23(s,2H),5.10(dd,J＝12.8,5.4Hz,1H),4.83(s,1H),3.86(s,2H),3.40(s,2H),2.88(d,J＝11.3Hz,1H),2.70–2.56(m,2H),2.06–1.91(m,4H),1.81(s,1H),1.61(s,6H).
实施例A44
LCMS([M+H]+):884.3
1HNMR(400MHz,DMSO-d6)δ11.09(s,1H),8.66(s,1H),8.32-8.26(m,2H),8.15-8.12(m,3H),7.96(d,J＝8.3Hz,1H),7.78(t,J＝7.9Hz,1H),7.46(d,J＝7.3Hz,1H),7.39(d,J＝8.5Hz,2H),7.16–7.09(m,2H),5.30–5.00(m,4H),3.88–3.58(m,4H),2.93-2.86(m,1H),2.61–2.54(m,2H),2.32-2.27(m,1H),2.19–2.13(m,1H),2.04-2.03(m,1H),1.58(s,6H).
实施例A45
LCMS([M+H]+):911.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.76(d,J＝2.4Hz,1H),8.32–8.24(m,5H),8.06(dd,J＝8.4,2.4Hz,1H),7.80–7.76(m,1H),7.61(d,J＝8.3Hz,2H),7.46(d,J＝7.2Hz,1H),7.37(d,J＝8.7Hz,1H),5.22(s,2H),5.10(dd,J＝12.8,5.4Hz,1H),3.55(m,7H),2.89(t,J＝12.8Hz,1H),2.67-2.54(m,2H),2.04–1.99(m,1H),1.60(s,6H).
实施例A46
将中间体46-1(5.85g,0.03mol)，化合物46-2(5.4g,0.06mol)，TBAC(4.17g,0.015mol),依次加入到120mlDCM中，冷却至0℃后滴加60ml33％的NaOH溶液，室温反应过夜，反应结束后，200ml水洗，200mlDCM萃取，100ml饱和食盐水洗涤，无水硫酸钠干燥，旋干得粗品，柱层析PE:EA＝2:1-1:1得到4.08g无色油状中间体46-3，产率66.7％.
将中间体46-3(4.08g,0.02mmol)，TsCl(5.72g,0.03mol)，三乙胺(4.04g,0.04mol)，DMAP(244mg,0.002mol)依次加入到100mlDCM中，室温反应一小时，反应结束后，100ml水洗，100mlDCM萃取，100ml饱和食盐水洗涤，无水硫酸钠干燥，旋干上层析柱PE:EA＝20:1-10:1得到6g无色液体46-4,产率83.7％.
将中间体46-5(5.02g,0.029mol)，化合物46-6(4.83g,0.035mol)，Pd(dppf)Cl2(2.12g,0.0029mol)，Na2CO3(6.15g,0.058mol)加入到150ml二氧六环和50ml水中，N2保护下，90℃搅拌过夜，反应结束后过滤，用100ml水洗涤，200mlEA萃取2次，饱和食盐水100ml洗涤，无水硫酸钠干燥，旋干上层析柱DCM:MeOH＝100:1-50:1-20:1得到5.5g棕色固体中间体46-7，产率92.6％。
将中间体46-7(1.19g,9.6mmol)，中间体46-4(4.13g,11.52mmol)和碳酸钾(2.65g,19.2mmol)加入到20mlDMF中，100℃反应2小时，反应结束后，用100ml水洗涤，100mlEA萃取2次，饱和食盐水100ml洗涤2次，无水硫酸钠干燥，旋干上层析柱PE:EA＝5:1-2:1得到2g浅棕色油状物中间体46-8，产率56％.
将中间体46-8(2.01g,5.4mmol)，TMSCN(2.68g,27.0mmol)，ZnCl2(147mg,1.08mmol)依次加入到20ml的丙酮中，室温反应1小时，反应结束后，100ml水洗，100mlEA萃取，100ml饱和食盐水洗涤，无水硫酸钠干燥，旋干得到2.2g棕色油状物46-9，产率92.8％.
将中间体46-9(2.2g,5mmol)，化合物46-10(2.46g,10mmol)加入到20mlDMF中，室温搅拌过夜，加入20ml二氧六环和20ml6N的盐酸，90℃搅拌1小时，反应结束后，100ml水洗涤，100mlEA萃取2次，饱和食盐水洗涤，无水硫酸钠干燥，旋干上层析柱PE:EA＝5:1-2:1得到1.2g浅棕色中间体46-11，产率38％
将46-11(140mg，0.22mmol)，46-12(103mg，0.22mmol)，HATU(167mg，0.44mmol)，三乙胺(66mg，0.66mmol)依次加入到10mlDCM中，室温搅拌一小时，反应结束后，用20ml水洗涤，20mlDCM萃取，20ml饱和食盐水洗涤，无水硫酸钠干燥，旋蒸，上后制备板DCM:MeOH＝10:1,得到100mg，再上制备柱得到60mg白色固体A46，纯度98％，产率26％
LCMS([M+H]+):1043.2
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝9.7Hz,1H),8.68–8.57(m,2H),8.30(q,J＝8.5Hz,2H),8.10(dd,J＝8.7,4.1Hz,3H),7.95(dd,J＝8.5,2.4Hz,1H),7.47–7.36(m,5H),7.06(d,J＝8.9Hz,2H),5.17(d,J＝3.5Hz,1H),4.58(d,J＝9.6Hz,1H),4.50–4.33(m,3H),4.27(dd,J＝15.8,5.6Hz,1H),4.09(t,J＝6.2Hz,2H),3.96(s,2H),3.70–3.54(m,4H),2.44(d,J＝7.2Hz,3H),2.07(dd,J＝12.4,8.3Hz,1H),1.95–1.80(m,3H),1.75(dd,J＝13.9,6.2Hz,2H),1.59(s,6H),0.94(d,J＝6.9Hz,9H).
实施例A47-A142采用与实施例A1相似的操作，用与之相对应的试剂合成。
实施例A47
LCMS([M+H]+):1020.2
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.59–8.50(m,2H),8.32–8.24(m,2H),7.82(ddd,J＝14.0,13.5,7.5Hz,3H),7.42(dt,J＝16.1,8.3Hz,5H),5.13(d,J＝3.5Hz,1H),4.54(d,J＝9.4Hz,1H),4.43(dd,J＝15.7,7.2Hz,2H),4.34(s,1H),4.21(dd,J＝15.9,5.4Hz,1H),3.71–3.59(m,2H),3.01(dd,J＝13.1,6.3Hz,2H),2.83–2.74(m,2H),2.44(s,3H),2.29–2.20(m,1H),2.13(q,J＝7.7Hz,3H),1.92(dd,J＝14.8,7.9Hz,3H),1.53(s,6H),1.51–1.34(m,4H),1.28–1.17(m,3H),0.92(d,J＝7.9Hz,9H).
实施例A48
LCMS([M+H]+):971.2
1HNMR(400MHz,DMSO-d6)δ8.98(d,J＝5.3Hz,1H),8.66(d,J＝2.3Hz,1H),8.60(t,J＝6.1Hz,1H),8.29(q,J＝8.7Hz,2H),8.13(d,J＝8.9Hz,3H),7.98–7.89(m,2H),7.45–7.31(m,4H),7.10(d,J＝8.9Hz,2H),5.16(d,J＝3.5Hz,1H),4.79–4.69(m,2H),4.60(d,J＝9.4Hz,1H),4.48–4.33(m,3H),4.25(dd,J＝15.9,5.4Hz,1H),3.65(dd,J＝23.5,8.8Hz,2H),2.44(d,J＝6.2Hz,3H),1.99(ddd,J＝31.9,16.9,10.7Hz,3H),1.58(s,6H),0.93(d,J＝10.6Hz,9H).
实施例A49
LCMS([M+H]+):999.2
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝8.8Hz,1H),8.65(d,J＝2.4Hz,1H),8.56(t,J＝6.0Hz,1H),8.29(q,J＝8.5Hz,2H),8.09(dd,J＝17.2,8.8Hz,3H),7.99(d,J＝9.3Hz,1H),7.94(dd,J＝8.5,2.5Hz,1H),7.40(q,J＝8.4Hz,4H),7.07(d,J＝8.9Hz,2H),5.14(d,J＝3.5Hz,1H),4.57(d,J＝9.4Hz,1H),4.47–4.39(m,2H),4.36(s,1H),4.21(dd,J＝15.9,5.5Hz,1H),4.05(d,J＝2.2Hz,2H),3.67(s,2H),2.47–2.31(m,5H),2.07–1.87(m,4H),1.58(s,6H),0.93(d,J＝7.7Hz,9H).
实施例A50
LCMS([M+H]+):985.1
1HNMR(400MHz,DMSO-d6)δ8.94(s,1H),8.60(t,J＝6.0Hz,1H),8.27(d,J＝4.5Hz,2H),7.80(d,J＝9.7Hz,1H),7.55(d,J＝8.5Hz,2H),7.41(s,5H),5.15(d,J＝3.4Hz,1H),4.51(d,J＝9.7Hz,1H),4.44(t,J＝8.2Hz,1H),4.35(d,J＝5.8Hz,2H),4.30(d,J＝5.9Hz,1H),3.70–3.57(m,2H),3.04(d,J＝16.2Hz,1H),2.95(d,J＝16.0Hz,1H),2.74(s,3H),2.44(s,3H),2.35(d,J＝12.3Hz,2H),2.06(dd,J＝13.7,6.8Hz,1H),1.90(ddd,J＝12.8,8.9,4.4Hz,3H),1.51(s,7H),0.95(s,9H).
实施例A51
LCMS([M+H]+):1043.2
1HNMR(400MHz,DMSO-d6)δ9.01(d,J＝1.8Hz,1H),8.98–8.95(m,1H),8.63(t,J＝6.0Hz,1H),8.57(d,J＝2.0Hz,1H),8.33–8.25(m,2H),8.19(s,1H),7.72(d,J＝8.7Hz,2H),7.46–7.34(m,5H),7.07(d,J＝8.8Hz,2H),5.20(d,J＝3.3Hz,1H),4.56(d,J＝9.7Hz,1H),4.45(t,J＝8.3Hz,1H),4.41–4.35(m,2H),4.27(d,J＝5.4Hz,1H),4.07(t,J＝6.2Hz,2H),3.93(s,2H),3.66–3.62(m,2H),3.57–3.54(m,2H),2.42(s,3H),2.11–2.03(m,1H),2.00–1.99(m,1H),1.94–1.87(m,1H),1.83–1.81(m,2H),1.77–1.69(m,2H),1.60(d,J＝2.6Hz,6H),0.94(s,9H).
实施例A52
LCMS([M+H]+):1013.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝6.8Hz,1H),8.65(d,J＝2.4Hz,1H),8.56(t,J＝5.8Hz,1H),8.29(q,J＝8.5Hz,2H),8.11(d,J＝8.8Hz,3H),7.96–7.89(m,2H),7.40(q,J＝8.4Hz,4H),7.07(d,J＝8.9Hz,2H),5.13(d,J＝3.5Hz,1H),4.57(d,J＝9.3Hz,1H),4.48–4.39(m,2H),4.36(s,1H),4.21(dd,J＝15.9,5.5Hz,1H),4.06(t,J＝5.7Hz,2H),3.73–3.62(m,2H),2.44(d,J＝3.5Hz,3H),2.41–2.32(m,1H),2.23(dd,J＝14.0,6.9Hz,1H),2.04(dd,J＝19.1,6.1Hz,1H),1.95–1.86(m,1H),1.78–1.63(m,4H),1.58(s,6H),0.95(s,9H).
实施例A53
LCMS([M+H]+):1054.3
1HNMR(400MHz,DMSO-d6):8.91(s,1H),8.69(s,1H),8.10(d,J＝12Hz2H),7.96-7.87(m,4H),7.83(d,J＝8Hz2H),7.44-7.41(t,1H),7.34-7.36(t,4H),6.81(s,1H),6.37-6.39(d,J＝8Hz1H),4.72-4.76(t,1H),4.55-4.61(t,3H),4.33-4.38(m,1H),4.08-4.13(m,1H),3.62-3.65(m,1H),3.45-3.49(m,2H),2.42-2.49(m,5H),2.15-2.33(m,4H),1.61-1.67(m,10H),1.38-1.44(m,2H),0.97(s,9H).
实施例A54
LCMS([M+H]+):1085.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝6.7Hz,1H),8.66–8.58(m,2H),8.29(q,J＝8.5Hz,2H),8.10(dd,J＝8.7,1.9Hz,3H),7.94(dd,J＝8.5,2.5Hz,1H),7.46–7.37(m,5H),7.06(d,J＝8.9Hz,2H),5.27(s,1H),4.44(ddd,J＝32.8,16.1,7.3Hz,3H),4.28(dd,J＝15.7,5.8Hz,1H),4.09(t,J＝6.2Hz,2H),3.94(t,J＝7.4Hz,3H),3.84(dd,J＝11.7,4.1Hz,1H),3.55(t,J＝6.2Hz,2H),2.44(d,J＝5.8Hz,3H),2.26(dd,J＝13.6,7.8Hz,1H),2.12(ddd,J＝13.7,9.0,4.9Hz,1H),1.98(d,J＝13.4Hz,3H),1.82(dd,J＝14.0,6.2Hz,2H),1.78–1.69(m,2H),1.58(s,6H),1.35(s,1H),0.94(d,J＝8.2Hz,9H).
实施例A55
LCMS([M+H]+):1061.3
1HNMR(400MHz,DMSO-d6)δ8.97–(m,1H),8.67(d,J＝2.3Hz,1H),8.60(t,J＝6.0Hz,1H),8.34–8.24(m,2H),8.17(d,J＝8.5Hz,1H),8.03–7.93(m,3H),7.45–7.35(m,5H),7.29(t,J＝8.6Hz,1H),5.16(d,J＝3.5Hz,1H),4.56(d,J＝9.5Hz,1H),4.49–4.34(m,3H),4.28–4.23(m,1H),4.17(t,J＝6.2Hz,2H),3.96(d,J＝1.7Hz,2H),3.70–3.53(m,5H),2.44–2.42(m,3H),2.09–2.04(m,1H),1.93–1.83(m,3H),1.77–1.72(m,2H),1.58(s,6H),0.94–0.92(m,9H)
实施例A56
LCMS([M+H]+):1081.3
1HNMR(400MHz,DMSO-d6)δ8.97–8.95(m,1H),8.75(d,J＝2.4Hz,1H),8.62–8.43(m,3H),8.33–8.20(m,5H),8.4–8.00(m,3H),7.45–7.35(m,4H),5.19–5.12(m,1H),4.54(dd,J＝9.3,2.6Hz,1H),4.50–4.33(m,4H),4.29–4.20(m,1H),3.70–3.63(m,2H),2.89(m,1H),2.79–2.57(m,4H),2.43(s,3H),2.34–2.18(m,3H),2.04(m,1H),1.99–1.86(m,2H),1.82(m,1H),1.59(s,6H),0.94(d,J＝4.8Hz,9H).
实施例A57
LCMS([M+H]+):1068.2
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝8.2Hz,1H),8.70(d,J＝2.0Hz,1H),8.59(t,J＝6.1Hz,1H),8.50(d,J＝2.2Hz,1H),8.46(d,J＝8.9Hz,1H),8.27(dd,J＝17.1,7.1Hz,3H),8.02(dd,J＝8.5,2.3Hz,1H),7.44–7.35(m,6H),5.15(d,J＝3.4Hz,1H),4.56(d,J＝9.6Hz,1H),4.48–4.38(m,2H),4.36(d,J＝6.0Hz,4H),4.27(t,J＝6.1Hz,3H),3.96(d,J＝3.2Hz,2H),3.69–3.62(m,2H),3.59(t,J＝6.2Hz,5H),2.43(d,J＝6.7Hz,3H),2.03(dd,J＝22.7,10.5Hz,2H),1.88(d,J＝8.0Hz,6H),1.80–1.73(m,2H),1.58(s,6H),0.93(d,J＝7.9Hz,9H).
实施例A58
LCMS([M+H]+):1081.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝8.2Hz,1H),8.75(d,J＝2.5Hz,1H),8.59(t,J＝6.2Hz,1H),8.47(d,J＝9.5Hz,1H),8.30(q,J＝8.5Hz,2H),8.21(dd,J＝18.2,8.4Hz,3H),8.05(dd,J＝8.4,2.5Hz,1H),7.49(d,J＝8.2Hz,2H),7.44(d,J＝8.2Hz,2H),7.37(d,J＝8.3Hz,2H),5.32(t,J＝4.7Hz,1H),5.14(d,J＝3.4Hz,1H),4.56(d,J＝9.5Hz,1H),4.44(dd,J＝16.8,8.7Hz,2H),4.35(s,1H),4.21(dd,J＝15.9,5.5Hz,1H),3.64(dd,J＝23.6,8.3Hz,4H),2.65(d,J＝12.2Hz,3H),2.44(d,J＝8.5Hz,5H),2.28(d,J＝15.5Hz,1H),2.00(dd,J＝14.8,7.2Hz,3H),1.91(dd,J＝17.3,8.6Hz,1H),1.60(s,6H),1.45(s,1H),0.95(s,8H).
实施例A59
LCMS([M+H]+):1080.3
1HNMR(400MHz,DMSO-d6)δ8.99(s,1H),8.76(d,J＝2.3Hz,1H),8.60–8.54(m,2H),8.34–8.23(m,5H),8.06(dd,J＝8.5,2.4Hz,1H),8.01(d,J＝8.5Hz,2H),7.72(d,J＝9.3Hz,1H),7.41(q,J＝8.4Hz,4H),5.14(m,1H),4.52(m,1H),4.44(m,2H),4.36(m,1H),4.22(m,1H),3.69–3.61(m,2H),3.16(m,2H),2.45(s,3H),2.36(m,1H),2.07–1.99(m,1H),1.90(m,1H),1.80(m,3H),1.69(m,1H),1.61(s,6H),1.31(m,4H),0.93(m,,9H).
实施例A60
LCMS([M+H]+):1074.3
1HNMR(400MHz,DMSO-d6)δ9.25(t,J＝6.0Hz,1H),8.98(s,1H),8.76(d,J＝2.4Hz,1H),8.58(t,J＝6.0Hz,1H),8.31–8.26(m,5H),8.06(dd,J＝8.5,2.6Hz,3H),7.91(d,J＝9.1Hz,1H),7.85(d,J＝8.2Hz,2H),7.45–7.39(m,6H),5.15(d,J＝3.6Hz,1H),4.77(d,J＝9.1Hz,1H),4.56(d,J＝5.8Hz,2H),4.49–4.35(m,3H),4.24(dd,J＝15.9,5.5Hz,1H),3.73(d,J＝3.1Hz,2H),2.44(s,3H),2.06–1.88(m,2H),1.60(s,6H),1.03(s,9H).
实施例A61
LCMS([M+H]+):1135.3
1HNMR(400MHz,DMSO-d6):8.99(s,1H),8.76(s,1H),8.56(s,1H),8.21-8.31(m,5H),8.05(d,J＝8Hz1H),7.73-7.76(d,J＝12Hz1H),7.55(d,J＝8Hz2H),7.38-7.43(m,4H),5.14(s,1H),4.36-4.54(m,5H),4.21-4.24(m,1H),3.64(m,3H),3.06(s,2H),2.86(s,2H),2.45(s,3H),2.35(s,1H),2.02-2.14(m,4H),1.68-1.90(m,5H),1.58-1.60(m,6H),1.44-1.48(m,4H),0.94(s,9H).
实施例A62
LCMS([M+H]+):1111.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝9.9Hz,2H),8.60(t,J＝5.8Hz,1H),8.49(d,J＝1.8Hz,1H),8.27(d,J＝12.3Hz,2H),7.50(d,J＝8.5Hz,2H),7.46–7.35(m,5H),7.05(d,J＝8.7Hz,2H),5.17(s,1H),4.57(d,J＝9.6Hz,1H),4.50–4.33(m,3H),4.26(m,1H),4.09(m,2H),3.95(m,2H),3.69–3.54(m,5H),2.44(m,3H),2.00(m,3H),1.89–1.79(m,2H),1.80–1.70(m,2H),1.64(d,J＝7.1Hz,6H),1.24(m,2H),0.95(s,9H).
实施例A63
LCMS([M+H]+):1061.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝10.8Hz,1H),8.60(s,2H),8.29(d,J＝12.7Hz,2H),8.11(d,J＝11.7Hz,1H),7.96(d,J＝7.9Hz,2H),7.40(d,J＝7.7Hz,5H),7.09(d,J＝8.7Hz,2H),5.17(d,J＝3.1Hz,1H),4.57(d,J＝9.5Hz,1H),4.50–4.32(m,3H),4.26(dd,J＝15.7,5.4Hz,1H),4.09(t,J＝5.9Hz,2H),3.96(s,2H),3.70–3.51(m,4H),2.43(d,J＝7.2Hz,3H),2.07(t,J＝9.8Hz,1H),1.96–1.79(m,3H),1.79–1.69(m,2H),1.61(s,6H),0.94(s,9H).
实施例A64
LCMS([M+H]+):1054.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝7.5Hz,1H),8.67(d,J＝2.4Hz,1H),8.55(t,J＝6.0Hz,1H),8.29(q,J＝8.5Hz,2H),8.16–8.05(m,3H),8.01–7.93(m,2H),7.39(q,J＝8.3Hz,4H),6.99(dd,J＝30.6,8.8Hz,2H),5.17–5.09(m,1H),4.55(d,J＝9.4Hz,1H),4.47–4.38(m,2H),4.34(s,1H),4.31–4.16(m,3H),4.07–3.96(m,2H),3.66(dt,J＝16.6,7.2Hz,2H),3.13–2.99(m,2H),2.43(d,J＝6.5Hz,3H),2.36–2.26(m,1H),2.25–2.14(m,1H),2.02(d,J＝7.7Hz,1H),1.89(ddd,J＝40.5,20.4,16.0Hz,4H),1.58(s,6H),0.93(d,J＝9.0Hz,9H).
实施例A65
LCMS([M+H]+):1068.4
1HNMR(400MHz,DMSO-d6):8.95(s,1H),8.74-8.77(d,J＝12Hz1H),8.62-8.66(m,2H),8.26-8.33(m,2H),8.04-8.10(m,3H),7.96-7.94(d,J＝8Hz1H),7.39-7.47(m,4H),6.99-7.01(d,J＝8Hz2H),5.16(s,1H),4.19-4.59(m,6H),3.62-3.68(m,2H),2.76-2.82(m,2H),2.61(s,1H),2.44(m,4H),2.27-2.35(m,3H),1.92-2.05(m,4H),2.02-2.14(m,4H),1.74-1.80(m,2H),1.59(s,6H),1.23(s,1H),0.97(s,9H).
实施例A66
LCMS([M+H]+):1057.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝10.1Hz,1H),8.65(d,J＝2.3Hz,1H),8.47(t,J＝5.9Hz,1H),8.33–8.24(m,2H),8.10(t,J＝9.1Hz,3H),7.94(dd,J＝8.5,2.4Hz,1H),7.39(s,4H),7.06(t,J＝9.9Hz,2H),5.15(dd,J＝11.0,3.5Hz,1H),5.06(s,1H),4.33(dt,J＝14.5,8.1Hz,4H),4.23(d,J＝12.2Hz,1H),4.09(t,J＝6.2Hz,2H),3.62(dd,J＝10.6,4.3Hz,1H),3.53(dt,J＝12.1,6.0Hz,2H),3.03–2.92(m,3H),2.43(d,J＝5.8Hz,3H),2.07–1.98(m,1H),1.94–1.78(m,3H),1.71(dd,J＝14.2,6.3Hz,2H),1.58(s,6H),1.08–0.88(m,9H).
实施例A67
LCMS([M+H]+):1146.3
1HNMR(400MHz,DMSO-d6)δ8.97–8.96(m,1H),8.69(d,J＝2.4,1H),8.59(t,J＝5.9Hz,1H),8.32–8.24(m,2H),8.17–8.12(m,3H),8.00(dd,J＝8.5,2.5Hz,1H),7.39–7.18(m,12H),5.15(d,J＝3.5Hz,1H),4.92(s,2H),4.51(d,J＝9.6Hz,1H),4.44(t,J＝8.2Hz,1H),4.40–4.34(m,2H),4.26(dd,J＝15.9,5.7Hz,1H),3.85(s,2H),3.65–3.57(m,2H),3.42(m,2H),2.41(s,3H),2.25(m,2H),2.08–2.02(m,1H),1.92–1.87(m,1H),1.84–1.78(m,2H),1.56(s,6H),0.86(s,9H).
实施例A68
LCMS([M+H]+):1042.3
1HNMR(400MHz,DMSO-d6)δ8.99(s,1H),8.58(d,J＝2.6Hz,2H),8.30(q,J＝8.6Hz,2H),8.04–7.95(m,3H),7.85(t,J＝7.8Hz,2H),7.40(d,J＝2.7Hz,4H),6.77(d,J＝8.9Hz,2H),5.33(m,1H),5.16(m,1H),4.57(m,1H),4.45(m,3H),4.41–4.34(m,2H),4.26(m,2H),4.244.04(m,2H),3.66(m,2H),3.60(m,2H),2.45(s,3H),2.04–1.99(m,2H),1.58(s,6H),1.53–1.43(m,4H),0.91(d,J＝11.8Hz,9H).
实施例A69
LCMS([M+H]+):1067.4
1HNMR(400MHz,DMSO-d6)δ8.99–8.94(m,1H),8.70(d,J＝2.4Hz,1H),8.59(t,J＝5.6Hz,1H),8.32–8.26(m,2H),8.17(d,J＝8.3Hz,1H),8.08(d,J＝7.2Hz,2H),7.99(d,J＝8.2Hz,1H),7.78(d,J＝9.2Hz,1H),7.41–7.38(m,6H),5.15(d,J＝3.4Hz,1H),4.51(d,J＝9.6Hz,1H),4.45–4.36(m,3H),4.30–4.25(m,1H),3.66(m,2H),3.60(m,2H),2.82(m,6H),2.54(m,4H),2.45(m,3H),2.09–1.83(m,4H),1.59(s,6H),0.94(m,9H).
实施例A70
LCMS([M+H]+):1079.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝10.8Hz,1H),8.66–8.57(m,2H),8.33–8.26(m,2H),8.16(dd,J＝11.9,1.8Hz,1H),7.83(d,J＝10.6Hz,2H),7.46–7.31(m,6H),5.17(d,J＝3.5Hz,1H),4.57(d,J＝9.6Hz,1H),4.49–4.33(m,3H),4.32–4.16(m,3H),4.01–3.90(m,2H),3.63(ddd,J＝27.9,11.5,4.8Hz,4H),2.44(d,J＝7.4Hz,3H),2.07(dd,J＝12.5,7.3Hz,1H),1.95–1.83(m,3H),1.76(dd,J＝14.0,6.1Hz,2H),1.61(s,6H),0.94(d,J＝7.0Hz,9H).
实施例A71
LCMS([M+H]+):1015.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.92(m,1H),8.63–8.60(m,2H),8.32–8.26(m,2H),8.13–8.03(m,3H),7.93(dd,J＝8.5,2.5Hz,1H),7.51(d,J＝9.5Hz,1H),7.40(dd,J＝19.6,8.4Hz,4H),7.15(d,J＝8.9Hz,2H),5.17(d,J＝3.6Hz,1H),4.61(d,J＝9.6Hz,1H),4.48–4.39(m,2H),4.36(m,1H),4.29–4.21(m,3H),4.07(s,2H),3.89–3.88(m,2H),3.71–3.66(m,1H),3.63–3.60(m,1H),2.39(s,3H),2.10–1.87(m,2H),1.57(s,6H),0.96(s,9H).
实施例A72
LCMS([M+H]+):1047.3
1HNMR(400MHz,DMSO-d6)δ8.95(s,1H),8.67(d,J＝2.5Hz,1H),8.59(t,J＝6.0Hz,1H),8.32–8.25(m,2H),8.15(d,J＝8.5Hz,1H),7.97(dt,J＝8.5,2.3Hz,3H),7.45(d,J＝9.5Hz,1H),7.38(d,J＝1.7Hz,4H),7.36–7.31(m,1H),5.16(d,J＝3.5Hz,1H),4.57(d,J＝9.5Hz,1H),4.46(t,J＝8.2Hz,1H),4.38(dd,J＝15.8,6.0Hz,2H),4.29(d,J＝5.7Hz,1H),4.24(t,J＝6.4Hz,2H),3.98(d,J＝1.5Hz,2H),3.70–3.59(m,4H),2.42(s,3H),2.11–2.03(m,3H),1.90(ddd,J＝13.0,8.9,4.5Hz,1H),1.58(s,6H),0.94(s,9H).
实施例A73
LCMS([M+H]+):1058.3
1HNMR(400MHz,DMSO-d6):8.96(s,1H),8.65-8.66(d,J＝4Hz1H),8.60-8.61(m,1H),8.27-8.31(m,2H),8.09-8.11(m,3H),7.93-7.96(m,1H),7.37-7.44(m,5H),7.04-7.06(d,J＝8Hz2H),5.16-5.17(d,J＝4Hz1H),4.56-4.58(d,J＝8Hz2H),4.36-4.44(m,5H),4.24-4.28(m,2H),4.04-4.07(m,2H),3.94(s,2H),3.60-3.68(m,3H),3.51-3.54(m,3H),2.45(s,3H),2.0-2.07(m,6H),1.77-1.79(m,3H),1.63-1.65(m,3H),1.53-1.58(m,3H),1.24(s,6),0.95(s,9H).
实施例A74
LCMS([M+H]+):1129.2
1HNMR(400MHz,DMSO-d6)δ8.99(t,J＝3.0Hz,1H),8.95(m,1H),8.60(t,J＝6.0Hz,1H),8.53(d,J＝2.1Hz,1H),8.32–8.24(m,2H),7.40(m,6H),7.32(m,2H),5.16(m,1H),4.57(m,1H),4.46(m,1H),4.39(m,2H),4.26(m,1H),4.18(m,2H),3.97(m,2H),3.71–3.62(m,2H),3.58(m,2H),2.44(s,3H),2.10–1.93(m,2H),1.92–1.84(m,2H),1.76(m,2H),1.64(d,J＝7.1Hz,6H),0.95(s,9H).
实施例A75
LCMS([M+H]+):1136.3
1HNMR(400MHz,DMSO-d6)δ9.02(d,J＝1.9Hz,1H),8.95(m,1H),8.60(t,J＝6.0Hz,1H),8.56(d,J＝2.1Hz,1H),8.31–8.24(m,2H),7.91(d,J＝2.2Hz,1H),7.88–7.81(m,1H),7.46–7.37(m,6H),5.17(d,J＝3.5Hz,1H),4.57(m,1H),4.46(m,1H),4.39(m,2H),4.32–4.24(m,3H),3.97(m,2H),3.71–3.63(m,2H),3.60(m,2H),2.44(m,3H),2.11–2.03(m,1H),1.91(m,3H),1.79(m,2H),1.64(d,J＝7.7Hz,6H),0.94(d,J＝7.0Hz,9H).
实施例A76
LCMS([M+H]+):1059.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝8.3Hz,1H),8.65(d,J＝2.4Hz,1H),8.58(t,J＝6.0Hz,1H),8.29(q,J＝8.5Hz,2H),8.09(dd,J＝8.8,2.3Hz,3H),7.94(dd,J＝8.5,2.5Hz,1H),7.48–7.35(m,5H),7.08(t,J＝10.5Hz,2H),5.15(d,J＝3.5Hz,1H),4.57(d,J＝9.6Hz,1H),4.45(t,J＝8.2Hz,1H),4.38(dd,J＝15.9,6.3Hz,2H),4.31–4.16(m,3H),3.97(d,J＝15.2Hz,2H),3.82(dd,J＝8.8,4.3Hz,2H),3.72–3.58(m,6H),2.43(d,J＝8.5Hz,3H),2.11–1.85(m,3H),1.58(s,6H),0.93(d,J＝8.2Hz,9H).
实施例A77
LCMS([M+H]+):1097.3
1HNMR(400MHz,DMSO-d6)δ8.95(d,J＝15.1Hz,1H),8.66(s,1H),8.60(t,J＝5.9Hz,1H),8.27(s,2H),8.22(dd,J＝11.8,1.9Hz,1H),7.78–7.70(m,2H),7.45–7.34(m,5H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.48–4.32(m,4H),4.25(dd,J＝12.5,6.3Hz,2H),3.94(s,2H),3.65(dd,J＝12.9,9.3Hz,2H),3.55(t,J＝6.3Hz,2H),2.43(d,J＝10.2Hz,3H),2.10–1.86(m,4H),1.78(ddd,J＝19.5,13.8,7.0Hz,4H),1.61(s,6H),0.92(d,J＝8.4Hz,9H).
实施例A78
LCMS([M+H]+):1086.3
1HNMR(400MHz,DMSO-d6):8.95(s,1H),8.66(s,1H),8.59-8.62(m,1H),8.29-8.30(m,5H),8.20-8.23(m,1H),7.40-7.43(m,6H),5.16-5.17(d,J＝4Hz1H),4.56-4.57(d,J＝8Hz1H),4.36-4.44(m,2H),4.29-4.31(m,2H),4.24-4.28(m,3H),3.97(s,2H),3.58-3.67(m,5H),2.43(s,3H),1.99-2.06(m,2H),1.89-1.92(m,4H),1.77-1.79(m,2H),1.62(s,6H),0.94(s,9H).
实施例A79
LCMS([M+H]+):1147.3
1HNMR(400MHz,DMSO-d6)δ9.01(d,J＝2.1Hz,1H),8.94(s,1H),8.60(t,J＝6.0Hz,1H),8.57(d,J＝2.2Hz,1H),8.28(s,2H),7.46–7.31(m,7H),5.15(d,J＝3.6Hz,1H),4.56(d,J＝9.6Hz,1H),4.49–4.32(m,3H),4.29–4.21(m,3H),3.95(s,2H),3.70–3.59(m,2H),3.56(t,J＝6.3Hz,2H),2.42(s,3H),2.06(dd,J＝13.1,7.7Hz,1H),1.90(ddd,J＝13.1,8.8,4.5Hz,1H),1.85–1.72(m,4H),1.63(d,J＝7.5Hz,6H),0.94(s,9H).
实施例A80
LCMS([M+H]+):1066.3
1HNMR(400MHz,DMSO-d6)δ8.97–8.95(m,1H),8.66(d,J＝2.5Hz,1H),8.56(t,J＝6.0Hz,1H),8.34–8.24(m,2H),8.22–8.06(m,5H),7.95(dd,J＝8.5,2.5Hz,1H),7.39(q,J＝8.4Hz,4H),7.18(d,J＝8.9Hz,2H),5.21(s,2H),5.17(d,J＝3.5Hz,1H),4.67–4.50(m,3H),4.47–4.39(m,2H),4.36(s,1H),4.21(dd,J＝15.8,5.5Hz,1H),3.66–3.65(m,2H),2.98–2.92(m,1H),2.83–2.73(m,1H),2.43(s,3H),2.08–2.00(m,1H),1.90–1.87(m,1H),1.58(s,6H),0.87(s,9H).
实施例A81
LCMS([M+H]+):1080.1
1HNMR(400MHz,DMSO-d6)δ8.97–8.96(m,1H),8.66(d,J＝2.5Hz,1H),8.56(t,J＝6.0Hz,1H),8.34–8.23(m,3H),8.13(d,J＝9.0Hz,3H),8.03–7.92(m,2H),7.40(q,J＝8.4Hz,4H),7.19(d,J＝9.0Hz,2H),5.23(m,2H),5.14(d,J＝3.6Hz,1H),4.54(d,J＝9.3Hz,1H),4.45–4.36(m,5H),4.21(dd,J＝15.9,5.5Hz,1H),3.70–3.61(m,2H),2.44–2.43(m,3H),2.33–2.17(m,2H),2.07–2.04(m,3H),1.93–1.87(m,1H),1.58(s,6H),0.93(s,9H).
实施例A82
LCMS([M+H]+):1033.3
1HNMR(400MHz,DMSO-d6):8.95(s,1H),8.68(s,1H),8.57-8.60(m,1H),8.26-8.32(m,2H),8.15-8.17(d,J＝8Hz1H),7.97-8.02(m,3H),7.34-7.40(m,6H),5.16(s,1H),4.57-4.60(d,J＝12Hz1H),4.22-4.35(m,6H),4.05-4.09(m,1H),3.9-3.92(m,2H),3.61-3.70(m,3H),2.43(s,3H),1.88-2.06(m,4H),1.6(s,6H),1.77-1.79(m,2H),1.62(s,6H),0.94(s,9H).
实施例A83
LCMS([M+H]+):1077.3
1HNMR(400MHz,DMSO-d6)δ9.00–8.97(m,1H),8.71(d,J＝2.3Hz,1H),8.61(t,J＝6.0Hz,1H),8.35–8.29(m,2H),8.25(d,J＝2.2Hz,1H),8.21(d,J＝8.5Hz,1H),8.13(dd,J＝8.7,2.2Hz,1H),8.01(dd,J＝8.5,2.5Hz,1H),7.48–7.38(m,5H),7.30(d,J＝8.9Hz,1H),5.18(d,J＝3.5Hz,1H),4.60(d,J＝9.6Hz,1H),4.52–4.36(m,3H),4.29(dd,J＝15.8,5.8Hz,1H),4.22(t,J＝6.2Hz,2H),4.04–3.92(m,2H),3.72–3.60(m,4H),2.47–2.45(m,3H),2.14–1.98(m,1H),1.97–1.87(m,3H),1.83–1.78(m,2H),1.61(s,6H),0.97(s,9H).
实施例A84
LCMS([M+H]+):1111.3
1HNMR(400MHz,DMSO-d6):δ8.94(s,1H),8.73–8.68(m,1H),8.58(t,J＝6.0Hz,1H),8.39(d,J＝5.9Hz,2H),8.34–8.20(m,3H),8.01(dd,J＝8.5,2.5Hz,1H),7.46–7.33(m,6H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.51–4.20(m,6H),3.95(d,J＝1.7Hz,2H),3.72–3.59(m,2H),3.57(t,J＝6.3Hz,2H),2.42(s,3H),2.14–1.67(m,6H),1.59(s,6H),0.94(s,9H).
实施例A85
LCMS([M+H]+):1077.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.69(t,J＝7.4Hz,1H),8.63–8.56(m,1H),8.30(s,2H),8.17(t,J＝8.4Hz,1H),8.08–7.93(m,3H),7.47(d,J＝9.6Hz,1H),7.41(s,4H),7.33(q,J＝8.3Hz,1H),5.17(t,J＝10.1Hz,1H),4.59(t,J＝9.3Hz,1H),4.48(q,J＝8.1Hz,1H),4.44–4.35(m,2H),4.31(s,3H),4.02(s,2H),3.92–3.79(m,2H),3.70(s,6H),2.45(s,3H),2.14–2.04(m,1H),1.93(tt,J＝15.1,7.6Hz,1H),1.61(s,6H),0.96(d,J＝7.7Hz,9H).
实施例A86
LCMS([M+H]+):1053.3
1HNMR(400MHz,DMSO-d6)δ8.99–8.98(m,1H),8.70(d,J＝2.5Hz,1H),8.59(t,J＝6.1Hz,1H),8.34–8.24(m,2H),8.16(d,J＝8.5Hz,1H),8.10(d,J＝8.3Hz,2H),7.99(dd,J＝8.5,2.5Hz,1H),7.78(d,J＝9.6Hz,1H),7.49–7.37(m,6H),5.14(d,J＝3.4Hz,1H),4.49(d,J＝9.7Hz,1H),4.46–4.33(m,3H),4.27(dd,J＝15.7,5.7Hz,1H),3.69–3.52(m,6H),2.99(dd,J＝41.9,16.1Hz,2H),2.52(m,3H),2.46–2.44(m,6H),2.06–1.85(m,2H),1.59(s,6H),0.94(s,9H).
实施例A87
LCMS([M+H]+)：1070.3
1HNMR(400MHz,DMSO-d6)δ8.92(s,1H),8.66(s,1H),8.59(t,J＝6.2Hz,1H),8.28(s,2H),8.22(d,J＝11.7Hz,1H),7.73(d,J＝9.3Hz,2H),7.45–7.33(m,5H),4.57(d,J＝9.6Hz,1H),4.40(t,J＝17.8Hz,5H),4.24–4.19(m,1H),4.04(s,2H),3.85(s,2H),3.66(s,2H),2.42(d,J＝16.6Hz,4H),2.08–1.96(m,3H),1.61(s,6H),0.91(d,J＝8.9Hz,8H).
实施例A88
LCMS([M+H]+):1028.3
1HNMR(400MHz,DMSO-d6)δ8.89(s,1H),8.54(dd,J＝11.8,5.8Hz,2H),8.22(s,2H),8.13(dd,J＝9.7,1.9Hz,1H),7.48(d,J＝9.0Hz,1H),7.32(d,J＝10.3Hz,7H),5.09(d,J＝3.5Hz,1H),4.51(d,J＝9.6Hz,1H),4.39(t,J＝8.2Hz,1H),4.32(dd,J＝15.8,6.2Hz,2H),4.20(dd,J＝15.7,5.7Hz,1H),4.11(t,J＝6.2Hz,2H),3.93–3.83(m,2H),3.57(ddd,J＝26.4,11.6,4.9Hz,4H),2.37(s,3H),2.04–1.95(m,1H),1.88–1.74(m,3H),1.70(dd,J＝13.9,6.1Hz,2H),1.54(s,6H),0.88(s,9H).
实施例A89
LCMS([M+H]+):1093.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.63(s,1H),8.60(t,J＝6.0Hz,1H),8.28(s,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.86–7.80(m,2H),7.39(s,6H),5.16(d,J＝3.5Hz,1H),4.57(d,J＝9.6Hz,1H),4.49–4.39(m,1H),4.37(d,J＝6.1Hz,2H),4.26(dd,J＝15.8,5.7Hz,1H),4.15(t,J＝6.4Hz,2H),3.95(d,J＝1.7Hz,2H),3.66(dt,J＝21.8,7.3Hz,2H),3.53(t,J＝6.3Hz,2H),2.43(s,3H),2.09–2.03(m,1H),1.90(ddd,J＝19.8,10.0,5.6Hz,1H),1.86(s,2H),1.69–1.63(m,2H),1.61(s,6H),1.54(dd,J＝15.0,8.0Hz,2H),0.95(s,9H).
实施例A90
LCMS([M+H]+):1095.3
1HNMR(400MHz,DMSO-d6)δ8.97–8.95(m,1H),8.62(s,1H),8.58(t,J＝6.0Hz,1H),8.31–8.26(m,2H),8.15(dd,J＝11.9,1.9Hz,1H),7.85–7.81(m,2H),7.46–7.30(m,6H),5.15(d,J＝3.6Hz,1H),4.57(d,J＝9.6Hz,1H),4.47–4.36(m,3H),4.32–4.23(m,3H),4.03–3.95(m,2H),3.87-3.82(m,2H),3.69–3.63(m,6H),2.44-2.42(m,3H),2.09-2.04(m,1H),1.90(ddd,J＝12.9,8.8,4.5Hz,1H),1.61-1.55(m,6H),0.94-0.92(m,9H).
实施例A91
LCMS([M+H]+):1051.3
1HNMR(400MHz,DMSO-d6)δ8.95(s,1H),8.63(s,1H),8.59(t,J＝6.0Hz,1H),8.29(s,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.87–7.79(m,2H),7.47(t,J＝6.9Hz,1H),7.40(d,J＝4.2Hz,5H),5.16(s,1H),4.59(d,J＝9.6Hz,1H),4.49–4.39(m,2H),4.38–4.33(m,3H),4.24(dd,J＝15.9,5.5Hz,1H),4.10(s,2H),3.96–3.88(m,2H),3.69(dd,J＝10.6,3.8Hz,1H),3.63(d,J＝10.9Hz,1H),2.43(s,3H),2.10–2.02(m,1H),1.92(ddd,J＝12.9,8.8,4.5Hz,1H),1.62(s,6H),0.94(s,9H).
实施例A92
LCMS([M+H]+):1083.2
1HNMR(400MHz,DMSO-d6)δ8.95(m,2H),8.61(t,J＝6.0Hz,1H),8.48(d,J＝2.2Hz,1H),8.30–8.24(m,2H),7.49(m,3H),7.39(m,4H),7.14(d,J＝8.8Hz,2H),5.16(m,1H),4.61(m,1H),4.45(m,2H),4.41–4.34(m,2H),4.26–4.22(m,2H),4.08(m,2H),3.88(m,2H),3.71–3.67(m,1H),3.63(m,1H),2.39(s,3H),2.04(m,1H),1.94–1.88(m,1H),1.63(d,J＝7.0Hz,6H),0.95(d,J＝7.6Hz,9H).
实施例A93
LCMS([M+H]+):1127.2
1HNMR(400MHz,DMSO-d6)δ8.99–8.93(m,2H),8.58(t,J＝5.9Hz,1H),8.49(d,J＝2.2Hz,1H),8.31–8.23(m,2H),7.50(d,J＝8.6Hz,2H),7.45(d,J＝9.6Hz,1H),7.47–7.36(m,5H),7.07(t,J＝10.6Hz,2H),5.15(d,J＝3.6Hz,1H),4.57(d,J＝9.6Hz,1H),4.45(t,J＝8.1Hz,1H),4.38(dd,J＝15.8,6.2Hz,2H),4.25(dd,J＝15.7,5.7Hz,1H),4.20(dd,J＝9.9,5.2Hz,2H),3.98(d,J＝15.7Hz,2H),3.87–3.79(m,2H),3.71–3.58(m,6H),2.43(d,J＝7.2Hz,3H),2.06(dd,J＝13.5,7.1Hz,1H),1.90(ddd,J＝12.9,8.8,4.4Hz,1H),1.63(d,J＝7.0Hz,6H),0.93(d,J＝7.0Hz,9H).
实施例A94
LCMS([M+H]+):1079.3
1HNMR(400MHz,DMSO-d6)δ8.98-8.95(m,1H),8.66(s,1H),8.59(t,J＝6.0Hz,1H),8.31–8.26(m,2H),8.17(dd,J＝10.2,1.8Hz,1H),7.59(t,J＝8.5Hz,1H),7.43–7.37(m,5H),7.01–6.94(m,2H),5.16(d,J＝3.5Hz,1H),4.57(d,J＝9.6Hz,1H),4.45(t,J＝8.3Hz,1H),4.41-4.36(m,2H),4.26(dd,J＝15.7,5.6Hz,1H),4.11(t,J＝6.2Hz,2H),4.00–3.90(m,2H),3.69-3.60(m,2H),3.56(t,J＝6.2Hz,2H),2.45-2.43(m,3H),2.09–2.04(m,1H),1.94–1.88(m,1H),1.87–1.81(m,2H),1.76-1.71(m,2H),1.62(s,6H),0.94-0.92(d,J＝6.4Hz,9H).
实施例A95
LCMS([M+H]+)：1129.2
1HNMR(400MHz,DMSO-d6)δ9.02(s,1H),8.95(s,1H),8.60(s,1H),8.55(s,2H),8.28(s,2H),7.45–7.32(m,6H),6.92(dd,J＝25.4,10.3Hz,2H),4.56(d,J＝9.5Hz,1H),4.48–4.34(m,3H),4.26(dd,J＝15.6,5.3Hz,1H),4.09(d,J＝6.2Hz,2H),3.96(s,2H),3.64(d,J＝13.8Hz,2H),3.56(d,J＝6.1Hz,2H),2.44(d,J＝6.4Hz,3H),2.02(dd,J＝20.8,7.9Hz,2H),1.83(d,J＝7.6Hz,2H),1.74(d,J＝7.0Hz,2H),1.63(d,J＝7.9Hz,6H),0.94(s,9H).
实施例A96
LCMS([M+H]+):1116.2
1HNMR(400MHz,DMSO-d6)δ8.97-8.95(m,1H),8.63(s,1H),8.56(t,J＝6.0Hz,1H),8.30-8.26(m,3H),8.16(dd,J＝11.8,1.9Hz,1H),8.00(d,J＝9.3Hz,1H),7.90–7.81(m,2H),7.57(t,J＝8.8Hz,1H),7.39(q,J＝8.4Hz,4H),5.32-5.30(m,2H),4.54(d,J＝9.3Hz,1H),4.40-4.35(m,5H),4.24-4.18(m,1H),3.65(d,J＝10.2Hz,2H),2.43(d,J＝3.7Hz,3H),2.33–2.16(m,2H),2.09–2.00(m,3H),1.90(ddd,J＝12.9,8.6,4.6Hz,1H),1.61-1.55(m,6H),0.930.92(m,9H).
实施例A97
LCMS([M+H]+)：1111.3
1HNMR(400MHz,DMSO-d6)δ8.95(d,J＝11.5Hz,1H),8.66(s,1H),8.59(t,J＝5.7Hz,1H),8.27(s,2H),8.22(dd,J＝11.8,1.9Hz,1H),7.74(d,J＝9.3Hz,3H),7.44–7.33(m,5H),5.16(d,J＝3.5Hz,1H),4.55(d,J＝9.7Hz,1H),4.43(dd,J＝16.8,8.4Hz,2H),4.37(d,J＝6.6Hz,2H),4.22(t,J＝6.2Hz,2H),3.93(s,2H),3.65(d,J＝3.3Hz,2H),3.51(d,J＝2.6Hz,2H),2.43(d,J＝9.7Hz,3H),2.09–1.97(m,2H),1.78–1.71(m,2H),1.67–1.50(m,10H),0.92(d,J＝7.5Hz,9H).
实施例A98
LCMS([M+H]+):1044.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.65–8.55(m,3H),8.32–8.23(m,2H),8.19(dd,J＝9.5,2.4Hz,1H),8.02(d,J＝8.5Hz,1H),7.95(dd,J＝8.5,2.2Hz,1H),7.39(d,J＝9.9Hz,5H),6.51(d,J＝9.5Hz,1H),5.16(d,J＝3.4Hz,1H),4.55(d,J＝9.5Hz,1H),4.43(dd,J＝15.3,7.2Hz,1H),4.36(dd,J＝15.4,6.2Hz,2H),4.25(dd,J＝15.7,5.6Hz,1H),4.04(t,J＝6.8Hz,2H),3.99–3.86(m,2H),3.64(dt,J＝20.6,7.2Hz,2H),3.51(t,J＝6.2Hz,2H),2.43(s,3H),2.06(dd,J＝13.1,7.1Hz,1H),1.94–1.85(m,1H),1.83–1.71(m,2H),1.58(d,J＝16.3Hz,8H),0.90(d,J＝7.9Hz,9H).
实施例A99
LCMS([M+H]+):1113.3
1HNMR(400MHz,DMSO-d6)δ8.95(d,J＝12.2Hz,1H),8.66(s,1H),8.59(t,J＝5.9Hz,1H),8.29(d,J＝11.9Hz,2H),8.21(dd,J＝11.8,1.7Hz,1H),7.74(t,J＝7.6Hz,2H),7.45–7.33(m,5H),5.16(m,1H),4.56(m,1H),4.41(m,5H),4.24(m,1H),3.94(m,2H),3.83–3.74(m,2H),3.71–3.57(m,6H),2.43(m,3H),2.06(m,1H),1.95–1.86(m,1H),1.60(s,6H),0.92(d,J＝8.3Hz,9H).
实施例A100
LCMS([M+H]+):1044.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝11.6Hz,1H),8.92(d,J＝2.4Hz,1H),8.70(d,J＝2.4Hz,1H),8.60(t,J＝6.0Hz,1H),8.41(dd,J＝8.7,2.5Hz,1H),8.33–8.25(m,2H),8.19–8.15(m,1H),8.00(dd,J＝8.5,2.5Hz,1H),7.44–7.35(m,5H),6.92(d,J＝8.7Hz,1H),5.16(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.48–4.32(m,5H),4.25(dd,J＝15.8,5.6Hz,1H),4.00–3.89(m,2H),3.65(dt,J＝21.3,7.3Hz,2H),3.56(t,J＝6.4Hz,2H),2.43(d,J＝8.5Hz,3H),2.11–2.02(m,1H),1.91(ddd,J＝12.9,8.9,4.3Hz,1H),1.83(dd,J＝14.5,6.3Hz,2H),1.76–1.67(m,2H),1.58(s,6H),0.92(d,J＝7.0Hz,9H).
实施例A101
LCMS([M+H]+):1178.3
1HNMR(400MHz,DMSO-d6)δ9.00(d,J＝9.1Hz,1H),8.96(s,1H),8.59(dd,J＝15.5,9.3Hz,2H),8.31–8.25(m,2H),7.40(s,9H),5.16(d,J＝3.5Hz,1H),4.58(d,J＝9.6Hz,1H),4.46(t,J＝8.2Hz,1H),4.39(dd,J＝15.7,6.0Hz,2H),4.27(dd,J＝15.7,5.7Hz,1H),4.17(t,J＝6.2Hz,2H),4.00–3.92(m,2H),3.64(ddd,J＝26.2,11.7,5.0Hz,4H),2.44(s,3H),1.95–1.83(m,3H),1.80–1.72(m,2H),1.63(d,J＝9.8Hz,6H),0.95(s,9H).
实施例A102
LCMS([M+H]+)：1049.4
1HNMR(400MHz,DMSO-d6)δ10.81(s,1H),8.62(s,1H),8.31–8.24(m,2H),8.15(dd,J＝11.9,1.9Hz,1H),8.01(d,J＝8.3Hz,1H),7.85(d,J＝10.8Hz,2H),7.36(t,J＝8.7Hz,1H),4.67–4.55(m,1H),4.19(t,J＝6.3Hz,2H),3.93(s,2H),3.56(td,J＝9.3,3.1Hz,2H),2.74(ddd,J＝18.8,13.5,5.5Hz,1H),2.11–1.91(m,2H),1.90–1.83(m,2H),1.76(dd,J＝14.2,6.3Hz,2H),1.61(s,6H).
实施例A103
LCMS([M+H]+):1178.2
1HNMR(400MHz,DMSO-d6)δ9.00(s,1H),8.77(d,J＝2.3Hz,1H),8.65(t,J＝6.0Hz,1H),8.34(s,3H),8.10(dd,J＝8.5,2.5Hz,1H),8.03–7.95(m,2H),7.45(d,J＝2.3Hz,5H),5.20(d,J＝3.5Hz,1H),4.61(d,J＝9.6Hz,1H),4.54–4.39(m,3H),4.35–4.24(m,3H),4.04–3.93(m,2H),3.76–3.55(m,4H),2.48(s,3H),2.15–2.07(m,1H),1.95(ddd,J＝22.9,11.6,7.2Hz,1H),1.90–1.76(m,4H),1.64(s,6H),1.29(s,2H),0.99(s,9H).
实施例A104
LCMS([M+H]+)：1104.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝21.9Hz,1H),8.62(dt,J＝12.1,6.9Hz,3H),8.32–8.25(m,2H),8.16(dd,J＝11.8,1.9Hz,1H),7.86–7.78(m,2H),7.44(d,J＝8.3Hz,2H),7.37(dd,J＝11.7,8.8Hz,3H),5.15(s,1H),4.57(d,J＝9.5Hz,2H),4.50–4.41(m,2H),4.37(s,1H),4.22(dd,J＝15.9,5.3Hz,1H),3.67(dt,J＝21.4,7.5Hz,2H),2.76(d,J＝32.2Hz,2H),2.61(dd,J＝11.8,6.0Hz,1H),2.43(s,3H),2.41–2.24(m,4H),2.02(dd,J＝12.9,5.6Hz,4H),1.94–1.88(m,1H),1.78(dd,J＝21.9,9.1Hz,2H),1.62(s,6H),0.96(d,J＝6.4Hz,9H).
实施例A105
LCMS([M+H]+):1098.3
1HNMR(400MHz,DMSO-d6)δ8.97-8.97(m,1H),8.77(d,J＝2.4Hz,1H),8.55(t,J＝6.0Hz,1H),8.42(s,1H),8.33-8.26(m,3H),8091–8.04(m,3H),7.75-7.71(m,2H),7.40(q,J＝8.4Hz,4H),5.13(d,J＝3.5Hz,1H),4.51(d,J＝9.3Hz,1H),4.46–4.39(m,2H),4.35(s,1H),4.22(dd,J＝15.8,5.4Hz,1H),3.69-3.61(m,2H),3.14(t,J＝6.1Hz,2H),2.44(s,3H),2.38-2.33(m,1H),2.07–2.00(m,1H),1.94–1.86(m,1H),1.80(d,J＝11.2Hz,3H),1.69(d,J＝10.8Hz,1H),1.60-1.58(m,6H),1.51(s,1H),1.38–1.28(m,2H),1.05–0.88(m,11H).
实施例A106
LCMS([M+H]+):1035.3
1HNMR(400MHz,MeOD)δ8.87(s,1H),8.13–8.05(m,2H),8.01(d,J＝8.4Hz,1H),7.54(dd,J＝9.1,2.7Hz,1H),7.50–7.39(m,4H),6.90(m,1H),4.72(s,1H),4.64–4.50(m,3H),4.37(m,1H),4.08–3.94(m,2H),3.89(m,1H),3.82(m,1H),3.63(m,6H),2.66–2.58(m,4H),2.53–2.45(m,5H),2.30–2.22(m,1H),2.11(m,1H),1.72(m,4H),1.56(dd,J＝5.6,4.9Hz,6H),1.05(d,J＝9.6Hz,9H).
实施例A107
LCMS([M+H]+):1080.3
1HNMR(400MHz,DMSO-d6)δ8.98(d,J＝3.3Hz,1H),8.62(s,1H),8.58(t,J＝6.2Hz,1H),8.28(d,J＝3.2Hz,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.85(d,J＝10.9Hz,2H),7.46–7.33(m,5H),5.38(s,1H),4.68(d,J＝7.9Hz,1H),4.51(t,J＝8.3Hz,1H),4.40(dd,J＝15.8,6.3Hz,1H),4.27(dd,J＝15.8,5.7Hz,1H),4.19(t,J＝6.3Hz,2H),4.12(s,2H),3.96(d,J＝12.1Hz,1H),3.90(d,J＝7.9Hz,1H),3.75(dd,J＝12.2,4.0Hz,1H),3.54(t,J＝6.3Hz,2H),2.44(s,3H),2.27(d,J＝7.6Hz,1H),2.16–2.08(m,1H),2.04–1.95(m,1H),1.89–1.79(m,2H),1.74–1.66(m,2H),1.61(s,6H),0.89(d,J＝10.4Hz,9H).
实施例A108
LCMS([M+H]+):1143.3
1HNMR(400MHz,DMSO-d6)δ8.99(d,J＝2.0Hz,1H),8.97(s,1H),8.52(d,J＝2.1Hz,1H),8.44(d,J＝7.7Hz,1H),8.30–8.24(m,2H),7.48–7.30(m,8H),5.14(m,1H),4.90(m,1H),4.56(m,1H),4.47(m,1H),4.29(m,1H),4.19(m,2H),4.01–3.88(m,2H),3.65–3.53(m,4H),2.45(s,3H),2.11–2.03(m,1H),1.93–1.83(m,2H),1.82–1.71(m,3H),1.63(d,J＝7.2Hz,6H),1.36(d,J＝7.0Hz,3H),0.94(s,9H).
实施例A109
LCMS([M+H]+):1143.3
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.63(s,1H),8.44(d,J＝7.7Hz,1H),8.28(s,2H),8.20(dd,J＝9.7,1.9Hz,1H),7.57(d,J＝9.3Hz,1H),7.40(dt,J＝16.2,8.3Hz,8H),5.13(d,J＝3.5Hz,1H),4.89(dd,J＝14.3,7.2Hz,1H),4.56(d,J＝9.6Hz,1H),4.45(dd,J＝15.3,7.1Hz,1H),4.27(d,J＝17.5Hz,1H),4.19(s,2H),3.96(d,J＝1.3Hz,2H),3.59(d,J＝6.1Hz,4H),2.45(s,3H),2.05(dd,J＝20.1,11.5Hz,1H),1.86(dd,J＝13.7,6.2Hz,2H),1.77(dd,J＝13.1,7.7Hz,3H),1.61(s,6H),1.37(d,J＝7.0Hz,2H),0.94(s,9H).
实施例A110
LCMS([M+H]+)：1093.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.62(s,1H),8.43(d,J＝7.7Hz,1H),8.31–8.24(m,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.85(d,J＝11.0Hz,2H),7.38(dt,J＝23.4,6.5Hz,6H),5.13(d,J＝3.5Hz,1H),4.93–4.87(m,1H),4.54(d,J＝9.6Hz,1H),4.45(t,J＝8.1Hz,1H),4.28(s,1H),4.20(t,J＝6.3Hz,2H),3.96(t,J＝8.8Hz,2H),3.57(t,J＝6.2Hz,4H),2.45(s,3H),2.10–1.95(m,3H),1.91–1.83(m,2H),1.81–1.71(m,3H),1.61(s,6H),1.36(d,J＝7.0Hz,3H),0.93(s,9H).
实施例A111
LCMS([M+H]+):1062.3
1HNMR(400MHz,DMSO-d6)δ8.99(s,2H),8.97-8.95(m,1H),8.59(t,J＝5.9Hz,1H),8.31–8.23(m,3H),8.14(dd,J＝12.6,1.9Hz,1H),7.42–7.32(m,6H),5.16(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.45(t,J＝8.2Hz,1H),4.41-4.36(m,2H),4.26(dd,J＝15.9,5.6Hz,1H),4.20(t,J＝6.2Hz,2H),4.00–3.90(m,2H),3.66-3.55(m,4H),2.44-2.42(m,3H),2.11–2.02(m,1H),2.00–1.83(m,4H),1.76-1.72(m,2H),1.62(s,6H),0.93-0.92(m,9H).
实施例A112
LCMS([M+H]+)：1107.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.62(s,1H),8.42(d,J＝7.7Hz,1H),8.28(d,J＝3.3Hz,2H),8.15(dd,J＝11.9,1.9Hz,1H),7.85(d,J＝10.5Hz,2H),7.42(d,J＝8.3Hz,2H),7.39–7.30(m,4H),5.13(s,1H),4.94–4.84(m,1H),4.54(d,J＝9.6Hz,1H),4.45(t,J＝8.2Hz,1H),4.28(s,1H),4.17(t,J＝6.4Hz,2H),3.98–3.86(m,2H),3.64–3.48(m,4H),2.44(s,3H),2.10–2.02(m,1H),1.81(ddd,J＝17.4,11.1,5.4Hz,3H),1.66(dd,J＝14.1,7.2Hz,2H),1.60(s,6H),1.57–1.50(m,2H),1.35(d,J＝7.0Hz,3H),0.93(s,9H).
实施例A113
LCMS([M+H]+):1125.2
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.71(d,J＝2.4Hz,1H),8.47–8.40(m,3H),8.34–8.23(m,3H),8.01(dd,J＝8.5,2.5Hz,1H),7.45-7.41(m,3H),7.37–7.33(m,3H),5.14(d,J＝3.5Hz,1H),4.95–4.86(m,1H),4.54(d,J＝9.6Hz,1H),4.45(t,J＝8.2Hz,1H),4.28-4.24(m,3H),3.98–3.88(m,2H),3.59–3.55(m,4H),2.45(s,3H),2.10–2.02(m,1H),1.88-1.83(m,2H),1.77-1.74(m,3H),1.58(s,6H),1.36(d,J＝7.0Hz,3H),0.93(s,9H).
实施例A114
LCMS([M+H]+):1050.3
1HNMR(400MHz,DMSO-d6)δ9.01(d,J＝2.0Hz,1H),8.57(d,J＝2.1Hz,1H),8.52(t,J＝6.0Hz,1H),8.31–8.23(m,2H),7.43–7.33(m,3H),7.32–7.22(m,4H),7.17(dd,J＝11.1,4.3Hz,1H),5.14(m,1H),4.56(m,1H),4.43(m,1H),4.35(m,2H),4.30–4.17(m,3H),3.98–3.87(m,2H),3.69–3.53(m,4H),2.01(m,1H),1.83(m,5H),1.63(d,J＝7.6Hz,6H),0.93(d,J＝11.3Hz,9H).
实施例A115
LCMS([M+H]+):1161.2
1HNMR(400MHz,DMSO-d6)δ9.01(d,J＝2.0Hz,1H),8.97(s,1H),8.57(d,J＝2.1Hz,1H),8.43(d,J＝7.7Hz,1H),8.31–8.23(m,2H),7.47–7.41(m,2H),7.36(m,5H),5.13(m,1H),4.90(m,1H),4.54(d,J＝9.6Hz,1H),4.45(m,1H),4.26(m,3H),3.99–3.87(m,2H),3.57(m,4H),2.45(s,3H),2.09–2.00(m,1H),1.78(m,5H),1.63(d,J＝7.6Hz,6H),1.37(d,J＝7.0Hz,3H),0.93(s,9H).
实施例A116
LCMS([M+H]+):1093.3
1HNMR(400MHz,DMSO-d6)δ9.01(d,J＝1.9Hz,1H),8.58(m,2H),8.31–8.23(m,2H),7.90(s,1H),7.80(m,2H),7.42–7.32(m,5H),7.27(s,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.47–4.32(m,3H),4.27(m,3H),3.99–3.88(m,2H),3.70–3.53(m,4H),2.07–1.99(m,1H),1.93–1.70(m,5H),1.63(d,J＝7.7Hz,6H),0.93(d,J＝11.4Hz,9H).
实施例A117
LCMS([M+H]+)：1039.3
1HNMR(400MHz,DMSO-d6)δ8.59(dd,J＝13.7,7.7Hz,2H),8.32–8.25(m,2H),8.15(dd,J＝11.9,1.9Hz,1H),7.91(s,1H),7.88–7.81(m,2H),7.79(t,J＝6.4Hz,2H),7.40–7.31(m,4H),7.28(s,1H),5.15(s,1H),4.56(d,J＝9.6Hz,1H),4.46–4.32(m,3H),4.25(dd,J＝15.7,5.6Hz,1H),4.16(t,J＝6.4Hz,2H),3.99–3.89(m,2H),3.68–3.58(m,2H),3.52(t,J＝6.3Hz,2H),2.06–1.95(m,2H),1.92–1.78(m,3H),1.69–1.58(m,7H),1.53(dd,J＝15.1,8.0Hz,2H),0.93(d,J＝10.3Hz,9H).
实施例A118
LCMS([M+H]+)：996.3
1HNMR(400MHz,DMSO-d6)δ8.62(s,1H),8.51(t,J＝6.0Hz,1H),8.32–8.24(m,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.88–7.81(m,2H),7.39–7.23(m,6H),7.22–7.15(m,1H),5.14(s,1H),4.56(d,J＝9.6Hz,1H),4.43(t,J＝8.2Hz,1H),4.33(dd,J＝15.2,6.2Hz,2H),4.19(dt,J＝13.2,6.1Hz,3H),3.98–3.87(m,2H),3.69–3.57(m,2H),3.52(t,J＝6.3Hz,2H),2.07–1.95(m,2H),1.92–1.80(m,3H),1.70–1.49(m,10H),0.93(d,J＝10.6Hz,9H).
实施例A119
LCMS([M+H]+)：1025.3
1HNMR(400MHz,DMSO-d6)δ8.62(s,1H),8.59(t,J＝6.0Hz,1H),8.32–8.25(m,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.91(s,1H),7.88–7.82(m,2H),7.79(d,J＝8.3Hz,2H),7.37(dd,J＝18.8,9.2Hz,4H),7.28(s,1H),5.15(s,1H),4.56(d,J＝9.6Hz,1H),4.47–4.32(m,3H),4.30–4.17(m,3H),4.02–3.89(m,2H),3.70–3.61(m,2H),3.57(t,J＝6.3Hz,2H),2.02(dt,J＝14.4,9.8Hz,2H),1.92–1.82(m,3H),1.75(dd,J＝14.4,6.3Hz,2H),1.61(s,6H),0.93(d,J＝11.2Hz,9H).
实施例A120
LCMS([M+H]+)：982.4
1HNMR(400MHz,DMSO-d6)δ8.63(s,1H),8.51(t,J＝6.0Hz,1H),8.31–8.25(m,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.89–7.81(m,2H),7.37(dd,J＝16.6,9.1Hz,2H),7.32–7.23(m,4H),7.21–7.15(m,1H),5.14(d,J＝3.2Hz,1H),4.56(d,J＝9.6Hz,1H),4.43(t,J＝8.3Hz,1H),4.34(dd,J＝15.3,6.4Hz,2H),4.25–4.17(m,3H),4.00–3.91(m,2H),3.62(ddd,J＝23.4,11.7,5.1Hz,4H),2.03(dd,J＝15.2,10.1Hz,1H),1.92–1.82(m,3H),1.75(dd,J＝14.2,6.4Hz,2H),1.61(s,6H),0.93(d,J＝10.8Hz,9H).
实施例A121
LCMS([M+H]+):1014.3
1HNMR(400MHz,DMSO-d6)δ8.71(d,J＝2.4Hz,1H),8.53(t,J＝6.0Hz,1H),8.45–8.38(m,2H),8.33-8.24(m,3H),8.01(dd,J＝8.5,2.5Hz,1H),7.40(dd,J＝17.2,9.6Hz,2H),7.33–7.23(m,4H),7.19-7.15(m,1H),5.16(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.43(t,J＝8.2Hz,1H),4.35-4.31(m,2H),4.27-4.18(m,3H),4.00–3.88(m,2H),3.68-3.55(m,4H),2.07-2.01(m,1H),1.93–1.82(m,3H),1.78-1.73(m,2H),1.58(s,6H),0.94-0.91(m,9H).
实施例A122
LCMS([M+H]+):1057.3
1HNMR(400MHz,DMSO-d6)δ8.70(d,J＝2.4Hz,1H),8.59(t,J＝6.0Hz,1H),8.41(m,2H),8.34–8.22(m,3H),8.01(dd,J＝8.5,2.4Hz,1H),7.91(s,1H),7.83-7.78(m,2H),7.45–7.32(m,4H),7.28(s,1H),5.16(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.47–4.32(m,3H),4.30–4.22(m,3H),4.00–3.90(m,2H),3.69–3.54(m,4H),2.07–1.99(m,1H),1.93–1.81(m,3H),1.80–1.70(m,2H),1.58(s,6H),0.93(d,J＝11.2Hz,9H).
实施例A123
LCMS([M+H]+):1065.3
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.64(s,1H),8.43(d,J＝7.7Hz,1H),8.29(d,J＝3.5Hz,2H),8.17(dd,J＝11.9,1.8Hz,1H),7.88(d,J＝4.2Hz,2H),7.86(s,1H),7.50–7.22(m,7H),5.14(d,J＝3.5Hz,1H),4.95–4.86(m,1H),4.56(d,J＝9.5Hz,1H),4.45(t,J＝8.1Hz,1H),4.40–4.33(m,2H),4.29(s,1H),4.07(d,J＝17.5Hz,2H),3.93(d,J＝4.0Hz,2H),3.66–3.56(m,2H),2.45(s,3H),2.14–1.96(m,1H),1.78(ddd,J＝13.0,8.8,4.4Hz,1H),1.62(s,6H),1.37(d,J＝7.0Hz,1H),1.24(s,1H),0.94(s,9H).
实施例A124
LCMS([M+H]+):1111.3
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.67(s,1H),8.44(d,J＝7.7Hz,1H),8.28–8.22(m,3H),7.80-7.76(m,2H),7.43(d,J＝8.2Hz,2H),7.37–7.33(m,3H),5.14(d,J＝3.4Hz,1H),4.90(t,J＝7.2Hz,1H),4.54(d,J＝9.6Hz,1H),4.44(t,J＝8.2Hz,1H),4.28(t,J＝5.9Hz,3H),3.94–3.87(m,2H),3.62-3.54(m,4H),2.45(s,3H),2.08–2.03(m,1H),1.83–1.73(m,5H),1.61(s,6H),1.37(d,J＝7.0Hz,3H),0.92(s,9H).
实施例A125
LCMS([M+H]+):977.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.55(t,J＝6.1Hz,1H),8.50(d,J＝1.1Hz,1H),8.30–8.21(m,2H),8.12(dd,J＝9.5,1.9Hz,1H),7.90(d,J＝9.4Hz,1H),7.40(q,J＝8.4Hz,4H),5.12(d,J＝3.6Hz,1H),4.55(d,J＝9.4Hz,1H),4.47–4.38(m,2H),4.35(s,1H),4.21(dd,J＝15.9,5.5Hz,1H),3.66(d,J＝4.1Hz,2H),3.39(s,2H),2.58(t,J＝6.5Hz,2H),2.44(s,3H),2.35(dt,J＝14.1,7.1Hz,1H),2.19(dt,J＝14.0,7.0Hz,1H),2.02(dd,J＝17.4,9.7Hz,1H),1.94–1.86(m,1H),1.67(dd,J＝14.4,7.4Hz,2H),1.60(d,J＝6.7Hz,8H),0.93(d,J＝8.7Hz,9H).
实施例A126
LCMS([M+H]+):1058.3
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.95(d,J＝2.2Hz,1H),8.70(d,J＝2.1Hz,1H),8.49–8.40(m,2H),8.29(q,J＝8.5Hz,2H),8.19(d,J＝8.5Hz,1H),8.01(dd,J＝8.5,2.5Hz,1H),7.38(dt,J＝19.1,9.5Hz,5H),6.97(d,J＝8.8Hz,1H),5.13(d,J＝3.5Hz,1H),4.95–4.85(m,1H),4.54(d,J＝9.6Hz,1H),4.45(t,J＝8.2Hz,1H),4.38(t,J＝6.5Hz,2H),4.28(s,1H),4.00–3.87(m,2H),3.64–3.51(m,4H),2.45(s,3H),2.11–1.94(m,2H),1.87–1.69(m,5H),1.59(s,6H),1.37(d,J＝7.0Hz,3H),0.93(s,9H).
实施例A127
LCMS([M+H]+):990.3
1HNMR(400MHz,DMSO-d6)δ8.94(d,J＝2.4Hz,1H),8.70(d,J＝2.3Hz,1H),8.59(t,J＝6.0Hz,1H),8.44(dd,J＝8.7,2.5Hz,1H),8.29(q,J＝8.5Hz,2H),8.18(d,J＝8.5Hz,1H),8.00(dd,J＝8.5,2.5Hz,1H),7.91(s,1H),7.80(t,J＝9.7Hz,2H),7.37(dd,J＝12.0,9.0Hz,3H),7.28(s,1H),6.96(d,J＝8.8Hz,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.47–4.32(m,5H),4.26(dd,J＝16.1,5.7Hz,1H),4.01–3.89(m,2H),3.70–3.51(m,4H),2.09–2.01(m,1H),1.93–1.79(m,3H),1.73(dd,J＝14.4,6.3Hz,2H),1.58(s,6H),0.92(d,J＝10.7Hz,9H).
实施例A128
LCMS([M+H]+):947.3
1HNMR(400MHz,DMSO-d6)δ8.94(d,J＝2.3Hz,1H),8.70(d,J＝2.4Hz,1H),8.52(t,J＝6.0Hz,1H),8.44(dd,J＝8.7,2.5Hz,1H),8.29(q,J＝8.5Hz,2H),8.19(d,J＝8.6Hz,1H),8.00(dd,J＝8.5,2.5Hz,1H),7.38(d,J＝9.6Hz,1H),7.33–7.23(m,4H),7.18(t,J＝6.7Hz,1H),6.96(d,J＝8.7Hz,1H),5.14(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.43(t,J＝8.3Hz,1H),4.40–4.31(m,4H),4.21(dd,J＝15.5,5.6Hz,1H),4.00–3.87(m,2H),3.62(ddd,J＝27.3,11.7,5.1Hz,4H),2.03(dd,J＝20.1,12.9Hz,1H),1.92–1.79(m,3H),1.73(dd,J＝14.4,6.2Hz,2H),1.59(s,6H),0.92(d,J＝11.0Hz,9H).
实施例A129
LCMS([M+H]+):997.3
1HNMR(400MHz,DMSO-d6)δ8.63(s,1H),8.57(t,J＝6.0Hz,1H),8.32–8.24(m,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.91–7.82(m,3H),7.79(t,J＝6.5Hz,2H),7.47(d,J＝9.5Hz,1H),7.43–7.33(m,3H),7.27(s,1H),5.15(d,J＝3.6Hz,1H),4.57(d,J＝9.5Hz,1H),4.46–4.37(m,2H),4.37–4.31(m,3H),4.25(dd,J＝15.9,5.5Hz,1H),4.07(d,J＝19.9Hz,2H),3.95–3.87(m,2H),3.65(dt,J＝22.5,7.3Hz,2H),2.06–1.99(m,1H),1.88(ddd,J＝13.0,8.8,4.5Hz,1H),1.61(s,6H),0.93(d,J＝12.7Hz,9H).
实施例A130
LCMS([M+H]+):954.3
1HNMR(400MHz,DMSO-d6)δ8.66–8.60(m,1H),8.51(t,J＝6.0Hz,1H),8.33–8.24(m,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.92–7.81(m,2H),7.47(d,J＝9.5Hz,1H),7.40(t,J＝9.0Hz,1H),7.34–7.14(m,5H),5.15(d,J＝3.5Hz,1H),4.57(d,J＝9.6Hz,1H),4.44(dd,J＝13.9,5.7Hz,1H),4.39–4.31(m,4H),4.19(dd,J＝15.6,5.6Hz,1H),4.11–4.02(m,2H),3.95–3.87(m,2H),3.65(dt,J＝23.5,7.4Hz,2H),2.09–1.99(m,1H),1.88(ddd,J＝12.9,8.7,4.5Hz,1H),1.61(s,6H),0.92(d,J＝11.6Hz,9H).
实施例A131
LCMS([M+H]+):1075.3
1HNMR(400MHz,DMSO-d6)δ8.62(d,J＝0.9Hz,1H),8.59(t,J＝6.0Hz,1H),8.32–8.24(m,2H),8.19(dd,J＝9.7,1.9Hz,1H),7.91(s,1H),7.80(dd,J＝12.8,8.3Hz,2H),7.59–7.53(m,1H),7.44–7.32(m,5H),7.28(s,1H),5.15(d,J＝3.5Hz,1H),4.57(d,J＝9.6Hz,1H),4.47–4.32(m,3H),4.26(dd,J＝15.9,5.6Hz,1H),4.18(t,J＝6.2Hz,2H),4.01–3.89(m,2H),3.67(dd,J＝10.7,3.7Hz,1H),3.59(dd,J＝15.2,8.9Hz,3H),2.06(dd,J＝15.0,6.3Hz,1H),1.92–1.81(m,3H),1.80–1.71(m,2H),1.60(s,6H),0.93(d,J＝10.4Hz,9H).
实施例A132
LCMS([M+H]+):1032.3
1HNMR(400MHz,DMSO-d6)δ8.64–8.60(m,1H),8.52(t,J＝6.0Hz,1H),8.32–8.25(m,2H),8.19(dd,J＝9.7,1.9Hz,1H),7.58–7.53(m,1H),7.39(dd,J＝6.5,3.8Hz,3H),7.32–7.23(m,4H),7.20–7.13(m,1H),5.15(d,J＝3.5Hz,1H),4.57(d,J＝9.6Hz,1H),4.44(t,J＝8.2Hz,1H),4.34(dd,J＝15.4,6.3Hz,2H),4.24–4.14(m,3H),4.03–3.87(m,2H),3.62(ddd,J＝22.7,11.6,5.1Hz,4H),2.09–2.00(m,1H),1.88(tt,J＝12.2,5.9Hz,3H),1.76(dd,J＝14.2,6.2Hz,2H),1.61(s,6H),0.93(d,J＝10.7Hz,9H).
实施例A133
LCMS([M+H]+):1071.3
1HNMR(400MHz,DMSO-d6)δ8.99–8.90(m,1H),8.52(t,J＝8.4Hz,1H),8.31–8.24(m,2H),7.55(d,J＝8.4Hz,1H),7.42(dq,J＝10.9,8.4Hz,7H),7.27(d,J＝7.8Hz,1H),5.26–5.11(m,2H),4.57(d,J＝9.2Hz,1H),4.46(t,J＝8.3Hz,1H),4.28(s,1H),3.84(d,J＝46.3Hz,1H),3.58(dd,J＝22.1,10.4Hz,3H),3.24(d,J＝10.2Hz,1H),3.06(d,J＝9.7Hz,1H),2.97–2.76(m,3H),2.44(d,J＝5.4Hz,3H),2.02(dd,J＝15.9,8.5Hz,1H),1.76(s,3H),1.52(s,6H),1.49–1.41(m,1H),1.36(d,J＝12.3Hz,3H),1.17(d,J＝27.1Hz,2H),0.96(d,J＝5.8Hz,9H).
实施例A134
LCMS([M+H]+):1040.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.58(t,J＝6.0Hz,1H),8.54(d,J＝2.4Hz,1H),8.44(t,J＝5.9Hz,1H),8.33–8.23(m,2H),7.91(d,J＝9.1Hz,1H),7.87–7.77(m,3H),7.48(d,J＝8.3Hz,1H),7.44–7.36(m,4H),7.33(d,J＝8.2Hz,2H),5.15(d,J＝3.5Hz,1H),4.76(d,J＝9.1Hz,1H),4.48–4.17(m,6H),3.73(s,2H),2.85(dd,J＝19.4,11.8Hz,2H),2.44(d,J＝4.5Hz,3H),2.26(t,J＝7.3Hz,2H),2.11–1.91(m,4H),1.53(s,6H),1.01(d,J＝11.4Hz,9H).
实施例A135
LCMS([M+H]+):1032.3
1HNMR(400MHz,DMSO-d6)δ8.99-8.97(m,1H),8.65-8.58(m,2H),8.33–8.22(m,2H),7.89(s,1H),7.77(s,1H),7.45–7.34(m,6H),6.80(s,1H),5.20(d,J＝3.2Hz,1H),4.56(d,J＝9.5Hz,1H),4.51–4.32(m,4H),4.30–4.19(m,2H),3.99–3.90(m,2H),3.69–3.58(m,2H),3.55–3.47(m,3H),2.90–2.67(m,5H),2.45–2.41(m,4H),2.10-2.05(m,1H),1.90(td,J＝8.6,4.2Hz,1H),1.62(s,2H),1.54(s,6H),0.95-0.93(m,9H).
实施例A136
LCMS([M+H]+):1176.3
1HNMR(400MHz,DMSO-d6)δ8.98(d,J＝1.8Hz,1H),8.63(brs,1H),8.51(m,1H),8.32–8.24(m,2H),8.16(dd,J＝11.9,1.8Hz,1H),7.84(m,2H),7.48–7.37(m,5H),7.27(dd,J＝9.2,2.5Hz,1H),5.26–5.17(m,1H),5.14(m,1H),4.72(m,1H),4.58(m,1H),4.46(m,1H),4.29(m,1H),3.83(m,1H),3.74–3.41(m,3H),3.22(m,2H),2.96–2.83(m,2H),2.45(d,J＝5.5Hz,3H),2.04(m,1H),2.00–1.88(m,2H),1.83–1.73(m,1H),1.61(s,6H),1.53–1.43(m,1H),1.40–1.31(m,2H),1.21(m,2H),0.96(d,J＝6.5Hz,9H).
实施例A137
LCMS([M+H]+):906.4
1HNMR(400MHz,DMSO-d6)δ8.63(brs,1H),8.31–8.25(m,2H),8.16(dd,J＝11.9,1.8Hz,1H),7.90–7.81(m,3H),7.41–7.28(m,2H),5.12(d,J＝3.5Hz,1H),4.54(d,J＝9.6Hz,1H),4.32(m,2H),4.19(m,2H),3.92(m,2H),3.63(m,1H),3.60–3.52(m,3H),2.55(d,J＝8.0Hz,3H),1.97(m,1H),1.83(m,3H),1.79–1.70(m,2H),1.61(s,6H),0.91(d,J＝15.4Hz,9H).
实施例A138
LCMS([M+H]+):1062.2
1HNMR(400MHz,DMSO-d6)δ12.45(s,1H),8.94(d,J＝7.6Hz,1H),8.62(s,1H),8.34–8.23(m,2H),8.15(dd,J＝11.9,1.8Hz,1H),7.84(d,J＝10.8Hz,2H),7.55(s,2H),7.39–7.29(m,2H),7.23(brs,1H),5.28(d,J＝3.7Hz,1H),5.21(t,J＝7.8Hz,1H),4.60(d,J＝9.6Hz,1H),4.53(brs,1H),4.17(m,2H),4.04–3.86(m,3H),3.76–3.68(m,1H),3.55(m,2H),2.45(s,3H),2.24(m,2H),1.84(m,2H),1.78–1.67(m,2H),1.60(s,6H),0.89(d,J＝27.7Hz,9H).
实施例A139
LCMS([M+H]+):1114.3
1HNMR(400MHz,DMSO-d6)δ9.12(s,1H),8.98(s,1H),8.57(d,J＝7.9Hz,1H),8.26(s,2H),8.21(s,1H),7.63(s,1H),7.58(d,J＝8.0Hz,1H),7.44(d,J＝6.8Hz,3H),7.37(d,J＝7.7Hz,2H),7.20(s,1H),5.23(s,2H),5.16(d,J＝3.4Hz,1H),4.57(d,J＝9.2Hz,1H),4.44(t,J＝8.2Hz,1H),4.28(s,1H),3.58(s,2H),3.23–2.93(m,6H),2.66(s,2H),2.45(d,J＝6.9Hz,3H),2.19–1.93(m,6H),1.72(s,3H),1.52(s,6H),1.37(d,J＝10.2Hz,2H),0.97(d,J＝5.3Hz,9H).
实施例A140
LCMS([M+H]+):1046.3
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.59–8.50(m,2H),8.33–8.22(m,2H),7.84–7.75(m,2H),7.70(d,J＝9.3Hz,1H),7.47(d,J＝8.3Hz,1H),7.40(q,J＝8.4Hz,4H),5.12(d,J＝3.4Hz,1H),4.50(d,J＝9.3Hz,1H),4.43(dd,J＝15.3,7.0Hz,2H),4.34(s,1H),4.21(dd,J＝15.9,5.4Hz,1H),3.64(dt,J＝18.7,7.4Hz,2H),2.90(t,J＝6.1Hz,2H),2.84–2.75(m,2H),2.44(s,3H),2.31(t,J＝11.9Hz,1H),2.16(t,J＝7.3Hz,2H),2.06–1.85(m,4H),1.81–1.61(m,5H),1.53(s,6H),1.31(dd,J＝23.9,11.4Hz,4H),0.91(d,J＝9.5Hz,9H).
实施例A141
LCMS([M+H]+):1034.3
1HNMR(400MHz,DMSO-d6)δ8.99-8.97(m,1H),8.60(t,J＝5.9Hz,1H),8.56(s,1H),8.32–8.24(m,2H),7.85(d,J＝8.0Hz,1H),7.50(d,J＝8.2Hz,1H),7.42-7.39(m,5H),5.17(d,J＝3.3Hz,1H),4.56(d,J＝9.5Hz,1H),4.44(t,J＝8.4Hz,1H),4.35(m,2H),4.25(dd,J＝15.5,5.7Hz,1H),3.94(s,2H),3.67–3.59(m,2H),3.51(m,2H),2.49-2.43(m,3H),2.06-1.87(m,9H),1.61(s,5H),1.52(s,6H),1.23(s,3H),0.95-0.93(m,9H).
实施例A142
LCMS([M+H]+):1063.3
1HNMR(400MHz,DMSO-d6)δ8.98-8.95(m,1H),8.62(s,1H),8.45-8.39(m,1H),8.31-8.28(m,2H),8.16(d,J＝11.9Hz,1H),7.867.81(m,2H),7.42–7.33(m,5H),5.19–5.05(m,1H),4.78–4.41(m,1H),4.48–4.23(m,4H),4.19–3.64(m,4H),3.67–3.41(m,6H),2.44–2.41(m,3H),2.04–2.01(m,2H),1.93–1.81(m,5H),1.73–1.61(m,9H).
以下实施例A143-A362中A155,A156,A179,A180,A181,A182,A187-A195,A197,A199,A200采用与实施例A1相似的操作，用与之相对应的试剂合成；其余采用与实施例A46相似的操作，用与之相对应的试剂合成。
实施例A143
LCMS([M+H]+):1149.4
1HNMR(400MHz,DMSO-d6)δ8.98(d,J＝7.4Hz,1H),8.60(t,J＝5.9Hz,1H),8.50(d,J＝2.5Hz,1H),8.32–8.24(m,2H),8.15(d,J＝8.9Hz,1H),7.93(dd,J＝8.9,2.6Hz,1H),7.46–7.32(m,5H),5.18(d,J＝2.6Hz,1H),4.57(d,J＝9.6Hz,1H),4.50–4.32(m,3H),4.25(dd,J＝15.8,5.6Hz,1H),3.98–3.87(m,4H),3.65(dt,J＝22.0,7.2Hz,2H),3.52(t,J＝5.5Hz,2H),3.28(d,J＝8.2Hz,2H),2.86–2.75(m,2H),2.47–2.39(m,5H),2.10–2.01(m,1H),1.98–1.85(m,1H),1.56(t,J＝10.2Hz,10H),0.94(d,J＝7.6Hz,9H).
实施例A144
LCMS([M+H]+):1147.3
1HNMR(400MHz,DMSO-d6)δ8.99(s,1H),8.69(s,1H),8.45(d,J＝7.6Hz,1H),8.29(s,3H),7.80(d,J＝9.2Hz,2H),7.44(d,J＝8.3Hz,3H),7.37(d,J＝8.3Hz,2H),5.15(d,J＝3.5Hz,3H),4.91(p,J＝6.9Hz,1H),4.71–4.42(m,4H),4.26(d,J＝19.1Hz,1H),4.07(s,4H),3.65–3.42(m,2H),2.46(s,3H),2.09–1.99(m,1H),1.82–1.72(m,1H),1.62(s,6H),1.37(d,J＝7.0Hz,3H),0.94(s,9H).
实施例A145
LCMS([M+H]+):1047.4
1HNMR(400MHz,DMSO-d6)δ8.97(m,1H),8.67(d,J＝2.4Hz,1H),8.57(s,1H),8.33–8.26(m,2H),8.17(d,J＝8.5Hz,1H),8.05–7.94(m,3H),7.46–7.34(m,4H),7.30(t,J＝8.7Hz,1H),5.08–4.96(m,1H),4.55–4.51(m,1H),4.43–4.32(m,2H),4.25(dd,J＝15.8,5.6Hz,1H),4.19–4.11(m,2H),3.64(d,J＝10.4Hz,1H),3.58–3.52(m,1H),3.44(dd,J＝14.8,6.2Hz,4H),3.19–3.09(m,1H),2.64(m,1H),2.43(d,J＝6.4Hz,4H),2.10–1.74(m,5H),1.67(dt,J＝13.9,6.8Hz,2H),1.58(s,6H),0.90(d,J＝5.8Hz,9H).
实施例A146
LCMS([M+H]+):1171.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.64(s,2H),8.29(s,2H),8.21(dd,J＝9.7,1.8Hz,1H),7.56(d,J＝9.1Hz,1H),7.39(d,J＝8.1Hz,7H),5.30(d,J＝18.9Hz,1H),4.58–4.34(m,3H),4.34–4.24(m,1H),4.18(s,2H),3.97(s,3H),3.89–3.79(m,1H),3.57(s,2H),2.44(s,3H),2.27(dd,J＝13.7,7.6Hz,1H),2.12(ddd,J＝13.8,9.3,4.9Hz,1H),2.01(s,3H),1.85(dd,J＝14.0,6.4Hz,2H),1.79–1.70(m,2H),1.61(s,6H),0.95(d,J＝8.5Hz,9H).
实施例A147
LCMS([M+H]+):1097.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.64(s,2H),8.29(s,2H),8.18(dd,J＝11.8,1.5Hz,1H),7.84(s,2H),7.51(d,J＝9.5Hz,1H),7.40(s,5H),5.20–4.97(m,2H),4.58(d,J＝9.5Hz,1H),4.41(d,J＝36.4Hz,7H),4.01(s,2H),3.67(d,J＝4.9Hz,4H),2.43(s,3H),2.11–2.00(m,3H),1.91(ddd,J＝12.9,8.8,4.4Hz,1H),1.61(s,6H),0.94(d,J＝7.1Hz,9H).
实施例A148
LCMS([M+H]+):1086.4
1HNMR(400MHz,DMSO-d6)δ8.95(d,J＝12.0Hz,2H),8.71(s,1H),8.64(s,1H),8.43(d,J＝8.5Hz,1H),8.30(d,J＝6.2Hz,2H),8.19(d,J＝8.5Hz,1H),8.01(d,J＝7.8Hz,1H),7.47–7.36(m,5H),6.94(d,J＝8.6Hz,1H),5.28(s,1H),4.40(ddd,J＝32.5,21.3,6.8Hz,6H),3.94(d,J＝12.2Hz,3H),3.85(s,1H),3.55(s,2H),2.43(s,3H),2.32–2.19(m,1H),2.13(s,1H),1.99(d,J＝15.0Hz,3H),1.83(d,J＝7.0Hz,2H),1.72(s,2H),1.59(s,6H),0.95(s,9H).
实施例A149
LCMS([M+H]+):1128.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.67(s,1H),8.45(d,J＝7.7Hz,1H),8.32–8.20(m,3H),7.83–7.73(m,2H),7.39(dt,J＝27.3,8.6Hz,5H),5.18–4.85(m,3H),4.59–4.34(m,4H),4.26(d,J＝17.8Hz,1H),4.04–3.90(m,2H),3.57(ddd,J＝60.5,30.4,8.4Hz,4H),2.45(s,3H),2.08–1.96(m,3H),1.81–1.72(m,1H),1.61(s,6H),1.42(dd,J＝41.5,7.0Hz,3H),0.93(s,9H).
实施例A150
LCMS([M+H]+):1115.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.64(m,2H),8.29(s,2H),8.19(dd,J＝11.8,1.8Hz,1H),7.87(t,J＝8.6Hz,2H),7.57(d,J＝8.2Hz,1H),7.41(m,6H),5.17(m,2H),4.59(m,)1H),4.49–4.42(m,2H),4.38(m,2H),4.30–4.24(m,1H),4.10(m,2H),4.03–3.86(m,2H),3.66(m,2H),2.44(s,3H),2.05(m,1H),1.96–1.85(m,1H),1.62(s,6H),0.94(d,J＝7.5Hz,9H).
实施例A151
LCMS([M+H]+):1121.3
1HNMR(400MHz,DMSO-d6)δ8.98(d,J＝7.2Hz,1H),8.63(s,2H),8.30(d,J＝11.6Hz,2H),8.17(d,J＝11.9Hz,1H),7.84(d,J＝10.4Hz,2H),7.50–7.30(m,6H),5.28(m,1H),4.45(m,3H),4.28(m,1H),4.19(m,2H),4.01–3.90(m,3H),3.84(m,1H),3.56(m,2H),2.44(d,J＝5.5Hz,3H),2.27(m,1H),2.12(m,1H),1.99(d,J＝14.4Hz,3H),1.93–1.82(m,2H),1.75(m,2H),1.61(s,6H),0.95(d,J＝8.7Hz,9H).
实施例A152
LCMS([M+H]+):1139.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝10.2Hz,1H),8.62(dd,J＝17.8,11.9Hz,2H),8.32–8.19(m,3H),7.74(t,J＝7.5Hz,2H),7.47–7.31(m,5H),5.27(s,1H),4.44(ddd,J＝22.0,16.5,7.4Hz,3H),4.27(dd,J＝11.4,5.7Hz,3H),3.99–3.89(m,3H),3.83(dd,J＝11.7,4.1Hz,1H),3.54(t,J＝5.5Hz,2H),2.43(d,J＝7.7Hz,3H),2.26(dd,J＝13.7,7.9Hz,1H),2.12(ddd,J＝13.6,8.9,4.8Hz,1H),2.00(s,3H),1.77(ddd,J＝19.6,14.0,7.1Hz,4H),1.61(s,6H),0.93(d,J＝9.9Hz,9H).
实施例A153
LCMS([M+H]+):1152.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.67(s,1H),8.47(d,J＝7.6Hz,1H),8.33–8.18(m,3H),7.78(t,J＝7.5Hz,2H),7.39(dt,J＝14.2,7.2Hz,5H),5.17(d,J＝22.5Hz,1H),4.96–4.84(m,1H),4.53–4.39(m,2H),4.27(t,J＝6.0Hz,2H),4.00–3.85(m,3H),3.76(dd,J＝11.7,3.8Hz,1H),3.54(t,J＝5.1Hz,2H),2.45(s,3H),2.26(dd,J＝13.4,7.5Hz,1H),2.05–1.92(m,4H),1.77(ddd,J＝19.4,13.5,6.9Hz,4H),1.61(s,6H),1.42(dd,J＝38.8,6.9Hz,3H),0.94(s,9H).
实施例A154
LCMS([M+H]+):1165.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝6.6Hz,1H),8.63–8.58(m,2H),8.34–8.25(m,2H),8.20(dd,J＝9.7,1.8Hz,1H),7.57(dd,J＝18.1,9.0Hz,2H),7.50–7.36(m,6H),5.33–5.01(m,3H),4.64–4.32(m,6H),4.25(dd,J＝15.7,5.5Hz,1H),4.15–4.04(m,2H),4.04–3.81(m,2H),3.69–3060(m 2H),2.44(d,J＝3.2Hz,3H),2.10–2.03(m,1H),1.90(ddd,J＝12.9,8.7,4.4Hz,1H),1.61(s,6H),0.93(d,J＝7.0Hz,9H).
实施例A155
LCMS([M+H]+):944.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.63(d,J＝0.9Hz,1H),8.49(t,J＝5.6Hz,1H),8.29(d,J＝3.2Hz,2H),8.20(dd,J＝9.7,1.9Hz,1H),7.86(d,J＝8.3Hz,1H),7.58(d,J＝9.2Hz,1H),7.47(d,J＝2.2Hz,1H),7.43–7.34(m,3H),5.11(dd,J＝12.9,5.4Hz,1H),4.78(s,2H),4.24(t,J＝5.5Hz,2H),3.59(dd,J＝11.0,5.5Hz,2H),2.88(ddd,J＝17.3,14.0,5.3Hz,1H),2.70–2.51(m,2H),2.10–1.97(m,1H),1.61(s,6H).
实施例A156
LCMS([M+H]+):944.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.63(d,J＝0.9Hz,1H),8.49(t,J＝5.6Hz,1H),8.29(d,J＝3.2Hz,2H),8.20(dd,J＝9.7,1.9Hz,1H),7.86(d,J＝8.3Hz,1H),7.58(d,J＝9.2Hz,1H),7.47(d,J＝2.2Hz,1H),7.43–7.34(m,3H),5.11(dd,J＝12.9,5.4Hz,1H),4.78(s,2H),4.24(t,J＝5.5Hz,2H),3.59(dd,J＝11.0,5.5Hz,2H),2.88(ddd,J＝17.3,14.0,5.3Hz,1H),2.70–2.51(m,2H),2.10–1.97(m,1H),1.61(s,6H).
实施例A157
LCMS([M+H]+):1111.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.71(s,1H),8.61(s,1H),8.29(t,J＝7.9Hz,2H),8.03(d,J＝7.4Hz,1H),7.69(d,J＝8.2Hz,1H),7.56(d,J＝8.6Hz,1H),7.37(d,J＝25.5Hz,7H),5.17(s,1H),4.58(d,J＝9.4Hz,1H),4.51–4.32(m,3H),4.29(d,J＝4.8Hz,1H),4.17(s,2H),3.97(s,2H),3.75–3.50(m,4H),2.43(s,3H),2.08(s,2H),1.98–1.68(m,5H),1.59(s,6H),0.95(s,9H).
实施例A158
LCMS([M+H]+):1061.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝10.0Hz,1H),8.73(d,J＝2.1Hz,1H),8.60(t,J＝5.9Hz,1H),8.34–8.25(m,2H),7.97(dd,J＝18.2,8.8Hz,3H),7.47–7.34(m,5H),7.00–6.90(m,2H),5.15(d,J＝3.5Hz,1H),4.57(d,J＝9.5Hz,1H),4.49–4.32(m,3H),4.26(dd,J＝15.7,5.6Hz,1H),4.10(t,J＝6.3Hz,2H),4.01–3.89(m,2H),3.71–3.52(m,4H),2.43(d,J＝7.2Hz,3H),2.07(dd,J＝12.2,7.9Hz,1H),2.01–1.89(m,1H),1.88–1.79(m,2H),1.74(dd,J＝14.1,6.3Hz,2H),1.59(s,6H),0.93(s,9H).
实施例A159
LCMS([M+H]+):1097.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.64(s,2H),8.28(s,2H),8.17(dd,J＝11.9,1.8Hz,1H),7.84(s,2H),7.48(t,J＝9.0Hz,1H),7.40(d,J＝1.4Hz,5H),5.16(d,J＝3.5Hz,1H),5.08–4.84(m,1H),4.58(d,J＝8.2Hz,1H),4.50–4.33(m,3H),4.29(s,3H),4.06(s,2H),3.88–3.59(m,4H),2.44(s,3H),2.24–2.10(m,2H),2.10(s,1H),1.91(ddd,J＝12.9,8.8,4.4Hz,1H),1.62(s,6H),0.95(s,9H).
实施例A160
LCMS([M+H]+):1012.3
1HNMR(400MHz,DMSO-d6)δ12.19(d,J＝61.4Hz,1H),8.73(s,1H),8.63(s,1H),8.29(s,2H),8.16(d,J＝10.5Hz,1H),7.93–7.77(m,2H),7.35(dd,J＝18.8,9.2Hz,2H),7.25(s,1H),5.20(d,J＝3.6Hz,1H),5.06(t,J＝7.8Hz,1H),4.57(d,J＝9.5Hz,1H),4.43(d,J＝31.3Hz,1H),4.19(t,J＝6.2Hz,2H),3.96(s,2H),3.85(d,J＝6.4Hz,1H),3.68–3.51(m,4H),2.47(s,3H),2.15(d,J＝4.4Hz,2H),1.85(d,J＝7.7Hz,2H),1.79–1.69(m,2H),1.62(s,6H),0.89(s,9H).
实施例A161
LCMS([M+H]+):1035.3
1HNMR(400MHz,DMSO-d6)δ8.63(s,1H),8.28(s,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.85(d,J＝10.6Hz,2H),7.41(dd,J＝37.5,4.4Hz,7H),6.90(s,1H),5.61(dd,J＝27.6,5.7Hz,1H),5.42–5.30(m,1H),5.00–4.83(m,1H),4.64(dt,J＝15.2,6.8Hz,1H),4.51(d,J＝9.5Hz,1H),4.26(d,J＝29.6Hz,1H),4.23(s,2H),3.95(s,2H),3.58(d,J＝6.8Hz,6H),2.87(ddd,J＝13.2,8.4,4.9Hz,1H),1.95–1.80(m,3H),1.76(dd,J＝14.0,6.1Hz,2H),1.61(s,6H),0.97(s,3H),0.68(s,6H).
实施例A162
LCMS([M+H]+):1115.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.64(s,2H),8.28(s,2H),8.17(dd,J＝11.9,1.8Hz,1H),7.86(d,J＝10.5Hz,2H),7.59(d,J＝9.4Hz,1H),7.40(d,J＝2.9Hz,5H),5.16(d,J＝3.5Hz,1H),4.58(d,J＝9.5Hz,1H),4.44(dt,J＝14.1,7.1Hz,2H),4.39(d,J＝11.9Hz,4H),4.25(dd,J＝15.7,5.5Hz,1H),4.14(s,2H),3.93(t,J＝13.5Hz,2H),3.66(dt,J＝20.8,7.3Hz,2H),2.44(s,3H),2.08(s,2H),1.96–1.86(m,1H),1.62(s,6H),0.93(d,J＝7.3Hz,9H).
实施例A163
LCMS([M+H]+):1115.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝5.7Hz,1H),8.64(s,1H),8.58(t,J＝5.9Hz,1H),8.28(m,2H),8.18(dd,J＝11.8,1.8Hz,1H),7.86(t,J＝9.1Hz,2H),7.51(d,J＝9.5Hz,1H),7.46(d,J＝8.6Hz,1H),7.41(d,J＝9.3Hz,4H),5.15(m,1H),4.59(m,2H),4.47–4.41(m,2H),4.37(m,2H),4.25(m,2H),4.00(m,2H),3.75(m,2H),3.70–3.62(m,2H),2.43(s,3H),2.05(m,2H),2.02–1.97(m,2H),1.62(s,6H),0.93(s,9H).
实施例A164
LCMS([M+H]+):1085.4
1HNMR(400MHz,DMSO-d6)δ8.63(s,1H),8.34–8.26(m,2H),8.20(dd,J＝9.7,1.9Hz,1H),7.62–7.54(m,1H),7.51–7.30(m,8H),6.94(d,J＝32.8Hz,1H),5.61(dd,J＝28.0,5.7Hz,1H),5.40–5.31(m,1H),4.97(dd,J＝23.3,6.4Hz,1H),4.64(dt,J＝15.1,6.9Hz,1H),4.52(d,J＝9.5Hz,1H),4.30(s,1H),4.19(t,J＝6.0Hz,2H),4.00–3.84(m,2H),3.64–3.49(m,7H),2.87(ddd,J＝13.2,8.4,5.0Hz,1H),1.95–1.69(m,5H),1.61(s,6H),0.97(s,2H),0.68(s,7H).
实施例A165
LCMS([M+H]+):1062.3
1HNMR(400MHz,DMSO-d6)δ12.31–12.05(m,1H),8.73(d,J＝10.2Hz,1H),8.62(s,1H),8.34–8.24(m,2H),8.19(dd,J＝9.7,1.7Hz,1H),7.55(d,J＝9.1Hz,1H),7.43–7.29(m,3H),7.25(d,J＝5.5Hz,1H),5.20(d,J＝3.7Hz,1H),5.06(t,J＝7.7Hz,1H),4.57(d,J＝9.5Hz,1H),4.49–4.33(m,1H),4.17(t,J＝6.1Hz,2H),4.01–3.90(m,2H),3.82(dt,J＝34.8,17.4Hz,1H),3.68–3.52(m,3H),2.48–2.39(m,3H),2.25–2.10(m,2H),1.83(dd,J＝13.7,6.3Hz,2H),1.78–1.68(m,2H),1.61(s,6H),0.95–0.80(m,9H).
实施例A166
LCMS([M+H]+):1147.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝8.0Hz,1H),8.66–8.56(m,2H),8.28(s,2H),8.20(d,J＝9.7Hz,1H),7.57(d,J＝8.2Hz,1H),7.49(d,J＝9.5Hz,1H),7.40(d,J＝4.2Hz,5H),5.15(d,J＝3.4Hz,1H),5.03(s,1H),4.92(s,1H),4.57(d,J＝9.5Hz,1H),4.49–4.33(m,3H),4.25(dd,J＝15.6,5.7Hz,3H),4.05(d,J＝9.5Hz,2H),3.88–3.58(m,5H),2.44(d,J＝4.7Hz,3H),2.22–1.86(m,6H),1.61(s,6H),0.94(s,9H).
实施例A167
LCMS([M+H]+):1165.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.63(s,1H),8.58(t,J＝6.0Hz,1H),8.28(s,2H),8.20(dd,J＝9.7,1.8Hz,1H),7.59(d,J＝8.6Hz,1H),7.55–7.44(m,3H),7.39(s,4H),5.14(d,J＝2.5Hz,1H),4.59(dd,J＝16.1,11.3Hz,3H),4.49–4.31(m,3H),4.25(dd,J＝15.8,5.6Hz,1H),4.01(s,2H),3.75(t,J＝6.2Hz,2H),3.70–3.57(m,2H),2.44(d,J＝4.1Hz,5H),2.07–2.00(m,1H),1.90(ddd,J＝13.0,8.8,4.5Hz,1H),1.61(s,6H),0.91(d,J＝6.4Hz,9H).
实施例A168
LCMS([M+H]+):1165.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.66–8.56(m,2H),8.29(d,J＝3.4Hz,2H),8.20(dd,J＝9.7,1.8Hz,1H),7.59(dd,J＝13.2,9.3Hz,2H),7.46–7.33(m,6H),5.15(d,J＝3.4Hz,1H),4.58(d,J＝9.5Hz,1H),4.50–4.32(m,5H),4.25(dd,J＝15.8,5.6Hz,1H),4.15(s,2H),3.93(t,J＝13.7Hz,2H),3.71–3.57(m,2H),2.60–2.52(m,1H),2.43(s,5H),2.05(d,J＝8.6Hz,1H),1.91(ddd,J＝13.0,8.9,4.5Hz,1H),1.61(s,6H),0.93(d,J＝6.1Hz,9H).
实施例A169
LCMS([M+H]+):1079.3
1HNMR(400MHz,DMSO-d6)δ8.97–8.96(m,1H),8.66(d,J＝2.2Hz,1H),8.59(t,J＝5.9Hz,1H),8.32–8.26(m,2H),8.13(d,J＝8.7Hz,3H),7.96(dd,J＝8.5,2.4Hz,1H),7.54(d,J＝8.8Hz,1H),7.45–7.35(m,4H),7.14(d,J＝8.8Hz,2H),5.32–4.96(m,3H),4.58(d,J＝9.4Hz,1H),4.48–4.32(m,5H),4.25(dd,J＝15.8,5.6Hz,1H),4.15–4.04(m,2H),4.02–3.87(m,2H),3.70–3.61(m,2H),2.43(s,3H),2.07–2.04(m,1H),1.96–1.86(m,1H),1.58(s,6H),0.94(d,J＝6.9Hz,9H).
实施例A170
LCMS([M+H]+):1020.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.97(m,1H),8.66(d,J＝2.3Hz,1H),8.59(t,J＝5.9Hz,1H),8.36(t,J＝5.5Hz,1H),8.33–8.23(m,2H),7.96(dd,J＝8.3,2.4Hz,1H),7.79(d,J＝8.3Hz,1H),7.51(d,J＝15.4Hz,1H),7.46–7.35(m,5H),7.14(d,J＝15.4Hz,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.45(t,J＝8.2Hz,1H),4.40–4.34(m,2H),4.29–4.24(m,1H),3.98–3.86(m,2H),3.68–3.59(m,2H),3.50(t,J＝6.0Hz,2H),3.26–3.18(m,2H),2.44(s,3H),2.06–2.01(m,1H),1.95–1.86(m,1H),1.59–1.56(m,10H),0.93(d,J＝6.8Hz,9H).
实施例A171
LCMS([M+H]+):1061.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝6.8Hz,1H),8.66(d,J＝2.3Hz,1H),8.59(t,J＝5.9Hz,1H),8.29(q,J＝8.5Hz,2H),8.11(d,J＝8.7Hz,3H),7.95(dd,J＝8.5,2.3Hz,1H),7.48(d,J＝9.5Hz,1H),7.45–7.36(m,4H),7.09(d,J＝8.8Hz,2H),5.16(d,J＝3.4Hz,1H),4.95(dd,J＝47.5,6.7Hz,1H),4.57(d,J＝9.5Hz,1H),4.50–4.33(m,3H),4.25(dd,J＝15.8,5.6Hz,1H),4.18(t,J＝6.1Hz,2H),4.11–3.99(m,2H),3.88–3.58(m,4H),2.44(d,J＝4.4Hz,3H),2.15(d,J＝6.1Hz,1H),2.10(d,J＝7.6Hz,2H),1.91(ddd,J＝13.0,8.9,4.4Hz,1H),1.58(s,6H),0.94(s,9H).
实施例A172
LCMS([M+H]+):1116.3
1HNMR(400MHz,DMSO-d6)δ8.97–8.88(m,1H),8.63(s,1H),8.44(dd,J＝51.5,8.1Hz,1H),8.33–8.23(m,2H),8.16(d,J＝11.9Hz,1H),8.07–7.93(m,1H),7.81(dt,J＝12.1,10.3Hz,2H),7.49–7.28(m,4H),7.26–7.14(m,1H),6.22(d,J＝9.7Hz,1H),5.36–4.89(m,2H),4.50–3.39(m,7H),3.20(m,2H),2.69–2.54(m,2H),2.46–2.36(m,3H),2.34–2.11(m,4H),2.05–1.73(m,4H),1.62(s,7H),0.96(dd,J＝6.5,2.9Hz,3H),0.78(dd,J＝12.0,6.7Hz,3H).
实施例A173
LCMS([M+H]+):1038.3
1HNMR(400MHz,DMSO-d6)δ9.00–8.86(m,1H),8.59(m,1H),8.46(m,1H),8.30–8.27(m,2H),7.91–7.87(m,1H),7.69–7.54(m,1H),7.49–7.33(m,4H),6.25–6.16(m,1H),5.32–5.09(m,2H),4.40–4.20(m,2H),3.94–3.49(m,5H),3.05–2.81(m,5H),2.46–2.43(m,3H),2.27–2.18(m,4H),1.99(m,1H),1.79(m,3H),1.55–1.45(m,8H),0.97–0.73(m,6H).
实施例A174
LCMS([M+H]+):1081.4
1HNMR(400MHz,DMSO-d6)δ8.97–8.59(m,3H),7.41–7.29(m,8H),6.25–6.21(m,2H),5.11–5.07(m,3H),4.39–4.20(m,5H),3.85–3.73(m,4H),2.67–2.56(m,5H),2.43(s,6H),2.29–2.23(m,3H),2.19–2.16(m,7H),2.00–1.97(m,3H),1.81–1.78(m,2H),0.97–0.93(m,6H),0.78(dd,J＝14.2,6.8Hz,6H).
实施例A175
LCMS([M+H]+):1079.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.66(d,J＝2.2Hz,1H),8.59(t,J＝5.9Hz,1H),8.29(q,J＝8.5Hz,2H),8.12(d,J＝8.8Hz,3H),7.95(dd,J＝8.5,2.4Hz,1H),7.59(d,J＝9.5Hz,1H),7.39(q,J＝8.3Hz,4H),7.10(d,J＝8.8Hz,2H),5.16(d,J＝3.4Hz,1H),4.57(d,J＝9.5Hz,1H),4.49–4.33(m,3H),4.31–4.20(m,3H),4.12(d,J＝16.6Hz,2H),3.91(t,J＝13.3Hz,2H),3.66(dt,J＝21.0,7.1Hz,2H),2.52(d,J＝7.6Hz,1H),2.43(s,4H),2.06(dd,J＝12.9,6.9Hz,1H),1.96–1.86(m,1H),1.58(s,6H),0.93(d,J＝7.0Hz,9H).
实施例A176
LCMS([M+H]+):1037.1
1HNMR(400MHz,DMSO-d6)δ9.02–8.87(m,1H),8.61(d,J＝133.7Hz,1H),8.32–8.22(m,2H),7.66–7.25(m,8H),6.28–6.14(m,1H),5.38–4.87(m,2H),4.33(ddd,J＝58.1,32.8,20.0Hz,2H),3.96–3.49(m,4H),3.24–2.65(m,6H),2.47–2.41(m,3H),2.33–2.09(m,4H),2.00(d,J＝7.5Hz,1H),1.78(s,3H),1.52(s,8H),0.84(ddd,J＝32.0,22.1,6.4Hz,6H).
实施例A177
LCMS([M+H]+):1158.4
1HNMR(400MHz,DMSO-d6)δ9.00–8.84(m,1H),8.63(s,1H),8.41(dd,J＝59.3,8.0Hz,1H),8.29(d,J＝11.9Hz,2H),8.20–8.12(m,1H),7.83(t,J＝10.7Hz,3H),7.50–7.25(m,5H),6.22(d,J＝9.8Hz,1H),5.37–5.03(m,2H),4.50–4.23(m,2H),4.14–4.02(m,2H),3.88–3.69(m,1H),3.49(m,2H),3.10–2.87(m,2H),2.68–2.52(m,2H),2.45(d,J＝3.3Hz,3H),2.35–2.13(m,4H),2.00(m,1H),1.89–1.65(m,3H),1.61(s,6H),1.41–1.25(m,4H),1.20(m,1H),1.00–0.94(m,2H),0.78(dd,J＝12.6,6.7Hz,3H).
实施例A178
LCMS([M+H]+):1142.3
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.77(m,0.5H),8.63(s,1H),8.44(m,0.5H),8.30–8.28(m,2H),8.17(d,J＝11.7Hz,1H),7.87–7.83(m,2H),7.51–7.32(m,5H),6.25–6.16(m,1H),5.33–4.72(m,4H),4.48–4.16(m,2H),4.01–3.38(m,6H),2.95–2.84(m,2H),2.45–2.44(m,3H),2.28–2.17(m,4H),2.05–1.75(m,4H),1.61(s,7H),1.03–0.69(m,6H).
实施例A179
LCMS([M+H]+):984.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.63(s,1H),8.31–8.27(m,2H),8.20(dd,J＝9.7,1.8Hz,1H),7.81–7.77(m,1H),7.60–7.58(m,1H),7.49–7.45(m,3H),7.37(d,J＝8.7Hz,1H),5.23(s,2H),5.11(dd,J＝12.9,5.4Hz,1H),4.91(m,1H),3.85(s,1H),3.72(s,1H),3.43–3.38(m,2H),2.94–2.85(m,1H),2.62–2.54(m,2H),2.08(m,1H),2.02–1.99(m,2H),1.81(m,1H),1.61(s,7H).
实施例A180
LCMS([M+H]+):984.2
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.64(s,1H),8.32–8.29(m,2H),8.21(dd,J＝9.7,1.7Hz,1H),7.85(d,J＝8.3Hz,1H),7.60(d,J＝8.5Hz,1H),7.50–7.46(m,3H),7.37(dd,J＝8.3,2.2Hz,1H),5.19(s,2H),5.13(dd,J＝12.9,5.3Hz,1H),4.92(m,1H),3.87(s,1H),3.73(s,1H),3.43–3.39(m,2H),2.97–2.84(m,1H),2.63–2.56(m,2H),2.08(s,1H),2.04–2.00(m,2H),1.78(m,1H),1.62(s,7H).
实施例A181
LCMS([M+H]+):943.2
1HNMR(400MHz,DMSO-d6)δ11.08(s,1H),8.63(s,1H),8.47(t,J＝5.5Hz,1H),8.32–8.26(m,2H),8.20(dd,J＝9.7,1.9Hz,1H),7.62–7.55(m,2H),7.47(d,J＝2.4Hz,1H),7.38(dd,J＝8.6,2.3Hz,1H),7.21(d,J＝8.6Hz,1H),7.03(d,J＝7.0Hz,1H),6.79(t,J＝5.9Hz,1H),5.05(m,1H),4.69(m,2H),3.49–3.37(m,4H),2.88(m,1H),2.64–2.51(m,2H),2.00(m 1H),1.61(s,6H).
实施例A182
LCMS([M+H]+):911.2
1HNMR(400MHz,DMSO-d6)δ11.09(s,1H),8.67(s,1H),8.41(s,1H),8.29(s,2H),8.23(dd,J＝11.8,1.8Hz,1H),7.76(d,J＝9.5Hz,2H),7.64–7.54(m,1H),7.20(d,J＝8.6Hz,1H),7.03(d,J＝7.0Hz,1H),6.77(s,1H),5.05(s,1H),4.71(s,2H),3.54–3.35(m,4H),2.98–2.80(m,1H),2.57(s,2H),2.07–1.94(m,1H),1.62(s,6H).
实施例A183
LCMS([M+H]+):1192.3
1HNMR(400MHz,DMSO-d6)δ8.99(d,J＝4.1Hz,1H),8.79(s,1H),8.62(s,1H),8.45(d,J＝5.1Hz,1H),8.28(s,2H),8.23–8.16(m,1H),7.62–7.29(m,7H),6.28–6.16(m,1H),5.41–4.74(m,5H),4.47–4.24(m,2H),4.01–3.64(m,4H),3.62–3.35(m,4H),2.89(d,J＝22.1Hz,3H),2.46(d,J＝3.8Hz,3H),2.38–2.11(m,5H),2.05–1.75(m,5H),1.61(s,8H),1.02–0.67(m,7H).
实施例A184
LCMS([M+H]+):1080.2
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝6.2Hz,1H),8.28(d,J＝4.8Hz,2H),7.85(s,2H),7.55(d,J＝8.2Hz,2H),7.41(dt,J＝17.3,11.0Hz,6H),6.23(d,J＝10.8Hz,1H),5.24–5.10(m,2H),4.34(dd,J＝28.4,19.6Hz,3H),3.80(dd,J＝40.6,9.2Hz,3H),3.14(s,4H),2.64(s,5H),2.46(s,4H),2.19(d,J＝8.8Hz,9H),2.06–1.95(m,3H),1.80(s,4H),1.61(s,3H),1.52(s,6H),1.02–0.71(m,9H).
实施例A185
LCMS([M+H]+):1005.4
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝9.6Hz,1H),8.68–8.56(m,2H),8.09(d,J＝8.8Hz,3H),7.94(dd,J＝8.5,2.5Hz,1H),7.84(dd,J＝8.4,1.6Hz,1H),7.53(dd,J＝8.4,6.4Hz,1H),7.46–7.36(m,5H),7.05(d,J＝8.9Hz,2H),5.16(s,1H),4.57(m,1H),4.49–4.33(m,3H),4.26(m,,1H),4.13(m,3H),4.08(m,2H),4.01–3.89(m,2H),3.70–3.53(m,4H),2.43(d,J＝7.2Hz,3H),2.11–2.03(m,1H),1.95–1.79(m,3H),1.74(m,2H),1.56(s,6H),0.93(d,J＝6.9Hz,9H).
实施例A186
LCMS([M+H]+):1185.4
1HNMR(400MHz,DMSO-d6)δ9.00–8.93(m,1H),8.64(s,1H),8.29(d,J＝3.6Hz,2H),8.17(dd,J＝11.8,1.8Hz,1H),7.85(t,J＝11.1Hz,2H),7.49–7.27(m,5H),6.23(d,J＝12.4Hz,1H),5.21(d,J＝7.4Hz,1H),5.10(s,1H),4.65(d,J＝36.0Hz,1H),4.36(s,1H),4.28(s,1H),3.76(d,J＝9.7Hz,1H),3.59–3.43(m,2H),3.34–3.12(m,10H),2.70–2.54(m,3H),2.46(s,3H),2.20(d,J＝10.2Hz,3H),2.13–1.96(m,3H),1.92–1.68(m,3H),1.62(s,6H),1.24(s,1H),0.97(t,J＝6.2Hz,2H),0.82–0.71(m,3H).
实施例A187
LCMS([M+H]+):860.2
1HNMR(400MHz,DMSO-d6)δ11.12(s,1H),8.22(d,J＝2.8Hz,1H),7.92–7.70(m,5H),7.47(dd,J＝25.9,7.8Hz,2H),7.29(dd,J＝8.7,2.8Hz,1H),7.05(d,J＝7.3Hz,2H),6.43(s,1H),5.40–5.09(m,4H),4.77(,1H),4.10–3.89(m,5H),2.94–2.86(m,2H),2.67–2.57(m,2H),2.03(m,2H),1.68(s,6H).
实施例A188
LCMS([M+H]+):860.2
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.23(d,J＝2.7Hz,1H),7.92–7.86(m,3H),7.75(d,J＝8.7Hz,2H),7.49(s,1H),7.37(m,1H),7.29(dd,J＝8.7,2.9Hz,1H),7.05(d,J＝8.6Hz,2H),6.45(s,1H),5.55–4.99(m,4H),4.77(s,1H),4.20–4.03(m,4H),3.89–3.73(m,4H),2.88(m,1H),2.61(m,2H),2.03–1.99(m,2H),1.69(s,6H).
实施例A189
LCMS([M+H]+):951.8
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.68(s,1H),8.32–8.20(m,3H),7.82(dd,J＝11.7,8.7Hz,3H),7.46(d,J＝2.2Hz,1H),7.36(dd,J＝8.3,2.3Hz,1H),5.23–5.06(m,3H),4.57(s,1H),3.84(s,1H),3.72(s,1H),3.35(s,2H),2.97–2.82(m,1H),2.57(dd,J＝19.9,10.6Hz,2H),2.03(d,J＝5.7Hz,2H),1.95(s,1H),1.83(s,1H),1.61(s,6H).
实施例A190
LCMS([M+H]+):912.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.66(s,1H),8.28(s,2H),8.25–8.17(m,2H),7.77(dd,J＝16.9,8.6Hz,3H),7.47(d,J＝7.2Hz,1H),7.40(d,J＝8.5Hz,1H),5.10(dd,J＝12.9,5.4Hz,1H),4.81(s,2H),4.31(t,J＝5.3Hz,2H),3.57(d,J＝3.9Hz,2H),2.96–2.79(m,1H),2.55(dd,J＝20.2,10.7Hz,2H),2.03(dd,J＝14.8,9.7Hz,1H),1.61(s,6H).
实施例A191
LCMS([M+H]+):951.8
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.68(s,1H),8.31–8.21(m,3H),7.79(dd,J＝14.1,8.7Hz,3H),7.45(d,J＝7.2Hz,1H),7.36(d,J＝8.6Hz,1H),5.23(s,2H),5.11(dd,J＝12.9,5.4Hz,1H),4.57(s,1H),3.77(d,J＝48.3Hz,2H),3.34(s,2H),2.88(dd,J＝17.4,5.6Hz,1H),2.57(dd,J＝19.5,10.4Hz,2H),2.07–2.01(m,2H),1.95(s,1H),1.86(s,1H),1.68(d,J＝8.4Hz,1H),1.61(s,6H).
实施例A192
LCMS([M+H]+):912.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.66(s,1H),8.44(t,J＝5.6Hz,1H),8.29(d,J＝11.3Hz,2H),8.25–8.19(m,1H),7.85(d,J＝8.3Hz,1H),7.81–7.71(m,2H),7.46(d,J＝2.2Hz,1H),7.39(dd,J＝8.3,2.3Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.76(s,2H),4.30(t,J＝5.5Hz,2H),3.55(q,J＝5.5Hz,2H),2.88(ddd,J＝17.5,14.3,5.5Hz,1H),2.64–2.51(m,2H),2.04(dd,J＝9.0,3.7Hz,1H),1.61(s,6H).
实施例A193
LCMS([M+H]+):856.2
1HNMR(400MHz,DMSO-d6)δ11.16(s,1H),8.69(s,1H),8.35(t,J＝5.6Hz,1H),8.23(dd,J＝11.9,1.9Hz,1H),7.91(t,J＝8.7Hz,3H),7.86–7.78(m,1H),7.61–7.51(m,2H),7.44(m,2H),5.14(m,1H),4.90(m,2H),4.30(m,2H),4.20(d,J＝2.5Hz,3H),3.75–3.62(m,2H),3.00–2.89(m,1H),2.69–2.58(m,2H),2.13–2.04(m,1H),1.66(d,J＝2.9Hz,6H).
实施例A194
LCMS([M+H]+):896.2
1HNMR(400MHz,DMSO-d6)δ11.11(s,1H),8.64(s,1H),8.17(dd,J＝11.9,1.8Hz,1H),7.94–7.74(m,4H),7.50(ddd,J＝13.8,9.0,4.2Hz,3H),7.36(dd,J＝8.3,2.3Hz,1H),5.25–5.07(m,3H),4.89–4.74(m,1H),4.14(d,J＝2.6Hz,3H),3.92–3.81(m,1H),3.73(d,J＝12.7Hz,1H),3.40(dd,J＝21.0,6.7Hz,2H),2.89(ddd,J＝17.4,14.5,5.4Hz,1H),2.65–2.51(m,2H),2.08(s,1H),2.07–1.95(m,2H),1.81(d,J＝8.2Hz,1H),1.61(t,J＝11.2Hz,7H).
实施例A195
LCMS([M+H]+):896.2
1HNMR(400MHz,DMSO-d6)δ11.16(s,1H),8.69(s,1H),8.23(dd,J＝11.9,1.8Hz,1H),7.87(dt,J＝15.8,9.5Hz,4H),7.55(ddd,J＝19.1,11.5,6.8Hz,3H),7.42(d,J＝8.6Hz,1H),5.28(s,2H),5.16(dd,J＝12.9,5.4Hz,1H),4.88(d,J＝3.4Hz,1H),4.19(d,J＝2.5Hz,3H),3.92(d,J＝13.0Hz,1H),3.78(d,J＝13.7Hz,1H),3.52–3.38(m,2H),2.95(ddd,J＝17.4,13.9,5.4Hz,1H),2.69–2.56(m,2H),2.11(dt,J＝11.1,9.1Hz,3H),1.88(d,J＝7.9Hz,1H),1.68(dd,J＝22.4,6.0Hz,7H).
实施例A196
LCMS([M+H]+):1091.4
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝10.7Hz,1H),8.66–8.57(m,2H),8.20(dd,J＝9.7,1.9Hz,1H),7.86(dd,J＝8.4,1.6Hz,1H),7.57–7.48(m,2H),7.45–7.33(m,7H),5.16(d,J＝3.5Hz,1H),4.57(d,J＝9.6Hz,1H),4.49–4.32(m,3H),4.26(dd,J＝15.7,5.6Hz,1H),4.17(t,J＝6.2Hz,2H),4.14(d,J＝2.6Hz,3H),4.01–3.89(m,2H),3.63(ddd,J＝27.0,11.6,5.0Hz,4H),2.44(d,J＝7.1Hz,3H),2.11–2.03(m,1H),1.89(tdd,J＝17.0,11.5,5.2Hz,3H),1.79–1.71(m,2H),1.59(d,J＝5.6Hz,6H),0.93(d,J＝6.5Hz,9H).
实施例A197
LCMS([M+H]+):856.2
1HNMR(400MHz,DMSO-d6)δ11.10(s,1H),8.63(s,1H),8.51(s,1H),8.16(dd,J＝11.9,1.9Hz,1H),7.89–7.80(m,4H),7.51(dd,J＝8.4,6.4Hz,1H),7.46(d,J＝2.2Hz,1H),7.42–7.33(m,2H),5.11(m,1H),4.78(m,2H),4.23(m,2H),4.14(d,J＝2.6Hz,3H),3.60(m,2H),2.88(m,1H),2.64–2.51(m,2H),2.04(m,1H),1.59(d,J＝3.2Hz,6H).
实施例A198
LCMS([M+H]+):976.3
1HNMR(400MHz,DMSO-d6)δ12.13(s,1H),8.72(s,1H),8.65(d,J＝2.3Hz,1H),8.29(d,J＝7.1Hz,2H),8.10(d,J＝8.7Hz,3H),7.94(dd,J＝8.5,2.5Hz,1H),7.32(d,J＝9.6Hz,1H),7.25(s,1H),7.07(d,J＝8.9Hz,2H),5.21(d,J＝3.6Hz,1H),5.05(t,J＝7.8Hz,1H),4.57(d,J＝9.6Hz,1H),4.45(s,1H),4.08(t,J＝6.2Hz,2H),3.95(d,J＝2.1Hz,2H),3.84(dd,J＝10.7,4.3Hz,1H),3.63(d,J＝9.2Hz,1H),3.55(t,J＝6.3Hz,2H),2.46(s,3H),2.26–2.11(m,2H),1.86–1.77(m,2H),1.77–1.68(m,2H),1.58(s,6H),0.88(s,9H).
实施例A199
LCMS([M+H]+):820.2
1HNMR(400MHz,DMSO-d6)δ11.15(s,1H),8.65(s,1H),8.24(s,1H),8.11(d,J＝8.4Hz,3H),7.95(d,J＝7.8Hz,1H),7.85(d,J＝8.2Hz,1H),7.76(t,J＝7.8Hz,1H),7.59–7.36(m,3H),7.09(d,J＝8.4Hz,2H),5.11(dd,J＝12.6,5.1Hz,1H),4.83(s,2H),4.14(s,5H),3.60(d,J＝4.4Hz,2H),2.90(t,J＝13.2Hz,1H),2.60(d,J＝18.5Hz,2H),2.04(dd,J＝14.0,7.3Hz,1H),1.57(s,6H).
实施例A200
LCMS([M+H]+):820.2
1HNMR(400MHz,DMSO-d6)δ11.13(s,1H),8.66(d,J＝2.4Hz,1H),8.50(t,J＝5.6Hz,1H),8.12(d,J＝8.8Hz,3H),7.96(dd,J＝8.5,2.5Hz,1H),7.86(d,J＝8.3Hz,2H),7.54(dd,J＝8.4,6.4Hz,1H),7.47(d,J＝2.2Hz,1H),7.40(dd,J＝8.3,2.3Hz,1H),7.08(d,J＝8.9Hz,2H),5.12(dd,J＝12.9,5.4Hz,1H),4.79(s,2H),4.13(t,J＝4.6Hz,5H),3.57(dd,J＝11.0,5.5Hz,2H),2.88(ddd,J＝17.0,13.9,5.2Hz,1H),2.58(dd,J＝21.5,6.6Hz,2H),2.04(dd,J＝10.6,5.3Hz,1H),1.57(s,6H).
实施例A201
LCMS([M+H]+):955.3
1HNMR(400MHz,DMSO-d6)δ11.89(s,1H),8.65(d,J＝2.3Hz,1H),8.29(d,J＝6.9Hz,2H),8.10(d,J＝8.7Hz,3H),7.93(dd,J＝8.4,2.4Hz,1H),7.69(d,J＝6.8Hz,2H),7.45(s,1H),7.34(d,J＝9.6Hz,3H),7.18–7.02(m,3H),5.22(s,1H),5.08(s,1H),4.57(d,J＝9.4Hz,1H),4.48(s,1H),4.08(t,J＝6.0Hz,2H),3.95(s,2H),3.86(d,J＝7.6Hz,1H),3.64(d,J＝10.9Hz,1H),3.55(s,1H),2.20(d,J＝27.5Hz,2H),2.04–1.93(m,1H),1.81(d,J＝7.6Hz,2H),1.76–1.68(m,2H),1.58(s,6H),0.90(d,J＝27.2Hz,9H).
实施例A202
LCMS([M+H]+):1041.3
1HNMR(400MHz,DMSO-d6)δ12.07(d,J＝149.8Hz,1H),8.63(s,1H),8.28(s,2H),8.23–8.16(m,1H),7.65(dd,J＝35.7,7.4Hz,2H),7.54(t,J＝7.2Hz,1H),7.48–7.22(m,6H),7.15(dt,J＝25.3,7.4Hz,1H),5.21(d,J＝3.5Hz,1H),5.13–5.02(m,1H),4.58(d,J＝9.5Hz,1H),4.48(s,1H),4.17(t,J＝6.0Hz,2H),4.02–3.82(m,3H),3.64(d,J＝9.6Hz,1H),3.56(t,J＝6.2Hz,2H),2.28–2.19(m,1H),2.18–2.10(m,1H),1.89–1.79(m,2H),1.79–1.69(m,2H),1.60(s,6H),0.96–0.81(m,9H).
实施例A203
LCMS([M+H]+):962.3
1HNMR(400MHz,DMSO-d6)δ12.60–12.02(m,1H),8.96–8.81(m,1H),8.65(d,J＝2.2Hz,1H),8.29(q,J＝8.5Hz,2H),8.08(t,J＝12.4Hz,3H),8.01–7.91(m,2H),7.45(d,J＝1.8Hz,1H),7.33(d,J＝9.5Hz,1H),7.08(t,J＝13.6Hz,2H),5.22(m,1H),5.04(m,1H),4.57(m,1H),4.45(m,1H),4.07(m,2H),4.01–3.88(m,2H),3.84(m,1H),3.63(m,1H),3.55(m,2H),2.26–2.10(m,2H),1.80(m,2H),1.72(m,2H),1.58(m,6H),0.98–0.81(m,9H).
实施例A204
LCMS([M+H]+):1048.3
1HNMR(400MHz,DMSO-d6)δ12.17(d,J＝70.6Hz,1H),8.99–8.80(m,1H),8.63(s,1H),8.30(d,J＝11.6Hz,2H),8.20(dd,J＝9.7,1.7Hz,1H),8.01(d,J＝28.8Hz,1H),7.55(d,J＝9.2Hz,1H),7.44(t,J＝4.8Hz,1H),7.37(d,J＝6.7Hz,2H),7.33(d,J＝9.6Hz,1H),5.21(m,1H),5.04(m,1H),4.57(m,1H),4.44(s,1H),4.17(m,2H),4.03–3.90(m,2H),3.84(m,1H),3.63(m,1H),3.56(m,2H),2.26–2.09(m,2H),1.83(m,2H),1.74(m,2H),1.60(m,6H),0.97–0.81(m,9H).
实施例A205
LCMS([M+H]+):1062.1
1HNMR(400MHz,DMSO-d6)δ12.22(s,1H),8.77(d,J＝10.0Hz,1H),8.62(s,1H),8.29(s,2H),8.20(d,J＝9.8Hz,1H),7.56(d,J＝8.5Hz,1H),7.37(t,J＝10.7Hz,3H),7.22(s,1H),6.37(d,J＝7.9Hz,1H),5.38–5.29(m,1H),5.06(d,J＝7.3Hz,1H),4.57(d,J＝9.5Hz,1H),4.38(s,2H),4.20–4.08(m,3H),4.00–3.82(m,4H),3.75–3.64(m,2H),3.57(s,2H),3.43(s,2H),2.45(s,3H),1.99(dd,J＝14.4,7.0Hz,3H),1.75(s,2H),1.63(d,J＝18.2Hz,6H),1.45(s,1H),0.89(d,J＝35.1Hz,7H),0.59(s,2H).
实施例A206
LCMS([M+H]+):976.1
1HNMR(400MHz,DMSO-d6)δ12.13(d,J＝72.7Hz,1H),8.77(d,J＝7.7Hz,1H),8.65(s,1H),8.29(q,J＝8.6Hz,2H),8.11(dd,J＝8.4,4.7Hz,3H),7.95(dd,J＝8.4,2.5Hz,1H),7.41–7.19(m,2H),7.06(dd,J＝15.5,8.9Hz,2H),6.32(dd,J＝40.6,6.2Hz,1H),5.67(d,J＝9.3Hz,0H),5.07(d,J＝7.6Hz,1H),4.76(d,J＝8.9Hz,0H),4.56(d,J＝9.4Hz,1H),4.38(s,1H),4.13–3.83(m,5H),3.69(dd,J＝22.9,8.1Hz,1H),3.56(s,1H),3.41(d,J＝8.3Hz,2H),2.46(d,J＝12.6Hz,3H),2.09–1.97(m,1H),1.76(dd,J＝39.5,6.4Hz,3H),1.66–1.52(m,7H),0.94(s,6H),0.59(s,3H).
实施例A207
LCMS([M+H]+):973.3
1HNMR(400MHz,DMSO-d6)δ12.31–11.85(m,1H),8.65(d,J＝2.3Hz,1H),8.35–8.24(m,2H),8.11(t,J＝6.9Hz,3H),7.93(dd,J＝8.5,2.4Hz,1H),7.68(ddd,J＝30.2,8.7,5.5Hz,2H),7.48–7.18(m,2H),7.17–7.03(m,4H),5.37–5.19(m,1H),5.14–5.04(m,1H),4.57(m,1H),4.47(m,1H),4.08(m,2H),4.01–3.90(m,2H),3.86(m,1H),3.64(m,1H),3.56(m,2H),2.30–2.09(m,2H),1.89–1.77(m,2H),1.77–1.67(m,2H),1.58(s,6H),0.98–0.79(m,9H).
实施例A208
LCMS([M+H]+):973.3
1HNMR(400MHz,DMSO-d6)δ12.32–11.83(m,1H),8.63(s,1H),8.34–8.25(m,2H),8.20(dd,J＝9.7,1.8Hz,1H),7.67(m,2H),7.55(d,J＝9.1Hz,1H),7.48–7.08(m,6H),5.20(d,J＝3.7Hz,1H),5.06(t,J＝7.8Hz,1H),4.58(d,J＝9.6Hz,1H),4.47(m,1H),4.17(m,2H),3.96(m,2H),3.85(m,1H),3.69–3.52(m,3H),2.27–2.06(m,2H),1.92–1.80(m,2H),1.74(m,2H),1.60(s,6H),0.99–0.78(m,9H).
实施例A209
LCMS([M+H]+):961.3
1HNMR(400MHz,DMSO-d6)δ12.40–11.86(m,1H),8.65(d,J＝2.4Hz,1H),8.32–8.26(m,2H),8.10(d,J＝8.7Hz,3H),7.94(dd,J＝8.5,2.5Hz,1H),7.41–7.28(m,2H),7.28–7.22(m,1H),7.20–7.11(m,1H),7.07(d,J＝8.9Hz,2H),7.03–6.95(m,1H),5.21(d,J＝3.7Hz,1H),5.13–4.98(m,1H),4.57(d,J＝9.6Hz,1H),4.46–4.44(m,1H),4.08(t,J＝6.2Hz,2H),4.01–3.89(m,2H),3.84(dd,J＝10.6,4.3Hz,1H),3.67–3.62(m,1H),3.60–3.54(m,2H),2.23–2.11(m,2H),1.83–1.78(m,2H),1.75–1.70(m,2H),1.58(s,6H),0.93–0.85(m,9H).
实施例A210
LCMS([M+H]+):1047.3
1HNMR(400MHz,DMSO-d6)δ12.35–11.92(m,1H),8.63(s,1H),8.32–8.27(m,2H),8.20(dd,J＝9.7,1.8Hz,1H),7.55(d,J＝9.2Hz,1H),7.39–7.30(m,4H),7.27–7.23(m,1H),7.16(d,J＝2.5Hz,1H),7.00–6.96(m,1H),5.20(d,J＝3.7Hz,1H),5.09–5.02(m,1H),4.57(d,J＝9.6Hz,1H),4.46–4.43(m,1H),4.17(t,J＝6.1Hz,2H),4.00–3.92(m,2H),3.84(dd,J＝10.6,4.3Hz,1H),3.64–3.55(m,3H),2.22–2.10(m,2H),1.86–1.82(m,2H),1.77–1.72(m,2H),1.60(s,6H),0.93–0.84(m,9H).
实施例A211
LCMS([M+H]+):973.3
1HNMR(400MHz,DMSO-d6)δ12.04(s,1H),8.65(d,J＝2.4Hz,1H),8.34–8.25(m,2H),8.10(d,J＝8.8Hz,3H),7.93(dd,J＝8.5,2.5Hz,1H),7.65–7.44(m,3H),7.34(d,J＝9.5Hz,2H),7.06(d,J＝8.9Hz,2H),6.96(s,1H),5.24(s,1H),5.09(t,J＝7.8Hz,1H),4.58(d,J＝9.6Hz,1H),4.47(d,J＝9.5Hz,1H),4.07(t,J＝6.1Hz,2H),4.01–3.73(m,3H),3.64(dd,J＝14.4,7.8Hz,1H),3.55(t,J＝6.3Hz,2H),2.31–2.11(m,2H),1.81(dt,J＝13.7,6.3Hz,2H),1.71(dq,J＝15.4,8.3,7.0Hz,2H),1.58(s,6H),0.91(d,J＝23.4Hz,9H).
实施例A212
LCMS([M+H]+):1059.3
1HNMR(400MHz,DMSO-d6)δ12.17(d,J＝148.3Hz,1H),8.63(s,1H),8.28(s,2H),8.19(dd,J＝9.7,1.6Hz,1H),7.61–7.42(m,4H),7.42–7.27(m,4H),6.93(td,J＝8.6,2.3Hz,1H),5.21(d,J＝3.6Hz,1H),5.07(t,J＝7.7Hz,1H),4.59(d,J＝9.5Hz,1H),4.46(d,J＝13.4Hz,1H),4.17(t,J＝5.9Hz,2H),3.96(s,2H),3.87(dd,J＝10.4,4.1Hz,1H),3.69–3.60(m,1H),3.56(t,J＝6.2Hz,2H),2.32–2.10(m,2H),1.92–1.79(m,2H),1.74(dt,J＝13.3,6.4Hz,2H),1.60(s,6H),0.96–0.80(m,9H).
实施例A213
LCMS([M+H]+):1042.3
1HNMR(400MHz,DMSO-d6)δ12.51–12.00(m,1H),8.89(dd,J＝19.1,1.9Hz,1H),8.63(s,1H),8.41–8.32(m,1H),8.32–8.25(m,2H),8.19(dd,J＝9.7,1.9Hz,1H),8.00(ddd,J＝13.9,7.9,6.0Hz,1H),7.61(dd,J＝12.5,2.0Hz,1H),7.55(d,J＝9.2Hz,1H),7.43–7.28(m,4H),5.25(t,J＝23.5Hz,1H),5.09(d,J＝7.9Hz,1H),4.57(t,J＝8.1Hz,1H),4.52–4.32(m,1H),4.17(t,J＝6.1Hz,2H),4.05–3.91(m,2H),3.87(dd,J＝10.5,4.1Hz,1H),3.60(dt,J＝12.4,8.3Hz,3H),2.29–2.11(m,2H),1.93–1.68(m,4H),1.60(s,6H),1.00–0.77(m,9H).
实施例A214
LCMS([M+H]+):956.4
1HNMR(400MHz,DMSO-d6)δ12.17(s,1H),8.92(dd,J＝7.7,1.9Hz,1H),8.66(d,J＝2.4Hz,1H),8.36(dd,J＝4.7,1.4Hz,1H),8.34–8.24(m,2H),8.11(t,J＝7.4Hz,3H),8.03(dt,J＝7.9,1.8Hz,1H),7.94(dd,J＝8.5,2.5Hz,1H),7.62(s,1H),7.41–7.30(m,2H),7.07(d,J＝8.9Hz,2H),5.24(d,J＝3.0Hz,1H),5.10(t,J＝7.8Hz,1H),4.59(d,J＝9.6Hz,1H),4.54–4.41(m,1H),4.08(t,J＝6.2Hz,2H),4.02–3.83(m,3H),3.71(dd,J＝38.2,12.9Hz,1H),3.56(t,J＝6.2Hz,2H),2.36–2.10(m,2H),1.92–1.67(m,4H),1.59(s,6H),0.92(d,J＝22.6Hz,9H).
实施例A215
LCMS([M+H]+):1041.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝10.6Hz,1H),8.60(dd,J＝11.6,5.6Hz,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.84(dd,J＝13.0,6.2Hz,3H),7.51(dd,J＝8.4,6.4Hz,1H),7.47–7.29(m,6H),5.16(m,1H),4.57(m,1H),4.50–4.33(m,3H),4.31–4.15(m,3H),4.13(d,J＝2.6Hz,3H),4.02–3.89(m,2H),3.71–3.52(m,4H),2.43(d,J＝7.3Hz,3H),2.07(m,1H),1.89(m,3H),1.80–1.69(m,2H),1.59(d,J＝3.2Hz,6H),0.93(d,J＝7.1Hz,9H).
实施例A216
LCMS([M+H]+):953.3
1HNMR(400MHz,DMSO-d6)δ8.96–8.93(m,1H),8.70(t,J＝6.0Hz,1H),8.65(d,J＝2.4Hz,1H),8.32–8.26(m,2H),8.11(d,J＝8.9Hz,3H),7.94(dd,J＝8.5,2.5Hz,1H),7.78(d,J＝0.7Hz,1H),7.36(d,J＝9.6Hz,1H),7.08(d,J＝8.9Hz,2H),5.16(d,J＝3.5Hz,1H),4.55(d,J＝9.6Hz,1H),4.47(d,J＝6.0Hz,2H),4.39–4.33(m,2H),4.09(t,J＝6.2Hz,2H),3.99–3.90(m,2H),3.68–3.60(m,2H),3.55(t,J＝6.3Hz,2H),2.03–1.98(m,1H),1.86–1.81(m,3H),1.76–1.71(m,2H),1.58(s,6H),0.92(d,J＝14.3Hz,9H).
实施例A217
LCMS([M+H]+):1038.3
1HNMR(400MHz,DMSO-d6)δ8.96–8.93(m,1H),8.70(t,J＝5.9Hz,1H),8.63(d,J＝0.9Hz,1H),8.31–8.27(m,2H),8.20(dd,J＝9.7,1.9Hz,1H),7.79(d,J＝0.6Hz,1H),7.58–7.55(m,1H),7.39–7.35(m,3H),5.15(d,J＝3.5Hz,1H),4.55(d,J＝9.6Hz,1H),4.47(d,J＝6.0Hz,2H),4.39–4.33(m,2H),4.18(t,J＝6.2Hz,2H),3.99–3.90(m,2H),3.68–3.55(m,4H),2.03–1.98(m,1H),1.86–1.80(m,3H),1.78–1.72(m,2H),1.61(s,6H),0.94–0.90(m,9H).
实施例A218
LCMS([M+H]+):937.3
1HNMR(400MHz,DMSO-d6)δ8.65(d,J＝2.5Hz,1H),8.56(t,J＝5.7Hz,1H),8.34–8.21(m,3H),8.11(d,J＝8.9Hz,3H),7.94(dd,J＝8.5,2.5Hz,1H),7.36(d,J＝9.5Hz,1H),7.08(d,J＝8.9Hz,2H),7.03(d,J＝6.5Hz,1H),5.15(m,1H),4.55(m,1H),4.42–4.29(m,4H),4.09(m,2H),4.01–3.87(m,2H),3.61(m,4H),2.02(m,1H),1.91–1.79(m,3H),1.78–1.69(m,2H),1.58(s,6H),0.91(d,J＝10.5Hz,9H).
实施例A219
LCMS([M+H]+):1023.3
1HNMR(400MHz,DMSO-d6)δ8.62(d,J＝0.9Hz,1H),8.56(t,J＝5.7Hz,1H),8.34–8.23(m,3H),8.19(dd,J＝9.7,1.9Hz,1H),7.59–7.53(m,1H),7.38(dd,J＝8.7,6.0Hz,3H),7.03(d,J＝6.7Hz,1H),5.15(m,1H),4.56(m,1H),4.43–4.24(m,4H),4.19(m,2H),4.02–3.86(m,2H),3.61(m,4H),2.02(m,1H),1.91–1.79(m,3H),1.79–1.70(m,2H),1.60(s,6H),0.91(d,J＝10.6Hz,9H).
实施例A220
LCMS([M+H]+):990.3
1HNMR(400MHz,DMSO-d6)δ8.72(s,1H),8.65(d,J＝2.4Hz,1H),8.35–8.24(m,2H),8.11(t,J＝8.5Hz,3H),7.93(dd,J＝8.5,2.5Hz,1H),7.36–7.27(m,2H),7.06(d,J＝8.9Hz,2H),5.23(m,1H),5.07(m,1H),4.55(m,2H),4.08(m,2H),3.94(s,2H),3.86(m,1H),3.78–3.62(m,4H),3.55(m,2H),2.45(s,3H),2.21–2.13(m,1H),1.81(m,2H),1.72(m,2H),1.58(m,6H),0.92–0.75(m,9H).
实施例A221
LCMS([M+H]+):1076.3
1HNMR(400MHz,DMSO-d6)δ8.72(d,J＝4.1Hz,1H),8.63(s,1H),8.33–8.25(m,2H),8.19(dd,J＝9.7,1.8Hz,1H),7.55(d,J＝8.5Hz,1H),7.41–7.25(m,4H),5.22(d,J＝3.8Hz,1H),5.06(t,J＝7.9Hz,1H),4.61–4.47(m,2H),4.17(m,2H),3.95(m,2H),3.86(m,1H),3.73(d,J＝11.7Hz,3H),3.66(m,1H),3.56(m,2H),2.44(s,3H),2.17(m,1H),1.83(m,2H),1.74(m,2H),1.61(s,6H),0.82(d,J＝19.6Hz,9H).
实施例A222
LCMS([M+H]+):939.3
1HNMR(400MHz,DMSO-d6)δ11.59(s,1H),8.65(d,J＝2.4Hz,1H),8.55(d,J＝0.6Hz,1H),8.32–8.26(m,2H),8.11–8.08(m,3H),7.95–7.93(m,1H),7.64–7.59(m,1H),7.33(d,J＝9.5Hz,1H),7.09–7.05(m,2H),5.27(d,J＝3.5Hz,1H),4.58–4.52(m,2H),4.38(s,1H),4.07(t,J＝6.2Hz,2H),3.99–3.91(m,2H),3.73–3.64(m,2H),3.55(t,J＝6.2Hz,2H),2.16–2.11(m,1H),1.94–1.88(m,1H),1.80(dd,J＝14.0,6.2Hz,2H),1.72(dd,J＝13.8,6.1Hz,2H),1.58(s,6H),0.94–0.91(m,9H).
实施例A223
LCMS([M+H]+):1025.3
1HNMR(400MHz,DMSO-d6)δ11.58(s,1H),8.62(d,J＝1.0Hz,1H),8.56–8.54(m,1H),8.31–8.26(m,2H),8.19(dd,J＝9.7,1.9Hz,1H),7.58(d,J＝0.7Hz,1H),7.54–7.52(m,1H),7.38–7.33(m,3H),5.26(d,J＝3.5Hz,1H),4.58–4.51(m,2H),4.38(s,1H),4.16(t,J＝6.2Hz,2H),3.99–3.91(m,2H),3.73–3.64(m,2H),3.56(t,J＝6.2Hz,2H),2.16–2.10(m,1H),1.94–1.80(m,3H),1.76–1.71(m,2H),1.61(s,6H),0.94–0.91(m,9H).
实施例A224
LCMS([M+H]+):1046.2
1HNMR(400MHz,DMSO-d6)δ12.11(s,1H),8.30(d,J＝11.4Hz,2H),8.19(dd,J＝9.7,1.8Hz,1H),8.12(d,J＝6.3Hz,1H),7.55(d,J＝9.2Hz,1H),7.37(d,J＝6.6Hz,2H),7.32(d,J＝9.6Hz,1H),7.24(t,J＝6.8Hz,1H),5.20(d,J＝3.7Hz,1H),5.07(t,J＝7.7Hz,1H),4.56(d,J＝9.5Hz,1H),4.48(s,1H),4.17(t,J＝6.2Hz,2H),4.02–3.90(m,2H),3.84(dd,J＝10.6,4.3Hz,1H),3.63(d,J＝10.3Hz,1H),3.56(t,J＝6.2Hz,2H),2.31(d,J＝14.1Hz,3H),2.24–2.09(m,2H),1.90–1.79(m,2H),1.74(dd,J＝13.8,6.4Hz,2H),1.61(s,6H),0.88(d,J＝30.2Hz,9H).
实施例A225
LCMS([M+H]+):960.0
1HNMR(400MHz,DMSO-d6)δ12.19(d,J＝61.7Hz,1H),8.65(d,J＝2.3Hz,1H),8.33–8.26(m,2H),8.10(d,J＝8.7Hz,4H),7.94(dd,J＝8.5,2.4Hz,1H),7.32(d,J＝9.5Hz,1H),7.25(t,J＝4.1Hz,1H),7.07(d,J＝8.9Hz,2H),5.21(d,J＝3.7Hz,1H),5.08(t,J＝7.6Hz,1H),4.56(d,J＝9.5Hz,1H),4.49(s,1H),4.08(t,J＝6.2Hz,2H),4.01–3.89(m,2H),3.84(dd,J＝10.5,4.3Hz,1H),3.63(d,J＝10.3Hz,1H),3.60–3.49(m,2H),2.35(d,J＝43.7Hz,3H),2.26–2.09(m,2H),1.81(dd,J＝13.9,6.2Hz,2H),1.76–1.66(m,2H),1.58(s,6H),0.89(d,J＝30.6Hz,9H).
实施例A226
LCMS([M+H]+):1078.3
1HNMR(400MHz,DMSO-d6)δ10.64(s,1H),8.96(s,1H),8.69(d,J＝2.3Hz,1H),8.63(t,J＝6.1Hz,1H),8.39–8.17(m,8H),8.00–7.96(m,2H),7.91–7.88(m,2H),7.79–7.75(m,1H),7.40(q,J＝8.4Hz,3H),5.32–5.26(m,2H),4.76(d,J＝9.1Hz,1H),4.49(d,J＝7.9Hz,1H),4.43–4.39(m,2H),4.27(d,J＝5.3Hz,1H),2.43(s,2H),2.11–2.08(m,1H),2.02–1.90(m,2H),1.59(s,6H),1.03–1.01(m,7H).
实施例A227
LCMS([M+H]+):1043.0
1HNMR(400MHz,DMSO-d6)δ12.22(s,1H),9.10–8.93(m,3H),8.61(s,1H),8.31–8.24(m,2H),8.17(dd,J＝9.6,1.9Hz,1H),7.73(t,J＝5.0Hz,1H),7.54(dd,J＝11.0,6.2Hz,1H),7.42–7.28(m,3H),5.25(d,J＝3.6Hz,1H),5.07(t,J＝7.9Hz,1H),4.58(d,J＝9.6Hz,1H),4.46(s,1H),4.16(t,J＝6.1Hz,2H),3.95(s,2H),3.89–3.85(m,1H),2.18(dd,J＝7.5,4.0Hz,2H),2.04–1.91(m,1H),1.88–1.78(m,2H),1.73(dd,J＝13.7,6.2Hz,2H),1.60(d,J＝3.6Hz,6H),0.98–0.79(m,9H).
实施例A228
LCMS([M+H]+):957.1
1HNMR(400MHz,DMSO-d6)δ12.26(s,1H),9.05(s,1H),9.05–8.94(m,1H),8.64(d,J＝2.2Hz,1H),8.33–8.23(m,2H),8.09(t,J＝7.3Hz,3H),7.93(dd,J＝8.5,2.4Hz,1H),7.73(s,1H),7.32(d,J＝9.5Hz,1H),7.07(t,J＝7.2Hz,2H),5.33–5.21(m,1H),5.08(t,J＝7.9Hz,1H),4.57(d,J＝9.6Hz,1H),4.47(s,1H),4.07(t,J＝6.2Hz,2H),4.00–3.83(m,3H),3.67(s,1H),2.18(dd,J＝7.5,4.1Hz,1H),1.80(dd,J＝14.0,6.3Hz,2H),1.70(dd,J＝13.7,7.0Hz,2H),1.57(s,6H),0.97–0.79(m,9H).
实施例A229
LCMS([M+H]+):1065.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.66(d,J＝2.2Hz,1H),8.61(t,J＝5.9Hz,1H),8.34–8.24(m,2H),8.13(dd,J＝8.5,4.7Hz,3H),8.07(dd,J＝8.8,5.6Hz,1H),7.95(dd,J＝8.5,2.2Hz,1H),7.72(t,J＝7.8Hz,1H),7.40(q,J＝7.9Hz,6H),7.18(d,J＝8.8Hz,2H),5.28(s,2H),5.18(d,J＝3.4Hz,1H),4.75(m,1H),4.53–4.35(m,3H),4.26(m,1H),3.73(m,2H),2.44(s,3H),2.07(m,1H),1.93(m,1H),1.58(s,6H),1.01(d,J＝9.1Hz,9H).
实施例A230
LCMS([M+H]+):978.3
1HNMR(400MHz,DMSO-d6)δ9.23(d,J＝4.7Hz,1H),8.65(d,J＝2.4Hz,1H),8.34–8.24(m,2H),8.10(dd,J＝8.8,2.4Hz,3H),7.94(dd,J＝8.5,2.5Hz,1H),7.39(d,J＝9.5Hz,1H),7.06(d,J＝8.9Hz,2H),5.41–5.34(m,1H),5.26(m,1H),4.62(m,1H),4.46(m,1H),4.07(m,2H),4.01–3.84(m,3H),3.73(m,1H),3.54(m,2H),2.69(m,3H),2.33–2.18(m,2H),1.80(m,2H),1.72(m,2H),1.58(s,6H),0.93(d,J＝5.2Hz,9H).
实施例A231
LCMS([M+H]+):1064.2
1HNMR(400MHz,DMSO-d6)δ9.24(s,1H),8.62(s,1H),8.29(d,J＝3.1Hz,2H),8.19(dd,J＝9.7,1.9Hz,1H),7.54(d,J＝9.2Hz,1H),7.38(dd,J＝11.7,8.1Hz,3H),5.37(d,J＝3.9Hz,1H),5.25(t,J＝8.1Hz,1H),4.62(m,1H),4.45(m,1H),4.16(m,2H),3.98(m,2H),3.89(m,1H),3.72(m,1H),3.55(m,2H),2.69(d,J＝14.7Hz,3H),2.34–2.18(m,2H),1.82(m,2H),1.73(m,2H),1.61(s,6H),0.91(s,9H).
实施例A232
LCMS([M+H]+):959.4
1HNMR(400MHz,DMSO-d6)δ9.09(s,1H),8.71(d,J＝2.3Hz,1H),8.36(d,J＝6.3Hz,2H),8.24–8.11(m,3H),8.01(dd,J＝8.5,2.4Hz,1H),7.72(d,J＝45.5Hz,2H),7.40(d,J＝9.5Hz,1H),7.13(d,J＝8.9Hz,2H),5.18(t,J＝7.9Hz,1H),4.64(d,J＝9.5Hz,1H),4.15(t,J＝6.2Hz,2H),4.02(dd,J＝10.5,8.9Hz,5H),3.91(s,1H),3.73(d,J＝10.6Hz,2H),3.62(t,J＝6.3Hz,3H),2.26(d,J＝7.2Hz,3H),1.93–1.73(m,4H),1.65(s,6H),0.95(d,J＝28.8Hz,9H).
实施例A233
LCMS([M+H]+):1045.3
1HNMR(400MHz,DMSO-d6)δ8.81(s,1H),8.62(s,1H),8.34–8.23(m,2H),8.18(dd,J＝9.7,1.7Hz,1H),7.64–7.52(m,2H),7.49(d,J＝4.2Hz,1H),7.42–7.26(m,3H),5.29(d,J＝7.2Hz,1H),5.09(t,J＝7.8Hz,1H),4.57(d,J＝9.6Hz,1H),4.47(s,1H),4.16(t,J＝6.1Hz,2H),3.98–3.82(m,7H),2.25–2.13(m,3H),1.89–1.78(m,2H),1.74(dd,J＝14.0,6.3Hz,2H),1.60(d,J＝2.7Hz,6H),1.26(td,J＝7.3,3.9Hz,2H),0.87(d,J＝25.8Hz,9H).
实施例A234
LCMS([M+H]+):1012.3
1HNMR(400MHz,DMSO-d6)δ11.98(s,1H),8.64(d,J＝2.4Hz,1H),8.36–8.24(m,4H),8.09(d,J＝8.8Hz,3H),7.95–7.90(m,1H),7.77(s,4H),7.57(s,1H),7.32(d,J＝9.4Hz,1H),7.06(d,J＝8.8Hz,2H),5.21(s,1H),5.08(t,J＝7.6Hz,1H),4.58(d,J＝9.4Hz,1H),4.49(s,1H),4.08(t,J＝6.2Hz,2H),4.00–3.91(m,2H),3.86(d,J＝6.2Hz,1H),3.64(d,J＝10.4Hz,1H),3.56(t,J＝6.3Hz,2H),2.77(d,J＝4.4Hz,3H),2.04–1.93(m,1H),1.87–1.67(m,4H),1.58(s,6H),1.51–1.41(m,1H),0.97–0.85(m,9H).
实施例A235
LCMS([M+H]+):1098.3
1HNMR(400MHz,DMSO-d6)δ8.95(s,1H),8.63(s,1H),8.59(t,J＝6.0Hz,1H),8.29(s,2H),8.16(dd,J＝11.9,1.9Hz,1H),7.87–7.79(m,2H),7.47(t,J＝6.9Hz,1H),7.40(d,J＝4.2Hz,5H),5.16(s,1H),4.59(d,J＝9.6Hz,1H),4.49–4.39(m,2H),4.38–4.33(m,3H),4.24(dd,J＝15.9,5.5Hz,1H),4.10(s,2H),3.96–3.88(m,2H),3.69(dd,J＝10.6,3.8Hz,1H),3.63(d,J＝10.9Hz,1H),2.43(s,3H),2.10–2.02(m,1H),1.92(ddd,J＝12.9,8.8,4.5Hz,1H),1.62(s,6H),0.94(s,9H).
实施例A236
LCMS([M+H]+):1078.3
1HNMR(400MHz,DMSO-d6)δ10.75(s,1H),8.98(s,1H),8.70(d,J＝2.5Hz,1H),8.60(t,J＝6.1Hz,1H),8.41(d,J＝9.0Hz,1H),8.33–8.26(m,2H),8.21–8.17(m,3H),7.91–7.86(m,1H),7.88(dd,J＝14.7,7.1Hz,4H),7.82–7.75(m,1H),7.44–7.39(m,4H),5.18(d,J＝3.6Hz,1H),4.81(d,J＝9.0Hz,1H),4.50–4.40(m,3H),4.25(dd,J＝15.9,5.6Hz,1H),3.74(s,2H),2.45(s,3H),2.09–2.05(m,1H),1.97–1.90(m,1H),1.60(s,6H),1.05–1.02(m,9H).
实施例A237
LCMS([M+H]+):1063.3
1HNMR(400MHz,DMSO-d6)δ8.94(s,1H),8.62(s,1H),8.37(s,1H),8.29–8.28(m,2H),8.19(dd,J＝9.7,1.9Hz,1H),7.54(d,J＝9.3Hz,1H),7.38–7.34(m,3H),5.32(d,J＝3.8Hz,1H),5.07(t,J＝8.2Hz,1H),4.61(d,J＝9.6Hz,1H),4.43(s,1H),4.16(t,J＝6.2Hz,2H),3.96(s,2H),3.86(dd,J＝10.6,4.1Hz,1H),3.70(d,J＝11.0Hz,1H),3.56(t,J＝6.3Hz,2H),2.48(s,3H),2.30–2.23(m,1H),2.10–2.06(m,1H),1.84–1.82(m,2H),1.75–1.71(m,2H),1.61(s,6H),0.94–0.91(m,9H).
实施例A238
LCMS([M+H]+):1079.1
1HNMR(400MHz,DMSO-d6)δ8.92(d,J＝3.6Hz,1H),8.62(s,1H),8.33–8.25(m,2H),8.19(dd,J＝9.7,1.8Hz,1H),7.73(d,J＝5.5Hz,1H),7.55(d,J＝9.2Hz,1H),7.40(dd,J＝17.2,7.9Hz,3H),5.36(t,J＝7.4Hz,1H),5.29(s,1H),4.63(d,J＝9.5Hz,1H),4.44(s,1H),4.17(t,J＝6.2Hz,2H),4.04–3.90(m,2H),3.85(dd,J＝10.7,4.6Hz,1H),3.69(dd,J＝10.7,2.9Hz,1H),3.57(t,J＝6.2Hz,2H),2.58(s,3H),2.26(dd,J＝7.2,4.8Hz,2H),1.84(dd,J＝13.8,6.3Hz,2H),1.79–1.68(m,2H),1.60(s,6H),0.93(s,9H).
实施例A239
LCMS([M+H]+):1065.3
1HNMR(400MHz,DMSO-d6)δ8.95(d,J＝23.2Hz,1H),8.65(dd,J＝6.7,2.4Hz,1H),8.58(t,J＝6.0Hz,1H),8.34–8.22(m,3H),8.18–8.07(m,3H),7.95(dd,J＝8.5,2.5Hz,1H),7.81–7.64(m,3H),7.46–7.37(m,3H),7.13(dd,J＝51.5,8.9Hz,3H),5.17(d,J＝3.5Hz,1H),4.77(d,J＝9.1Hz,1H),4.45(dd,J＝16.8,8.9Hz,2H),4.39(d,J＝6.4Hz,1H),4.24(dd,J＝15.8,5.4Hz,1H),4.13–4.05(m,1H),3.73(s,2H),2.58(s,1H),2.44(s,3H),2.10–2.02(m,1H),1.96–1.89(m,1H),1.58(s,6H),1.09–0.89(m,9H).
实施例A240
LCMS([M+H]+):1074.3
1HNMR(400MHz,DMSO-d6)δ10.40–10.38(m,1H),8.97(d,J＝10.0Hz,1H),8.69(d,J＝2.6Hz,1H),8.59(t,J＝6.0Hz,1H),8.33–8.28(m,2H),8.27–8.15(m,4H),8.02–7.89(m,5H),7.48–7.37(m,6H),5.14(d,J＝3.5Hz,1H),4.55(d,J＝9.4Hz,1H),4.47–4.41(m,2H),4.35(s,1H),4.22(dd,J＝15.8,5.4Hz,1H),3.77(d,J＝14.0Hz,1H),3.68–3.62(m,2H),3.57(d,J＝13.9Hz,1H),2.45–2.43(m,3H),2.08–1.99(m,1H),1.95–1.87(m,1H),1.59(s,6H),0.93–0.90(m,9H).
实施例A241
LCMS([M+H]+):1110.3
1HNMR(400MHz,DMSO-d6)δ11.98(s,1H),8.62(s,1H),8.36–8.27(m,4H),8.19(d,J＝9.7Hz,1H),7.85–7.74(m,5H),7.59–7.53(m,2H),7.41–7.31(m,4H),5.32(t,J＝4.7Hz,2H),5.20(d,J＝3.7Hz,1H),5.08(t,J＝7.8Hz,2H),4.58(d,J＝9.4Hz,1H),4.48(s,1H),4.16(d,J＝6.5Hz,2H),3.96(s,2H),3.86(s,2H),3.66(s,1H),3.57(d,J＝6.2Hz,3H),2.77(d,J＝4.4Hz,3H),2.03–1.94(m,4H),1.84(s,2H),1.73(s,2H),1.60(s,6H),1.45(s,2H),0.95–0.85(m,8H).
实施例A242
LCMS([M+H]+):993.1
1HNMR(400MHz,DMSO-d6)δ8.92(s,1H),8.65(d,J＝2.4Hz,1H),8.29(q,J＝8.4Hz,2H),8.10(d,J＝8.8Hz,3H),7.93(dd,J＝8.5,2.5Hz,1H),7.74(d,J＝11.5Hz,1H),7.41(d,J＝9.5Hz,1H),7.07(d,J＝8.9Hz,2H),5.36(t,J＝7.5Hz,1H),5.29(d,J＝4.1Hz,1H),4.63(d,J＝9.4Hz,1H),4.44(d,J＝3.8Hz,1H),4.08(t,J＝6.2Hz,2H),4.02–3.91(m,2H),3.85(dd,J＝10.6,4.6Hz,1H),3.69(dd,J＝10.9,2.9Hz,1H),3.56(t,J＝6.2Hz,2H),2.57(d,J＝4.9Hz,3H),2.26(dd,J＝7.4,4.6Hz,2H),1.81(dd,J＝14.0,6.5Hz,2H),1.77–1.68(m,2H),1.58(s,6H),0.92(d,J＝6.1Hz,9H).
实施例A243
LCMS([M+H]+):1088.4
1HNMR(400MHz,DMSO-d6)δ10.41(s,1H),8.98(s,1H),8.66(d,J＝2.4Hz,1H),8.57(t,J＝6.0Hz,1H),8.34–8.24(m,2H),8.14–8.09(m,4H),7.96(dd,J＝8.5,2.4Hz,1H),7.76(d,J＝8.8Hz,2H),7.40(q,J＝8.3Hz,4H),7.24(q,J＝8.2Hz,4H),5.12(d,J＝3.5Hz,1H),4.51(d,J＝9.3Hz,1H),4.43(dd,J＝15.5,7.1Hz,2H),4.33(s,1H),4.21(dd,J＝15.9,5.3Hz,1H),3.65–3.61(m,4H),3.45(s,2H),2.44–2.43(m,3H),2.06–1.97(m,1H),1.93–1.85(m,1H),1.58(s,6H),0.92–0.89(m,9H).
实施例A244
LCMS([M+H]+):1074.3
1HNMR(400MHz,DMSO-d6)δ10.43(s,1H),8.97(d,J＝6.1Hz,1H),8.67(d,J＝2.2Hz,1H),8.58(t,J＝6.0Hz,1H),8.29(q,J＝8.6Hz,2H),8.13(dd,J＝8.6,3.1Hz,3H),7.99–7.91(m,2H),7.85(d,J＝8.2Hz,2H),7.76(d,J＝8.7Hz,2H),7.54–7.35(m,6H),5.16(m,1H),4.77(m,1H),4.50–4.35(m,3H),4.24(m,1H),3.74(m,4H),2.43(d,J＝5.9Hz,3H),2.06–1.89(m,2H),1.58(s,6H),1.01(d,J＝10.8Hz,9H).
实施例A245
LCMS([M+H]+):997.1
1HNMR(400MHz,DMSO-d6)δ9.03(s,1H),8.65(d,J＝2.3Hz,1H),8.29(q,J＝8.6Hz,2H),8.16–8.05(m,3H),7.94(dd,J＝8.5,2.4Hz,1H),7.41(s,1H),7.36(d,J＝9.6Hz,1H),7.06(d,J＝8.8Hz,2H),5.32(d,J＝3.8Hz,1H),5.10(t,J＝8.0Hz,1H),4.61(d,J＝9.5Hz,1H),4.43(s,1H),4.07(t,J＝6.2Hz,2H),4.01–3.90(m,2H),3.86(dd,J＝10.6,4.2Hz,1H),3.70(d,J＝10.3Hz,1H),3.55(t,J＝6.2Hz,2H),2.49–2.48(m,3H),2.28–2.20(m,1H),2.15–2.05(m,1H),1.86–1.76(m,2H),1.76–1.66(m,2H),1.58(s,6H),0.92(s,9H).
实施例A246
LCMS([M+H]+):1063.1
1HNMR(400MHz,DMSO-d6)δ9.04(d,J＝4.8Hz,1H),8.62(s,1H),8.32–8.25(m,2H),8.19(dd,J＝9.7,1.8Hz,1H),7.54(d,J＝9.2Hz,1H),7.37(dd,J＝12.6,6.5Hz,4H),5.32(d,J＝3.9Hz,1H),5.09(t,J＝8.1Hz,1H),4.61(d,J＝9.5Hz,1H),4.43(s,1H),4.16(t,J＝6.1Hz,2H),3.96(s,2H),3.86(dd,J＝10.6,4.1Hz,1H),3.70(d,J＝10.8Hz,1H),3.56(t,J＝6.2Hz,2H),2.28–2.20(m,1H),2.15–2.08(m,1H),1.88–1.79(m,2H),1.74(dd,J＝13.9,6.2Hz,2H),1.61(s,6H),0.92(s,9H).
实施例A247
LCMS([M+H]+):1039.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝3.8Hz,1H),8.60(t,J＝6.0Hz,1H),8.29–8.21(m,2H),8.19(d,J＝2.6Hz,1H),7.76(dd,J＝8.8,2.7Hz,1H),7.45–7.33(m,5H),6.96(d,J＝8.8Hz,1H),5.18(d,J＝3.5Hz,1H),4.55(m,1H),4.49–4.32(m,3H),4.30–4.20(m,3H),3.95–3.86(m,2H),3.64(m,2H),3.53(m,2H),3.36(m,2H),2.43(d,J＝4.8Hz,3H),2.06(m,1H),1.90(m,1H),1.81–1.66(m,4H),1.53(m,8H),1.46–1.36(m,2H),0.92(d,J＝6.9Hz,9H).
实施例A248
LCMS([M+H]+):1025.1
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝4.6Hz,1H),8.60(t,J＝6.0Hz,1H),8.29–8.22(m,2H),8.19(d,J＝2.5Hz,1H),7.77(dd,J＝8.8,2.7Hz,1H),7.46–7.32(m,5H),7.01–6.94(m,1H),5.18(d,J＝2.7Hz,1H),4.55(d,J＝9.6Hz,1H),4.48–4.33(m,3H),4.26(dt,J＝15.9,6.0Hz,3H),3.94–3.85(m,2H),3.70–3.46(m,8H),2.43(d,J＝4.6Hz,3H),2.06(t,J＝10.3Hz,1H),1.95–1.85(m,1H),1.83–1.69(m,4H),1.61(dt,J＝13.0,6.4Hz,2H),1.51(s,6H),0.92(d,J＝7.2Hz,9H).
实施例A252
LCMS([M+H]+):1088.4
1HNMR(400MHz,DMSO-d6)δ10.36(s,1H),8.98(s,1H),8.69(d,J＝2.5Hz,1H),8.56(t,J＝6.0Hz,1H),8.34–8.25(m,2H),8.17(d,J＝8.8Hz,3H),7.99–7.95(m,4H),7.91(d,J＝8.2Hz,2H),7.40(q,J＝8.4Hz,6H),5.16(d,J＝3.5Hz,1H),4.56(d,J＝9.4Hz,1H),4.46–4.41(m,2H),4.36(s,1H),4.22(dd,J＝15.8,5.5Hz,1H),3.67–3.64(m,2H),2.96–2.87(m,2H),2.69–2.62(m,1H),2.44(s,3H),2.09–2.00(m,1H),1.96–1.86(m,1H),1.59(s,6H),0.91–0.89(m,9H).
实施例A254
LCMS([M+H]+):1011.1
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝8.0Hz,1H),8.58(t,J＝6.0Hz,1H),8.30–8.22(m,2H),8.18(d,J＝2.5Hz,1H),7.76(dd,J＝8.8,2.7Hz,1H),7.49–7.34(m,5H),6.95(d,J＝8.8Hz,1H),5.16(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.47–4.32(m,3H),4.25(dt,J＝15.8,5.9Hz,3H),3.94(d,J＝16.8Hz,2H),3.68–3.49(m,8H),2.43(d,J＝6.8Hz,3H),2.04(dd,J＝18.4,10.1Hz,1H),1.95–1.85(m,1H),1.76(dd,J＝14.2,6.5Hz,2H),1.66(dd,J＝14.1,6.5Hz,2H),1.51(s,6H),0.92(d,J＝8.6Hz,9H).
实施例A255
LCMS([M+H]+):983.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝8.5Hz,1H),8.63(dt,J＝40.5,5.8Hz,1H),8.31–8.23(m,2H),8.21–8.16(m,1H),7.77(dd,J＝8.8,2.1Hz,1H),7.48–7.35(m,5H),7.02(t,J＝9.6Hz,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.49–4.33(m,5H),4.25(dd,J＝15.8,5.6Hz,1H),3.97(d,J＝15.4Hz,2H),3.88–3.76(m,2H),3.71–3.58(m,6H),2.44(d,J＝6.2Hz,3H),2.12–2.01(m,1H),1.96–1.85(m,1H),1.51(d,J＝3.5Hz,6H),0.92(d,J＝7.4Hz,9H).
实施例A256
LCMS([M+H]+):1160.3
1HNMR(400MHz,DMSO-d6)δ10.68(s,1H),8.97(s,1H),8.65(s,1H),8.58(t,J＝5.7Hz,1H),8.41(s,1H),8.34–8.18(m,5H),7.94(d,J＝8.0Hz,2H),7.65(d,J＝8.4Hz,1H),7.47(d,J＝8.1Hz,2H),7.41(q,J＝8.2Hz,4H),5.16(d,J＝3.3Hz,1H),4.54(d,J＝9.3Hz,1H),4.48–4.40(m,2H),4.35(s,1H),4.22(dd,J＝15.9,5.4Hz,1H),3.78(d,J＝13.8Hz,1H),3.65(d,J＝5.2Hz,2H),3.59(s,1H),2.45(s,3H),2.03(d,J＝7.0Hz,1H),1.92(d,J＝12.9Hz,1H),1.68–1.55(m,6H),0.93(s,9H).
实施例A257
LCMS([M+H]+):939.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.96(m,1H),8.59(t,J＝5.9Hz,1H),8.32–8.24(m,2H),8.21(d,J＝2.6Hz,1H),7.74(d,J＝8.8Hz,1H),7.50(d,J＝9.5Hz,1H),7.46–7.35(m,4H),7.18–7.10(m,1H),5.16(d,J＝3.5Hz,1H),4.59(d,J＝9.6Hz,1H),4.54–4.42(m,3H),4.39–4.25(m,3H),4.06–4.01(m,2H),3.88(t,J＝4.3Hz,2H),3.72–3.57(m,2H),2.45–2.42(m,3H),2.11–2.02(m,1H),1.97–1.88(m,1H),1.57–1.42(m,6H),0.95(s,9H).
实施例A260
LCMS([M+H]+):923.3
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.55(t,J＝6.0Hz,1H),8.31–8.23(m,2H),8.20(d,J＝2.6Hz,1H),7.96(d,J＝9.3Hz,1H),7.79(dd,J＝8.8,2.6Hz,1H),7.40(q,J＝8.3Hz,4H),6.99(d,J＝8.8Hz,1H),5.13(d,J＝3.5Hz,1H),4.56(d,J＝9.3Hz,1H),4.48–4.39(m,2H),4.35(s,1H),4.30(t,J＝6.5Hz,2H),4.22(dd,J＝15.8,5.4Hz,1H),3.74–3.61(m,2H),2.47–2.39(m,4H),2.36–2.29(m,1H),2.10–1.85(m,4H),1.52–1.50(m,6H),0.94–0.92(m,9H).
实施例A262
LCMS([M+H]+):997.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝9.3Hz,1H),8.59(t,J＝6.0Hz,1H),8.30–8.23(m,2H),8.19(dd,J＝7.2,2.6Hz,1H),7.77(dd,J＝8.8,2.7Hz,1H),7.48–7.35(m,5H),6.97(dd,J＝17.2,8.9Hz,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.49–4.31(m,5H),4.24(m,1H),3.95(m,2H),3.71–3.53(m,8H),2.44(M,J＝6.2Hz,3H),2.10–1.95(m,3H),1.90(m,1H),1.51(d,J＝1.8Hz,6H),0.92(d,J＝7.7Hz,9H).
实施例A263
LCMS([M+H]+):895.2
1HNMR(400MHz,DMSO-d6)δ8.98(d,J＝0.8Hz,1H),8.58(t,J＝6.0Hz,1H),8.31–8.22(m,2H),8.21–8.15(m,1H),7.85(ddd,J＝8.5,7.1,5.6Hz,2H),7.44–7.35(m,4H),7.13(d,J＝8.8Hz,1H),5.15(d,J＝3.4Hz,1H),4.91(q,J＝14.9Hz,2H),4.57(d,J＝9.5Hz,1H),4.49–4.33(m,3H),4.24(dd,J＝15.9,5.5Hz,1H),3.64(dt,J＝23.4,7.3Hz,2H),2.44(s,3H),2.09–2.01(m,1H),1.95–1.85(m,1H),1.49(dd,J＝18.1,7.2Hz,6H),0.89(d,J＝15.8Hz,9H).
实施例A264
LCMS([M+H]+):913.2
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.59(t,J＝6.0Hz,1H),8.28–8.22(m,2H),8.11(d,J＝9.4Hz,1H),8.03(ddd,J＝9.1,5.9,2.1Hz,2H),7.41(q,J＝8.4Hz,4H),5.08(d,J＝14.6Hz,2H),5.01–4.95(m,1H),4.58(d,J＝9.4Hz,1H),4.43(ddd,J＝32.4,19.0,11.7Hz,3H),4.24(dd,J＝15.8,5.5Hz,1H),3.70–3.58(m,2H),2.45(s,3H),2.11–2.02(m,1H),1.91(ddd,J＝12.9,8.7,4.5Hz,1H),1.56–1.45(m,6H),0.92(d,J＝14.2Hz,9H).
实施例A265
LCMS([M+H]+):1001.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝9.6Hz,1H),8.58(t,J＝6.0Hz,1H),8.29–8.21(m,2H),8.05(t,J＝1.9Hz,1H),7.96(dd,J＝10.7,2.1Hz,1H),7.47–7.36(m,5H),4.56(dd,J＝10.9,6.1Hz,3H),4.41(ddd,J＝24.7,14.3,8.5Hz,3H),4.29–4.21(m,1H),3.95(d,J＝17.0Hz,2H),3.91–3.79(m,2H),3.73–3.56(m,4H),2.44(d,J＝6.2Hz,3H),2.08–2.01(m,1H),1.90(ddd,J＝13.0,8.8,4.5Hz,1H),1.54(s,6H),0.91(d,J＝8.3Hz,9H).
实施例A266
LCMS([M+H]+):1051.3
1HNMR(400MHz,DMSO-d6)δ8.84(d,J＝6.8Hz,1H),8.47(t,J＝2.5Hz,1H),8.22(d,J＝2.5Hz,1H),8.19–8.10(m,2H),7.86(t,J＝5.9Hz,1H),7.43(ddd,J＝23.9,17.3,8.9Hz,5H),4.77–4.52(m,6H),4.46–4.32(m,2H),4.05–3.89(m,4H),3.89–3.70(m,6H),2.47(d,J＝3.3Hz,3H),2.20–2.13(m,2H),1.72(d,J＝4.2Hz,3H),1.67(d,J＝4.6Hz,3H),0.99(s,9H).
实施例A267
LCMS([M+H]+):1015.3
1HNMR(400MHz,DMSO-d6)δ8.84(d,J＝7.8Hz,1H),8.19–8.10(m,2H),8.06(dd,J＝4.9,3.0Hz,1H),7.87(t,J＝5.8Hz,1H),7.78(dd,J＝10.5,2.2Hz,1H),7.51–7.32(m,5H),4.72–4.51(m,7H),4.47(d,J＝3.5Hz,1H),4.34(dd,J＝15.4,5.2Hz,1H),3.98(m,2H),3.88–3.83(m,1H),3.80–3.64(m,8H),2.47(d,J＝2.7Hz,3H),2.18–2.10(m,5H),1.66(d,J＝13.8Hz,6H),1.00(s,9H).
实施例A268
LCMS([M+H]+):957.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.97(m,1H),8.58(t,J＝6.0Hz,1H),8.31–8.21(m,2H),8.08(d,J＝2.0Hz,1H),7.95(dt,J＝10.7,1.9Hz,1H),7.51–7.33(m,5H),5.16(d,J＝3.5Hz,1H),4.67–4.52(m,3H),4.48–4.33(m,3H),4.25(dd,J＝15.8,5.7Hz,1H),4.07–4.03(m,2H),3.92(t,J＝4.6Hz,2H),3.69–3.60(m,2H),2.45–2.43(m,3H),2.08–2.01(m,1H),1.96–1.85(m,1H),1.54(s,6H),0.92–0.90(m,9H).
实施例A269
LCMS([M+H]+):1007.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.64–8.49(m,2H),8.36–8.17(m,3H),7.43–7.39(m,5H),5.14(d,J＝3.1Hz,1H),4.72–4.52(m,3H),4.47–4.32(m,3H),4.25(dd,J＝15.4,5.5Hz,1H),4.07–4.03(m,2H),3.92(s,2H),3.64(dd,J＝25.7,8.9Hz,2H),2.43(s,3H),2.05–2.03(m,1H),1.90(s,1H),1.56(d,J＝4.3Hz,6H),0.92–0.90(m,9H).
实施例A270
LCMS([M+H]+):1095.3
1HNMR(400MHz,DMSO-d6)δ8.96–8.95(m,1H),8.58(t,J＝6.0Hz,1H),8.50(d,J＝2.3Hz,1H),8.30–8.19(m,3H),7.46–7.34(m,5H),5.18(d,J＝3.5Hz,1H),4.58–4.54(m,3H),4.47–4.31(m,3H),4.24(dd,J＝15.8,5.6Hz,1H),3.95–3.91(m,2H),3.81–3.75(m,2H),3.65–3.54(m,12H),2.44–2.43(m,3H),2.06(t,J＝10.3Hz,1H),1.95–1.84(m,1H),1.55(d,J＝5.5Hz,6H),0.93–0.91(m,9H).
实施例A271
LCMS([M+H]+):1065.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝11.1Hz,1H),8.57(t,J＝6.0Hz,1H),8.50(t,J＝3.7Hz,1H),8.32–8.19(m,3H),7.47–7.33(m,5H),5.14(d,J＝3.5Hz,1H),4.59–4.48(m,3H),4.48–4.32(m,3H),4.24(m,1H),3.94(m,2H),3.70–3.52(m,8H),2.44(d,J＝7.4Hz,3H),2.09–1.96(m,3H),1.90(m,1H),1.56(d,J＝4.8Hz,6H),0.91(d,J＝8.7Hz,9H).
实施例A272
LCMS([M+H]+):1093.1
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝5.7Hz,1H),8.59(t,J＝6.1Hz,1H),8.51(d,J＝2.3Hz,1H),8.31–8.20(m,3H),7.46–7.33(m,5H),5.14(d,J＝3.4Hz,1H),4.55(d,J＝9.6Hz,1H),4.50–4.33(m,6H),4.25(dd,J＝15.8,5.7Hz,2H),3.91(s,2H),3.69–3.59(m,3H),3.53(t,J＝6.4Hz,2H),3.45(dd,J＝14.1,6.6Hz,5H),2.68(d,J＝7.8Hz,2H),2.43(s,3H),2.10–1.94(m,3H),1.90(s,2H),1.84–1.73(m,4H),1.69–1.60(m,2H),1.56(d,J＝4.9Hz,5H),0.92(d,J＝7.5Hz,9H).
实施例A274
LCMS([M+H]+):997.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝11.0Hz,1H),8.58(t,J＝6.0Hz,1H),8.32–8.20(m,2H),8.00(s,1H),7.65(d,J＝1.9Hz,1H),7.48–7.31(m,5H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.52–4.31(m,5H),4.24(dd,J＝15.8,5.6Hz,1H),3.97(d,J＝15.8Hz,2H),3.90–3.76(m,2H),3.74–3.58(m,6H),2.44(d,J＝7.2Hz,3H),2.19(d,J＝9.4Hz,3H),2.13–2.01(m,1H),1.91(ddd,J＝13.0,8.8,4.5Hz,1H),1.51(d,J＝5.4Hz,6H),0.92(d,J＝7.4Hz,9H).
实施例A275
LCMS([M+H]+):1045.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.97(m,1H),8.59(t,J＝6.0Hz,1H),8.26–8.23(m,2H),8.07(d,J＝2.1Hz,1H),7.97(dd,J＝10.7,2.1Hz,1H),7.48–7.35(m,5H),5.15(d,J＝3.5Hz,1H),4.60–4.49(m,3H),4.48–4.32(m,3H),4.24(dd,J＝15.8,5.5Hz,1H),3.96–3.92(m,2H),3.84–3.75(m,2H),3.70–3.55(m,10H),2.45–2.43(m,3H),2.08–2.03(m,1H),1.90(ddd,J＝12.7,8.6,4.4Hz,1H),1.54(d,J＝1.2Hz,6H),0.94–0.91(d,J＝8.6Hz,9H).
实施例A276
LCMS([M+H]+):1079.3
1HNMR(400MHz,DMSO-d6)δ8.95(s,1H),8.58(t,J＝6.0Hz,1H),8.50(d,J＝2.3Hz,1H),8.30–8.19(m,3H),7.40(d,J＝6.6Hz,5H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.51–4.31(m,5H),4.25(dd,J＝15.8,5.6Hz,1H),3.96(s,2H),3.68–3.48(m,8H),2.43(s,3H),2.10–2.02(m,1H),1.90(ddd,J＝12.9,8.9,4.5Hz,1H),1.86–1.75(m,2H),1.67(p,J＝6.5Hz,2H),1.56(d,J＝5.1Hz,6H),0.93(s,9H).
实施例A277
LCMS([M+H]+):1041.4
1HNMR(400MHz,DMSO-d6)δ8.98–8.96(m,1H),8.60(t,J＝6.0Hz,1H),8.31–8.22(m,2H),8.02(d,J＝2.3Hz,1H),7.66(s,1H),7.47–7.34(m,5H),5.18–5.17(m,1H),4.56(d,J＝9.6Hz,1H),4.46–4.36(m,5H),4.24(dd,J＝15.8,5.7Hz,1H),3.96–3.92(m,2H),3.80–3.74(m,2H),3.66–3.58(m,10H),2.44–2.43(m,3H),2.19–2.18(m,3H),2.11–1.97(m,2H),1.94–1.85(m,1H),1.51(d,J＝6.2Hz,6H),0.93–0.91(m,9H).
实施例A278
LCMS([M+H]+):997.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝8.7Hz,1H),8.59(t,J＝5.9Hz,1H),8.31(dt,J＝40.9,6.0Hz,2H),7.74–7.55(m,1H),7.48–7.36(m,5H),6.85–6.73(m,1H),5.15(d,J＝3.4Hz,1H),4.56(d,J＝9.6Hz,1H),4.48–4.31(m,5H),4.29–4.17(m,1H),3.96(d,J＝15.1Hz,2H),3.85–3.74(m,2H),3.70–3.57(m,6H),2.44(d,J＝7.0Hz,3H),2.33(dd,J＝19.2,7.7Hz,3H),2.06(dd,J＝14.3,6.0Hz,1H),1.90(ddd,J＝13.0,8.8,4.5Hz,1H),1.63–1.55(m,3H),1.50–1.41(m,3H),0.92(d,J＝7.8Hz,9H).
实施例A279
LCMS([M+H]+):1029.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.58(t,J＝5.9Hz,1H),8.25(d,J＝3.6Hz,2H),8.06(dd,J＝6.2,2.1Hz,1H),7.95(dd,J＝10.7,2.1Hz,1H),7.39(s,5H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.41(dq,J＝14.3,7.7,7.3Hz,5H),4.24(dd,J＝15.8,5.6Hz,1H),3.97(s,2H),3.71–3.53(m,6H),3.53–3.47(m,2H),2.43(s,3H),2.06(dd,J＝15.1,6.4Hz,1H),1.90(ddd,J＝13.0,8.9,4.6Hz,1H),1.86–1.76(m,2H),1.72–1.63(m,2H),1.54(s,6H),0.93(d,J＝9.4Hz,9H).
实施例A280
LCMS([M+H]+):1107.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝5.0Hz,1H),8.59(t,J＝6.0Hz,1H),8.51(d,J＝2.3Hz,1H),8.30–8.19(m,3H),7.47–7.31(m,5H),5.14(d,J＝3.5Hz,1H),4.55(d,J＝9.6Hz,1H),4.41(m,5H),4.25(m,1H),3.89(m,2H),3.64(m,2H),3.53(m,2H),3.44(m,2H),3.36(m,2H),2.44(d,J＝5.1Hz,3H),2.06(m,1H),1.90(m,1H),1.83–1.70(m,4H),1.62–1.50(m,8H),1.49–1.39(m,2H),0.92(d,J＝7.4Hz,9H).
实施例A281
LCMS([M+H]+):997.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.58(t,J＝6.0Hz,1H),8.26(s,2H),8.03(s,1H),7.40(s,5H),6.94–6.84(m,1H),5.14(d,J＝3.5Hz,1H),4.56(d,J＝8.7Hz,1H),4.43(s,5H),4.24(dd,J＝15.8,5.6Hz,1H),3.98(s,2H),3.89–3.75(m,2H),3.63(d,J＝9.7Hz,6H),2.43(s,3H),2.23(d,J＝17.3Hz,3H),2.06(dd,J＝14.0,6.3Hz,1H),1.96–1.85(m,1H),1.67–1.57(m,3H),1.51–1.37(m,3H),0.92(d,J＝8.2Hz,9H).
实施例A282
LCMS([M+H]+):953.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.97(m,1H),8.58(t,J＝6.0Hz,1H),8.29–8.23(m,2H),8.03(d,J＝2.4Hz,1H),7.68–7.65(m,1H),7.46–7.37(m,6H),5.16(d,J＝3.5Hz,1H),4.61–4.48(m,3H),4.48–4.36(m,3H),4.25(dd,J＝15.7,5.7Hz,1H),4.08–4.03(m,2H),3.90(t,J＝4.4Hz,2H),3.69–3.59(m,2H),2.45–2.43(m,3H),2.24–2.22(m,3H),2.08–2.02(m,1H),1.90(ddd,J＝12.8,8.7,4.4Hz,1H),1.51(d,J＝5.2Hz,6H),0.92–0.90(m,11H).
实施例A283
LCMS([M+H]+):1041.4
1HNMR(400MHz,DMSO-d6)δ8.98–8.27(m,1H),8.59(t,J＝5.9Hz,1H),8.39–8.23(m,2H),8.09(d,J＝31.1Hz,1H),7.48–7.36(m,5H),6.90–6.87(m,1H),5.16(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.47–4.33(m,5H),4.24(dd,J＝15.8,5.5Hz,1H),3.96–3.92(m,2H),3.73(s,2H),3.61–3.57(m,10H),2.44(d,J＝4.6Hz,3H),2.24(d,J＝17.2Hz,3H),2.07–1.99(m,2H),1.95–1.86(m,1H),1.63(d,J＝12.4Hz,3H),1.43(d,J＝9.7Hz,3H),0.94–0.92(m,9H).
实施例A284
LCMS([M+H]+):1025.3
1HNMR(400MHz,DMSO-d6)δ8.95(s,1H),8.58(t,J＝6.0Hz,1H),8.26(d,J＝4.2Hz,2H),8.01(d,J＝2.4Hz,1H),7.64(d,J＝1.8Hz,1H),7.40(d,J＝9.6Hz,5H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.48–4.20(m,6H),3.97(s,2H),3.71–3.46(m,8H),2.43(s,3H),2.17(s,3H),2.10–2.02(m,1H),1.90(ddd,J＝12.9,8.8,4.5Hz,1H),1.84–1.74(m,2H),1.68(dt,J＝13.2,6.4Hz,2H),1.51(d,J＝6.0Hz,6H),0.94(s,9H).
实施例A285
LCMS([M+H]+):1043.1
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝5.3Hz,1H),8.60(t,J＝6.0Hz,1H),8.30–8.20(m,2H),8.07(d,J＝2.1Hz,1H),7.95(dd,J＝10.7,2.1Hz,1H),7.47–7.32(m,5H),5.15(d,J＝3.5Hz,1H),4.55(d,J＝9.6Hz,1H),4.50–4.32(m,5H),4.25(dd,J＝15.7,5.6Hz,1H),3.98–3.83(m,2H),3.71–3.50(m,4H),3.44(dt,J＝14.6,6.3Hz,4H),2.44(d,J＝4.7Hz,3H),2.06(dd,J＝13.3,6.7Hz,1H),1.95–1.85(m,1H),1.85–1.73(m,4H),1.64(dd,J＝14.5,6.4Hz,2H),1.54(d,J＝1.7Hz,6H),0.93(d,J＝7.6Hz,9H).
实施例A286
LCMS([M+H]+):1039.2
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝5.9Hz,1H),8.60(t,J＝5.9Hz,1H),8.31–8.22(m,2H),8.02(d,J＝2.2Hz,1H),7.64(d,J＝1.7Hz,1H),7.47–7.32(m,5H),5.15(d,J＝3.5Hz,1H),4.55(d,J＝9.6Hz,1H),4.49–4.20(m,6H),3.90(d,J＝18.8Hz,2H),3.71–3.50(m,4H),3.50–3.39(m,4H),2.44(d,J＝4.9Hz,3H),2.18(s,3H),2.11–2.02(m,1H),1.96–1.84(m,1H),1.84–1.72(m,4H),1.65(dd,J＝14.5,6.4Hz,2H),1.51(d,J＝6.1Hz,6H),0.92(d,J＝7.5Hz,9H).
实施例A287
LCMS([M+H]+):1053.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝4.7Hz,1H),8.60(t,J＝6.0Hz,1H),8.30–8.22(m,2H),8.02(d,J＝2.3Hz,1H),7.64(d,J＝1.8Hz,1H),7.48–7.31(m,5H),5.15(d,J＝3.5Hz,1H),4.55(d,J＝9.6Hz,1H),4.49–4.19(m,6H),3.96–3.83(m,2H),3.71–3.50(m,4H),3.44(m,2H),3.37(m,2H),2.44(d,J＝5.1Hz,3H),2.18(m,3H),2.06(m,1H),1.90(m,1H),1.83–1.68(m,4H),1.60–1.38(m,10H),0.92(d,J＝7.4Hz,9H).
实施例A288
LCMS([M+H]+):1041.4
1HNMR(400MHz,DMSO-d6)δ8.98–8.97(m,1H),8.59(t,J＝5.8Hz,1H),8.40–8.21(m,2H),7.66(dd,J＝42.8,8.7Hz,1H),7.48–7.33(m,5H),6.80(dd,J＝13.4,8.6Hz,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.48–4.32(m,5H),4.24(dd,J＝15.8,5.6Hz,1H),3.96–3.92(m,2H),3.77–3.71(m,2H),3.67–3.55(m,10H),2.44(d,J＝4.4Hz,3H),2.34(d,J＝19.4Hz,3H),2.10–2.02(m,1H),1.94–1.85(m,1H),1.60(d,J＝12.4Hz,3H),1.46(d,J＝11.1Hz,3H),0.94–0.92(m,9H).
实施例A289
LCMS([M+H]+):1061.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.96(m,1H),8.59(t,J＝5.9Hz,1H),8.29–8.21(m,2H),8.20(d,J＝2.3Hz,1H),8.15(d,J＝2.3Hz,1H),7.47–7.35(m,5H),5.15(d,J＝3.5Hz,1H),4.60–4.48(m,3H),4.47–4.33(m,3H),4.24(dd,J＝15.8,5.5Hz,1H),3.96–3.92(m,2H),3.82–3.75(m,2H),3.70–3.55(m,10H),2.45–2.44(m,3H),2.08–2.03(m,1H),1.90(ddd,J＝12.8,8.7,4.4Hz,1H),1.54(s,6H),0.94–0.92(m,9H).
实施例A290
LCMS([M+H]+):1057.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.61(t,J＝5.7Hz,1H),8.25(s,2H),8.07(d,J＝1.6Hz,1H),7.95(d,J＝10.7Hz,1H),7.48–7.31(m,5H),5.16(d,J＝3.2Hz,1H),4.62–4.19(m,7H),3.90(m,2H),3.71–3.58(m,2H),3.54(m,2H),3.45(m,2H),3.38(m,2H),2.44(s,3H),2.07(m,1H),1.97–1.86(m,1H),1.77(m,4H),1.54(m,8H),1.49–1.38(m,2H),0.94(s,9H).
实施例A291
LCMS([M+H]+):1017.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.58(s,1H),8.26(d,J＝8.8Hz,2H),7.46–7.38(m,4H),7.31–7.19(m,3H),5.37–5.27(m,1H),5.14(s,1H),4.56(d,J＝8.7Hz,1H),4.51–4.40(m,3H),4.36(d,J＝8.9Hz,2H),4.26(d,J＝5.5Hz,2H),3.98(s,2H),3.81(d,J＝4.7Hz,3H),3.68–3.58(m,6H),2.46–2.29(m,1H),1.68–1.61(m,4H),1.52–1.46(m,3H),1.02–0.84(m,9H).
实施例A292
LCMS([M+H]+):1013.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝7.8Hz,1H),8.58(t,J＝6.0Hz,1H),8.33–8.19(m,2H),8.08–7.90(m,1H),7.49–7.35(m,5H),6.67(d,J＝11.7Hz,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝8.7Hz,1H),4.41(ddd,J＝22.3,12.2,7.0Hz,5H),4.25(dd,J＝15.7,5.6Hz,1H),3.97(d,J＝15.6Hz,2H),3.86–3.74(m,5H),3.72–3.58(m,6H),2.44(d,J＝5.5Hz,3H),2.10–2.00(m,1H),1.90(ddd,J＝12.9,8.8,4.5Hz,1H),1.55(dd,J＝7.8,2.8Hz,3H),1.39(d,J＝14.8Hz,3H),0.92(d,J＝8.7Hz,9H).
实施例A293
LCMS([M+H]+):1039.2
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝4.8Hz,1H),8.60(t,J＝6.0Hz,1H),8.32(dt,J＝40.6,6.0Hz,2H),7.65(dd,J＝42.9,8.6Hz,1H),7.46–7.32(m,5H),6.77(dd,J＝13.7,8.7Hz,1H),5.15(d,J＝3.2Hz,1H),4.55(d,J＝9.6Hz,1H),4.48–4.32(m,3H),4.31–4.20(m,3H),3.95–3.86(m,2H),3.64(dt,J＝23.6,7.4Hz,2H),3.54(t,J＝6.5Hz,2H),3.44(dt,J＝18.1,6.3Hz,4H),2.44(d,J＝4.6Hz,3H),2.33(d,J＝19.3Hz,3H),2.06(dd,J＝14.1,6.4Hz,1H),1.90(ddd,J＝13.0,8.9,4.5Hz,1H),1.83–1.69(m,4H),1.66–1.55(m,5H),1.46(d,J＝11.5Hz,3H),0.93(d,J＝7.6Hz,9H).
实施例A294
LCMS([M+H]+):1039.1
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝4.5Hz,1H),8.60(t,J＝6.1Hz,1H),8.40–8.23(m,2H),8.09(d,J＝31.1Hz,1H),7.47–7.33(m,5H),6.86(d,J＝9.8Hz,1H),5.15(d,J＝3.4Hz,1H),4.55(d,J＝9.6Hz,1H),4.48–4.32(m,3H),4.31–4.20(m,3H),3.96–3.86(m,2H),3.64(dt,J＝23.6,7.4Hz,2H),3.54(t,J＝6.4Hz,2H),3.43(dt,J＝18.8,6.3Hz,5H),2.44(d,J＝4.5Hz,3H),2.24(d,J＝17.2Hz,3H),2.10–2.02(m,1H),1.90(ddd,J＝13.0,8.8,4.5Hz,1H),1.83–1.69(m,4H),1.62(t,J＝11.2Hz,5H),1.43(d,J＝9.9Hz,3H),0.93(d,J＝7.6Hz,9H).
实施例A295
LCMS([M+H]+):953.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.96(m,1H),8.61–8.59(m,1H),8.40–8.24(m,2H),7.70–7.54(m,1H),7.51–7.36(m,5H),6.97–6.86(m,1H),5.16(d,J＝3.4Hz,1H),4.58(d,J＝9.5Hz,1H),4.52–4.22(m,7H),4.06(s,2H),3.88–3.87(m,2H),3.64(dd,J＝26.7,8.8Hz,2H),2.45–2.42(m,3H),2.36–2.31(m,3H),2.09–2.04(m,1H),1.96–1.87(m,1H),1.63–1.51(m,3H),1.50–1.42(m,3H),0.94(s,9H).
实施例A296
LCMS([M+H]+):953.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.96(m,1H),8.61–8.60(m,1H),8.41–8.23(m,2H),8.14–8.06(m,1H),7.56–7.36(m,5H),7.03(dd,J＝17.2,8.2Hz,1H),5.17(d,J＝3.4Hz,1H),4.60(dd,J＝9.6,4.8Hz,1H),4.52–4.26(m,6H),4.12–4.00(m,2H),3.87–3.82(m,2H),3.72–3.60(m,2H),2.45–2.42(m,3H),2.20(dd,J＝18.4,5.6Hz,3H),2.09–2.04(m,1H),1.95–1.86(m,1H),1.63(dd,J＝11.9,3.5Hz,3H),1.45–1.38(m,3H),0.95–0.93(m,9H).
实施例A297
LCMS([M+H]+):1059.5
1HNMR(400MHz,DMSO-d6)δ8.98(d,J＝4.1Hz,1H),8.60(t,J＝6.0Hz,1H),8.31(dt,J＝22.9,12.5Hz,3H),7.48–7.34(m,5H),7.25(dd,J＝7.5,1.5Hz,1H),5.15(d,J＝3.3Hz,1H),4.55(d,J＝9.6Hz,1H),4.48–4.29(m,7H),4.24(dd,J＝15.8,5.8Hz,1H),3.90(d,J＝16.2Hz,2H),3.69–3.58(m,2H),3.54(t,J＝6.5Hz,2H),3.46(t,J＝6.4Hz,5H),3.41(t,J＝6.3Hz,2H),2.44(d,J＝4.5Hz,3H),2.06(dd,J＝14.0,6.2Hz,2H),1.94–1.86(m,1H),1.78(dt,J＝16.9,8.4Hz,4H),1.63(dd,J＝17.3,8.5Hz,5H),1.55–1.46(m,3H),0.93(d,J＝7.7Hz,9H).
实施例A298
LCMS([M+H]+):1059.5
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝5.4Hz,1H),8.60(t,J＝5.9Hz,1H),8.23(dt,J＝7.8,5.4Hz,3H),8.14(d,J＝2.3Hz,1H),7.47–7.32(m,5H),5.15(d,J＝3.5Hz,1H),4.55(d,J＝9.6Hz,1H),4.47–4.32(m,5H),4.25(dd,J＝15.8,5.5Hz,1H),3.90(d,J＝16.7Hz,2H),3.69–3.57(m,2H),3.54(t,J＝6.4Hz,2H),3.45(dt,J＝12.6,6.4Hz,4H),2.44(d,J＝4.6Hz,3H),2.10–2.02(m,1H),1.90(ddd,J＝12.9,8.8,4.3Hz,1H),1.79(dd,J＝11.9,5.9Hz,4H),1.66(dd,J＝14.4,6.4Hz,2H),1.54(s,6H),0.93(d,J＝7.6Hz,9H).
实施例A299
LCMS([M+H]+):969.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.57(s,1H),8.26(s,2H),7.98(s,1H),7.55(d,J＝9.6Hz,1H),7.40(d,J＝2.8Hz,4H),6.95(dd,J＝21.2,14.5Hz,1H),5.11(dd,J＝60.7,3.0Hz,1H),4.73–4.58(m,1H),4.47(s,6H),4.07(d,J＝2.9Hz,2H),3.85(d,J＝22.2Hz,5H),3.73–3.61(m,2H),2.51(s,3H),2.22–1.84(m,2H),1.56(d,J＝7.9Hz,3H),1.44–1.30(m,3H),0.97(d,J＝9.5Hz,9H).
实施例A300
LCMS([M+H]+):969.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝6.8Hz,1H),8.60(dd,J＝12.2,7.6Hz,1H),8.37–8.19(m,2H),7.74–7.56(m,1H),7.53–7.35(m,5H),6.70–6.57(m,1H),5.16(d,J＝3.3Hz,1H),4.63–4.55(m,1H),4.55–4.32(m,5H),4.27(dd,J＝15.5,5.5Hz,1H),4.04(d,J＝19.4Hz,2H),3.88(d,J＝4.2Hz,5H),3.66(dt,J＝24.3,7.3Hz,2H),2.44(d,J＝9.9Hz,3H),2.06(dd,J＝12.6,7.9Hz,1H),1.98–1.85(m,1H),1.58–1.35(m,6H),0.94(d,J＝6.6Hz,9H).
实施例A301
LCMS([M+H]+):1053.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.60(t,J＝6.0Hz,1H),8.40–8.23(m,2H),8.09(d,J＝31.0Hz,1H),7.47–7.31(m,5H),6.86(t,J＝7.0Hz,1H),5.15(d,J＝3.4Hz,1H),4.55(m,1H),4.49–4.32(m,3H),4.30–4.21(m,3H),3.96–3.86(m,2H),3.64(m,2H),3.53(m,2H),3.44(m,2H),3.36(m,2H),2.44(d,J＝4.7Hz,3H),2.24(d,J＝17.5Hz,3H),2.06(m,1H),1.90(m,1H),1.75(m,4H),1.63(d,J＝12.4Hz,3H),1.58–1.48(m,2H),1.47–1.35(m,5H),0.93(d,J＝7.1Hz,9H).
实施例A302
LCMS([M+H]+):1025.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝7.8Hz,1H),8.59(t,J＝6.0Hz,1H),8.40–8.23(m,2H),8.08(d,J＝31.1Hz,1H),7.40(d,J＝10.0Hz,5H),6.84(d,J＝9.5Hz,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.46–4.33(m,3H),4.24(d,J＝12.7Hz,3H),3.97(s,2H),3.70–3.57(m,5H),3.55(d,J＝4.7Hz,2H),3.49(s,2H),2.44(d,J＝6.7Hz,3H),2.23(d,J＝17.1Hz,3H),2.10–2.02(m,1H),1.95–1.86(m,1H),1.75(d,J＝6.8Hz,2H),1.64(t,J＝12.0Hz,5H),1.43(d,J＝9.8Hz,3H),0.93(d,J＝8.8Hz,9H).
实施例A303
LCMS([M+H]+):1053.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝4.0Hz,1H),8.60(t,J＝6.0Hz,1H),8.31(dt,J＝40.0,5.8Hz,2H),7.64(dd,J＝40.8,8.7Hz,1H),7.47–7.32(m,5H),6.77(dd,J＝13.7,8.7Hz,1H),5.16(d,J＝2.8Hz,1H),4.55(d,J＝9.6Hz,1H),4.48–4.33(m,3H),4.30–4.19(m,3H),3.92(m,2H),3.64(m,2H),3.53(m,2H),3.44(m,2H),2.44(d,J＝4.7Hz,3H),2.33(m,3H),2.06(m,1H),1.94–1.86(m,1H),1.82–1.66(m,4H),1.59(d,J＝12.5Hz,3H),1.52(m,2H),1.49–1.37(m,5H),0.92(d,J＝7.3Hz,9H).
实施例A304
LCMS([M+H]+):1025.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.59(t,J＝5.9Hz,1H),8.41–8.22(m,2H),7.64(dd,J＝42.3,8.7Hz,1H),7.39(s,5H),6.75(dd,J＝13.2,8.7Hz,1H),5.15(d,J＝3.1Hz,1H),4.57(d,J＝9.6Hz,1H),4.48–4.33(m,3H),4.24(dd,J＝16.0,5.3Hz,3H),3.97(s,2H),3.71–3.58(m,4H),3.58–3.43(m,4H),2.43(s,3H),2.33(dd,J＝19.3,5.0Hz,3H),2.06(dd,J＝14.2,6.9Hz,1H),1.90(ddd,J＝13.0,8.8,4.5Hz,1H),1.76(p,J＝6.7Hz,2H),1.67(q,J＝6.3Hz,2H),1.59(d,J＝12.6Hz,3H),1.45(d,J＝11.3Hz,3H),0.94(s,9H).
实施例A305
LCMS([M+H]+):1073.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝4.3Hz,1H),8.60(t,J＝6.0Hz,1H),8.28–8.21(m,2H),8.20(d,J＝2.3Hz,1H),8.13(d,J＝2.3Hz,1H),7.49–7.30(m,5H),5.16(d,J＝3.5Hz,1H),4.55(m,1H),4.48–4.33(m,5H),4.24(m,1H),3.95–3.86(m,2H),3.64(m,2H),3.53(m,2H),3.45(m,2H),3.38(m,2H),2.44(d,J＝4.8Hz,3H),2.06(m,1H),1.90(m,1H),1.82–1.72(m,4H),1.60–1.50(m,8H),1.50–1.39(m,2H),0.92(d,J＝7.4Hz,9H).
实施例A306
LCMS([M+H]+):1057.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝4.7Hz,1H),8.59(t,J＝5.9Hz,1H),8.35–8.20(m,2H),8.07–7.92(m,1H),7.48–7.36(m,5H),6.66(d,J＝9.7Hz,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.49–4.33(m,5H),4.25(dd,J＝15.8,5.6Hz,1H),3.95(d,J＝16.2Hz,2H),3.83(d,J＝3.6Hz,3H),3.76–3.70(m,2H),3.69–3.53(m,10H),2.44(d,J＝4.3Hz,3H),2.10–2.01(m,1H),1.94–1.85(m,1H),1.55(d,J＝10.3Hz,3H),1.39(d,J＝14.7Hz,3H),0.93(d,J＝8.9Hz,9H).
实施例A307
LCMS([M+H]+):1041.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.59(t,J＝6.0Hz,1H),8.36–8.21(m,2H),8.06–7.92(m,1H),7.47–7.35(m,5H),6.58(s,1H),5.15(d,J＝3.1Hz,1H),4.56(d,J＝9.6Hz,1H),4.48–4.33(m,3H),4.31–4.20(m,3H),3.97(s,2H),3.82(d,J＝3.7Hz,3H),3.71–3.46(m,9H),2.43(s,3H),2.11–2.01(m,1H),1.90(ddd,J＝13.0,8.9,4.5Hz,1H),1.75(q,J＝6.7Hz,2H),1.67(q,J＝6.4Hz,2H),1.54(d,J＝10.3Hz,3H),1.39(d,J＝14.8Hz,3H),0.94(s,9H).
实施例A308
LCMS([M+H]+):1045.3
1HNMR(400MHz,DMSO-d6)δ8.95(s,1H),8.59(t,J＝6.0Hz,1H),8.29–8.16(m,3H),8.13(d,J＝2.3Hz,1H),7.40(d,J＝10.0Hz,5H),5.16(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.42(dt,J＝21.3,7.5Hz,5H),4.24(dd,J＝15.8,5.6Hz,1H),3.97(s,2H),3.64(dtd,J＝16.7,11.7,11.2,4.5Hz,4H),3.58–3.48(m,4H),2.43(s,3H),2.10–2.01(m,1H),1.91(ddd,J＝13.0,8.8,4.5Hz,1H),1.81(dt,J＝14.5,6.3Hz,2H),1.69(q,J＝6.4Hz,2H),1.54(s,6H),0.94(s,9H).
实施例A309
LCMS([M+H]+):1057.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝5.3Hz,1H),8.59(t,J＝6.0Hz,1H),8.36–8.20(m,2H),7.78–7.60(m,1H),7.46–7.35(m,5H),6.57–6.49(m,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.48–4.32(m,5H),4.24(dd,J＝15.8,5.6Hz,1H),3.94(d,J＝16.1Hz,2H),3.87(t,J＝4.1Hz,3H),3.79–3.72(m,2H),3.70–3.53(m,10H),2.44(d,J＝4.7Hz,3H),2.09–2.01(m,1H),1.90(ddd,J＝13.0,8.9,4.5Hz,1H),1.53(d,J＝11.0Hz,3H),1.43(d,J＝16.0Hz,3H),0.93(d,J＝8.8Hz,9H).
实施例A310
LCMS([M+H]+):1055.1
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.60(t,J＝5.7Hz,1H),8.36–8.18(m,2H),8.00(d,J＝35.8Hz,1H),7.49–7.31(m,5H),6.60(s,1H),5.15(d,J＝3.1Hz,1H),4.56(d,J＝9.6Hz,1H),4.49–4.19(m,6H),3.90(d,J＝16.7Hz,2H),3.83(d,J＝3.3Hz,3H),3.70–3.51(m,4H),3.44(dt,J＝18.7,6.0Hz,4H),2.44(s,3H),2.06(dd,J＝12.4,7.4Hz,1H),1.91(dd,J＝14.9,6.2Hz,1H),1.84–1.69(m,4H),1.68–1.59(m,2H),1.55(d,J＝10.5Hz,3H),1.39(d,J＝14.9Hz,3H),0.94(s,9H).
实施例A311
LCMS([M+H]+):973.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.96(m,1H),8.58(s,1H),8.36–8.23(m,3H),7.50(dd,J＝9.5,4.5Hz,1H),7.46–7.36(m,5H),5.16(d,J＝3.5Hz,1H),4.60(dd,J＝9.6,3.0Hz,1H),4.55–4.44(m,4H),4.38–4.26(m,4H),4.06(s,2H),3.88(m,2H),3.68(dd,J＝10.6,3.5Hz,2H),3.61(d,J＝10.6Hz,2H),2.42(s,3H),2.09–2.04(m,1H),1.93–1.88(m,1H),1.64(d,J＝9.1Hz,3H),1.48(dd,J＝13.3,4.5Hz,3H),0.94(s,9H).
实施例A312
LCMS([M+H]+):1073.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝4.3Hz,1H),8.60(t,J＝6.0Hz,1H),8.28–8.21(m,2H),8.20(d,J＝2.3Hz,1H),8.13(d,J＝2.3Hz,1H),7.49–7.30(m,5H),5.16(d,J＝3.5Hz,1H),4.55(m,1H),4.48–4.33(m,5H),4.24(m,1H),3.95–3.86(m,2H),3.64(m,2H),3.53(m,2H),3.45(m,2H),3.38(m,2H),2.44(d,J＝4.8Hz,3H),2.06(m,1H),1.90(m,1H),1.82–1.72(m,4H),1.60–1.50(m,8H),1.50–1.39(m,2H),0.92(d,J＝7.4Hz,9H).
实施例A313
LCMS([M+H]+):1069.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝3.2Hz,1H),8.60(t,J＝6.0Hz,1H),8.35–8.20(m,2H),8.00(d,J＝35.8Hz,1H),7.48–7.32(m,5H),6.61(d,J＝4.5Hz,1H),5.15(d,J＝3.5Hz,1H),4.55(d,J＝9.6Hz,1H),4.48–4.33(m,3H),4.31–4.20(m,3H),3.95–3.87(m,2H),3.83(d,J＝3.7Hz,3H),3.64(m,2H),3.54(m,2H),3.45(m,2H),3.37(m,2H),2.44(d,J＝4.5Hz,3H),2.06(m,1H),1.90(m,1H),1.82–1.75(m,2H),1.70(m,2H),1.59–1.48(m,5H),1.42(m,5H),0.93(d,J＝7.6Hz,9H).
实施例A314
LCMS([M+H]+):1061.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.97(m,1H),8.59(t,J＝6.0Hz,1H),8.41–8.30(m,1H),8.27–8.25(m,2H),7.45–7.37(m,5H),7.30(dd,J＝7.1,1.8Hz,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.47–4.33(m,5H),4.24(dd,J＝15.7,5.5Hz,1H),3.97–3.92(m,2H),3.77–3.72(m,2H),3.67–3.56(m,10H),2.45–2.44(m,3H),2.08–2.03(m,1H),1.90(ddd,J＝13.0,8.8,4.5Hz,1H),1.65(d,J＝9.9Hz,3H),1.49(d,J＝12.6Hz,3H),0.93(d,J＝8.7Hz,9H).
实施例A315
LCMS([M+H]+):1045.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.59(t,J＝6.0Hz,1H),8.41–8.23(m,3H),7.40(d,J＝10.0Hz,5H),7.29–7.19(m,1H),5.15(d,J＝3.3Hz,1H),4.57(d,J＝9.6Hz,1H),4.48–4.20(m,6H),3.97(s,2H),3.71–3.46(m,8H),2.43(s,3H),2.06(dd,J＝13.6,6.8Hz,1H),1.90(ddd,J＝13.0,8.8,4.5Hz,1H),1.78(p,J＝6.7Hz,2H),1.66(q,J＝9.8,8.0Hz,5H),1.49(d,J＝12.6Hz,3H),0.94(s,9H).
实施例A316
LCMS([M+H]+):982.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.97(m,1H),8.58(t,J＝6.0Hz,1H),8.38(d,J＝2.7Hz,1H),8.29–8.27(m,3H),7.83(d,J＝11.8Hz,2H),7.58(d,J＝9.4Hz,1H),7.40(s,4H),5.19(d,J＝3.5Hz,1H),4.64(m,2H),4.56(d,J＝9.4Hz,1H),4.45(d,J＝8.0Hz,1H),4.38–4.36(m,2H),4.25(d,J＝10.1Hz,1H),4.09(s,2H),3.96–3.92(m,2H),3.67(m,2H),2.44(d,J＝3.0Hz,3H),2.06–2.04(m,1H),1.93–1.88(m,1H),1.54(d,J＝5.4Hz,6H),0.93–0.91(m,9H).
实施例A317
LCMS([M+H]+):1041.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.59(t,J＝5.9Hz,1H),8.36–8.20(m,2H),7.78–7.57(m,1H),7.40(d,J＝9.3Hz,5H),6.55–6.44(m,1H),5.15(d,J＝3.3Hz,1H),4.57(d,J＝9.6Hz,1H),4.49–4.33(m,3H),4.27(dt,J＝17.6,8.5Hz,3H),3.97(s,2H),3.86(d,J＝4.1Hz,3H),3.72–3.46(m,8H),2.43(s,3H),2.06(q,J＝7.6Hz,1H),1.91(ddd,J＝12.9,8.9,4.4Hz,1H),1.78(q,J＝6.6Hz,2H),1.73–1.61(m,2H),1.53(d,J＝10.6Hz,3H),1.42(d,J＝15.9Hz,3H),0.93(d,J＝8.7Hz,9H).
实施例A318
LCMS([M+H]+):1055.1
1HNMR(400MHz,DMSO-d6)δ9.01–8.92(m,1H),8.60(t,J＝5.9Hz,1H),8.36–8.19(m,2H),7.68(dd,J＝48.8,8.3Hz,1H),7.49–7.32(m,5H),6.55–6.44(m,1H),5.15(d,J＝3.4Hz,1H),4.55(d,J＝9.6Hz,1H),4.49–4.32(m,3H),4.26(dt,J＝15.8,6.1Hz,3H),3.89(dd,J＝14.3,7.8Hz,5H),3.64(dt,J＝23.3,7.2Hz,2H),3.54(t,J＝6.4Hz,2H),3.44(dt,J＝16.2,6.3Hz,4H),2.44(d,J＝4.9Hz,3H),2.06(dd,J＝13.3,7.1Hz,1H),1.94–1.86(m,1H),1.83–1.72(m,4H),1.62(dt,J＝13.1,6.4Hz,2H),1.53(d,J＝11.1Hz,3H),1.43(d,J＝16.2Hz,3H),0.93(d,J＝7.5Hz,9H).
实施例A319
LCMS([M+H]+):1011.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝9.6Hz,1H),8.59(t,J＝6.0Hz,1H),8.32(dt,J＝40.7,5.9Hz,2H),7.74–7.55(m,1H),7.48–7.34(m,5H),6.80–6.62(m,1H),5.15(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.33(dddd,J＝25.1,21.4,15.9,6.8Hz,5H),4.00–3.91(m,2H),3.71–3.54(m,8H),2.48–2.39(m,4H),2.33(dd,J＝19.6,5.7Hz,3H),2.11–1.86(m,4H),1.60(d,J＝11.8Hz,3H),1.52–1.37(m,3H),0.93(d,J＝7.9Hz,9H).
实施例A320
LCMS([M+H]+):1011.3
1HNMR(400MHz,DMSO-d6)δ8.95(s,1H),8.59(t,J＝5.9Hz,1H),8.41–8.23(m,2H),8.17–8.02(m,1H),7.41(d,J＝12.4Hz,5H),6.84(t,J＝10.5Hz,1H),5.16(d,J＝3.5Hz,1H),4.57(d,J＝9.6Hz,1H),4.49–4.29(m,5H),4.24(dd,J＝15.9,5.5Hz,1H),3.97(s,2H),3.71–3.53(m,8H),2.43(s,3H),2.24(dd,J＝17.6,4.8Hz,3H),2.11–1.86(m,4H),1.63(d,J＝12.2Hz,3H),1.48–1.38(m,3H),0.93(d,J＝7.5Hz,9H).
实施例A321
LCMS([M+H]+):1027.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝8.8Hz,1H),8.59(t,J＝5.9Hz,1H),8.34–8.20(m,2H),8.06–7.92(m,1H),7.46–7.34(m,5H),6.61(d,J＝16.7Hz,1H),5.15(m,1H),4.57(m,1H),4.48–4.30(m,5H),4.29–4.21(m,1H),3.95(m,2H),3.85–3.79(m,3H),3.71–3.53(m,8H),2.44(d,J＝5.9Hz,3H),1.97(m,4H),1.55(d,J＝10.2Hz,3H),1.39(d,J＝14.7Hz,3H),0.93(d,J＝8.2Hz,9H).
实施例A322
LCMS([M+H]+):1011.3
1HNMR(400MHz,DMSO-d6)δ8.96(d,J＝11.8Hz,1H),8.59(t,J＝6.0Hz,1H),8.32–8.20(m,2H),8.02(dd,J＝7.0,2.4Hz,1H),7.64(d,J＝1.9Hz,1H),7.47–7.31(m,5H),5.08(dd,J＝62.4,3.2Hz,1H),4.56(d,J＝9.6Hz,1H),4.50–4.30(m,5H),4.24(dd,J＝15.9,5.6Hz,1H),3.95(d,J＝16.8Hz,2H),3.71–3.51(m,8H),2.44(d,J＝7.3Hz,3H),2.18(d,J＝12.2Hz,3H),2.10–1.86(m,4H),1.51(d,J＝5.9Hz,6H),0.92(d,J＝8.0Hz,9H).
实施例A323
LCMS([M+H]+):1097.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝4.6Hz,1H),8.60(t,J＝6.1Hz,1H),8.43(d,J＝2.6Hz,1H),8.24(dd,J＝12.9,3.3Hz,3H),7.46–7.33(m,5H),5.16(s,1H),4.55(d,J＝9.6Hz,1H),4.47–4.34(m,5H),4.24(m,1H),3.91(m,2H),3.85(d,J＝18.4Hz,3H),3.64(m,2H),3.53(m,2H),3.44(m,4H),2.44(d,J＝4.9Hz,3H),2.11–1.94(m,3H),1.94–1.87(m,1H),1.77(m,4H),1.50(m,10H),0.92(d,J＝7.6Hz,9H).
实施例A324
LCMS([M+H]+):1031.5
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝9.3Hz,1H),8.59(t,J＝5.8Hz,1H),8.40–8.23(m,3H),7.41(d,J＝10.3Hz,5H),7.22(d,J＝7.2Hz,1H),5.15(s,1H),4.56(d,J＝9.6Hz,1H),4.41(dt,J＝12.2,7.3Hz,5H),4.24(dd,J＝15.7,5.4Hz,1H),3.95(d,J＝16.9Hz,2H),3.70–3.56(m,8H),2.44(d,J＝6.0Hz,3H),2.07–1.96(m,3H),1.94–1.86(m,1H),1.64(d,J＝9.7Hz,3H),1.49(d,J＝11.8Hz,3H),0.92(d,J＝8.4Hz,9H).
实施例A325
LCMS([M+H]+):1031.5
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝10.8Hz,1H),8.58(t,J＝6.1Hz,1H),8.30–8.11(m,4H),7.41(d,J＝9.4Hz,5H),5.15(d,J＝3.2Hz,1H),4.56(d,J＝9.6Hz,1H),4.48–4.33(m,5H),4.24(dd,J＝15.7,5.4Hz,1H),3.95(d,J＝17.1Hz,2H),3.68–3.56(m,8H),2.44(d,J＝6.4Hz,3H),2.04(dd,J＝14.3,8.1Hz,3H),1.94–1.86(m,1H),1.54(s,6H),0.92(d,J＝7.9Hz,9H).
实施例A326
LCMS([M+H]+):1085.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝6.9Hz,1H),8.59(t,J＝6.0Hz,1H),8.43(d,J＝2.6Hz,1H),8.30–8.21(m,3H),7.47–7.35(m,5H),5.15(d,J＝3.5Hz,1H),4.60–4.49(m,3H),4.48–4.33(m,3H),4.25(dd,J＝15.7,5.6Hz,1H),3.94(d,J＝16.4Hz,2H),3.86–3.75(m,5H),3.71–3.54(m,10H),2.44(d,J＝5.1Hz,3H),2.10–2.02(m,1H),1.90(ddd,J＝13.0,8.9,4.5Hz,1H),1.55(d,J＝4.5Hz,6H),0.93(d,J＝8.8Hz,9H).
实施例A327
LCMS([M+H]+):997.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.58(t,J＝6.0Hz,1H),8.44(d,J＝2.6Hz,1H),8.31–8.22(m,3H),7.47–7.36(m,5H),5.16(d,J＝3.5Hz,1H),4.64–4.54(m,3H),4.48–4.32(m,3H),4.25(dd,J＝15.7,5.6Hz,1H),4.17–4.08(m,2H),3.96–3.90(m,2H),3.84(s,3H),3.68–3.59(m,2H),2.45–2.44(m,3H),2.08–2.03(m,1H),1.95–1.85(m,1H),1.54(d,J＝4.6Hz,6H),0.97–0.86(m,9H).
实施例A328
LCMS([M+H]+):1070.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.96(m,1H),8.60(t,J＝6.0Hz,1H),8.38(d,J＝2.6Hz,1H),8.32–8.24(m,3H),7.93(s,1H),7.75(s,1H),7.47–7.37(m,5H),5.17(d,J＝3.5Hz,1H),4.61–4.54(m,3H),4.47–4.37(m,2H),4.27–4.22(m,1H),3.97(s,2H),3.84–3.79(m,2H),3.66–3.56(m,10H),2.44–2.43(m,3H),2.09–1.95(m,2H),1.94–1.86(m,1H),1.54(d,J＝5.2Hz,6H),0.93–0.91(m,9H).
实施例A329
LCMS([M+H]+):1026.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.96(m,1H),8.59(t,J＝5.9Hz,1H),8.40–8.23(m,4H),7.95(s,1H),7.77(s,1H),7.50–7.36(m,5H),5.15(d,J＝3.5Hz,1H),4.66–4.53(m,3H),4.48–4.33(m,3H),4.28–4.22(m,1H),3.97(s,2H),3.90–3.87(m,2H),3.72–3.59(m,6H),2.44–2.43(m,3H),2.08–2.03(m,1H),1.91(ddd,J＝13.0,8.9,4.5Hz,1H),1.53(d,J＝4.7Hz,6H),0.91–0.89(m,9H).
实施例A330
LCMS([M+H]+):1017.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝9.9Hz,1H),8.59(t,J＝6.0Hz,1H),8.30–8.19(m,2H),8.19–8.11(m,2H),7.49–7.35(m,5H),5.15(d,J＝3.5Hz,1H),4.55(dd,J＝9.4,5.1Hz,3H),4.49–4.32(m,3H),4.24(dd,J＝15.8,5.6Hz,1H),3.98(s,2H),3.92–3.78(m,2H),3.75–3.57(m,6H),2.44(d,J＝6.2Hz,3H),2.11–2.01(m,1H),1.91(td,J＝8.7,4.5Hz,1H),1.54(s,6H),0.92(d,J＝7.9Hz,9H).
实施例A331
LCMS([M+H]+):1013.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.58(t,J＝5.9Hz,1H),8.37–8.20(m,2H),7.79–7.58(m,1H),7.52–7.33(m,5H),6.53(dd,J＝5.9,2.2Hz,1H),5.15(d,J＝3.5Hz,1H),4.57(d,J＝9.6Hz,1H),4.42(dd,J＝26.1,15.3Hz,5H),4.26(d,J＝5.5Hz,1H),3.99(s,2H),3.84(dd,J＝13.9,4.8Hz,5H),3.64(d,J＝12.3Hz,6H),2.44(d,J＝7.4Hz,3H),2.11–2.00(m,1H),1.95–1.85(m,1H),1.58–1.47(m,3H),1.47–1.37(m,3H),0.92(d,J＝9.7Hz,9H).
实施例A332
LCMS([M+H]+):982.3
1HNMR(400MHz,DMSO-d6)δ8.97(t,J＝5.0Hz,1H),8.60(d,J＝5.7Hz,1H),8.24(d,J＝7.5Hz,2H),7.98(d,J＝18.4Hz,1H),7.90–7.70(m,1H),7.61(d,J＝9.8Hz,1H),7.51(d,J＝9.6Hz,1H),7.41(d,J＝7.6Hz,4H),7.29(dd,J＝14.3,8.9Hz,1H),5.17(d,J＝3.4Hz,1H),4.61(d,J＝9.3Hz,3H),4.41(d,J＝37.2Hz,3H),4.29(d,J＝5.0Hz,1H),4.08(s,2H),3.89(s,2H),3.74–3.56(m,2H),2.43(s,3H),2.07(dd,J＝12.5,8.3Hz,1H),1.93(dd,J＝8.7,4.4Hz,1H),1.62(dd,J＝13.1,4.1Hz,3H),1.43(dd,J＝13.7,7.5Hz,3H),0.95(s,9H).
实施例A333
LCMS([M+H]+):1041.3
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝10.3Hz,1H),8.60(t,J＝5.9Hz,1H),8.46–8.39(m,1H),8.30–8.22(m,3H),7.49–7.36(m,5H),5.16(d,J＝3.5Hz,1H),4.55(dd,J＝9.4,5.0Hz,3H),4.47–4.32(m,3H),4.24(dd,J＝15.8,5.6Hz,1H),3.96(d,J＝17.0Hz,2H),3.91–3.79(m,5H),3.75–3.58(m,6H),2.44(d,J＝6.5Hz,3H),2.06(dd,J＝15.2,5.9Hz,1H),1.90(ddd,J＝12.9,8.9,4.4Hz,1H),1.54(d,J＝4.2Hz,6H),0.91(d,J＝8.5Hz,9H).
实施例A334
LCMS([M+H]+):1082.4
1HNMR(400MHz,DMSO-d6)δ8.98–8.97(m,1H),8.61(t,J＝5.9Hz,1H),8.37(d,J＝2.6Hz,1H),8.29–8.22(m,3H),7.91(s,1H),7.68(s,1H),7.46–7.33(m,5H),5.17(d,J＝3.4Hz,1H),4.55(d,J＝9.6Hz,1H),4.47–4.33(m,5H),4.27–4.22(m,1H),3.92–3.88(m,2H),3.68–3.59(m,2H),3.53(t,J＝6.3Hz,2H),3.45(d,J＝6.3Hz,2H),2.45–2.43(m,3H),2.10–2.02(m,1H),1.94–1.86(m,1H),1.82–1.76(m,4H),1.54(d,J＝5.2Hz,8H),1.43(dd,J＝14.5,7.8Hz,2H),0.93–0.91(m,9H).
实施例A335
LCMS([M+H]+):1054.4
1HNMR(400MHz,DMSO-d6)δ8.98–8.96(m,1H),8.60(t,J＝5.9Hz,1H),8.35(d,J＝2.5Hz,1H),8.29–8.21(m,3H),7.90(s,1H),7.69(s,1H),7.46–7.36(m,5H),5.16(d,J＝3.4Hz,1H),4.56(d,J＝9.6Hz,1H),4.49–4.33(m,5H),4.25(dd,J＝15.6,5.4Hz,1H),3.97(s,2H),3.69–3.60(m,4H),3.55(m,2H),3.51–3.48(m,2H),2.45–2.43(m,3H),2.08–2.03(m,1H),1.94–1.80(m,3H),1.68(dd,J＝14.5,6.6Hz,2H),1.53(d,J＝4.8Hz,6H),0.93–0.91(m,9H).
实施例A336
LCMS([M+H]+):1040.3
1HNMR(400MHz,DMSO-d6)δ8.98–8.96(m,1H),8.60(t,J＝5.9Hz,1H),8.35(d,J＝2.2Hz,1H),8.26–8.25(m,3H),7.90(s,1H),7.80(s,1H),7.49–7.35(m,5H),5.16(d,J＝3.4Hz,1H),4.60–4.48(m,3H),4.47–4.31(m,3H),4.27–4.22(m,1H),3.98–3.93(m,2H),3.70–3.54(m,8H),2.44–2.43(m,3H),2.08–2.05(m,3H),1.94–1.85(m,1H),1.53(d,J＝5.1Hz,6H),0.92–0.90(m,9H).
实施例A337
LCMS([M+H]+):1069.3
1HNMR(400MHz,DMSO-d6)δ8.95(s,1H),8.60(t,J＝6.0Hz,1H),8.43(dd,J＝6.0,2.5Hz,1H),8.29–8.21(m,3H),7.40(d,J＝5.5Hz,5H),5.16(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.47–4.33(m,5H),4.24(dd,J＝15.7,5.5Hz,1H),3.97(s,2H),3.83(d,J＝5.6Hz,3H),3.69–3.58(m,4H),3.58–3.49(m,4H),2.43(s,3H),2.08–2.02(m,1H),1.90(ddd,J＝12.9,8.9,4.4Hz,1H),1.82–1.75(m,2H),1.71(q,J＝6.3Hz,2H),1.54(d,J＝4.2Hz,6H),0.93(s,9H).
实施例A338
LCMS([M+H]+):1119.3
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.59(t,J＝6.0Hz,1H),8.28–8.22(m,2H),8.07(d,J＝2.0Hz,1H),7.96(dd,J＝10.7,1.8Hz,1H),7.86(d,J＝8.8Hz,2H),7.79(d,J＝9.0Hz,1H),7.44–7.37(m,4H),6.97(m,2H),5.16(m,1H),4.75(m,1H),4.42(m,5H),4.24(m,1H),4.08(m,2H),3.72(m,2H),3.52(m,2H),3.41(m,2H),2.46–2.42(m,3H),2.09–1.87(m,5H),1.83–1.74(m,2H),1.62–1.51(m,8H),1.46(m,2H),1.00(d,J＝11.6Hz,9H).
实施例A339
LCMS([M+H]+):1101.3
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.59(t,J＝5.9Hz,1H),8.30–8.23(m,2H),8.20(d,J＝2.5Hz,1H),7.86(d,J＝8.7Hz,2H),7.78(dd,J＝13.5,5.3Hz,2H),7.44–7.37(m,4H),6.97(d,J＝8.8Hz,3H),5.16(d,J＝3.5Hz,1H),4.75(d,J＝9.1Hz,1H),4.42(dt,J＝13.9,7.8Hz,3H),4.32–4.22(m,3H),4.08(m,2H),3.72(m,2H),3.52(m,2H),3.41(m,2H),2.43(d,J＝7.0Hz,3H),2.09–1.88(m,5H),1.78–1.70(m,2H),1.61–1.40(m,10H),1.00(d,J＝11.4Hz,9H).
实施例A340
LCMS([M+H]+):1083.1
1HNMR(400MHz,DMSO-d6)δ8.97(d,J＝5.6Hz,1H),8.60(t,J＝6.0Hz,1H),8.43(d,J＝2.6Hz,1H),8.30–8.21(m,3H),7.48–7.33(m,5H),5.15(d,J＝3.4Hz,1H),4.55(d,J＝9.6Hz,1H),4.48–4.33(m,5H),4.25(dd,J＝15.7,5.5Hz,1H),3.92(s,2H),3.83(s,3H),3.64(dt,J＝23.1,7.2Hz,2H),3.54(t,J＝6.4Hz,2H),3.45(dt,J＝12.9,6.3Hz,4H),2.44(d,J＝4.7Hz,3H),2.06(dd,J＝13.5,6.8Hz,1H),1.94–1.86(m,1H),1.78(dq,J＝11.9,6.1Hz,4H),1.67(dd,J＝13.9,6.5Hz,2H),1.54(d,J＝4.3Hz,6H),0.92(d,J＝7.7Hz,9H).
实施例A341
LCMS([M+H]+):1068.1
1HNMR(400MHz,DMSO-d6)δ8.98(d,J＝5.0Hz,1H),8.61(t,J＝5.9Hz,1H),8.36(d,J＝2.5Hz,1H),8.31–8.22(m,3H),7.91(s,1H),7.69(s,1H),7.46–7.34(m,5H),5.17(d,J＝3.4Hz,1H),4.55(d,J＝9.5Hz,1H),4.50–4.33(m,5H),4.25(dd,J＝15.9,5.5Hz,1H),3.90(d,J＝16.1Hz,2H),3.64(dt,J＝22.6,7.3Hz,2H),3.53(t,J＝6.4Hz,2H),3.49–3.40(m,5H),2.44(d,J＝4.3Hz,3H),2.06(dd,J＝13.5,6.6Hz,1H),1.80(ddt,J＝18.7,12.5,6.4Hz,4H),1.64(dd,J＝14.5,6.5Hz,2H),1.54(d,J＝5.2Hz,6H),0.92(d,J＝8.1Hz,9H).
实施例A347
LCMS([M+H]+):1072.3
1HNMR(400MHz,DMSO-d6)δ8.98(d,J＝7.8Hz,1H),8.65–8.53(m,2H),8.28(d,J＝3.8Hz,2H),8.22(d,J＝2.6Hz,1H),8.00(dd,J＝8.7,2.6Hz,1H),7.93(d,J＝8.7Hz,2H),7.49(d,J＝9.6Hz,1H),7.40(s,4H),7.30(dd,J＝8.6,4.1Hz,3H),5.18(d,J＝3.4Hz,1H),4.58(d,J＝9.6Hz,1H),4.48–4.22(m,4H),3.97(s,2H),3.69–3.59(m,2H),3.56(t,J＝6.3Hz,2H),2.44(s,3H),2.10–1.86(m,2H),1.86–1.78(m,2H),1.55(s,6H),1.24(s,2H),0.94(s,9H).
实施例A348
LCMS([M+H]+):1153.3
1HNMR(400MHz,DMSO-d6)δ8.99(s,1H),8.60(m,1H),8.52(d,J＝2.0Hz,1H),8.31–8.21(m,3H),7.84(dd,J＝24.7,8.9Hz,3H),7.41(t,J＝4.2Hz,4H),6.98(d,J＝8.8Hz,2H),5.17(m,1H),4.76(m,1H),4.46(m,5H),4.25(m,1H),4.09(m,2H),3.73(m,2H),3.52(m,2H),3.40(m,2H),2.45(m,3H),2.08(m,1H),1.96(t,J＝6.2Hz,3H),1.77(m,2H),1.57(m,8H),1.48(m,2H),1.01(d,J＝11.7Hz,9H).
实施例A349
LCMS([M+H]+):1127.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.63(s,1H),8.46(d,J＝5.2Hz,2H),8.25(d,J＝6.5Hz,2H),7.50–7.35(m,5H),7.15(d,J＝9.0Hz,2H),6.99(d,J＝9.0Hz,2H),5.18(d,J＝3.4Hz,1H),4.58(d,J＝9.6Hz,1H),4.41(dd,J＝31.2,7.2Hz,3H),4.29(d,J＝5.6Hz,1H),4.02(t,J＝6.2Hz,2H),3.97(d,J＝1.2Hz,2H),3.77–3.60(m,2H),3.56(t,J＝6.2Hz,2H),2.45(d,J＝6.9Hz,3H),2.08(s,2H),1.78(dt,J＝14.0,6.6Hz,5H),1.57(d,J＝4.0Hz,6H),0.94(d,J＝6.7Hz,9H).
实施例A350
LCMS([M+H]+):1077.3
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.64(s,1H),8.27(s,2H),8.15(dd,J＝10.5,1.6Hz,1H),8.01(d,J＝1.6Hz,1H),7.42(d,J＝10.9Hz,5H),7.17(d,J＝8.9Hz,2H),6.99(d,J＝8.9Hz,2H),5.19(d,J＝3.2Hz,1H),4.58(d,J＝9.6Hz,1H),4.50–4.19(m,4H),4.01(dd,J＝16.3,10.5Hz,4H),3.75–3.51(m,4H),2.45(d,J＝6.9Hz,3H),2.08(s,1H),1.97–1.66(m,5H),1.55(s,6H),0.95(s,9H).
实施例A351
LCMS([M+H]+):1058.3
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.63(s,1H),8.28(d,J＝4.9Hz,2H),8.19(d,J＝2.4Hz,1H),7.93(dd,J＝8.7,2.5Hz,1H),7.42(d,J＝11.1Hz,5H),7.14(dd,J＝17.8,8.8Hz,3H),6.98(d,J＝8.9Hz,2H),5.18(d,J＝3.4Hz,1H),4.58(d,J＝9.6Hz,1H),4.41(dd,J＝30.8,7.2Hz,3H),4.28(d,J＝5.6Hz,1H),4.00(dd,J＝15.5,9.3Hz,4H),3.61(dt,J＝12.3,4.6Hz,4H),2.45(d,J＝7.2Hz,3H),2.08(s,1H),1.78(dt,J＝13.9,6.6Hz,5H),1.53(d,J＝1.8Hz,6H),0.94(d,J＝6.6Hz,9H).
实施例A352
LCMS([M+H]+):1073.3
1HNMR(400MHz,DMSO-d6)δ8.99(s,1H),8.59(t,J＝6.0Hz,1H),8.27(d,J＝4.2Hz,2H),8.21(d,J＝2.4Hz,1H),7.86(d,J＝8.6Hz,2H),7.84–7.76(m,2H),7.45–7.36(m,4H),7.00(d,J＝8.7Hz,3H),5.32(t,J＝4.9Hz,1H),5.16(s,1H),4.76(d,J＝9.0Hz,1H),4.45(t,J＝7.7Hz,2H),4.42–4.35(m,2H),4.32(t,J＝6.5Hz,2H),4.24(dd,J＝15.7,5.6Hz,1H),4.16(t,J＝4.6Hz,2H),3.74(d,J＝7.9Hz,3H),3.53(q,J＝5.4,4.4Hz,3H),3.17(d,J＝3.9Hz,2H),2.45(s,4H),1.98(ddd,J＝29.2,14.0,7.9Hz,5H),1.80(t,J＝7.4Hz,2H),1.68(t,J＝7.4Hz,2H),1.52(d,J＝2.3Hz,6H),1.02(s,9H).
实施例A353
LCMS([M+H]+):1057.4
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.60(t,J＝6.0Hz,1H),8.31–8.23(m,2H),8.21(d,J＝2.5Hz,1H),7.86(d,J＝8.7Hz,2H),7.83–7.75(m,2H),7.45–7.37(m,4H),6.98(t,J＝8.6Hz,3H),5.16(d,J＝3.5Hz,1H),4.76(d,J＝9.1Hz,1H),4.47–4.37(m,3H),4.31(t,J＝6.5Hz,2H),4.24(dd,J＝15.8,5.5Hz,1H),4.04(t,J＝6.3Hz,2H),3.73(s,2H),2.45–2.43(m,3H),2.04(d,J＝8.2Hz,1H),1.91(ddd,J＝12.7,8.5,4.5Hz,1H),1.77(d,J＝5.8Hz,4H),1.56–1.46(m,10H),1.02–0.99(m,9H).
实施例A354
LCMS([M+H]+):1127.3
1HNMR(400MHz,DMSO-d6)δ8.99(m,1H),8.60(t,J＝6.0Hz,1H),8.53(m,1H),8.26(m,3H),7.84(dd,J＝21.0,8.9Hz,3H),7.41(m,4H),6.99(d,J＝8.7Hz,2H),5.17(m,1H),4.76(m,1H),4.55(m,2H),4.43(m,3H),4.25(m,1H),4.20–4.11(m,2H),3.79–3.69(m,4H),3.65(m,2H),2.45(m,3H),2.05(m,3H),1.92(m,1H),1.57(d,J＝4.9Hz,6H),1.02(s,9H).
实施例A355
LCMS([M+H]+)::1056.1
1HNMR(400MHz,DMSO-d6)δ8.96(s,1H),8.61(t,J＝6.0Hz,1H),8.42(d,J＝1.9Hz,1H),8.25(dd,J＝9.4,3.1Hz,3H),7.48–7.34(m,5H),5.17(d,J＝3.5Hz,1H),4.56(d,J＝9.6Hz,1H),4.45(d,J＝5.2Hz,6H),3.98(s,2H),3.83(s,3H),3.72–3.53(m,8H),2.43(s,3H),2.01(s,4H),1.55(d,J＝4.4Hz,6H),0.92(d,J＝9.6Hz,9H).
实施例A356
LCMS([M+H]+):1043.1
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.70(t,J＝5.9Hz,1H),8.66(s,1H),8.29(s,2H),8.14–8.07(m,3H),7.95(dd,J＝8.5,2.1Hz,1H),7.41(d,J＝9.0Hz,5H),7.06(d,J＝8.7Hz,2H),5.47(d,J＝7.2Hz,1H),4.53(d,J＝9.2Hz,1H),4.41(dt,J＝14.7,7.4Hz,2H),4.33–4.20(m,2H),4.09(s,2H),3.95(d,J＝3.7Hz,2H),3.89(dd,J＝10.0,5.7Hz,1H),3.56(s,2H),3.47(dd,J＝9.9,5.4Hz,1H),2.43(s,3H),2.40–2.31(m,1H),1.87–1.80(m,2H),1.77–1.70(m,3H),1.59(s,6H),0.96(s,9H).
实施例A357
LCMS([M+H]+):1040.1
1HNMR(400MHz,DMSO-d6)δ8.98(d,J＝8.3Hz,1H),8.66–8.56(m,2H),8.52(s,1H),8.49(s,1H),8.30–8.19(m,2H),7.95(d,J＝8.6Hz,2H),7.48(d,J＝9.4Hz,1H),7.40(s,4H),7.35(d,J＝8.6Hz,2H),5.18(d,J＝3.4Hz,1H),4.58(d,J＝9.5Hz,1H),4.49–4.22(m,4H),3.95(d,J＝12.1Hz,2H),3.64(dd,J＝22.9,8.9Hz,2H),3.56(t,J＝6.2Hz,2H),2.44(s,3H),2.11–1.88(m,2H),1.84(dd,J＝15.5,9.0Hz,2H),1.58(d,J＝4.2Hz,6H),1.24(s,2H),0.94(s,9H).
实施例A358
LCMS([M+H]+):1090.2
1HNMR(400MHz,DMSO-d6)δ8.97(s,1H),8.60(d,J＝17.4Hz,2H),8.32–8.19(m,3H),8.06(s,1H),7.94(d,J＝8.6Hz,2H),7.49(d,J＝9.8Hz,1H),7.40(s,6H),5.18(s,1H),4.58(d,J＝9.5Hz,1H),4.49–4.20(m,4H),3.97(s,2H),3.56(s,4H),2.44(s,3H),2.00(d,J＝52.2Hz,2H),1.82(s,2H),1.57(s,6H),1.24(s,2H),0.94(s,9H).
实施例A359
LCMS([M+H]+):1077.3
1HNMR(400MHz,DMSO-d6)δ8.99(m,1H),8.60(t,J＝6.0Hz,1H),8.53(s,1H),8.26(s,3H),7.84(dd,J＝21.0,8.9Hz,3H),7.41(s,4H),6.99(d,J＝8.7Hz,2H),5.17(m,1H),4.76(m,1H),4.55(m,2H),4.43(m,3H),4.25(m,1H),4.20–4.11(m,2H),3.79–3.69(m,4H),3.65(m,2H),2.45(m,3H),2.05(dd,J＝13.6,7.6Hz,3H),1.92(m,1H),1.57(d,J＝4.9Hz,6H),1.02(s,9H).
实施例A360
LCMS([M+H]+):1029.3
1HNMR(400MHz,DMSO-d6)δ8.99(s,1H),8.60(t,J＝5.9Hz,1H),8.25(dd,J＝22.4,3.1Hz,3H),7.91–7.73(m,4H),7.48–7.35(m,4H),7.00(dd,J＝8.7,3.5Hz,3H),5.17(m,1H),4.76(m,1H),4.51–4.33(m,5H),4.30–4.21(m,1H),4.21–4.13(m,2H),3.76(m,4H),3.65(m,2H),2.45(d,J＝5.9Hz,3H),2.11–1.97(m,3H),1.92(m,1H),1.53(s,6H),1.01(d,J＝11.9Hz,9H).
实施例A361
LCMS([M+H]+):1075.4
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.60(t,J＝6.0Hz,1H),8.26–8.23(m,2H),8.08(d,J＝1.9Hz,1H),7.97(dd,J＝10.7,1.9Hz,1H),7.86(d,J＝8.7Hz,2H),7.79(d,J＝9.0Hz,1H),7.46–7.37(m,4H),6.97(d,J＝8.7Hz,2H),5.17(d,J＝3.5Hz,1H),4.75(d,J＝9.1Hz,1H),4.47–4.37(m,5H),4.24(dd,J＝15.8,5.5Hz,1H),4.04(t,J＝6.3Hz,2H),3.72(s,2H),2.45–2.43(m,3H),2.03(d,J＝8.0Hz,1H),1.96–1.87(m,1H),1.81–1.76(m,4H),1.58–1.46(m,10H),1.02–0.99(m,9H).
实施例A362
LCMS([M+H]+):1125.4
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.60(t,J＝6.0Hz,1H),8.52(d,J＝2.0Hz,1H),8.32–8.20(m,3H),7.87–7.78(m,3H),7.46–7.36(m,4H),6.96(d,J＝8.8Hz,2H),5.16(d,J＝3.5Hz,1H),4.75(d,J＝9.1Hz,1H),4.50–4.37(m,5H),4.24(dd,J＝15.7,5.5Hz,1H),4.03(t,J＝6.3Hz,2H),3.72(s,2H),2.44–2.43(m,3H),2.03(d,J＝8.0Hz,1H),1.91(ddd,J＝12.7,8.6,4.5Hz,1H),1.80–1.75(m,4H),1.56(d,J＝4.7Hz,6H),1.50(m,4H),1.02–0.99(m,9H).
二、生物学活性测定：
活性测定实施例1：化合物对LNCaP细胞AR表达的影响
1.细胞株与细胞培养
人前列腺癌细胞LNCaP(上海中科院细胞库)。LNCaP培养于含10％胎牛血清的1640培养液中。细胞贴壁成簇生长，与底物贴附力弱，增殖慢，倍增时间为72h，细胞间粘连紧密，需用含0.025％EDTA的0.05％胰酶消化。每3天传代1次。细胞培养于37℃恒温，体积分数为0.05的CO2，饱和湿度的培养箱中。
2.细胞铺板：取对数生长期的细胞Lncap，倒掉上清，PBS洗一遍，加入适当0.05％胰酶消化液充分消化成单细胞悬液，离心重悬计数使细胞量约为每孔15000个，接种于96孔板，放置于37℃，5％CO2过夜培养24h。
3.化合物溶液的制备与加入
各称取化合物约2mg，用DMSO溶解，使其母液浓度为10mmol/L。稀释过程(终浓度稀释为：2，0.667，0.222，0.074，0.0245，0.008，0.003，0.001，0.0003，0.0001μmol/L)：取10个1.5mL离心管，编号分别为1、2、3、4、5、6、7、8、9、10，在1号管中加入80μLDMSO，在2到10号管中加入60μLDMSO，从母液中吸取20μL到1号管中，混匀；从1号管中吸取30μL到2号管中，混匀。从2号管中吸取30μL到3号管中，混匀，以此类推，获得4-10号样品，分别得到各不同浓度的化合物的工作液。分别从上述1-10号管中吸取2μL到各对应的无菌深孔板，加198μL培养液，混匀。每孔加入11ul至过夜培养的96孔细胞板中，即获得相对应的所需浓度(2，0.667，0.222，0.074，0.0245，0.008，0.003，0.001，0.0003，0.0001μmol/L)。
4.ELISA法测药物对细胞表达AR的影响
药物作用24h后，吸掉上清，加200μLPBS洗涤，再吸掉上清，加100μL细胞裂解液冰上裂解20min,4℃、4000转/min离心20min，取上清待用。上清检测步骤按ELISA试剂盒说明书：
4.1从已平衡至室温的密封袋中取出试验所需板条，未用的板条和干燥剂请放回铝箔袋内压实自封条，密封口袋，放回4℃。
4.2空白孔加标准品和标本稀释液，其余相应孔中加不同浓度标准品(10ul/孔)以及样品稀释液(90ul/孔)用封板胶纸封住反应孔，4℃冷藏过夜。
4.3每孔加一抗稀释液(100ul/孔)。用封板胶纸封住反应孔，37℃孵箱孵育60min。
4.4每孔加二抗稀释液(100ul/孔)。用封板胶纸封住反应孔，37℃孵箱孵育30min。
4.5加入显色底物(TMB)100ul/孔，室温孵育30min。
4.6加入终止液100ul/孔,混匀后酶标仪测量OD450值。
5.结果分析
试验结果所得到的数据ODTsample，不加细胞的培养基组为空白组ODBlank，只加DMSO不加药的细胞组为对照组ODControl。抑制率inhi％＝(1-(ODTsample-ODBlank)/(ODControl-ODBlank))*100％，通过XLFit软件计算出化合物的DC50值，具体结果见表1
表1：化合物对LNCaP细胞的DC50值
以上结果表明，本发明提供的化合物对LNCaP细胞具有很好的增殖抑制作用，说明本发明化合物具备成为抗肿瘤药物，特别是前列腺癌的治疗药物。
活性测定实施例2：Western blot试验
1.细胞处理
Lncap细胞在指数生长期时，消化细胞后将细胞铺板至6孔板中，每孔1×106个细胞，细胞贴壁生长一天后，加药物培养，药物处理24h后提取蛋白质。
2.细胞蛋白质提取
6孔板中细胞去除培养基，用PBS洗一遍后用胰酶将细胞消化后分别离心收集于1.5mL离心管中，每管中加入100μLRIPA裂解液(含100μMPMSF)，充分混合后冰上静置30min，之后用离心机4℃12000rpm离心20min，取上清用于WB实验，样品可放于-80℃保存。
3蛋白质浓度测定
使用BCA蛋白浓度测定试剂盒，按照下表配制BSA标准测定溶液和待测样品(待测样品可稀释后检测)，使用96孔板加样，各孔用PBS补足至20μl后，分别加入200μlBCA工作液(按试剂盒配制)，混匀后于60℃放置10min后于562nm处检测吸光度，记录读数后以标准品浓度梯度作标准曲线，代入样品吸光度计算样品蛋白质浓度。
4Westernbloting实验标准流程
4.1蛋白质变性：取蛋白裂解液，加入5×LoadingBuffer，100℃变性5min。
4.2上样及电泳：使用10％预制胶及专用电泳液，每孔上样同质量蛋白样品及蛋白marker后，200V电泳30min。
4.3封闭：将胶取下后切下多余部分，通过湿转法转移到PVDF膜上(PVDF膜需要先用甲醇活化1min后使用)，300mA，2h，转膜过程中大量产热，需要用冰盒降温。
4.4封闭：将转膜结束的PVDF膜放于5％脱脂牛奶中室温摇晃封闭1h。
4.5孵育一抗：将PVDF膜按照marker上指示分子量大小分别剪开，分别置于AR和GAPDH一抗中，抗体按照1:1000比例用TBST稀释，4℃摇床封闭过夜。
4.6孵育二抗：孵育一抗后的PVDF膜在摇床上用TBST清洗3次，每次10min，清洗后将膜分别置于对应种属二抗中，摇床振荡室温孵育2h。
4.7洗膜及曝光：孵育二抗结束后将膜放于TBST中摇床振荡清洗3次，每次10min，洗膜后使用ECL法激发膜上荧光。
所得实验结果见图1，其表明本发明提供的化合物对LNCaP细胞AR蛋白具有很好的降解作用，说明本发明化合物具备成为抗肿瘤药物，特别是前列腺癌的治疗药物。
活性测定实施例3：化合物在小鼠中的药代动力学研究
1.实验设计
本次试验选用3只雄性小鼠，分成1组，3只/组。给药前所有动物禁食过夜。
2.实验方法
2.1给药剂量
灌胃给药剂量为10mg/kg，给药体积为10mL/kg。
2.2药液配制
根据动物体重结合给药剂量先算得所需给药溶液的量，称取适量的供试品，先加最终体积的5％的乙醇溶解，再加最终体积5％的SolutolHS15，最后加PBS到目标体积，涡旋混匀充分溶解得到灌胃给药溶液(1mg/mL)，所有溶液现配现用。
2.3给药方法
给药前，将药液放置在动物实验室的磁力搅拌器上搅拌，至少10min。给药过程中，继续保持涡旋状态，确保药液均匀。灌胃给药理论给药体积为10mL/kg，使用配有灌胃针头的注射器给药。
给药前动物称量并记录参与实验的动物体重，根据体重计算每只动物的给药体积。给药结束后，迅速将动物转移回实验笼具内收集样品。
2.4动物状态观察
给药后立即观察动物有无异常反应，若无异常反应，则实验期间每天观察动物两次，若发现有异常反应，应及时记录并增加观察次数直至动物恢复正常或实验结束。
2.5样品采集和保存
所有实验动物给药前禁食过夜，给药后于相应时间点采血至含有肝素钠抗凝剂的采血管中，采集全血后，立即轻轻晃动采血管并置于冰上，然后离心(4℃、4000rpm，10min)，收集上清血浆样品，分析前置于约-80℃冰箱保存。
2.6血浆样品处理和分析
采集得到的血浆样品交由药代部进行样品提取处理，采用含有内标的有机试剂进行蛋白沉淀法提取血浆中的受试物(乙腈：血浆＝4:1,v/v)，提取处理后的样品交由LC-MS/MS进行定量浓度分析。根据分析得到的每只动物的血药浓度，采用Kinetica软件(version5.0)按照非房室模型计算主要的药动学参数eAUC30-120用以评估暴露量；试验结果见表2：
表2：本发明化合物在小鼠中的药代动力学参数
活性测定实施例4：化合物对LNCaP小鼠移植瘤的PK/PD实验研究
1.实验材料
1.1受试样品
称取以上化合物于2.5mL离心管中，加入终体积5％EtOH,5％solutolHSinPBS配。配制终浓度为5mg/mL。
1.2肿瘤细胞
LNCaP细胞购自中国科学院上海生命科学研究院，培养在含10％胎牛血清的RPMI-1640培养液中。细胞生长至80～90％融合，约2-3天传代，细胞生长至足够数量后接种SCID小鼠。
1.3实验动物
SCID小鼠，雄性，6-7w，21只，购自北京维通利华股份公司。小鼠饲养于苏州康迈博诊断科技有限公司SPF级动物房，温度20～25℃，湿度40％～70％，每日光照/黑暗各12小时。动物分笼饲养，每笼5只，可自由摄食饮水，饲料辐照灭菌，水为高压灭菌。
2.研究方法
2.1肿瘤模型构建
体外培养LNCaP细胞至足够量，胰酶消化离心，预冷的PBS重悬后再离心。加入适量预冷的PBS和基质胶调整细胞浓度至7.5×107个/mL。预冷的1mL注射器吸取细胞悬液，注射至裸鼠右侧背部皮下，成规则的小丘形，每只0.2mL，即1.5×107个/只。
2.2分组与给药方案
接种肿瘤细胞后，观察肿瘤大小。待肿瘤增长至200mm3左右，选取形状良好，肿瘤大小合适的老鼠按照肿瘤体积进行系统随机分组。从裸鼠肿瘤模型中选取若干小鼠，每组3只，通过口服给予化合物，给药3天结束后取肿瘤检测AR的表达情况。
2.3血浆化合物浓度检测
血液采集：给药前、给药后3天后采集2小时血样检测药物浓度。收集血样于小鼠眼眶后静脉丛取血30μL(血浆)至肝素化离心管中，然后在4℃、4000rpm条件下离心10min后转移上层血浆，-80℃保存。
所得实验结果见图2。
活性测定实施例5：激素依赖性的前列腺癌症长期药效试验
1.肿瘤模型构建
1.5*10^7LNCaP(人前列腺癌)购自中国科学院细胞库，培养在含10％胎牛血清的RPMI-1640培养液中。细胞生长至80～90％融合，约4-5天传代，细胞生长至足够数量后接种裸鼠。
2.实验动物
SCID裸小鼠，6～7周龄，18-20g，购自北京维通利华有限责任公司。小鼠饲养于SPF级动物房，温度20～25℃，湿度40％～70％，每日光照/黑暗各12小时。动物分笼饲养，每笼5只，可自由摄食饮水，饲料辐照灭菌，水为高压灭菌。饲养至10～11周龄时分组实验。将LNCaP肿瘤细胞直接接种于裸鼠右侧后背。
3.分组与给药方案设计
在平均肿瘤体积达到200-300mm3时，选取形状良好的肿瘤按照肿瘤体积进行随机数字分组，并标记入选动物,分成5个组，每组5只。给药溶媒：5％EtOH,5％solutolHS15inPBS。灌胃相应剂量的化合物。
4.统计分析
数据均以均值±标准差(Mean±SD)表示。统计采用单因素多水平方差分析，各用药组与模型组的比较采用Stundent’st或秩和检验，计算p值，p<0.05为两组间有显著性差异,化合物A88的肿瘤生长抑制率(TGI)结果如表3。
表3：化合物A88的肿瘤生长抑制率
| 给药剂量 | 3天 | 7天 | 10天 | 14天 |
| 10mpk | 19.81％ | 38.44％ | 31.33％ | 13.15％ |
| 25mpk | 14.98％ | 36.36％ | 37.51％ | 24.68％ |
| 50mpk | 22.30％ | 51.85％ | 42.62％ | 24.47％ |
活性测定实施例6：利用ELISA方法检测化合物对前列腺癌细胞株Lncap中AR蛋白活性的降解作用。
1、试验材料
LNCaP：1.5*10^7LNCaP(人前列腺癌)购自中国科学院细胞库，培养在含10％胎牛血清的RPMI-1640培养液中。在条件为37℃，5％饱和湿度的CO2培养箱中常规培养Lncap细胞。待培养至覆盖率达80％左右时，按照1:3比例传代。
ELISA试剂盒：TotalAndrogenReceptorSandwichELISAKit(品牌CST，货号#12850)。
2、试验方法
2.1细胞铺板
细胞离心后用新鲜培养基稀释至1.5×104个/100ul,铺到96孔板中，每孔100ul。
2.2细胞加药
受试化合物配制:称取化合物，用DMSO稀释化合物浓度为10mM储液备用。根据实验需求，将药物由2uM起三倍稀释10个浓度梯度，最终向每孔加入2μl药物，空白对照组加入2μlDMSO。
2.324小时后，除去培养基，并用冰冷的1XPBS冲洗细胞一次。除去PBS，向每个孔板中加入0.5ml冰冷的1XCellLysisBuffer加上1mMPMSF，并在冰上孵育20分钟。4000RPM4℃离心10min后备用。
2.4ELISAkit中试剂及抗体准备
微孔板：使用前将其全部置于室温下。
检测抗体：冻干，呈绿色蛋糕或粉末状。加入1.0ml的检测抗体稀释剂(绿色溶液)以产生浓缩的原液。在室温下孵育5min，偶尔轻轻混匀以完全溶解。要制成最终的工作溶液，请在干净的试管中将全部1.0ml体积的重构检测抗体添加到10.0ml检测抗体稀释剂中，然后轻轻混合。
HRP抗体：冻干，呈红色蛋糕或粉末状。加入1.0mlHRP稀释剂(红色溶液)以产生浓缩的储备溶液。在室温下孵育5min，偶尔轻轻混匀以完全溶解。要制成最终的工作溶液，请在干净的试管中将完整的1.0ml体积的重组HRP-LinkedAntibody加入10.0mlHRPDiluent中。
检测抗体稀释剂：绿色稀释剂，用于重组和稀释检测抗体
HRP稀释剂：红色稀释剂，用于重组和稀释HRP连接的抗体
样品稀释液：蓝色稀释液，用于稀释细胞裂解液。
1X洗涤缓冲液：通过在纯净水中稀释20X洗涤缓冲液
3.5 ELISA
3.5.1将准备好的细胞裂解液20μl加到适当的孔中，并加入70ul抗体稀释剂，用胶带密封并用力压在微孔的顶部。在37℃下孵育平板2h。
3.5.2轻轻撕下胶带并清洗孔：将板内容物丢弃到容器中。用1X洗涤缓冲液洗涤4次，每孔每次200μl。每次清洗时，请用足够强度的新鲜毛巾敲打板，以除去每个孔中的残留溶液，但不要让孔在任何时候完全干燥。用不起毛的纸巾清洁所有孔的底部。
3.5.3向每个孔中添加100μl重构的检测抗体(绿色)。用胶带密封并在37℃下孵育平板1h。
3.5.4重复洗涤程序
3.5.5向每个孔中添加100μl重构的HRP-Linked二抗(红色)用胶带密封并在37℃下将板孵育30min。
3.5.6重复洗涤程序
3.5.7向每个孔中添加100μlTMB底物。用胶带密封，然后将板在37℃下孵育10min或在25℃下孵育30min。
3.5.8向每个孔中添加100μlSTOP溶液。轻轻摇动几秒钟。酶标仪读取450nm的吸光度。
4.试验结果
采用化合物A46作为受试化合物，其对Lncap细胞株中的AR蛋白的抑制率随浓度变化的结果，表明该化合物对AR活性有良好抑制作用，并且经该组数据统计可得A46化合物的IC50(抑制率为50％时的药物浓度)为49nM。
活性测试实施例7：化合物对雌性金黄地鼠痤疮的体内药效
1、试验目的：金黄地鼠侧腹皮脂腺斑是雄性激素依赖器官，丙酸睾酮(雄性激素)促使皮脂腺增大。本实验主要为了研究CB-03-01(阳性药物)，Flutamide(阳性药物)，化合物在雌性金黄地鼠痤疮模型(雄性激素依赖)中对皮脂腺增大的抑制作用，来进一步观察化合物的体内药效，为针对由雄激素引起的痤疮症状临床试验提供依据。
2、试验材料：
2.1供试品
雄激素(丙酸睾酮-TP)；CB-03-01(Clascoterone，CAS号19608-29-8)；Flutamide(氟他胺，CAS号13311-84-7)；本发明化合物A46。
2.2试验动物，详见表4
表4试验动物信息
| 品系种属： | 金黄地鼠 |
| 动物等级： | 清洁级 |
| 性别和数量<sup>a</sup>： | 雌性，72只 |
| 鼠龄(体重)<sup>b</sup>： | 7-8周，90-110g |
| 动物来源： | 北京维通利华实验动物技术有限公司 |
| 动物识别： | 苦味酸标记 |
2.3给药溶媒：丙酮。
3.试验设计
本次实验从72只雌性金黄地鼠中，按照皮脂腺大小和体重，将金黄地鼠平均分配到各组，6只/每组，共7组，连续给药21天。具体动物分组，给药方案等信息详见下表5：
表5试验分组及其给药方案
注：TP代表丙酸睾酮。
按照表格中方案，每次给药25μL，均匀涂抹皮脂腺，每天给药一次。
动物分组与状态观察：分组前，称体重，并将两侧皮脂腺处进行剃毛，观察皮脂腺大小。给药后及给药期间内每天上下午观察动物两次。给药后第21天，观察记录皮脂腺大小及动物体重。
皮脂腺的大小即是其面积，游标卡尺记录其长边(a)和短边(b)，根据长方形面积计算公式得皮脂腺的面积(S)，造模组及给药组的ΔS＝S-S(vehicle)。生长抑制率(％)＝(ΔS(丙酮睾酮组)-ΔS(给药组))/ΔS(丙酮睾酮组)*100％。
4.试验结果
4.1对雌性金黄地鼠皮脂腺斑生长的抑制作用
试验结果如图3所示，由图3实验结果可以看出，丙酸睾酮(TP)涂抹21天后，雌性金黄地鼠的皮脂腺斑明显变大，面积达到了40-50mm2。各组给药后，与建模组比较，阳性药物CB-03-01(400μg，1.6％)，Flutamide(400μg，1.6％)组的皮脂腺斑生长抑制率分别为69.53％(p<0.001)，40.74％(P<0.01)。A46药物100μg(0.4％)剂量组的皮脂腺斑生长抑制率为19.24％(P>0.05)，未表现出明显的抑制作用。A46的200μg(0.8％),400μg(1.6％)和800μg(3.2％)剂量组皮脂腺斑生长抑制率分别为35.20％(P<0.01)，49.54％(p<0.001)，51.61％(P<0.001),与建模组相比较，具有统计性差异。在A46设定为0.4％，0.8％，1.6％，3.2％剂量中，与建模组相比较痤疮药效时，0.8％剂量开始起效有统计性差异。与阳性药物比较，A46药物400μg(1.6％)和800μg(3.2％)剂量在抑制皮脂腺斑面积作用上均优于药物Flutamide(400μg，1.6％)。
A46化合物给药21天后对雄性激素引起的金黄地鼠皮脂腺斑面积增大的抑制作用，如下表6所示：
表6化合物对金黄地鼠皮脂腺斑生长抑制率
4.2对雌性金黄地鼠体重的影响作用
实验开始前，各组金黄地鼠的体重没有显著性差异。实验开始后，各组体重呈缓慢增长趋势，在实验21天，各组地鼠体重均无显著性差异。说明全部受试物在所设定的浓度下经皮给药不会对小鼠的体重产生明显影响(如图4所示)。
活性测定实施例8：化合物对C57小鼠雄激素脱发模型的毛发再生作用
1、试验目的
本研究的目的是通过经皮肤涂抹给药途径，在C57BL/6J小鼠体内对比本发明制备的化合物作为AR蛋白降解剂对雄激素脱发模型的毛发再生作用，为后续临床实验提供数据支持。
2.试验原理
用脱毛膏将小鼠进行脱毛后，皮下注射一定剂量的二氢睾酮(DHT)溶液，可以导致小鼠的毛发再生延迟，用来模拟AR介导的雄激素脱发模型。本发明化合物做为一种AR蛋白的降解剂，对AR介导的雄激素脱发模型的毛发生长促进作用可以一定程度的反映其疗效优劣。
3、受试化合物
受试化合物I名称：二羟睾酮DHT；受试化合物II名称：本发明化合物A46；受试化合物III名称：米诺地尔。
4、试验动物：品系：C57BL/6N小鼠；年龄：6-7周；性别：雄性；动物数量：70只(10只备用)；饲养环境：无特定病原体(SpecificpathogenFree,SPF)。
5.实验设计
5.1模型建立
将70只小鼠深度麻醉，先用动物剃毛器将小鼠背部毛发剔除，然后将脱毛膏(Veethttps://item.jd.com/6291245.html)在小鼠皮肤表面涂抹均匀，静置7-10分钟后用脱毛刮逆毛方向轻轻将毛刮干净，最后用清水充分洗净皮肤表面残留的脱毛膏，避免其灼伤小鼠皮肤。
5.2分组
本次实验共分6组，DHT给药开始时间为脱毛当天，A46给药时间为脱毛后第2天，计为第1天(脱毛当天计为第0天)。随机选取36只状态良好的小鼠分组如下表7：
表7小鼠分组及其给药方案
5.3受试化合物配置方法
药物配制方法及保存条件如下表8所示；
表8受试药物配置方法
5.4观察检测指标
1)体重/g：从第一天给药开始，每周称量并记录两次体重。
2)发再生(anagen)评分(0分：所有区域未见肤色转黑；1分：灰色肤色区域转黑；2分：可见短毛；3分：毛发稀疏；4分：毛发浓密；5分：毛发完全生长)。
在剃毛后第1天对所有小鼠进行拍照，然后从第4天开始每天对小鼠进行拍照和评分，直至实验终点。
3)实验结束时按需进行取皮取血操作。
5.5停药及实验终止标准
在发生以下情况时，单只动物或者整组动物的在体实验部分将被终止。动物将在死亡或者昏迷前被安乐死。
当动物健康状况持续恶化，动物连续遭受痛苦，无法饮食或饮水；或当动物消瘦，体重下降超过20％时。
5.6统计分析
数据均以均值±标准误(AVE±SEM)表示。统计采用单因素多水平方差分析，各用药组与模型组的比较采用Stundent’st或秩和检验，计算p值，p<0.05为两组间有显著性差异,p<0.01为两组间有极显著性差异。
6.实验结果
本实验共设6个组，分别是Vehicle、DHT(30mg/kg)浓度组、DHT(30mg/kg)+米诺地尔5％浓度组、DHT(30mg/kg)+A46 0.5％浓度组、DHT(30mg/kg)+A46 1％浓度组和DHT(30mg/kg)+A463％浓度组。对C57小鼠雄激素脱发模型的毛发再生作用结果见下表9所示：
表9对C57小鼠雄激素脱发模型的毛发再生作用(AVER，n＝6)
从结果中可以看出，DHT(30mg/kg)浓度组在给药17天后毛发发育的评分为0.5，几乎没有毛发的发育，显著地低于Vehicle组，显示造模成功。DHT(30mg/kg)+米诺地尔5％浓度组的评分均值为2.33，显著地高于DHT(30mg/kg)模型组，展现了良好的生发效果。DHT(30mg/kg)+A460.5％浓度组与造模组DHT(二氢睾酮)组相比评分略高，但并无统计性差异。A461％浓度剂量与3％浓度剂量组在Day17时的评分与5％米诺地尔组大致相当，且分值与DHT(二氢睾酮)组，具有显著差异(p<0.05；p<0.01)。
(2)体重变化
小鼠体重的变化在整个给药期间结果如图5所示，由图可以看出，在整个给药期间，所有受试物组及溶剂对照组的体重均保持平稳且略有上升，说明全部受试物在所设定的浓度下经皮给药不会对小鼠的体重产生影响。
活性测试测试实施例8：化合物与阳性对照化合物在LNCaP细胞AR蛋白降解作用的比对
1、实验材料
LNCaP：LNCaP(人前列腺癌)购自中国科学院细胞库，培养在含10％胎牛血清的RPMI-1640培养液中。在条件为37℃，5％饱和湿度的CO2培养箱中常规培养Lncap细胞。待培养至覆盖率达80％左右时，按照1:3比例传代。
2、实验试剂
注：ARD-69制备参考J.Med.Chem.2019,62,2,941–964中教导完成。
3.使用仪器
| 使用仪器 | 型号 |
| 酶标仪 | BioTek Synergy H1 Hybird reader |
| 化学发光凝胶成像仪 | AllianceQ9 Advance |
4.Western blot步骤
4.1细胞培养：
取液氮罐冻存的Lncap，细胞复苏培养至生长对数期，将其铺6至孔板中(每孔约10^6个细胞)，加药物处理。
4.2药物处理
称取适量的化合物溶于DMSO溶剂中，涡旋混匀，配置成10mM的储存溶液，分别加药作用Lncap细胞，control组为只加DMSO处理，药物处理组分别加入对应的化合物处理，其作用的终浓度分别为50nM和200nM,阳性对照组ARD-69的作用浓度为100nM。24h后收集细胞。
4.3收集细胞
取出经化合物作用后的细胞六孔板及其他未加药细胞系，弃去培养基，PBS洗涤，胰酶消化，终止，吹打，离心，PBS再次洗涤，完全弃去PBS。
4.4裂解细胞收集蛋白
收集的细胞加入适量的裂解液(裂解液中加入蛋白酶体抑制剂PMSF)，冰上裂解30min，12000rpm离心20min，取上清。
4.5 BCA法测定蛋白总量
①配制梯度浓度的标准蛋白，取20μL于96孔板中，每个标准品做一个复孔；
②取2μL蛋白裂解液溶于18μL的PBS中，每个样品做一个复孔；
③每个孔加200μL的BCA工作液，37℃孵育30min；
④测定562nm吸光度；
⑤计算每个样品的蛋白浓度，计算50μg所需的蛋白裂解液体积。
4.6 Western blot检测蛋白表达水平
变性：取蛋白裂解液，加入适量的5×蛋白上样缓冲液，100℃变性5min。
电泳：使用10％预制胶电泳200V 30min；
转膜：切去浓缩胶，将分离胶上的蛋白通过湿转法转移到PVDF膜上,270mA，2h。
封闭：将PVDF膜置于5％的脱脂牛奶中室温封闭1h。
一抗：将PVDF膜按Mark的分子量大小剪开，分别置于AR和β-Actin抗体中，4℃摇床孵育过夜。
洗膜：将PVDF膜置于PBST中，摇床振荡清洗4次，每次6min。
二抗：将PVDF膜置于AR和β-Actin抗体对应的二抗(山羊抗兔和山羊抗鼠)溶液中，摇床振荡室温孵育1～2h。
洗膜：将PVDF膜置于PBST中，摇床振荡清洗4次，每次6min。
曝光：显影液激发PVDF上的荧光。
所得实验结果见图6-17，其表明本发明提供的化合物对LNCaP细胞AR蛋白具有很好的降解作用(基本达到或优于ARD-69的降解作用效果)，说明本发明化合物具备成为抗肿瘤药物，特别是前列腺癌的治疗药物。
本发明内容仅仅举例说明了要求保护的一些具体实施方案，其中一个或更多个技术方案中所记载的技术特征可以与任意的一个或多个技术方案相组合，这些经组合而得到的技术方案也在本申请保护范围内，就像这些经组合而得到的技术方案已经在本发明公开内容中具体记载一样。
Claims (64)
1.式(I)所示的双官能化合物或其药学上可用的盐、溶剂化物、立体异构体和前药：
ABM-L-ULM(I)，
其中ABM具有式(IV)结构，其中
表示连接部分的连接点：
Z1选自：氢、卤素、氰基、任选地被一个或更多个卤素所取代的C1-4烷基和任选地被一个或更多个卤素所取代的C1-4烷氧基；
X选自：卤素、羟基、氰基和任选地被一个或更多个卤素所取代的C1-4烷氧基；
Y1、Y2各自独立地选自：O、S；
R1、R2各自独立地选自：H、卤素、任选被卤素、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，或R1、R2连同它们所连接的原子一起形成含有0到2个杂原子的3到8元环；
W1选自：化学键，C6-10芳基，5-10元杂芳基、联C6-10芳基或联5-10元杂芳基，各自任选地被1-10个RW1取代；
每个RW1独立地选自：H、卤基、氰基、羟基、胺基、-COORW11、-CONRW11RW12、任选被卤素、羟基、氰基、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，C3-6环烷基、C4-6环杂烷基、C6-10芳基或5-10元杂芳基；RW11和RW12各自独立地选自：氢、任选被卤素取代的C1-6烷基或C3-6环烷基；
L是连接ABM和ULM的化学连接部分；
ULM是羟脑苷脂E3泛素连接酶结合部分(CLM)或VHLE3连接酶结合部分(VLM)。
2.式(I)所示的双官能化合物或其药学上可用的盐、溶剂化物、立体异构体和前药：
ABM-L-ULM(I)，
其中ABM具有式(IV)结构，其中
表示连接部分的连接点：
Z1选自：氢、卤素、氰基、任选地被一个或更多个卤素所取代的C1-4烷基和任选地被一个或更多个卤素所取代的C1-4烷氧基；
X选自：卤素、羟基、氰基和任选地被一个或更多个卤素所取代的C1-4烷氧基；
Y1、Y2各自独立地选自：O、S；
R1、R2各自独立地选自：H、卤素、任选被卤素、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，或R1、R2连同它们所连接的原子一起形成含有0到2个杂原子的3到8元环；
W1选自：化学键，C6-10芳基，5-10元杂芳基、联C6-10芳基或联5-10元杂芳基，各自任选地被1-10个RW1取代；
每个RW1独立地选自：H、卤基、氰基、羟基、胺基、任选被卤素、羟基、氰基、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，C3-6环烷基、C4-6环杂烷基、C6-10芳基或5-10元杂芳基；
L是连接ABM和ULM的化学连接部分；
ULM是羟脑苷脂E3泛素连接酶结合部分(CLM)或VHLE3连接酶结合部分(VLM)。
3.根据权利要求1或2所述的双官能化合物，其中Z1选自卤素、氰基、甲基、CH2F、CHF2、CF3、甲氧基和CF3O；
X选自：卤素、羟基、氰基、C1-3烷氧基和CF3O；
Y1、Y2各自独立地选自：O、S；
R1、R2各自独立地选自：任选被卤素、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，或R1、R2连同它们所连接的原子一起形成C3-6环烷基；
W1选自：化学键，C6-10芳基，5-10元杂芳基、联C6-10芳基或联5-10元杂芳基，各自任选地被1、2或3个RW1取代；并且
每个RW1独立地选自：氢、卤基、氰基、任选被卤素、羟基、氰基取代的C1-6烷基或C1-6烷氧基。
4.根据前述权利要求任一项所述的双官能化合物，其中W1选自：化学键、苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基，各自任选地被1、2或3个RW1取代；并且
每个RW1独立地选自：氢、卤基、氰基、任选被卤素、羟基、氰基取代的C1-6烷基或C1-6烷氧基、-COORW11、-CONRW11RW12；RW11和RW12各自独立地选自：氢、任选被卤素取代的C1-6烷基。
5.根据权利要求1或2所述的双官能化合物，其中Z1选自卤素、氰基、甲基、CH2F、CHF2、CF3、甲氧基和CF3O；
X选自：卤素、羟基、氰基、C1-3烷氧基和CF3O；
Y1、Y2各自独立地选自：O、S；
R1、R2各自独立地选自：任选被卤素、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，或R1、R2连同它们所连接的原子一起形成C3-6环烷基；
W1选自：化学键，C6-10芳基，5-10元杂芳基、联C6-10芳基或联5-10元杂芳基，各自任选地被1、2或3个RW1取代；并且
每个RW1独立地选自：氢、卤基、氰基、任选被卤素、羟基、氰基取代的C1-6烷基或C1-6烷氧基、-COORW11、-CONRW11RW12；RW11和RW12各自独立地选自：氢、任选被卤素取代的C1-6烷基。
6.根据权利要求1或2所述的双官能化合物，其中Z1选自：卤素、氰基、甲基、CH2F、CHF2、CF3、甲氧基和CF3O；
X选自：卤素；
Y1、Y2各自独立地选自：O、S；
R1、R2各自独立地选自：甲基，或R1、R2连同它们所连接的原子一起形成C3-6环烷基；
W1选自：化学键，
其各自任选地被1、2或3个RW1取代；并且
每个RW1独立地选自：氢、卤基、氰基、任选被卤素取代的C1-3烷基或C1-3烷氧基。
7.根据权利要求1或2所述的双官能化合物，其中Z1选自：卤素、氰基、甲基、CH2F、CHF2、CF3、甲氧基和CF3O；
X选自：卤素；
Y1、Y2各自独立地选自：O、S；
R1、R2各自独立地选自：甲基，或R1、R2连同它们所连接的原子一起形成C3-6环烷基；
W1选自：化学键，
其各自任选地被1、2或3个RW1取代；并且
每个RW1独立地选自：氢、卤基、氰基、任选被卤素取代的C1-3烷基或C1-3烷氧基、-COORW11、-CONRW11RW12；RW11和RW12各自独立地选自：氢、任选被卤素取代的C1-6烷基。
8.根据权利要求1或2所述的双官能化合物，其中Z1选自：CF3；
X选自：F；
Y1、Y2各自独立地选自：O、S；
R1、R2各自独立地选自：甲基，或R1、R2连同它们所连接的原子一起形成C3-4环烷基；
W1选自：化学键，
其各自任选地被1、2或3个RW1取代；并且
每个RW1独立地选自：氢、卤基、氰基、任选被F取代的C1-3烷基或C1-3烷氧基。
9.根据权利要求1或2所述的双官能化合物，其中Z1选自：CF3；
X选自：F；
Y1、Y2各自独立地选自：O、S；
R1、R2各自独立地选自：甲基，或R1、R2连同它们所连接的原子一起形成C3-4环烷基；
W1选自：化学键，
其各自任选地被1、2或3个RW1取代；并且
每个RW1独立地选自：氢、卤基、氰基、任选被F取代的C1-3烷基或C1-3烷氧基、-CONH2、-COOC1-3烷基。
10.根据权利要求1或2所述的双官能化合物，其中ABM选自如下结构，其中
表示连接部分的连接点：
11.根据权利要求1或2所述的双官能化合物，其中ABM选自如下结构，其中
表示连接部分的连接点：
12.根据权利要求1或2所述的双官能化合物，其为式(II)结构的双官能化合物：
ABM-L-CLM(II)，
其中，ABM如权利要求1中定义；
CLM为式(V)所示结构片段或其立体异构体，其中
表示连接部分的连接点：
W选自：CH2、CHR11、C＝O、NH或-N-C1-6烷基；
每个T独立地选自：O或S；
G选自：H、C1-6烷基或羟基；
Q1、Q2、Q3和Q4独立地选自：CR′或N；
A选自：H、C1-6烷基、C3-6环烷基、或卤素；
R11选自：卤素、氰基、任选被卤素取代的C1-6烷基或C1-6烷氧基、C3-6环烷基、-CONR′R″、-OR′、或-NR′R″；
R′和R″各自独立地选自：氢、卤素、胺基、氰基、任选被卤素取代的C1-6烷基或C1-6烷氧基、C3-6环烷基；
连接基团(L)选自如下通式结构表示的基团：
-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-CO-(CH2)o-O-；
-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-；
-(CH2)m-CO-N(R31)-；
-O-(CH2)n-N(R31)-CO-(CH2)o-O-；
-Cy-CO-N(R31)-(CH2)n-N(R31)-CO-(CH2)o-O-；
-C≡C-Cy-(CH2)n-N(R31)-CO-(CH2)o-O-；
-O-(CH2)n-N(R31)-；
-C≡C-(Cy)p-CO-(CH2)o-O-；
-O-(Cy)p-CO-(CH2)o-O-；
-O-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-；
-(CH2)m-CO-Cy-CO-(CH2)o-O-；
-(Cy)q-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-CO-(CH2)o-O-；
-(Cy)q-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-；
-(Cy)q-(CH2)m-CO-N(R31)-；
-(Cy)q-O-(CH2)n-N(R31)-CO-(CH2)o-O-；
-(Cy)q-Cy-CO-N(R31)-(CH2)n-N(R31)-CO-(CH2)o-O-；
-(Cy)q-C≡C-Cy-(CH2)n-N(R31)-CO-(CH2)o-O-；
-(Cy)q-O-(CH2)n-N(R31)-；
-(Cy)q-(Cy)q-C≡C-(Cy)p-CO-(CH2)o-O-；
-(Cy)q-O-(Cy)p-CO-(CH2)o-O-；
-(Cy)q-O-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-；
-(Cy)q-(CH2)m-CO-Cy-CO-(CH2)o-O-；
-(CH2)m-O-(CH2)n-CO-N(R31)-(CH2)o-N(R31)-CO-(CH2)t-O-；
-CO-N(R31)-(CH2)m-N(R31)-(CH2)n-CO-N(R31)-；
-(Cy)q-O-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-CO-(CH2)t-O-；
其中m、n、o、p、q和t各自独立地选自：0、1、2、3、4、5、6，其条件是当所述数目是零时，不存在N-O或O-O键，各个R31独立地选自基团H、甲基或乙基，Cy选自C6-10芳基,C3-6杂芳基，C3-6环烷基,C3-6杂环烷基，优选
其各自任选地被1、2或3个RCy取代；并且
每个RCy独立地选自：H、卤基、氰基、任选被卤素取代的C1-3烷基或C1-3烷氧基。
13.根据权利要求1或2所述的双官能化合物，其为式(II)结构的双官能化合物：
ABM-L-CLM(II)，
其中，ABM如权利要求1中定义；
CLM为式(V)所示结构片段或其立体异构体，其中
表示连接部分的连接点：
W选自：CH2、CHR11、C＝O、NH或-N-C1-6烷基；
每个T独立地选自：O或S；
G选自：H、C1-6烷基或羟基；
Q1、Q2、Q3和Q4独立地选自：CR′或N；
A选自：H、C1-6烷基、C3-6环烷基、或卤素；
R11选自：卤素、氰基、任选被卤素取代的C1-6烷基或C1-6烷氧基、C3-6环烷基、-CONR′R″、-OR′、或-NR′R″；
R′和R″各自独立地选自：氢、卤素、胺基、氰基、任选被卤素取代的C1-6烷基或C1-6烷氧基、C3-6环烷基；
连接基团(L)选自如下通式结构表示的基团：
-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-CO-(CH2)o-O-；
-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-；
-(CH2)m-CO-N(R31)-；
-O-(CH2)n-N(R31)-CO-(CH2)o-O-；
-Cy-CO-N(R31)-(CH2)n-N(R31)-CO-(CH2)o-O-；
-C≡C-Cy-(CH2)n-N(R31)-CO-(CH2)o-O-；
-O-(CH2)n-N(R31)-；
-C≡C-(Cy)p-CO-(CH2)o-O-；
-O-(Cy)p-CO-(CH2)o-O-；
-O-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-；
-(CH2)m-CO-Cy-CO-(CH2)o-O-；
-(Cy)q-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-CO-(CH2)o-O-；
-(Cy)q-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-；
-(Cy)q-(CH2)m-CO-N(R31)-；
-(Cy)q-O-(CH2)n-N(R31)-CO-(CH2)o-O-；
-(Cy)q-Cy-CO-N(R31)-(CH2)n-N(R31)-CO-(CH2)o-O-；
-(Cy)q-C≡C-Cy-(CH2)n-N(R31)-CO-(CH2)o-O-；
-(Cy)q-O-(CH2)n-N(R31)-；
-(Cy)q-(Cy)q-C≡C-(Cy)p-CO-(CH2)o-O-；
-(Cy)q-O-(Cy)p-CO-(CH2)o-O-；
-(Cy)q-O-(CH2)m-CO-N(R31)-(CH2)n-N(R31)-；
-(Cy)q-(CH2)m-CO-Cy-CO-(CH2)o-O-；
其中m、n、o、p和q各自独立地选自：0、1、2、3、4、5、6，其条件是当所述数目是零时，不存在N-O或O-O键，各个R31独立地选自基团H、甲基或乙基，Cy选自C3-6芳基,C3-6杂芳基，C3-6环烷基,C3-6杂环烷基，优选
其各自任选地被1、2或3个RCy取代；并且
每个RCy独立地选自：H、卤基、氰基、任选被卤素取代的C1-3烷基或C1-3烷氧基。
14.根据权利要求12或13所述的双官能化合物，其中W选自：CH2、CHR11或C＝O；
每个T独立地选自：O或S；
G选自：氢、或C1-6烷基；
Q1、Q2、Q3和Q4独立地选自：CH；
A选自：氢、C1-6烷基或卤素；
R11选自：卤素、氰基、-CF3、OCF3、甲基、-CONR′R″、-OR′、或-NR′R″；
R′和R″各自独立地选自：氢、卤素、氰基、胺基、-CF3、OCF3或甲基。
15.根据权利要求12或13所述的双官能化合物，其中CLM为式(V)-1所示结构片段或其立体异构体，其中
表示连接部分的连接点：
其中：
W选自：CH2或C＝O；
A选自：氢或C1-6烷基。
16.根据权利要求12或13所述的双官能化合物，其中CLM为式(V)-2或(V)-3所示结构片段或其立体异构体，其中
表示连接部分的连接点：
17.根据权利要求12或13所述的双官能化合物，其中连接基团(L)选自如下基团：
18.根据权利要求12或13所述的双官能化合物，其中连接基团(L)选自如下基团：
19.根据权利要求1或2所述的双官能化合物，其为式(III)结构的双官能化合物：
ABM-L-VLM(III)，
其中，ABM如权利要求1中定义；
VLM为式(VI)所示结构片段或其立体异构体：
Y3是NRY3RY4、ORY3、SRY3、
R21和R22独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基；
RY3和RY4独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基、任选地被卤素、羟基、氰基取代的C1-6烷基-CO-、任选地被卤素、羟基、氰基取代的C3-6环烷基-CO-；或RY3、R21和它们所连接的碳原子和氮原子一起形成任选地被取代的5-6元杂环烷基；
XY3是O或S；
R23、R24各自独立地选自：H、任选地被卤素、羟基、氰基取代的C1-6烷基；
W2是C6-10芳基或5-10元杂芳基；
R25是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C1-6烷基，任选地被卤素、羟基、氰基取代的C1-6烷氧基，NR25aR25b，CONR25aR25b，C6-10芳基，6-10元杂芳基，噻吩基，或
其中R25a、R25b各自独立地选自：H、任选地被卤素、羟基、氰基取代的C1-6烷基；R27是H、卤素、任选地被卤素、羟基、氰基取代的C1-6烷基，且Xa是S、O或NR28；R28是氢、任选地被卤素取代的C1-6烷基；所述C6-10芳基、6-10元杂芳基、噻吩基任选被一个或更多个选自氢、卤素、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基、-CONHC1-6烷基、-COOC1-6烷基的基团取代；
R26是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C1-6烷基，任选地被卤素、羟基、氰基取代的C1-6烷氧基；
或VLM为式(VI)-4或式(VI)-5所示结构片段或其立体异构体：
其中，R21，R22，Xa如上定义；R27a，R27b各自独立地选自：H、C1-6烷基、5-10元杂芳基；
或VLM为式(VI)-6、式(VI)-7或式(VI)-8所示结构片段或其立体异构体：
其中，R21，R22，R25，R26如上定义；XV是S、O或NR29；R29是氢、任选地被卤素取代的C1-6烷基；W是CH或N；
连接基团(L)选自如下通式结构表示的基团：
-(CH2)m-CO-N(R31)-(CH2)n-CO-；
-O-(CH2)m-O-(CH2)n-CO-；
-O-(CH2)m-CO-；
-C≡C-(Cy)p-(CH2)m-CO-；
-CO-N(R31)-(CH2)m-(Cy)p-(CH2)n-CO-；
-CO-(Cy)p-(CH2)n-CO-；
-O-(CH2)m-(Cy)p-(CH2)n-CO-；
-N(R31)-CO-(CH2)m-O-(CH2)n-CO-；
-N(R31)-(CH2)m-O-(CH2)n-CO-；
-(CH2)m-(Cy)p-(CH2)n-CO-；
-O-(CH2)m-O-(CH2)n-O-(CH2)o-CO-；
-(Cy)p-(CH2)n-O-(CH2)o-CO-；
-C≡C-(CH2)m-CO-；
-(CH2)m-CO-N(R31)-(CH2)n-(Cy)p-CO-；
-C≡C-(Cy)p-(CH2)m-N(R31)-CO-；
-(Cy)q-(CH2)m-CO-N(R31)-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-O-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-CO-；
-(Cy)q-C≡C-(Cy)p-(CH2)m-CO-；
-(Cy)q-CO-N(R31)-(CH2)m-(Cy)p-(CH2)n-CO-；
-(Cy)q-CO-(Cy)p-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-(Cy)p-(CH2)n-CO-；
-(Cy)q-N(R31)-CO-(CH2)m-O-(CH2)n-CO-；
-(Cy)q-N(R31)-(CH2)m-O-(CH2)n-CO-；
-(Cy)q-(CH2)m-(Cy)p-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-O-(CH2)n-O-(CH2)o-CO-；
-(Cy)q-(Cy)p-(CH2)n-O-(CH2)o-CO-；
-(Cy)q-C≡C-(CH2)m-CO-；
-(Cy)q-(CH2)m-CO-N(R31)-(CH2)n-(Cy)p-CO-；
-(Cy)q-C≡C-(Cy)p-(CH2)m-N(R31)-CO-；
-O-(CH2)m-O-(CH2)n-；
-CH＝CH-CO-N(R31)-(CH2)m-O-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-N(R31)-CO-；
-(Cy)q-O-(Cy)p-(CH2)m-N(R31)-CO-；
-(Cy)q-N(R31)-CO-(CH2)m-(Cy)p-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-(Cy)p-CO-；
-O-(CH2)m-O-(CH2)n-O-(CH2)o-O-(CH2)t-CO-；
-O-(Cy)q-CO-N(R31)-(CH2)m-O-(CH2)n-CO-；
-O-(Cy)q-O-(CH2)m-O-(CH2)n-CO-；
-O-(CH2)m-O-(CH2)n-O-(CH2)o-(Cy)q-CO-；
-O-(CH2)m-O-(CH2)n-(Cy)q-CO-；
其中m、n、o、p、q和t各自独立地选自：0、1、2、3、4、5、6，其条件是当所述数目是零时，不存在N-O或O-O键，各个-CH2-中的一个或两个氢原子可以被氟原子替代，各个R31独立地选自基团氢、甲基、乙基、或苄基，Cy选自C6-10芳基,C3-6杂芳基，C3-6环烷基,C3-6杂环烷基，优选
其各自任选地被1、2或3个RCy取代；并且
每个RCy独立地选自：氢、卤基、氰基、任选被卤素取代的C1-3烷基或C1-3烷氧基。
20.根据权利要求1或2所述的双官能化合物，其为式(III)结构的双官能化合物：
ABM-L-VLM(III)，
其中，ABM如权利要求1中定义；
VLM为式(VI)所示结构片段或其立体异构体：
Y3是NRY3RY4、ORY3、SRY3；
R21和R22独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基；
RY3和RY4独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基、任选地被卤素、羟基、氰基取代的C1-6烷基-CO-、任选地被卤素、羟基、氰基取代的C3-6环烷基-CO-；或RY3、R21和它们所连接的碳原子和氮原子一起形成任选地被取代的5-6元杂环烷基；
R23、R24各自独立地选自：H、任选地被卤素、羟基、氰基取代的C1-6烷基；
W2是C6-10芳基或5-10元杂芳基；
R25是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C1-6烷基，任选地被卤素、羟基、氰基取代的C1-6烷氧基，NR25aR25b，CONR25aR25b，C6-10芳基，或
其中R25a、R25b各自独立地选自：H、任选地被卤素、羟基、氰基取代的C1-6烷基；R27是H、卤素、任选地被卤素、羟基、氰基取代的C1-6烷基，且Xa是S或O；
R26是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C1-6烷基，任选地被卤素、羟基、氰基取代的C1-6烷氧基；
或VLM为式(VI)-4或式(VI)-5所示结构片段或其立体异构体：
其中，R21，R22，Xa如上定义；R27a，R27b各自独立地选自：H、C1-6烷基；
连接基团(L)选自如下通式结构表示的基团：
-(CH2)m-CO-N(R31)-(CH2)n-CO-；
-O-(CH2)m-O-(CH2)n-CO-；
-O-(CH2)m-CO-；
-C≡C-(Cy)p-(CH2)m-CO-；
-CO-N(R31)-(CH2)m-(Cy)p-(CH2)n-CO-；
-CO-(Cy)p-(CH2)n-CO-；
-O-(CH2)m-(Cy)p-(CH2)n-CO-；
-N(R31)-CO-(CH2)m-O-(CH2)n-CO-；
-N(R31)-(CH2)m-O-(CH2)n-CO-；
-(CH2)m-(Cy)p-(CH2)n-CO-；
-O-(CH2)m-O-(CH2)n-O-(CH2)o-CO-；
-(Cy)p-(CH2)n-O-(CH2)o-CO-；
-C≡C-(CH2)m-CO-；
-(CH2)m-CO-N(R31)-(CH2)n-(Cy)p-CO-；
-C≡C-(Cy)p-(CH2)m-N(R31)-CO-；
-(Cy)q-(CH2)m-CO-N(R31)-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-O-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-CO-；
-(Cy)q-C≡C-(Cy)p-(CH2)m-CO-；
-(Cy)q-CO-N(R31)-(CH2)m-(Cy)p-(CH2)n-CO-；
-(Cy)q-CO-(Cy)p-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-(Cy)p-(CH2)n-CO-；
-(Cy)q-N(R31)-CO-(CH2)m-O-(CH2)n-CO-；
-(Cy)q-N(R31)-(CH2)m-O-(CH2)n-CO-；
-(Cy)q-(CH2)m-(Cy)p-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-O-(CH2)n-O-(CH2)o-CO-；
-(Cy)q-(Cy)p-(CH2)n-O-(CH2)o-CO-；
-(Cy)q-C≡C-(CH2)m-CO-；
-(Cy)q-(CH2)m-CO-N(R31)-(CH2)n-(Cy)p-CO-；
-(Cy)q-C≡C-(Cy)p-(CH2)m-N(R31)-CO-；
其中m、n、o、p和q各自独立地选自：0、1、2、3、4、5、6，其条件是当所述数目是零时，不存在N-O或O-O键，各个R31独立地选自基团氢、甲基、乙基、或苄基，Cy选自C3-6环烷基,C3-6杂环烷基，优选
其各自任选地被1、2或3个RCy取代；并且
每个RCy独立地选自：氢、卤基、氰基、任选被卤素取代的C1-3烷基或C1-3烷氧基。
21.根据权利要求19或20所述的双官能化合物，其中Y3是NRY3RY4、ORY3；
R21和R22独立地选自：氢、C1-6烷基；
RY3和RY4独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基-CO-；或RY3、R21和它们所连接的碳原子和氮原子一起形成任选地被取代的5-6元杂环烷基；
R23、R24各自独立地选自：氢、C1-6烷基；
W2是苯基；
R25是氢，卤素，C1-6烷基，CONR25aR25b，或
其中R25a、R25b各自独立地选自：H、C1-6烷基；R27是H、C1-6烷基，且Xa是S；
R26是H，C1-6烷基。
22.根据权利要求19或20所述的双官能化合物，其中Y3是NRY3RY4、ORY3；
R21和R22独立地选自：氢、C1-6烷基；
RY3和RY4独立地选自：氢、C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基-CO-；或RY3、R21和它们所连接的碳原子和氮原子一起形成任选地被取代的5元杂环烷基；
R23、R24各自独立地选自：氢、C1-6烷基；
W2是苯基；
R25是CONR25aR25b，或
其中R25a、R25b各自独立地选自：H、C1-6烷基；R27是C1-6烷基，且Xa是S；
R26是氢。
23.根据权利要求19或20所述的双官能化合物，其中Y3是
RY3选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基；
XY3是O或S。
24.根据权利要求19或20所述的双官能化合物，其中Y3是
25.根据权利要求19或20所述的双官能化合物，其中所述VLM选自如下的结构片段或其立体异构体，其中
表示连接部分的连接点：
26.根据权利要求19或20所述的双官能化合物，其中VLM为式(VI)-1所示结构片段或其立体异构体：
其中，Y3，R21，R23，R25如权利要求19或20中定义。
27.根据权利要求19或20所述的双官能化合物，其中VLM为式(VI)-2所示结构片段或其立体异构体：
Y5是NRY5、O；
R21和R22独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基；
RY5是氢、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基、任选地被卤素、羟基、氰基取代的C1-6烷基-CO-、任选地被卤素、羟基、氰基取代的C3-6环烷基-CO-；或RY5、R21和它们所连接的碳原子和氮原子一起形成任选地被取代的5-6元杂环烷基；
R23、R24各自独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基；
W2是C6-10芳基或5-10元杂芳基；
R25是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C1-6烷基，任选地被卤素、羟基、氰基取代的C1-6烷氧基，NR25aR25b，CONR25aR25b，C6-10芳基，或
其中R25a、R25b各自独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基；R27是H、卤素、任选地被卤素、羟基、氰基取代的C1-6烷基，且Xa是S或O；
R26是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C1-6烷基，任选地被卤素、羟基、氰基取代的C1-6烷氧基。
28.根据权利要求19或20所述的双官能化合物，其中VLM为式(VI)-2所示结构片段或其立体异构体：
Y5是NRY5、O；
R21和R22独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基；
RY5是氢、任选地被卤素、羟基、氰基取代的C1-6烷基、任选地被卤素、羟基、氰基取代的C3-6环烷基、任选地被卤素、羟基、氰基取代的C1-6烷基-CO-、任选地被卤素、羟基、氰基取代的C3-6环烷基-CO-；或RY5、R21和它们所连接的碳原子和氮原子一起形成任选地被取代的5-6元杂环烷基；
R23、R24各自独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基；
W2是5-6元杂芳基；
R25是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C1-6烷基，任选地被卤素、羟基、氰基取代的C1-6烷氧基，NR25aR25b，CONR25aR25b，C6-10芳基，6-10元杂芳基，噻吩基，或
其中R25a、R25b各自独立地选自：氢、任选地被卤素、羟基、氰基取代的C1-6烷基；R27是H、卤素、任选地被卤素、羟基、氰基取代的C1-6烷基，且Xa是S、O或NR28；R28是氢、任选地被卤素取代的C1-6烷基；所述C6-10芳基、6-10元杂芳基、噻吩基任选被一个或更多个选自氢、卤素、任选地被卤素取代的C1-6烷基、任选地被卤素取代的C3-6环烷基、-CONHC1-6烷基、-COOC1-6烷基的基团取代；
R26是氢，卤素，氰基，羟基，硝基，任选地被卤素、羟基、氰基取代的C1-6烷基，任选地被卤素、羟基、氰基取代的C1-6烷氧基。
29.根据权利要求27所述的双官能化合物，其中Y5是NRY5、O；
R21和R22独立地选自：氢、C1-6烷基；
RY5是氢、C1-6烷基；或RY5、R21和它们所连接的碳原子和氮原子一起形成任选地被取代的5元杂环烷基；
R23、R24各自独立地选自：氢、C1-6烷基；
W2是苯基；
R25是CONR25aR25b，或
其中R25a、R25b各自独立地选自：H、C1-6烷基；R27是C1-6烷基，且Xa是S；
R26是氢。
30.根据权利要求19-29任一项所述的双官能化合物，其中R21选自：甲基、乙基、正丙基、异丙基、正丁基、2-甲基丙基、仲丁基、叔丁基、正戊基、异戊基或新戊基。
31.根据权利要求27所述的双官能化合物，其中Y5是NRY5、O；
R21选自：甲基、乙基、正丙基、异丙基、正丁基、2-甲基丙基、仲丁基、叔丁基、正戊基、异戊基或新戊基；
R22选自：氢；
RY5是氢、C1-6烷基；
R23、R24各自独立地选自：氢、C1-6烷基；
W2是
R25是
其中R27是C1-3烷基，且Xa是S；
R26是氢。
32.根据权利要求28所述的双官能化合物，其中Y5是NRY5、O；
R21和R22独立地选自：氢、C1-6烷基；
RY5是氢、C1-6烷基；或RY5、R21和它们所连接的碳原子和氮原子一起形成任选地被取代的5元杂环烷基；
R23、R24各自独立地选自：氢、C1-6烷基；
W2是噁唑基或噻唑基；
R25是氢；
R26是氢。
33.根据权利要求32所述的双官能化合物，其中Y5是NRY5、O；
R21选自：甲基、乙基、正丙基、异丙基、正丁基、2-甲基丙基、仲丁基、叔丁基、正戊基、异戊基或新戊基；
R22选自：氢；
RY5是氢、C1-6烷基；
R23、R24各自独立地选自：氢、C1-6烷基；
W2是噁唑基或噻唑基；
R25是氢；
R26是氢。
34.根据权利要求19或20所述的双官能化合物，其中所述VLM选自如下的结构片段或其立体异构体，其中
表示连接部分的连接点：
35.根据权利要求27所述的双官能化合物，其中VLM为式(VI)-3所示结构片段或其立体异构体：
其中，Y5，R21，R23，R25如权利要求27中定义。
36.根据权利要求19或20所述的双官能化合物，其中所述VLM选自如下的结构片段或其立体异构体，其中
表示连接部分的连接点：
37.根据权利要求19或20所述的双官能化合物，其中所述VLM为式(VI)-5所示结构片段或其立体异构体：
R21和R22独立地选自：氢、C1-6烷基；
R27a，R27b各自独立地选自：H、5-6元杂芳基，优选H、噻唑基。
38.根据权利要求19或20所述的双官能化合物，其中所述VLM选自如下的结构片段或其立体异构体，其中
表示连接部分的连接点：
39.根据权利要求19或20所述的双官能化合物，其中所述VLM为式(VI)-61所示结构片段或其立体异构体：
R21和R22独立地选自：氢、C1-6烷基；
R29是任选地被卤素取代的C1-6烷基。
40.根据权利要求19或20所述的双官能化合物，其中所述VLM选自如下的结构片段或其立体异构体，其中
表示连接部分的连接点：
41.根据权利要求19或20所述的双官能化合物，其中所述VLM为式(VI)-71或式(VI)-81所示结构片段或其立体异构体：
R21和R22独立地选自：氢、C1-6烷基；
R25是苯基，吡啶基，嘧啶基，噻吩基，或
R27是C1-6烷基，且Xa是S、O或NR28；R28是C1-6烷基；所述苯基、吡啶基、嘧啶基、噻吩基任选被一个或更多个选自卤素、C1-6烷基、-CONHC1-6烷基的基团取代；
XV是S、O或NR29；R29是氢、C1-6烷基；W是CH。
42.根据权利要求19或20所述的双官能化合物，其中所述VLM选自如下的结构片段或其立体异构体，其中
表示连接部分的连接点：
43.根据权利要求19-42任一项所述的双官能化合物，其中Cy选自C6-10芳基,C3-6杂芳基，C3-6环烷基,C3-6杂环烷基，优选苯基、吡啶基、三唑基、氮杂环丁基、四氢吡咯基、哌啶基、哌嗪基、氧代哌嗪基、四氢吡啶基、氧代二氢吡啶基、进一步优选
其各自任选地被1、2或3个RCy取代；并且
每个RCy独立地选自：氢、卤基、氰基、任选被卤素取代的C1-3烷基。
44.根据权利要求19或20所述的双官能化合物，其中连接基团(L)选自如下基团：
-O-(CH2)m-O-(CH2)n-CO-；
-O-(CH2)m-CO-；
-O-(CH2)m-O-(CH2)n-O-(CH2)o-CO-；
-(Cy)p-(CH2)n-O-(CH2)o-CO-；
-(Cy)q-O-(CH2)m-O-(CH2)n-CO-；
-(Cy)q-O-(CH2)m-CO-；
-(Cy)q-O-(CH2)m-O-(CH2)n-O-(CH2)o-CO-；
-O-(Cy)q-O-(CH2)m-O-(CH2)n-CO-；
-O-(CH2)m-O-(CH2)n-O-(CH2)o-(Cy)q-CO-；
-O-(CH2)m-O-(CH2)n-(Cy)q-CO-；
其中m、n和o各自独立地选自：1、2、3、4、5、6，q选自：1，Cy选自C6-10芳基,C3-6杂芳基，C3-6环烷基,C3-6杂环烷基，优选苯基、吡啶基、三唑基、氮杂环丁基、四氢吡咯基、哌啶基、哌嗪基、氧代哌嗪基、四氢吡啶基、氧代二氢吡啶基，进一步优选
其各自任选地被1、2或3个RCy取代；并且
每个RCy独立地选自：氢、卤基、氰基、任选被卤素取代的C1-3烷基。
45.根据权利要求19或20所述的双官能化合物，其中连接基团(L)选自如下基团：
46.根据权利要求19或20所述的双官能化合物，其中连接基团(L)选自如下基团：
47.根据权利要求1或2所述的双官能化合物，其中所述化合物选自：
48.一种药物组合物，其包含有效量的权利要求1-47任一项所述的双官能化合物或其药学上可用的盐、溶剂化物、立体异构体和前药，以及药学上可接受的载体。
49.根据权利要求48所述药物组合物，其进一步包含至少一种其它生物活性剂。
50.根据权利要求49所述药物组合物，其中其他生物活性剂是抗癌剂。
51.权利要求1-47任一项所述的双官能化合物或其药学上可用的盐、溶剂化物、立体异构体和前药在制备将内源蛋白质募集到E3泛素连接酶进行降解的药物中的用途。
52.权利要求1-47任一项所述的双官能化合物或其药学上可用的盐、溶剂化物、立体异构体和前药在制备将雄激素受体降解或抑制的药物中的用途。
53.根据权利要求51或52所述的用途，其中与内源蛋白质募集到E3泛素连接酶或雄激素受体相关疾病选自：痤疮、多毛症、皮脂腺增大、脱发、哮喘、多发性硬化症、癌症、肯尼亚病(Kenney′sdisease)、纤毛病、腭裂、糖尿病、心脏病、高血压、发炎性肠病、智力迟钝、情绪障碍、肥胖症、屈光不正、不育症、安格尔曼综合症(Angelmansyndrome)、卡纳万疾病(Canavandisease)、腹腔病、夏-马-图三氏病(Charcot-Marie-Toothdisease)、囊肿性纤维化、杜氏肌营养不良(Duchennemusculardystrophy)、血色病、血友病、克氏综合症(Klinefelter′ssyndrome)、神经纤维瘤、苯丙酮尿症、多囊性肾病(PKDl)或4(PKD2)、普拉德-威利综合症(Prader-Willisyndrome)、镰状细胞病、泰伊-萨克斯二氏病(Tay-Sachsdisease)、特纳综合症(Turnersyndrome)；
所述癌症是鳞状细胞癌、基底细胞癌、腺癌、肝细胞癌和肾细胞癌瘤；膀胱、肠道、乳房、子宫颈、结肠、食道、头、肾脏、肝脏、肺、颈、卵巢、胰腺、前列腺和胃的癌症；白血病；良性和恶性淋巴瘤，尤其伯基特氏淋巴瘤(Burkitt′slymphoma)和非霍奇金淋巴瘤(Non-Hodgkin′slymphoma)；良性和恶性黑色素瘤；骨髓增生性疾病；肉瘤，包括尤文氏肉瘤(Ewing′ssarcoma)、血管内皮瘤、卡波西肉瘤(Kaposi′ssarcoma)、脂肪肉瘤、肌肉瘤、末梢神经上皮瘤、滑膜肉瘤、神经胶质瘤、星形细胞瘤、寡突神经胶质细胞瘤、室管膜瘤、神经胶母细胞瘤、神经母细胞瘤、神经节神经胶质瘤、髓母细胞瘤、松果体细胞肿瘤、脑膜瘤、脑膜肉瘤、神经纤维瘤和许旺细胞瘤(Schwannomas)；肠道癌、乳癌、前列腺癌、子宫颈癌、子宫癌、肺癌、卵巢癌、睾丸癌、甲状腺癌、星形细胞瘤、食道癌、胰脏癌、胃癌、肝癌、结肠癌、黑色素瘤；癌肉瘤、霍奇金氏疾病、维尔姆斯瘤或畸胎癌。
54.根据权利要求53所述的用途，其中所述疾病是癌症、痤疮、皮脂腺增大、脱发或肯尼迪病。
55.根据权利要求54所述的用途，其中所述疾病是前列腺癌、痤疮或脱发。
56.一种在需要其的受试者中将内源蛋白质募集到E3泛素连接酶进行降解的方法，所述方法包括给予权利要求1-47任一项所述的双官能化合物或其药学上可用的盐、溶剂化物、立体异构体和前药。
57.一种在需要其的受试者中将雄激素受体降解或抑制的方法，所述方法包括给予权利要求1-47任一项所述的双官能化合物或其药学上可用的盐、溶剂化物、立体异构体和前药。
58.根据权利要求56或57所述的方法，其中与内源蛋白质募集到E3泛素连接酶或雄激素受体相关疾病选自：痤疮、多毛症、皮脂腺增大、脱发、哮喘、多发性硬化症、癌症、肯尼亚病(Kenney′sdisease)、纤毛病、腭裂、糖尿病、心脏病、高血压、发炎性肠病、智力迟钝、情绪障碍、肥胖症、屈光不正、不育症、安格尔曼综合症(Angelmansyndrome)、卡纳万疾病(Canavandisease)、腹腔病、夏-马-图三氏病(Charcot-Marie-Toothdisease)、囊肿性纤维化、杜氏肌营养不良(Duchennemusculardystrophy)、血色病、血友病、克氏综合症(Klinefelter′ssyndrome)、神经纤维瘤、苯丙酮尿症、多囊性肾病(PKDl)或4(PKD2)、普拉德-威利综合症(Prader-Willisyndrome)、镰状细胞病、泰伊-萨克斯二氏病(Tay-Sachsdisease)、特纳综合症(Turnersyndrome)；
所述癌症是鳞状细胞癌、基底细胞癌、腺癌、肝细胞癌和肾细胞癌瘤；膀胱、肠道、乳房、子宫颈、结肠、食道、头、肾脏、肝脏、肺、颈、卵巢、胰腺、前列腺和胃的癌症；白血病；良性和恶性淋巴瘤，尤其伯基特氏淋巴瘤(Burkitt′slymphoma)和非霍奇金淋巴瘤(Non-Hodgkin′slymphoma)；良性和恶性黑色素瘤；骨髓增生性疾病；肉瘤，包括尤文氏肉瘤(Ewing′ssarcoma)、血管内皮瘤、卡波西肉瘤(Kaposi′ssarcoma)、脂肪肉瘤、肌肉瘤、末梢神经上皮瘤、滑膜肉瘤、神经胶质瘤、星形细胞瘤、寡突神经胶质细胞瘤、室管膜瘤、神经胶母细胞瘤、神经母细胞瘤、神经节神经胶质瘤、髓母细胞瘤、松果体细胞肿瘤、脑膜瘤、脑膜肉瘤、神经纤维瘤和许旺细胞瘤(Schwannomas)；肠道癌、乳癌、前列腺癌、子宫颈癌、子宫癌、肺癌、卵巢癌、睾丸癌、甲状腺癌、星形细胞瘤、食道癌、胰脏癌、胃癌、肝癌、结肠癌、黑色素瘤；癌肉瘤、霍奇金氏疾病、维尔姆斯瘤或畸胎癌。
59.根据权利要求58所述的方法，其中所述疾病是癌症、痤疮、皮脂腺增大、脱发或肯尼迪病。
60.根据权利要求59所述的方法，其中所述疾病是前列腺癌、痤疮或脱发。
61.一种治疗受试者的疾病或病症的方法，其包含以下步骤：向有需要的受试者施用组合物，所述组合物包含药学上可接受的载体和有效量的权利要求1-47任一项所述的双官能化合物或其药学上可用的盐、溶剂化物、立体异构体和前药。
62.根据权利要求61所述的方法，其中所述疾病或病症选自：痤疮、多毛症、皮脂腺增大、脱发、哮喘、多发性硬化症、癌症、肯尼亚病(Kenney′sdisease)、纤毛病、腭裂、糖尿病、心脏病、高血压、发炎性肠病、智力迟钝、情绪障碍、肥胖症、屈光不正、不育症、安格尔曼综合症(Angelmansyndrome)、卡纳万疾病(Canavandisease)、腹腔病、夏-马-图三氏病(Charcot-Marie-Toothdisease)、囊肿性纤维化、杜氏肌营养不良(Duchennemusculardystrophy)、血色病、血友病、克氏综合症(Klinefelter′ssyndrome)、神经纤维瘤、苯丙酮尿症、多囊性肾病(PKDl)或4(PKD2)、普拉德-威利综合症(Prader-Willisyndrome)、镰状细胞病、泰伊-萨克斯二氏病(Tay-Sachsdisease)、特纳综合症(Turnersyndrome)；
所述癌症是鳞状细胞癌、基底细胞癌、腺癌、肝细胞癌和肾细胞癌瘤；膀胱、肠道、乳房、子宫颈、结肠、食道、头、肾脏、肝脏、肺、颈、卵巢、胰腺、前列腺和胃的癌症；白血病；良性和恶性淋巴瘤，尤其伯基特氏淋巴瘤(Burkitt′slymphoma)和非霍奇金淋巴瘤(Non-Hodgkin′slymphoma)；良性和恶性黑色素瘤；骨髓增生性疾病；肉瘤，包括尤文氏肉瘤(Ewing′ssarcoma)、血管内皮瘤、卡波西肉瘤(Kaposi′ssarcoma)、脂肪肉瘤、肌肉瘤、末梢神经上皮瘤、滑膜肉瘤、神经胶质瘤、星形细胞瘤、寡突神经胶质细胞瘤、室管膜瘤、神经胶母细胞瘤、神经母细胞瘤、神经节神经胶质瘤、髓母细胞瘤、松果体细胞肿瘤、脑膜瘤、脑膜肉瘤、神经纤维瘤和许旺细胞瘤(Schwannomas)；肠道癌、乳癌、前列腺癌、子宫颈癌、子宫癌、肺癌、卵巢癌、睾丸癌、甲状腺癌、星形细胞瘤、食道癌、胰脏癌、胃癌、肝癌、结肠癌、黑色素瘤；癌肉瘤、霍奇金氏疾病、维尔姆斯瘤或畸胎癌。
63.根据权利要求62所述的用途，其中所述疾病是癌症、痤疮、皮脂腺增大、脱发或肯尼迪病。
64.根据权利要求63所述的用途，其中所述疾病是前列腺癌、痤疮或脱发。
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| WO2023193789A1 (en) * | 2022-04-08 | 2023-10-12 | Beijing Neox Biotech Limited | Wee1 degrading compounds |
| WO2024022483A1 (en) * | 2022-07-28 | 2024-02-01 | Suzhou Kintor Pharmaceuticals, Inc. | A bifunctional pharmaceutical intermediate and its preparation method and use |
| WO2024208266A1 (zh) * | 2023-04-04 | 2024-10-10 | 苏州开拓药业股份有限公司 | 一种杂环化合物在治疗间质性肺炎中的用途 |
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Also Published As
| Publication number | Publication date |
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| TW202146399A (zh) | 2021-12-16 |
| CN113387930B (zh) | 2022-07-12 |
| US20230054270A1 (en) | 2023-02-23 |
| TWI836196B (zh) | 2024-03-21 |
| WO2021180160A1 (zh) | 2021-09-16 |
| EP4119546A4 (en) | 2024-09-25 |
| EP4119546A1 (en) | 2023-01-18 |
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