TWI836196B - 一種雙官能化合物及其製備方法和用途 - Google Patents

一種雙官能化合物及其製備方法和用途 Download PDF

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TWI836196B
TWI836196B TW110108729A TW110108729A TWI836196B TW I836196 B TWI836196 B TW I836196B TW 110108729 A TW110108729 A TW 110108729A TW 110108729 A TW110108729 A TW 110108729A TW I836196 B TWI836196 B TW I836196B
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友之 童
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Abstract

本發明涉及一種雙官能化合物及其製備方法和用途，其中雙官能化合物包含結合到E3泛素連接酶結合部分；結合到雄激素受體的靶蛋白結合部分；和將E3泛素連接酶結合部分和靶蛋白結合部分連接的連接部分。本申請雙官能化合物使雄激素受體鄰近泛素連接酶定位，以實現雄激素受體的降解或抑制。

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一種雙官能化合物及其製備方法和用途
本發明屬於藥物領域，具體涉及一種雙官能化合物及其製備方法和用途，其中雙官能化合物包含結合到E3泛素連接酶結合部分；結合到雄激素受體的靶蛋白結合部分；和將E3泛素連接酶結合部分和靶蛋白結合部分連接的連接部分。本申請雙官能化合物使雄激素受體鄰近泛素連接酶定位，以實現雄激素受體的降解或抑制。
雄激素受體(Androgen Receptor,AR)屬於被雄激素活化的細胞核激素受體家族。在沒有雄激素存在下，AR被胞質溶膠中的熱休克蛋白90(Hsp90)結合。當雄激素結合AR時，它的構象變成從Hsp90釋放AR並暴露核定位元信號(Nuclear Localization Signal,NLS)。後者能使AR轉移進細胞核中，AR作為轉錄因數起作用以促進負責雄性性別特徵的基因表達。AR缺乏會導致雄激素不敏感綜合症。
儘管AR負責雄性性別特徵的發育，它也是某些形式的癌症中充分記載的癌基因，例如前列腺癌。AR活性的一種通常測量的靶基因是分泌的前列腺特異性抗原(Prostatic Specific Antigen,PSA)蛋白。前列腺癌的當前治療方案包括兩種方案。第一個方案依賴於雄激素的減少，而第二個策略目標在於抑制AR功能。儘管開發了有效的靶向療法，大多數患者發生抗藥性，且疾病持續進展。用於治療前列腺癌的一個替代方案包括消除AR蛋白。因為AR是許多形式的前列腺癌中的腫瘤發生的關鍵驅動器，它的消除將會導致治療上有益的應答。
本領域中繼續需要與異常AR調節或活性有關的疾病和病症(例如，癌症、前列腺癌和甘迺迪氏病的有效治療。
本發明提供一種雙官能化合物，其作用是將內源蛋白質募集到E3泛素連接酶進行降解。具體地，本發明提供了雙功能化合物或蛋白酶解靶向嵌合(Proteolysis Targeting Chimera,PROTAC)化合物，其用作雄激素受體(AR)的靶向泛素化和降解的調節劑。另外，本發明提供了使用有效量的如本文中所述的化合物用於治療或改善疾病狀況(包括癌症，例如，前列腺癌和甘迺迪氏病)的方法。
在一個方面，本發明提供了起將內源性蛋白(例如，AR蛋白)募集至E3泛素連接酶用於泛素化和降解的作用的化合物。
在某些實施方案中，式(I)所示的雙官能化合物或其藥學上可用的鹽、溶劑化物、立體異構體和前藥：ABM-L-ULM (I)，其中ABM具有式(IV)結構，其中
Figure 110108729-A0305-02-0004-716
表示連接部分的連接點：
Figure 110108729-A0305-02-0004-783
Z1選自：氫、鹵素、氰基、任選地被一個或更多個鹵素所取代的C1-4烷基和任選地被一個或更多個鹵素所取代的C1-4烷氧基；X選自：鹵素、羥基、氰基和任選地被一個或更多個鹵素所取代的C1-4烷氧基；Y1、Y2各自獨立地選自：O、S；R1、R2各自獨立地選自：H、鹵素、任選被鹵素、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，或R1、R2連同它們所連接的原子一起形成含有0到2個雜原子的3到8元環；W1選自：化學鍵，C6-10芳基，5-10元雜芳基、聯C6-10芳基或聯5-10元 雜芳基，各自任選地被1-10個RW1取代；每個RW1獨立地選自：H、鹵基、氰基、羥基、胺基、-COORW11、-CONRW11RW12、任選被鹵素、羥基、氰基、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，C3-6環烷基、C4-6環雜烷基、C6-10芳基或5-10元雜芳基；RW11和RW12各自獨立地選自：氫、任選被鹵素取代的C1-6烷基或C3-6環烷基；L是連接ABM和ULM的化學連接部分；ULM是羥腦苷脂E3泛素連接酶結合部分(CLM)或VHLE3連接酶結合部分(VLM)。
在某些實施方案中，雙官能化合物為下述式I結構的雙官能化合物，及其鹽、多晶型物和前藥：ABM-L-ULM (I)，其中ABM是雄激素受體(AR)結合部分，L是連接ABM和ULM的化學連接部分，ULM是E3連接酶結合部分，例如，羥腦苷脂E3泛素連接酶結合部分(CLM)或VHLE3連接酶結合部分(VLM)。
所述ABM具有式(IV)結構，其中
Figure 110108729-A0305-02-0005-717
表示連接部分的連接點：
Figure 110108729-A0305-02-0005-2
其中：Z1選自：氫、鹵素、氰基、任選地被一個或更多個鹵素所取代的C1-4烷基和任選地被一個或更多個鹵素所取代的C1-4烷氧基；X選自：鹵素、羥基、氰基和任選地被一個或更多個鹵素所取代的C1-4烷氧基；Y1、Y2各自獨立地選自：O、S；R1、R2各自獨立地選自：氫、鹵素、任選被鹵素、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，或R1、R2連同它們所連接的原子一起形成含有0到2個雜原子的3到8元環； W1選自：化學鍵，C6-10芳基，5-10元雜芳基、聯C6-10芳基或聯5-10元雜芳基，各自任選地被1-10個RW1取代；每個RW1獨立地選自：氫、鹵基、氰基、羥基、胺基、任選被鹵素、羥基、氰基、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，C3-6環烷基、C4-6環雜烷基、C6-10芳基或5-10元雜芳基。
在某些實施方案中，Z1選自鹵素、氰基、甲基、CH2F、CHF2、CF3、甲氧基和CF3O；X選自：鹵素、羥基、氰基、C1-3烷氧基和CF3O；Y1、Y2各自獨立地選自：O、S；R1、R2各自獨立地選自：任選被鹵素、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，或R1、R2連同它們所連接的原子一起形成C3-6環烷基；W1選自：化學鍵，C6-10芳基，5-10元雜芳基、聯C6-10芳基或聯5-10元雜芳基，各自任選地被1、2或3個RW1取代；並且每個RW1獨立地選自：氫、鹵基、氰基、任選被鹵素、羥基、氰基取代的C1-6烷基或C1-6烷氧基。
在本發明的某些實施方案中，W1選自：化學鍵、苯基、吡啶基、嘧啶基、吡嗪基、噠嗪基，各自任選地被1、2或3個RW1取代；並且每個RW1獨立地選自：氫、鹵基、氰基、任選被鹵素、羥基、氰基取代的C1-6烷基或C1-6烷氧基、-COORW11、-CONRW11RW12；RW11和RW12各自獨立地選自：氫、任選被鹵素取代的C1-6烷基。
在某些實施方案中，Z1選自鹵素、氰基、甲基、CH2F、CHF2、CF3、甲氧基和CF3O；X選自：鹵素、羥基、氰基、C1-3烷氧基和CF3O；Y1、Y2各自獨立地選自：O、S；R1、R2各自獨立地選自：任選被鹵素、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，或R1、R2連同它們所連接的原子一起形成C3-6環烷基；W1選自：化學鍵，C6-10芳基，5-10元雜芳基、聯C6-10芳基或聯5-10元 雜芳基，各自任選地被1、2或3個RW1取代；並且每個RW1獨立地選自：氫、鹵基、氰基、任選被鹵素、羥基、氰基取代的C1-6烷基或C1-6烷氧基、-COORW11、-CONRW11RW12；RW11和RW12各自獨立地選自：氫、任選被鹵素取代的C1-6烷基。
在某些實施方案中，Z1選自：鹵素、氰基、甲基、CH2F、CHF2、CF3、甲氧基和CF3O；X選自：鹵素；Y1、Y2各自獨立地選自：O、S；R1、R2各自獨立地選自：甲基，或R1、R2連同它們所連接的原子一起形成C3-6環烷基； W1選自：化學鍵，
Figure 110108729-A0305-02-0007-3
、
Figure 110108729-A0305-02-0007-4
、
Figure 110108729-A0305-02-0007-5
、
Figure 110108729-A0305-02-0007-6
、
Figure 110108729-A0305-02-0007-7
、
Figure 110108729-A0305-02-0007-8
，其各自任選地被1、2或3個RW1取代；並且 每個RW1獨立地選自：氫、鹵基、氰基、任選被鹵素取代的C1-3烷基或C1-3烷氧基。
在某些實施方案中，Z1選自：鹵素、氰基、甲基、CH2F、CHF2、CF3、甲氧基和CF3O；X選自：鹵素；Y1、Y2各自獨立地選自：O、S；R1、R2各自獨立地選自：甲基，或R1、R2連同它們所連接的原子一起形成C3-6環烷基； W1選自：化學鍵，
Figure 110108729-A0305-02-0007-12
、
Figure 110108729-A0305-02-0007-13
、
Figure 110108729-A0305-02-0007-14
、
Figure 110108729-A0305-02-0007-15
、
Figure 110108729-A0305-02-0007-731
、
Figure 110108729-A0305-02-0007-730
，其各自任選地被1、2或3個RW1取代；並且 每個RW1獨立地選自：氫、鹵基、氰基、任選被鹵素取代的C1-3烷基或C1-3烷氧基、-COORW11、-CONRW11RW12；RW11和RW12各自獨立地選自：氫、任選被鹵素取代的C1-6烷基。
在某些實施方案中，Z1選自：CF3；X選自：F；Y1、Y2各自獨立地選自：O、S；R1、R2各自獨立地選自：甲基，或R1、R2連同它們所連接的原子一起形成C3-4環烷基； W1選自：化學鍵，
Figure 110108729-A0305-02-0008-16
、
Figure 110108729-A0305-02-0008-732
、
Figure 110108729-A0305-02-0008-19
，其各自任選地 被1、2或3個RW1取代；並且每個RW1獨立地選自：氫、鹵基、氰基、任選被F取代的C1-3烷基或C1-3烷氧基。
在某些實施方案中，Z1選自：CF3；X選自：F；Y1、Y2各自獨立地選自：O、S；R1、R2各自獨立地選自：甲基，或R1、R2連同它們所連接的原子一起形成C3-4環烷基； W1選自：化學鍵，
Figure 110108729-A0305-02-0008-20
、
Figure 110108729-A0305-02-0008-733
、
Figure 110108729-A0305-02-0008-734
，其各自任選地 被1、2或3個RW1取代；並且每個RW1獨立地選自：氫、鹵基、氰基、任選被F取代的C1-3烷基或C1-3烷氧基、-CONH2、-COOC1-3烷基。
在某些實施方案中，ABM選自如下化合物片段，其中
Figure 110108729-A0305-02-0008-720
表示連接部分的連接點：
Figure 110108729-A0305-02-0008-24
Figure 110108729-A0305-02-0009-25
在某些實施方案中，ABM選自如下化合物片段，其中
Figure 110108729-A0305-02-0009-719
表示連接部分的連接點：
Figure 110108729-A0305-02-0009-27
在第一種方案中，本發明提供一種具有式(II)結構的雙官能化合物，及其鹽、多晶型物和前藥：ABM-L-CLM (II)， 其中ABM是雄激素受體(AR)結合部分，L是連接ABM和CLM的化學連接部分，CLM是羥腦苷脂E3泛素連接酶結合部分。
其中，ABM定義如上。
在某些實施方案中，CLM包含衍生自醯亞胺、硫代醯亞胺、醯胺或硫代醯胺的化學基團，其結合到羥腦苷脂E3泛素連接酶。
在某些實施方案中，CLM是鄰苯二醯亞胺基或其類似物。
在某些實施方案中，CLM為式(V)所示結構片段或其立體異構體，其中
Figure 110108729-A0305-02-0010-723
表示連接部分的連接點：
Figure 110108729-A0305-02-0010-28
其中W選自：CH2、CHR11、C=O、NH或-N-C1-6烷基；每個T獨立地選自：O或S；G選自：氫、C1-6烷基或羥基；Q1、Q2、Q3和Q4獨立地選自：CR′或N；A選自：氫、C1-6烷基、C3-6環烷基、或鹵素；R11選自：鹵素、氰基、任選被鹵素取代的C1-6烷基或C1-6烷氧基、C3-6環烷基、-CONR′R〃、-OR′、或-NR′R〃；R′和R〃各自獨立地選自：氫、鹵素、胺基、氰基、任選被鹵素取代的C1-6烷基或C1-6烷氧基、C3-6環烷基。
在某些實施方案中，W選自：CH2、CHR11或C=O；每個T獨立地選自：O或S；G選自：氫、或C1-6烷基；Q1、Q2、Q3和Q4獨立地選自：CH；A選自：氫、C1-6烷基或鹵素；R11選自：鹵素、氰基、-CF3、OCF3、甲基、-CONR′R〃、-OR′、或- NR′R〃；R′和R〃各自獨立地選自：氫、鹵素、氰基、胺基、-CF3、OCF3或甲基。
在某些實施方案中，CLM為式(V)-1所示結構片段或其立體異構體，其中
Figure 110108729-A0305-02-0011-721
表示連接部分的連接點：：
Figure 110108729-A0305-02-0011-29
其中：W選自：CH2或C=O；A選自：氫或C1-6烷基。
在某些實施方案中，CLM為式(V)-2或(V)-3所示結構片段或其立體異構體，其中
Figure 110108729-A0305-02-0011-722
表示連接部分的連接點：
Figure 110108729-A0305-02-0011-31
在某些實施方案中，CLM是沙立度胺、來那度胺、泊馬度胺或其類似物的片段。
Figure 110108729-A0305-02-0011-32
沙立度胺；
Figure 110108729-A0305-02-0011-735
來那度胺
Figure 110108729-A0305-02-0011-33
泊馬度胺； 在本發明的方案中，連接基團(L)選自如下通式結構表示的基團：-(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各自獨立地選自：0、1、2、3、4、5、6，其條件是當所述數目是零時，不存在N-O或O-O鍵，各個R31獨立地選自基團氫、甲基或乙基，Cy選自C6-10芳基，C3-6雜芳基，C3-6環烷基，C3-6雜環烷基，優選
Figure 110108729-A0305-02-0012-35
，
Figure 110108729-A0305-02-0012-36
，
Figure 110108729-A0305-02-0012-37
，
Figure 110108729-A0305-02-0012-38
，
Figure 110108729-A0305-02-0012-40
，
Figure 110108729-A0305-02-0012-43
，其各自任選地被1、 2或3個RCy取代；並且 每個RCy獨立地選自：氫、鹵基、氰基、任選被鹵素取代的C1-3烷基或C1-3烷氧基。
在優選的本發明的方案中，連接基團(L)選自如下通式結構表示的基團：-(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各自獨立地選自：0、1、2、3、4、5、6，其條件是當所述數目是零時，不存在N-O或O-O鍵，各個R31獨立地選自基團氫、 甲基或乙基，Cy選自C3-6芳基，C3-6雜芳基，C3-6環烷基，C3-6雜環烷基，優選
Figure 110108729-A0305-02-0014-45
，
Figure 110108729-A0305-02-0014-46
，
Figure 110108729-A0305-02-0014-47
，
Figure 110108729-A0305-02-0014-48
，
Figure 110108729-A0305-02-0014-49
，
Figure 110108729-A0305-02-0014-50
，其各自任選地被1、 2或3個RCy取代；並且每個RCy獨立地選自：氫、鹵基、氰基、任選被鹵素取代的C1-3烷基或C1-3烷氧基。
在某些實施方案中，連接基團(L)選自基團：
Figure 110108729-A0305-02-0014-44
Figure 110108729-A0305-02-0015-51
在某些實施方案中，連接基團(L)選自基團：
Figure 110108729-A0305-02-0015-52
在本發明第二種方案中，本發明提供了具有式(III)結構的化合物，及其鹽、多晶型物和前藥：ABM-L-VLM (III)，其中，ABM如定義如上； VLM為式(VI)所示結構片段或其立體異構體：
Figure 110108729-A0305-02-0016-53
Y3是NRY3RY4、ORY3、SRY3、
Figure 110108729-A0305-02-0016-55
； R21和R22獨立地選自：氫、任選地被鹵素、羥基、氰基取代的C1-6烷基、任選地被鹵素、羥基、氰基取代的C3-6環烷基；RY3和RY4獨立地選自：氫、任選地被鹵素、羥基、氰基取代的C1-6烷基、任選地被鹵素、羥基、氰基取代的C3-6環烷基、任選地被鹵素、羥基、氰基取代的C1-6烷基-CO-、任選地被鹵素、羥基、氰基取代的C3-6環烷基-CO-；或RY3、R21和它們所連接的碳原子和氮原子一起形成任選地被取代的5-6元雜環烷基；XY3是O或S；R23、R24各自獨立地選自：H、任選地被鹵素、羥基、氰基取代的C1-6烷基；W2是C6-10芳基或5-10元雜芳基；R25是氫，鹵素，氰基，羥基，硝基，任選地被鹵素、羥基、氰基取代的C1-6烷基，任選地被鹵素、羥基、氰基取代的C1-6烷氧基，NR25aR25b， CONR25aR25b，C6-10芳基，6-10元雜芳基，噻吩基，或
Figure 110108729-A0305-02-0016-57
，其中R25a、 R25b各自獨立地選自：H、任選地被鹵素、羥基、氰基取代的C1-6烷基；R27是H、鹵素、任選地被鹵素、羥基、氰基取代的C1-6烷基，且Xa是S、O或NR28；R28是氫、任選地被鹵素取代的C1-6烷基；所述C6-10芳基、6-10元雜芳基、噻吩基任選被一個或更多個選自氫、鹵素、任選地被鹵素、羥基、氰基取代的C1-6烷基、任選地被鹵素、羥基、氰基取代的C3-6環烷基、-CONHC1-6烷基、-COOC1-6烷基的基團取代； R26是氫，鹵素，氰基，羥基，硝基，任選地被鹵素、羥基、氰基取代的C1-6烷基，任選地被鹵素、羥基、氰基取代的C1-6烷氧基；“---”是連接基團L與上述結構式中任意一個H原子去掉後的基團相連。
在優選的本發明第二種方案中，本發明提供了具有式(III)結構的化合物，及其鹽、多晶型物和前藥：ABM-L-VLM (III)，其中ABM是AR結合部分，L是連接ABM和VLM化學連接部分，VLM是VHLE3連接酶結合部分。在某些實施方案中，所述VLM包含羥基脯氨醯基部分。
其中，ABM定義如上；VLM為式(VI)所示結構片段或其立體異構體：
Figure 110108729-A0305-02-0017-58
其中，Y3是NRY3RY4、ORY3、SRY3；R21和R22獨立地選自：氫、任選地被鹵素、羥基、氰基取代的C1-6烷基、任選地被鹵素、羥基、氰基取代的C3-6環烷基；RY3和RY4獨立地選自：氫、任選地被鹵素、羥基、氰基取代的C1-6烷基、任選地被鹵素、羥基、氰基取代的C3-6環烷基、任選地被鹵素、羥基、氰基取代的C1-6烷基-CO-、任選地被鹵素、羥基、氰基取代的C3-6環烷基-CO-；或RY3、R21和它們所連接的碳原子和氮原子一起形成任選地被取代的5-6元雜環烷基；R23、R24各自獨立地選自：氫、任選地被鹵素、羥基、氰基取代的C1-6烷 基；W2是C6-10芳基或5-10元雜芳基；R25是氫，鹵素，氰基，羥基，硝基，任選地被鹵素、羥基、氰基取代的C1-6烷基，任選地被鹵素、羥基、氰基取代的C1-6烷氧基，NR25aR25b，CONR25aR25b， C6-10芳基，或
Figure 110108729-A0305-02-0018-61
，其中R25a、R25b各自獨立地選自：氫、任選地被鹵素、 羥基、氰基取代的C1-6烷基；R27是氫、鹵素、任選地被鹵素、羥基、氰基取代的C1-6烷基，且Xa是S或O；R26是氫，鹵素，氰基，羥基，硝基，任選地被鹵素、羥基、氰基取代的C1-6烷基，任選地被鹵素、羥基、氰基取代的C1-6烷氧基；“---”是連接基團L與上述結構式中任意一個氫原子去掉後的基團相連。
在某些實施方案中，Y3是NRY3RY4、ORY3；R21和R22獨立地選自：氫、C1-6烷基；RY3和RY4獨立地選自：氫、任選地被鹵素、羥基、氰基取代的C1-6烷基、任選地被鹵素、羥基、氰基取代的C3-6環烷基-CO-；或RY3、R21和它們所連接的碳原子和氮原子一起形成任選地被取代的5-6元雜環烷基；R23、R24各自獨立地選自：氫、C1-6烷基；W2是苯基； R25是氫，鹵素，C1-6烷基，CONR25aR25b，或
Figure 110108729-A0305-02-0018-65
，其中R25a、R25b各 自獨立地選自：氫、C1-6烷基；R27是氫、C1-6烷基，且Xa是S；R26是氫，C1-6烷基。
在某些實施方案中，Y3是NRY3RY4、ORY3；R21和R22獨立地選自：氫、C1-6烷基；RY3和RY4獨立地選自：氫、C1-6烷基、任選地被鹵素、羥基、氰基取代的C3-6環烷基-CO-；或RY3、R21和它們所連接的碳原子和氮原子一起形成任選地被取代的5元雜環烷基；R23、R24各自獨立地選自：氫、C1-6烷基；W2是苯基； R25是CONR25aR25b，或
Figure 110108729-A0305-02-0019-66
，其中R25a、R25b各自獨立地選自：氫、C1-6烷基；R27是C1-6烷基，且Xa是S；R26是氫。
在某些實施方案中，Y3是
Figure 110108729-A0305-02-0019-67
；RY3選自：氫、任選地被鹵素、羥基、氰基取代的C1-6烷基、任選地被鹵素、羥基、氰基取代的C3-6環烷基；XY3是O或S。
在某些實施方案中，其中Y3是
Figure 110108729-A0305-02-0019-68
。
在某些實施方案中，所述VLM選自如下的結構片段或其立體異構體，其中
Figure 110108729-A0305-02-0019-724
表示連接部分的連接點：
Figure 110108729-A0305-02-0019-69
在某些實施方案中，VLM為式(VI)-1所示結構片段或其立體異構體：
Figure 110108729-A0305-02-0019-70
其中，Y3，R21，R23，R25定義如上。
在某些實施方案中，VLM為式(VI)-2所示結構片段或其立體異構體：
Figure 110108729-A0305-02-0020-71
其中，Y5是NRY5、O；R21和R22獨立地選自：氫、任選地被鹵素、羥基、氰基取代的C1-6烷基、任選地被鹵素、羥基、氰基取代的C3-6環烷基；RY5是氫、任選地被鹵素、羥基、氰基取代的C1-6烷基、任選地被鹵素、羥基、氰基取代的C3-6環烷基、任選地被鹵素、羥基、氰基取代的C1-6烷基-CO-、任選地被鹵素、羥基、氰基取代的C3-6環烷基-CO-；或RY5、R21和它們所連接的碳原子和氮原子一起形成任選地被取代的5-6元雜環烷基；R23、R24各自獨立地選自：氫、任選地被鹵素、羥基、氰基取代的C1-6烷基；W2是C6-10芳基或5-10元雜芳基；R25是氫，鹵素，氰基，羥基，硝基，任選地被鹵素、羥基、氰基取代的C1-6烷基，任選地被鹵素、羥基、氰基取代的C1-6烷氧基，NR25aR25b，CONR25aR25b， C6-10芳基，或
Figure 110108729-A0305-02-0020-73
，其中R25a、R25b各自獨立地選自：氫、任選地被鹵素、 羥基、氰基取代的C1-6烷基；R27是氫、鹵素、任選地被鹵素、羥基、氰基取代的C1-6烷基，且Xa是S或O；R26是氫，鹵素，氰基，羥基，硝基，任選地被鹵素、羥基、氰基取代的C1-6烷基，任選地被鹵素、羥基、氰基取代的C1-6烷氧基。
在某些實施方案中，VLM為式(VI)-2所示結構片段或其立體異構體：
Figure 110108729-A0305-02-0021-75
Y5是NRY5、O；R21和R22獨立地選自：氫、任選地被鹵素、羥基、氰基取代的C1-6烷基、任選地被鹵素、羥基、氰基取代的C3-6環烷基；RY5是氫、任選地被鹵素、羥基、氰基取代的C1-6烷基、任選地被鹵素、羥基、氰基取代的C3-6環烷基、任選地被鹵素、羥基、氰基取代的C1-6烷基-CO-、任選地被鹵素、羥基、氰基取代的C3-6環烷基-CO-；或RY5、R21和它們所連接的碳原子和氮原子一起形成任選地被取代的5-6元雜環烷基；R23、R24各自獨立地選自：氫、任選地被鹵素、羥基、氰基取代的C1-6烷基；W2是5-6元雜芳基；R25是氫，鹵素，氰基，羥基，硝基，任選地被鹵素、羥基、氰基取代的C1-6烷基，任選地被鹵素、羥基、氰基取代的C1-6烷氧基，NR25aR25b，CONR25aR25b， C6-10芳基，6-10元雜芳基，噻吩基，或
Figure 110108729-A0305-02-0021-76
，其中R25a、R25b各自獨立地選 自：氫、任選地被鹵素、羥基、氰基取代的C1-6烷基；R27是H、鹵素、任選地被鹵素、羥基、氰基取代的C1-6烷基，且Xa是S、O或NR28；R28是氫、任選地被鹵素取代的C1-6烷基；所述C6-10芳基、6-10元雜芳基、噻吩基任選被一個或更多個選自氫、鹵素、任選地被鹵素取代的C1-6烷基、任選地被鹵素取代的C3-6環烷基、-CONHC1-6烷基、-COOC1-6烷基的基團取代；R26是氫，鹵素，氰基，羥基，硝基，任選地被鹵素、羥基、氰基取代的C1-6烷基，任選地被鹵素、羥基、氰基取代的C1-6烷氧基。
在某些實施方案中，Y5是NRY5、O； R21和R22獨立地選自：氫、C1-6烷基；RY5是氫、C1-6烷基；或RY5、R21和它們所連接的碳原子和氮原子一起形成任選地被取代的5元雜環烷基；R23、R24各自獨立地選自：氫、C1-6烷基；W2是苯基； R25是CONR25aR25b，或
Figure 110108729-A0305-02-0022-77
，其中R25a、R25b各自獨立地選自：氫、C1- 6烷基；R27是C1-6烷基，且Xa是S；R26是氫。
在本發明的某些實施方案中，R21選自：甲基、乙基、正丙基、異丙基、正丁基、2-甲基丙基、仲丁基、叔丁基、正戊基、異戊基或新戊基。
在某些實施方案中，Y5是NRY5、O；R21選自：甲基、乙基、正丙基、異丙基、正丁基、2-甲基丙基、仲丁基、叔丁基、正戊基、異戊基或新戊基；R22選自：氫；RY5是氫、C1-6烷基；R23、R24各自獨立地選自：氫、C1-6烷基； W2是
Figure 110108729-A0305-02-0022-78
； R25是
Figure 110108729-A0305-02-0022-736
，其中R27是C1-3烷基，且Xa是S； R26是氫。
在某些實施方案中，Y5是NRY5、O；R21和R22獨立地選自：氫、C1-6烷基；RY5是氫、C1-6烷基；或RY5、R21和它們所連接的碳原子和氮原子一起形成任選地被取代的5元雜環烷基；R23、R24各自獨立地選自：氫、C1-6烷基；W2是噁唑基或噻唑基；R25是氫； R26是氫。
在某些實施方案中，其中Y5是NRY5、O；R21選自：甲基、乙基、正丙基、異丙基、正丁基、2-甲基丙基、仲丁基、叔丁基、正戊基、異戊基或新戊基；R22選自：氫；RY5是氫、C1-6烷基；R23、R24各自獨立地選自：氫、C1-6烷基；W2是噁唑基或噻唑基；R25是氫；R26是氫。
在某些實施方案中，所述VLM選自如下的結構片段或其立體異構體，其中
Figure 110108729-A0305-02-0023-729
表示連接部分的連接點：
Figure 110108729-A0305-02-0023-80
在某些實施方案中，VLM為式(VI)-3所示結構片段或其立體異構體：
Figure 110108729-A0305-02-0023-83
其中，Y5，R21，R23，R25定義如上。
在另一個實施方案中，VLM為式(VI)-4或(VI)-5所示結構片段或其立體異構體：
Figure 110108729-A0305-02-0024-84
 其中，R21，R22，Xa定義如上；R27a，R27b各自獨立地選自：氫、C1-6烷基。
在某些實施方案中，所述VLM選自如下的結構片段或其立體異構體，其中
Figure 110108729-A0305-02-0024-728
表示連接部分的連接點：
Figure 110108729-A0305-02-0024-86
在某些實施方案中，VLM為式(VI)-5所示結構片段或其立體異構體：
Figure 110108729-A0305-02-0025-87
 R21和R22獨立地選自：氫、C1-6烷基；R27a，R27b各自獨立地選自：H、5-6元雜芳基，優選H、噻唑基。
在某些實施方案中，所述VLM選自如下的結構片段或其立體異構體，其中
Figure 110108729-A0305-02-0025-726
表示連接部分的連接點：
Figure 110108729-A0305-02-0025-90
在某些實施方案中，VLM為式(VI)-61所示結構片段或其立體異構體：
Figure 110108729-A0305-02-0025-89
R21和R22獨立地選自：氫、C1-6烷基；R29是任選地被鹵素取代的C1-6烷基。
在某些實施方案中，所述VLM選自如下的結構片段或其立體異構體，其中
Figure 110108729-A0305-02-0025-727
表示連接部分的連接點：
Figure 110108729-A0305-02-0026-91
在某些實施方案中，VLM為式(VI)-71或式(VI)-81所示結構片段或其立體異構體：
Figure 110108729-A0305-02-0026-92
R21和R22獨立地選自：氫、C1-6烷基； R25是苯基，吡啶基，嘧啶基，噻吩基，或
Figure 110108729-A0305-02-0026-95
，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、噻吩基任選被一個或更多個選自鹵素、C1-6烷基、-CONHC1-6烷基的基團取代；XV是S、O或NR29；R29是氫、C1-6烷基；W是CH。
在某些實施方案中，所述VLM選自如下的結構片段或其立體異構體，其中
Figure 110108729-A0305-02-0026-725
表示連接部分的連接點：
Figure 110108729-A0305-02-0026-93
Figure 110108729-A0305-02-0027-94
在某些實施方案中，連接基團(L)選自如下通式結構表示的基團：-(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各自獨立地選自：0、1、2、3、4、5、6，其條件是當所述數目是零時，不存在N-O或O-O鍵，各個-CH2-中的一個或兩個氫原子可以被氟原子替代，各個R31獨立地選自基團氫、甲基、乙基、或苄基， Cy選自C6-10芳基，C3-6雜芳基，C3-6環烷基，C3-6雜環烷基，優選
Figure 110108729-A0305-02-0029-102
，
Figure 110108729-A0305-02-0029-97
Figure 110108729-A0305-02-0029-98
，
Figure 110108729-A0305-02-0029-99
，
Figure 110108729-A0305-02-0029-100
，
Figure 110108729-A0305-02-0029-101
；其各自任選地被1、2或3個 RCy取代；並且每個RCy獨立地選自：氫、鹵基、氰基、任選被鹵素取代的C1-3烷基或C1-3烷氧基。
在某些實施方案中，連接基團(L)選自如下通式結構表示的基團：-(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各自獨立地選自：0、1、2、3、4、5、6，其條件是當所述數目是零時，不存在N-O或O-O鍵，各個R31獨立地選自基團氫、 甲基、乙基、或苄基，Cy選自C3-6環烷基，C3-6雜環烷基，優選
Figure 110108729-A0305-02-0030-116
，
Figure 110108729-A0305-02-0030-111
Figure 110108729-A0305-02-0030-112
，
Figure 110108729-A0305-02-0030-113
，
Figure 110108729-A0305-02-0030-114
；其各自任選地被1、2或3個RCy取代；並 且每個RCy獨立地選自：氫、鹵基、氰基、任選被鹵素取代的C1-3烷基或C1-3烷氧基。
在本發明的某些實施方案中，Cy選自C6-10芳基，C3-6雜芳基，C3-6環烷基，C3-6雜環烷基，優選苯基、吡啶基、三唑基、氮雜環丁基、四氫吡咯基、呱啶基、呱嗪基、氧代呱嗪基、四氫吡啶基、氧代二氫吡啶基，進一步優選
Figure 110108729-A0305-02-0031-118
Figure 110108729-A0305-02-0031-119
，
Figure 110108729-A0305-02-0031-121
，
Figure 110108729-A0305-02-0031-123
，
Figure 110108729-A0305-02-0031-125
，
Figure 110108729-A0305-02-0031-126
，
Figure 110108729-A0305-02-0031-127
；其各 自任選地被1、2或3個RCy取代；並且每個RCy獨立地選自：氫、鹵基、氰基、任選被鹵素取代的C1-3烷基。
在某些實施方案中，連接基團(L)選自如下基團：-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各自獨立地選自：1、2、3、4、5、6，q選自：1，Cy選自C6-10芳基，C3-6雜芳基，C3-6環烷基，C3-6雜環烷基，優選苯基、吡啶基、三唑基、氮雜環丁基、四氫吡咯基、呱啶基、呱嗪基、氧代呱嗪基、四氫吡啶基、 氧代二氫吡啶基，進一步優選
Figure 110108729-A0305-02-0031-129
，
Figure 110108729-A0305-02-0031-784
Figure 110108729-A0305-02-0032-130
，
Figure 110108729-A0305-02-0032-131
，
Figure 110108729-A0305-02-0032-132
，
Figure 110108729-A0305-02-0032-133
；其各自任選地被1、2或3個RCy取代；並且每個RCy獨立地選自：氫、鹵基、氰基、任選被鹵素取代的C1-3烷基。
在某些實施方案中，連接基團(L)選自基團：
Figure 110108729-A0305-02-0032-103
Figure 110108729-A0305-02-0033-104
Figure 110108729-A0305-02-0034-105
在某些實施方案中，連接基團(L)選自基團：
Figure 110108729-A0305-02-0034-106
Figure 110108729-A0305-02-0035-107
Figure 110108729-A0305-02-0036-108
本發明具體化合物如下：
Figure 110108729-A0305-02-0036-109
Figure 110108729-A0305-02-0037-134
Figure 110108729-A0305-02-0038-135
Figure 110108729-A0305-02-0039-137
Figure 110108729-A0305-02-0040-138
Figure 110108729-A0305-02-0041-139
Figure 110108729-A0305-02-0042-140
Figure 110108729-A0305-02-0043-142
Figure 110108729-A0305-02-0044-143
Figure 110108729-A0305-02-0045-145
Figure 110108729-A0305-02-0046-146
Figure 110108729-A0305-02-0047-147
Figure 110108729-A0305-02-0048-148
Figure 110108729-A0305-02-0049-149
Figure 110108729-A0305-02-0050-150
Figure 110108729-A0305-02-0051-151
Figure 110108729-A0305-02-0052-152
Figure 110108729-A0305-02-0053-153
Figure 110108729-A0305-02-0054-154
Figure 110108729-A0305-02-0055-155
Figure 110108729-A0305-02-0056-156
Figure 110108729-A0305-02-0057-157
Figure 110108729-A0305-02-0058-158
Figure 110108729-A0305-02-0059-159
Figure 110108729-A0305-02-0060-160
Figure 110108729-A0305-02-0061-161
Figure 110108729-A0305-02-0062-162
Figure 110108729-A0305-02-0063-163
Figure 110108729-A0305-02-0064-164
Figure 110108729-A0305-02-0065-165
Figure 110108729-A0305-02-0066-166
Figure 110108729-A0305-02-0067-167
Figure 110108729-A0305-02-0068-168
Figure 110108729-A0305-02-0069-169
Figure 110108729-A0305-02-0070-170
Figure 110108729-A0305-02-0071-171
Figure 110108729-A0305-02-0072-172
Figure 110108729-A0305-02-0073-173
Figure 110108729-A0305-02-0074-174
Figure 110108729-A0305-02-0075-175
Figure 110108729-A0305-02-0076-176
Figure 110108729-A0305-02-0077-177
Figure 110108729-A0305-02-0078-178
Figure 110108729-A0305-02-0079-179
Figure 110108729-A0305-02-0080-180
Figure 110108729-A0305-02-0081-181
Figure 110108729-A0305-02-0082-182
Figure 110108729-A0305-02-0083-183
Figure 110108729-A0305-02-0084-184
Figure 110108729-A0305-02-0085-185
Figure 110108729-A0305-02-0086-186
Figure 110108729-A0305-02-0087-187
Figure 110108729-A0305-02-0088-188
Figure 110108729-A0305-02-0089-189
Figure 110108729-A0305-02-0090-190
Figure 110108729-A0305-02-0091-191
Figure 110108729-A0305-02-0092-192
Figure 110108729-A0305-02-0093-193
Figure 110108729-A0305-02-0094-194
Figure 110108729-A0305-02-0095-195
Figure 110108729-A0305-02-0096-196
Figure 110108729-A0305-02-0097-197
Figure 110108729-A0305-02-0098-198
Figure 110108729-A0305-02-0099-199
Figure 110108729-A0305-02-0100-200
Figure 110108729-A0305-02-0101-201
Figure 110108729-A0305-02-0102-202
本發明的另一方面提供一種組合物，其包含有效量的本發明雙官能化合物和藥學上可接受的載體。
本發明的藥學上可接受的載體包括離子交換劑、氧化鋁、硬脂酸鋁、卵磷脂、血清蛋白質、緩衝物質(例如磷酸鹽、甘氨酸、山梨酸、山梨酸鉀)、飽和植物脂肪酸的偏甘油酯混合物、水、鹽或電解質。
在一個實施方案中，使用保護化合物以免從身體快速排除的載體製備活性化合物，例如控釋型配製物，包括植入物和微囊封遞送系統。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、膠原蛋白、聚原酸酯以及聚乳酸。用於製備此類配製物的方法對於所屬領域的技術人員來說是顯而易見的。
脂質體懸浮液也可以是藥學上可接受的載體，脂質體配製物可以如下製備：將適當脂質(例如硬脂醯基磷脂醯基乙醇胺、硬脂醯基磷脂醯基膽鹼、花生四烯醯基磷脂醯基膽鹼和膽固醇)溶解於無機溶劑中，然後蒸發，在容器表面上留下乾燥脂質的薄膜。然後將活性化合物的水溶液引入容器中。然後用手旋轉容器以使脂質材料脫離容器的側面，並且分散脂質聚集體，從而形成脂質體懸浮液。
在本發明的方案中，組合物進一步包含至少一種其它生物活性劑。
在本發明的方案中，生物活性劑是抗癌劑。
本發明的另一個方面提供一種治療組合物，其包含有效量的至少兩種不同的本發明所述的化合物。
本發明的另一個方面提供一種在需要其的受試者中將內源蛋白質募集到E3泛素連接酶進行降解的方法，所述方法包括給予本發明所述的化合物。
本發明的另一個方面提供一種在需要其的受試者中將雄激素受體降解或抑制的方法，所述方法包括給予本發明所述的化合物。
本發明的另一方面提供了一種治療受試者的疾病或病症的方法，其包含以下步驟：向有需要的受試者施用組合物，所述組合物包含藥學上可接受的載體和有效量的本發明所述的化合物。
在某些實施方案中，所述疾病或病症是痤瘡、多毛症、皮脂腺增大、脫髮、哮喘、多發性硬化症、癌症、肯亞病(Kenney′sdisease)、纖毛病、齶裂、糖尿病、心臟病、高血壓、發炎性腸病、智力遲鈍、情緒障礙、肥胖症、屈光不正、不育症、安格爾曼綜合症(Angelmansyndrome)、卡納萬疾病(Canavandisease)、腹腔病、夏-馬-圖三氏病(Charcot-Marie-Toothdisease)、囊腫性纖維化、杜氏肌營養不良(Duchennemusculardystrophy)、血色病、血友病、克氏綜合症(Klinefelter′ssyndrome)、神經纖維瘤、苯丙酮尿症、多囊性腎病(PKD1)或4(PKD2)、普拉德-威利綜合症(Prader-Willisyndrome)、鐮狀細胞病、泰伊-薩克斯二氏病(Tay-Sachsdisease)、特納綜合症(Turnersyndrome)。其中所述癌症是鱗狀細胞癌、基底細胞癌、腺癌、肝細胞癌和腎細胞癌瘤；膀胱、腸道、乳房、子宮頸、結腸、食道、頭、腎臟、肝臟、肺、頸、卵巢、胰腺、前列腺和胃的癌症；白血病；良性和惡性淋巴瘤，尤其伯基特氏淋巴瘤(Burkitt′slymphoma)和非霍奇金淋巴瘤(Non-Hodgkin′slymphoma)；良性和惡性黑色素瘤；骨髓增生性疾病；肉瘤，包括尤文氏肉瘤(Ewing′ssarcoma)、血管內皮瘤、卡波西肉瘤(Kaposi′ssarcoma)、脂肪肉瘤、肌肉瘤、末梢神經上皮瘤、滑膜肉瘤、神經膠質瘤、星形細胞瘤、寡突神經膠質細胞瘤、室管膜瘤、神經膠母細胞瘤、神經母細胞瘤、神經節神經膠質瘤、髓母細胞瘤、松果體細胞腫瘤、腦 膜瘤、腦膜肉瘤、神經纖維瘤和許旺細胞瘤(Schwannomas)；腸道癌、乳癌、前列腺癌、子宮頸癌、子宮癌、肺癌、卵巢癌、睾丸癌、甲狀腺癌、星形細胞瘤、食道癌、胰臟癌、胃癌、肝癌、結腸癌、黑色素瘤；癌肉瘤、霍奇金氏疾病、維爾姆斯瘤或畸胎癌。
在本發明的方案中，所述疾病或病症是癌症、痤瘡、多毛症、皮脂腺增大、脫髮、或甘迺迪病。
在本發明的方案中，所述疾病或病症是前列腺癌、痤瘡或脫髮。
在另一方面，說明書提供了治療組合物，其包含有效量的如本發明所述化合物或其鹽形式和藥學上可接受的載體。治療組合物調節患者或受試者中的蛋白質降解，並且能夠用於治療或改善通過降解的蛋白質調節的疾病狀態或病狀。在某些實施方案中，如本發明所述的治療組合物能夠用於實現所關注蛋白質的降解和/或抑制，以便治療或改善疾病，例如癌症。
定義
除非另外定義，否則本文所用的術語具有與本領域所屬領域的普通技術人員通常所理解相同的含義。說明書中所用的術語僅用於描述特定實施方案並且不希望限制本發明。
術語“烴基”應指含有碳和氫並且可以是完全飽和、部分不飽和或芳香族並且包括芳基、烷基、烯基和炔基的化合物。
術語“烷基”在其上下文內應該指可以任選地被取代的直鏈、支鏈鏈或環狀完全飽和烴基或烷基，優選C1-C10，更優選C1-C6，或者C1-C3烷基。烷基實例是甲基、乙基、正丁基、仲丁基、正己基、正庚基、正辛基、正壬基、正癸基、異丙基、2-甲基丙基、環丙基、環丙基甲基、環丁基、環戊基、環戊基乙基、環己基乙基和環己基等等。
術語“烯基”是指含有至少一個C=C鍵的直鏈、支鏈鏈或環狀C2-C10(優選C2-C6)烴基。
術語“炔基”是指含有至少一個C≡C鍵的直鏈、支鏈鏈或環狀C2-C10(優選C2-C6)烴基。
術語“亞烷基”在使用時是指可以任選地被取代的-(CH2)n-基團(n一般是整數0-6)。被取代時，亞烷基優選地在一個或多個亞甲基上被C1-C6烷基(包括環丙基或叔丁基)取代，而且可以被一個或多個鹵基(優選1到3個鹵基)或一個或兩個羥基或C1-6烷基氧基。
術語“未被取代”應該指僅被氫原子取代。
術語“被取代”指分子任一處的碳(或氮)位置處獨立地存在一個或多個取代基，優選1-5個取代基，最優選1-3個取代基，取代基可以為：羥基、硫醇、羧基、氰基、硝基、鹵素(優選地，1、2或3個鹵素，尤其在烷基上，尤其甲基，例如三氟甲基)、烷基(優選C1-C10，更優選地，C1-C6)、鹵代烷基、芳基(尤其苯基和被取代的苯基，例如苯甲基或苯甲醯基)、烷氧基(優選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)、醯基(優選C1-C6醯基)、C1-C6烷基胺、C1-C6二烷基胺，被一或兩個C1-C6烷基取代的醯胺基(包括任選地被一個或兩個C1-C6烷基取代的甲醯胺)、羧基、C1-C6酯等。術語“任選地被取代”包括被取代和未被取代兩種情況。
術語“芳基”是指具有單環(例如苯基)或稠環(例如萘基、蒽基、菲基等)的被取代或未被取代的C6-C16芳香族基團，優選C6-C10芳香族基團。
術語“雜芳基”是指含有至少一個雜原子(例如N、O或S)的5-16元芳香族基團，優選5-10元芳香族基團，可以指任選地被取代的喹啉、任選地被取代的吲哚、任選地被取代的吲哚嗪、任選地被取代的氮雜吲哚嗪、任選地被取代的苯並咪唑、苯並二唑、苯並呋喃、任選地被取代的咪唑、任選地被取代的異噁唑、任選地被取代的噁唑(優選被甲基取代)、任選地被取代的二唑、任選地被取代的三唑、四唑、任選地被取代的苯並呋喃、任選地被取代的噻吩、任選地被取代的噻唑(優選被甲基和/或硫醇取代)、任選地被取代的異噻唑、任選地被取代的三唑、任選地被取代的吡啶(2-吡啶、3-吡啶或4-吡啶)。
術語“芳烷基”和“雜芳基烷基”是指分別包含芳基或雜芳基的基團，以及符合上述定義的烷基和/或雜烷基和/或碳環和/或雜環烷基環系統。
術語“雜環基”是指含有至少一個雜原子(例如N、O或S)的3-10元環 基，優選3-6元環基，且可以是芳香族(雜芳基)或非芳香族。其包括：氮雜環丁烷基、苯並咪唑基、1，4-苯並二噁烷基、1，3-苯並間二氧雜環戊烯基、苯並噁唑基、苯並噻唑基、苯並噻吩基、二氫咪唑基、二氫吡喃基、二氫呋喃基、二噁烷基、二氧雜環戊烷基、亞乙基脲、1，3-二氧雜環戊烷、1，3-二噁烷、1，4-二噁烷、呋喃基、高呱啶基、咪唑基、咪唑啉基、咪唑啶基、吲哚啉基、吲哚基、異喹啉基、異噻唑啶基、異噻唑基、異噁唑啶基、異噁唑基、嗎啉基、萘啶基、噁唑啶基、噁唑基、吡啶酮、2-吡咯烷酮、吡啶、呱嗪基、N-甲基呱嗪基、呱啶基、鄰苯二甲醯亞胺、丁二醯亞胺、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、四氫呋喃基、四氫吡喃基、四氫喹啉、噻唑啶基、噻唑基、噻吩基、四氫噻吩、噁烷、氧雜環丁烷基、氧硫雜環戊烷基、噻烷等等。
術語“環烷基”是指C3-C20的單環或多環烷基，優選C3-C15的單環或多環烷基，最優選C3-C10的單環或多環烷基，包括環丙基、環丁基、環戊基、環己基、環庚基等。
“雜環烷基”是指3-20元的單環或多環烷基，優選3-15元的單環或多環烷基，最優選3-10元的單環或多環烷基，，其中其環狀結構中的至少一個環碳原子被選自由N、O、S或P組成的組的雜原子置換。
“鹵素”是指F、Cl、Br、I。
術語“藥學上可接受的鹽”用於描述本文所述的一種或多種化合物的鹽形式，提供其是為了增加化合物在患者胃腸道的胃汁液中的溶解度以便促進化合物的溶解和生物利用度。藥學上可接受的鹽在適用時包括衍生自藥學上可接受的無機或有機堿和酸的鹽。適合的鹽包括衍生自鹼金屬(例如鉀和鈉)、鹼土金屬(例如鈣、鎂和銨鹽)以及藥學領域中眾所周知的許多其它酸和堿的鹽。
製備適用于本發明的藥學上可接受的酸加成鹽所用的酸是形成無毒酸加成鹽的酸，即，含有藥理學上可接受的陰離子的鹽，例如鹽酸鹽、氫溴酸鹽、氫碘化物、硝酸鹽、硫酸鹽、硫酸氫鹽、磷酸鹽、酸式磷酸鹽、乙酸鹽、乳酸鹽、檸檬酸鹽、酸式檸檬酸鹽、酒石酸鹽、酒石酸鹽、酒石酸氫鹽、丁二酸鹽、 順丁烯二酸鹽、反丁烯二酸鹽、葡糖酸鹽、葡糖二酸鹽、苯甲酸鹽、甲烷磺酸鹽、乙烷磺酸鹽、苯磺酸鹽、對甲苯磺酸鹽和雙羥萘酸鹽鹽，以及多種其它鹽。
術語“有效”可以意指但不限於活性醫藥成分的量/劑量，當在其預定用途的背景下使用時，其在需要此類治療或接受此類治療的受試者中實現或足以預防病狀、病症或疾病狀態，抑制其發生，改善、延遲或治療其症狀(在一定程度上，優選完全緩解症狀)。
術語“藥學上可接受的載體”可以意指與藥物施用相容的任何和所有溶劑、分散介質、包衣、抗細菌劑等。
除非另外指明，術語“化合物”是指本文公開的任何特定化合物並且包括互變異構體、區位異構體、幾何異構體，以及適用時，立體異構體，包括光學異構體(對映異構體)和其它立體異構體(非對映異構體)，以及其藥學上可接受的鹽和衍生物(包括前藥形式)。其在上下文中使用時，術語化合物通常不僅指單一化合物，而且可以包括其它化合物，例如立體異構體、區位異構體和/或光學異構體(包括外消旋混合物)，以及所公開化合物的特定對映異構體或對映異構體增濃混合物。所述術語在上下文中還指化合物的前藥形式，其已經修飾以促進化合物施用和遞送到活性部位。
本發明附圖示出了本發明的若干實施方案，且與說明書一起用於解釋本發明的原理。附圖僅出於圖示本發明的實施方案的目的並且不被解釋為限制本發明。結合展示本發明的說明性實施方案的附圖，從以下詳細描述中將顯而易知本發明的其它目標、特點和優點，其中：圖1為本發明化合物對LNCaP細胞AR蛋白的降解實驗結果；圖2為本發明化合物對LNCaP小鼠移植瘤的PK/PD實驗結果；圖3為本發明化合物對雌性金黃地鼠皮脂腺斑生長的抑制結果；圖4為本發明化合物及其對照藥給藥後第21天對金黃地鼠體重的影響作用； 圖5為本發明化合物及其對照藥給藥後對C57BL/6小鼠體重的影響圖；圖6為本發明化合物A279與陽性化合物ARD-69對LNCaP細胞AR蛋白的降解實驗結果對比；圖7為本發明化合物A283-A286與陽性化合物ARD-69對LNCaP細胞AR蛋白的降解實驗結果對比；圖8為本發明化合物A288與陽性化合物ARD-69對LNCaP細胞AR蛋白的降解實驗結果對比；圖9為本發明化合物A307與陽性化合物ARD-69對LNCaP細胞AR蛋白的降解實驗結果對比；圖10為本發明化合物A308與陽性化合物ARD-69對LNCaP細胞AR蛋白的降解實驗結果對比；圖11為本發明化合物A309-A313與陽性化合物ARD-69對LNCaP細胞AR蛋白的降解實驗結果對比；圖12為本發明化合物A314、A315、A317和A318與陽性化合物ARD-69對LNCaP細胞AR蛋白的降解實驗結果對比；圖13為本發明化合物A320-A324和A318與陽性化合物ARD-69對LNCaP細胞AR蛋白的降解實驗結果對比；圖14為本發明化合物A340和A318與陽性化合物ARD-69對LNCaP細胞AR蛋白的降解實驗結果對比；圖15為本發明化合物A347-A351和A318與陽性化合物ARD-69對LNCaP細胞AR蛋白的降解實驗結果對比；圖16為本發明化合物A352-A354和A318與陽性化合物ARD-69對LNCaP細胞AR蛋白的降解實驗結果對比；圖17為本發明化合物A357-A358和A318與陽性化合物ARD-69對LNCaP細胞AR蛋白的降解實驗結果對比。
下面將結合附圖以及進一步的詳細說明來舉例說明本發明。需要指出的是，以下說明僅僅是對本發明要求保護的技術方案的舉例說明，並非對這些技術方案的任何限制。本發明的保護範圍以所附權利要求書記載的內容為准。
一、製備實施例
ABM-L-CLM的合成
實施例A1
Figure 110108729-A0305-02-0109-206
將1-1(2g,10mmol)，TMSCN(3g,30mmol)，ZnCl2(136mg,1mmol)依次加入到50ml丙酮中，室溫反應1h，反應結束後，100ml水洗，100mlEA萃取，50ml飽和食鹽水洗滌，無水硫酸鈉乾燥，旋幹得2.3g產物1-2，產率88%，產品不經純化直接用於下一步。
Figure 110108729-A0305-02-0109-207
將1-2(2.3g,8.8mmol)，1-3(4.3g,17.6mmol)依次加入到10mlDMF中，室溫反應過夜，反應結束後，加入20ml甲醇，20ml6NHCl，90℃反應1h，反應結束用50ml水洗，50mlEA萃取，20ml飽和食鹽水洗滌，無水硫酸鈉乾燥，旋幹上層析柱PE：EA=5：1-2：1得到400mg產物1-4，產率9.2%。
Figure 110108729-A0305-02-0109-208
將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，室溫攪拌一小時，反應結束後，用50ml水洗滌，50mlDCM萃取，20ml飽和食鹽水洗滌，無水硫酸鈉乾燥，旋蒸，上厚製備板DCM：MeOH=15：1，得到150mg產物1-6，產率37%。
Figure 110108729-A0305-02-0110-204
將1-6(150mg)加入大2mlTHF中，冷卻至0℃，通入HCl氣體，0℃反應2h，反應結束後，用飽和碳酸氫鈉溶液調節pH=8，20mlEA萃取，10ml飽和食鹽水洗滌，無水硫酸鈉乾燥，旋幹得到80mg產物1-7，產率63%。
Figure 110108729-A0305-02-0110-205
將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，室溫攪拌一小時，反應結束後，用20ml水洗滌，20mlEA萃取，20ml飽和食鹽水洗滌，無水硫酸鈉乾燥，旋蒸，上後製備板DCM：MeOH=10：1，得到50mg，再HPLC製備得25mg白色固體A1，純度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).
實施例A2-A45採用與實施例A1相似的操作，用與之相對應的試劑合成。
實施例A2
Figure 110108729-A0305-02-0111-210
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).
實施例A3
Figure 110108729-A0305-02-0111-211
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).
實施例A4
Figure 110108729-A0305-02-0112-212
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).
實施例A5
Figure 110108729-A0305-02-0112-214
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).
實施例A6
Figure 110108729-A0305-02-0112-215
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).
實施例A7
Figure 110108729-A0305-02-0113-314
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).
實施例A8
Figure 110108729-A0305-02-0113-315
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).
實施例A9
Figure 110108729-A0305-02-0114-316
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).
實施例A10
Figure 110108729-A0305-02-0114-317
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).
實施例A11
Figure 110108729-A0305-02-0114-318
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).
實施例A12
Figure 110108729-A0305-02-0115-319
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).
實施例A13
Figure 110108729-A0305-02-0115-320
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).
實施例A14
Figure 110108729-A0305-02-0116-322
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).
實施例A15
Figure 110108729-A0305-02-0116-323
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).
實施例A16
Figure 110108729-A0305-02-0117-324
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).
實施例A17
Figure 110108729-A0305-02-0117-325
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).
實施例A18
Figure 110108729-A0305-02-0118-326
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).
實施例A19
Figure 110108729-A0305-02-0118-328
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).
實施例A20
Figure 110108729-A0305-02-0119-329
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).
實施例A21
Figure 110108729-A0305-02-0119-332
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).
實施例A22
Figure 110108729-A0305-02-0120-333
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).
實施例A23
Figure 110108729-A0305-02-0120-334
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).
實施例A24
Figure 110108729-A0305-02-0121-335
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).
實施例A25
Figure 110108729-A0305-02-0121-337
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).
實施例A26
Figure 110108729-A0305-02-0122-338
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).
實施例A27
Figure 110108729-A0305-02-0122-714
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=1 2.1Hz,2H),1.52(s,6H).
實施例A28
Figure 110108729-A0305-02-0123-737
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).
實施例A29
Figure 110108729-A0305-02-0123-738
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).
實施例A30
Figure 110108729-A0305-02-0124-342
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).
實施例A31
Figure 110108729-A0305-02-0124-344
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).
實施例A32
Figure 110108729-A0305-02-0125-346
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).
實施例A33
Figure 110108729-A0305-02-0125-739
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),2.7 8(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).
實施例A34
Figure 110108729-A0305-02-0126-350
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).
實施例A35
Figure 110108729-A0305-02-0126-351
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=7.2H z,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).
實施例A36
Figure 110108729-A0305-02-0127-352
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).
實施例A37
Figure 110108729-A0305-02-0127-353
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).
實施例A38
Figure 110108729-A0305-02-0128-216
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).
實施例A39
Figure 110108729-A0305-02-0128-740
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).
實施例A40
Figure 110108729-A0305-02-0129-221
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).
實施例A41
Figure 110108729-A0305-02-0130-222
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).
實施例A42
Figure 110108729-A0305-02-0130-223
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).
實施例A43
Figure 110108729-A0305-02-0131-224
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).
實施例A44
Figure 110108729-A0305-02-0131-741
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).
實施例A45
Figure 110108729-A0305-02-0132-226
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).
實施例A46
Figure 110108729-A0305-02-0132-742
將中間體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，冷卻至0℃後滴加60ml33%的NaOH溶液，室溫反應過夜，反應結束後，200ml水洗，200mlDCM萃取，100ml飽和食鹽水洗滌，無水硫酸鈉乾燥，旋幹得粗品，柱層析PE：EA=2：1-1：1得到4.08g無色油狀中間體46-3，產率66.7%.
Figure 110108729-A0305-02-0132-743
將中間體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，室溫反應一小時，反應結束後，100ml水洗，100mlDCM萃取，100ml飽和食鹽水洗滌，無水硫酸鈉乾燥，旋幹上層析柱PE：EA=20：1-10：1得到6g無色液體46-4，產率83.7%.
Figure 110108729-A0305-02-0133-229
將中間體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二氧六環和50ml水中，N2保護下，90℃攪拌過夜，反應結束後過濾，用100ml水洗滌，200mlEA萃取2次，飽和食鹽水100ml洗滌，無水硫酸鈉乾燥，旋幹上層析柱DCM：MeOH=100：1-50：1-20：1得到5.5g棕色固體中間體46-7，產率92.6%。
Figure 110108729-A0305-02-0133-230
將中間體46-7(1.19g,9.6mmol)，中間體46-4(4.13g,11.52mmol)和碳酸鉀(2.65g,19.2mmol)加入到20mlDMF中，100℃反應2小時，反應結束後，用100ml水洗滌，100mlEA萃取2次，飽和食鹽水100ml洗滌2次，無水硫酸鈉乾燥，旋幹上層析柱PE：EA=5：1-2：1得到2g淺棕色油狀物中間體46-8，產率56%.
Figure 110108729-A0305-02-0133-744
將中間體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，室溫反應1小時，反應結束後，100ml水洗，100mlEA萃取，100ml飽和食鹽水洗滌，無水硫酸鈉乾燥，旋幹得到2.2g棕色油狀物46-9，產率92.8%.
Figure 110108729-A0305-02-0134-232
將中間體46-9(2.2g,5mmol)，化合物46-10(2.46g,10mmol)加入到20mlDMF中，室溫攪拌過夜，加入20ml二氧六環和20ml6N的鹽酸，90℃攪拌1小時，反應結束後，100ml水洗滌，100mlEA萃取2次，飽和食鹽水洗滌，無水硫酸鈉乾燥，旋幹上層析柱PE：EA=5：1-2：1得到1.2g淺棕色中間體46-11，產率38%
Figure 110108729-A0305-02-0134-233
將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，室溫攪拌一小時，反應結束後，用20ml水洗滌，20mlDCM萃取，20ml飽和食鹽水洗滌，無水硫酸鈉乾燥，旋蒸，上後製備板DCM：MeOH=10：1，得到100mg，再上製備柱得到60mg白色固體A46，純度98%，產率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).
實施例A47-A142採用與實施例A1相似的操作，用與之相對應的試劑合成。
實施例A47
Figure 110108729-A0305-02-0135-235
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).
實施例A48
Figure 110108729-A0305-02-0135-236
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).
實施例A49
Figure 110108729-A0305-02-0136-237
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).
實施例A50
Figure 110108729-A0305-02-0136-238
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).
實施例A51
Figure 110108729-A0305-02-0137-752
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).
實施例A52
Figure 110108729-A0305-02-0137-745
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).
實施例A53
Figure 110108729-A0305-02-0138-243
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).
實施例A54
Figure 110108729-A0305-02-0138-746
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).
實施例A55
Figure 110108729-A0305-02-0139-751
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)
實施例A56
Figure 110108729-A0305-02-0139-247
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).
實施例A57
Figure 110108729-A0305-02-0140-354
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).
實施例A58
Figure 110108729-A0305-02-0140-355
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).
實施例A59
Figure 110108729-A0305-02-0141-356
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).
實施例A60
Figure 110108729-A0305-02-0141-750
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=9.1H z,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).
實施例A61
Figure 110108729-A0305-02-0142-358
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).
實施例A62
Figure 110108729-A0305-02-0142-749
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).
實施例A63
Figure 110108729-A0305-02-0143-753
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).
實施例A64
Figure 110108729-A0305-02-0143-747
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).
實施例A65
Figure 110108729-A0305-02-0144-365
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).
實施例A66
Figure 110108729-A0305-02-0144-366
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).
實施例A67
Figure 110108729-A0305-02-0145-367
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).
實施例A68
Figure 110108729-A0305-02-0146-368
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).
實施例A69
Figure 110108729-A0305-02-0146-370
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).
實施例A70
Figure 110108729-A0305-02-0147-371
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).
實施例A71
Figure 110108729-A0305-02-0147-372
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).
實施例A72
Figure 110108729-A0305-02-0148-373
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).
實施例A73
Figure 110108729-A0305-02-0148-715
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).
實施例A74
Figure 110108729-A0305-02-0149-376
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).
實施例A75
Figure 110108729-A0305-02-0149-377
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).
實施例A76
Figure 110108729-A0305-02-0150-378
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).
實施例A77
Figure 110108729-A0305-02-0150-379
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).
實施例A78
Figure 110108729-A0305-02-0151-380
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).
實施例A79
Figure 110108729-A0305-02-0151-381
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).
實施例A80
Figure 110108729-A0305-02-0152-382
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).
實施例A81
Figure 110108729-A0305-02-0153-383
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).
實施例A82
Figure 110108729-A0305-02-0153-384
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).
實施例A83
Figure 110108729-A0305-02-0154-385
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).
實施例A84
Figure 110108729-A0305-02-0154-387
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).
實施例A85
Figure 110108729-A0305-02-0155-388
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).
實施例A86
Figure 110108729-A0305-02-0155-389
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).
實施例A87
Figure 110108729-A0305-02-0156-390
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).
實施例A88
Figure 110108729-A0305-02-0156-391
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(d d,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).
實施例A89
Figure 110108729-A0305-02-0157-392
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).
實施例A90
Figure 110108729-A0305-02-0157-394
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).
實施例A91
Figure 110108729-A0305-02-0158-754
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).
實施例A92
Figure 110108729-A0305-02-0158-396
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).
實施例A93
Figure 110108729-A0305-02-0159-397
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).
實施例A94
Figure 110108729-A0305-02-0159-398
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).
實施例A95
Figure 110108729-A0305-02-0160-399
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).
實施例A96
Figure 110108729-A0305-02-0161-400
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).
實施例A97
Figure 110108729-A0305-02-0161-402
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=6.6H z,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).
實施例A98
Figure 110108729-A0305-02-0162-403
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).
實施例A99
Figure 110108729-A0305-02-0162-404
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).
實施例A100
Figure 110108729-A0305-02-0163-406
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).
實施例A101
Figure 110108729-A0305-02-0163-407
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).
實施例A102
Figure 110108729-A0305-02-0164-409
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).
實施例A103
Figure 110108729-A0305-02-0164-411
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).
實施例A104
Figure 110108729-A0305-02-0165-412
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).
實施例A105
Figure 110108729-A0305-02-0165-413
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).
實施例A106
Figure 110108729-A0305-02-0166-415
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).
實施例A107
Figure 110108729-A0305-02-0167-416
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).
實施例A108
Figure 110108729-A0305-02-0167-417
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).
實施例A109
Figure 110108729-A0305-02-0168-785
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).
實施例A110
Figure 110108729-A0305-02-0168-786
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=23.4,6.5 Hz,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).
實施例A111
Figure 110108729-A0305-02-0169-420
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).
實施例A112
Figure 110108729-A0305-02-0169-755
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).
實施例A113
Figure 110108729-A0305-02-0170-422
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).
實施例A114
Figure 110108729-A0305-02-0170-424
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).
實施例A115
Figure 110108729-A0305-02-0171-423
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).
實施例A116
Figure 110108729-A0305-02-0172-425
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).
實施例A117
Figure 110108729-A0305-02-0172-426
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).
實施例A118
Figure 110108729-A0305-02-0173-427
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).
實施例A119
Figure 110108729-A0305-02-0173-428
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).
實施例A120
Figure 110108729-A0305-02-0174-429
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).
實施例A121
Figure 110108729-A0305-02-0174-430
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).
實施例A122
Figure 110108729-A0305-02-0175-432
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).
實施例A123
Figure 110108729-A0305-02-0175-433
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).
實施例A124
Figure 110108729-A0305-02-0176-434
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).
實施例A125
Figure 110108729-A0305-02-0176-435
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).
實施例A126
Figure 110108729-A0305-02-0177-436
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).
實施例A127
Figure 110108729-A0305-02-0177-787
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=8.7,2.5 Hz,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).
實施例A128
Figure 110108729-A0305-02-0178-438
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).
實施例A129
Figure 110108729-A0305-02-0178-439
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).
實施例A130
Figure 110108729-A0305-02-0179-440
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).
實施例A131
Figure 110108729-A0305-02-0179-441
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).
實施例A132
Figure 110108729-A0305-02-0180-443
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).
實施例A133
Figure 110108729-A0305-02-0180-444
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).
實施例A134
Figure 110108729-A0305-02-0181-445
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).
實施例A135
Figure 110108729-A0305-02-0181-757
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).
實施例A136
Figure 110108729-A0305-02-0182-449
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).
實施例A137
Figure 110108729-A0305-02-0183-450
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).
實施例A138
Figure 110108729-A0305-02-0183-451
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).
實施例A139
Figure 110108729-A0305-02-0184-452
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).
實施例A140
Figure 110108729-A0305-02-0184-454
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).
實施例A141
Figure 110108729-A0305-02-0185-455
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).
實施例A142
Figure 110108729-A0305-02-0185-456
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).
以下實施例A143-A362中A155,A156,A179,A180,A181,A182,A187-A195,A197,A199,A200採用與實施例A1相似的操作，用與之相對應的試劑合成；其餘採用與實施例A46相似的操作，用與之相對應的試劑合成。
實施例A143
Figure 110108729-A0305-02-0186-458
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).
實施例A144
Figure 110108729-A0305-02-0186-459
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).
實施例A145
Figure 110108729-A0305-02-0187-460
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).
實施例A146
Figure 110108729-A0305-02-0188-461
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).
實施例A147
Figure 110108729-A0305-02-0188-758
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).
實施例A148
Figure 110108729-A0305-02-0189-463
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).
實施例A149
Figure 110108729-A0305-02-0189-465
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).
實施例A150
Figure 110108729-A0305-02-0190-466
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).
實施例A151
Figure 110108729-A0305-02-0190-467
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).
實施例A152
Figure 110108729-A0305-02-0191-468
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).
實施例A153
Figure 110108729-A0305-02-0192-469
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).
實施例A154
Figure 110108729-A0305-02-0192-470
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).
實施例A155
Figure 110108729-A0305-02-0193-471
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).
實施例A156
Figure 110108729-A0305-02-0193-474
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).
實施例A157
Figure 110108729-A0305-02-0194-476
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).
實施例A158
Figure 110108729-A0305-02-0194-477
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).
實施例A159
Figure 110108729-A0305-02-0195-478
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).
實施例A160
Figure 110108729-A0305-02-0195-759
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).
實施例A161
Figure 110108729-A0305-02-0196-481
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).
實施例A162
Figure 110108729-A0305-02-0197-482
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).
實施例A163
Figure 110108729-A0305-02-0197-483
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).
實施例A164
Figure 110108729-A0305-02-0198-485
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).
實施例A165
Figure 110108729-A0305-02-0198-486
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).
實施例A166
Figure 110108729-A0305-02-0199-487
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).
實施例A167
Figure 110108729-A0305-02-0200-488
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).
實施例A168
Figure 110108729-A0305-02-0200-760
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).
實施例A169
Figure 110108729-A0305-02-0201-489
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).
實施例A170
Figure 110108729-A0305-02-0201-490
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).
實施例A171
Figure 110108729-A0305-02-0202-491
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).
實施例A172
Figure 110108729-A0305-02-0203-493
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).
實施例A173
Figure 110108729-A0305-02-0203-494
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).
實施例A174
Figure 110108729-A0305-02-0204-495
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).
實施例A175
Figure 110108729-A0305-02-0204-496
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).
實施例A176
Figure 110108729-A0305-02-0205-497
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).
實施例A177
Figure 110108729-A0305-02-0205-761
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).
實施例A178
Figure 110108729-A0305-02-0206-501
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).
實施例A179
Figure 110108729-A0305-02-0206-502
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).
實施例A180
Figure 110108729-A0305-02-0207-503
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).
實施例A181
Figure 110108729-A0305-02-0207-762
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).
實施例A182
Figure 110108729-A0305-02-0208-763
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).
實施例A183
Figure 110108729-A0305-02-0208-506
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).
實施例A184
Figure 110108729-A0305-02-0209-508
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).
實施例A185
Figure 110108729-A0305-02-0209-509
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).
實施例A186
Figure 110108729-A0305-02-0210-511
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).
實施例A187
Figure 110108729-A0305-02-0211-512
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).
實施例A188
Figure 110108729-A0305-02-0211-513
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).
實施例A189
Figure 110108729-A0305-02-0212-515
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).
實施例A190
Figure 110108729-A0305-02-0212-516
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).
實施例A191
Figure 110108729-A0305-02-0213-518
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).
實施例A192
Figure 110108729-A0305-02-0213-519
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).
實施例A193
Figure 110108729-A0305-02-0214-520
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).
實施例A194
Figure 110108729-A0305-02-0214-521
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).
實施例A195
Figure 110108729-A0305-02-0215-523
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).
實施例A196
Figure 110108729-A0305-02-0215-524
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=7.1 Hz,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).
實施例A197
Figure 110108729-A0305-02-0216-525
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).
實施例A198
Figure 110108729-A0305-02-0216-526
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).
實施例A199
Figure 110108729-A0305-02-0217-528
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).
實施例A200
Figure 110108729-A0305-02-0217-529
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).
實施例A201
Figure 110108729-A0305-02-0218-531
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).
實施例A202
Figure 110108729-A0305-02-0218-532
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).
實施例A203
Figure 110108729-A0305-02-0219-533
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).
實施例A204
Figure 110108729-A0305-02-0219-534
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).
實施例A205
Figure 110108729-A0305-02-0220-535
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).
實施例A206
Figure 110108729-A0305-02-0220-537
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).
實施例A207
Figure 110108729-A0305-02-0221-539
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).
實施例A208
Figure 110108729-A0305-02-0222-540
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).
實施例A209
Figure 110108729-A0305-02-0222-764
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).
實施例A210
Figure 110108729-A0305-02-0223-542
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).
實施例A211
Figure 110108729-A0305-02-0223-544
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).
實施例A212
Figure 110108729-A0305-02-0224-546
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).
實施例A213
Figure 110108729-A0305-02-0225-547
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).
實施例A214
Figure 110108729-A0305-02-0225-548
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).
實施例A215
Figure 110108729-A0305-02-0226-549
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).
實施例A216
Figure 110108729-A0305-02-0226-550
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).
實施例A217
Figure 110108729-A0305-02-0227-552
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).
實施例A218
Figure 110108729-A0305-02-0228-553
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).
實施例A219
Figure 110108729-A0305-02-0228-765
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).
實施例A220
Figure 110108729-A0305-02-0229-555
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).
實施例A221
Figure 110108729-A0305-02-0229-556
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).
實施例A222
Figure 110108729-A0305-02-0230-557
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).
實施例A223
Figure 110108729-A0305-02-0230-558
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).
實施例A224
Figure 110108729-A0305-02-0231-559
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).
實施例A225
Figure 110108729-A0305-02-0231-560
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).
實施例A226
Figure 110108729-A0305-02-0232-562
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).
實施例A227
Figure 110108729-A0305-02-0232-564
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).
實施例A228
Figure 110108729-A0305-02-0233-565
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).
實施例A229
Figure 110108729-A0305-02-0233-566
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).
實施例A230
Figure 110108729-A0305-02-0234-567
LCMS([M+H]+)：978.3
1HNMR(400MHz,DMSO-d6)δ9.23(d,J=4.7Hz,1H),8.65(d,J=2.4Hz,1H),834-8.24(m,2H),8.10(dd,J=8.8,2.4Hz,3H),7.94(dd,J=8.5,2.5Hz,1H),739(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).
實施例A231
Figure 110108729-A0305-02-0234-766
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).
實施例A232
Figure 110108729-A0305-02-0235-569
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).
實施例A233
Figure 110108729-A0305-02-0235-767
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).
實施例A234
Figure 110108729-A0305-02-0236-571
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).
實施例A235
Figure 110108729-A0305-02-0237-573
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).
實施例A236
Figure 110108729-A0305-02-0237-574
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).
實施例A237
Figure 110108729-A0305-02-0238-575
LCMS([M+H]+)：1063.3
1HNMR(400MHz,DMSO-d6)δ8.94(s,1H),8.62(s,1H),8.37(s,1H),8.298.28(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),210-2.06(m,1H),1.84-1.82(m,2H),1.75-1.71(m,2H),1.61(s,6H),094-0.91(m,9H).
實施例A238
Figure 110108729-A0305-02-0238-576
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).
實施例A239
Figure 110108729-A0305-02-0239-577
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).
實施例A240
Figure 110108729-A0305-02-0240-580
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).
實施例A241
Figure 110108729-A0305-02-0240-768
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),508(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).
實施例A242
Figure 110108729-A0305-02-0241-582
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).
實施例A243
Figure 110108729-A0305-02-0241-583
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).
實施例A244
Figure 110108729-A0305-02-0242-586
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).
實施例A245
Figure 110108729-A0305-02-0243-587
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).
實施例A246
Figure 110108729-A0305-02-0243-588
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).
實施例A247
Figure 110108729-A0305-02-0244-590
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).
實施例A248
Figure 110108729-A0305-02-0244-592
LCMS([M+H]+)：1025.1
1HNMR(400MHz,DMSO-d6)δ8.96(d,J=4.6Hz,1H),8.60(t,J=6.0Hz,1H),829-8.22(m,2H),8.19(d,J=2.5Hz,1H),7.77(dd,J=8.8,2.7Hz,1H),7.46-732(m,5H),7.01-6.94(m,1H),5.18(d,J=2.7Hz,1H),4.55(d,J=9.6Hz,1H),448-4.33(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),183-1.69(m,4H),1.61(dt,J=13.0,6.4Hz,2H),1.51(s,6H),0.92(d,J=7.2Hz,9H).
實施例A252
Figure 110108729-A0305-02-0245-593
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).
實施例A254
Figure 110108729-A0305-02-0245-769
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).
實施例A255
Figure 110108729-A0305-02-0246-595
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).
實施例A256
Figure 110108729-A0305-02-0247-596
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).
實施例A257
Figure 110108729-A0305-02-0247-597
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).
實施例A260
Figure 110108729-A0305-02-0248-598
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).
實施例A262
Figure 110108729-A0305-02-0248-600
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).
實施例A263
Figure 110108729-A0305-02-0249-601
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).
實施例A264
Figure 110108729-A0305-02-0249-770
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).
實施例A265
Figure 110108729-A0305-02-0250-603
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).
實施例A266
Figure 110108729-A0305-02-0250-604
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).
實施例A267
Figure 110108729-A0305-02-0251-771
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).
實施例A268
Figure 110108729-A0305-02-0251-606
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).
實施例A269
Figure 110108729-A0305-02-0252-609
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).
實施例A270
Figure 110108729-A0305-02-0252-610
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).
實施例A271
Figure 110108729-A0305-02-0253-612
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).
實施例A272
Figure 110108729-A0305-02-0253-613
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).
實施例A274
Figure 110108729-A0305-02-0254-614
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).
實施例A275
Figure 110108729-A0305-02-0254-615
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).
實施例A276
Figure 110108729-A0305-02-0255-616
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).
實施例A277
Figure 110108729-A0305-02-0255-617
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).
實施例A278
Figure 110108729-A0305-02-0256-618
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).
實施例A279
Figure 110108729-A0305-02-0256-619
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).
實施例A280
Figure 110108729-A0305-02-0257-620
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).
實施例A281
Figure 110108729-A0305-02-0257-621
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).
實施例A282
Figure 110108729-A0305-02-0258-622
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=157,5.7Hz,1H),4.08-403(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).
實施例A283
Figure 110108729-A0305-02-0258-772
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).
實施例A284
Figure 110108729-A0305-02-0259-623
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).
實施例A285
Figure 110108729-A0305-02-0259-624
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).
實施例A286
Figure 110108729-A0305-02-0260-625
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).
實施例A287
Figure 110108729-A0305-02-0261-626
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).
實施例A288
Figure 110108729-A0305-02-0261-627
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).
實施例A289
Figure 110108729-A0305-02-0262-629
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).
實施例A290
Figure 110108729-A0305-02-0262-631
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).
實施例A291
Figure 110108729-A0305-02-0263-632
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).
實施例A292
Figure 110108729-A0305-02-0263-633
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).
實施例A293
Figure 110108729-A0305-02-0264-774
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).
實施例A294
Figure 110108729-A0305-02-0264-635
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=17.2 Hz,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).
實施例A295
Figure 110108729-A0305-02-0265-636
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).
實施例A296
Figure 110108729-A0305-02-0265-638
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).
實施例A297
Figure 110108729-A0305-02-0266-639
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).
實施例A298
Figure 110108729-A0305-02-0266-641
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).
實施例A299
Figure 110108729-A0305-02-0267-642
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).
實施例A300
Figure 110108729-A0305-02-0267-643
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),427(dd,J=15.5,5.5Hz,1H),4.04(d,J=19.4Hz,2H),3.88(d,J=4.2Hz,5H),366 (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).
實施例A301
Figure 110108729-A0305-02-0268-644
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).
實施例A302
Figure 110108729-A0305-02-0268-645
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).
實施例A303
Figure 110108729-A0305-02-0269-646
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).
實施例A304
Figure 110108729-A0305-02-0270-647
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).
實施例A305
Figure 110108729-A0305-02-0270-648
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).
實施例A306
Figure 110108729-A0305-02-0271-649
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).
實施例A307
Figure 110108729-A0305-02-0271-654
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).
實施例A308
Figure 110108729-A0305-02-0272-651
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).
實施例A309
Figure 110108729-A0305-02-0272-655
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).
實施例A310
Figure 110108729-A0305-02-0273-775
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).
實施例A311
Figure 110108729-A0305-02-0273-658
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).
實施例A312
Figure 110108729-A0305-02-0274-660
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).
實施例A313
Figure 110108729-A0305-02-0274-661
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).
實施例A314
Figure 110108729-A0305-02-0275-662
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),456(d,J=9.6Hz,1H),4.47-4.33(m,5H),4.24(dd,J=15.7,5.5Hz,1H),3.97-392(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).
實施例A315
Figure 110108729-A0305-02-0276-663
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).
實施例A316
Figure 110108729-A0305-02-0276-665
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).
實施例A317
Figure 110108729-A0305-02-0277-666
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).
實施例A318
Figure 110108729-A0305-02-0277-667
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).
實施例A319
Figure 110108729-A0305-02-0278-668
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).
實施例A320
Figure 110108729-A0305-02-0278-669
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).
實施例A321
Figure 110108729-A0305-02-0279-673
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).
實施例A322
Figure 110108729-A0305-02-0279-672
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).
實施例A323
Figure 110108729-A0305-02-0280-674
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).
實施例A324
Figure 110108729-A0305-02-0280-675
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).
實施例A325
Figure 110108729-A0305-02-0281-677
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).
實施例A326
Figure 110108729-A0305-02-0281-678
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).
實施例A327
Figure 110108729-A0305-02-0282-679
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).
實施例A328
Figure 110108729-A0305-02-0282-680
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).
實施例A329
Figure 110108729-A0305-02-0283-681
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).
實施例A330
Figure 110108729-A0305-02-0283-682
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).
實施例A331
Figure 110108729-A0305-02-0284-683
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).
實施例A332
Figure 110108729-A0305-02-0284-684
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).
實施例A333
Figure 110108729-A0305-02-0285-685
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).
實施例A334
Figure 110108729-A0305-02-0285-686
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).
實施例A335
Figure 110108729-A0305-02-0286-687
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).
實施例A336
Figure 110108729-A0305-02-0286-688
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),2.082.05(m,3H),1.94-1.85(m,1H),1.53(d,J=5.1Hz,6H),0.92-0.90(m,9H).
實施例A337
Figure 110108729-A0305-02-0287-776
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).
實施例A338
Figure 110108729-A0305-02-0287-691
LCMS([M+H]+)：1119.3
1HNMR(400MHz,DMSO-d6)δ8.98(s,1H),8.59(t,J=6.0Hz,1H),8.288.22(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).
實施例A339
Figure 110108729-A0305-02-0288-692
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).
實施例A340
Figure 110108729-A0305-02-0288-693
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=3.4 Hz,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).
實施例A341
Figure 110108729-A0305-02-0289-694
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).
實施例A347
Figure 110108729-A0305-02-0290-695
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).
實施例A348
Figure 110108729-A0305-02-0290-696
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).
實施例A349
Figure 110108729-A0305-02-0291-697
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).
實施例A350
Figure 110108729-A0305-02-0291-698
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).
實施例A351
Figure 110108729-A0305-02-0292-699
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).
實施例A352
Figure 110108729-A0305-02-0292-701
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).
實施例A353
Figure 110108729-A0305-02-0293-702
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).
實施例A354
Figure 110108729-A0305-02-0293-703
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).
實施例A355
Figure 110108729-A0305-02-0294-706
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).
實施例A356
Figure 110108729-A0305-02-0294-705
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).
實施例A357
Figure 110108729-A0305-02-0295-707
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).
實施例A358
Figure 110108729-A0305-02-0295-709
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).
實施例A359
Figure 110108729-A0305-02-0296-710
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).
實施例A360
Figure 110108729-A0305-02-0296-711
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).
實施例A361
Figure 110108729-A0305-02-0297-712
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).
實施例A362
Figure 110108729-A0305-02-0297-777
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、生物學活性測定：
活性測定實施例1：化合物對LNCaP細胞AR表達的影響
1．細胞株與細胞培養
人前列腺癌細胞LNCaP(上海中科院細胞庫)。LNCaP培養于含10%胎牛血清的1640培養液中。細胞貼壁成簇生長，與底物貼附力弱，增殖慢，倍增時間為72h，細胞間粘連緊密，需用含0.025%EDTA的0.05%胰酶消化。每3天傳代1次。細胞培養於37℃恒溫，體積分數為0.05的CO2，飽和濕度的培養箱中。
2．細胞鋪板：取對數生長期的細胞Lncap，倒掉上清，PBS洗一遍，加入適當0.05%胰酶消化液充分消化成單細胞懸液，離心重懸計數使細胞量約為每孔15000個，接種于96孔板，放置於37℃，5%CO2過夜培養24h。
3．化合物溶液的製備與加入
各稱取化合物約2mg，用DMSO溶解，使其母液濃度為10mmol/L。稀釋過程(終濃度稀釋為：2，0.667，0.222，0.074，0.0245，0.008，0.003，0.001，0.0003，0.0001μmol/L)：取10個1.5mL離心管，編號分別為1、2、3、4、5、6、7、8、9、10，在1號管中加入80μLDMSO，在2到10號管中加入60μLDMSO，從母液中吸取20μL到1號管中，混勻；從1號管中吸取30μL到2號管中，混勻。從2號管中吸取30μL到3號管中，混勻，以此類推，獲得4-10號樣品，分別得到各不同濃度的化合物的工作液。分別從上述1-10號管中吸取2μL到各對應的無菌深孔板，加198μL培養液，混勻。每孔加入11ul 至過夜培養的96孔細胞板中，即獲得相對應的所需濃度(2，0.667，0.222，0.074，0.0245，0.008，0.003，0.001，0.0003，0.0001μmol/L)。
4．ELISA法測藥物對細胞表達AR的影響
藥物作用24h後，吸掉上清，加200μLPBS洗滌，再吸掉上清，加100μL細胞裂解液冰上裂解20min,4℃、4000轉/min離心20min，取上清待用。上清檢測步驟按ELISA試劑盒說明書：
4.1 從已平衡至室溫的密封袋中取出試驗所需板條，未用的板條和乾燥劑請放回鋁箔袋內壓實自封條，密封口袋，放回4℃。
4.2 空白孔加標準品和標本稀釋液，其餘相應孔中加不同濃度標準品(10ul/孔)以及樣品稀釋液(90ul/孔)用封板膠紙封住反應孔，4℃冷藏過夜。
4.3 每孔加一抗稀釋液(100ul/孔)。用封板膠紙封住反應孔，37℃孵箱孵育60min。
4.4 每孔加二抗稀釋液(100ul/孔)。用封板膠紙封住反應孔，37℃孵箱孵育30min。
4.5 加入顯色底物(TMB)100ul/孔，室溫孵育30min。
4.6 加入終止液100ul/孔，混勻後酶標儀測量OD450值。
5．結果分析
試驗結果所得到的資料ODTsample，不加細胞的培養基組為空白組ODBlank，只加DMSO不加藥的細胞組為對照組ODControl。抑制率inhi%=(1-(ODTsample-ODBlank)/(ODControl-ODBlank))*100%，通過XLFit軟體計算出化合物的DC50值，具體結果見表1
Figure 110108729-A0305-02-0299-248
Figure 110108729-A0305-02-0300-249
Figure 110108729-A0305-02-0301-250
以上結果表明，本發明提供的化合物對LNCaP細胞具有很好的增殖抑制作用，說明本發明化合物具備成為抗腫瘤藥物，特別是前列腺癌的治療藥物。
活性測定實施例2：Western blot試驗
1．細胞處理
Lncap細胞在指數生長期時，消化細胞後將細胞鋪板至6孔板中，每孔1×106個細胞，細胞貼壁生長一天后，加藥物培養，藥物處理24h後提取蛋白質。
2．細胞蛋白質提取
6孔板中細胞去除培養基，用PBS洗一遍後用胰酶將細胞消化後分別離心收集於1.5mL離心管中，每管中加入100μLRIPA裂解液(含100μMPMSF)，充分混合後冰上靜置30min，之後用離心機4℃ 12000rpm離心20min，取上清用於WB實驗，樣品可放於-80℃保存。
3 蛋白質濃度測定
使用BCA蛋白濃度測定試劑盒，按照下表配製BSA標準測定溶液和待測樣品(待測樣品可稀釋後檢測)，使用96孔板加樣，各孔用PBS補足至20μl後，分別加入200μlBCA工作液(按試劑盒配製)，混勻後於60℃放置10min後於562nm處檢測吸光度，記錄讀數後以標準品濃度梯度作標準曲線，代入樣品吸光度計算樣品蛋白質濃度。
4 Westernbloting實驗標準流程
4.1 蛋白質變性：取蛋白裂解液，加入5×LoadingBuffer，100℃變性5min。
4.2 上樣及電泳：使用10%預製膠及專用電泳液，每孔上樣同品質蛋白樣品及蛋白marker後，200V電泳30min。
4.3 封閉：將膠取下後切下多餘部分，通過濕轉法轉移到PVDF膜上(PVDF膜需要先用甲醇活化1min後使用)，300mA，2h，轉膜過程中大量產熱，需要用冰盒降溫。
4.4 封閉：將轉膜結束的PVDF膜放於5%脫脂牛奶中室溫搖晃封閉1h。
4.5 孵育一抗：將PVDF膜按照marker上指示分子量大小分別剪開，分別置於AR和GAPDH一抗中，抗體按照1：1000比例用TBST稀釋，4℃搖床封閉過夜。
4.6 孵育二抗：孵育一抗後的PVDF膜在搖床上用TBST清洗3次，每次10min，清洗後將膜分別置於對應種屬二抗中，搖床振盪室溫孵育2h。
4.7 洗膜及曝光：孵育二抗結束後將膜放於TBST中搖床振盪清洗3次，每次10min，洗膜後使用ECL法激發膜上螢光。
所得實驗結果見圖1，其表明本發明提供的化合物對LNCaP細胞AR蛋白具有很好的降解作用，說明本發明化合物具備成為抗腫瘤藥物，特別是前列腺癌的治療藥物。
活性測定實施例3：化合物在小鼠中的藥代動力學研究
1．實驗設計
本次試驗選用3只雄性小鼠，分成1組，3只/組。給藥前所有動物禁食過夜。
2．實驗方法
2.1 給藥劑量
灌胃給藥劑量為10mg/kg，給藥體積為10mL/kg。
2.2 藥液配製
根據動物體重結合給藥劑量先算得所需給藥溶液的量，稱取適量的供試品，先加最終體積的5%的乙醇溶解，再加最終體積5%的SolutolHS15，最後加PBS到目標體積，渦旋混勻充分溶解得到灌胃給藥溶液(1mg/mL)，所有溶液現配現用。
2.3 給藥方法
給藥前，將藥液放置在動物實驗室的磁力攪拌器上攪拌，至少10min。給藥過程中，繼續保持渦旋狀態，確保藥液均勻。灌胃給藥理論給藥體積為10mL/kg，使用配有灌胃針頭的注射器給藥。
給藥前動物稱量並記錄參與實驗的動物體重，根據體重計算每只動物的給藥體積。給藥結束後，迅速將動物轉移回實驗籠具內收集樣品。
2.4 動物狀態觀察
給藥後立即觀察動物有無異常反應，若無異常反應，則實驗期間每天觀察 動物兩次，若發現有異常反應，應及時記錄並增加觀察次數直至動物恢復正常或實驗結束。
2.5 樣品採集和保存
所有實驗動物給藥前禁食過夜，給藥後於相應時間點采血至含有肝素鈉抗凝劑的采血管中，採集全血後，立即輕輕晃動采血管並置於冰上，然後離心(4℃、4000rpm，10min)，收集上清血漿樣品，分析前置於約-80℃冰箱保存。
2.6 血漿樣品處理和分析
採集得到的血漿樣品交由藥代部進行樣品提取處理，採用含有內標的有機試劑進行蛋白沉澱法提取血漿中的受試物(乙腈：血漿=4：1,v/v)，提取處理後的樣品交由LC-MS/MS進行定量濃度分析。根據分析得到的每只動物的血藥濃度，採用Kinetica軟體(version5.0)按照非房室模型計算主要的藥動學參數eAUC30-120用以評估暴露量；試驗結果見表2：
Figure 110108729-A0305-02-0304-251
Figure 110108729-A0305-02-0305-252
活性測定實施例4：化合物對LNCaP小鼠移植瘤的PK/PD實驗研究
1.實驗材料
1.1 受試樣品
稱取以上化合物於2.5mL離心管中，加入終體積5%EtOH,5%solutolHSinPBS配。配製終濃度為5mg/mL。
1.2 腫瘤細胞
LNCaP細胞購自中國科學院上海生命科學研究院，培養在含10%胎牛血清的RPMI-1640培養液中。細胞生長至80~90%融合，約2-3天傳代，細胞生長至足夠數量後接種SCID小鼠。
1.3 實驗動物
SCID小鼠，雄性，6-7w，21只，購自北京維通利華股份公司。小鼠飼養于蘇州康邁博診斷科技有限公司SPF級動物房，溫度20~25℃，濕度40%~70%，每日光照/黑暗各12小時。動物分籠飼養，每籠5只，可自由攝食飲水，飼料輻照滅菌，水為高壓滅菌。
2.研究方法
2.1 腫瘤模型構建
體外培養LNCaP細胞至足夠量，胰酶消化離心，預冷的PBS重懸後再離心。加入適量預冷的PBS和基質膠調整細胞濃度至7.5×107個/mL。預冷的1mL注射器吸取細胞懸液，注射至裸鼠右側背部皮下，成規則的小丘形，每只0.2mL，即1.5×107個/只。
2.2 分組與給藥方案
接種腫瘤細胞後，觀察腫瘤大小。待腫瘤增長至200mm3左右，選取形狀 良好，腫瘤大小合適的老鼠按照腫瘤體積進行系統隨機分組。從裸鼠腫瘤模型中選取若干小鼠，每組3只，通過口服給予化合物，給藥3天結束後取腫瘤檢測AR的表達情況。
2.3 血漿化合物濃度檢測
血液採集：給藥前、給藥後3天后採集2小時血樣檢測藥物濃度。收集血樣於小鼠眼眶後靜脈叢取血30μL(血漿)至肝素化離心管中，然後在4℃、4000rpm條件下離心10min後轉移上層血漿，-80℃保存。
所得實驗結果見圖2。
活性測定實施例5：激素依賴性的前列腺癌症長期藥效試驗
1.腫瘤模型構建
1.5*10^7LNCaP(人前列腺癌)購自中國科學院細胞庫，培養在含10%胎牛血清的RPMI-1640培養液中。細胞生長至80~90%融合，約4-5天傳代，細胞生長至足夠數量後接種裸鼠。
2.實驗動物
SCID裸小鼠，6~7周齡，18-20g，購自北京維通利華有限責任公司。小鼠飼養於SPF級動物房，溫度20~25℃，濕度40%~70%，每日光照/黑暗各12小時。動物分籠飼養，每籠5只，可自由攝食飲水，飼料輻照滅菌，水為高壓滅菌。飼養至10~11周齡時分組實驗。將LNCaP腫瘤細胞直接接種於裸鼠右側後背。
3.分組與給藥方案設計
在平均腫瘤體積達到200-300mm3時，選取形狀良好的腫瘤按照腫瘤體積進行亂數字分組，並標記入選動物，分成5個組，每組5只。給藥溶媒：5%EtOH,5%solutolHS15inPBS。灌胃相應劑量的化合物。
4.統計分析
資料均以均值±標準差(Mean±SD)表示。統計採用單因素多水平方差分析，各用藥組與模型組的比較採用Stundent’ st或秩和檢驗，計算p值，p<0.05 為兩組間有顯著性差異，化合物A88的腫瘤生長抑制率(TGI)結果如表3。
Figure 110108729-A0305-02-0307-254
活性測定實施例6：利用ELISA方法檢測化合物對前列腺癌細胞株Lncap中AR蛋白活性的降解作用。
1、試驗材料
LNCaP：1.5*10^7LNCaP(人前列腺癌)購自中國科學院細胞庫，培養在含10%胎牛血清的RPMI-1640培養液中。在條件為37℃，5%飽和濕度的CO2培養箱中常規培養Lncap細胞。待培養至覆蓋率達80%左右時，按照1：3比例傳代。
ELISA試劑盒：TotalAndrogenReceptorSandwichELISAKit(品牌CST，貨號#12850)。
2、試驗方法
2.1 細胞鋪板
細胞離心後用新鮮培養基稀釋至1.5×104個/100ul,鋪到96孔板中，每孔100ul。
2.2 細胞加藥
受試化合物配製：稱取化合物，用DMSO稀釋化合物濃度為10mM儲液備用。根據實驗需求，將藥物由2uM起三倍稀釋10個濃度梯度，最終向每孔加入2μl藥物，空白對照組加入2μlDMSO。
2.3 24小時後，除去培養基，並用冰冷的1XPBS沖洗細胞一次。除去PBS，向每個孔板中加入0.5ml冰冷的1XCellLysisBuffer加上1mMPMSF，並在冰上孵育20分鐘。4000RPM4℃離心10min後備用。
2.4 ELISAkit中試劑及抗體準備
微孔板：使用前將其全部置於室溫下。
檢測抗體：凍幹，呈綠色蛋糕或粉末狀。加入1.0ml的檢測抗體稀釋劑(綠色溶液)以產生濃縮的原液。在室溫下孵育5min，偶爾輕輕混勻以完全溶解。要製成最終的工作溶液，請在乾淨的試管中將全部1.0ml體積的重構檢測抗體添加到10.0ml檢測抗體稀釋劑中，然後輕輕混合。
HRP抗體：凍幹，呈紅色蛋糕或粉末狀。加入1.0mlHRP稀釋劑(紅色溶液)以產生濃縮的儲備溶液。在室溫下孵育5min，偶爾輕輕混勻以完全溶解。要製成最終的工作溶液，請在乾淨的試管中將完整的1.0ml體積的重組HRP-LinkedAntibody加入10.0mlHRPDiluent中。
檢測抗體稀釋劑：綠色稀釋劑，用於重組和稀釋檢測抗體
HRP稀釋劑：紅色稀釋劑，用於重組和稀釋HRP連接的抗體
樣品稀釋液：藍色稀釋液，用於稀釋細胞裂解液。
1X洗滌緩衝液：通過在純淨水中稀釋20X洗滌緩衝液
3.5 ELISA
3.5.1 將準備好的細胞裂解液20μl加到適當的孔中，並加入70ul抗體稀釋劑，用膠帶密封並用力壓在微孔的頂部。在37℃下孵育平板2h。
3.5.2 輕輕撕下膠帶並清洗孔：將板內容物丟棄到容器中。用1X洗滌緩衝液洗滌4次，每孔每次200μl。每次清洗時，請用足夠強度的新鮮毛巾敲打板，以除去每個孔中的殘留溶液，但不要讓孔在任何時候完全乾燥。用不起毛的紙巾清潔所有孔的底部。
3.5.3 向每個孔中添加100μl重構的檢測抗體(綠色)。用膠帶密封並在37℃下孵育平板1h。
3.5.4 重複洗滌程式
3.5.5 向每個孔中添加100μl重構的HRP-Linked二抗(紅色)用膠帶密封並在37℃下將板孵育30min。
3.5.6 重複洗滌程式
3.5.7 向每個孔中添加100μlTMB底物。用膠帶密封，然後將板在37℃下 孵育10min或在25℃下孵育30min。
3.5.8 向每個孔中添加100μlSTOP溶液。輕輕搖動幾秒鐘。酶標儀讀取450nm的吸光度。
4.試驗結果
採用化合物A46作為受試化合物，其對Lncap細胞株中的AR蛋白的抑制率隨濃度變化的結果，表明該化合物對AR活性有良好抑制作用，並且經該組資料統計可得A46化合物的IC50(抑制率為50%時的藥物濃度)為49nM。
活性測試實施例7：化合物對雌性金黃地鼠痤瘡的體內藥效
1、試驗目的：金黃地鼠側腹皮脂腺斑是雄性激素依賴器官，丙酸睾酮(雄性激素)促使皮脂腺增大。本實驗主要為了研究CB-03-01(陽性藥物)，Flutamide(陽性藥物)，化合物在雌性金黃地鼠痤瘡模型(雄性激素依賴)中對皮脂腺增大的抑制作用，來進一步觀察化合物的體內藥效，為針對由雄激素引起的痤瘡症狀臨床試驗提供依據。
2、試驗材料：
2.1 供試品
雄激素(丙酸睾酮-TP)；CB-03-01(Clascoterone，CAS號19608-29-8)；Flutamide(氟他胺，CAS號13311-84-7)；本發明化合物A46。
2.2 試驗動物，詳見表4
Figure 110108729-A0305-02-0309-255
2.3 給藥溶媒：丙酮。
3.試驗設計
本次實驗從72只雌性金黃地鼠中，按照皮脂腺大小和體重，將金黃地鼠 平均分配到各組，6只/每組，共7組，連續給藥21天。具體動物分組，給藥方案等資訊詳見下表5：
Figure 110108729-A0305-02-0310-779
Figure 110108729-A0305-02-0311-257
按照表格中方案，每次給藥25μL，均勻塗抹皮脂腺，每天給藥一次。
動物分組與狀態觀察：分組前，稱體重，並將兩側皮脂腺處進行剃毛，觀察皮脂腺大小。給藥後及給藥期間內每天上下午觀察動物兩次。給藥後第21天，觀察記錄皮脂腺大小及動物體重。
皮脂腺的大小即是其面積，遊標卡尺記錄其長邊(a)和短邊(b)，根據長方形面積計算公式得皮脂腺的面積(S)，造模組及給藥組的△S=S-S(vehicle)。生長抑制率(%)=(△S(丙酮睾酮組)-△S(給藥組))/△S(丙酮睾酮組)*100%。
4.試驗結果
4.1 對雌性金黃地鼠皮脂腺斑生長的抑制作用
試驗結果如圖3所示，由圖3實驗結果可以看出，丙酸睾酮(TP)塗抹21天后，雌性金黃地鼠的皮脂腺斑明顯變大，面積達到了40-50mm2。各組給藥後，與建模組比較，陽性藥物CB-03-01(400μg，1.6%)，Flutamide(400μg，1.6%)組的皮脂腺斑生長抑制率分別為69.53%(p<0.001)，40.74%(P<0.01)。A46藥物100μg(0.4%)劑量組的皮脂腺斑生長抑制率為19.24%(P>0.05)，未表現出明顯的抑制作用。A46的200μg(0.8%),400μg(1.6%)和800μg(3.2%)劑量組皮脂腺斑生長抑制率分別為35.20%(P<0.01)，49.54%(p<0.001)，51.61%(P<0.001)，與建模組相比較，具有統計性差異。在A46設定為0.4%，0.8%，1.6%，3.2%劑量中，與建模組相比較痤瘡藥效時，0.8%劑量開始起效有統計性差異。與陽性藥物比較，A46藥物400μg(1.6%)和800μg(3.2%)劑量在抑制皮脂腺斑面積作用上均優於藥物Flutamide(400μg，1.6%)。
A46化合物給藥21天后對雄性激素引起的金黃地鼠皮脂腺斑面積增大的 抑制作用，如下表6所示：
Figure 110108729-A0305-02-0312-258
4.2 對雌性金黃地鼠體重的影響作用
實驗開始前，各組金黃地鼠的體重沒有顯著性差異。實驗開始後，各組體重呈緩慢增長趨勢，在實驗21天，各組地鼠體重均無顯著性差異。說明全部受試物在所設定的濃度下經皮給藥不會對小鼠的體重產生明顯影響(如圖4所示)。
活性測定實施例7：化合物對C57小鼠雄激素脫髮模型的毛髮再生作用
1、試驗目的
本研究的目的是通過經皮膚塗抹給藥途徑，在C57BL/6J小鼠體內對比本 發明製備的化合物作為AR蛋白降解劑對雄激素脫髮模型的毛髮再生作用，為後續臨床實驗提供資料支援。
2.試驗原理
用脫毛膏將小鼠進行脫毛後，皮下注射一定劑量的二氫睾酮(DHT)溶液，可以導致小鼠的毛髮再生延遲，用來模擬AR介導的雄激素脫髮模型。本發明化合物做為一種AR蛋白的降解劑，對AR介導的雄激素脫髮模型的毛髮生長促進作用可以一定程度的反映其療效優劣。
3、受試化合物
受試化合物I名稱：二羥睾酮DHT；受試化合物II名稱：本發明化合物A46；受試化合物III名稱：米諾地爾。
4、試驗動物：品系：C57BL/6N小鼠；年齡：6-7周；性別：雄性；動物數量：70只(10只備用)；飼養環境：無特定病原體(SpecificpathogenFree,SPF)。
5.實驗設計
5.1 模型建立
將70只小鼠深度麻醉，先用動物剃毛器將小鼠背部毛髮剔除，然後將脫毛膏(Veethttps：//item.jd.com/6291245.html)在小鼠皮膚表面塗抹均勻，靜置7-10分鐘後用脫毛刮逆毛方向輕輕將毛刮乾淨，最後用清水充分洗淨皮膚表面殘留的脫毛膏，避免其灼傷小鼠皮膚。
5.2 分組
本次實驗共分6組，DHT給藥開始時間為脫毛當天，A46給藥時間為脫毛後第2天，計為第1天(脫毛當天計為第0天)。隨機選取36只狀態良好的小鼠分組如下表7：
Figure 110108729-A0305-02-0313-259
Figure 110108729-A0305-02-0314-260
5.3 受試化合物配置方法
藥物配製方法及保存條件如下表8所示；
Figure 110108729-A0305-02-0314-262
Figure 110108729-A0305-02-0315-263
5.4 觀察檢測指標
1)體重/g：從第一天給藥開始，每週稱量並記錄兩次體重。
2)發再生(anagen)評分(0分：所有區域未見膚色轉黑；1分：灰色膚色區域轉黑；2分：可見短毛；3分：毛髮稀疏；4分：毛髮濃密；5分：毛髮完全生長)。
在剃毛後第1天對所有小鼠進行拍照，然後從第4天開始每天對小鼠進行拍照和評分，直至實驗終點。
3)實驗結束時按需進行取皮取血操作。
5.5 停藥及實驗終止標準
在發生以下情況時，單只動物或者整組動物的在體實驗部分將被終止。動物將在死亡或者昏迷前被安樂死。
當動物健康狀況持續惡化，動物連續遭受痛苦，無法飲食或飲水；或當動物消瘦，體重下降超過20%時。
5.6 統計分析
資料均以均值±標準誤(AVE±SEM)表示。統計採用單因素多水平方差分析，各用藥組與模型組的比較採用Stundent’ st或秩和檢驗，計算p值，p<0.05為兩組間有顯著性差異，p<0.01為兩組間有極顯著性差異。
6.實驗結果
本實驗共設6個組，分別是Vehicle、DHT(30mg/kg)濃度組、DHT(30mg/kg)+米諾地爾5%濃度組、DHT(30mg/kg)+A46 0.5%濃度組、DHT(30mg/kg)+A46 1%濃度組和DHT(30mg/kg)+A463%濃度組。對C57小鼠雄激素脫髮模型的毛髮再生作用結果見下表9所示：
Figure 110108729-A0305-02-0316-264
從結果中可以看出，DHT(30mg/kg)濃度組在給藥17天后毛髮發育的評分為0.5，幾乎沒有毛髮的發育，顯著地低於Vehicle組，顯示造模成功。DHT(30mg/kg)+米諾地爾5%濃度組的評分均值為2.33，顯著地高於DHT(30mg/kg)模型組，展現了良好的生髮效果。DHT(30mg/kg)+A460.5%濃度組與造模組DHT(二氫睾酮)組相比評分略高，但並無統計性差異。A461%濃度劑量與3%濃度劑量組在Day17時的評分與5%米諾地爾組大致相當，且分值與DHT(二氫睾酮)組，具有顯著差異(p<0.05；p<0.01)。
(2)體重變化
小鼠體重的變化在整個給藥期間結果如圖5所示，由圖可以看出，在整個給藥期間，所有受試物組及溶劑對照組的體重均保持平穩且略有上升，說明全部受試物在所設定的濃度下經皮給藥不會對小鼠的體重產生影響。
活性測試測試實施例8：化合物與陽性對照化合物在LNCaP細胞AR蛋白降解作用的比對
1、實驗材料
LNCaP：LNCaP(人前列腺癌)購自中國科學院細胞庫，培養在含10%胎牛血清的RPMI-1640培養液中。在條件為37℃，5%飽和濕度的CO2培養箱中常規培養Lncap細胞。待培養至覆蓋率達80%左右時，按照1：3比例傳代。
2、實驗試劑
Figure 110108729-A0305-02-0317-265
3.使用儀器
Figure 110108729-A0305-02-0317-780
4.Western blot步驟
4.1 細胞培養：
取液氮罐凍存的Lncap，細胞復蘇培養至生長對數期，將其鋪6至孔板中(每孔約10^6個細胞)，加藥物處理。
4.2 藥物處理
稱取適量的化合物溶於DMSO溶劑中，渦旋混勻，配置成10mM的儲存溶液，分別加藥作用Lncap細胞，control組為只加DMSO處理，藥物處理組分別加入對應的化合物處理，其作用的終濃度分別為50nM和200nM，陽性對照組ARD-69的作用濃度為100nM。24h後收集細胞。
4.3 收集細胞
取出經化合物作用後的細胞六孔板及其他未加藥細胞系，棄去培養基，PBS洗滌，胰酶消化，終止，吹打，離心，PBS再次洗滌，完全棄去PBS。
4.4 裂解細胞收集蛋白
收集的細胞加入適量的裂解液(裂解液中加入蛋白酶體抑制劑PMSF)，冰上裂解30min，12000rpm離心20min，取上清。
4.5 BCA法測定蛋白總量
Figure 110108729-A0305-02-0318-727
配製梯度濃度的標準蛋白，取20μL于96孔板中，每個標準品做一個複孔；
Figure 110108729-A0305-02-0318-723
取2μL蛋白裂解液溶於18μL的PBS中，每個樣品做一個複孔；
Figure 110108729-A0305-02-0318-724
每個孔加200μL的BCA工作液，37℃孵育30min；
Figure 110108729-A0305-02-0318-725
測定562nm吸光度；
Figure 110108729-A0305-02-0318-726
計算每個樣品的蛋白濃度，計算50μg所需的蛋白裂解液體積。
4.6 Western blot檢測蛋白表達水準
變性：取蛋白裂解液，加入適量的5×蛋白上樣緩衝液，100℃變性5min。
電泳：使用10%預製膠電泳200V 30min；轉膜：切去濃縮膠，將分離膠上的蛋白通過濕轉法轉移到PVDF膜上，270mA，2h。
封閉：將PVDF膜置於5%的脫脂牛奶中室溫封閉1h。
一抗：將PVDF膜按Mark的分子量大小剪開，分別置於AR和β-Actin抗體中，4℃搖床孵育過夜。
洗膜：將PVDF膜置於PBST中，搖床振盪清洗4次，每次6min。
二抗：將PVDF膜置於AR和β-Actin抗體對應的二抗(山羊抗兔和山羊抗鼠)溶液中，搖床振盪室溫孵育1~2h。
洗膜：將PVDF膜置於PBST中，搖床振盪清洗4次，每次6min。
曝光：顯影液激發PVDF上的螢光。
所得實驗結果見圖6-17，其表明本發明提供的化合物對LNCaP細胞AR 蛋白具有很好的降解作用(基本達到或優於ARD-69的降解作用效果)，說明本發明化合物具備成為抗腫瘤藥物，特別是前列腺癌的治療藥物。
本發明內容僅僅舉例說明了要求保護的一些具體實施方案，其中一個或更多個技術方案中所記載的技術特徵可以與任意的一個或多個技術方案相組合，這些經組合而得到的技術方案也在本申請保護範圍內，就像這些經組合而得到的技術方案已經在本發明公開內容中具體記載一樣。
AR:雄激素受體
A21:化合物編號
A22:化合物編號
A23:化合物編號
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Claims (20)

  1. 式(III)所示的雙官能化合物或其藥學上可用的鹽、立體異構體：ABM-L-VLM(III)，其中ABM具有式(IV)結構，其中
    Figure 110108729-A0305-02-0320-717
    表示連接部分的連接點：
    Figure 110108729-A0305-02-0320-781
     Z1選自：被一個或更多個鹵素所取代的C1-4烷基，以及C1-4烷氧基；X選自：鹵素；Y1、Y2各自獨立地選自：O、S；R1、R2各自獨立地選自：H、鹵素、任選被鹵素、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，或R1、R2連同它們所連接的原子一起形成含有0到2個雜原子的3到8元環；W1選自：化學鍵，C6-10芳基，5-10元雜芳基、聯C6-10芳基或聯5-10元雜芳基，各自任選地被1-10個RW1取代；每個RW1獨立地選自：H、鹵基、氰基、羥基、胺基、-COORW11、-CONRW11RW12、任選被鹵素、羥基、氰基、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，C3-6環烷基、C4-6環雜烷基、C6-10芳基或5-10元雜芳基；RW11和RW12各自獨立地選自：氫、任選被鹵素取代的C1-6烷基或C3-6環烷基；L是連接ABM和VLM的化學連接部分，L選自-O-(CH2)m-O-(CH2)n-CO-和-O-(CH2)m-O-(CH2)n-O-(CH2)o-CO-，其中m、n、o各自獨立地選自：1、2、3、4；VLM是式(VI)-2所示結構片段或其立體異構體：
    Figure 110108729-A0305-02-0321-268
     Y5是NRY5、O；R21選自：甲基、乙基、正丙基、異丙基、正丁基、2-甲基丙基、仲丁基、叔丁基、正戊基、異戊基或新戊基；R22選自：氫；RY5是氫、C1-6烷基；R23、R24各自獨立地選自：氫、C1-6烷基； W2是
    Figure 110108729-A0305-02-0321-272
    ； R25是
    Figure 110108729-A0305-02-0321-273
    ，其中R27是C1-3烷基，且Xa是S；R26是氫。
  2. 式(III)所示的雙官能化合物或其藥學上可用的鹽、立體異構體：ABM-L-VLM(III)，其中ABM具有式(IV)結構，其中
    Figure 110108729-A0305-02-0321-718
    表示連接部分的連接點：
    Figure 110108729-A0305-02-0321-274
     Z1選自：被一個或更多個鹵素所取代的C1-4烷基，以及C1-4烷氧基；X選自：鹵素；Y1、Y2各自獨立地選自：O、S；R1、R2各自獨立地選自：H、鹵素、任選被鹵素、C1-6烷氧基取代的C1-6 烷基或C1-6烷氧基，或R1、R2連同它們所連接的原子一起形成含有0到2個雜原子的3到8元環；W1選自：化學鍵，C6-10芳基，5-10元雜芳基、聯C6-10芳基或聯5-10元雜芳基，各自任選地被1-10個RW1取代；每個RW1獨立地選自：H、鹵基、氰基、羥基、胺基、任選被鹵素、羥基、氰基、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，C3-6環烷基、C4-6環雜烷基、C6-10芳基或5-10元雜芳基；L是連接ABM和VLM的化學連接部分，L選自-O-(CH2)m-O-(CH2)n-CO-和-O-(CH2)m-O-(CH2)n-O-(CH2)o-CO-，其中m、n、o各自獨立地選自：1、2、3、4；VLM是式(VI)-2所示結構片段或其立體異構體：
    Figure 110108729-A0305-02-0322-271
     Y5是NRY5、O；R21選自：甲基、乙基、正丙基、異丙基、正丁基、2-甲基丙基、仲丁基、叔丁基、正戊基、異戊基或新戊基；R22選自：氫；RY5是氫、C1-6烷基；R23、R24各自獨立地選自：氫、C1-6烷基； W2是
    Figure 110108729-A0305-02-0322-275
    ； R25是
    Figure 110108729-A0305-02-0322-276
    ，其中R27是C1-3烷基，且Xa是S； R26是氫。
  3. 如請求項1或2所述的雙官能化合物或其藥學上可用的鹽、立體異構體，其中Z1選自CH2F、CHF2、CF3和甲氧基；X選自：鹵素；Y1、Y2各自獨立地選自：O、S；R1、R2各自獨立地選自：任選被鹵素、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，或R1、R2連同它們所連接的原子一起形成C3-6環烷基；W1選自：化學鍵，C6-10芳基，5-10元雜芳基、聯C6-10芳基或聯5-10元雜芳基，各自任選地被1、2或3個RW1取代；並且每個RW1獨立地選自：氫、鹵基、氰基、任選被鹵素、羥基、氰基取代的C1-6烷基或C1-6烷氧基。
  4. 如請求項1所述的雙官能化合物或其藥學上可用的鹽、立體異構體，其中W1選自：化學鍵、苯基、吡啶基、嘧啶基、吡嗪基、噠嗪基，各自任選地被1、2或3個RW1取代；並且每個RW1獨立地選自：氫、鹵基、氰基、任選被鹵素、羥基、氰基取代的C1-6烷基或C1-6烷氧基、-COORW11、-CONRW11RW12；RW11和RW12各自獨立地選自：氫、任選被鹵素取代的C1-6烷基。
  5. 如請求項1所述的雙官能化合物或其藥學上可用的鹽、立體異構體，其中Z1選自CH2F、CHF2、CF3和甲氧基；X選自：鹵素；Y1、Y2各自獨立地選自：O、S；R1、R2各自獨立地選自：任選被鹵素、C1-6烷氧基取代的C1-6烷基或C1-6烷氧基，或R1、R2連同它們所連接的原子一起形成C3-6環烷基；W1選自：化學鍵，C6-10芳基，5-10元雜芳基、聯C6-10芳基或聯5-10元雜芳基，各自任選地被1、2或3個RW1取代；並且每個RW1獨立地選自：氫、鹵基、氰基、任選被鹵素、羥基、氰基取代的 C1-6烷基或C1-6烷氧基、-COORW11、-CONRW11RW12；RW11和RW12各自獨立地選自：氫、任選被鹵素取代的C1-6烷基。
  6. 如請求項1或2所述的雙官能化合物或其藥學上可用的鹽、立體異構體，其中Z1選自：CH2F、CHF2、CF3和甲氧基；X選自：鹵素；Y1、Y2各自獨立地選自：O、S；R1、R2各自獨立地選自：甲基，或R1、R2連同它們所連接的原子一起形成C3-6環烷基； W1選自：化學鍵，
    Figure 110108729-A0305-02-0324-291
    、
    Figure 110108729-A0305-02-0324-293
    、
    Figure 110108729-A0305-02-0324-294
    、
    Figure 110108729-A0305-02-0324-295
    、
    Figure 110108729-A0305-02-0324-298
    、
    Figure 110108729-A0305-02-0324-297
    ，其各自任選地被1、2或3個RW1取代；並且 每個RW1獨立地選自：氫、鹵基、氰基、任選被鹵素取代的C1-3烷基或C1-3烷氧基。
  7. 如請求項1所述的雙官能化合物或其藥學上可用的鹽、立體異構體，其中Z1選自：CH2F、CHF2、CF3和甲氧基；X選自：鹵素；Y1、Y2各自獨立地選自：O、S；R1、R2各自獨立地選自：甲基，或R1、R2連同它們所連接的原子一起形成C3-6環烷基； W1選自：化學鍵，
    Figure 110108729-A0305-02-0324-302
    、
    Figure 110108729-A0305-02-0324-782
    、
    Figure 110108729-A0305-02-0324-305
    、
    Figure 110108729-A0305-02-0324-306
    、
    Figure 110108729-A0305-02-0324-300
    、
    Figure 110108729-A0305-02-0324-301
    ，其各自任選地被1、2或3個RW1取代；並且 每個RW1獨立地選自：氫、鹵基、氰基、任選被鹵素取代的C1-3烷基或C1-3烷氧基、-COORW11、-CONRW11RW12；RW11和RW12各自獨立地選自：氫、任選被鹵素取代的C1-6烷基。
  8. 如請求項1或2所述的雙官能化合物或其藥學上可用的鹽、立體異構 體，其中Z1選自：CF3；X選自：F；Y1、Y2各自獨立地選自：O、S；R1、R2各自獨立地選自：甲基，或R1、R2連同它們所連接的原子一起形成C3-4環烷基； W1選自：化學鍵，
    Figure 110108729-A0305-02-0325-307
    、
    Figure 110108729-A0305-02-0325-309
    、
    Figure 110108729-A0305-02-0325-310
    ，其各自任選地 被1、2或3個RW1取代；並且每個RW1獨立地選自：氫、鹵基、氰基、任選被F取代的C1-3烷基或C1-3烷氧基。
  9. 如請求項1所述的雙官能化合物或其藥學上可用的鹽、立體異構體，其中Z1選自：CF3；X選自：F；Y1、Y2各自獨立地選自：O、S；R1、R2各自獨立地選自：甲基，或R1、R2連同它們所連接的原子一起形成C3-4環烷基； W1選自：化學鍵，
    Figure 110108729-A0305-02-0325-311
    、
    Figure 110108729-A0305-02-0325-312
    、
    Figure 110108729-A0305-02-0325-313
    ，其各自任選地 被1、2或3個RW1取代；並且每個RW1獨立地選自：氫、鹵基、氰基、任選被F取代的C1-3烷基或C1-3烷氧基、-CONH2、-COOC1-3烷基。
  10. 如請求項1或2所述的雙官能化合物或其藥學上可用的鹽、立體異構體，其中ABM選自如下結構，其中
    Figure 110108729-A0305-02-0325-719
    表示連接部分的連接點：
    Figure 110108729-A0305-02-0325-716
    Figure 110108729-A0305-02-0326-278
  11. 如請求項1所述的雙官能化合物或其藥學上可用的鹽、立體異構體，其中ABM選自如下結構，其中
    Figure 110108729-A0305-02-0326-720
    表示連接部分的連接點：
    Figure 110108729-A0305-02-0326-280
    Figure 110108729-A0305-02-0327-281
  12. 如請求項1或2所述的雙官能化合物或其藥學上可用的鹽、立體異構體，其中所述VLM選自如下的結構片段或其立體異構體，其中
    Figure 110108729-A0305-02-0327-721
    表示連接部分的連接點：
    Figure 110108729-A0305-02-0327-283
  13. 如請求項1或2所述的雙官能化合物或其藥學上可用的鹽、立體異構體，其中連接基團(L)選自如下基團：
    Figure 110108729-A0305-02-0327-285
  14. 如請求項1或2所述的雙官能化合物或其藥學上可用的鹽、立體異構體，其中所述化合物選自：
    Figure 110108729-A0305-02-0327-287
    Figure 110108729-A0305-02-0328-288
  15. 如請求項1或2所述的雙官能化合物或其藥學上可用的鹽、立體異構體，其中所述化合物是：
    Figure 110108729-A0305-02-0328-289
  16. 一種藥物組合物，其包含有效量的請求項1至15任一項所述的雙官能化合物或其藥學上可用的鹽、立體異構體，以及藥學上可接受的載體。
  17. 如請求項16所述藥物組合物，其進一步包含至少一種其它生物活性劑。
  18. 如請求項17所述藥物組合物，其中其它生物活性劑是抗癌劑。
  19. 請求項1至15任一項所述的雙官能化合物或其藥學上可用的鹽、立體異構體在製備治療痤瘡、皮脂腺增大、脫髮、前列腺癌的藥物中的用途。
  20. 請求項1至15任一項所述的雙官能化合物或其藥學上可用的鹽、立體 異構體在製備治療疾病的藥物中的用途，其中所述疾病是前列腺癌、痤瘡或脫髮。
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