WO2019196812A1 - 蛋白降解靶向化合物、其抗肿瘤应用、其中间体及中间体应用 - Google Patents

蛋白降解靶向化合物、其抗肿瘤应用、其中间体及中间体应用 Download PDF

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WO2019196812A1
WO2019196812A1 PCT/CN2019/081840 CN2019081840W WO2019196812A1 WO 2019196812 A1 WO2019196812 A1 WO 2019196812A1 CN 2019081840 W CN2019081840 W CN 2019081840W WO 2019196812 A1 WO2019196812 A1 WO 2019196812A1
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WIPO (PCT)
Prior art keywords
dioxopiperidin
thio
ethoxy
dione
oxoisoindol
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PCT/CN2019/081840
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English (en)
French (fr)
Inventor
杨小宝
姜标
孙仁红
任超伟
孙宁
孔莹
李岩
陈金聚
阴倩倩
宋肖玲
赵全菊
仇星
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上海科技大学
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Priority to JP2020555408A priority Critical patent/JP7367908B2/ja
Priority to EP19786024.0A priority patent/EP3778590A4/en
Priority to AU2019251151A priority patent/AU2019251151B2/en
Priority to KR1020207032131A priority patent/KR102548191B1/ko
Priority to CA3096790A priority patent/CA3096790C/en
Priority to US17/046,690 priority patent/US20220117982A1/en
Publication of WO2019196812A1 publication Critical patent/WO2019196812A1/zh

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Definitions

  • the present disclosure relates to protein degradation targeting compounds, their anti-tumor applications, their intermediates and intermediate applications.
  • PROTAD Proteinolysis Targeting Drug
  • the first part is composed of small molecule drugs or compounds with specific proteins
  • the second part is composed of linking units of different lengths
  • the third part is with pan A functionalized E3 ligase ligand consisting of a ligand.
  • the E3 Cereblon (CRBN)/Cullin4A ubiquitinated ligase ligand has a phthalimide backbone, namely thalidomide and its analogs, pomamide and lenalidomide.
  • the currently published E3 CRBN ligands are covalently bound to the linker unit via a carbon-nitrogen bond using thalidomide, pomamide and lenalidomide. So far, no reports and related studies have found that thalidomide, pomamide and lenalidomide are covalently bonded to the linking unit via a carbon-sulfur bond.
  • the present disclosure provides a compound of formula (I):
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the present disclosure also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament:
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof, of the present disclosure for use in the prevention and/or treatment of cancer.
  • the present disclosure also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention and/or treatment of cancer.
  • the present disclosure also provides a method of treating or preventing cancer comprising administering to a subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof .
  • the present disclosure further provides the use of a compound of formula (III), or a salt, enantiomer, stereoisomer, solvate, polymorph thereof, for the preparation of a compound of formula (I) as described above.
  • the present disclosure further provides the use of a compound of formula (IV), or a salt, enantiomer, stereoisomer, solvate, polymorph thereof, for the preparation of a compound of formula (I) as described above.
  • the present disclosure further provides the compound of formula (IV), or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the present disclosure further provides the compound of formula (IV), or a pharmaceutically acceptable salt thereof, for use in the prevention and/or treatment of cancer.
  • the present disclosure further provides the use of a compound of formula (IV), or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention and/or treatment of cancer.
  • the present disclosure further provides a method of treating or preventing cancer comprising administering to a subject a therapeutically effective amount of the compound of formula (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof .
  • Figures 1-14 show that Western-blot detection of the novel design of the E3 ligase ligand of the present disclosure is applied to the PROTAD series of compounds compared to the commercial parent inhibitor dasatinib, bosutinib, PROTAD of the present disclosure
  • the compounds are effective in degrading BCR-ABL and c-ABL proteins.
  • Figure 15a and Figure 15b show the use of Western-blot to detect a novel design of the PROTAD series of compounds comprising E3 ligase ligands of the present disclosure, compared to the carbon-nitrogen bond covalently bound PROTAD compound (SIAIS 151072), the carbon of the present disclosure
  • the sulfur-bonded covalently bound PROTAD compound can effectively degrade BCR-ABL and c-ABL proteins, while the carbon-nitrogen bond covalently bound PROTAD compound is significantly weaker in degrading BCR-ABL and c-ABL proteins, indicating carbon-sulfur bonds. Covalent attachment of PROTAD compounds is more advantageous.
  • Figures 16a-c show the use of Western-blot to detect a novel design of the PROTAD series of compounds containing E3 ligase ligands in the present disclosure, compared to the COTA, carbon-oxygen bond covalently bound PROTAD compounds (SIAIS213110, SIAIS271066)
  • the PROTAD compound covalently bonded to the carbon-sulfur bond of the present disclosure can effectively degrade the BRD2 and BRD4 proteins, and the ability of the PROTAD compound covalently bonded to the carbon-nitrogen bond and the carbon-oxygen bond to degrade the BRD2 and BRD4 proteins is significantly weaker, thereby indicating the carbon-sulfur bond. Covalent attachment of PROTAD compounds is more advantageous.
  • an aspect of the present disclosure provides a compound of formula (I):
  • SMBP is covalently linked to the ULM via a linking group LIN;
  • SMBP represents a small molecule compound or a derivative thereof capable of binding a protein
  • LIN-ULM represents the chemical structure of the following formula (II):
  • Ring atom A represents CH 2 or CO
  • ring atoms B, X, Y, Z are the same or different and each independently represents CH or N, and R represents S, SO, SO 2 or piperazine subunit;
  • LIN is a linking group representing -U-alkylene-, wherein
  • the alkylene group is a linear or branched alkylene group optionally interrupted one or more times by one or more groups selected from the group consisting of O, CONH, NHCO, NH, alkynylene, and aene. a base, cycloalkylene, arylene, heterocyclylene, heteroarylene or any combination thereof, wherein the linear or branched alkylene group is optionally substituted with one or more substituents, And
  • the group U represents CO or NH, or the group U does not exist;
  • LIN is represented by -U-alkylene-, wherein one of the ends of the -U-alkylene- (for example, group U) can be attached to the SMBP and the other end (alkylene) is attached.
  • group U the ends of the -U-alkylene-
  • alkylene an alkylene group
  • the SMBP is a small molecule drug targeting a CDK4/6 small molecule drug, targeting an ALK target, a small molecule drug targeting a Bcr-abl target, and a small target of a PARP target.
  • the SMBP represents:
  • Rebsini Abemaciclib, Pabuxorib, Crozinib, Coloritinib, Buginib, Electinib, Estratinib, TAE684, ASP3026, GSK1838705A, AZD3463, Imatinib , dasatinib, bosutinib, punatinib, olaapali, nilapali, rupacal, toremifene, tamoxifen, 4-hydroxytamoxifen, JQ -1, I-BET762 or their derivatives.
  • the SMBP represents a portion of a compound represented by the following structural formula:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 34 And R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 , R 61 , R 62 , R 63 , R 64 , R 65 , R 66 are each independently H or
  • the ring atom Q is N or CH, wherein CH is further attached to the group LIN via NH or a piperazine subunit;
  • X 1 is Cl or H, Y 1 is H or OH, Z 1 is H or methyl, and W 1 is H; or in one embodiment, X 1 is Cl or H, Y 1 is H or OH, Z 1 is H or methyl, and W 1 is OH.
  • X 1 is Cl, Y 1 is H, Z 1 is H or methyl, and W 1 is H.
  • X 1 is Cl, Y 1 is OH, Z 1 is H or a methyl group, and W 1 is H.
  • X 1 is H, Y 1 is H, Z 1 is H or methyl, and W 1 is H.
  • X 1 is H, Y 1 is OH, Z 1 is H or methyl, and W 1 is H.
  • X 1 is H, Y 1 is OH, Z 1 is H or methyl, and W 1 is H.
  • X 1 is H, Y 1 is OH, Z 1 is H or methyl, and W 1 is OH.
  • the ring atom A represents CH 2 or CO
  • the ring atoms B, X, Y, Z are the same and both represent CH
  • R represents S, SO, SO 2 or Piperazine subunit.
  • the ring atom A represents CH 2 or CO
  • the ring atoms B, X, Y, Z are the same and both represent CH
  • R represents S.
  • the ring atom A represents CH 2 or CO
  • the ring atoms B, X, Y, Z are the same and both represent CH
  • R represents SO.
  • the ring atom A represents CH 2 or CO
  • the ring atoms B, X, Y, Z are the same and both represent CH
  • R represents SO 2
  • the ring atom A represents CH 2 or CO
  • the ring atoms B, X, Y, Z are the same and both represent CH
  • R represents a piperazine subunit.
  • formula (II) is also the following structural formula:
  • formula (II) is also the following structural formula:
  • formula (II) is also the following structural formula:
  • formula (II) is also the following structural formula:
  • formula (II) is also the following structural formula:
  • the LIN represents:
  • N1, n2, n3, n4, n5, n6, m1, m2 each independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;
  • group U represents CO or NH, or the group U is absent.
  • the LIN is preferably -UC 1-30 alkylene-.
  • the LIN is preferably -U-methylene or -UC 2-30 alkylene-, wherein the C 2-30 alkylene is a linear or branched C 2 -30 alkylene (preferably C 2 -C 29 alkylene chain, C 2 -C 28 alkylene chain, C 2 -C 27 alkylene chain, C 2 -C 26 alkylene chain, C 2 - C 25 alkylene chain, C 2 -C 24 alkylene chain, C 2 -C 23 alkylene chain, C 2 -C 22 alkylene chain, C 2 -C 21 alkylene chain, C 2 - C 20 alkylene chain, C 2 -C 19 alkylene chain, C 2 -C 18 alkylene chain, C 2 -C 17 alkylene chain, C 2 -C 16 alkylene chain, C 2 - C 15 alkylene chain, C 2 -C 14 alkylene
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U-(CH 2 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U-(CH 2 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U-(CH 2 14 -; -U-(CH 2 ) 15 -; -U-(CH 2 ) 16 -; -U-(CH 2 ) 17 -; -U-(CH 2 ) 18 -; -U-(CH 2 19 -; -U-(CH 2 19 -; -U
  • group U represents CO or NH, or the group U is absent.
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene group is optionally one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof interrupted one or more times, and the group U represents CO or NH, or group U does not exist.
  • the LIN represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2- (O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 ) 5 -, -U- CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U -CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -O-(CH 2 ) 2 -, -U-CH 2- (O(CH
  • group U represents CO or NH, or the group U is absent.
  • the LIN is -U-alkylene-, the alkylene group (preferably a C 1-30 alkylene chain, particularly preferably a C 2 -C 29 alkylene chain, C 2 -C 28 alkylene chain, C 2 -C 27 alkylene chain, C 2 -C 26 alkylene chain, C 2 -C 25 alkylene chain, C 2 -C 24 alkylene chain, C 2 -C 23 alkylene chain, C 2 -C 22 alkylene chain, C 2 -C 21 alkylene chain, C 2 -C 20 alkylene chain, C 2 -C 19 alkylene chain, a C 2 -C 18 alkylene chain, a C 2 -C 17 alkylene chain, a C 2 -C 16 alkylene chain, a C 2 -C 15 alkylene chain, a C 2 -C 14 alkylene chain, C 2 -C 13 alkylene chain, C 2 -C 12 alkylene chain, C 2 -
  • the LIN is preferably -UC 1-30 alkylene-
  • the C 1-30 alkylene group is one or more selected from the group consisting of a hydroxyl group, an amino group, a thiol group, a halogen or a substituted or substituted C 1 -C 30 alkylene chain substituted with a substituent (preferably a C 1 -C 29 alkylene chain, a C 1 -C 28 alkylene chain, a C 1 -C 27 alkylene group)
  • Base chain C 1 -C 26 alkylene chain, C 1 -C 25 alkylene chain, C 1 -C 24 alkylene chain, C 1 -C 23 alkylene chain, C 1 -C 22 alkylene
  • Base chain C 1 -C 21 alkylene chain, C 1 -C 20 alkylene chain, C 1 -C 19 alkylene chain, C 1 -C 18 alkylene chain, C 1 -C 17 alkylene
  • C 1 -C 16 alkylene chain preferably
  • the number of the substituents may be, for example, 1-30, 1-25, 1-20, or 1-15, 1-10, 1-9, 1-8. , 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10 , 9, 8, 7, 6, 5, 4, 3, 2, or 1.
  • the LIN represents:
  • N11, n12, n13, n14, n15, n16, m11, m12 respectively represent 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 An integer of 17, 18, 19 or 20;
  • group U represents CO or NH, or the group U is absent.
  • the LIN preferably represents: -U-(CH 2 ) 3 -triazolyl-(CH 2 ) 5 -, -U-(CH 2 ) 2 -triazolyl-(CH 2 ) 5- , -U-CH 2 -triazolyl-(CH 2 ) 5 -, -U-(CH 2 ) 2 -triazolyl-(CH 2 ) 4 -, -U-(CH 2 ) 3 -Triazolyl-(CH 2 ) 2 -O(CH 2 ) 2 -, -U-(CH 2 ) 2 -triazolyl-(CH 2 ) 2 -O(CH 2 ) 2 - or -U-CH 2 -Triazolyl-(CH 2 ) 2 -O(CH 2 ) 2 -.
  • the LIN preferably represents:
  • group U represents CO or NH, or the group U is absent.
  • the LIN preferably represents:
  • group U represents CO or NH, or the group U is absent.
  • the LIN is preferably -U-CH 2 NHCOCH 2 -, -U-(CH 2 ) 2 NHCO(CH 2 ) 2 -, -U-(CH 2 ) 3 NHCO(CH 2 ) 3 -, -U-(CH 2 ) 3 NHCO(CH 2 ) 4 -, -U-(CH 2 ) 4 NHCO(CH 2 ) 4 -, -U-(CH 2 ) 5 NHCO(CH 2 ) 5 -, -U-(CH 2 ) 6 NHCO(CH 2 ) 7 -, -U-(CH 2 ) 6 NHCO(CH 2 ) 6 -, -U-(CH 2 ) 7 NHCO(CH 2 ) 7 - , -U-(CH 2 ) 8 NHCO(CH 2 ) 8 , -U- (CH 2 ) 9 NHCO(CH 2 ) 9 -, -U-(CH 2 ) 9 NHCO(
  • group U represents CO or NH, or the group U is absent.
  • the compound of formula (I) is also a compound of formula (Ia-2):
  • the compound of formula (I) is also a compound of formula (Ia-3):
  • group LIN, R, ring atom A is as defined herein, and the groups R 1 , R 2 , R 3 , R 4 are as defined herein.
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 )
  • the LIN is preferably -UC 2-40 alkylene- (preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • said LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • said LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -O
  • the compound of formula (I) is also a compound of formula (Ib-2):
  • the compound of formula (I) is also a compound of formula (Ib-3):
  • group LIN, R, ring atom A is as defined herein, and the groups R 5 , R 6 , R 7 , R 8 are as defined herein.
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • said LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • said LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • said LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -O
  • the compound of formula (I) is also a compound of formula (Ic-2):
  • the compound of formula (I) is also a compound of formula (Ic-3):
  • group LIN, R, ring atom A is as defined herein, and the groups R 9 , R 10 , R 11 , R 12 are as defined herein.
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • said LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • said LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -O
  • the compound of formula (I) is also a compound of formula (Id-2):
  • the compound of formula (I) is also a compound of formula (Id-3):
  • group LIN, R, ring atom A is as defined herein, and the groups R 13 , R 14 , R 15 , R 16 are as defined herein.
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • said LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • said LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -O
  • the compound of formula (I) is also a compound of formula (Ie-2):
  • the compound of formula (I) is also a compound of formula (Ie-3):
  • group LIN, R, ring atom A is as defined herein, and the groups R 17 , R 18 , R 19 , R 20 are as defined herein.
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • said LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • said LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -O
  • the compound of formula (I) is also a compound of formula (If-2):
  • group LIN, R, ring atom A, B, X, Y, Z are as defined herein, and the ring atom Q, the groups R 21 , R 22 , R 23 , R 24 are as defined herein .
  • the compound of formula (I) is also a compound of formula (If-2-1):
  • group LIN, R, ring atom A, group R 21 , R 22 , R 23 , R 24 are as defined herein, and ring atom Q is N or CH, wherein CH is passed through NH or piperazine subunit Connect to the group LIN.
  • the compound of formula (I) is also a compound of formula (If-2-2):
  • group LIN, R, ring atom A, group R 21 , R 22 , R 23 , R 24 are as defined herein.
  • the compound of formula (I) is also a compound of formula (If-2-3):
  • group LIN, R, ring atom A, group R 21 , R 22 , R 23 , R 24 are as defined herein.
  • the compound of formula (I) is also a compound of formula (If-2-4):
  • group LIN, R, ring atom A, group R 21 , R 22 , R 23 , R 24 are as defined herein.
  • LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U-(CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U- (CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U-(CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U- (CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U-(CH 2 ) 14 -; -U-(CH 2 ) 15 -; -U- (CH 2 ) 16 -; -
  • LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-) wherein the alkylene chain is optionally substituted by one or more O, CONH, NHCO, NH, alkyne a group, an alkenylene group, a cycloalkylene group, an arylene group, a heterocyclylene group or a heteroarylene group, or any combination thereof, interrupted one or more times, and the group U represents CO or NH, or the group U does not exist. .
  • the LIN preferably represents :-U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 - , wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • the LIN preferably represents :-U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 ) 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 - , -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 - (O(CH 2 ) 2 ) 9 -, -U-CH 2 -
  • the compound of formula (I) is also a compound of formula (If-3):
  • group LIN, R, ring atom A, B, X, Y, Z are as defined herein, and the groups R 21 , R 22 , R 23 , R 24 are each independently H or methyl, and The ring atom Q is CH, wherein CH is attached to the group LIN through N(CH 3 ).
  • the compound of formula (I) is also a compound of formula (If-3-1):
  • group LIN, R, ring atom A, B, X, Y, Z are as defined herein, and the groups R 21 , R 22 , R 23 , R 24 are each independently H or methyl, and The ring atom Q is CH, wherein CH is attached to the group LIN through N(CH 3 ).
  • the compound of formula (I) is also a compound of formula (If-3-2):
  • group LIN, R, ring atom A is as defined herein, and the groups R 21 , R 22 , R 23 , R 24 are each independently H or methyl.
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or group U does not exist.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U -(CH 2 ) 3 -; -U-(CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U -(CH 2 ) 8 -; -U-(CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U -(CH 2 ) 13 -; -U-(CH 2 ) 14 -; -U-(CH 2 ) 15 -; -U-(CH 2 ) 16 -; -U-(CH 2 ) 17 -; -
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 An alkylene-) wherein the alkylene chain is optionally substituted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene Or the heteroarylene or any combination thereof is interrupted one or more times, and the group U represents CO or NH, or the group U is absent.
  • the LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -or-U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or a group U does not exist.
  • the LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U- CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U -CH 2 -(O(CH 2 ) 2 ) 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, - U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -
  • the compound of formula (I) is also a compound of formula (Ig-2):
  • the compound of formula (I) is also a compound of formula (Ig-3):
  • group LIN, R, ring atom A is as defined herein, and the groups R 25 , R 26 , R 27 , R 28 are as defined herein.
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • said LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • said LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -O
  • the compound of formula (I) is also a compound of formula (Ih-2):
  • group LIN, R, ring atom A, B, X, Y, Z are as defined herein, and the groups R 29 , R 30 , R 31 , R 32 , R 33 are as defined herein.
  • the compound of formula (I) is also a compound of formula (Ih-3):
  • group LIN, R, ring atom A is as defined herein, and the groups R 29 , R 30 , R 31 , R 32 , R 33 are as defined herein.
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • the LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • said LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -O
  • the compound of formula (I) is also a compound of formula (Ii-2):
  • group LIN, R, ring atom A, B, X, Y, Z are as defined herein, and the groups R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 is as defined herein.
  • the compound of formula (I) is also a compound of formula (Ii-3):
  • group LIN, R, ring atom A is as defined herein, and the groups R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 are as defined herein .
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • said LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • said LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -O
  • the compound of formula (I) is also a compound of formula (Ij-2):
  • the compound of formula (I) is also a compound of formula (Ij-3):
  • group LIN, R, ring atom A is as defined herein, and the groups R 42 , R 43 , R 44 , R 45 are as defined herein.
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • said LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • said LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -O
  • the compound of formula (I) is also a compound of formula (Il-2):
  • the compound of formula (I) is also a compound of formula (Il-3):
  • group LIN, R, ring atom A is as defined herein, and the groups R 50 , R 51 , R 52 , R 53 are as defined herein.
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • the LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • the LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -
  • the compound of formula (I) is also a compound of formula (Im-2):
  • the compound of formula (I) is also a compound of formula (Im-3):
  • group LIN, R, ring atom A is as defined herein, and the groups R 54 , R 55 , R 56 , R 57 are as defined herein.
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • the LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • the LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -
  • the compound of formula (I) is also a compound of formula (In-2):
  • group LIN, R, ring atom A, B, X, Y, Z are as defined herein, and the groups R 58 , R 59 , R 60 , R 61 are as defined herein.
  • the compound of formula (I) is also a compound of formula (In-3):
  • group LIN, R, ring atom A is as defined herein, and the groups R 58 , R 59 , R 60 , R 61 are as defined herein.
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 ) 14
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • said LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • the LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -O-
  • the compound of formula (I) is also a compound of formula (Io-2):
  • group LIN, R, ring atom A, B, X, Y, Z are as defined herein, and the groups R 62 , R 63 , R 64 , R 65 are as defined herein.
  • the compound of formula (I) is also a compound of formula (Io-3):
  • group LIN, R, ring atom A is as defined herein, and the groups R 62 , R 63 , R 64 , R 65 are as defined herein.
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • said LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • said LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -O
  • the compound of formula (I) is also a compound of formula (Ip-2):
  • the compound of formula (I) is also a compound of formula (Ip-3):
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • said LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • said LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -O
  • the compound of formula (I) is also a compound of formula (Iq-2):
  • the compound of formula (I) is also a compound of formula (Iq-3):
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • said LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • said LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -O
  • the compound of formula (I) is also a compound of formula (Ir-2):
  • the compound of formula (I) is also a compound of formula (Ir-3):
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • the LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • the LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -
  • the compound of formula (I) is also a compound of formula (Is-2):
  • the compound of formula (I) is also a compound of formula (Is-3):
  • group LIN, R, ring atom A is as defined herein, and the groups X 1 , Y 1 , Z 1 , W 1 are as defined herein.
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • the LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • the LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -
  • the compound of formula (I) is also a compound of formula (It-2):
  • the compound of formula (I) is also a compound of formula (It-2-1):
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; U-(CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -;- U-(CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -;- U-(CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein The alkylene chain is optionally substituted by one or more of O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any of them
  • the combination is interrupted one or more times, and the group U represents CO or NH, or the group U does not exist.
  • the LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) N1 -(O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • the LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 2 ) 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH) 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 - (O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2
  • the compound of formula (I) is also a compound of formula (Iu-2):
  • the compound of formula (I) is also a compound of formula (Iu-3):
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • said LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • said LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -O
  • the compound of formula (I) is also a compound of formula (Iv-2):
  • the compound of formula (I) is also a compound of formula (Iv-3):
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • said LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • said LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -O
  • the compound of formula (I) is also a compound of formula (Iw-2):
  • the compound of formula (I) is also a compound of formula (Iw-3):
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • said LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • said LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -O
  • the compound of formula (I) is also a compound of formula (Ix-2):
  • the compound of formula (I) is also a compound of formula (Ix-3):
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • said LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • said LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, - U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -O
  • the compound of formula (I) is also a compound of formula (Iy-2):
  • the compound of formula (I) is also a compound of formula (Iy-3):
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; -U- (CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -; -U- (CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -; -U- (CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein the alkylene
  • the base chain is optionally interrupted by one or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof
  • the group U represents CO or NH, or the group U does not exist.
  • said LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) n1 - (O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • said LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 ) 2 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2 -O
  • the SMBP represents a chemical moiety represented by the formula (It-3):
  • the compound of formula (I) is also a compound of formula (It-3-1):
  • the compound of formula (I) is also a compound of formula (It-3-2):
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; U-(CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -;- U-(CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -;- U-(CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein The alkylene chain is optionally substituted by one or more of O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any of them
  • the combination is interrupted one or more times, and the group U represents CO or NH, or the group U does not exist.
  • the LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) N1 -(O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • the LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 2 ) 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH) 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2
  • the SMBP represents a chemical moiety represented by the formula (It-4):
  • the compound of formula (I) is also a compound of formula (It-4-1):
  • the compound of formula (I) is also a compound of formula (It-4-2):
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; U-(CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -;- U-(CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -;- U-(CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein The alkylene chain is optionally one or more of O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any of them
  • the combination is interrupted one or more times, and the group U represents CO or NH, or the group U does not exist.
  • the LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) N1 -(O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • the LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 2 ) 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH) 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2
  • the SMBP represents a chemical moiety represented by the formula (It-5):
  • the compound of formula (I) is also a compound of formula (It-5-1):
  • the compound of formula (I) is also a compound of formula (It-5-2):
  • the LIN represents -UC 1-30 alkylene-; and the group U represents CO or NH, or the group U is absent.
  • the LIN represents: -U-CH 2 -; -U-(CH 2 ) 2 -; -U-(CH 2 ) 3 -; U-(CH 2 ) 4 -; -U-(CH 2 ) 5 -; -U-(CH 2 ) 6 -; -U-(CH 2 ) 7 -; -U-(CH 2 ) 8 -;- U-(CH 2 ) 9 -; -U-(CH 2 ) 10 -; -U-(CH 2 ) 11 -; -U-(CH 2 ) 12 -; -U-(CH 2 ) 13 -;- U-(CH 2 )
  • the LIN is preferably -UC 2-40 alkylene-(preferably -UC 2-30 alkylene-), wherein The alkylene chain is optionally substituted by one or more of O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any of them
  • the combination is interrupted one or more times, and the group U represents CO or NH, or the group U does not exist.
  • the LIN preferably represents: -U-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 - or -U-(CH 2 ) N1 -(O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, wherein n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; and wherein the group U represents CO or NH, or the group U is absent.
  • the LIN preferably represents: -U-CH 2 -O-(CH 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 2 -, -U-CH 2 -(O(CH 2 ) 2 ) 3 -, -U-CH 2 -(O(CH 2 ) 2 ) 4 -, -U-CH 2 -(O(CH 2 2 ) 5 -, -U-CH 2 -(O(CH 2 ) 2 ) 6 -, -U-CH 2 -(O(CH 2 ) 2 ) 7 -, -U-CH 2 -(O(CH) 2 ) 2 ) 8 -, -U-CH 2 -(O(CH 2 ) 2 ) 9 -, -U-CH 2 -(O(CH 2 ) 2 ) 10 -, -U-(CH 2 ) 2
  • Another aspect of the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as described in the present disclosure, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present disclosure further includes at least one additional drug for treating or preventing cancer.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof, of the present disclosure is for use as a medicament.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof, of the present disclosure for use in the prevention and/or treatment of cancer.
  • the cancer is selected from the group consisting of: a tumor associated with a cyclin-dependent kinase (CDK4/6), including: advanced breast cancer in a postmenopausal woman, breast cancer, advanced breast cancer, metastatic breast cancer, central nervous system Tumors; tumors associated with anaplastic lymphoma kinase (ALK), including: non-small cell lung cancer, ROS1-positive non-small cell lung cancer, anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer, metastatic non-small cell lung cancer; Tumors associated with the Bcr-abl target, including: myelodysplastic syndrome, bone marrow and extramedullary proliferation, gastrointestinal stromal tumors, aggressive systemic mastocytosis, eosinophilia, protuberance Dermal fibrosarcoma, chronic eosinophilic leukemia, acute lymphocytic leukemia, chronic myeloid leukemia; tumors associated with aplastic
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof, of the present disclosure is for use in the preparation of a medicament for preventing and/or treating cancer.
  • the cancer is selected from the group consisting of: a tumor associated with a cyclin-dependent kinase (CDK4/6), including: advanced breast cancer in a postmenopausal woman, breast cancer, advanced breast cancer, metastatic breast cancer, a central Neuronal tumors; tumors associated with anaplastic lymphoma kinase (ALK), including: non-small cell lung cancer, ROS1-positive non-small cell lung cancer, anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer, metastatic non-small cell lung cancer Tumors associated with Bcr-abl targets, including: myelodysplastic syndrome, bone marrow and extramedullary proliferation, gastrointestinal stromal tumors, aggressive systemic mastocytosis,
  • the cancer is selected from the group consisting of: a tumor associated with a cyclin-dependent kinase (CDK4/6), including: advanced breast cancer in a postmenopausal woman, breast cancer, advanced breast cancer, metastatic breast cancer, central nervous system Tumors; tumors associated with anaplastic lymphoma kinase (ALK), including: non-small cell lung cancer, ROS1-positive non-small cell lung cancer, anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer, metastatic non-small cell lung cancer; Tumors associated with the Bcr-abl target, including: myelodysplastic syndrome, bone marrow and extramedullary proliferation, gastrointestinal stromal tumors, aggressive systemic masto
  • the compound of the formula (I), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure is at least one selected from the nasal cavity Administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, pleural administration, peritoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration Administration, administration of epidural, intrathecal, and intravenous administration to the subject.
  • Another aspect of the present disclosure provides a compound of formula (III):
  • A represents CH 2 or CO
  • B, X, Y, and Z are the same or different and each independently represents CH or N
  • R represents SH, S(O)-alkyl, or SO 2 -alkyl, piperazinyl
  • the compound of formula (III) is an intermediate compound used to prepare a compound of formula (I).
  • the compound of formula (III) is also any of the following structural formulae:
  • A represents CH 2 or CO
  • B, X, Y, Z are the same and each represents CH
  • R represents SH, S(O)-alkyl, SO 2 -alkyl, or Piperazinyl.
  • A represents CH 2 or CO
  • B, X, Y, and Z are the same and both represent CH
  • R represents SH.
  • A represents CH 2 or CO
  • B, X, Y, Z are the same and both represent CH
  • R represents S(O)-alkyl.
  • A represents CH 2 or CO
  • B, X, Y, Z are the same and both represent CH
  • R represents SO 2 -alkyl.
  • A represents CH 2 or CO
  • B, X, Y, and Z are the same and each represents CH
  • R represents a piperazinyl group.
  • the S(O)-alkyl group is S(O)-C 1-4 alkyl, such as S(O)-C 1-3 alkyl, S(O)-C 1-2 Alkyl, S(O)-C 2-4 alkyl or S(O)-C 2-3 alkyl.
  • the S(O)-alkyl group is S(O)-CH 3 , S(O)-ethyl, S(O)-propyl, S(O)-butyl, S ( O)-Isobutyl, S(O)-tert-butyl.
  • the SO 2 -alkyl group is SO 2 -C 1-4 alkyl, such as SO 2 -C 1-3 alkyl, SO 2 -C 1-2 alkyl, SO 2 -C 2 -4 alkyl or SO 2 -C 2-3 alkyl.
  • the SO 2 -alkyl group is SO 2 —CH 3 , SO 2 —ethyl, SO 2 —propyl, SO 2 —butyl, SO 2 —isobutyl, SO 2 —tert. base.
  • Another aspect of the present disclosure provides the compound of the formula (III) or a salt, an enantiomer, a stereoisomer, a solvate thereof, a polymorph thereof for use in the preparation of the formula (I) according to claim 1.
  • the use of the compound is not limited to the following compounds.
  • Another aspect of the present disclosure provides a compound of formula (IV):
  • A represents CH 2 or CO
  • B, X, Y, Z are the same or different and each independently represents CH or N, and R represents S, SO, SO 2 or piperazine subunit;
  • LIN is a linking group representing a W-alkylene group, wherein
  • the alkylene group is a linear or branched alkylene group optionally interrupted one or more times by one or more groups selected from the group consisting of O, CONH, NHCO, NH, alkynylene, and aene. a base, cycloalkylene, arylene, heterocyclylene, heteroarylene or any combination thereof, wherein the linear or branched alkylene group is optionally substituted with one or more substituents, And
  • W represents hydrogen, a leaving group, CHO, COOH or NH 2 , which is capable of covalently linking LIN of the compound of formula (IV) to a small molecule compound SMBP capable of binding to a protein;
  • the ring atom A represents CH 2 or CO
  • the ring atoms B, X, Y, Z are the same and both represent CH
  • R represents S, SO, SO 2 or Piperazine subunit.
  • the ring atom A represents CH 2 or CO
  • the ring atoms B, X, Y, Z are the same and both represent CH
  • R represents S.
  • the ring atom A represents CH 2 or CO
  • the ring atoms B, X, Y, Z are the same and both represent CH
  • R represents SO.
  • the ring atom A represents CH 2 or CO
  • the ring atoms B, X, Y, Z are the same and both represent CH
  • R represents SO 2
  • the ring atom A represents CH 2 or CO
  • the ring atoms B, X, Y, Z are the same and each represents CH
  • R represents a piperazine subunit.
  • Formula (IV) is also any one of the following structural formulas:
  • the formula (IV) is also the following structural formula:
  • the small molecule compound SMBP capable of binding proteins is a small molecule drug targeting a CDK4/6 small molecule drug, targeting an ALK target small molecule drug, targeting a Bcr-abl target, Small molecule drugs that target PARP targets, small molecule drugs that target ER targets, or small molecule drugs that target BET targets.
  • the small molecule compound SMBP capable of binding to a protein is: Rebizzini, Abemaciclib, Pabucillin, Crizotinib, Coloritinib, Buginib , erlotinib, essartinib, TAE684, ASP3026, GSK1838705A, AZD3463, AZD3463, imatinib, dasatinib, bosutinib, punatinib, olapaly, nilapali , rupacal, toremifene, tamoxifen, 4-hydroxytamoxifen, JQ-1, I-BET762 or derivatives thereof.
  • the SMBP is a compound represented by the following formula or structural formula:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 34 And R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 , R 61 , R 62 , R 63 , R 64 , R 65 , R 66 are each independently H or
  • the ring atom Q 1 is NH or CH, wherein CH is substituted by NH 2 or piperazinyl;
  • X 1 is Cl or H
  • Y 1 is H or OH
  • Z 1 is H or methyl
  • W 1 is H
  • X 1 is Cl or H
  • Y 1 is H or OH
  • Z 1 is H or methyl
  • W 1 is OH
  • the SMBP is a compound represented by the following structural formula:
  • the SMBP is a compound represented by the following structural formula:
  • the W represents COOH, NH 2 , N 3 , CHO, halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy.
  • the LIN represents:
  • N1, n2, n3, n4, n5, n6, m1, m2 each independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;
  • W is as defined above.
  • the LIN is preferably WC 1-30 alkylene-.
  • the LIN is preferably a W-methylene group or a WC 2-30 alkylene group, wherein the C 2-30 alkylene group is a linear or branched C 2-30 subunit.
  • Alkyl (preferably C 2 -C 29 alkylene chain, C 2 -C 28 alkylene chain, C 2 -C 27 alkylene chain, C 2 -C 26 alkylene chain, C 2 -C 25 Alkyl chain, C 2 -C 24 alkylene chain, C 2 -C 23 alkylene chain, C 2 -C 22 alkylene chain, C 2 -C 21 alkylene chain, C 2 -C 20 Alkyl chain, C 2 -C 19 alkylene chain, C 2 -C 18 alkylene chain, C 2 -C 17 alkylene chain, C 2 -C 16 alkylene chain, C 2 -C 15 Alkyl chain, C 2 -C 14 alkylene chain, C 2 -C 13 alkylene chain, C 2 -C 12 alkylene chain, C 2 -C 11 alkylene chain, C 2 -C 10 Alkyl chain, C 2 -C 9 alkylene chain, C 2 -C 8 alkylene chain, C 2 -C 7 al
  • the LIN preferably represents: W-CH 2 -; W-(CH 2 ) 2 -; W-(CH 2 ) 3 -; W-(CH 2 ) 4- (W-(CH 2 ) 5 -; W-(CH 2 ) 6 -; W-(CH 2 ) 7 -; W-(CH 2 ) 8 -; W-(CH 2 ) 9 -; W- (CH 2 ) 10 -; W-(CH 2 ) 11 -; W-(CH 2 ) 12 -; W-(CH 2 ) 13 -; W-(CH 2 ) 14 -; W-(CH 2 ) 15 -; W-(CH 2 ) 16 -; W-(CH 2 ) 17 -; W-(CH 2 ) 18 -; W-(CH 2 ) 19 -; W-(CH 2 ) 20 -; W-( CH 2 ) 21 -; W-(CH 2 ) 22 -;
  • the LIN is preferably WC 2-40 alkylene-(preferably WC 2-30 alkylene-), wherein the alkylene chain is optionally One or more O, CONH, NHCO, NH, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene or heteroarylene or any combination thereof interrupted one or more times, and W is as defined above.
  • the LIN preferably represents: W-CH 2 -O-(CH 2 ) 2 -, W-CH 2 -(O(CH 2 ) 2 ) 2 -, W-CH 2 -(O(CH 2 ) 2 ) 3 -, W-CH 2 -(O(CH 2 ) 2 ) 4 -, W-CH 2 -(O(CH 2 ) 2 ) 5 -, W- CH 2 -(O(CH 2 ) 2 ) 6 -, W-CH 2 -(O(CH 2 ) 2 ) 7 -, W-CH 2 -(O(CH 2 ) 2 ) 8 -, W-CH 2 -(O(CH 2 ) 2 ) 9 -, W-CH 2 -(O(CH 2 ) 2 ) 10 -, W-(CH 2 ) 2 -O-(CH 2 ) 2 -, W-(CH 2 -(O(CH 2 ) 2 ) 10 -, W-(CH 2 ) 2
  • the LIN is W-alkylene-, the alkylene group (preferably a C 1-30 alkylene chain, particularly preferably a C 2 -C 29 alkylene) Base chain, C 2 -C 28 alkylene chain, C 2 -C 27 alkylene chain, C 2 -C 26 alkylene chain, C 2 -C 25 alkylene chain, C 2 -C 24 alkylene Base chain, C 2 -C 23 alkylene chain, C 2 -C 22 alkylene chain, C 2 -C 21 alkylene chain, C 2 -C 20 alkylene chain, C 2 -C 19 alkylene Base chain, C 2 -C 18 alkylene chain, C 2 -C 17 alkylene chain, C 2 -C 16 alkylene chain, C 2 -C 15 alkylene chain, C 2 -C 14 alkylene Base chain, C 2 -C 13 alkylene chain, C 2 -C 12 alkylene chain, C 2 -C 11
  • the LIN is preferably WC 1-30 alkylene-, and the C 1-30 alkylene group is one or more selected from the group consisting of a hydroxyl group, an amino group, and a fluorenyl group.
  • a linear or branched C 1 -C 30 alkylene chain substituted with a substituent of a halogen or a combination thereof preferably a C 1 -C 29 alkylene chain, a C 1 -C 28 alkylene chain, C 1 - C 27 alkylene chain, C 1 -C 26 alkylene chain, C 1 -C 25 alkylene chain, C 1 -C 24 alkylene chain, C 1 -C 23 alkylene chain, C 1 - C 22 alkylene chain, C 1 -C 21 alkylene chain, C 1 -C 20 alkylene chain, C 1 -C 19 alkylene chain, C 1 -C 18 alkylene chain, C 1 - C 17 alkylene chain, C 1 -C 16 alkylene chain, C 1 -C 15 alkylene chain, C 1 -C 14 alkylene chain, C 1 -C 13 alkylene chain, C 1 - C 12 alkylene chain, C 1 -C 11 alkylene chain, C 1 -
  • the number of the substituents may be, for example, 1-30, 1-25, 1-20, or 1-15, 1-10, 1- 9,1-8,1-7,1-6,1-5,1-4,1-3, or 1-2, or 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1.
  • the LIN represents: W-(CH 2 ) n11 -triazolyl-(CH 2 ) n12 -, W-(CH 2 ) n11 -triazole -(CH 2 ) n12 -(O(CH 2 ) n13 ) m11 -, W-(CH 2 ) n11 -(O(CH 2 ) n12 ) m11 -O-(CH 2 ) n13 -triazolyl- (CH 2 ) n14 -(O(CH 2 ) n15 ) m12 -O-(CH 2 ) n16 -, W-(CH 2 ) n11 -triazolyl-(CH 2 ) n12 -(O(CH 2 ) N13 ) m11 -O-(CH 2 ) n14 - or W-(CH 2 ) n11 -(O(CH 2 ) n11 -(O(CH 2 ) n12
  • N11, n12, n13, n14, n15, n16, m11, m12 respectively represent 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 An integer of 17, 18, 19 or 20;
  • the LIN preferably represents: W-(CH 2 ) 3 -triazolyl-(CH 2 ) 5 -, W-(CH 2 ) 2 - sub-three Azyl-(CH 2 ) 5 -, W-CH 2 -triazolyl-(CH 2 ) 5 -, W-(CH 2 ) 2 -triazolyl-(CH 2 ) 4 -, W-( CH 2 ) 3 -i-triazolyl-(CH 2 ) 2 -O(CH 2 ) 2 -, W-(CH 2 ) 2 -triazolyl-(CH 2 ) 2 -O(CH 2 ) 2 - Or W-CH 2 -triazolyl-(CH 2 ) 2 -O(CH 2 ) 2 - wherein the group W is as defined above.
  • the LIN preferably represents:
  • the LIN preferably represents: W-CH 2 CONHCH 2 -, W-(CH 2 ) 2 CONH(CH 2 ) 2 -, W-(CH 2 ) 3 CONH(CH 2 ) 3 -, W-(CH 2 ) 3 CONH(CH 2 ) 4 -, W-(CH 2 ) 4 CONH(CH 2 ) 4 -, W-(CH 2 ) 5 CONH(CH 2 ) 5- , W-(CH 2 ) 6 CONH(CH 2 ) 7 -, W-(CH 2 ) 6 CONH(CH 2 ) 6 -, W-(CH 2 ) 7 CONH(CH 2 ) 7 -, W- (CH 2 ) 8 CONH(CH 2 ) 8 , W-(CH 2 ) 9 CONH(CH 2 ) 9 -, W-(CH 2 ) 10 CONH(CH 2 ) 10 -, W-(CH 2 ) 5
  • the LIN preferably represents: W-CH 2 NHCOCH 2 -, W-(CH 2 ) 2 NHCO(CH 2 ) 2 -, W-(CH 2 ) 3 NHCO(CH 2 ) 3 -, W-(CH 2 ) 3 NHCO(CH 2 ) 4 -, W-(CH 2 ) 4 NHCO(CH 2 ) 4 -, W-(CH 2 ) 5 NHCO(CH 2 ) 5 -, W-(CH 2 ) 6 NHCO(CH 2 ) 7 -, W-(CH 2 ) 6 NHCO(CH 2 ) 6 -, W-(CH 2 ) 7 NHCO(CH 2 ) 7 -, W- (CH 2 ) 8 NHCO(CH 2 ) 8 , W-(CH 2 ) 9 NHCO(CH 2 ) 9 -, W-(CH 2 ) 10 NHCO(CH 2 ) 10 -, W-(CH 2 ) 9 NHCO(CH 2 )
  • the LIN represents: W-(CH 2 ) 4 NHCOCH 2 -, W-(CH 2 ) 2 -O-CH 2 -phenylene-CH 2 - O-(CH 2 ) 2 -, W-CH 2 -phenylene-CH 2 -, W-(CH 2 ) 3 -phenylene-(CH 2 ) 3 -, W-(CH 2 ) 2 -O -CH 2 -piperazinyl-CH 2 -O-(CH 2 ) 2 -, or W-(CH 2 ) 3 -ipiperazinyl-(CH 2 ) 3 -.
  • the LIN of the compound of the above formula (I) is represented by -U-alkylene-, wherein the -U-alkylene-alkylene group is attached to the SMBP, and the group U is attached.
  • the corresponding group LIN in the corresponding compound of the formula (IV) as an intermediate correspondingly represents an alkyl group -W 2 -, the group W 2 corresponding to the group U and linked a group R in (IV), wherein the alkyl group corresponds to a monovalent group of an alkylene group in the -U-alkylene group, which has a corresponding monovalent group of the alkylene group a definition, that is, a straight or branched alkyl group optionally interrupted one or more times by one or more groups selected from the group consisting of O, CONH, NHCO, NH, alkynylene, alkenylene, sub a cycloalkyl, arylene, heterocyclylene, heteroarylene
  • W 2 corresponds to the group U, indicating CO or NH, or W 2 is absent.
  • the LIN in the compound of the formula (IV) represents an alkyl-W 2 -
  • the group W 2 is bonded to the group R in the formula (IV)
  • the alkyl group can be passed Conventional methods well known to those skilled in the art are linked to the aforementioned small molecule compound SMBP capable of binding to a protein.
  • Another aspect of the present disclosure provides the compound of the formula (IV) or a salt, an enantiomer, a stereoisomer, a solvate thereof, a polymorph thereof for use in the preparation of the formula (I) according to claim 1.
  • the use of the compound is not limited to the following compounds.
  • Another aspect of the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (IV), or a pharmaceutically acceptable salt thereof, as described in the present disclosure, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present disclosure further includes at least one additional drug for treating or preventing cancer.
  • the compound of formula (IV), or a pharmaceutically acceptable salt thereof, of the present disclosure is for use as a medicament.
  • a compound of formula (IV), or a pharmaceutically acceptable salt thereof, of the present disclosure for use in the prevention and/or treatment of cancer.
  • the cancer is selected from the group consisting of: multiple myeloma, myelodysplastic syndrome (MDS), previously treated myelodysplastic syndrome, plasma cell myeloma, transplant-related cancer, myelofibrosis, plasma Cell myeloma, bone marrow disease, neutropenia; leukemia, acute myeloid leukemia, anemia, chronic myeloid leukemia, B-cell chronic lymphocytic leukemia, acute myeloid leukemia (AML), CD20-positive, primary lymphoma , B-cell lymphoma, recurrent B-cell non-Hodgkin's lymphoma, recurrent diffuse large B-cell lymphoma, recurrent primary mediastinal (thymus) large B-cell, recurrent transformed non-Hodgkin
  • the compound of formula (IV), or a pharmaceutically acceptable salt thereof, of the present disclosure is for use in the preparation of a medicament for preventing and/or treating cancer.
  • the cancer is selected from the group consisting of: multiple myeloma, myelodysplastic syndrome (MDS), previously treated myelodysplastic syndrome, plasma cell myeloma, transplant-related cancer, myelofibrosis, Plasma cell myeloma, bone marrow disease, neutropenia; leukemia, acute myeloid leukemia, anemia, chronic myeloid leukemia, B cell chronic lymphocytic leukemia, acute myeloid leukemia (AML), CD20 positive, primary lymphoid Tumor, B-cell lymphoma, recurrent B-cell non-Hodgkin's lymphoma, recurrent diffuse large B-cell lymphoma, recurrent primary mediastinal (thymus) large B-cell
  • MDS myelodysplastic syndrome
  • cancer is selected from the group consisting of: multiple myeloma, myelodysplastic syndrome (MDS), previously treated myelodysplastic syndrome, plasma cell myeloma, transplant-related cancer, myelofibrosis, plasma Cell myeloma, bone marrow disease, neutropenia; leukemia, acute myeloid leukemia, anemia, chronic myeloid leukemia, B-cell chronic lymphocytic leukemia, acute myeloid leukemia (AML), CD20-positive, primary lymphoma , B-cell lymphoma, recurrent B-cell non-Hodgkin's lymphoma, recurrent diffuse large B-cell lymphoma, recurrent primary mediastinal (thy
  • the compound of the formula (IV), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure is at least one selected from the nasal cavity Administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, pleural administration, peritoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration Administration, administration of epidural, intrathecal, and intravenous administration to the subject.
  • the compound of the formula (I) of the present disclosure is also referred to as a degradation agent, a protein degradation targeting drug PROTAD, or a PROTAD small molecule (PROTAD compound), and these names are used interchangeably.
  • Both are piperazines of Abemaciclib to remove the ethyl-derived structure on nitrogen, wherein R 5 , R 6 , R 7 and R 8 are each independently H or methyl.
  • Both are piperazine-derived structures of Palbociclib, wherein R 9 , R 10 , R 11 and R 12 are each independently H or methyl.
  • Each is a piperidine-derived structure of crizotinib wherein R 13 , R 14 , R 15 and R 16 are each independently H or methyl.
  • Each is a piperidine-derived structure of Ceritinib wherein R 17 , R 18 , R 19 and R 20 are each independently H or methyl.
  • Both are derivatized structures derived from the piperidine-piperazinyl group of Brigatinib, wherein R 21 , R 22 , R 23 , R 24 are each independently H or methyl, and the ring atom Q is N or CH, wherein CH is attached to the group LIN via NH or a piperazine subunit, or the ring atom Q is CH, wherein CH is attached to the group LIN through N(CH 3 ), and the ring atom Q 1 is NH or CH, Wherein CH is substituted by NH 2 or piperazinyl.
  • Both are structures derived from the modification of the piperidine-morpholinyl group of Alectinib, wherein R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 34.
  • R 35 , R 36 , R 37 , R 38 , R 39 , R 40 and R 41 are each independently H or methyl, and R 33 represents H, methyl or ethyl.
  • Both are the structures obtained by the piperazine of Imatinib to remove the methyl group on the nitrogen, wherein R 50 , R 51 , R 52 and R 53 are each independently H or methyl.
  • Both are the structures obtained by the piperazine of dasatinib to remove the ethanol group on the nitrogen, wherein R 54 , R 55 , R 56 and R 57 are each independently H or methyl.
  • Both are piperazines of Bosutinib which remove the methyl-derived structure on nitrogen, wherein R 58 , R 59 , R 60 and R 61 are each independently H or methyl.
  • Both are the structures obtained by the piperazine of punatinib to remove the methyl group on the nitrogen, wherein R 62 , R 63 , R 64 and R 65 are each independently H or methyl.
  • Both are the structures obtained by the piperazine of Olaparib to remove the cyclopropanyl group on the nitrogen.
  • Both are structures derived from piperidine derived from Niraparib.
  • Rucaparib also known as Rikapab
  • R 66 is H or methyl
  • Formula (Is) or (Is1) represents a derivative of toremifene or a fraction thereof, X 1 is Cl, Y 1 is H, Z 1 is H or methyl, and W 1 is H;
  • Formula (Is) or (Is1) represents a derivative of 4-hydroxytoramifene or a fraction thereof, X 1 is Cl, Y 1 is OH, Z 1 is H or methyl, and W 1 is H;
  • Both are structures derived from the hydrolysis product of JQ-1 tert-butyl ester.
  • Both are structures obtained by removing nitrogen ethyl groups from I-BET762.
  • Both are TAE684 to remove the structure derived from methylation of piperazine.
  • Both are ASP3026 to remove the structure derived from methylation of piperazine.
  • Both are GSK1838705A to remove the methyl-derived structure on dimethylamine, wherein R 67 is H, methyl or ethyl.
  • Both are structures derived from AZD3463 primary amines.
  • the bond broken by the wavy line shows the point at which the depicted group is attached to other portions of the molecule.
  • the portion of the compound representing the formula (II) is attached to the SMBP moiety of the compound of formula (I) via a linking group LIN.
  • the ULM in the compound of the formula (I) represents a monovalent group obtained by removing one hydrogen from the R group of the structure of the following formula (III):
  • A represents -CH 2 - or -CO-
  • B, X, Y, Z are the same or different and each independently represents -CH 2 - or -N-
  • R represents -SH, -S(O)-alkyl ( Preference is given to -S(O)-CH 3 ), -SO 2 -alkyl (preferably -SO 2 -CH 3 ) or piperazinyl.
  • LIN and “linker” are used interchangeably and each refer to a linking group or linking unit in a compound of Formula I.
  • halogen atom or halogen, used alone or in combination, means fluorine, chlorine, bromine or iodine, and is preferably F, Cl or Br.
  • alkyl used alone or in combination, refers to a straight or branched alkyl group.
  • C x -C y alkyl (x and y each being an integer) refers to a straight or branched alkyl group containing from x to y carbon atoms.
  • C 1-10 alkyl as used in the present disclosure, alone or in combination, means a straight or branched alkyl group having 1 to 10 carbon atoms.
  • the C 1-10 alkyl group of the present disclosure is preferably a C 1 - 9 alkyl group, more preferably a C 1-8 alkyl group, still more preferably a C 2-8 alkyl group, more preferably a C 1-7 alkyl group, or even More preferably, it is a C 1-6 alkyl group, a C 1-5 alkyl group, or a C 1-4 alkyl group.
  • C 1-3 alkyl refers to an alkyl group having 1 to 3 carbon atoms, and representative examples thereof include a methyl group, an ethyl group, a n-propyl group, and an isopropyl group.
  • alkyl group is optionally substituted, and the substituent is preferably one or more selected from the group consisting of halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, and three. a substituent of a fluoromethyl group, a heterocyclic group or a combination thereof.
  • alkylene (which is used interchangeably with “alkylene chain”), alone or in combination, refers to a straight or branched divalent saturated hydrocarbon group consisting of carbon and hydrogen atoms.
  • Cx- Cy alkylene (x and y each being an integer) refers to a straight or branched alkylene group containing from x to y carbon atoms.
  • the C 1 -C 30 alkylene group of the present disclosure is preferably a C 1 -C 29 alkylene group, a C 1 -C 28 alkylene group, a C 1 -C 27 alkylene group, a C 1 -C 26 alkylene group, C 1 -C 25 alkylene, C 1 -C 24 alkylene, C 1 -C 23 alkylene, C 1 -C 22 alkylene, C 1 -C 21 alkylene, C 1 -C 20 Alkyl, C 1 -C 19 alkylene, C 1 -C 18 alkylene, C 1 -C 17 alkylene, C 1 -C 16 alkylene, C 1 -C 15 alkylene, C 1 -C 14 alkylene, C 1 -C 13 alkylene, C 1 -C 12 alkylene, C 1 -C 11 alkylene, C 1 -C 10 alkylene, C 1 -C 9 alkylene , C 1 -C 8 alkylene, C 1
  • Representative examples include, but are not limited to, methylene, ethylene, propylene, isopropylidene, butylene, isobutylene, sec-butyl, tert-butyl, pentylene, isoamyl , nalopentyl, atpentylene, hexylene, heptylene, octylene, fluorenylene, fluorenylene, undecylene, dodecylene, decylene, ya Tetraalkyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, undecylene, decylene, arsenyl, sub-twenty Dialkyl, tetracosyl, tetracosyl, halopentadecyl, dihexadecyl, heptacosyl, septylene, sub-nine Alkyl, and tridecy
  • the "alkylene group” is optionally substituted, and the substituent is preferably one or more selected from the group consisting of a hydroxyl group, an amino group, a thiol group, a halogen group, a cyano group, a C 1-3 alkyl group, and a C 1 group. a substituent of -3 alkoxy, trifluoromethyl, heterocyclic or a combination thereof.
  • arylene refers to a divalent aromatic hydrocarbon group containing from 5 to 14 carbon atoms and optionally one or more fused rings, such as phenylene or sub. Naphthyl or anthracenylene.
  • the "arylene” is an optionally substituted arylene.
  • the substituted arylene group means an arylene group substituted by a substituent 1-3 times, wherein the substituent is selected from a C 1-3 alkyl group, a C 1-3 alkoxy group, a trifluoromethyl group, a decyl group, and a cyano group. , halogen, amino or hydroxyl.
  • C 1-3 alkoxy used alone or in combination means a straight or branched alkoxy group having 1 to 3 carbon atoms.
  • Representative examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy. Preferred are methoxy and ethoxy.
  • cycloalkyl used alone or in combination, refers to a single ring having from 3 to 12 carbon atoms saturated and partially unsaturated (ie having one or more double bonds, but not fully conjugated). Or a bicyclic cyclic hydrocarbon group.
  • C 3 -C 10 cycloalkyl means a monocyclic saturated and partially unsaturated having 3 to 10 carbon atoms (i.e., having one or more double bonds, but not fully conjugated) cyclic or bicyclic hydrocarbon.
  • cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decahydronaphthalene, octahydrogen And cyclopentadiene, octahydro-1H-indole, spiro group.
  • the "cycloalkyl” is optionally substituted, and the substituent is preferably one or more selected from the group consisting of trifluoromethyl, decyl, hydroxy, amino, halogen, cyano, C 1-3 a substituent of an alkyl group, a C 1-3 alkoxy group, a trifluoromethyl group, a heterocyclic group or a combination thereof.
  • cycloalkylene used alone or in combination, refers to a single having from 3 to 12 carbon atoms saturated and partially unsaturated (ie having one or more double bonds, but not fully conjugated).
  • a cyclic or bicyclic cyclic hydrocarbon divalent group used alone or in combination, refers to a single having from 3 to 12 carbon atoms saturated and partially unsaturated (ie having one or more double bonds, but not fully conjugated).
  • cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexylene, cycloheptylene, and subring Octyl, dedecalinyl, octahydrocyclopentadienyl subunit, octahydro-1H-fluorene subunit, sirocyclo.
  • a cycloalkylene group can be unsubstituted or substituted according to well-defined definitions.
  • the substituted substituent of the "cycloalkylene” is preferably one or more selected from the group consisting of halogen, fluorenyl, hydroxy, amino, cyano, C 1-3 alkyl, C 1-3 alkane. a substituent of an oxy group, a trifluoromethyl group, a heterocyclic group or a combination thereof.
  • heteroarylene used alone or in combination means having one or more (for example, 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3).
  • heteroarylene groups include, but are not limited to, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienylene, thiazolyl, isoisothiazolyl, A thiadiazole group, a pyridostylene group, an imidazolyl group, a pyrazolyl group, a tributazolyl group, a pyridylene group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, an anthranylene group, a pyridinium group Sulfhydryl, benzofuranyl, isophthalonitrile, benzothiophenyl, carbazolyl, benzimidazolyl, benzoxazolyl, benzoxisoxazolyl, phenylene Thiazolyl, benzotrithiazolyl, benzotriazolyl, benzo[2,1,3]
  • the heteroarylene group may be unsubstituted or substituted according to well-defined definitions.
  • the substituted heteroarylene group means a heteroarylene group which is substituted 1-3 times with a substituent, wherein the substituent is preferably selected from a C 1-3 alkyl group, a C 1-3 alkoxy group, a cyano group, a trifluoromethyl group.
  • heterocyclylene used alone or in combination, refers to a divalent single of 4- to 6-membered saturated or partially unsaturated (ie, having one or more double bonds but not fully conjugated).
  • a cyclic group comprising one or more heteroatoms independently selected from the group consisting of sulfur, oxygen and nitrogen.
  • heterocyclylene examples include, but are not limited to, sulfabutyl, oxetylene, pyrrolidinyl, imidazolidinyl, pyridazolidinyl, arazolyl, arylene Tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidine, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and Dioxolyl.
  • the heterocyclylene group can be unsubstituted or substituted as defined.
  • the substituent of the substituted heterocyclylene is preferably one or more selected from the group consisting of C 1-3 alkyl, C 1-3 alkoxy, cyano, trifluoromethyl, heterocyclic, halogen, amino or hydroxy. Substituent.
  • alkynylene used alone or in combination, means having from 2 to 10 (preferably from 2 to 6, more preferably from 2 to 4) carbon atoms having one or more carbon-carbon triple bonds.
  • preferred alkynylene groups include, but are not limited to, ethynylene, 1-propynylene, 1-butynylene, and 1,3-diacetylene.
  • alkenylene used alone or in combination, means 2 to 10 (preferably 2 to 6, more preferably 2 to 4) carbon atoms having one or more carbon-carbon double bonds.
  • the term "leaving group”, used alone or in combination, is a term well known to those skilled in the art, which may also be referred to as a leaving group, in a chemical reaction from a reactant. Carrying a pair of electron-off molecular fragments (ionic or neutral molecules) is a term used in nucleophilic substitution reactions and elimination reactions. Common ionic leaving groups are Cl - , Br - , I - and sulfonates (such as p-toluenesulfonate, TsO - ), and the neutral molecular leaving groups are water, ammonia and alcohol.
  • an appropriate leaving group for example, but not limited to -N 3, a halogen, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy Wait.
  • Salts or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs of the compounds of formula I described herein are also encompassed within the scope of the disclosure.
  • the salt or pharmaceutically acceptable salt of the compound of Formula I refers to a non-toxic inorganic or organic acid and/or base addition salt.
  • examples include: sulfates, hydrochlorides, citrates, maleates, sulfonates, or p-toluenesulfonates, and the like.
  • Salts or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs of the compounds of formula IV of the present disclosure are also encompassed within the scope of the present disclosure.
  • the salt or pharmaceutically acceptable salt of the compound of Formula IV refers to a non-toxic inorganic or organic acid and/or base addition salt.
  • examples include: sulfates, hydrochlorides, citrates, maleates, sulfonates, or p-toluenesulfonates, and the like.
  • “Pharmaceutically acceptable carrier” means a pharmaceutically acceptable material such as a filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, A useful compound is carried or transported into a patient or administered to a patient such that it can perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another organ or part of the body.
  • the carrier is compatible with the other ingredients of the formulation, including the compounds useful in the present disclosure, and is not deleterious to the patient, and the carrier must be "acceptable.”
  • materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, B Cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil And soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide And aluminum hydroxide;
  • treating refers to administering to a subject a compound of formula I or a compound of formula IV, or a pharmaceutically acceptable salt thereof, according to the invention, or a compound of formula I or a compound of formula IV or A pharmaceutical composition of a pharmaceutically acceptable salt to slow (reduce) the development of an undesired disease or condition, such as cancer or tumor.
  • beneficial or desirable clinical outcomes of the invention include, but are not limited to, alleviating symptoms, reducing the severity of the disease, stabilizing the condition of the disease, delaying or delaying progression of the disease, ameliorating or palliating the condition, and alleviating the disease.
  • the "therapeutically effective amount" of a compound of the present disclosure depends on the age, sex and weight of the patient, the current medical condition of the patient, and the cancer progression of the patient being treated. Those skilled in the art will be able to determine appropriate dosages based on these and other factors.
  • room temperature refers to ambient temperature, such as a temperature of 20-30 °C.
  • the compound developed by the present disclosure belongs to a specific protein-targeting degradation agent, which is composed of three parts: SMLP (Small Molecules Binding Protein), E3 ligase ligand with ubiquitination function. And link unit (linker or LIN).
  • SMLP Small Molecules Binding Protein
  • E3 ligase ligand with ubiquitination function and link unit (linker or LIN).
  • link unit link unit
  • the present disclosure selects a small molecule compound (SMBP) capable of binding a protein as an anchoring element, and a specific protein-targeting degradation agent is developed by binding an E3 ligase ligand to the SMBP via a linker.
  • SMBP small molecule compound
  • E3 ligase specifically ubiquitinates the target protein to achieve degradation and elimination of the target protein, and finally the target protein can be removed from the tumor cell.
  • the compounds of the present disclosure not only inhibit tumorigenesis and progression, but also potentially overcome the production of targeted drug resistance.
  • the novel structure of the E3 ligase ligand designed and developed by the present disclosure has been successfully applied to a specific protein-targeting degradation agent, and provides a new therapeutic strategy for tumor patients in the context of precision medicine.
  • Solvents and reagents are processed as follows:
  • the selected target protein inhibitor SMBP is: demethylated imatinib, palbociclib, Abemaciclib derivative, Ribocicib, Rucaparib , Alectinib derivative A, Alectinib derivative B, Alectinib derivative C, delapnosyl Olaparib derivative, Niraparib, Toremifene derivative A, tamoxifen derivative A are purchased directly; dasatinib derivative (SIAIS151055), bosutinib derivative (SIAIS151151) , JQ-1 derivative A (SIAIS171018), JQ-1 derivative B (SIAIS213113), JQ-1 derivative C (SIAIS213130), Brigatinib derivative A (SIAIS1197135), Buginib derivative B (SIAIS 151101), Buginib Derivative C (SIAIS 164005), Ponatinib Derivative (SIAIS 151190B), toremifene Derivative B (SIAIS 208164) for laboratory use as described below Method synthesis.
  • Compound SIAIS 1204137 was prepared according to the method of Scheme 1 described above under suitable conditions as understood in the art, except that tert-butyl 2-(2-(p-toluenesulfonyloxy)ethoxy)acetate was used as the linker.
  • Compound SIAIS 1204147 was prepared according to the method of Scheme 1, under suitable conditions as understood in the art, except that 14-(p-toluenesulfonyloxy)-3,6,9,12-tetraoxa-10- was employed.
  • Compound SIAIS 1204149 was prepared according to the method of Scheme 1 described above under suitable conditions as understood in the art, except that 17-(p-toluenesulfonyloxy)-3,6,9,12,15-pentaoxy was employed.
  • the compound SIAIS 1213129 was prepared according to the method of Scheme 1 described above under suitable conditions as understood in the art, except that tert-butyl 2-(2-(p-toluenesulfonyloxy)ethoxy)acetate was used as the linker.
  • Compound SIAIS 1213135 was prepared according to the method of Scheme 1 described above under suitable conditions as understood in the art, except that 14-(p-toluenesulfonyloxy)-3,6,9,12-tetraoxa-10- was employed.
  • Tert-butyl tetraalkylate was used as the bromo substrate of the linker and the thiophenol substrate SIAIS171075 was used to obtain the target compound SIAIS1213135 (light yellow oil, 181 mg, yield 49%), 1 H NMR (500 MHz, CDCl 3 ) ⁇ 8.
  • Compound SIAIS 1213137 was prepared according to the method of Scheme 1 described above under suitable conditions as understood in the art, except that 17-(p-toluenesulfonyloxy)-3,6,9,12,15-pentaoxy was employed.
  • the tert-butyl heptadecanoate was used as the bromo substrate of the linker and the thiophenol substrate SIAIS171075 was used to obtain the target compound SIAIS1213137 (light yellow oil, 209 mg, yield 52%),
  • Step 1 Preparation of 2-(2,6-dioxopiperidin-3-yl)-4-mercaptoisoindoline-1,3-dione according to Scheme 2 (SIAIS 151014): Compound 2-(2, 6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (20 g, 72.4 mmol) was added to a 250 mL egg-shaped bottle followed by anhydrous N,N- Dimethylformamide (150 mL) was added with a solution of sodium sulphate (28 g, 108.6 mmol), and then stirred at room temperature for 6 h.
  • the filter cake was washed three times with water; then the filter cake was beaten with 100 mL of anhydrous acetone, suction filtered, and the filter cake was washed three times with acetone, and dried under reduced pressure to give intermediate compound (SIAIS151014) ( Off-white solid, 14 g, yield 67%).
  • Step 2 General method for preparing a sulfur-substituted pomamide amine carbon chain carboxylic acid series LIN-ULM from the compound SIAIS151014 according to Scheme 2
  • the intermediate compound SIAIS151014 (3.4 mmol, 1 equiv) was added to a 100 mL egg-shaped flask, followed by the addition of anhydrous N,N-dimethylformamide (10 mL) and anhydrous potassium carbonate (6.8 mmol, 2 equi).
  • the corresponding brominated substrate (4.1 mmol, 1.2 equiv) as a linker was slowly added dropwise, and the mixture was stirred at room temperature for 0.5 h.
  • Compound SIAIS 151045 was prepared according to the method of Scheme 2, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was tert-butyl 2-bromoacetate. The title compound SIAIS 151045 (light yellow solid, 0.69 g, yield 80%) was obtained.
  • Compound SIAIS 151139B was prepared according to the method of Scheme 2, under suitable conditions as understood in the art, except that the bromo substrate employed as the linker was tert-butyl 4-bromobutyrate. The title compound SIAIS 151139B (light yellow solid, 0.71 g, yield 82%) was obtained.
  • Compound SIAIS 151140B was prepared according to the method of Scheme 2, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was tert-butyl 5-bromopentanoate. The title compound SIAIS151140B (light yellow solid, 0.9 g, yield 74%) was obtained.
  • Compound SIAIS 151142B was prepared according to the method of Scheme 2, under suitable conditions as understood in the art, except that the bromo substrate employed as the linker was tert-butyl 7-bromoheptanoate. The title compound SIAIS 151142B (light yellow solid, 0.7 g, yield 80%) was obtained.
  • the compound SIAIS151014 (2.8 mmol, 1 equiv) was added to a 100 mL egg-shaped flask, followed by anhydrous N,N-dimethylformamide (20 mL) and anhydrous potassium carbonate (5.6 mmol, 2 equiv), stirring slowly at room temperature The corresponding bromine (3.4 mmol, 1.2 equiv) was added dropwise, and the mixture was stirred at room temperature for 1 h.
  • the obtained alkylation product was added to a 25 mL egg-shaped flask, followed by anhydrous dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL), and stirred at room temperature for 12 h.
  • the solvent was evaporated under reduced pressure.
  • Column separation, eluent (v/v): acetonitrile / (water + 0.05% TFA) 10% - 100%, the solvent was evaporated under reduced pressure and lyophilized to give the corresponding carbon chain amino series LIN-ULM.
  • Compound SIAIS171026 was prepared according to the method of Scheme 3, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was tert-butyl(2-bromoethyl)carbamate. .
  • the title compound SIAIS171026 (light yellow solid, 200 mg, yield 58%) was obtained.
  • Compound SIAIS 171025 was prepared according to the method of Scheme 3, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was tert-butyl(3-bromopropyl)carbamate. .
  • the title compound SIAIS171025 (light yellow solid, 300 mg, yield 77%) was obtained.
  • Compound SIAIS 171023 was prepared according to the method of Scheme 3, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was tert-butyl(4-bromobutyl)carbamate. .
  • the title compound SIAIS171023 (light yellow solid, 310 mg, yield: 79%) was obtained.
  • Compound SIAIS 171027 was prepared according to the method of Scheme 3, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was tert-butyl(5-bromopentyl)carbamate. .
  • the title compound SIAIS171027 (light yellow solid, 210 mg, yield 53%) was obtained.
  • Compound SIAIS 171028 was prepared according to the method of Scheme 3, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was tert-butyl(6-bromohexyl)carbamate. The title compound SIAIS171028 (light yellow solid, 330 mg, yield 83%) was obtained.
  • Compound SIAIS171033 was prepared according to the method of Scheme 3, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was tert-butyl(7-bromoheptyl)carbamate. .
  • the title compound SIAIS171033 (light yellow solid, 400 mg, yield 71%) was obtained.
  • Compound SIAIS 171047 was prepared according to the method of Scheme 3, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was tert-butyl (8-bromooctyl)carbamate. The title compound SIAIS 171047 (light yellow solid, 600 mg, yield 83%) was obtained.
  • Step 1 Preparation of 3-(4-(benzylthio)-1-oxoisoindol-2-yl)piperidine-2,6-dione (SIAIS 171088) according to Scheme 4:
  • Step 2 Preparation of 3-(4-mercapto-1-oxoisoindol-2-yl)piperidine-2,6-dione according to Scheme 4 (SIAIS 171095):
  • Step 3 General procedure for the preparation of a thiol-substituted lenalidomide carbon chain carboxylic acid series LIN-ULM from the compound SIAIS 171095 according to Scheme 4
  • Compound SIAIS 171090 was prepared according to the method of Scheme 4, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was tert-butyl 2-bromoacetate. The title compound SIAIS 171090 (white solid, 77 mg, mp.
  • Compound SIAIS 171086 was prepared according to the method of Scheme 4, under suitable conditions as understood in the art, except that the bromo substrate employed as the linker was tert-butyl 3-bromopropionate. The title compound SIAIS 171086 (white solid, 40 mg, step 3, total yield 32%) was obtained.
  • Compound SIAIS 171089 was prepared according to the method of Scheme 4, under suitable conditions as understood in the art, except that the bromo substrate employed as the linker was tert-butyl 4-bromobutyrate. The title compound SIAIS 171089 (white solid, 50 mg, step 3, total yield 38%) was obtained.
  • Compound SIAIS 171079 was prepared according to the method of Scheme 4, under suitable conditions as understood in the art, except that the bromo substrate employed as the linker was tert-butyl 5-bromopentanoate. The title compound SIAIS 171079 (white solid, 30 mg, step 3, total yield 22%) was obtained.
  • Compound SIAIS 171091 was prepared according to the method of Scheme 4, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was tert-butyl 6-bromohexanoate. The title compound SIAIS 171091 (white solid, 75 mg, step 3, total yield 53%) was obtained.
  • Compound SIAIS 171092 was prepared according to the method of Scheme 4, under suitable conditions as understood in the art, except that the bromo substrate employed as the linker was tert-butyl 7-bromoheptanoate. The title compound SIAIS 171092 (white solid, 79 mg, step 3, total yield 54%) was obtained.
  • Compound SIAIS 1220099 was prepared according to the method of Scheme 4, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was tert-butyl 11-bromoundecanoate. The title compound SIAIS1220099 (white solid, 593 mg, yield: 64%) was obtained.
  • Compound SIAIS 171123 was prepared according to the method of Scheme 5, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was tert-butyl(2-bromoethyl)carbamate. .
  • the title compound SIAIS 171123 (white solid, 68 mg, mp.
  • Compound SIAIS 171124 was prepared according to the method of Scheme 5, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was tert-butyl(3-bromopropyl)carbamate. .
  • the title compound SIAIS 171124 (white solid, 68 mg, mp.
  • Compound SIAIS 171131 was prepared according to the method of Scheme 5, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was tert-butyl(4-bromobutyl)carbamate. .
  • the title compound SIAIS 171131 (light yellow solid, 76 mg, two-step total yield 60%) was obtained.
  • Compound SIAIS 171132 was prepared according to the method of Scheme 5, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was tert-butyl(5-bromopentyl)carbamate. .
  • the title compound SIAIS 171132 yield as pale yellow solid, 95 mg, mp.
  • Compound SIAIS 171134 was prepared according to the method of Scheme 5, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was tert-butyl(6-bromohexyl)carbamate.
  • the title compound SIAIS 171134 yield as pale yellow solid, 78 mg, mp.
  • Compound SIAIS 171135 was prepared according to the method of Scheme 5, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was tert-butyl(7-bromoheptyl)carbamate. .
  • the title compound SIAIS 171135 (white solid, 100 mg, a two-step total yield of 71%) was obtained.
  • Compound SIAIS 171136 was prepared according to the method of Scheme 5, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was tert-butyl (8-bromooctyl)carbamate. .
  • the title compound SIAIS 171136 (white solid, 100 mg, two-step total yield 68%) was obtained.
  • Compound SIAIS 213096 was prepared according to the method of Scheme 6, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was (2-(2-bromoethoxy)ethyl). Tert-butyl carbamate. The title compound SIAIS 213096 (white solid, 41 mg, 62.4% yield) was obtained.
  • Compound SIAIS 213068 was prepared according to the method of Scheme 6, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was (2-(2-(2-bromoethoxy)). Ethyl ethoxy)ethyl)carbamic acid tert-butyl ester. The title compound SIAIS 213068 (yield as pale yellow solid, 120 mg, yield of 40.7% in two steps) was obtained.
  • the compound SIAIS213111 was prepared according to the method of Scheme 4, under suitable conditions as understood in the art, except that the brominated substrate used as the linker was (2-(2-(2-(2-bromo-B)). Oxy)ethoxy)ethoxy)ethyl)carbamic acid tert-butyl ester.
  • the title compound SIAIS 213111 (colorless oily liquid, 140 mg, a two-step yield of 85.6%) was obtained.
  • Compound SIAIS 213137 was prepared according to the method of Scheme 7, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was 1,2-dibromoethane.
  • the title compound SIAIS213137 (light yellow solid, 78 mg, yield 18.7%) was obtained.
  • Compound SIAIS 213132 was prepared according to the method of Scheme 7, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was 1,3-dibromopropane.
  • the title compound SIAIS213132 (light yellow solid, 130 mg, yield 30.1%) was obtained.
  • Compound SIAIS 213134 was prepared according to the method of Scheme 7, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was 1,4-dibromobutane.
  • the title compound SIAIS 213134 (light yellow solid, 170 mg, yield 38.1%) was obtained.
  • Compound SIAIS 213135 was prepared according to the method of Scheme 7, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was 1,5-dibromopentane.
  • the title compound SIAIS213135 (light yellow solid, 190 mg, yield 41.1%) was obtained.
  • SIAIS 1216133 was prepared according to the method of Scheme 7, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was 1,6-dibromohexane. The title compound SIAIS1216133 (white solid, 339 mg, yield 38%) was obtained.
  • Compound SIAIS 1216137 was prepared according to the method of Scheme 7, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was 1,8-dibromooctane. The title compound SIAIS1216137 (white solid, 351 mg, yield 38%) was obtained.
  • Compound SIAIS 1220059 was prepared according to the method of Scheme 7, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was 1,9-dibromodecane.
  • the title compound SIAIS1220059 (white solid, 400 mg, yield 42%) was obtained.
  • Compound SIAIS 1220013 was prepared according to the method of Scheme 7, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was 1,10-dibromodecane.
  • the title compound SIAIS1220013 (light yellow solid, 329 mg, yield 33%) was obtained.
  • Compound SIAIS 1220015 was prepared according to the method of Scheme 7, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was 1,11-dibromoundecane. The title compound SIAIS 1220015 (white solid, 276 mg, yield 27%) was obtained.
  • SIAIS 1220141 was prepared according to the method of Scheme 7, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was 1,11-dibromoundecane. The title compound SIAIS1220141 (light yellow solid, 247 mg, yield 27%) was obtained.
  • the bromo compound (1 equiv) was added to a 25 mL reaction flask, followed by anhydrous N,N-dimethylformamide (10 mL), and sodium azide (1.2 equiv) was slowly added with stirring at room temperature, and stirred at room temperature for 1 h. After the reaction of the starting material was completed, it was quenched with water and extracted with ethyl acetate. The organic phase was washed twice with water and brine, and dried over anhydrous sodium sulfate.
  • SIAIS 213163 was prepared according to the method of Scheme 9, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was SIAIS 213162.
  • Compound SIAIS 213161 was prepared according to the method of Scheme 9, under suitable conditions as understood in the art, except that the brominated substrate employed as the linker was SIAIS 213159.
  • the compound SIAIS151014 (0.69 mmol, 1 equiv) was added to a 25 mL reaction flask, followed by anhydrous N,N-dimethylformamide (6 mL) and anhydrous potassium carbonate (1.38 mmol, 2 equiv).
  • Compound SIAIS 213066 was prepared according to the method of Scheme 10, under suitable conditions as understood in the art, using the brominated substrate as a linker (2-(2-(2-bromoethoxy)ethoxy)) tert-Butyl ethyl carbamate gave the title compound SIAIS 213066 (light yellow solid, 120 mg, yield 41.3% in two steps).
  • SIAIS151144 or SIAIS171090 (1equiv), tert-butyl (4-aminobutyl)carbamate (1equiv), anhydrous N,N-dimethylformamide (2 mL), HATU (1.5) at room temperature.
  • Equiv DIPEA (3 equiv), stirred at room temperature overnight.
  • SIAIS 213073 was prepared according to the method of Scheme 11, under suitable conditions as understood in the art, except that the acid substrate employed was SIAIS 151144. The title compound SIAIS 213073 (yield as pale yellow solid, 45 mg, yield of 75.1% in two steps) was obtained.
  • SIAIS 213092 was prepared according to the method of Scheme 11, under suitable conditions as understood in the art, except that the acid substrate used was SIAIS 171090, which afforded the title compound SIAIS 213092 (light yellow solid, 60 mg, yield of two steps: 99. %).
  • Step 1 The compound (SIAIS 151033) (1.1 mmol, 1 equiv) was added to a 100 mL egg-shaped flask, followed by anhydrous dichloromethane (20 mL), and m-chloroperoxybenzoic acid (4.4 mmol, 4 equiv) was slowly added with stirring at room temperature. After the addition, slowly warmed to 40 ° C and stirred for 4 h.
  • SIAIS 151033 1.1 mmol, 1 equiv
  • Step 2 The compound of the sulfoxide or sulfone is added to a 25 mL egg-shaped bottle, followed by the addition of 88% formic acid (5 mL), and stirred at room temperature for 12 h.
  • the reaction solvent is evaporated under reduced pressure, and lyophilized with water to obtain a tert-butyl ester. Hydrolyzed product (SIAIS 151107; SIAIS 151106).
  • Compound SIAIS 151048B was prepared according to the method of Scheme 12, under suitable conditions as understood in the art, except that the bromo substrate employed as the linker was tert-butyl 2-bromoacetate. The title compound SIAIS151048B (light yellow solid, 0.2 g, yield 39%) was obtained.
  • Compound SIAIS 151048A was prepared according to the method of Scheme 12, under suitable conditions as understood in the art, except that the bromo substrate employed as the linker was tert-butyl 2-bromoacetate. The title compound SIAIS151048A (light yellow solid, 0.3 g, yield 59%) was obtained.
  • Compound SIAIS 151107 was prepared according to the method of Scheme 12, under suitable conditions as understood in the art, except that the bromo substrate employed as the linker was tert-butyl 2-bromoacetate. The title compound SIAIS 151107 (light yellow solid, 0.16 g, yield: 92%) was obtained.
  • Step 1 Preparation of tert-butyl 4-(3-methoxy-4-nitrophenyl) piperazine-1-carboxylate according to Scheme 14 (SIAIS 1197111):
  • Step 2 Preparation of tert-butyl 4-(4-amino-3-methoxyphenyl) piperazine-1-carboxylate according to Scheme 14 (SIAIS 1197129):

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Abstract

本公开涉及式(I)化合物及其抗肿瘤应用，和其中间体式(III)化合物、式(IV)化合物及其应用。式(I)化合物对特定靶蛋白具有降解作用，其主要由三部分组成，第一部分能够结合蛋白的小分子化合物(SMBP，Small Molecules Binding Protein)；第二部分LIN是链接单元(Linker)；第三部分ULM是具有泛素化功能的配体(ULM,Ubiquitin Ligase BindingMoiety)；其中SMBP和LIN共价结合，且LIN与ULM共价结合。本公开设计合成的一系列化合物具有广泛的药理活性，有降解特定蛋白和/或抑制活性的功能，可用于相关的肿瘤治疗。

Description

蛋白降解靶向化合物、其抗肿瘤应用、其中间体及中间体应用 技术领域
本公开涉及蛋白降解靶向化合物、其抗肿瘤应用、其中间体及中间体应用。
背景技术
蛋白降解靶向药物PROTAD(Proteolysis Targeting Drug)是一个三元复合体，第一部分为具有结合特定蛋白的小分子药物或者化合物构成；第二部分由不同长度的链接单元构成；第三部分为具有泛素化功能的E3连接酶配体组成。通过设计PROTAD小分子化合物可以靶向结合特定蛋白，并通过E3配体招募E3泛素化连接酶，使得靶蛋白和E3连接酶通过PROTAD小分子被连接起来，进而E3连接酶使得靶蛋白被泛素化进而在蛋白酶体的作用下使得靶蛋白被降解。
E3 Cereblon(CRBN)/Cullin4A泛素化连接酶配体是具有邻苯二甲酰亚胺骨架,即沙利度胺及其类似物泊马度胺和来那度胺。然而目前所公开发表的E3 CRBN配体采用沙利度胺、泊马度胺和来那度胺与链接单元通过碳氮键共价结合。到目前为止，未见报道和相关研究有沙利度胺、泊马度胺和来那度胺与链接单元通过碳硫键共价结合。因此，设计不同杂原子E3泛素化连接酶配体研究其同受体结合的能力以及作用强度有非常重要的意义，进而设计了全新的含有硫元素的E3泛素化连接酶配体并将其应用到PROTAD小分子药物。
基于以上原因，我们提出并设计了全新的含硫E3连接酶配体并将其应用到PROTAD小分子药物的设计当中。
发明概述
一方面，本公开提供一种式(I)化合物：
Figure PCTCN2019081840-appb-000001
或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中SMBP、LIN、ULM以及所有取代基如发明详述中所定义。
本公开还提供一种医药组合物，其包含所述的式(I)化合物或其医药学上可接受的盐，及至少一种医药学上可接受的载体。
本公开还提供一种所述的式(I)化合物，或其医药学上可接受的盐，其是用作药剂：
Figure PCTCN2019081840-appb-000002
本公开所述的式(I)化合物，或其医药学上可接受的盐，其用于预防及/或治疗癌症。
本公开还提供一种所述的式(I)化合物或其医药学上可接受的盐的用途，其是用于制备用以预防及/或治疗癌症的药剂。
本公开还提供一种治疗或预防癌症的方法，其包括向受试者施用治疗有效量的所述的式(I)化合物，或其医药学上可接受的盐，或所述的药物组合物。
另一方面，本公开提供式(III)化合物：
Figure PCTCN2019081840-appb-000003
或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中A、B、X、Y、Z以及R取代基如发明详述中所定义。
另一方面，本公开提供式(IV)化合物：
Figure PCTCN2019081840-appb-000004
或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中A、B、X、Y、Z、R、LIN以及所有取代基如发明详述中所定义。
本公开进一步提供式(III)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物用于制备如前所述的式(I)化合物的用途。
本公开进一步提供式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物用于制备如前所述的式(I)化合物的用途。
本公开进一步提供所述的式(IV)化合物，或其医药学上可接受的盐，其是用作药剂。
本公开进一步提供所述的式(IV)化合物，或其医药学上可接受的盐，其用于预防及/或治疗癌症。
本公开进一步提供一种所述的式(IV)化合物或其医药学上可接受的盐的用途，其是用于制备用以预防及/或治疗癌症的药剂。
本公开进一步提供一种治疗或预防癌症的方法，其包括向受试者施用治疗有效量的所述的式(IV)化合物，或其医药学上可接受的盐，或所述的药物组合物。
附图说明
图1-14显示了Western-blot检测本公开的全新设计的E3连接酶配体应用到了PROTAD系列化合物，相比于商品化母本抑制剂达沙替尼、伯舒替尼，本公开的PROTAD化合物可以有效降解BCR-ABL和c-ABL蛋白。
图15a和图15b显示了采用Western-blot检测本公开的全新设计的包含E3连接酶配体的PROTAD系列化合物，相比于碳氮键共价结合的PROTAD化合物(SIAIS151072)来说，本公开碳硫键共价结合的PROTAD化合物可以有效降解BCR-ABL和c-ABL蛋白，而碳氮键共价结合的PROTAD化合物降解BCR-ABL和c-ABL蛋白的能力明显更弱，进而说明碳硫键共价结合PROTAD化合物更具有优势。
图16a-c显示了采用Western-blot检测本公开的全新设计的包含E3连接酶配体的PROTAD系列化合物，相比于碳氮、碳氧键共价结合的PROTAD化合物(SIAIS213110、SIAIS271066)来说，本公开碳硫键共价结合的PROTAD化合物可以有效降解BRD2和BRD4蛋白，而碳氮键、碳氧键共价结合的PROTAD化合物降解BRD2和BRD4蛋白的能力明显更弱，进而说明碳硫键共价结合PROTAD化合物更具有优势。
具体实施方式
因此，本公开的一方面提供一种式(I)化合物：
Figure PCTCN2019081840-appb-000005
其中SMBP通过连接基团LIN共价连接ULM；
其中SMBP表示能够结合蛋白的小分子化合物或其衍生物；
LIN-ULM表示以下式(II)的化学结构：
Figure PCTCN2019081840-appb-000006
其中
环原子A表示CH 2或CO，环原子B、X、Y、Z相同或不同且分别独立地表示CH或N，R表示S、SO、SO 2或哌嗪亚基；以及
LIN是连接基团，表示-U-亚烷基-，其中
所述亚烷基是可选地被一或多个选自以下的基团中断一或多次的直链或支链的亚烷基：O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基、亚杂芳基或它们的任意组合，其中所述直链或支链的亚烷基可选地被一或多个取代基取代，且
基团U表示CO或NH，或基团U不存在；
或其盐、对映异构体、立体异构体、溶剂化物、多晶型物。
在本文中，LIN表示为-U-亚烷基-，其中该-U-亚烷基-的两端中的一端(例如基团U)可以连接至SMBP，而另一端(亚烷基)连接至ULM；或者该-U-亚烷基-的两端中的一端(例如亚烷基)可以连接至SMBP，而另一端(基团U)连接至ULM。
在本公开的一实施方式中，所述SMBP是靶向CDK4/6小分子药物、靶向ALK靶点小分子药物、靶向Bcr-abl靶点的小分子药物、靶向PARP靶点的小分子药物、靶向ER靶点的小分子药物或靶向BET靶点的小分子药物。
在本公开的一实施方式中，所述SMBP表示：
瑞博西尼、Abemaciclib、帕布昔利布、克唑替尼、色瑞替尼、布加替尼、艾乐替尼、爱沙替尼、TAE684、ASP3026、GSK1838705A、AZD3463、伊马替尼、达沙替尼、伯舒替尼、普纳替尼、奥拉帕利、尼拉帕利、芦卡帕利、托瑞米芬、他莫昔芬、4-羟基他莫昔芬、JQ-1、I-BET762或它们的衍生物。
在本公开的一实施方式中，所述SMBP表示由以下结构通式所表示的化合物部分：
Figure PCTCN2019081840-appb-000007
Figure PCTCN2019081840-appb-000008
Figure PCTCN2019081840-appb-000009
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30、R 31、R 32、R 34、R 35、R 36、R 37、R 38、R 39、R 40、R 41、R 42、R 43、R 44、R 45、R 50、R 51、R 52、R 53、R 54、R 55、R 56、R 57、R 58、R 59、R 60、R 61、R 62、R 63、R 64、R 65、R 66各自独立地为H或甲基，R 33和R 67各自独立地表示H、甲基或乙基；以及
其中在式(If)中，环原子Q是N或CH，其中CH进一步通过NH或哌嗪亚基连接至基团LIN；以及
其中在式(Is)中，X 1是Cl或H，Y 1是H或OH，Z 1是H或甲基，W 1是H；或在一实施方案中，X 1是Cl或H，Y 1是H或OH，Z 1是H或甲基，W 1是OH。
在本公开的一实施方式中，在式(Is)中，X 1是Cl，Y 1是H，Z 1是H或甲基，W 1是H。在本公开的一实施方式中，在式(Is)中，X 1是Cl，Y 1是OH，Z 1是H或甲基，W 1是H。在本公开的一实施方式中，在式(Is)中，X 1是H，Y 1是H，Z 1是H或甲基，W 1是H。在本公开的一实施方式中，在式(Is)中，X 1是H，Y 1是OH，Z 1是H或甲基，W 1是H。在本公开的一实施方式中，在式(Is)中，X 1是H，Y 1是OH，Z 1是H或甲基，W 1是OH。
在本公开的一实施方式中，在式(II)中，环原子A表示CH 2或CO，环原子B、X、Y、Z相同且均表示CH，以及R表示S、SO、SO 2或哌嗪亚基。在本公开的一子实施方式中，在式(II)中，环原子A表示CH 2或CO，环原子B、X、Y、Z相同且均表示CH，以及R表示S。在本公开的一子实施方式中，在式(II)中，环原子A表示CH 2或CO，环原子B、X、Y、Z相同且均表示CH，以及R表示SO。在本公开的一子实施方式中，在式(II)中，环原子A表示CH 2或CO，环原子B、X、Y、Z相同且均表示CH，以及R表示SO 2。在本公开的一子实施方式中，在式(II)中，环原子A表示CH 2或CO，环原子B、X、Y、Z相同且均表示CH，以及R表示哌嗪亚基。
在本公开的一实施方式中，式(II)亦为如下结构式：
Figure PCTCN2019081840-appb-000010
其中基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义。
在本公开的一实施方式中，式(II)亦为如下结构式：
Figure PCTCN2019081840-appb-000011
其中基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义。
在本公开的一实施方式中，式(II)亦为如下结构式：
Figure PCTCN2019081840-appb-000012
其中基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义。
在本公开的一实施方式中，式(II)亦为如下结构式：
Figure PCTCN2019081840-appb-000013
其中基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义。
在本公开的一实施方式中，式(II)亦为如下结构式：
Figure PCTCN2019081840-appb-000014
其中基团LIN、R、环原子A如在本文中所定义。
在本公开的一实施方式中，所述LIN表示：
-U-C 1-30亚烷基-，-U-(CH 2) n1-(O(CH 2) n2) m1-，-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，-U-(CR a1R a2) n1-(O(CR a3R a4) n2) m1-，-U-(CR a5R a6) n1-(O(CR a7R a8) n2) m1-(O(CR a9R a10) n3) m2-，-U-(CH 2) n1-(CONH-(CH 2) n2) m1-，-U-(CH 2) n1-(CONH-(CH 2) n2) m1-(O(CH 2) n3) m2-，-U-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-CONH-(CH 2) n4-(O(CH 2) n5) m2-O-(CH 2) n6-，-U-(CR a11R a12) n1-(O(CR a13R a14) n2) m1-O-(CR a15R a16) n3-CONH-(CR a17R a18) n4-(O(CR a19R a20) n5) m2-O-(CR a21R a22) n6-，-U-(CR a23R a24) n1-CONH-(O(CR a25R a26) n2) m1-，-U-(CH 2) n1-(NHCO-(CH 2) n2) m1-，-U-(CH 2) n1-(NHCO-(CH 2) n2) m1-(O(CH 2) n3) m2-，由一或多个亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次的直链或支链的-U-亚烷基链-，或其碳链被一或多个亚芳基或亚杂环基或亚杂芳基或它们的任意组合中断一或多次的-U-(CH 2) n1-(O(CH 2) n2) m1-；
R a1、R a2、R a3、R a4、R a5、R a6、R a7、R a8、R a9、R a10、R a11、R a12、R a13、R a14、R a15、R a16、R a17、R a18、R a19、R a20、R a21、R a22、R a23、R a24、R a25、R a26分别独立地表示H、直链或支链的C 1-C 10烷基或C 3-C 10环烷基，其中在相同的所述LIN中时，R a1、R a2、R a3、R a4，R a5、R a6、R a7、R a8、R a9、R a10，R a11、R a12、R a13、R a14、R a15、R a16、R a17、R a18、R a19、R a20、R a21、R a22，或R a23、R a24、R a25、R a26不同时为H；
n1、n2、n3、n4、n5、n6、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及
其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述LIN优选是-U-C 1-30亚烷基-。在本公开的一实施方式中，所述LIN优选是-U-亚甲基或-U-C 2-30亚烷基-，其中所述C 2-30亚烷基是直链或支链的C 2-30亚烷基(优选C 2-C 29亚烷基链，C 2-C 28亚烷基链，C 2-C 27亚烷基链，C 2-C 26亚烷基链，C 2-C 25亚烷基链，C 2-C 24亚烷基链，C 2-C 23亚烷基链，C 2-C 22亚烷基链，C 2-C 21亚烷基链，C 2-C 20亚烷基链，C 2-C 19亚烷基链，C 2-C 18亚烷基链，C 2-C 17亚烷基链，C 2-C 16亚烷基链，C 2-C 15亚烷基链，C 2-C 14亚烷基链，C 2-C 13亚烷基链，C 2-C 12亚烷基链，C 2-C 11亚烷基链，C 2-C 10亚烷基链，C 2-C 9亚烷基链，C 2-C 8亚烷基链，C 2-C 7亚烷基链，C 2-C 6亚烷基链，C 2-C 5亚烷基链，C 2-C 4亚烷基链，或C 2-C 3亚烷基链)，以及基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，优选地，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；
其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述LIN表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6- (O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；
其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述LIN是-U-亚烷基-，所述亚烷基(优选为C 1-30亚烷基链，尤其优选C 2-C 29亚烷基链，C 2-C 28亚烷基链，C 2-C 27亚烷基链，C 2-C 26亚烷基链，C 2-C 25亚烷基链，C 2-C 24亚烷基链，C 2-C 23亚烷基链，C 2-C 22亚烷基链，C 2-C 21亚烷基链，C 2-C 20亚烷基链，C 2-C 19亚烷基链，C 2-C 18亚烷基链，C 2-C 17亚烷基链，C 2-C 16亚烷基链，C 2-C 15亚烷基链，C 2-C 14亚烷基链，C 2-C 13亚烷基链，C 2-C 12亚烷基链，C 2-C 11亚烷基链，C 2-C 10亚烷基链，C 2-C 9亚烷基链，C 2-C 8亚烷基链，C 2-C 7亚烷基链，C 2-C 6亚烷基链，C 2-C 5亚烷基链，C 2-C 4亚烷基链，或C 2-C 3亚烷基链)是被一或多个取代基取代一或多次的直链或支链的亚烷基链，其中所述取代基选自羟基、氨基、巯基、卤素或其组合；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述LIN优选是-U-C 1-30亚烷基-，所述C 1-30亚烷基是由一或多个选自羟基、氨基、巯基、卤素或其组合的取代基取代的直链或支链的C 1-C 30亚烷基链(优选C 1-C 29亚烷基链，C 1-C 28亚烷基链，C 1-C 27亚烷基链，C 1-C 26亚烷基链，C 1-C 25亚烷基链，C 1-C 24亚烷基链，C 1-C 23亚烷基链，C 1-C 22亚烷基链，C 1-C 21亚烷基链，C 1-C 20亚烷基链，C 1-C 19亚烷基链，C 1-C 18亚烷基链，C 1-C 17亚烷基链，C 1-C 16亚烷基链，C 1-C 15亚烷基链，C 1-C 14亚烷基链，C 1-C 13亚烷基链，C 1-C 12亚烷基链，C 1-C 11亚烷基链，C 1-C 10亚烷基链，C 1-C 9亚烷基链，C 1-C 8亚烷基链，C 1-C 7亚烷基链，C 1-C 6亚烷基链，C 1-C 5亚烷基链，C 1-C 4亚烷基链，C 1-C 3亚烷基链，或C 1-C 2亚烷基链)，其中基团U表示CO或NH，或基团U不存在。在本公开的一子实施方式中，所述取代基的数目可以是例如1-30个，1-25个，1-20个，或者1-15，1-10，1-9，1-8，1-7，1-6，1-5，1-4，1-3，或1-2个，或是20、19、18、17、16、15、14、13、12、11、10、9、8、7、6、5、4、3、2、或1个。
在本公开的一实施方式中，所述LIN表示：
-U-(CH 2) n11-三唑基-(CH 2) n12-、-U-(CH 2) n11-三唑基-(CH 2) n12-(O(CH 2) n13) m11-、-U-(CH 2) n11-(O(CH 2) n12) m11-O-(CH 2) n13-三唑基-(CH 2) n14-(O(CH 2) n15) m12-O-(CH 2) n16-、-U-(CH 2) n11-三唑基-(CH 2) n12-(O(CH 2) n13) m11-O-(CH 2) n14-或-U-(CH 2) n11-(O(CH 2) n12) m11-O-(CH 2) n13-三唑基-(CH 2) n14-；
n11、n12、n13、n14、n15、n16、m11、m12分别独立地表示1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数；
其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述LIN优选表示：-U-(CH 2) 3-三唑基-(CH 2) 5-、-U-(CH 2) 2-三唑基-(CH 2) 5-、-U-CH 2-三唑基-(CH 2) 5-、-U-(CH 2) 2-三唑基-(CH 2) 4-、-U-(CH 2) 3-三唑基-(CH 2) 2-O(CH 2) 2-、-U-(CH 2) 2-三唑基-(CH 2) 2-O(CH 2) 2-或-U-CH 2-三唑基-(CH 2) 2-O(CH 2) 2-。
在本公开的一实施方式中，所述LIN优选表示：
Figure PCTCN2019081840-appb-000015
其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述LIN优选表示：
-U-CH 2CONHCH 2-、-U-(CH 2) 2CONH(CH 2) 2-、-U-(CH 2) 3CONH(CH 2) 3-、-U-(CH 2) 3CONH(CH 2) 4-、-U-(CH 2) 4CONH(CH 2) 4-、-U-(CH 2) 5CONH(CH 2) 5-、-U-(CH 2) 6CONH(CH 2) 7-、-U-(CH 2) 6CONH(CH 2) 6-、-U-(CH 2) 7CONH(CH 2) 7-、-U-(CH 2) 8CONH(CH 2) 8、-U-(CH 2) 9CONH(CH 2) 9-、-U-(CH 2) 10CONH(CH 2) 10-、-U-(CH 2) 2CONH(CH 2) 5-、-U-(CH 2) 2CONH(CH 2) 3-、-U-(CH 2) 2CONH(CH 2) 4-、或-U-(CH 2) 2CONH(CH 2) 2-O-(CH 2) 2-；
其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述LIN优选是-U-CH 2NHCOCH 2-、-U-(CH 2) 2NHCO(CH 2) 2-、-U-(CH 2) 3NHCO(CH 2) 3-、-U-(CH 2) 3NHCO(CH 2) 4-、-U-(CH 2) 4NHCO(CH 2) 4-、-U-(CH 2) 5NHCO(CH 2) 5-、-U-(CH 2) 6NHCO(CH 2) 7-、-U-(CH 2) 6NHCO(CH 2) 6-、-U-(CH 2) 7NHCO(CH 2) 7-、-U-(CH 2) 8NHCO(CH 2) 8、-U- (CH 2) 9NHCO(CH 2) 9-、-U-(CH 2) 10NHCO(CH 2) 10-、-U-(CH 2) 2NHCO(CH 2) 5-、-U-(CH 2) 2NHCO(CH 2) 3-、-U-(CH 2) 2NHCO(CH 2) 4-、-U-(CH 2) 4NHCO(CH 2) 8-或-U-(CH 2) 2NHCO(CH 2) 2-O-(CH 2) 2-；
其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ia-2)化合物：
Figure PCTCN2019081840-appb-000016
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义，以及基团R 1、R 2、R 3、R 4如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ia-3)化合物：
Figure PCTCN2019081840-appb-000017
其中，基团LIN、R、环原子A如在本文中所定义，以及基团R 1、R 2、R 3、R 4如在本文中所定义。
在本公开的式(Ia-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(Ia-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(Ia-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(Ia-3)化合物的一子实施方式中，所 述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(Ia-3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O- CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ib-2)化合物：
Figure PCTCN2019081840-appb-000018
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义，以及基团R 5、R 6、R 7、R 8如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ib-3)化合物：
Figure PCTCN2019081840-appb-000019
其中，基团LIN、R、环原子A如在本文中所定义，以及基团R 5、R 6、R 7、R 8如在本文中所定义。
在本公开的式(Ib-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(Ib-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(Ib-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(Ib-3)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、 15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(Ib-3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O- (CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ic-2)化合物：
Figure PCTCN2019081840-appb-000020
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义，以及基团R 9、R 10、R 11、R 12如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ic-3)化合物：
Figure PCTCN2019081840-appb-000021
其中，基团LIN、R、环原子A如在本文中所定义，以及基团R 9、R 10、R 11、R 12如在本文中所定义。
在本公开的式(Ic-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(Ic-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(Ic-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(Ic-3)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、 15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(Ic-3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O- (CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(Id-2)化合物：
Figure PCTCN2019081840-appb-000022
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义，以及基团R 13、R 14、R 15、R 16如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(Id-3)化合物：
Figure PCTCN2019081840-appb-000023
其中，基团LIN、R、环原子A如在本文中所定义，以及基团R 13、R 14、R 15、R 16如在本文中所定义。
在本公开的式(Id-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(Id-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(Id-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(Id-3)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、 15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(Id-3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O- (CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ie-2)化合物：
Figure PCTCN2019081840-appb-000024
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义，以及基团R 17、R 18、R 19、R 20如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ie-3)化合物：
Figure PCTCN2019081840-appb-000025
其中，基团LIN、R、环原子A如在本文中所定义，以及基团R 17、R 18、R 19、R 20如在本文中所定义。
在本公开的式(Ie-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(Ie-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(Ie-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(Ie-3)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、 15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(Ie-3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O- (CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(If-2)化合物：
Figure PCTCN2019081840-appb-000026
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义，以及环原子Q、基团R 21、R 22、R 23、R 24如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(If-2-1)化合物：
Figure PCTCN2019081840-appb-000027
其中，基团LIN、R、环原子A、基团R 21、R 22、R 23、R 24如在本文中所定义，以及环原子Q是N或CH，其中CH通过NH或哌嗪亚基连接至基团LIN。
在本公开的一实施方式中，所述式(I)化合物亦是式(If-2-2)化合物：
Figure PCTCN2019081840-appb-000028
其中，基团LIN、R、环原子A、基团R 21、R 22、R 23、R 24如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(If-2-3)化合物：
Figure PCTCN2019081840-appb-000029
其中，基团LIN、R、环原子A、基团R 21、R 22、R 23、R 24如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(If-2-4)化合物：
Figure PCTCN2019081840-appb-000030
其中，基团LIN、R、环原子A、基团R 21、R 22、R 23、R 24如在本文中所定义。
在本公开的式(If-2-1)、式(If-2-2)、式(If-2-3)、或式(If-2-4)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(If-2-1)、式(If-2-2)、式(If-2-3)、或式(If-2-4)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(If-2-1)、式(If-2-2)、式(If-2-3)、或式(If-2-4)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(If-2-1)、式(If-2-2)、式(If-2-3)、或式(If-2-4)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(If-2-1)、式(If-2-2)、式(If-2-3)、或式(If-2-4)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2- (O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(If-3)化合物：
Figure PCTCN2019081840-appb-000031
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义，以及基团R 21、R 22、R 23、R 24各自独立地为H或甲基，且环原子Q是CH，其中CH通过N(CH 3)连接至基团LIN。
在本公开的一实施方式中，所述式(I)化合物亦是式(If-3-1)化合物：
Figure PCTCN2019081840-appb-000032
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义，以及基团R 21、R 22、R 23、R 24各自独立地为H或甲基，且环原子Q是CH，其中CH通过N(CH 3)连接至基团LIN。
在本公开的一实施方式中，所述式(I)化合物亦是式(If-3-2)化合物：
Figure PCTCN2019081840-appb-000033
其中，基团LIN、R、环原子A如在本文中所定义，以及基团R 21、R 22、R 23、R 24各自独立地为H或甲基。
在本公开的式(If-3-1)或式(If-3-2)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(If-3-1)或式(If-3-2)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U- (CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(If-3-1)或式(If-3-2)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(If-3-1)或式(If-3-2)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(If-3-1)或式(If-3-2)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O- (CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ig-2)化合物：
Figure PCTCN2019081840-appb-000034
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义，以及基团R 25、R 26、R 27、R 28如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ig-3)化合物：
Figure PCTCN2019081840-appb-000035
其中，基团LIN、R、环原子A如在本文中所定义，以及基团R 25、R 26、R 27、R 28如在本文中所定义。
在本公开的式(Ig-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(Ig-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U- (CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(Ig-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(Ig-3)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(Ig-3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2- (O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ih-2)化合物：
Figure PCTCN2019081840-appb-000036
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义，以及基团R 29、R 30、R 31、R 32、R 33如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ih-3)化合物：
Figure PCTCN2019081840-appb-000037
其中，基团LIN、R、环原子A如在本文中所定义，以及基团R 29、R 30、R 31、R 32、R 33如在本文中所定义。
在本公开的式(Ih-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(Ih-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U- (CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(Ih-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(Ih-3)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(Ih-3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2- (O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ii-2)化合物：
Figure PCTCN2019081840-appb-000038
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义，以及基团R 34、R 35、R 36、R 37、R 38、R 39、R 40、R 41如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ii-3)化合物：
Figure PCTCN2019081840-appb-000039
其中，基团LIN、R、环原子A如在本文中所定义，以及基团R 34、R 35、R 36、R 37、R 38、R 39、R 40、R 41如在本文中所定义。
在本公开的式(Ii-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(Ii-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U- (CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(Ii-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(Ii-3)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(Ii-3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2- (O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ij-2)化合物：
Figure PCTCN2019081840-appb-000040
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义，以及基团R 42、R 43、R 44、R 45如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ij-3)化合物：
Figure PCTCN2019081840-appb-000041
其中，基团LIN、R、环原子A如在本文中所定义，以及基团R 42、R 43、R 44、R 45如在本文中所定义。
在本公开的式(Ij-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(Ij-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U- (CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(Ij-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(Ij-3)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(Ij-3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2- (O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(Il-2)化合物：
Figure PCTCN2019081840-appb-000042
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义，以及基团R 50、R 51、R 52、R 53如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(Il-3)化合物：
Figure PCTCN2019081840-appb-000043
其中，基团LIN、R、环原子A如在本文中所定义，以及基团R 50、R 51、R 52、R 53如在本文中所定义。
在本公开的式(Il-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(Il-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U- (CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(Il-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(Il-3)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(Il-3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2- (O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(Im-2)化合物：
Figure PCTCN2019081840-appb-000044
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义，以及基团R 54、R 55、R 56、R 57如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(Im-3)化合物：
Figure PCTCN2019081840-appb-000045
其中，基团LIN、R、环原子A如在本文中所定义，以及基团R 54、R 55、R 56、R 57如在本文中所定义。
在本公开的式(Im-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(Im-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U- (CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(Im-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(Im-3)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(Im-3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2- (O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(In-2)化合物：
Figure PCTCN2019081840-appb-000046
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义，以及基团R 58、R 59、R 60、R 61如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(In-3)化合物：
Figure PCTCN2019081840-appb-000047
其中，基团LIN、R、环原子A如在本文中所定义，以及基团R 58、R 59、R 60、R 61如在本文中所定义。
在本公开的式(In-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(In-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U- (CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(In-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(In-3)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(In-3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2- (O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(Io-2)化合物：
Figure PCTCN2019081840-appb-000048
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义，以及基团R 62、R 63、R 64、R 65如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(Io-3)化合物：
Figure PCTCN2019081840-appb-000049
其中，基团LIN、R、环原子A如在本文中所定义，以及基团R 62、R 63、R 64、R 65如在本文中所定义。
在本公开的式(Io-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(Io-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U- (CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(Io-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(Io-3)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(Io-3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2- (O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ip-2)化合物：
Figure PCTCN2019081840-appb-000050
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ip-3)化合物：
Figure PCTCN2019081840-appb-000051
其中，基团LIN、R、环原子A如在本文中所定义。
在本公开的式(Ip-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(Ip-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(Ip-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、 NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(Ip-3)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(Ip-3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3- (O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(Iq-2)化合物：
Figure PCTCN2019081840-appb-000052
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(Iq-3)化合物：
Figure PCTCN2019081840-appb-000053
其中，基团LIN、R、环原子A如在本文中所定义。
在本公开的式(Iq-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(Iq-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(Iq-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(Iq-3)化合物的一子实施方式中， 所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(Iq-3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O- CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ir-2)化合物：
Figure PCTCN2019081840-appb-000054
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义，以及基团R 66如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ir-3)化合物：
Figure PCTCN2019081840-appb-000055
其中，基团LIN、R、环原子A如在本文中所定义，以及基团R 66如在本文中所定义。
在本公开的式(Ir-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(Ir-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(Ir-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(Ir-3)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、 14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(Ir-3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O- (CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(Is-2)化合物：
Figure PCTCN2019081840-appb-000056
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义，以及基团X 1、Y 1、Z 1、W 1如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(Is-3)化合物：
Figure PCTCN2019081840-appb-000057
其中，基团LIN、R、环原子A如在本文中所定义，以及基团X 1、Y 1、Z 1、W 1如在本文中所定义。
在本公开的式(Is-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(Is-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(Is-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(Is-3)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(Is- 3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(It-2)化合物：
Figure PCTCN2019081840-appb-000058
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(It-2-1)化合物：
Figure PCTCN2019081840-appb-000059
其中，基团LIN、R、环原子A如在本文中所定义。
在本公开的式(It-2-1)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(It-2-1)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(It-2-1)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(It-2-1)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(It-2-1)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2- (O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(Iu-2)化合物：
Figure PCTCN2019081840-appb-000060
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(Iu-3)化合物：
Figure PCTCN2019081840-appb-000061
其中，基团LIN、R、环原子A如在本文中所定义。
在本公开的式(Iu-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(Iu-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(Iu-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(Iu-3)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(Iu-3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O- (CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(Iv-2)化合物：
Figure PCTCN2019081840-appb-000062
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(Iv-3)化合物：
Figure PCTCN2019081840-appb-000063
其中，基团LIN、R、环原子A如在本文中所定义。
在本公开的式(Iv-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(Iv-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(Iv-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(Iv-3)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(Iv-3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U- (CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(Iw-2)化合物：
Figure PCTCN2019081840-appb-000064
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(Iw-3)化合物：
Figure PCTCN2019081840-appb-000065
其中，基团LIN、R、环原子A如在本文中所定义。
在本公开的式(Iw-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(Iw-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(Iw-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(Iw-3)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(Iw-3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、- U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ix-2)化合物：
Figure PCTCN2019081840-appb-000066
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义，以及基团R 67如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(Ix-3)化合物：
Figure PCTCN2019081840-appb-000067
其中，基团LIN、R、环原子A如在本文中所定义，以及基团R 67如在本文中所定义。
在本公开的式(Ix-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(Ix-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(Ix-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(Ix-3)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(Ix-3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、- U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述式(I)化合物亦是式(Iy-2)化合物：
Figure PCTCN2019081840-appb-000068
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(Iy-3)化合物：
Figure PCTCN2019081840-appb-000069
其中，基团LIN、R、环原子A如在本文中所定义。
在本公开的式(Iy-3)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(Iy-3)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(Iy-3)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(Iy-3)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(Iy-3)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、- U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述SMBP表示由式(It-3)所表示的化学部分：
Figure PCTCN2019081840-appb-000070
在本公开的一实施方式中，所述式(I)化合物亦是式(It-3-1)化合物：
Figure PCTCN2019081840-appb-000071
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(It-3-2)化合物：
Figure PCTCN2019081840-appb-000072
其中，基团LIN、R、环原子A如在本文中所定义。
在本公开的式(It-3-2)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(It-3-2)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(It-3-2)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(It-3-2)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其 中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(It-3-2)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O- (CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述SMBP表示由式(It-4)所表示的化学部分：
Figure PCTCN2019081840-appb-000073
在本公开的一实施方式中，所述式(I)化合物亦是式(It-4-1)化合物：
Figure PCTCN2019081840-appb-000074
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(It-4-2)化合物：
Figure PCTCN2019081840-appb-000075
其中，基团LIN、R、环原子A如在本文中所定义。
在本公开的式(It-4-2)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(It-4-2)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(It-4-2)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、 NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(It-4-2)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(It-4-2)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3- (O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
在本公开的一实施方式中，所述SMBP表示由式(It-5)所表示的化学部分：
Figure PCTCN2019081840-appb-000076
在本公开的一实施方式中，所述式(I)化合物亦是式(It-5-1)化合物：
Figure PCTCN2019081840-appb-000077
其中，基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义。
在本公开的一实施方式中，所述式(I)化合物亦是式(It-5-2)化合物：
Figure PCTCN2019081840-appb-000078
其中，基团LIN、R、环原子A如在本文中所定义。
在本公开的式(It-5-2)化合物的一子实施方式中，所述LIN表示-U-C 1-30亚烷基-；以及基团U表示CO或NH，或基团U不存在。在式(It-5-2)化合物的一子实施方式中，所述LIN表示：-U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U- (CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-；其中基团U表示CO或NH，或基团U不存在。
在本公开的式(It-5-2)化合物的一子实施方式中，所述LIN优选是-U-C 2-40亚烷基-(优选-U-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及基团U表示CO或NH，或基团U不存在。在式(It-5-2)化合物的一子实施方式中，所述LIN优选表示：-U-(CH 2) n1-(O(CH 2) n2) m1-或-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，其中n1、n2、n3、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及其中基团U表示CO或NH，或基团U不存在。在式(It-5-2)化合物的一子实施方式中，所述LIN优选表示：-U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U-(CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2- (O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-；其中基团U表示CO或NH，或基团U不存在。
特别优选的是本公开表1中的以下式(I)化合物及其盐(尤其医药学上可接受的盐)：
表1 本公开式(I)化合物及其中文和英文名称
Figure PCTCN2019081840-appb-000079
Figure PCTCN2019081840-appb-000080
Figure PCTCN2019081840-appb-000081
Figure PCTCN2019081840-appb-000082
Figure PCTCN2019081840-appb-000083
Figure PCTCN2019081840-appb-000084
Figure PCTCN2019081840-appb-000085
Figure PCTCN2019081840-appb-000086
Figure PCTCN2019081840-appb-000087
Figure PCTCN2019081840-appb-000088
Figure PCTCN2019081840-appb-000089
Figure PCTCN2019081840-appb-000090
Figure PCTCN2019081840-appb-000091
Figure PCTCN2019081840-appb-000092
Figure PCTCN2019081840-appb-000093
Figure PCTCN2019081840-appb-000094
Figure PCTCN2019081840-appb-000095
Figure PCTCN2019081840-appb-000097
Figure PCTCN2019081840-appb-000098
Figure PCTCN2019081840-appb-000099
Figure PCTCN2019081840-appb-000100
Figure PCTCN2019081840-appb-000101
Figure PCTCN2019081840-appb-000102
Figure PCTCN2019081840-appb-000103
Figure PCTCN2019081840-appb-000104
Figure PCTCN2019081840-appb-000105
Figure PCTCN2019081840-appb-000106
Figure PCTCN2019081840-appb-000107
Figure PCTCN2019081840-appb-000108
Figure PCTCN2019081840-appb-000109
Figure PCTCN2019081840-appb-000110
Figure PCTCN2019081840-appb-000111
Figure PCTCN2019081840-appb-000112
Figure PCTCN2019081840-appb-000113
Figure PCTCN2019081840-appb-000114
Figure PCTCN2019081840-appb-000115
Figure PCTCN2019081840-appb-000116
Figure PCTCN2019081840-appb-000117
Figure PCTCN2019081840-appb-000118
Figure PCTCN2019081840-appb-000119
Figure PCTCN2019081840-appb-000120
Figure PCTCN2019081840-appb-000121
Figure PCTCN2019081840-appb-000122
Figure PCTCN2019081840-appb-000123
本公开的另一方面还提供一种医药组合物，其包含如本公开所述的式(I)化合物或其医药学上可接受的盐，及医药学上可接受的载体。
本公开所述的医药组合物，进一步包括至少一种额外的治疗或预防癌症的药物。
在本公开的另一方面，本公开所述的式(I)化合物，或其医药学上可接受的盐，其是用作药剂。
在本公开的另一方面，本公开所述的式(I)化合物，或其医药学上可接受的盐，其用于预防及/或治疗癌症。
在一实施方式中，所述癌症选自：与细胞周期蛋白依赖性激酶(CDK4/6)相关的肿瘤，包括：绝经妇女晚期乳腺癌,乳腺癌,晚期乳腺癌,转移性乳腺癌，中枢神经肿瘤；与间变性淋巴瘤激酶(ALK)相关的肿瘤，包括：非小细胞肺癌,ROS1阳性非小细胞肺癌，间变 性淋巴瘤激酶(ALK)阳性非小细胞肺癌,转移性非小细胞肺癌；与Bcr-abl靶点相关的肿瘤，包括：骨髓增生异常综合征,骨髓及外骨髓增殖,胃肠道间质瘤,侵略性系统性肥大细胞增多症,嗜酸性粒细胞增多症,隆凸性皮肤纤维肉瘤,慢性嗜酸性白血病,急性淋巴细胞白血病,慢性髓细胞性白血病；与聚腺苷二磷酸-核糖聚合酶(PARP)相关的肿瘤，包括：BRCA突变/HER-2阴性转移性乳腺癌,原发性腹膜癌,输卵管癌,上皮性卵巢癌,晚期卵巢癌,BRCA突变的晚期卵巢癌，胰腺癌，实体瘤；与雌激素受体(ER)相关的肿瘤，包括：乳腺癌，转移性乳腺癌；BET溴结构域(bromodomain and extra—terminal)蛋白(包含BRD2(溴结构域蛋白2)、BRD3(溴结构域蛋白3)、BRD4(溴结构域蛋白4)和BRDT靶蛋白)相关的肿瘤，包括：复发性胶质瘤,实体瘤，血液系统恶性肿瘤,乳腺癌。
在本公开的另一方面，本公开所述的式(I)化合物，或其医药学上可接受的盐，其是用于制备用以预防及/或治疗癌症的药剂。在一子实施方式中，所述癌症选自：与细胞周期蛋白依赖性激酶(CDK4/6)相关的肿瘤，包括：绝经妇女晚期乳腺癌,乳腺癌,晚期乳腺癌,转移性乳腺癌，中枢神经肿瘤；与间变性淋巴瘤激酶(ALK)相关的肿瘤，包括：非小细胞肺癌,ROS1阳性非小细胞肺癌，间变性淋巴瘤激酶(ALK)阳性非小细胞肺癌,转移性非小细胞肺癌；与Bcr-abl靶点相关的肿瘤，包括：骨髓增生异常综合征,骨髓及外骨髓增殖,胃肠道间质瘤,侵略性系统性肥大细胞增多症,嗜酸性粒细胞增多症,隆凸性皮肤纤维肉瘤,慢性嗜酸性白血病,急性淋巴细胞白血病,慢性髓细胞性白血病；与聚腺苷二磷酸-核糖聚合酶(PARP)相关的肿瘤，包括：BRCA突变/HER-2阴性转移性乳腺癌,原发性腹膜癌,输卵管癌,上皮性卵巢癌,晚期卵巢癌,BRCA突变的晚期卵巢癌，胰腺癌，实体瘤；与雌激素受体(ER)相关的肿瘤，包括：乳腺癌，转移性乳腺癌；BET溴结构域(bromodomain and extra—terminal)蛋白(包含BRD2(溴结构域蛋白2)、BRD3(溴结构域蛋白3)、BRD4(溴结构域蛋白4)和BRDT靶蛋白)相关的肿瘤，包括：复发性胶质瘤,实体瘤，血液系统恶性肿瘤,乳腺癌。
本公开的另一方面还提供治疗或预防癌症的方法，其包括向受试者施用治疗有效量的本公开所述的式(I)化合物，或其医药学上可接受的盐，或所述的药物组合物。在一实施方式中，所述癌症选自：与细胞周期蛋白依赖性激酶(CDK4/6)相关的肿瘤，包括：绝经妇女晚期乳腺癌,乳腺癌,晚期乳腺癌,转移性乳腺癌，中枢神经肿瘤；与间变性淋巴瘤激酶(ALK)相关的肿瘤，包括：非小细胞肺癌,ROS1阳性非小细胞肺癌，间变性淋巴瘤激酶(ALK)阳性非小细胞肺癌,转移性非小细胞肺癌；与Bcr-abl靶点相关的肿瘤，包括：骨髓增生异常综合征,骨髓及外骨髓增殖,胃肠道间质瘤,侵略性系统性肥大细胞增多症,嗜酸性粒细胞增多症,隆凸性皮肤纤维肉瘤,慢性嗜酸性白血病,急性淋巴细胞白血病,慢性髓细胞性白血病；与聚腺苷二磷酸-核糖聚合酶(PARP)相关的肿瘤，包括：BRCA突变/HER-2阴性转移性乳腺癌,原发性腹膜癌,输卵管癌,上皮性卵巢癌,晚期卵巢癌,BRCA突变的晚期卵巢癌，胰腺癌，实体瘤；与雌激素受体(ER)相关的肿瘤，包括：乳腺癌，转移性乳腺癌；BET溴结构域(bromodomain and extra—terminal)蛋白(包含BRD2(溴结构域蛋白2)、BRD3(溴结构 域蛋白3)、BRD4(溴结构域蛋白4)和BRDT靶蛋白)相关的肿瘤，包括：复发性胶质瘤,实体瘤，血液系统恶性肿瘤,乳腺癌。
在本公开所述的治疗或预防癌症的方法中，本公开所述的式(I)化合物，或其医药学上可接受的盐，或所述的药物组合物，通过至少一种选自鼻腔给药、吸入给药、局部给药、口服给药、口腔粘膜给药、直肠给药、胸膜腔给药、腹膜给药、阴道给药、肌内给药、皮下给药、经皮给药、硬膜外腔给药、鞘内给药和静脉给药的给药方式施用至所述受试者。
本公开的另一方面提供式(III)化合物：
Figure PCTCN2019081840-appb-000124
其中A表示CH 2或CO，B、X、Y、Z相同或不同且分别独立地表示CH或N，R表示SH、S(O)-烷基、或SO 2-烷基、哌嗪基；
或其盐、对映异构体、立体异构体、溶剂化物、多晶型物。
在本公开中，所述式(III)化合物是用于制备式(I)化合物的中间体化合物。
在本公开的一实施方式中，式(III)化合物亦是如下结构式中的任一个：
Figure PCTCN2019081840-appb-000125
其中基团R、环原子A、B、X、Y、Z如在本文中所定义。
在式(III)的一实施方式中，A表示CH 2或CO，B、X、Y、Z相同且均表示CH，R表示SH、S(O)-烷基、SO 2-烷基、或哌嗪基。
在式(III)的一子实施方式中，A表示CH 2或CO，B、X、Y、Z相同且均表示CH，R表示SH。在式(III)的一子实施方式中，A表示CH 2或CO，B、X、Y、Z相同且均表示CH，R表示S(O)-烷基。在式(III)的一子实施方式中，A表示CH 2或CO，B、X、Y、Z相同且均表示CH，R表示SO 2-烷基。在式(III)的一子实施方式中，A表示CH 2或CO，B、X、Y、Z相同且均表示CH，R表示哌嗪基。
在一实施方式中，所述S(O)-烷基是S(O)-C 1-4烷基，例如S(O)-C 1-3烷基、S(O)-C 1-2烷基、S(O)-C 2-4烷基或S(O)-C 2-3烷基。在一实施方式中，所述S(O)-烷基是S(O)-CH 3、S(O)-乙基、S(O)-丙基、S(O)-丁基、S(O)-异丁基、S(O)-叔丁基。
在一实施方式中，所述SO 2-烷基是SO 2-C 1-4烷基，例如SO 2-C 1-3烷基、SO 2-C 1-2烷基、SO 2-C 2-4烷基或SO 2-C 2-3烷基。在一实施方式中，所述SO 2-烷基是SO 2-CH 3、SO 2-乙基、SO 2-丙基、SO 2-丁基、SO 2-异丁基、SO 2-叔丁基。
特别优选的是本公开表2中的以下式(III)化合物及其盐：
表2 本公开式(III)化合物及其中英文名称
Figure PCTCN2019081840-appb-000126
本公开另一方面还提供所述式(III)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物用于制备如权利要求1所述的式(I)化合物的用途。
本公开的另一方面提供式(IV)化合物：
Figure PCTCN2019081840-appb-000127
其中A表示CH 2或CO，B、X、Y、Z相同或不同且分别独立地表示CH或N，R表示S、SO、SO 2或哌嗪亚基；
LIN是连接基团，表示W-亚烷基-，其中
所述亚烷基是可选地被一或多个选自以下的基团中断一或多次的直链或支链的亚烷基：O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基、亚杂芳基或它们的任意组合，其中所述直链或支链的亚烷基可选地被一或多个取代基取代，且
W表示氢、离去基团、CHO、COOH或NH 2，其能通过反应将式(IV)化合物的LIN共价连接至能够结合蛋白的小分子化合物SMBP；
或其盐、对映异构体、立体异构体、溶剂化物、多晶型物。
在本公开的一实施方式中，在式(IV)中，环原子A表示CH 2或CO，环原子B、X、Y、Z相同且均表示CH，以及R表示S、SO、SO 2或哌嗪亚基。在本公开的一子实施方式中，在式(IV)中，环原子A表示CH 2或CO，环原子B、X、Y、Z相同且均表示CH，以及R表示S。在本公开的一子实施方式中，在式(IV)中，环原子A表示CH 2或CO，环原子B、X、Y、Z相同且均表示CH，以及R表示SO。在本公开的一子实施方式中，在式(IV)中，环原子A表示CH 2或CO，环原子B、X、Y、Z相同且均表示CH，以及R表示SO 2。在本公开的一子实施方式中，在式(IV)中，环原子A表示CH 2或CO，环原子B、X、Y、Z相同且均表示CH，以及R表示哌嗪亚基。
在本公开的一实施方式中，式(IV)亦是以下结构式中的任一个：
Figure PCTCN2019081840-appb-000128
其中基团LIN、R、环原子A、B、X、Y、Z如在本文中所定义。
在本公开的一实施方式中，式(IV)亦是以下结构式：
Figure PCTCN2019081840-appb-000129
其中基团LIN、R、环原子A如在本文中所定义。
在本公开的一实施方式中，所述能够结合蛋白的小分子化合物SMBP是靶向CDK4/6小分子药物、靶向ALK靶点小分子药物、靶向Bcr-abl靶点的小分子药物、靶向PARP靶点的小分子药物、靶向ER靶点的小分子药物或靶向BET靶点的小分子药物。
在本公开的一实施方式中，优选地所述能够结合蛋白的小分子化合物SMBP是：瑞博西尼、Abemaciclib、帕布昔利布、克唑替尼、色瑞替尼、布加替尼、艾乐替尼、爱沙替尼、TAE684、ASP3026、GSK1838705A、AZD3463、AZD3463、伊马替尼、达沙替 尼、伯舒替尼、普纳替尼、奥拉帕利、尼拉帕利、芦卡帕利、托瑞米芬、他莫昔芬、4-羟基他莫昔芬、JQ-1、I-BET762或它们的衍生物。
在本公开的一实施方式中，所述SMBP是以下通式或结构式表示的化合物：
Figure PCTCN2019081840-appb-000130
Figure PCTCN2019081840-appb-000131
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30、R 31、R 32、R 34、R 35、R 36、R 37、R 38、R 39、R 40、R 41、R 42、R 43、R 44、R 45、R 50、R 51、R 52、R 53、R 54、R 55、R 56、R 57、R 58、R 59、R 60、R 61、R 62、R 63、R 64、R 65、R 66各自独立地为H或甲基，R 33和R 67各自独立地表示H、甲基或乙基；以及
其中在式(If1)中，环原子Q 1是NH或CH，其中CH被NH 2或哌嗪基取代；以及
其中在式(Is1)中，X 1是Cl或H，Y 1是H或OH，Z 1是H或甲基，且W 1是H；或者在一实施方案中，X 1是Cl或H，Y 1是H或OH，Z 1是H或甲基，且W 1是OH。
在本公开的一实施方式中，所述SMBP是以下结构式表示的化合物：
Figure PCTCN2019081840-appb-000132
在本公开的一实施方式中，所述SMBP是以下结构式表示的化合物：
Figure PCTCN2019081840-appb-000133
在本公开的一实施方式中，优选地，所述W表示COOH、NH 2、N 3、CHO、卤素、甲磺酰氧基、三氟甲磺酰氧基或对甲苯磺酰氧基。
在本公开的式(IV)的一实施方式中，优选地，所述LIN表示：
W-C 1-30亚烷基-、W-(CH 2) n1-(O(CH 2) n2) m1-、W-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-、W-(CR a1R a2) n1-(O(CR a3R a4) n2) m1-、W-(CR a5R a6) n1-(O(CR a7R a8) n2) m1-(O(CR a9R a10) n3) m2-、W-(CH 2) n1-(CONH-(CH 2) n2) m1-、W-(CH 2) n1-(CONH-(CH 2) n2) m1-(O(CH 2) n3) m2-、W-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-CONH-(CH 2) n4-(O(CH 2) n5) m2-O-(CH 2) n6-、W-(CR a11R a12) n1-(O(CR a13R a14) n2) m1-O-(CR a15R a16) n3-CONH-(CR a17R a18) n4-(O(CR a19R a20) n5) m2-O-(CR a21R a22) n6-、W-(CR a23R a24) n1-CONH-(O(CR a25R a26) n2) m1-、W-(CH 2) n1-(NHCO-(CH 2) n2) m1-、W-(CH 2) n1-(NHCO-(CH 2) n2) m1-(O(CH 2) n3) m2-、由一或多个亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次的直链或支链的W-亚烷基链、和其碳链被一或多个亚芳基或亚杂环基或亚杂芳基或它们的任意组合中断一或多次的W-(CH 2) n1-(O(CH 2) n2) m1-；
R a1、R a2、R a3、R a4、R a5、R a6、R a7、R a8、R a9、R a10、R a11、R a12、R a13、R a14、R a15、R a16、R a17、R a18、R a19、R a20、R a21、R a22、R a23、R a24、R a25、R a26分别独立地表示H、直链或支链的C 1-C 10烷基或C 3-C 10环烷基，其中在相同的所述LIN中时，R a1、R a2、R a3、R a4，R a5、R a6、R a7、R a8、R a9、R a10，R a11、R a12、R a13、R a14、R a15、R a16、R a17、R a18、R a19、R a20、R a21、R a22，或R a23、R a24、R a25、R a26不同时为H；
n1、n2、n3、n4、n5、n6、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20；以及
W如前所定义。
在本公开的式(IV)的一实施方式中，所述LIN优选是W-C 1-30亚烷基-。在本公开的一实施方式中，所述LIN优选是W-亚甲基或W-C 2-30亚烷基，其中所述C 2-30亚烷基是直链或支链的C 2-30亚烷基(优选C 2-C 29亚烷基链，C 2-C 28亚烷基链，C 2-C 27亚烷基链，C 2-C 26亚烷基链，C 2-C 25亚烷基链，C 2-C 24亚烷基链，C 2-C 23亚烷基链，C 2-C 22亚烷基链，C 2-C 21亚烷基链，C 2-C 20亚烷基链，C 2-C 19亚烷基链，C 2-C 18亚烷基链，C 2-C 17亚烷基链，C 2-C 16亚烷基链，C 2-C 15亚烷基链，C 2-C 14亚烷基链，C 2-C 13亚烷基链，C 2-C 12亚烷基链，C 2-C 11亚烷基链，C 2-C 10亚烷基链，C 2-C 9亚烷基链，C 2-C 8亚烷基链，C 2-C 7亚烷基链，C 2-C 6亚烷基链，C 2-C 5亚烷基链，C 2-C 4亚烷基链，或C 2-C 3亚烷基链)，以及W如前所定义。
在本公开的式(IV)的一实施方式中，所述LIN优选表示：W-CH 2-；W-(CH 2) 2-；W-(CH 2) 3-；W-(CH 2) 4-；W-(CH 2) 5-；W-(CH 2) 6-；W-(CH 2) 7-；W-(CH 2) 8-；W-(CH 2) 9-；W-(CH 2) 10-；W-(CH 2) 11-；W-(CH 2) 12-；W-(CH 2) 13-；W-(CH 2) 14-；W-(CH 2) 15-；W-(CH 2) 16-；W-(CH 2) 17-；W-(CH 2) 18-；W-(CH 2) 19-；W-(CH 2) 20-；W-(CH 2) 21-；W-(CH 2) 22-；W-(CH 2) 23-；W-(CH 2) 24-；W-(CH 2) 25-；W-(CH 2) 26-；W-(CH 2) 27-；W-(CH 2) 28-；W-(CH 2) 29-；或W-(CH 2) 30-，其中，W如前所定义。
在本公开的式(IV)的一实施方式中，所述LIN优选是W-C 2-40亚烷基-(优选W-C 2-30亚烷基-)，其中所述亚烷基链可选地被一或多个O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次，以及W如前所定义。
在本公开的式(IV)的一实施方式中，所述LIN优选表示：W-CH 2-O-(CH 2) 2-、W-CH 2-(O(CH 2) 2) 2-、W-CH 2-(O(CH 2) 2) 3-、W-CH 2-(O(CH 2) 2) 4-、W-CH 2-(O(CH 2) 2) 5-、W-CH 2-(O(CH 2) 2) 6-、W-CH 2-(O(CH 2) 2) 7-、W-CH 2-(O(CH 2) 2) 8-、W-CH 2-(O(CH 2) 2) 9-、W-CH 2-(O(CH 2) 2) 10-、W-(CH 2) 2-O-(CH 2) 2-、W-(CH 2) 2-(O(CH 2) 2) 2-、W-(CH 2) 2-(O(CH 2) 2) 3-、W-(CH 2) 2-(O(CH 2) 2) 4-、W-(CH 2) 2-(O(CH 2) 2) 5-、W-(CH 2) 2-(O(CH 2) 2) 6-、W-(CH 2) 2-(O(CH 2) 2) 7-、W-(CH 2) 2-(O(CH 2) 2) 8-、W-(CH 2) 2-(O(CH 2) 2) 9-、W-(CH 2) 2-(O(CH 2) 2) 10-、W-(CH 2) 3-O-(CH 2) 2-、W-(CH 2) 3-(O(CH 2) 2) 2-、W-(CH 2) 3-(O(CH 2) 2) 3-、W-(CH 2) 3-(O(CH 2) 2) 4-、W-(CH 2) 3-(O(CH 2) 2) 5-、W-(CH 2) 3-(O(CH 2) 2) 6-、W-(CH 2) 3-(O(CH 2) 2) 7-、W-(CH 2) 3-(O(CH 2) 2) 8-、W-(CH 2) 3-(O(CH 2) 2) 9-、W-(CH 2) 3-(O(CH 2) 2) 10-、W-(CH 2) 4-O-(CH 2) 2-、W-(CH 2) 4-(O(CH 2) 2) 2-、W-(CH 2) 4-(O(CH 2) 2) 3-、W-(CH 2) 4-(O(CH 2) 2) 4-、W-(CH 2) 4-(O(CH 2) 2) 5-、W-(CH 2) 4-(O(CH 2) 2) 6-、W-(CH 2) 4-(O(CH 2) 2) 7-、W-(CH 2) 4-(O(CH 2) 2) 8-、W-(CH 2) 4-(O(CH 2) 2) 9-、W-(CH 2) 4-(O(CH 2) 2) 10-、W-CH 2-O-(CH 2) 3-、W-CH 2-(O(CH 2) 3) 2-、W-CH 2-(O(CH 2) 3) 3-、W-CH 2-(O(CH 2) 3) 4-、W-CH 2-(O(CH 2) 3) 5-、W-CH 2-(O(CH 2) 3) 6-、W-CH 2-(O(CH 2) 3) 7-、W-CH 2-(O(CH 2) 3) 8-、W-CH 2-(O(CH 2) 3) 9-、W-CH 2-(O(CH 2) 3) 10-、W-(CH 2) 2-O-(CH 2) 3-、W-(CH 2) 2-(O(CH 2) 3) 2-、W-(CH 2) 2-(O(CH 2) 3) 3-、W-(CH 2) 2-(O(CH 2) 3) 4-、W-(CH 2) 2-(O(CH 2) 3) 5-、W-(CH 2) 2-(O(CH 2) 3) 6-、W-(CH 2) 2-(O(CH 2) 3) 7-、W-(CH 2) 2-(O(CH 2) 3) 8-、W-(CH 2) 2-(O(CH 2) 3) 9-、W-(CH 2) 2-(O(CH 2) 3) 10-、W-(CH 2) 3-O-(CH 2) 3-、W-(CH 2) 3-(O(CH 2) 3) 2-、W-(CH 2) 3-(O(CH 2) 3) 3-、W-(CH 2) 3-(O(CH 2) 3) 4-、W-(CH 2) 3-(O(CH 2) 3) 5-、W-(CH 2) 3-(O(CH 2) 3) 6-、W-(CH 2) 3-(O(CH 2) 3) 7-、W-(CH 2) 3-(O(CH 2) 3) 8-、W-(CH 2) 3-(O(CH 2) 3) 9-、W-(CH 2) 3- (O(CH 2) 3) 10-、W-CH 2-O-(CH 2) 2-O-(CH 2) 3-、W-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、W-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、W-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、W-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、W-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、W-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、W-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、W-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、W-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、W-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、W-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、W-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、W-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、W-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、W-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、W-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、W-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、W-CH 2-O-(CH 2) 3-O-(CH 2) 2-、W-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、W-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、W-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、W-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、W-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、W-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、W-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、W-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、W-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、W-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、W-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、W-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、W-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、W-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、W-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、W-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、W-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、W-CH 2-O-(CH 2) 2-O-CH 2-、W-(CH 2) 2-O-(CH 2) 2-O-CH 2-、W-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、W-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、W-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、W-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或W-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-，其中W如前所定义。
在本公开的式(IV)的一实施方式中，所述LIN是W-亚烷基-，所述亚烷基(优选C 1-30亚烷基链，尤其优选C 2-C 29亚烷基链，C 2-C 28亚烷基链，C 2-C 27亚烷基链，C 2-C 26亚烷基链，C 2-C 25亚烷基链，C 2-C 24亚烷基链，C 2-C 23亚烷基链，C 2-C 22亚烷基链，C 2-C 21亚烷基链，C 2-C 20亚烷基链，C 2-C 19亚烷基链，C 2-C 18亚烷基链，C 2-C 17亚烷基链，C 2-C 16亚烷基链，C 2-C 15亚烷基链，C 2-C 14亚烷基链，C 2-C 13亚烷基链，C 2-C 12亚烷基链，C 2-C 11亚烷基链，C 2-C 10亚烷基链，C 2-C 9亚烷基链，C 2-C 8亚烷基链，C 2-C 7亚烷基链，C 2-C 6亚烷基链，C 2-C 5亚烷基链，C 2-C 4亚烷基链，或C 2-C 3亚烷基链)是被一或多个取代基取代一或多次的直链或支链的亚烷基链，其中所述取代基选自羟基、氨基、巯基、卤素或其组合；其中基团W如前所定义。
在本公开的式(IV)的一实施方式中，所述LIN优选是W-C 1-30亚烷基-，所述C 1-30亚烷基是由一或多个选自羟基、氨基、巯基、卤素或其组合的取代基取代的直链或支链的C 1-C 30亚烷基链(优选C 1-C 29亚烷基链，C 1-C 28亚烷基链，C 1-C 27亚烷基链，C 1-C 26亚烷基链，C 1-C 25亚烷基链，C 1-C 24亚烷基链，C 1-C 23亚烷基链，C 1-C 22亚烷基链，C 1-C 21亚烷基链，C 1-C 20亚烷基链，C 1-C 19亚烷基链，C 1-C 18亚烷基链，C 1-C 17亚烷基链，C 1-C 16亚烷基链，C 1-C 15亚烷基链，C 1-C 14亚烷基链，C 1-C 13亚烷基链，C 1-C 12亚烷基链，C 1-C 11亚烷基链，C 1-C 10亚烷基链，C 1-C 9亚烷基链，C 1-C 8亚烷基链，C 1-C 7亚烷基链，C 1-C 6亚烷基链，C 1-C 5亚烷基链，C 1-C 4亚烷基链，C 1-C 3亚烷基链，或C 1-C 2亚烷基链)，其中基团W如前所定义。在本公开的式(IV)的一子实施方式中，所述取代基的数目可以是例如1-30个，1-25个，1-20个， 或者1-15，1-10，1-9，1-8，1-7，1-6，1-5，1-4，1-3，或1-2个，或是20、19、18、17、16、15、14、13、12、11、10、9、8、7、6、5、4、3、2、或1个。
在本公开的式(IV)的一实施方式中，所述LIN表示：W-(CH 2) n11-亚三唑基-(CH 2) n12-、W-(CH 2) n11-亚三唑基-(CH 2) n12-(O(CH 2) n13) m11-、W-(CH 2) n11-(O(CH 2) n12) m11-O-(CH 2) n13-亚三唑基-(CH 2) n14-(O(CH 2) n15) m12-O-(CH 2) n16-、W-(CH 2) n11-亚三唑基-(CH 2) n12-(O(CH 2) n13) m11-O-(CH 2) n14-或W-(CH 2) n11-(O(CH 2) n12) m11-O-(CH 2) n13-亚三唑基-(CH 2) n14-；以及
n11、n12、n13、n14、n15、n16、m11、m12分别独立地表示1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数；
其中基团W如前所定义。
在本公开的式(IV)的一实施方式中，所述LIN优选表示：W-(CH 2) 3-亚三唑基-(CH 2) 5-、W-(CH 2) 2-亚三唑基-(CH 2) 5-、W-CH 2-亚三唑基-(CH 2) 5-、W-(CH 2) 2-亚三唑基-(CH 2) 4-、W-(CH 2) 3-亚三唑基-(CH 2) 2-O(CH 2) 2-、W-(CH 2) 2-亚三唑基-(CH 2) 2-O(CH 2) 2-或W-CH 2-亚三唑基-(CH 2) 2-O(CH 2) 2-，其中基团W如前所定义。
在本公开的式(IV)的一实施方式中，所述LIN优选表示：
Figure PCTCN2019081840-appb-000134
其中基团W如前所定义。
在本公开的式(IV)的一实施方式中，所述LIN优选表示：W-CH 2CONHCH 2-、W-(CH 2) 2CONH(CH 2) 2-、W-(CH 2) 3CONH(CH 2) 3-、W-(CH 2) 3CONH(CH 2) 4-、W-(CH 2) 4CONH(CH 2) 4-、W-(CH 2) 5CONH(CH 2) 5-、W-(CH 2) 6CONH(CH 2) 7-、W-(CH 2) 6CONH(CH 2) 6-、W-(CH 2) 7CONH(CH 2) 7-、W-(CH 2) 8CONH(CH 2) 8、W-(CH 2) 9CONH(CH 2) 9-、W-(CH 2) 10CONH(CH 2) 10-、W-(CH 2) 2CONH(CH 2) 5-、W- (CH 2) 2CONH(CH 2) 3-、W-(CH 2) 2CONH(CH 2) 4-、或W-(CH 2) 2CONH(CH 2) 2-O-(CH 2) 2-；其中基团W如前所定义。
在本公开的式(IV)的一实施方式中，所述LIN优选表示：W-CH 2NHCOCH 2-、W-(CH 2) 2NHCO(CH 2) 2-、W-(CH 2) 3NHCO(CH 2) 3-、W-(CH 2) 3NHCO(CH 2) 4-、W-(CH 2) 4NHCO(CH 2) 4-、W-(CH 2) 5NHCO(CH 2) 5-、W-(CH 2) 6NHCO(CH 2) 7-、W-(CH 2) 6NHCO(CH 2) 6-、W-(CH 2) 7NHCO(CH 2) 7-、W-(CH 2) 8NHCO(CH 2) 8、W-(CH 2) 9NHCO(CH 2) 9-、W-(CH 2) 10NHCO(CH 2) 10-、W-(CH 2) 2NHCO(CH 2) 5-、W-(CH 2) 2NHCO(CH 2) 3-、W-(CH 2) 2NHCO(CH 2) 4-、W-(CH 2) 4NHCO(CH 2) 8-或W-(CH 2) 2NHCO(CH 2) 2-O-(CH 2) 2-；其中基团W如前所定义。
在本公开的式(IV)的一实施方式中，所述LIN表示：W-(CH 2) 4NHCOCH 2-、W-(CH 2) 2-O-CH 2-亚苯基-CH 2-O-(CH 2) 2-、W-CH 2-亚苯基-CH 2-、W-(CH 2) 3-亚苯基-(CH 2) 3-、W-(CH 2) 2-O-CH 2-亚哌嗪基-CH 2-O-(CH 2) 2-、或W-(CH 2) 3-亚哌嗪基-(CH 2) 3-。
在本公开的一实施方式中，在前述式(I)化合物的LIN表示为-U-亚烷基-，其中该-U-亚烷基-的亚烷基连接至SMBP，且基团U连接至ULM的情况下，对应的作为中间体的所述式(IV)化合物中的所述基团LIN对应地表示烷基-W 2-，所述基团W 2对应于基团U且连接式(IV)中的基团R，其中所述烷基对应于所述-U-亚烷基-中的亚烷基的一价基团，其具有所述亚烷基的对应一价基团的定义，即是可选地被一或多个选自以下的基团中断一或多次的直链或支链的烷基：O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基、亚杂芳基或它们的任意组合，其中所述直链或支链的烷基可选地被一或多个取代基取代，且
W 2对应于基团U，表示CO或NH，或W 2不存在。
在本文中，当所述式(IV)化合物中的所述LIN表示烷基-W 2-时，所述基团W 2连接式(IV)中的基团R，且所述烷基可通过本领域技术人员所熟知的常规方法与前述能够结合蛋白的小分子化合物SMBP连接。
特别优选的是本公开表3中的以下式(IV)化合物及其盐：
表3 本公开式(IV)化合物及其中英文名称
Figure PCTCN2019081840-appb-000135
Figure PCTCN2019081840-appb-000136
Figure PCTCN2019081840-appb-000137
Figure PCTCN2019081840-appb-000138
Figure PCTCN2019081840-appb-000139
Figure PCTCN2019081840-appb-000140
Figure PCTCN2019081840-appb-000141
Figure PCTCN2019081840-appb-000142
Figure PCTCN2019081840-appb-000143
Figure PCTCN2019081840-appb-000144
Figure PCTCN2019081840-appb-000145
Figure PCTCN2019081840-appb-000146
Figure PCTCN2019081840-appb-000147
Figure PCTCN2019081840-appb-000148
Figure PCTCN2019081840-appb-000149
Figure PCTCN2019081840-appb-000150
Figure PCTCN2019081840-appb-000151
Figure PCTCN2019081840-appb-000152
Figure PCTCN2019081840-appb-000153
Figure PCTCN2019081840-appb-000154
Figure PCTCN2019081840-appb-000155
Figure PCTCN2019081840-appb-000156
Figure PCTCN2019081840-appb-000157
Figure PCTCN2019081840-appb-000158
Figure PCTCN2019081840-appb-000159
Figure PCTCN2019081840-appb-000160
Figure PCTCN2019081840-appb-000161
Figure PCTCN2019081840-appb-000162
Figure PCTCN2019081840-appb-000163
Figure PCTCN2019081840-appb-000165
Figure PCTCN2019081840-appb-000166
Figure PCTCN2019081840-appb-000167
Figure PCTCN2019081840-appb-000168
Figure PCTCN2019081840-appb-000169
Figure PCTCN2019081840-appb-000170
Figure PCTCN2019081840-appb-000171
本公开另一方面还提供所述式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物用于制备如权利要求1所述的式(I)化合物的用途。
本公开的另一方面还提供一种医药组合物，其包含如本公开所述的式(IV)化合物或其医药学上可接受的盐，及医药学上可接受的载体。
本公开所述的医药组合物，进一步包括至少一种额外的治疗或预防癌症的药物。
在本公开的另一方面，本公开所述的式(IV)化合物，或其医药学上可接受的盐，其是用作药剂。
在本公开的另一方面，本公开所述的式(IV)化合物，或其医药学上可接受的盐，其用于预防及/或治疗癌症。在一实施方式中，所述癌症选自：多发性骨髓瘤、骨髓增生异常综合征(MDS)、既往治疗的骨髓增生异常综合征、浆细胞骨髓瘤、移植相关的癌症、骨髓纤维化、浆细胞骨髓瘤、骨髓疾病、中性粒细胞减少；白血病、急性髓细胞白血病、贫血、慢性粒细胞白血病、B细胞慢性淋巴细胞白血病、急性髓性白血病(AML)、CD20阳性、原发性淋巴瘤、B细胞淋巴瘤、复发性B细胞非霍奇金淋巴瘤、复发性弥漫性大B细胞淋巴瘤、复发性原发性纵隔(胸腺)大B细胞、复发性转化非霍奇金淋巴瘤、难治性B细胞非霍奇金淋巴瘤、难治性弥漫性大B细胞淋巴瘤、难治性原发性纵隔(胸腺)大B细胞、难治性转化的非霍奇金淋巴瘤、阴燃骨髓瘤、闷烧多发性骨髓瘤、或里希特综合症。
在本公开的另一方面，本公开所述的式(IV)化合物，或其医药学上可接受的盐，其是用于制备用以预防及/或治疗癌症的药剂。在一子实施方式中，所述癌症选自：多发性骨髓瘤、骨髓增生异常综合征(MDS)、既往治疗的骨髓增生异常综合征、浆细胞骨髓瘤、移植相关的癌症、骨髓纤维化、浆细胞骨髓瘤、骨髓疾病、中性粒细胞减少；白血病、急性髓细胞白血病、贫血、慢性粒细胞白血病、B细胞慢性淋巴细胞白血病、急性髓性白血病(AML)、CD20阳性、原发性淋巴瘤、B细胞淋巴瘤、复发性B细胞非霍奇金淋巴瘤、复发性弥漫性大B细胞淋巴瘤、复发性原发性纵隔(胸腺)大B细胞、复发性转化非霍奇金淋巴瘤、难治性B细胞非霍奇金淋巴瘤、难治性弥漫性大B细胞淋巴瘤、难治性原发性纵隔(胸腺)大B细胞、难治性转化的非霍奇金淋巴瘤、阴燃骨髓瘤、闷烧多发性骨髓瘤、或里希特综合症。
本公开的另一方面还提供治疗或预防癌症的方法，其包括向受试者施用治疗有效量的本公开所述的式(IV)化合物，或其医药学上可接受的盐，或所述的药物组合物。在一实施方式中，所述癌症选自：多发性骨髓瘤、骨髓增生异常综合征(MDS)、既往治疗的骨髓增生异常综合征、浆细胞骨髓瘤、移植相关的癌症、骨髓纤维化、浆细胞骨髓瘤、骨髓疾病、中性粒细胞减少；白血病、急性髓细胞白血病、贫血、慢性粒细胞白血病、B细胞慢性淋巴细胞白血病、急性髓性白血病(AML)、CD20阳性、原发性淋巴瘤、B细胞淋巴瘤、复发性B细胞非霍奇金淋巴瘤、复发性弥漫性大B细胞淋巴瘤、复发性原发性纵隔(胸腺)大B细胞、复发性转化非霍奇金淋巴瘤、难治性B细胞非霍奇金淋巴瘤、难治性弥漫性大B细胞淋巴瘤、难治性原发性纵隔(胸腺)大B细胞、难治性转化的非霍奇金淋巴瘤、阴燃骨髓瘤、闷烧多发性骨髓瘤、或里希特综合症。
在本公开所述的治疗或预防癌症的方法中，本公开所述的式(IV)化合物，或其医药学上可接受的盐，或所述的药物组合物，通过至少一种选自鼻腔给药、吸入给药、局部给药、口服给药、口腔粘膜给药、直肠给药、胸膜腔给药、腹膜给药、阴道给药、肌内给 药、皮下给药、经皮给药、硬膜外腔给药、鞘内给药和静脉给药的给药方式施用至所述受试者。
定义
在本文中，本公开的式(I)化合物亦称为降解剂、蛋白降解靶向药物PROTAD、或PROTAD小分子(PROTAD化合物)，这些名称可以互换使用。
在本文中，式(Ia)表示的化合物部分和式(Ia1)的化合物：
Figure PCTCN2019081840-appb-000172
均是瑞博西尼(Ribociclib)的哌嗪衍生得到的结构，其中R 1、R 2、R 3、R 4各自独立地为H或甲基。
Figure PCTCN2019081840-appb-000173
在本文中，式(Ib)表示的化合物部分和式(Ib1)的化合物：
Figure PCTCN2019081840-appb-000174
均是Abemaciclib的哌嗪去除氮上的乙基衍生得到的结构，其中R 5、R 6、R 7、R 8各自独立地为H或甲基。
Figure PCTCN2019081840-appb-000175
在本文中，式(Ic)表示的化合物部分和式(Ic1)的化合物：
Figure PCTCN2019081840-appb-000176
均是帕布昔利布(Palbociclib)的哌嗪衍生得到的结构，其中R 9、R 10、R 11、R 12各自独立地为H或甲基。
Figure PCTCN2019081840-appb-000177
在本文中，式(Id)表示的化合物部分和式(Id1)的化合物：
Figure PCTCN2019081840-appb-000178
均是克唑替尼(Crizotinib)的哌啶衍生得到的结构，其中R 13、R 14、R 15、R 16各自独立地为H或甲基。
Figure PCTCN2019081840-appb-000179
在本文中，式(Ie)表示的化合物部分和式(Ie1)的化合物：
Figure PCTCN2019081840-appb-000180
均是色瑞替尼(Ceritinib)的哌啶衍生得到的结构，其中R 17、R 18、R 19、R 20各自独立地为H或甲基。
Figure PCTCN2019081840-appb-000181
在本文中，式(If)表示的化合物部分和式(If1)的化合物：
Figure PCTCN2019081840-appb-000182
均是布加替尼(Brigatinib)的哌啶-哌嗪基团衍生得到的衍生得到的结构，其中R 21、R 22、R 23、R 24各自独立地为H或甲基，环原子Q是N或CH，其中CH通过NH或哌嗪亚基连接至基团LIN，或者环原子Q是CH，其中CH通过N(CH 3)连接至基团LIN，以及环原子Q 1是NH或CH，其中CH被NH 2或哌嗪基取代。
Figure PCTCN2019081840-appb-000183
在本文中，式(Ig)、式(Ih)和式(Ii)表示的化合物部分以及式(Ig1)、式(Ih1)、式(Ii1)的化合物：
Figure PCTCN2019081840-appb-000184
均是艾乐替尼(Alectinib)的哌啶-吗啉基团改造后衍生得到的结构，其中R 25、R 26、R 27、R 28、R 29、R 30、R 31、R 32、R 34、R 35、R 36、R 37、R 38、R 39、R 40、R 41各自独立地为H或甲基，R 33表示H、甲基或乙基。
Figure PCTCN2019081840-appb-000185
在本文中，式(Ij)表示的化合物部分和式(Ij1)的化合物：
Figure PCTCN2019081840-appb-000186
是爱沙替尼(Ensartinib)的哌嗪去除氮上的甲基衍生得到的化合物部分，其中R 42、R 43、R 44、R 45各自独立地为H或甲基。
Figure PCTCN2019081840-appb-000187
在本文中，式(Il)表示的化合物部分和式(Il1)的化合物：
Figure PCTCN2019081840-appb-000188
均是伊马替尼(Imatinib)的哌嗪去除氮上的甲基衍生得到的结构，其中R 50、R 51、R 52、R 53各自独立地为H或甲基。
Figure PCTCN2019081840-appb-000189
在本文中，式(Im)表示的化合物部分和式(Im1)的化合物：
Figure PCTCN2019081840-appb-000190
均是达沙替尼(Dasatinib)的哌嗪去除氮上的乙醇基衍生得到的结构，其中R 54、R 55、R 56、R 57各自独立地为H或甲基。
Figure PCTCN2019081840-appb-000191
在本文中，式(In)表示的化合物部分和式(In1)的化合物：
Figure PCTCN2019081840-appb-000192
均是伯舒替尼(Bosutinib)的哌嗪去除氮上的甲基衍生得到的结构，其中R 58、R 59、R 60、R 61各自独立地为H或甲基。
Figure PCTCN2019081840-appb-000193
在本文中，式(Io)表示的化合物部分和式(Io1)的化合物：
Figure PCTCN2019081840-appb-000194
均是普纳替尼(Ponatinib)的哌嗪去除氮上的甲基衍生得到的结构，其中R 62、R 63、R 64、R 65各自独立地为H或甲基。
Figure PCTCN2019081840-appb-000195
在本文中，式(Ip)表示的化合物部分和式(Ip1)的化合物：
Figure PCTCN2019081840-appb-000196
均是奥拉帕利(Olaparib)的哌嗪去除氮上的环丙甲酰基衍生得到的结构。
Figure PCTCN2019081840-appb-000197
在本文中，式(Iq)表示的化合物部分和式(Iq1)的化合物：
Figure PCTCN2019081840-appb-000198
均是尼拉帕利(Niraparib)的哌啶衍生得到的结构。
Figure PCTCN2019081840-appb-000199
在本文中，式(Ir)表示的化合物部分和式(Ir1)的化合物：
Figure PCTCN2019081840-appb-000200
均是芦卡帕利(Rucaparib；又名瑞卡帕布)的甲胺衍生得到的结构，其中R 66为H或甲基。
Figure PCTCN2019081840-appb-000201
在本文中，式(Is)表示的化合物部分和式(Is1)的化合物：
Figure PCTCN2019081840-appb-000202
均是托瑞米芬(Toremifene)、他莫昔芬(Tamoxifen)、4-羟基他莫昔芬(4-Hydroxyltamoxifen)或4-羟基托瑞米芬(4-Hydroxyltoremifene)的氮衍生得到的结构，其中：
在式(Is)或(Is1)表示托瑞米芬的衍生物或其部分时，X 1是Cl，Y 1是H，Z 1是H或甲基，W 1是H；
式(Is)或(Is1)表示4-羟基托瑞米芬的衍生物或其部分时，X 1是Cl，Y 1是OH，Z 1是H或甲基，W 1是H；
式(Is)或(Is1)表示他莫昔芬的衍生物或其部分时，X 1是H，Y 1是H，Z 1是H或甲基，W 1是H；
式(Is)或(Is1)表示4-羟基他莫昔芬的衍生物或其部分时，X 1是H，Y 1是OH，Z 1是H或甲基，W 1是H；
式(Is)或(Is1)表示4，4'-双羟基他莫昔芬的衍生物或其部分时，X 1是H，Y 1是OH，Z 1是H或甲基，W 1是OH。
Figure PCTCN2019081840-appb-000203
在本文中，式(It)表示的化合物部分、式(It1)的化合物、式(It-3)、式(It-4)、式(It-5)表示的化合物部分：
Figure PCTCN2019081840-appb-000204
Figure PCTCN2019081840-appb-000205
均是JQ-1叔丁酯水解产物衍生得到的结构。
Figure PCTCN2019081840-appb-000206
在本文中，式(Iu)表示的化合物部分和式(Iu1)的化合物：
Figure PCTCN2019081840-appb-000207
均是I-BET762去除氮乙基衍生得到的结构。
Figure PCTCN2019081840-appb-000208
在本文中，式(Iv)表示的化合物部分和式(Iv1)的化合物：
Figure PCTCN2019081840-appb-000209
均是TAE684去除哌嗪上甲基衍生得到的结构。
Figure PCTCN2019081840-appb-000210
在本文中，式(Iw)表示的化合物部分和式(Iw1)的化合物：
Figure PCTCN2019081840-appb-000211
均是ASP3026去除哌嗪上甲基衍生得到的结构。
Figure PCTCN2019081840-appb-000212
在本文中，式(Ix)表示的化合物部分和式(Ix1)的化合物：
Figure PCTCN2019081840-appb-000213
均是GSK1838705A去除二甲基胺上的甲基衍生得到的结构，其中R 67为H、甲基或乙基。
Figure PCTCN2019081840-appb-000214
在本文中，式(Iy)表示的化合物部分和式(Iy1)的化合物：
Figure PCTCN2019081840-appb-000215
均是AZD3463伯胺衍生得到的结构。
Figure PCTCN2019081840-appb-000216
在本文中，由波形线断裂的键显示所绘示基团连接至分子的其他部分的点。例如，下文所绘示的基团
Figure PCTCN2019081840-appb-000217
表示所述式(II)的化合物部分是通过连接基团LIN连接至式(I)化合物的SMBP部分。
在本文中，所述式(I)化合物中的所述ULM表示由以下的式(III)结构的R基团去除一个氢后得到的一价基团：
Figure PCTCN2019081840-appb-000218
Figure PCTCN2019081840-appb-000219
其中A表示-CH 2-或-CO-，B、X、Y、Z相同或不同且分别独立地表示-CH 2-或-N-，R表示-SH、-S(O)-烷基(优选-S(O)-CH 3)、-SO 2-烷基(优选-SO 2-CH 3)或哌嗪基。
在本文中，术语“LIN”和“linker”可交换使用，均表示式I化合物中的连接基团或链接单元。
在本公开中，单独或组合使用的术语“卤素原子”或“卤素”是指氟、氯、溴或碘，且优选为F、Cl或Br。
在本公开中，单独或组合使用的术语“烷基”是指直链或支链的烷基。术语“C x-C y烷基”(x及y各自为整数)是指含有x至y个碳原子的直链或支链烷基。本公开中单独或组合使用的术语“C 1-10烷基”是指含有1至10个碳原子的直链或支链烷基。本公开的C 1-10烷基优选为C 1- 9烷基，较优选为C 1-8烷基，还较优选为C 2-8烷基，更优选为C 1-7烷基，甚至更优选为C 1-6烷基，C 1-5烷基，或C 1-4烷基。代表性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、特戊基、己基、庚基、辛基、壬基及癸基。本公开的术语“C 1-3烷基”是指含有1至3个碳原子的烷基，其代表性实例包括甲基、乙基、正丙基及异丙基。
在本公开中，所述“烷基”是可选地经取代的，取代基优选是一或多个选自卤素、氰基、C 1-3烷基、C 1-3烷氧基、三氟甲基、杂环基或其组合的取代基。
在本公开中，单独或组合使用的术语“亚烷基”(其与“亚烷基链”可互换使用)是指由碳和氢原子组成的直链或支链的二价饱和烃基团。术语“C x-C y亚烷基”(x及y各自为整数)是指含有x至y个碳原子的直链或支链的亚烷基。本公开的C 1-C 30亚烷基优选为C 1-C 29亚烷基，C 1-C 28亚烷基，C 1-C 27亚烷基，C 1-C 26亚烷基，C 1-C 25亚烷基，C 1-C 24亚烷基，C 1-C 23亚烷基，C 1-C 22亚烷基，C 1-C 21亚烷基，C 1-C 20亚烷基，C 1-C 19亚烷基，C 1-C 18亚烷基，C 1-C 17亚烷基，C 1-C 16亚烷基，C 1-C 15亚烷基，C 1-C 14亚烷基，C 1-C 13亚烷基，C 1-C 12亚烷基，C 1-C 11亚烷基，C 1-C 10亚烷基，C 1-C 9亚烷基，C 1-C 8亚烷基，C 1-C 7亚烷基，C 1-C 6亚烷基，C 1-C 5亚烷基，C 1-C 4亚烷基，C 1-C 3亚烷基，或C 1-C 2亚烷基。代表性实例包括但不限于亚甲基、亚乙基、亚丙基、亚异丙基、亚丁基、亚异丁基、亚仲丁基、亚叔丁基、亚戊基、亚异戊基、亚新戊基、亚特戊基、亚己基、亚庚基、亚辛基、亚壬基、亚癸基、亚十一烷基、亚十二烷基、亚十三烷基、亚十四烷基、亚十五烷基、亚十六烷基、亚十七烷基、亚十八烷基、亚十九烷基、亚二十烷基、亚二十一烷基、亚二十二烷基、亚二十三烷基、亚二十四烷基、亚二十五烷基、亚二十六烷基、亚二十七烷基、亚二十八烷基、亚二十九烷基、和亚三十烷基。
在本公开中，所述“亚烷基”是可选地经取代的，取代基优选是一或多个选自羟基、氨基、巯基、卤素、氰基、C 1-3烷基、C 1-3烷氧基、三氟甲基、杂环基或其组合的取代基。
在本公开中，单独或组合使用的术语“亚芳基”是指包含5至14个碳原子并且可选地包含一个或多个稠合环的二价芳香烃基团，例如亚苯基或亚萘基或亚芴基。在本公开 中，所述“亚芳基”是可选地经取代的亚芳基。经取代的亚芳基是指经取代基取代1-3次的亚芳基，其中取代基选自C 1-3烷基、C 1-3烷氧基、三氟甲基、巯基、氰基、卤素、氨基或羟基。
在本公开中，单独或组合使用的术语“C 1-3烷氧基”是指含有1至3个碳原子的直链或支链烷氧基。C 1-3烷氧基的代表性实例包括但不限于甲氧基、乙氧基、正丙氧基及异丙氧基。优选为甲氧基及乙氧基。
在本公开中，单独或组合使用的术语“环烷基”是指具有3至12个碳原子的饱和及部分不饱和(即具有一个或多个双键，但不是完全共轭)的单环或双环环烃基。术语“C 3-C 10环烷基”是指具有3至10个碳原子的饱和及部分不饱和(即具有一个或多个双键，但不是完全共轭)的单环或双环环烃基。环烷基的代表性实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环辛基、十氢萘、八氢并环戊二烯、八氢-1H-茚、螺环基。在本公开中，所述“环烷基”是可选地经取代的，取代基优选是一或多个选自三氟甲基、巯基、羟基、氨基、卤素、氰基、C 1-3烷基、C 1-3烷氧基、三氟甲基、杂环基或其组合的取代基。
在本公开中，单独或组合使用的术语“亚环烷基”是指具有3至12个碳原子的饱和及部分不饱和(即具有一个或多个双键，但不是完全共轭)的单环或双环环烃二价基团。亚环烷基的代表性实例包括但不限于亚环丙基、亚环丁基、亚环戊基、亚环戊烯基、亚环己基、亚环己烯基、亚环庚基、亚环辛基、亚十氢萘基、八氢并环戊二烯亚基、八氢-1H-茚亚基、亚螺环基。根据明确的定义，亚环烷基基团可未被取代或被取代。在本公开中，经取代的所述“亚环烷基”的取代基优选是一或多个选自卤素、巯基、羟基、氨基、氰基、C 1-3烷基、C 1-3烷氧基、三氟甲基、杂环基或其组合的取代基。
在本公开中，单独或组合使用的术语“亚杂芳基”是指含有1个或多个(例如1至6个、或者1至5个、或者1至4个、或者1至3个)独立选自氧、氮和硫的杂原子的5-至10-元单环或二环的二价芳香环基团。该种亚杂芳基基团的代表性实例包括但不限于亚呋喃基、亚噁唑基、亚异噁唑基、亚噁二唑基、亚噻吩基、亚噻唑基、亚异噻唑基、亚噻二唑基、亚吡咯基、亚咪唑基、亚吡唑基、亚三唑基、亚吡啶基、亚嘧啶基、亚哒嗪基、亚吡嗪基、亚吲哚基、亚异吲哚基、亚苯并呋喃基、亚异苯并呋喃基、亚苯并噻吩基、亚吲唑基、亚苯并咪唑基、亚苯并噁唑基、亚苯并异噁唑基、亚苯并噻唑基、亚苯并异噻唑基、亚苯并三唑基、亚苯并[2,1,3]噁二唑基、亚苯并[2,1,3]噻二唑基、亚苯并[1,2,3]噻二唑基、亚喹啉基、亚异喹啉基、亚萘啶基、亚噌啉基、亚喹唑啉基、亚喹喔啉基、亚酞嗪基、吡唑并[1,5-a]吡啶亚基、吡唑并[1,5-a]嘧啶亚基、咪唑并[1,2-a]吡啶亚基、1H-吡咯并[3,2-b]吡啶亚基、1H-吡咯并[2,3-b]吡啶亚基、4H-氟[3,2-b]吡咯亚基、吡咯并[2,1-b]噻唑亚基和咪唑并[2,1-b]噻唑亚基。根据明确的定义，亚杂芳基基团可未被取代或被取代。经取代的亚杂芳基是指经取代基取代1-3次的亚杂芳基，其中取代基优选选自C 1-3烷基、C 1-3烷氧基、氰基、三氟甲基、杂环基、卤素、氨基或羟基。
在本公开中，单独或组合使用的术语“亚杂环基”是指4-至6-元饱和或部分不饱和(即具有一个或多个双键，但不完全共轭)的二价单环基团，其包含有一个或多个独立地选自硫、氧和氮的杂原子。所述亚杂环基的代表性实例包括但不限于亚氮杂环丁基、亚氧杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚三唑基、亚四氢呋喃基、亚四氢噻吩基、亚四氢噻喃基、亚噁唑烷基、亚噻唑烷基、亚哌啶基、亚哌嗪基、亚吗啉基、亚硫代吗啉基和亚二氧杂环己基。所述亚杂环基可以是未取代的或如明确定义的取代的。取代的亚杂环基的取代基优选是一或多个选自C 1-3烷基、C 1-3烷氧基、氰基、三氟甲基、杂环基、卤素、氨基或羟基的取代基。
在本公开中，单独或组合使用的术语“亚炔基”是指具有一个或多个碳碳叁键的包含2至10个(优选2至6个、较优选2至4个)碳原子的直链或支链二价烃基。优选亚炔基的实例包括但不限于亚乙炔基、1-丙炔亚基、1-丁炔亚基和1,3-二炔亚基。
在本公开中，单独或组合使用的术语“亚烯基”是指具有一个或多个碳碳双键的包含2至10个(优选2至6个、较优选2至4个)碳原子的直链或支链二价烃基。优选亚烯基的实例包括但不限于亚乙烯基(例如-CH＝CH-)、1-丙烯亚基、1-丁烯亚基。
在本公开中，单独或组合使用的术语“离去基团(leaving group)”是本领域技术人员所熟知的术语，其还可称为离去基，是在化学反应中从一反应物中携带一对电子离去的分子片段(离子或中性分子)，是亲核取代反应与消除反应中应用的术语。常见离子性离去基有Cl -、Br -、I -和磺酸酯(如对甲苯磺酸酯，TsO -)，中性分子离去基有水、氨和醇。在本公开中，本领域技术人员可以根据需要选择适当的离去基团，例如但不限于-N 3、卤素、甲磺酰氧基、三氟甲磺酰氧基或对甲苯磺酰氧基等。
本公开所述式I化合物的盐或药学上可接受的盐、对映异构体、立体异构体、溶剂化物、多晶型物亦涵盖于本公开范围内。
在本公开的所有实施方式中，所述式I化合物的盐或药学上可接受的盐是指无毒无机的或有机的酸和/或碱加成盐。示例包括：硫酸盐、盐酸盐、枸橼酸盐、马来酸盐、磺酸盐、或对甲苯磺酸盐等。
本公开所述式IV化合物的盐或药学上可接受的盐、对映异构体、立体异构体、溶剂化物、多晶型物亦涵盖于本公开范围内。
在本公开的所有实施方式中，所述式IV化合物的盐或药学上可接受的盐是指无毒无机的或有机的酸和/或碱加成盐。示例包括：硫酸盐、盐酸盐、枸橼酸盐、马来酸盐、磺酸盐、或对甲苯磺酸盐等。
“药学上可接受的载体”是指药学上可接受的材料，例如填充剂、稳定剂、分散剂、悬浮剂、稀释剂、赋形剂、增稠剂、溶剂或包封材料，将本公开中有用的化合物携带或运输到患者体内或给予患者，使得其可以执行其预期功能。通常，这样的构建体从一个器官或身体的一部分携带或运输到另一个器官或身体的一部分。载体与制剂的其他成分(包括本公开中有用的化合物)相容并且对患者无害，载体必须是“可接受的”。可用作药学上可接受 的载体的材料的一些实例包括：糖，如乳糖，葡萄糖和蔗糖；淀粉，如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，例如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；粉状黄蓍胶；麦芽；明胶；滑石；赋形剂，如可可脂和栓剂蜡；油，如花生油，棉籽油，红花油，芝麻油，橄榄油，玉米油和大豆油；二醇，如丙二醇；多元醇，如甘油，山梨糖醇，甘露醇和聚乙二醇；酯类，如油酸乙酯和月桂酸乙酯；琼脂；缓冲剂，如氢氧化镁和氢氧化铝；表面活性剂磷酸盐缓冲溶液；和药物制剂中使用的其他无毒相容物质。
术语“治疗”或“处理”是指向受试者施用本发明所述的式I化合物或式IV化合物或其药学上可接受的盐，或包含作为活性成分的式I化合物或式IV化合物或其药学上可接受的盐的药物组合物，以减缓(减轻)不希望发生的疾病或病症，例如癌症或肿瘤的发展。本发明的有益的或期望的临床结果包括但不限于：减轻症状，减轻疾病的严重程度，稳定疾病的状态，延迟或延缓疾病进展，改善或缓和病情，以及缓解疾病。
本公开化合物的“治疗有效量”取决于患者的年龄，性别和体重，患者的当前医学状况以及所治疗患者的癌症进展情况。本领域技术人员能够根据这些和其它因素来确定合适的剂量。
本公开的术语“室温”是指周围环境温度，例如20-30℃的温度。
本公开研制开发的化合物属于一种靶向特定蛋白的降解剂，其由三部分组成：能够结合蛋白的小分子化合物(SMBP，Small Molecules Binding Protein)、具有泛素化功能的E3连接酶配体和链接单元(linker或LIN)。本公开选取能够结合蛋白的小分子化合物(SMBP)作为锚定元件，通过链接单元(linker)将E3连接酶配体和所述SMBP结合，开发了靶向特定蛋白的降解剂。通过SMBP对靶蛋白的特异识别，抑制靶蛋白的活性，同时E3连接酶特异性使靶蛋白泛素化从而达到靶蛋白的降解清除，最终可把靶蛋白从肿瘤细胞中清除。本公开的化合物不仅可抑制肿瘤的发生和进展，还可以潜在地克服对靶向药物耐药性的产生。本公开设计开发的新颖结构的E3连接酶配体成功应用到了靶向特定蛋白的降解剂，在精准医疗的背景下为肿瘤患者提供了一种新的治疗策略。
实施例
在下列说明中，为了提供对本公开的彻底了解而提出许多具体细节。本公开可在不具有部分或所有这些具体细节的情况下实施。在其他情况下，为了不对本公开造成不必要的混淆，不详述众所周知的过程操作。虽然本公开将结合具体实施例来进行说明，但应当理解的是，这并非旨在将本公开限制于这些实施例。
整个说明书及实例中使用下列缩写：
Boc              叔丁氧基羰基
n-BuOH           正丁醇
Bipy             联吡啶
tBuOH            叔丁醇
Con.             浓度
m-CPBA          间氯过氧苯甲酸
DME             乙二醇二甲醚
DMF             N,N-二甲基甲酰胺
DMSO            二甲基亚砜
DIPEA           N,N-二异丙基乙胺
EDCI            1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐
ESI             电喷雾离子化
equiv           当量
EtOH            乙醇
HOAT            1-羟基-7-偶氮苯并三氮唑
HPLC            高效液相层析
HRMS            高分辨率质谱
LC-MS           液相色谱-质谱联用
LRMS            低分辨率质谱
LC              液相层析
Me              甲基
MeCN            乙腈
MeOH            甲醇
MS              质谱
MW              微波
NMM             N-甲基吗啡啉
NMP             N-甲基吡咯烷酮
1H NMR           核磁共振氢谱
rt              室温
TFA             三氟乙酸
THF             四氢呋喃
TLC             薄层层析
TMS             三甲基硅烷基
TBHP            叔丁基过氧化氢
Xantphos        4,5-双二苯基膦-9,9-二甲基氧杂蒽
LIN-ULM         连接基团与ULM(Ubiquitin Ligase binding Moiety)共价连接形成的中间体
PROTAD          蛋白降解靶向药物(Proteolysis Targeting Drug)
在实施例中， 1H NMR谱采用Bruker-500MHz型核磁共振仪测定，用含0.1％TMS的CD 3OD做溶剂，其中 1H NMR谱以CD 3OD(δ＝3.31ppm)作为内标；或用含0.1％TMS的CDCl 3做溶剂，其中 1H NMR谱以CDCl 3(δ＝7.26ppm)作为内标；或使用含0.03％TMS的DMSO-d 6做溶剂，其中 1H NMR谱以DMSO-d 6(δ＝2.50ppm)作为内标；LRMS谱在AB Triple 4600型质谱仪上测定，HPLC制备在SHIMADZU LC-20AP型仪器上测定，HPLC纯度在SHIMADZU LC-30AP或Waters 1525型仪器上测定。所有反应未作特别说明均在空气氛围下进行；反应用TLC或LC-MS跟踪。
溶剂及试剂处理如下：
反应所用溶剂无水二氯甲烷、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、无水乙醇、无水甲醇等均购自国药集团；
HPLC制备所用的是制备级CH 3CN及去离子水；
选取的靶向蛋白抑制剂SMBP为：去甲基的伊马替尼(imatinib)，帕布昔利布(Palbociclib)，Abemaciclib衍生物，瑞博西尼(Ribocicib)，瑞卡帕布(Rucaparib)，艾乐替尼(Alectinib)衍生物A，艾乐替尼(Alectinib)衍生物B，艾乐替尼(Alectinib)衍生物C，去环丙甲酰基的奥拉帕尼(Olaparib)衍生物，尼拉帕尼(Niraparib)，托瑞米芬(Toremifene)衍生物A，他莫昔芬衍生物A均直接购买得到；达沙替尼衍生物(SIAIS151055)，伯舒替尼衍生物(SIAIS151151)，JQ-1衍生物A(SIAIS171018)，JQ-1衍生物B(SIAIS213113),JQ-1衍生物C(SIAIS213130)，布加替尼(Brigatinib)衍生物A(SIAIS1197135)、布加替尼衍生物B(SIAIS151101)、布加替尼衍生物C(SIAIS164005)，普纳替尼(Ponatinib)衍生物(SIAIS151190B)，拖瑞米芬(toremifene)衍生物B(SIAIS208164)为实验室通过下文所述方法合成。
LIN-ULM(LIN:Linker；ULM:Ubiquitin Ligase binding Moiety)
其它试剂和药品未经特别说明均从商业途径买来直接使用。
硫取代泊马度胺/来那度胺含PEG链羧酸系列LIN-ULM的通用制备方法：
Figure PCTCN2019081840-appb-000220
将相应的中间体化合物硫酚SIAIS151014或SIAIS171075(0.724mmol,1equiv)加入一个50mL的蛋形瓶中，随后加入无水N,N-二甲基甲酰胺(10mL)和无水碳酸钾(1.448mmol,2equiv)，室温搅拌下缓慢滴入相应的作为linker的对甲苯磺酸酯底物(0.869mmol,1.2equiv),滴完室温搅拌0.5h。原料反应完后，过滤除去不溶物后直接上样C18反相柱分离，洗脱剂：10％-100％(v1：v2)的乙腈：水，减压除溶剂得相应的叔丁醇酯中间产物；将该相 应的叔丁醇酯中间化合物加入25mL的蛋形瓶中，随后加入二氯甲烷(1mL)和三氟乙酸(3mL),室温搅拌反应1h。减压蒸去溶剂，加水冻干得相应的硫基取代来那度胺PEG链系列LIN-ULM。
中间体制备例1：制备2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙酸(SIAIS1204137)：
根据所述的方案1的方法、在本领域可理解的适当条件下制备化合物SIAIS1204137，不同之处在于采用2-(2-(对甲苯磺酰基氧基)乙氧基)乙酸叔丁酯作为linker的溴代底物以及采用硫酚底物SIAIS151014，得到目标化合物SIAIS1204137(淡黄色固体，185mg，收率69％)， 1H NMR(500MHz,DMSO)δ11.12(s,1H),7.83–7.73(m,2H),7.64(d,J＝6.6Hz,1H),5.12(dd,J＝12.8,5.4Hz,1H),4.08(s,2H),3.77(t,J＝6.4Hz,2H),3.14-3.07(m,2H),2.94–2.82(m,1H),2.66–2.55(m,2H),2.09-2.01(m,1H).HRMS(ESI)m/z:计算值C 17H 17N 2O 7S +[M+H] +,393.0751；实测值,393.0763.
中间体制备例2：2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酸(SIAIS1204139)：
根据所述的方案1的方法、在本领域可理解的适当条件下制备化合物SIAIS1204139，不同之处在于采用2-(2-(2-(对甲苯磺酰基氧基)乙氧基)乙氧基)乙酸叔丁酯作为linker的溴代底物以及采用硫酚底物SIAIS151014，得到目标化合物SIAIS1204139(淡黄色固体，190mg，收率63％)， 1H NMR(500MHz,DMSO)δ11.12(s,1H),7.83-7.76(m,2H),7.63(dd,J＝6.4,1.3Hz,1H),5.12(dd,J＝12.9,5.4Hz,1H),4.02(s,2H),3.72(t,J＝6.3Hz,2H),3.59(s,4H),3.39–3.30(m,2H),3.13-3.06(m,1H),2.64-2.52(m,2H),2.09-2.02(m,1H).HRMS(ESI)m/z:计算值C 19H 21BN 2O 8S +[M+H] +,437.1013；实测值,437.1032.
中间体制备例3：2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙酸(SIAIS1204141)：
根据所述的方案1的方法、在本领域可理解的适当条件下制备化合物SIAIS1204141，不同之处在于采用tert-butyl 2-(2-(2-(2-(对甲苯磺酰基氧基)乙氧基)乙氧基)乙氧基)乙酸叔丁酯作为linker的溴代底物以及采用硫酚底物SIAIS151014，得到目标化合物SIAIS1204141(淡黄色固体，246mg，收率74％)， 1H NMR(500MHz,DMSO)δ11.12(s,1H),7.85–7.73(m,2H),7.63(dd,J＝6.1,1.9Hz,1H),5.12(dd,J＝12.9,5.4Hz,1H),4.02(s,2H),3.71(t,J＝6.3Hz,2H),3.62–3.48(m,8H),3.35(t,J＝6.3Hz,2H),2.94-2.84(m,1H),2.63-2.52(m,2H),2.11–1.99(m,1H).HRMS(ESI)m/z:计算值C 21H 25N 2O 9S +[M+H] +,481.1275；实测值,481.1273.
中间体制备例4：14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十四烷酸(SIAIS1204147)：
根据所述的方案1的方法、在本领域可理解的适当条件下制备化合物SIAIS1204147，不同之处在于采用14-(对甲苯磺酰基氧基)-3,6,9,12-四氧杂十四烷酸叔丁酯作 为linker的溴代底物以及采用硫酚底物SIAIS151014，得到目标化合物SIAIS1204147(淡黄色固体，228mg，收率63％)， 1H NMR(500MHz,DMSO)δ11.12(s,1H),7.83–7.73(m,2H),7.63(dd,J＝6.2,1.7Hz,1H),5.12(dd,J＝12.9,5.4Hz,1H),4.01(s,2H),3.71(t,J＝6.3Hz,2H),3.59–3.54(m,4H),3.54–3.49(m,8H),3.35(t,J＝6.3Hz,2H),2.94–2.84(m,1H),2.64–2.56(m,1H),2.55–2.51(m,1H),2.08-2.02(m,1H).HRMS(ESI)m/z:计算值C 23H 29N 2O 10S +[M+H] +,525.1537；实测值,525.1536.
中间体制备例5：17-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酸(SIAIS1204149)：
根据所述的方案1的方法、在本领域可理解的适当条件下制备化合物SIAIS1204149，不同之处在于采用17-(对甲苯磺酰基氧基)-3,6,9,12,15-五氧杂十七烷酸叔丁酯的作为linker的溴代底物以及采用硫酚底物SIAIS151014，得到目标化合物SIAIS1204149(淡黄色固体，259mg，收率66％)， 1H NMR(500MHz,DMSO)δ11.12(s,1H),7.83–7.74(m,2H),7.63(dd,J＝6.2,1.8Hz,1H),5.12(dd,J＝12.9,5.4Hz,1H),4.01(s,2H),3.71(t,J＝6.3Hz,2H),3.60–3.55(m,4H),3.55–3.47(m,12H),3.35(t,J＝6.3Hz,2H),2.93-2.84(m,1H),2.64–2.56(m,1H),2.55–2.51(m,1H),2.08-2.02(m,1H).HRMS(ESI)m/z:计算值C 25H 33N 2O 11S +[M+H] +,569.1800；实测值,569.1814.
中间体制备例6：2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙酸(SIAIS1213129)：
根据所述的方案1的方法、在本领域可理解的适当条件下制备化合物SIAIS1213129，不同之处在于采用2-(2-(对甲苯磺酰基氧基)乙氧基)乙酸叔丁酯作为linker的溴代底物以及采用硫酚底物SIAIS171075，得到目标化合物SIAIS1213129(淡黄色固体，148mg，收率54％)， 1H NMR(500MHz,CDCl 3)δ8.90(s,1H),7.81(d,J＝7.5Hz,1H),7.68(d,J＝7.7Hz,1H),7.54(t,J＝7.7Hz,1H),5.33(dd,J＝13.4,5.1Hz,1H),4.60(d,J＝17.2Hz,1H),4.47(d,J＝17.2Hz,1H),4.11(s,2H),3.78-3.73(m,1H),3.72-3.66(m,1H),3.22(t,J＝6.2Hz,2H),2.98-2.93(m,1H),2.90–2.82(m,1H),2.53-2.43(m,1H),2.32-2.25(m,1H).HRMS(ESI)m/z:计算值C 17H 19N 2O 6S +[M+H] +,379.0958；实测值,379.0963.
中间体制备例7：2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酸(SIAIS1213131)：
根据所述的方案1的方法、在本领域可理解的适当条件下制备化合物SIAIS1213131，不同之处在于采用2-(2-(2-(对甲苯磺酰基氧基)乙氧基)乙氧基)乙酸叔丁酯作为linker的溴代底物以及采用硫酚底物SIAIS171075，得到目标化合物SIAIS1213131(淡黄色油状物，158mg，收率52％)， 1H NMR(500MHz,CDCl3)δ8.77(s,1H),7.68(d,J＝7.5Hz,1H),7.53(d,J＝7.7Hz,1H),7.42(t,J＝7.7Hz,1H),5.21(dd,J＝13.4,5.1Hz,1H),4.41(d,J＝17.1Hz,1H),4.32(d,J＝17.1Hz,1H),4.06(s,2H),3.65–3.59(m,4H),3.54(t,J＝4.1Hz,2H), 3.11(t,J＝6.1Hz,2H),2.88–2.83(m,1H),2.81–2.76(m,1H),2.42–2.34(m,1H),2.20–2.14(m,1H).HRMS(ESI)m/z:计算值C 19H 23N 2O 7S +[M+H]+,423.1200；实测值,423.1205.
中间体制备例8：2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙酸(SIAIS1213133)：
根据所述的方案1的方法、在本领域可理解的适当条件下制备化合物SIAIS1213133，不同之处在于采用2-(2-(2-(2-(对甲苯磺酰基氧基)乙氧基)乙氧基)乙氧基)乙酸叔丁酯作为linker的溴代底物以及采用硫酚底物SIAIS171075，得到目标化合物SIAIS1213133(淡黄色油状物，149mg，收率44％)， 1H NMR(500MHz,CDCl 3)δ8.91(s,1H),7.75(d,J＝7.5Hz,1H),7.61(d,J＝7.6Hz,1H),7.50(t,J＝7.7Hz,1H),5.29(dd,J＝13.4,5.1Hz,1H),4.49(d,J＝17.0Hz,1H),4.39(d,J＝17.1Hz,1H),4.17–4.15(m,2H),3.72–3.63(m,10H),3.20(t,J＝6.3Hz,2H),2.96-2.90(m,1H),2.90–2.82(m,1H),2.50-2.44(m,1H),2.28–2.22(m,1H).HRMS(ESI)m/z:计算值C 21H 27N 2O 8S +[M+H] +,467.1483；实测值,467.1467.
中间体制备例9：14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十四烷酸(SIAIS1213135)：
根据所述的方案1的方法、在本领域可理解的适当条件下制备化合物SIAIS1213135，不同之处在于采用14-(对甲苯磺酰基氧基)-3,6,9,12-四氧杂十四烷酸叔丁酯作为linker的溴代底物以及采用硫酚底物SIAIS171075，得到目标化合物SIAIS1213135(淡黄色油状物，181mg，收率49％)， 1H NMR(500MHz,CDCl 3)δ8.61(s,1H),7.78(dd,J＝7.6,0.7Hz,1H),7.63(dd,J＝7.8,0.8Hz,1H),7.50(t,J＝7.0Hz,1H),5.29(dd,J＝13.3,5.1Hz,1H),4.50(d,J＝17.0Hz,1H),4.40(d,J＝16.9Hz,1H),4.15(s,2H),3.72–3.66(m,14H),3.19(t,J＝6.6Hz,2H),2.95-2.93(m,1H),2.91–2.86(m,1H),2.52–2.46(m,1H),2.28–2.24(m,1H).HRMS(ESI)m/z:计算值C 23H 31N 2O 9S +[M+H] +,511.1745；实测值,511.1749.
中间体制备例10：17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酸(SIAIS1213137)：
根据所述的方案1的方法、在本领域可理解的适当条件下制备化合物SIAIS1213137，不同之处在于采用17-(对甲苯磺酰基氧基)-3,6,9,12,15-五氧杂十七烷酸叔丁酯作为linker的溴代底物以及采用硫酚底物SIAIS171075，得到目标化合物SIAIS1213137(淡黄色油状物，209mg，收率52％)， 1H NMR(500MHz,CDCl 3)δ8.71(s,1H),7.77(d,J＝7.0Hz,1H),7.64(dd,J＝7.7,0.7Hz,1H),7.54–7.49(m,1H),5.31(dd,J＝13.4,5.1Hz,1H),4.50(d,J＝17.0Hz,1H),4.40(d,J＝17.0Hz,1H),4.17(s,2H),3.76–3.74(m,2H),3.70–3.66(m,12H),3.64–3.61(m,4H),3.20(t,J＝6.5Hz,2H),2.98–2.94(m,1H),2.90–2.85(m,1H),2.53-2.43(m,1H),2.30–2.25(m,1H).HRMS(ESI)m/z:计算值C 25H 35N 2O 10S +[M+H] +,569.1800；实测值,569.1814.
硫取代泊马度胺碳链羧酸系列LIN-ULM的通用制备方法：
Figure PCTCN2019081840-appb-000221
步骤1：根据方案2制备2-(2,6-二氧代哌啶-3-基)-4-巯基异吲哚啉-1,3-二酮(SIAIS151014):将化合物2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮(20g,72.4mmol)加入一个250mL的蛋形瓶中，随后加入无水N,N-二甲基甲酰胺(150mL),室温搅拌下，分批加入九水硫化钠(28g,108.6mmol),加完后室温下搅拌6h。随后将反应液缓慢倾入400mL的冰水混合物中，搅拌下用6N的盐酸水溶液缓慢调至反应液的pH＝2–3,溶液颜色有血红色逐渐变为淡黄色，并有大量灰白色固体析出，室温搅拌0.5h，抽滤，滤饼用水洗涤3次；随后将滤饼用100mL的无水丙酮打浆，抽滤，滤饼用丙酮洗涤3次，减压干燥得中间体化合物(SIAIS151014)(灰白色固体，14g,收率67％)。 1H NMR(500MHz,DMSO)δ11.16(s,1H),7.79(d,J＝7.8Hz,1H),7.69(t,J＝7.6Hz,1H),7.64(d,J＝7.1Hz,1H),6.30(s,1H),5.14(dd,J＝12.9,5.4Hz,1H),2.93–2.84(m,1H),2.62–2.52(m,2H),2.09–2.02(m,1H).HRMS(ESI)m/z:计算值C 13H 11N 2O 4S +[M+H] +,291.0434；实测值,291.0119.
步骤2：根据方案2由化合物SIAIS151014制备硫取代泊马度胺碳链羧酸系列LIN-ULM的通用方法
将中间体化合物SIAIS151014(3.4mmol,1equiv)加入一个100mL的蛋形瓶中，随后加入无水N,N-二甲基甲酰胺(10mL)和无水碳酸钾(6.8mmol,2equiv)，室温搅拌下缓慢滴入相应的作为linker的溴代底物(4.1mmol,1.2equiv),滴完室温搅拌0.5h。原料反应完后，向反应混合物中倾入50mL的水，乙酸乙酯萃取(2x 50mL),合并有机相，水洗(3x 20mL),饱和食盐水洗(50mL),无水硫酸钠干燥，减压蒸去溶剂，粗品经柱层析(洗脱剂(v/v)：二氯甲烷/乙酸乙酯＝20:1)纯化旋蒸干得相应的叔丁醇酯中间产物；将该相应的叔丁醇酯中间化合物加入25mL的蛋形瓶中，随后加入88％的甲酸(10mL),室温搅拌12h。减压蒸去溶剂，加水冻干得相应的硫基取代泊马度胺烷基碳链系列LIN-ULM。
中间体制备例11：制备2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酸(SIAIS151045)
根据所述的方案2的方法、在本领域可理解的适当条件下制备化合物SIAIS151045，不同之处在于采用的作为linker的溴代底物是叔丁基2-溴乙酸酯。得到目标化合物SIAIS151045(淡黄色固体,0.69g,收率80％)。 1H NMR(500MHz,DMSO)δ13.06(s,1H),11.15(s,1H),7.80(dd,J＝8.1,7.3Hz,1H),7.66(t,J＝7.9Hz,2H),5.13(dd,J＝12.9,5.4Hz,1H), 4.09(s,2H),2.92–2.85(m,1H),2.66–2.51(m,2H),2.08–2.03(m,1H).HRMS(ESI)m/z:计算值C 15H 13N 2O 6S +[M+H] +,349.0489；实测值,349.0297.
中间体制备例12：制备3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酸(SIAIS151138B)
根据所述的方案2的方法、在本领域可理解的适当条件下制备化合物SIAIS151138B，不同之处在于采用的作为linker的溴代底物是叔丁基3-溴丙酸酯。得到目标化合物SIAIS151138B(淡黄色固体,0.64g,收率74％) 1H NMR(500MHz,DMSO)δ11.12(s,1H),7.81–7.76(m,2H),7.64(d,J＝6.7Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),3.32(t,J＝7.0Hz,2H),2.92–2.84(m,1H),2.66(t,J＝7.0Hz,2H),2.62–2.51(m,2H),2.07–2.00(m,1H).HRMS(ESI)m/z:计算值C 16H 15N 2O 6S +[M+H] +,363.0645；实测值,363.0802.
中间体制备例13：制备4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酸(SIAIS151139B)
根据所述的方案2的方法、在本领域可理解的适当条件下制备化合物SIAIS151139B，不同之处在于采用的作为linker的溴代底物是叔丁基4-溴丁酸酯。得到目标化合物SIAIS151139B(淡黄色固体,0.71g,收率82％)。 1H NMR(500MHz,DMSO)δ12.24(s,1H),11.12(s,1H),7.86–7.74(m,2H),7.63(d,J＝6.2Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),3.15(t,J＝7.2Hz,2H),2.92–2.84(m,1H),2.64–2.51(m,2H),2.42(t,J＝7.2Hz,2H),2.09–2.02(m,1H),1.93–1.83(m,2H).HRMS(ESI)m/z:计算值C 17H 17N 2O 6S +[M+H] +,377.0802；实测值,377.0962.
中间体制备例14：制备5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酸(SIAIS151140B)
根据所述的方案2的方法、在本领域可理解的适当条件下制备化合物SIAIS151140B，不同之处在于采用的作为linker的溴代底物是叔丁基5-溴戊酸酯。得到目标化合物SIAIS151140B(淡黄色固体,0.9g,收率74％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),7.83–7.71(m,2H),7.62(d,J＝6.9Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),3.13(t,J＝6.6Hz,2H),2.92–2.85(m,1H),2.64–2.52(m,2H),2.28(t,J＝6.6Hz,2H),2.08–2.02(m,1H),1.72–1.65(m,4H).HRMS(ESI)m/z:计算值C 18H 19N 2O 6S +[M+H] +,391.0958；实测值,391.1109.
中间体制备例15：制备6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酸(SIAIS151141B)
根据所述的方案2的方法、在本领域可理解的适当条件下制备化合物SIAIS151141B，不同之处在于采用的作为linker的溴代底物是叔丁基6-溴己酸酯。得到目标化合物SIAIS151141B(淡黄色固体,0.71g,收率74％)。 1H NMR(500MHz,DMSO)δ12.01(s,1H),11.12(s,1H),7.82–7.70(m,2H),7.62(d,J＝7.1Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),3.12(t,J＝7.2Hz,2H),2.92–2.85(m,1H),2.62–2.48(m,2H),2.22(t,J＝7.2Hz,2H),2.08– 2.03(m,1H),1.71–1.63(m,2H),1.59–1.51(m,2H),1.49–1.40(m,2H).HRMS(ESI)m/z:计算值C 19H 21N 2O 6S +[M+H] +,405.1115；实测值,405.1268.
中间体制备例16：制备7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酸(SIAIS151142B)
根据所述的方案2的方法、在本领域可理解的适当条件下制备化合物SIAIS151142B，不同之处在于采用的作为linker的溴代底物是叔丁基7-溴庚酸酯。得到目标化合物SIAIS151142B(淡黄色固体,0.7g,收率80％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),7.80–7.71(m,2H),7.62(d,J＝6.9Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),3.12(t,J＝7.3Hz,2H),2.92–2.85(m,1H),2.62–2.52(m,2H),2.20(t,J＝7.3Hz,2H),2.07–2.00(m,1H),1.69–1.62(m,2H),1.53–1.47(m,2H),1.46–1.41(m,2H),1.36–1.27(m,2H).HRMS(ESI)m/z:计算值C 20H 23N 2O 6S +[M+H] +,419.1271；实测值,419.1432.
硫取代泊马度胺碳链氨基系列LIN-ULM的通用制备方法：
Figure PCTCN2019081840-appb-000222
将化合物SIAIS151014(2.8mmol,1equiv)加入一个100mL的蛋形瓶中，随后加入无水N,N-二甲基甲酰胺(20mL)和无水碳酸钾(5.6mmol,2equiv)，室温搅拌下缓慢滴入相应的溴代物(3.4mmol,1.2equiv),滴完室温搅拌1h。原料反应完后，向反应混合物中倾入50mL的水，乙酸乙酯萃取(3x 50mL),合并有机相，水洗(3x 20mL),饱和食盐水洗(50mL),无水硫酸钠干燥，减压蒸去溶剂，粗品经反相C18柱分离，洗脱剂(v/v)：乙腈/(水+0.05％TFA)＝10％–100％，减压蒸去溶剂，冻干得相应的Boc保护的烷基化产物。将得到的烷基化产物加入25mL的蛋形瓶中，随后加入无水二氯甲烷(5mL)和三氟乙酸(0.5mL)，室温搅拌12h.减压蒸去反应溶剂，粗品经反相C18柱分离，洗脱剂(v/v)：乙腈/(水+0.05％TFA)＝10％–100％，减压蒸去溶剂，冻干得相应的碳链氨基系列LIN-ULM。
中间体制备例17：制备4-((2-氨基乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS171026)
根据所述的方案3的方法、在本领域可理解的适当条件下制备化合物SIAIS171026，不同之处在于采用的作为linker的溴代底物是叔丁基(2-溴乙基)氨基甲酸酯。得到目标化合物SIAIS171026(淡黄色固体,200mg,收率58％)。 1H NMR(500MHz,DMSO)δ11.14(s,1H),7.92(br.s,3H),7.88–7.79(m,2H),7.71(d,J＝6.6Hz,1H),5.14(dd,J＝12.9,5.4Hz,1H),3.35–3.30(m,2H),3.15–3.06(m,2H),2.94–2.85(m,1H),2.67–2.54(m,2H),2.10–2.01(m,1H).HRMS(ESI)m/z:计算值C 15H 16N 3O 4S +[M+H] +,334.0856；实测值,334.0858.
中间体制备例18：制备4-((3-氨基丙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS171025)
根据所述的方案3的方法、在本领域可理解的适当条件下制备化合物SIAIS171025，不同之处在于采用的作为linker的溴代底物是叔丁基(3-溴丙基)氨基甲酸酯。得到目标化合物SIAIS171025(淡黄色固体,300mg,收率77％)。 1H NMR(500MHz,DMSO)δ11.13(s,1H),7.93(br.s,3H),7.83–7.75(m,2H),7.69–7.62(m,1H),5.12(dd,J＝12.9,5.4Hz,1H),3.23(t,J＝7.2Hz,2H),3.00–2.97(m,2H),2.92–2.85(m,1H),2.64–2.51(m,2H),2.13–2.03(m,1H),1.99–1.91(m,2H).HRMS(ESI)m/z:计算值C 16H 18N 3O 4S +[M+H] +,348.1013；实测值,348.1029.
中间体制备例19：制备4-((4-氨基丁基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS171023)
根据所述的方案3的方法、在本领域可理解的适当条件下制备化合物SIAIS171023，不同之处在于采用的作为linker的溴代底物是叔丁基(4-溴丁基)氨基甲酸酯。得到目标化合物SIAIS171023(淡黄色固体,310mg,收率79％)。 1H NMR(500MHz,DMSO)δ11.13(s,1H),7.92(br.s,3H),7.82–7.73(m,2H),7.67–7.59(m,1H),5.12(dd,J＝12.9,5.4Hz,1H),3.15–3.10(m,2H),2.90–2.85(m,3H),2.70–2.51(m,2H),2.10–2.05(m,1H),1.79–1.67(m,4H).HRMS(ESI)m/z:计算值C 17H 20N 3O 4S +[M+H] +,362.1169；实测值,362.1441.
中间体制备例20：制备4-((5-氨基戊基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS171027)
根据所述的方案3的方法、在本领域可理解的适当条件下制备化合物SIAIS171027，不同之处在于采用的作为linker的溴代底物是叔丁基(5-溴戊基)氨基甲酸酯。得到目标化合物SIAIS171027(淡黄色固体,210mg,收率53％)。 1H NMR(500MHz,DMSO)δ11.13(s,1H),7.83–7.72(m,5H),7.72–7.61(m,1H),5.12(dd,J＝12.9,5.4Hz,1H),3.15–3.10(m,2H),2.91–2.79(m,3H),2.63–2.53(m,2H),2.30–2.17(m,1H),1.55–1.46(m,6H).HRMS(ESI)m/z:计算值C 18H 22N 3O 4S +[M+H] +,376.1326；实测值,376.0869.
中间体制备例21：制备4-((6-氨基己基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS171028)
根据所述的方案3的方法、在本领域可理解的适当条件下制备化合物SIAIS171028，不同之处在于采用的作为linker的溴代底物是叔丁基(6-溴己基)氨基甲酸酯。得到目标化合物SIAIS171028(淡黄色固体,330mg,收率83％)。 1H NMR(500MHz,DMSO)δ11.13(s,1H),7.79–7.75(m,2H),7.72–7.56(m,4H),5.12(dd,J＝12.9,5.4Hz,1H),3.14(t,J＝7.2Hz,2H),2.90–2.88(m,1H),2.83–2.77(m,2H),2.68–2.52(m,2H),2.10–2.06(m,1H),1.72–1.65(m,2H),1.55–1.52(m,2H),1.49–1.41(m,2H),1.35–1.31(m,2H).HRMS(ESI)m/z:计算值C 19H 24N 3O 4S +[M+H] +,390.1482；实测值,390.1477.
中间体制备例22：制备4-((7-氨基庚基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS171033)
根据所述的方案3的方法、在本领域可理解的适当条件下制备化合物SIAIS171033，不同之处在于采用的作为linker的溴代底物是叔丁基(7-溴庚基)氨基甲酸酯。得到目标化合物SIAIS171033(淡黄色固体,400mg,收率71％)。 1H NMR(500MHz,DMSO)δ11.13(s,1H),7.81–7.60(m,6H),5.11(dd,J＝12.8,5.4Hz,1H),3.14(t,J＝7.2Hz,2H),2.95–2.84(m,1H),2.80–2.74(m,2H),2.65–2.52(m,2H),2.10–1.99(m,1H),1.72–1.68(m,2H),1.55–1.45(m,4H),1.40–1.35(m,4H).HRMS(ESI)m/z:计算值C 20H 26N 3O 4S +[M+H] +,404.5045；实测值,404.1484.
中间体制备例23：制备4-((8-氨基辛基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS171047)
根据所述的方案3的方法、在本领域可理解的适当条件下制备化合物SIAIS171047，不同之处在于采用的作为linker的溴代底物是叔丁基(8-溴辛基)氨基甲酸酯.得到目标化合物SIAIS171047(淡黄色固体,600mg,收率83％)。 1H NMR(500MHz,DMSO)δ11.13(s,1H),7.79–7.59(m,6H),5.12(dd,J＝12.9,5.4Hz,1H),3.13(t,J＝7.2Hz,2H),2.95–2.85(m,1H),2.78–2.74(m,2H),2.67–2.52(m,2H),2.10–2.04(m,1H),1.73–1.64(m,2H),1.52–1.50(m,2H),1.47–1.41(m,2H),1.35–1.30(m,6H).HRMS(ESI)m/z:计算值C 21H 28N 3O 4S +[M+H] +,418.1795；实测值,418.0408.
硫基取代来那度胺碳链羧酸系列LIN-ULM的通用制备方法：
Figure PCTCN2019081840-appb-000223
步骤1：根据方案4制备3-(4-(苄基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS171088)：
将五水硫代硫酸钠(53.7g,216.3mmol),氯化苄(27.4g,216.3mmol),五水硫酸铜(77.4mg,0.31mmol)及联吡啶(0.72g,4.6mmol)一起加入装有甲醇(120mL)和水(120mL)的500mL的蛋形瓶中，随后缓慢升温至80℃并搅拌2h。随后将反应液降至室温，加入3-(4-氨基-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(即来那度胺)(8.0g,30.9mmol)， 最后缓慢滴加亚硝酸叔丁酯(4.78g,46.4mmol),滴毕，再次升温至80℃并搅拌8h。反应结束后，将反应液降至室温，加水(200mL)，乙酸乙酯萃取(2x 200mL),合并有机相，水洗(2x 50mL),饱和食盐水洗(50mL),无水硫酸钠干燥，减压蒸去溶剂，粗品经柱层析(洗脱剂(v/v)：石油醚/乙酸乙酯＝1:2)纯化得目标化合物(SIAIS171088)(白色固体,6.8g,收率60％)。 1H NMR(500MHz,CDCl 3)δ8.07(s,1H),7.75(t,J＝7.3Hz,1H),7.55(dd,J＝7.4,6.8Hz,1H),7.49–7.41(m,1H),7.27–7.17(m,5H),5.20–5.17(m,1H),4.22(d,J＝16.5Hz,1H),4.15–4.04(m,2H),3.92(d,J＝16.5Hz,1H),2.95–2.74(m,2H),2.32–2.22(m,1H),2.17–2.11(m,1H).HRMS(ESI)m/z:计算值C 20H 19N 2O 3S +[M+H] +,367.1111；实测值,367.1402.
步骤2：根据方案4制备3-(4-巯基-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS171095)：
将无水三氯化铝(2.61g,19.6mmol)及无水甲苯(70mL)加到250mL的蛋形瓶中，搅拌下缓慢加入化合物(SIAIS171088)(1.8g，4.9mmol),加毕，35℃下搅拌过夜。反应结束后，在搅拌下将20％的柠檬酸水溶液缓慢加入，有大量的固体析出，随后抽滤，滤饼分别用水和乙酸乙酯洗涤，滤饼干燥得目标化合物(SIAIS171095)(白色固体,1.15g,收率85％)。 1H NMR(500MHz,DMSO)δ11.01(s,1H),7.82–7.39(m,3H),5.73(s,1H),5.21–5.04(m,1H),4.40–4.20(m,2H),2.99–2.85(m,1H),2.67–2.56(m,1H),2.47–2.30(m,1H),2.05–1.95(m,1H).HRMS(ESI)m/z:计算值C 13H 13N 2O 3S +[M+H] +,277.0641；实测值,276.8348.
步骤3：根据方案4由化合物SIAIS171095制备硫基取代来那度胺碳链羧酸系列LIN-ULM通用方法
将化合物SIAIS171095(0.36mmol,1equiv)，相应的溴代底物(0.43mmol,1.2equiv)和无水碳酸钾(0.72mmol,2equiv)一起加入10mL的蛋形瓶中，随后加入无水N,N-二甲基甲酰胺(2mL),室温下搅拌2h。反应结束后，倾入50mL的水中，乙酸乙酯萃取(2x 50mL),合并有机相，水洗(2x 30mL),饱和食盐水洗(50mL),无水硫酸钠干燥，减压蒸去溶剂，粗品经反相C18柱分离，洗脱剂(v/v)：乙腈/(水+0.05％TFA)＝10％–100％，得相应的叔丁醇酯中间产物；随后将该相应的叔丁醇酯中间产物加入10mL蛋形瓶中，加入88％甲酸(3mL),室温搅拌12h。减压蒸去反应溶剂，加水冻干得相应的目标化合物。
中间体制备例24：制备2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酸(SIAIS171090)
根据所述的方案4的方法、在本领域可理解的适当条件下制备化合物SIAIS171090，不同之处在于采用的作为linker的溴代底物是叔丁基2-溴乙酸酯。得到目标化合物SIAIS171090(白色固体,77mg,步骤3总收率64％)。 1H NMR(500MHz,DMSO)δ12.88(s,1H),11.00(s,1H),7.68–7.45(m,3H),5.15–5.13(m,1H),4.32(dd,J＝56.2,17.3Hz,2H),3.94(s,2H),2.95–2.91(m,1H),2.63–2.59(m,1H),2.49–2.39(m,1H),2.08–1.92(m,1H).HRMS(ESI)m/z:计算值C 15H 15N 2O 5S +[M+H] +,335.0696；实测值,334.8134.
中间体制备例25：制备3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙酸(SIAIS171086)
根据所述的方案4的方法、在本领域可理解的适当条件下制备化合物SIAIS171086，不同之处在于采用的作为linker的溴代底物是叔丁基3-溴丙酸酯。得到目标化合物SIAIS171086(白色固体,40mg,步骤3总收率32％)。 1H NMR(500MHz,DMSO)δ10.99(s,1H),7.70–7.55(m,3H),5.13(dd,J＝13.3,5.1Hz,1H),4.40–4.18(m,2H),3.24(t,J＝7.0Hz,2H),2.95–2.87(m,1H),2.63–2.53(m,3H),2.47–2.34(m,1H),2.05–1.95(m,1H).HRMS(ESI)m/z:计算值C 16H 17N 2O 5S +[M+H] +,349.0853；实测值,348.8166.
中间体制备例26：制备4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁酸(SIAIS171089)
根据所述的方案4的方法、在本领域可理解的适当条件下制备化合物SIAIS171089，不同之处在于采用的作为linker的溴代底物是叔丁基4-溴丁酸酯。得到目标化合物SIAIS171089(白色固体,50mg,步骤3总收率38％)。 1H NMR(500MHz,DMSO)δ12.15(s,1H),10.99(s,1H),7.71–7.49(m,3H),5.13(dd,J＝13.3,5.1Hz,1H),4.41–4.18(m,2H),3.10(t,J＝7.3Hz,2H),2.92–2.88(m,1H),2.61–2.59(m,1H),2.49–2.42(m,1H),2.38(t,J＝7.2Hz,2H),2.05–1.96(m,1H),1.84–1.74(m,2H).HRMS(ESI)m/z:计算值C 17H 19N 2O 5S +[M+H] +,363.1009；实测值,362.8160.
中间体制备例27：制备5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酸(SIAIS171079)
根据所述的方案4的方法、在本领域可理解的适当条件下制备化合物SIAIS171079，不同之处在于采用的作为linker的溴代底物是叔丁基5-溴戊酸酯。得到目标化合物SIAIS171079(白色固体,30mg,步骤3总收率22％)。 1H NMR(500MHz,DMSO)δ12.01(s,1H),10.98(s,1H),7.66–7.55(m,3H),5.12(dd,J＝13.3,5.1Hz,1H),4.37–4.18(m,2H),3.10–3.05(m,2H),2.95–2.84(m,1H),2.65–2.61(m,1H),2.48–2.38(m,1H),2.27–2.20(m,3H),1.63–1.59(m,4H).HRMS(ESI)m/z:计算值C 18H 21N 2O 5S +[M+H] +,377.1166；实测值,376.8981.
中间体制备例28：制备6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酸(SIAIS171091)
根据所述的方案4的方法、在本领域可理解的适当条件下制备化合物SIAIS171091，不同之处在于采用的作为linker的溴代底物是叔丁基6-溴己酸酯。得到目标化合物SIAIS171091(白色固体,75mg,步骤3总收率53％)。 1H NMR(500MHz,DMSO)δ11.98(s,1H),10.98(s,1H),7.59–7.52(m,3H),5.12(dd,J＝13.4,5.1Hz,1H),4.26(dd,J＝40.9,20.5Hz,2H),3.07(t,J＝7.3Hz,2H),2.96–2.84(m,1H),2.64–2.60(m,1H),2.48–2.39(m,1H),2.19–2.15(m,2H),2.02–2.00(m,1H),1.70–1.35(m,6H).HRMS(ESI)m/z:计算值C 19H 23N 2O 5S +[M+H] +,391.1322；实测值,390.8150.
中间体制备例29：制备7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)庚酸(SIAIS171092)
根据所述的方案4的方法、在本领域可理解的适当条件下制备化合物SIAIS171092，不同之处在于采用的作为linker的溴代底物是叔丁基7-溴庚酸酯。得到目标化合物SIAIS171092(白色固体,79mg,步骤3总收率54％)。 1H NMR(500MHz,DMSO)δ11.99(s,1H),10.98(s,1H),7.66–7.45(m,3H),5.12(dd,J＝13.3,5.1Hz,1H),4.26(dd,J＝40.9,20.5Hz,2H),3.07(t,J＝7.3Hz,2H),2.97–2.83(m,1H),2.63–2.60(m,1H),2.47–2.35(m,1H),2.18(t,J＝7.3Hz,2H),2.06–1.93(m,1H),1.65–1.20(m,8H).HRMS(ESI)m/z:计算值C 20H 25N 2O 5S +[M+H] +,405.1479；实测值,404.8155.
中间体制备例30：制备11-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)十一烷酸(SIAIS1220099)
根据所述的方案4的方法、在本领域可理解的适当条件下制备化合物SIAIS1220099，不同之处在于采用的作为linker的溴代底物是叔丁基11-溴十一烷酸酯。得到目标化合物SIAIS1220099(白色固体，593mg，收率64％)。 1H NMR(500MHz,DMSO)δ11.97(s,1H),10.98(s,1H),7.62(d,J＝7.4Hz,1H),7.56(d,J＝6.6Hz,1H),7.52(t,J＝7.5Hz,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.35(d,J＝17.4Hz,1H),4.21(d,J＝17.4Hz,1H),3.07(t,J＝7.2Hz,2H),2.95–2.86(m,1H),2.59(d,J＝17.5Hz,1H),2.49–2.41(m,1H),2.17(t,J＝7.4Hz,2H),2.03–1.97(m,1H),1.62–1.55(m,2H),1.49-1.44(m,2H),1.43-1.35(m,2H),1.26-1.22(m,10H).HRMS(ESI)m/z:计算值C 24H 33N 2O 5S +[M+H] +,461.2105；实测值,461.2103.
硫基取代来那度胺碳链氨基系列LIN-ULM通用方法：
Figure PCTCN2019081840-appb-000224
将化合物SIAIS171095(0.36mmol,1equiv)加入一个10mL的反应瓶中，随后加入无水N,N-二甲基甲酰胺(2mL)和无水碳酸钾(0.72mmol,2equiv)，室温搅拌下缓慢加入相应的溴代物(0.43mmol,1.2equiv),滴完室温搅拌1h。原料反应完后，粗品经反相C18柱分离，洗脱剂(v/v)：乙腈/(水+0.05％TFA)＝10％–100％，减压蒸去溶剂，冻干得到Boc保护的烷基化中间体产物。
将步骤1得到的相应产物加入10mL的反应瓶中，随后加入无水二氯甲烷(2mL)和三氟乙酸(2mL)，室温搅拌12h.减压蒸去反应溶剂，粗品经反相C18柱分离，洗脱剂(v/v)：乙腈/(水+0.05％TFA)＝10％–100％，减压蒸去溶剂，冻干得相应的目标化合物。
中间体制备例31：制备3-(4-((2-氨基乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS171123)
根据所述的方案5的方法、在本领域可理解的适当条件下制备化合物SIAIS171123，不同之处在于采用的作为linker的溴代底物是叔丁基(2-溴乙基)氨基甲酸酯。得到目标化合物SIAIS171123(白色固体,68mg,两步总收率59％)。 1H NMR(500MHz,DMSO)δ11.02(s,1H),7.88(s,3H),7.73(dd,J＝7.7,0.8Hz,1H),7.66(dd,J＝7.5,0.7Hz,1H),7.59(t,J＝7.6Hz,1H),5.15(dd,J＝13.3,5.1Hz,1H),4.45–4.25(m,2H),3.32–3.26(m,2H),3.05–3.00(m,2H),2.96–2.87(m,1H),2.64–2.60(m,1H),2.48–2.41(m,1H),2.05–2.00(m,1H).HRMS(ESI)m/z:计算值C 15H 18N 3O 3S +[M+H] +,320.1063；实测值,320.1082.
中间体制备例32：制备3-(4-((3-氨基丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS171124)
根据所述的方案5的方法、在本领域可理解的适当条件下制备化合物SIAIS171124，不同之处在于采用的作为linker的溴代底物是叔丁基(3-溴丙基)氨基甲酸酯。得到目标化合物SIAIS171124(白色固体,68mg,两步总收率56％)。 1H NMR(500MHz,DMSO)δ11.00(s,1H),7.75–7.67(m,4H),7.63–7.49(m,2H),5.14(dd,J＝13.3,5.1Hz,1H),4.43–4.16(m,2H),3.22–3.11(m,2H),2.97–2.85(m,3H),2.67–2.56(m,1H),2.48–2.40(m,1H),2.05–1.95(m,1H),1.91–1.77(m,2H).HRMS(ESI)m/z:计算值C 16H 20N 3O 3S +[M+H] +,334.1220；实测值,334.1213.
中间体制备例33：制备3-(4-((4-氨基丁基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS171131)
根据所述的方案5的方法、在本领域可理解的适当条件下制备化合物SIAIS171131，不同之处在于采用的作为linker的溴代底物是叔丁基(4-溴丁基)氨基甲酸酯。得到目标化合物SIAIS171131(淡黄色固体,76mg,两步总收率60％)。 1H NMR(500MHz,DMSO)δ10.99(s,1H),7.81–7.47(m,6H),5.13(dd,J＝13.3,5.1Hz,1H),4.25(dd,J＝31.3,15.7Hz,2H),3.20–3.03(m,2H),2.96–2.85(m,1H),2.85–2.80(m,2H),2.63–2.60(m,1H),2.46–2.30(m,1H),2.06–1.94(m,1H),1.71–1.56(m,4H).HRMS(ESI)m/z:计算值C 17H 22N 3O 3S +[M+H] +,348.1376；实测值,348.1381.
中间体制备例34：制备3-(4-((5-氨基戊基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS171132)
根据所述的方案5的方法、在本领域可理解的适当条件下制备化合物SIAIS171132，不同之处在于采用的作为linker的溴代底物是叔丁基(5-溴戊基)氨基甲酸酯。得到目标化合物SIAIS171132(淡黄色固体,95mg,两步总收率73％)。 1H NMR(500MHz,DMSO)δ11.00(s,1H),7.85–7.45(m,6H),5.21–5.07(m,1H),4.42–4.16(m,2H),3.16–3.05(m,2H),2.92–2.85(m,1H),2.84–2.71(m,2H),2.64–2.60(m,1H),2.45–2.40(m,1H),2.07– 1.93(m,1H),1.66–1.58(m,2H),1.54–1.50(m,2H),1.49–1.44(m,2H).HRMS(ESI)m/z:计算值C 18H 24N 3O 3S +[M+H] +,362.1533；实测值,362.1537.
中间体制备例35：制备3-(4-((6-氨基己基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS171134)
根据所述的方案5的方法、在本领域可理解的适当条件下制备化合物SIAIS171134，不同之处在于采用的作为linker的溴代底物是叔丁基(6-溴己基)氨基甲酸酯。得到目标化合物SIAIS171134(淡黄色固体,78mg,两步总收率57％)。 1H NMR(500MHz,DMSO)δ11.00(s,1H),7.84–7.43(m,6H),5.16–5.13(m,1H),4.30–4.15(m,2H),3.14–3.03(m,2H),2.97–2.88(m,1H),2.82–2.72(m,2H),2.62(t,J＝14.7Hz,1H),2.49–2.39(m,1H),2.06–1.96(m,1H),1.68–1.56(m,2H),1.51–1.46(m,2H),1.45–1.37(m,2H),1.36–1.28(m,2H).HRMS(ESI)m/z:计算值C 19H 26N 3O 3S +[M+H] +,376.1689；实测值,376.1702.
中间体制备例36：制备3-(4-((7-氨基庚基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS171135)
根据所述的方案5的方法、在本领域可理解的适当条件下制备化合物SIAIS171135，不同之处在于采用的作为linker的溴代底物是叔丁基(7-溴庚基)氨基甲酸酯。得到目标化合物SIAIS171135(白色固体,100mg,两步总收率71％)。 1H NMR(500MHz,DMSO)δ10.99(s,1H),7.84–7.42(m,6H),5.13(dd,J＝13.3,5.1Hz,1H),4.37–4.18(m,2H),3.15–3.02(m,2H),2.92–2.88(m,1H),2.81–2.71(m,2H),2.61(t,J＝14.8Hz,1H),2.48–2.40(m,1H),2.05–1.98(m,1H),1.65–1.56(m,2H),1.54–1.46(m,2H),1.44–1.36(m,2H),1.33–1.23(m,4H).HRMS(ESI)m/z:计算值C 20H 28N 3O 3S +[M+H] +,390.1846；实测值,390.1846.
中间体制备例37：制备3-(4-((8-氨基辛基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS171136)
根据所述的方案5的方法、在本领域可理解的适当条件下制备化合物SIAIS171136，不同之处在于采用的作为linker的溴代底物是叔丁基(8-溴辛基)氨基甲酸酯。得到目标化合物SIAIS171136(白色固体,100mg,两步总收率68％)。 1H NMR(500MHz,DMSO)δ10.99(s,1H),7.75–7.47(m,6H),5.13(dd,J＝13.3,5.1Hz,1H),4.28(dd,J＝70.1,17.4Hz,2H),3.13–3.00(m,2H),2.98–2.84(m,1H),2.78–2.74(m,2H),2.64–2.59(m,1H),2.47–2.38(m,1H),2.06–1.93(m,1H),1.68–1.54(m,2H),1.52–1.48(m,2H),1.45–1.34(m,2H),1.30–1.20(m,6H).HRMS(ESI)m/z:计算值C 21H 30N 3O 3S +[M+H] +,404.2002；实测值,404.1996.
硫基取代来那度胺含PEG链氨基系列LIN-ULM通用方法：
Figure PCTCN2019081840-appb-000225
Figure PCTCN2019081840-appb-000226
将化合物SIAIS171095(0.36mmol,1equiv)加入一个10mL的反应瓶中，随后加入无水N,N-二甲基甲酰胺(3mL)和无水碳酸钾(0.72mmol,2equiv)，室温搅拌下缓慢加入不同的溴代物(0.43mmol,1.2equiv),滴完室温搅拌1h。原料反应完后，加水淬灭，乙酸乙酯萃取，浓缩后粗品经反相C18柱分离，洗脱剂(v/v)：乙腈/水＝10％–100％，减压蒸去溶剂，冻干得目标化合物；将该系列化合物加入10mL的反应瓶中，随后加入无水二氯甲烷(4mL)和三氟乙酸(1mL)，室温搅拌2h.减压蒸去反应溶剂，加水冻干得目标化合物。
中间体制备例38：制备3-(4-((2-(2-氨基乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS213096)
根据所述的方案6的方法、在本领域可理解的适当条件下制备化合物SIAIS213096，不同之处在于采用的作为linker的溴代底物是(2-(2-溴乙氧基)乙基)氨基甲酸叔丁酯。得到目标化合物SIAIS213096(白色固体,41mg,两步收率62.4％)。 1H NMR(500MHz,MeOD)δ7.69(ddd,J＝17.2,10.0,2.9Hz,2H),7.54(t,J＝7.7Hz,1H),5.17(dd,J＝13.4,5.2Hz,1H),4.52–4.39(m,2H),3.79–3.69(m,2H),3.63(ddd,J＝5.0,2.6,1.0Hz,2H),3.30–3.21(m,2H),3.10–3.03(m,2H),2.95–2.86(m,1H),2.79(ddd,J＝17.6,4.6,2.3Hz,1H),2.52(qd,J＝13.3,4.6Hz,1H),2.25–2.11(m,1H).LCMS(ESI)m/z:计算值C 17H 22N 3O 4S +[M+H] +,364.1326；实测值,364.3.
中间体制备例39：制备3-(4-((2-(2-(2-氨基乙氧基)乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS213068)
根据所述的方案6的方法、在本领域可理解的适当条件下制备化合物SIAIS213068，不同之处在于采用的作为linker的溴代底物是(2-(2-(2-溴乙氧基)乙氧基)乙基)氨基甲酸叔丁酯。得到目标化合物SIAIS213068(淡黄色固体,120mg,两步收率40.7％)。 1H NMR(500MHz,DMSO)δ11.03(s,1H),7.86(s,3H),7.69(dt,J＝7.7,3.9Hz,1H),7.63–7.50(m,2H),5.15(dd,J＝13.3,5.1Hz,1H),4.31(dd,J＝70.7,17.4Hz,2H),3.67–3.46(m,8H),3.32–3.23(m,2H),3.01–2.83(m,3H),2.61(d,J＝16.6Hz,1H),2.49–2.40(m,1H),2.09–1.95(m,1H).
中间体制备例40：制备3-(4-((2-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS213111)
根据所述的方案4的方法、在本领域可理解的适当条件下制备化合物SIAIS213111，不同之处在于采用的作为linker的溴代底物是(2-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)乙基)氨基甲酸叔丁酯。得到目标化合物SIAIS213111(无色油状液体,140mg,两步收率85.6％)。 1H NMR(500MHz,DMSO)δ11.00(s,1H),7.82(s,3H),7.69(dd,J＝7.7,0.8Hz,1H),7.59(dt,J＝11.3,5.6Hz,1H),7.54(t,J＝7.6Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.44–4.14(m,2H),3.62(t,J＝6.4Hz,2H),3.60–3.56(m,4H),3.55–3.51(m,6H),3.31–3.20(m,2H),2.99 –2.87(m,3H),2.60(d,J＝17.5Hz,1H),2.49–2.37(m,1H),2.06–1.94(m,1H).LCMS(ESI)m/z:计算值C 21H 30N 3O 6S +[M+H] +,452.1850；实测值,452.35.
硫基取代来那度胺碳链末端溴系列LIN-ULM通用方法：
Figure PCTCN2019081840-appb-000227
将化合物SIAIS171095(1equiv)加入一个25mL的反应瓶中，随后加入无水N,N-二甲基甲酰胺(10mL)和无水碳酸钾(2equiv)，室温搅拌下缓慢加入不同的二溴代物(1.2equiv),滴完室温搅拌1h。原料反应完后，加水淬灭，乙酸乙酯萃取，将有机相浓缩，粗品经反相C18柱分离，洗脱剂(v/v)：乙腈/水＝10％–100％，减压蒸去溶剂，冻干得目标化合物。
中间体制备例41：制备3-(4-(2-溴乙基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS213137)
根据所述的方案7的方法、在本领域可理解的适当条件下制备化合物SIAIS213137，不同之处在于采用的作为linker的溴代底物是1，2-二溴乙烷。得到目标化合物SIAIS213137(淡黄色固体,78mg,收率18.7％)。 1H NMR(500MHz,CDCl 3)δ8.00(s,1H),7.83–7.76(m,1H),7.57(t,J＝7.1Hz,1H),7.50(dd,J＝17.4,9.8Hz,1H),5.23(dt,J＝15.9,7.9Hz,1H),4.46(d,J＝16.5Hz,1H),4.37–4.27(m,1H),3.51–3.43(m,2H),3.41–3.33(m,2H),2.94(d,J＝15.1Hz,1H),2.90–2.78(m,1H),2.46–2.35(m,1H),2.29–2.20(m,1H).LCMS(ESI)m/z:计算值C 15H 16BrN 2O 3S +[M+H] +,383.0060\385.0039；实测值,383.11\385.12.
中间体制备例42：制备3-(4-(3-溴丙基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS213132)
根据所述的方案7的方法、在本领域可理解的适当条件下制备化合物SIAIS213132，不同之处在于采用的作为linker的溴代底物是1，3-二溴丙烷。得到目标化合物SIAIS213132(淡黄色固体,130mg,收率30.1％)。 1H NMR(500MHz,CDCl 3)δ8.01(s,1H),7.76(t,J＝11.2Hz,1H),7.57–7.43(m,2H),5.28–5.18(m,1H),4.46–4.25(m,2H),3.62–3.50(m,2H),3.16(t,J＝7.0Hz,2H),2.98–2.77(m,2H),2.46–2.33(m,1H),2.28–2.13(m,3H).LCMS(ESI)m/z:计算值C 16H 18BrN 2O 3S +[M+H] +,397.0216\399.0196；实测值,397.15\399.11.
中间体制备例43：制备3-(4-(4-溴丁基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS213134)
根据所述的方案7的方法、在本领域可理解的适当条件下制备化合物SIAIS213134，不同之处在于采用的作为linker的溴代底物是1，4-二溴丁烷。得到目标化合 物SIAIS213134(淡黄色固体,170mg,收率38.1％)。 1H NMR(500MHz,CDCl 3)δ8.00(s,1H),7.74(t,J＝8.7Hz,1H),7.55–7.44(m,2H),5.23(dt,J＝20.5,10.3Hz,1H),4.33(ddd,J＝33.1,25.9,11.5Hz,2H),3.48–3.35(m,2H),3.01(dd,J＝20.7,13.5Hz,2H),2.97–2.81(m,2H),2.41(ddd,J＝26.6,13.3,4.8Hz,1H),2.28–2.19(m,1H),2.09–1.96(m,2H),1.89–1.86(m,2H).LCMS(ESI)m/z:计算值C 17H 20BrN 2O 3S +[M+H] +,411.0373\413.0352；实测值,411.10\413.11.
中间体制备例44：制备3-(4-(5-溴戊基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS213135)
根据所述的方案7的方法、在本领域可理解的适当条件下制备化合物SIAIS213135，不同之处在于采用的作为linker的溴代底物是1，5-二溴戊烷。得到目标化合物SIAIS213135(淡黄色固体,190mg,收率41.1％)。 1H NMR(500MHz,CDCl 3)δ8.05(d,J＝28.3Hz,1H),7.76–7.69(m,1H),7.52–7.41(m,2H),5.26–5.18(m,1H),4.47–4.24(m,2H),3.41(t,J＝6.6Hz,2H),2.99(dd,J＝17.3,10.1Hz,2H),2.95–2.79(m,2H),2.39(tdd,J＝22.4,15.4,7.4Hz,1H),2.31–2.19(m,1H),1.93–1.84(m,2H),1.73–1.70(m,2H),1.69–1.63(m,2H).LCMS(ESI)m/z:计算值C 18H 22BrN 2O 3S +[M+H] +,425.0529\427.0509；实测值,425.10\427.10.
中间体制备例45：制备3-(4-(6-溴己基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS1216133)
根据所述的方案7的方法、在本领域可理解的适当条件下制备化合物SIAIS1216133，不同之处在于采用的作为linker的溴代底物是1，6-二溴己烷。得到目标化合物SIAIS1216133(白色固体，339mg，收率38％)。 1H NMR(500MHz,DMSO)δ11.01(s,1H),7.63(dd,J＝7.5,1.2Hz,1H),7.58–7.51(m,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.35(d,J＝17.4Hz,1H),4.21(d,J＝17.4Hz,1H),3.52(t,J＝6.7Hz,2H),3.08(t,J＝7.2Hz,2H),2.96-2.87(m,1H),2.59(d,J＝17.4Hz,1H),2.49–2.41(m,1H),2.04–1.97(m,1H),1.82–1.74(m,2H),1.63–1.56(m,2H),1.46–1.36(m,4H).HRMS(ESI)m/z:计算值C 19H 24BrN 2O 3S +[M+H] +,439.0686；实测值,439.0680。
中间体制备例46：制备3-(4-(7-溴庚基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS1216135)
根据所述的方案7的方法、在本领域可理解的适当条件下制备化合物SIAIS1216135，不同之处在于采用的作为linker的溴代底物是1，7-二溴庚烷。得到目标化合物SIAIS1216135(白色固体，212mg，收率23％)。 1H NMR(500MHz,DMSO)δ11.02(s,1H),7.63(dd,J＝7.5,0.9Hz,1H),7.58–7.51(m,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.35(d,J＝17.4Hz,1H),4.21(d,J＝17.4Hz,1H),3.52(t,J＝6.7Hz,2H),3.08(t,J＝7.2Hz,2H),2.96–2.87(m,1H),2.63-2.56(m,1H),2.49–2.40(m,1H),2.04-1.97(m,1H),1.82–1.73(m,2H),1.63–1.56 (m,2H),1.44–1.27(m,6H).HRMS(ESI)m/z:计算值C 20H 26BrN 2O 3S +[M+H] +,453.0842；实测值,453.0840.
中间体制备例47：制备3-(4-((8-溴辛基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS1216137)
根据所述的方案7的方法、在本领域可理解的适当条件下制备化合物SIAIS1216137，不同之处在于采用的作为linker的溴代底物是1，8-二溴辛烷。得到目标化合物SIAIS1216137(白色固体，351mg，收率38％)。 1H NMR(500MHz,DMSO)δ11.01(s,1H),7.63(dd,J＝7.5,1.1Hz,1H),7.57–7.51(m,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.35(d,J＝17.4Hz,1H),4.20(d,J＝17.4Hz,1H),3.51(t,J＝6.7Hz,2H),3.08(t,J＝7.3Hz,2H),2.95–2.87(m,1H),2.63-2.55(m,1H),2.49–2.41(m,1H),2.03–1.97(m,1H),1.81–1.73(m,2H),1.64-1.55(m,2H),1.44-1.32(m,4H),1.31–1.23(m,4H).HRMS(ESI)m/z:计算值C 21H 28BrN 2O 3S +[M+H] +,467.0999；实测值,467.0996.
中间体制备例48：制备3-(4-((9-溴壬基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS1220059)
根据所述的方案7的方法、在本领域可理解的适当条件下制备化合物SIAIS1220059，不同之处在于采用的作为linker的溴代底物是1，9-二溴壬烷。得到目标化合物SIAIS1220059(白色固体，400mg，收率42％)。 1H NMR(500MHz,DMSO)δ11.00(s,1H),7.62(dd,J＝7.5,0.9Hz,1H),7.59–7.50(m,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.35(d,J＝17.4Hz,1H),4.21(d,J＝17.4Hz,1H),3.51(t,J＝6.7Hz,2H),3.07(t,J＝7.2Hz,2H),2.95–2.86(m,1H),2.59(d,J＝17.4Hz,1H),2.49–2.40(m,1H),2.04–1.97(m,1H),1.81–1.72(m,2H),1.63–1.56(m,2H),1.42–1.31(m,4H),1.28-1.22(m,6H).HRMS(ESI)m/z:计算值C 22H 30BrN 2O 3S +[M+H] +,481.1155；实测值,481.1152.
中间体制备例49：制备3-(4-((10-溴癸基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS1220013)
根据所述的方案7的方法、在本领域可理解的适当条件下制备化合物SIAIS1220013，不同之处在于采用的作为linker的溴代底物是1，10-二溴癸烷。得到目标化合物SIAIS1220013(淡黄色固体，329mg，收率33％)。 1H NMR(500MHz,DMSO)δ11.01(s,1H),7.62(d,J＝7.5Hz,1H),7.58-7.51(m,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.35(d,J＝17.4Hz,1H),4.20(d,J＝17.4Hz,1H),3.52(t,J＝6.7Hz,2H),3.08(t,J＝7.2Hz,2H),2.95–2.87(m,1H),2.62-2.56(m,1H),2.49–2.42(m,1H),2.03–1.97(m,1H),1.81–1.73(m,2H),1.62–1.55(m,2H),1.43–1.32(m,4H),1.24(s,8H).HRMS(ESI)m/z:计算值C 23H 32BrN 2O 3S +[M+H] +,495.1312；实测值,495.1310.
中间体制备例50：制备3-(4-((11-溴十一烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS1220015)
根据所述的方案7的方法、在本领域可理解的适当条件下制备化合物SIAIS1220015，不同之处在于采用的作为linker的溴代底物是1，11-二溴十一烷。得到目标化合物SIAIS1220015(白色固体，276mg，收率27％)。 1H NMR(500MHz,DMSO)δ11.01(s,1H),7.64–7.60(m,1H),7.58–7.51(m,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.35(d,J＝17.4Hz,1H),4.20(d,J＝17.4Hz,1H),3.52(t,J＝6.7Hz,2H),3.08(t,J＝7.2Hz,2H),2.96–2.86(m,1H),2.63-2.56(m,1H),2.49–2.40(m,1H),2.03–1.96(m,1H),1.82–1.73(m,2H),1.62–1.54(m,2H),1.42-1.32(m,4H),1.24(s,10H).HRMS(ESI)m1/z:计算值C 24H 34BrN 2O 3S +[M+H] +,509.1468；实测值,509.1466.
中间体制备例51：制备3-(4-((12-溴十二烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS264005)
根据所述的方案7的方法、在本领域可理解的适当条件下制备化合物SIAIS264005，不同之处在于采用的作为linker的溴代底物是1，12-二溴十二烷。得到目标化合物SIAIS264005(白色固体，310mg，收率34％)。HRMS(ESI)m1/z:计算值C 25H 36BrN 2O 3S +[M+H] +,523.1625；实测值,523.1624.
中间体制备例52：制备3-(4-((4-(溴甲基)苄基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS1220141)
根据所述的方案7的方法、在本领域可理解的适当条件下制备化合物SIAIS1220141，不同之处在于采用的作为linker的溴代底物是1，11-二溴十一烷。得到目标化合物SIAIS1220141(淡黄色固体，247mg，收率27％)。 1H NMR(500MHz,DMSO)δ11.00(s,1H),7.67(dd,J＝7.7,0.7Hz,1H),7.58(d,J＝6.9Hz,1H),7.50(t,J＝7.6Hz,1H),7.43-7.31(m,4H),5.10(dd,J＝13.3,5.1Hz,1H),4.67(s,2H),4.34(s,2H),4.24(d,J＝17.4Hz,1H),4.13(d,J＝17.4Hz,1H),2.95-2.86(m,1H),2.58(d,J＝16.6Hz,1H),2.45–2.35(m,1H),2.00–1.94(m,1H).HRMS(ESI)m/z:计算值C 21H 20BrN 2O 3S +[M+H] +,459.0373；实测值,459.0370.
硫基取代泊马度胺碳链末端溴系列LIN-ULM通用方法：
Figure PCTCN2019081840-appb-000228
将化合物SIAIS151014(1equiv)加入一个25mL的反应瓶中，随后加入无水N,N-二甲基甲酰胺(10mL)和无水碳酸钾(2equiv)，室温搅拌下缓慢加入不同的二溴代物(1.2equiv),滴完室温搅拌1h。原料反应完后，加水淬灭，乙酸乙酯萃取，将有机相浓缩，粗品经反相C18柱分离，洗脱剂(v/v)：乙腈/水＝10％–100％，减压蒸去溶剂，冻干得目标化合物。
中间体制备例53：制备4-(2-溴乙基硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS213162)
根据所述的方案8的方法、在本领域可理解的适当条件下制备化合物SIAIS213162，不同之处在于采用的作为linker的溴代底物是1，2-二溴乙烷。得到目标化合物SIAIS213162(淡黄色固体,310mg,收率45.3％), 1H NMR(500MHz,CDCl 3)δ8.00(s,1H),7.74–7.65(m,2H),7.55(d,J＝7.5Hz,1H),4.97(dd,J＝12.4,5.3Hz,1H),3.61–3.46(m,4H),2.93–2.73(m,3H),2.19–2.09(m,1H).LCMS(ESI)m/z:计算值C 15H 14BrN 2O 4S +[M+H] +,396.9852\398.9832；实测值,397.01\399.00.
中间体制备例54：制备4-(3-溴丙基硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS213159)
根据所述的方案8的方法、在本领域可理解的适当条件下制备化合物SIAIS213159，不同之处在于采用的作为linker的溴代底物是1，3-二溴丙烷。得到目标化合物SIAIS213159(淡黄色固体,260mg,收率36.7％), 1H NMR(500MHz,CDCl 3)δ8.05(s,1H),7.67(td,J＝16.9,8.0Hz,2H),7.58(d,J＝7.8Hz,1H),4.98(dd,J＝12.4,5.3Hz,1H),3.58(t,J＝6.2Hz,2H),3.25(t,J＝7.1Hz,2H),2.96–2.69(m,3H),2.34–2.25(m,2H),2.20–2.11(m,1H).LCMS(ESI)m/z:计算值C 16H 16BrN 2O 4S +[M+H] +,411.0009\412.9988；实测值,411.01\413.06.
中间体制备例55：制备4-((4-溴丁基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS213165)
根据所述的方案8的方法、在本领域可理解的适当条件下制备化合物SIAIS213165，不同之处在于采用的作为linker的溴代底物是1，4-二溴丁烷。得到目标化合物SIAIS213165(淡黄色固体,520mg,收率35.4％), 1H NMR(500MHz,CDCl 3)δ8.01(s,1H),7.71–7.57(m,2H),7.51(t,J＝15.9Hz,1H),4.98(dd,J＝12.3,5.3Hz,1H),3.46(t,J＝6.4Hz,2H),3.10(t,J＝7.1Hz,2H),2.98–2.69(m,3H),2.20–2.12(m,1H),2.11–2.02(m,2H),2.00–1.88(m,2H).LCMS(ESI)m/z:计算值C 17H 18BrN 2O 4S +[M+H] +,425.0165\427.0145；实测值,425.00\427.01.
中间体制备例56：制备4-((5-溴戊基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS213166)
根据所述的方案8的方法、在本领域可理解的适当条件下制备化合物SIAIS213166，不同之处在于采用的作为linker的溴代底物是1，5-二溴戊烷。得到目标化合物SIAIS213166(淡黄色固体,540mg,收率35.8％), 1H NMR(500MHz,CDCl 3)δ8.01(s,1H),7.68–7.58(m,2H),7.50(dt,J＝15.0,7.5Hz,1H),4.97(dd,J＝12.4,5.3Hz,1H),3.43(t,J＝6.7Hz,2H),3.08(t,J＝7.3Hz,2H),2.97–2.65(m,3H),2.20–2.09(m,1H),1.97–1.87(m,2H),1.81(dt,J＝15.0,7.4Hz,2H),1.67(ddd,J＝15.7,9.1,6.1Hz,2H).LCMS(ESI)m/z:计算值C 18H 20BrN 2O 4S +[M+H] +,439.0322\441.0301；实测值,439.05\440.96.
硫基取代泊马度胺/来那度胺碳链末端叠氮系列LIN-ULM通用方法：
Figure PCTCN2019081840-appb-000229
将溴代物(1equiv)加入一个25mL的反应瓶中，随后加入无水N,N-二甲基甲酰胺(10mL)，室温搅拌下缓慢加入叠氮钠(1.2equiv),加完室温搅拌1h。原料反应完后，加水淬灭，乙酸乙酯萃取，有机相用水洗两遍，饱和食盐水洗一遍，无水硫酸钠干燥，过滤浓缩得到粗品目标化合物。
中间体制备例57：制备4-((2-叠氮基乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS213163)
根据所述的方案9的方法、在本领域可理解的适当条件下制备化合物SIAIS213163，不同之处在于采用的作为linker的溴代底物是SIAIS213162。得到目标化合物SIAIS213163(淡黄色固体,65mg,收率89.8％), 1H NMR(500MHz,CDCl 3)δ8.05(s,1H),7.67(t,J＝5.5Hz,2H),7.60–7.53(m,1H),5.03–4.93(m,1H),3.62(t,J＝7.0Hz,2H),3.28(t,J＝7.0Hz,2H),2.87–2.68(m,3H),2.18–2.09(m,1H).LCMS(ESI)m/z:计算值C 15H 14N 5O 4S +[M+H] +,360.0761；实测值,332.22.
中间体制备例58：制备4-((3-叠氮基丙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS213161)
根据所述的方案9的方法、在本领域可理解的适当条件下制备化合物SIAIS213161，不同之处在于采用的作为linker的溴代底物是SIAIS213159。得到目标化合物SIAIS213161(淡黄色固体,80mg,收率73.4％), 1H NMR(500MHz,CDCl 3)δ8.02(s,1H),7.72–7.59(m,2H),7.54(d,J＝7.8Hz,1H),4.97(dd,J＝12.4,5.4Hz,1H),3.52(t,J＝6.3Hz,2H),3.16(t,J＝7.2Hz,2H),2.92–2.70(m,3H),2.22–2.09(m,1H),2.07–1.96(m,2H).LCMS(ESI)m/z:计算值C 16H 16N 5O 4S +[M+H] +,374.0918；实测值,346.06.
中间体制备例59：制备3-(4-((3-叠氮基丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS287035)
根据所述的方案9的方法、在本领域可理解的适当条件下制备化合物SIAIS287035，不同之处在于采用的作为linker的溴代底物是SIAIS213132。得到目标化合物SIAIS287035(白色固体,21mg,收率23％), 1H NMR(500MHz,Chloroform-d)δ8.21(s,1H),7.74(dd,J＝1.5,7.0Hz,1H),7.47-7.54(m,2H),5.22-5.25(m,1H),4.43(d,J＝16.5Hz,1H),4.29(d,J＝16.5Hz,1H),3.47(t,J＝6.0Hz,2H),3.08(t,J＝6.0Hz,2H),2.91-2.93(m,1H),2.79-2.87(m,1H),2.36-2.45(m,1H),2.21-2.26(m,1H),1.89-1.95(m,2H).HRMS:calcd for HRMS(ESI)计算值C 16H 17N 5O 3S[M+H] +360.1052,实测值360.1154.
中间体制备例60：制备3-(4-((4-叠氮基丁基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS287036)
根据所述的方案9的方法、在本领域可理解的适当条件下制备化合物SIAIS287036，不同之处在于采用的作为linker的溴代底物是SIAIS213134。得到目标化合物SIAIS287036(白色固体,43mg,收率47％), 1H NMR(500MHz,Chloroform-d)δ8.07(s,1H),7.73(dd,J＝1.5,7.0Hz,1H),7.46-7.52(m,2H),5.22-5.26(m,1H),4.42(d,J＝16.5Hz,1H),4.29(d,J＝16.5Hz,1H),3.29-3.35(m,2H),3.00-3.04(m,2H),2.91-2.93(m,1H),2.80-2.88(m,1H),2.36-2.45(m,1H),2.19-2.26(m,1H),1.71-1.78(m,4H).HRMS(ESI)计算值C 17H 19N 5O 3S[M+H] +374.1209,实测值374.1282.
中间体制备例61：制备3-(4-((5-叠氮基戊基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS287037)
根据所述的方案9的方法、在本领域可理解的适当条件下制备化合物SIAIS287037，不同之处在于采用的作为linker的溴代底物是SIAIS213135。得到目标化合物SIAIS287037(白色固体,70mg,收率77％), 1H NMR(500MHz,Chloroform-d)δ8.27(s,1H),7.72(dd,J＝1.5,7.0Hz,1H),7.45-7.51(m,2H),5.21-5.25(m,1H),4.42(d,J＝16.5Hz,1H),4.28(d,J＝16.5Hz,1H),3.28(t,J＝6.5Hz,2H),3.00(t,J＝6.5Hz,2H),2.930-2.93(m,1H),2.79-2.87(m,1H),2.36-2.45(m,1H),2.21-2.26(m,1H),1.65-1.73(m,2H),1.58-1.64(m,2H),1.50-1.57(m,2H).HRMS(ESI)计算值C 18H 21N 5O 3S[M+H] +388.1365,实测值388.1443.
中间体制备例62：制备3-(4-((8-叠氮基辛基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS287038)
根据所述的方案9的方法、在本领域可理解的适当条件下制备化合物SIAIS287038，不同之处在于采用的作为linker的溴代底物是SIAIS1216137。得到目标化合物SIAIS287038(白色固体,65mg,收率71％), 1H NMR(500MHz,Chloroform-d)δ8.06(s,1H),7.71(dd,J＝1.5,7.0Hz,1H),7.45-7.50(m,2H),5.22-5.25(m,1H),4.41(d,J＝16.5Hz,1H),4.27(d,J＝16.5Hz,1H),3.26(t,J＝6.5Hz,2H),2.99(t,J＝6.5Hz,2H),2.91-2.92(m,1H),2.86-2.88(m,1H),2.35-2.43(m,1H),2.20-2.25(m,1H),1.64-1.70(m,2H),1.56-1.59(m,2H),1.42-1.46(m,2H),1.31-1.38(m,6H).HRMS(ESI)计算值C 21H 27N 5O 3S[M+H] +430.1835,实测值430.1909.
中间体制备例63：制备3-(4-((9-叠氮基壬基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS287039)
根据所述的方案9的方法、在本领域可理解的适当条件下制备化合物SIAIS287039，不同之处在于采用的作为linker的溴代底物是SIAIS1220059。得到目标化合物SIAIS287039(淡黄色固体,80mg,收率73.4％), 1H NMR(500MHz,Chloroform-d)δ8.17(s,1H),7.71(dd,J＝1.5,7.0Hz,1H),7.44-7.50(m,2H),5.22-5.25(m,1H),4.41(d,J＝16.5Hz,1H),4.27(d,J＝16.5Hz,1H),3.26(t,J＝6.5Hz,2H),2.98(t,J＝6.5Hz,2H),2.90-2.93(m,1H),2.80-2.87 (m,1H),2.35-2.44(m,1H),2.20-2.25(m,12H),1.63-1.67(m,2H),1.54-1.62(m,2H),1.41-1.45(m,2H),1.29-1.39(m,8H).HRMS(ESI)计算值C 22H 29N 5O 3S[M+H] +444.1991,实测值444.2063.
中间体制备例64：制备3-(4-((10-叠氮基癸基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS287040)
根据所述的方案9的方法、在本领域可理解的适当条件下制备化合物SIAIS287040，不同之处在于采用的作为linker的溴代底物是SIAIS1220013。得到目标化合物SIAIS287040(白色固体,66mg,收率72％), 1H NMR(500MHz,Chloroform-d)δ8.05(s,1H),7.71(dd,J＝1.5,7.0Hz,1H),7.44-7.50(m,2H),5.21-5.25(m,1H),4.41(d,J＝16.5Hz,1H),4.27(d,J＝16.5Hz,1H),3.26(t,J＝6.5Hz,2H),2.98(t,J＝6.5Hz,2H),2.90-2.93(m,1H),2.84-2.88(m,1H),2.35-2.44(m,1H),2.21-2.25(m,1H),1.62-1.68(m,2H),1.54-1.61(m,2H),1.41-1.47(m,2H),1.28-1.38(m,10H).HRMS(ESI)计算值C 23H 31N 5O 3S[M+H] +458.2148,实测值458.2239.
中间体制备例65：制备3-(4-((11-叠氮基十一烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS287041)
根据所述的方案9的方法、在本领域可理解的适当条件下制备化合物SIAIS287041，不同之处在于采用的作为linker的溴代底物是SIAIS1220015。得到目标化合物SIAIS287041(白色固体,60mg,收率65％), 1H NMR(500MHz,Chloroform-d)δ9.09(s,1H),7.69(dd,J＝1.5,7.0Hz,1H),7.44-7.50(m,2H),5.21-5.25(m,1H),4.42(d,J＝16.5Hz,1H),4.28(d,J＝16.5Hz,1H),3.26(t,J＝6.5Hz,2H),2.99(d,J＝6.5Hz,2H),2.98-3.02(m,1H),2.79-2.86(m,1H),2.35-2.44(m,1H),2.20-2.23(m,1H),1.64-1.70(m,2H),1.56-1.62(m,2H),1.41-1.45(m,2H),1.26-1.38(m,12H).HRMS(ESI)计算值C 24H 33N 5O 3S[M+H] +472.2304,实测值472.2388.
中间体制备例66：制备3-(4-((12-叠氮基十二烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS287042)
根据所述的方案9的方法、在本领域可理解的适当条件下制备化合物SIAIS287042，不同之处在于采用的作为linker的溴代底物是SIAIS264005。得到目标化合物SIAIS287042(白色固体,60mg,收率65％), 1H NMR(500MHz,Chloroform-d)δ7.97(s,1H),7.71(dd,J＝1.5,6.0Hz,1H),7.44-7.50(m,2H),5.21-5.25(m,1H),4.41(d,J＝16.5Hz,1H),4.27(d,J＝16.5Hz,1H),3.25(t,J＝6.5Hz,2H),2.98(t,J＝6.5Hz,2H),2.90-2.96(m,1H),2.80-2.88(m,1H),2.35-2.44(m,1H),2.20-2.25(m,1H),1.64-1.68(m,2H),1.56-1.59(m,2H),1.41-1.44(m,2H),1.26-1.39(m,14H).HRMS(ESI)计算值C 25H 35N 5O 3S[M+H] +486.2461,实测值486.2543.
一些特殊中间体LIN-ULM的通用制备方法：
Figure PCTCN2019081840-appb-000230
将化合物SIAIS151014(0.69mmol,1equiv)加入一个25mL的反应瓶中，随后加入无水N,N-二甲基甲酰胺(6mL)和无水碳酸钾(1.38mmol,2equiv)，室温搅拌下缓慢加入溴代物(0.83mmol,1.2equiv),滴完室温搅拌1h。原料反应完后，加水淬灭，乙酸乙酯萃取，浓缩后粗品经反相C18柱分离，洗脱剂(v/v)：乙腈/水＝10％–100％，减压蒸去溶剂，冻干得中间体化合物；将该化合物加入10mL的反应瓶中，随后加入无水二氯甲烷(4mL)和三氟乙酸(1mL)，室温搅拌2h.减压蒸去反应溶剂，加水冻干得目标化合物(SIAIS213066)。
中间体制备例67：制备4-((2-(2-(2-氨基乙氧基)乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS213066)
根据所述的方案10的方法、在本领域可理解的适当条件下制备化合物SIAIS213066，采用的作为linker的溴代底物是(2-(2-(2-溴乙氧基)乙氧基)乙基)氨基甲酸叔丁酯，得到目标化合物SIAIS213066(淡黄色固体,120mg,两步收率41.3％)。 1H NMR(500MHz,DMSO)δ11.16(d,J＝7.7Hz,1H),7.89(ddd,J＝21.0,10.5,3.6Hz,3H),7.82–7.74(m,2H),7.65(p,J＝4.9Hz,1H),5.18–5.05(m,1H),3.78–3.68(m,2H),3.63–3.58(m,6H),3.36(t,J＝6.2Hz,2H),3.04–2.94(m,2H),2.90(ddd,J＝17.2,13.9,5.4Hz,1H),2.68–2.53(m,2H),2.13–2.00(m,1H).
Figure PCTCN2019081840-appb-000231
室温下，在反应瓶中，加入SIAIS151144或SIAIS171090(1equiv)，(4-氨基丁基)氨基甲酸叔丁酯(1equiv),无水N,N-二甲基甲酰胺(2mL)，HATU(1.5equiv),DIPEA(3equiv)，室温下搅拌反应过夜。LC-MS检测反应结束后，粗品经反相C18柱分离，洗脱剂(v/v)：乙腈/(水+0.05％TFA)＝10％–100％，减压蒸去溶剂，冻干得目标化合物；将该系列化合物加入10mL的反应瓶中，随后加入无水二氯甲烷(4mL)和三氟乙酸(1mL)，室温搅拌3h.减压蒸去反应溶剂，加水冻干得相应的目标化合物(SIAIS213073；或SIAIS213092)。
中间体制备例68：制备N-(4-氨基丁基)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰胺(SIAIS213073)
根据所述的方案11的方法、在本领域可理解的适当条件下制备化合物SIAIS213073，不同之处在于采用的酸底物是SIAIS151144。得到目标化合物SIAIS213073(淡黄色固体,45mg,两步收率75.1％)。 1H NMR(500MHz,DMSO)δ11.13(s,1H),8.34(t,J＝5.7Hz,1H),7.74(ddd,J＝50.2,19.3,7.5Hz,6H),5.13(dd,J＝12.9,5.4Hz,1H),3.87(s,2H),3.10(q,J＝6.5Hz,2H),2.89(ddd,J＝17.2,14.0,5.4Hz,1H),2.77(dt,J＝12.8,6.2Hz,2H),2.66–2.51(m,2H),2.14–1.97(m,1H),1.54–1.42(m,4H).LCMS(ESI)m/z:计算值C 19H 23N 4O 5S +[M+H] +,419.1384；实测值,419.35.
中间体制备例69：制备N-(4-氨基丁基)-2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰胺(SIAIS213092)
根据所述的方案11的方法、在本领域可理解的适当条件下制备化合物SIAIS213092，不同之处在于采用的酸底物是SIAIS171090，得到目标化合物SIAIS213092(淡黄色固体,60mg,两步收率99.1％)。 1H NMR(500MHz,MeOD)δ7.72(d,J＝7.7Hz,2H),7.55(t,J＝7.7Hz,1H),5.17(dd,J＝13.4,5.2Hz,1H),4.51(q,J＝17.4Hz,2H),3.73–3.63(m,2H),3.19–3.10(m,2H),2.93–2.76(m,4H),2.53(qd,J＝13.3,4.7Hz,1H),2.19(dtd,J＝12.8,5.3,2.4Hz,1H),1.54–1.38(m,4H).LCMS(ESI)m/z:计算值C 19H 25N 4O 4S +[M+H] +,405.1591；实测值,405.34.
Figure PCTCN2019081840-appb-000232
步骤1：将化合物(SIAIS151033)(1.1mmol,1equiv)加入100mL的蛋形瓶中，随后加入无水二氯甲烷(20mL),室温搅拌下缓慢加入间氯过氧苯甲酸(4.4mmol,4equiv)，加完后缓慢升温至40℃并搅拌4h。反应结束后，将反应混合物降至室温，用10％碳酸氢钠水溶液调至反应液pH＝8-9，二氯甲烷萃取(2x 30mL),合并有机相，水洗(2x 20mL),饱和食盐水洗(50mL),无水硫酸钠干燥，减压蒸去溶剂，粗品(洗脱剂(v/v)：石油醚/乙酸乙酯＝1:1)纯化得到氧化产物亚砜或砜的化合物(SIAIS151048A；SIAIS151048B)。
步骤2：将所述亚砜或砜的化合物加入25mL的蛋形瓶中，随后加入88％的甲酸(5mL),室温搅拌12h.减压蒸去反应溶剂，加水冻干得到脱除叔丁酯的水解产物(SIAIS151107；SIAIS151106)。
中间体制备例70：制备叔丁基2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)乙酸酯(SIAIS151048B)
根据所述的方案12的方法、在本领域可理解的适当条件下制备化合物SIAIS151048B，不同之处在于采用的作为linker的溴代底物是叔丁基2-溴乙酸酯。得到目标化合物SIAIS151048B(淡黄色固体，0.2g,收率39％)。 1H NMR(500MHz,CDCl 3)δ8.40–8.35(m,1H),8.17(s,1H),8.06–8.00(m,2H),5.00–4.96(m,1H),4.09(d,J＝13.8Hz,1H),3.78(dd,J＝14.6,14.0Hz,1H),2.96–2.89(m,1H),2.88–2.71(m,2H),2.23–2.13(m,1H),1.41(d,J＝4.4Hz,9H).HRMS(ESI)m/z:计算值C 19H 21N 2O 7S +[M-56+H] +,365.0438；实测值,365.0295.
中间体制备例71：制备叔丁基2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)乙酸酯(SIAIS151048A)
根据所述的方案12的方法、在本领域可理解的适当条件下制备化合物SIAIS151048A，不同之处在于采用的作为linker的溴代底物是叔丁基2-溴乙酸酯。得到目标化合物SIAIS151048A(淡黄色固体,0.3g,收率59％)。 1H NMR(500MHz,CDCl 3)δ8.42(dd,J＝7.9,0.9Hz,1H),8.19(dd,J＝7.5,0.9Hz,1H),8.12(s,1H),8.00(t,J＝7.7Hz,1H),5.03(dd,J＝12.6,5.4Hz,1H),4.72–4.64(m,2H),2.96–2.72(m,3H),2.26–2.17(m,1H),1.30(s,9H).HRMS(ESI)m/z:计算值C 19H 21N 2O 8S +[M-56+H] +,381.0387；实测值,381.0241.
中间体制备例72：制备2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)乙酸(SIAIS151107)
根据所述的方案12的方法、在本领域可理解的适当条件下制备化合物SIAIS151107，不同之处在于采用的作为linker的溴代底物是叔丁基2-溴乙酸酯。得到目标化合物SIAIS151107(淡黄色固体,0.16g,收率92％)。 1H NMR(500MHz,DMSO)δ11.18(s,1H),8.24–8.20(m,1H),8.13(t,J＝7.6Hz,1H),8.10–8.08(m,1H),5.17(dd,J＝12.9,5.4Hz,1H),4.22(dd,J＝28.5,14.9Hz,1H),3.75(d,J＝14.9Hz,1H),2.92–2.84(m,1H),2.63–2.59(m,1H),2.48–2.44(m,1H),2.11–2.00(m,1H).HRMS(ESI)m/z:计算值C 15H 13N 2O 7S +[M+H] +,365.0438；实测值,365.0498.
中间体制备例73：制备2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)乙酸(SIAIS151106)
根据所述的方案12的方法、在本领域可理解的适当条件下制备化合物SIAIS151106，不同之处在于采用的作为linker的溴代底物是叔丁基2-溴乙酸酯。得到目标化合物SIAIS151106(淡黄色固体,0.25g,收率96％)。 1H NMR(500MHz,DMSO)δ11.20(s,1H),8.35–8.25(m,2H),8.14(t,J＝7.7Hz,1H),5.23(dd,J＝12.9,5.4Hz,1H),4.96–4.73(m,2H), 2.93–2.86(m,1H),2.66–2.51(m,2H),2.13–2.08(m,1H).HRMS(ESI)m/z:计算值C 15H 13N 2O 8S +[M+H] +,381.0387；实测值,381.0452.
中间体制备例74：根据方案6制备2-(2,6-二氧代哌啶-3-基)-4-(哌嗪-1-基)异吲哚啉-1,3-二酮(SIAIS151024)
Figure PCTCN2019081840-appb-000233
将2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮(200mg,0.72mmol)，无水哌嗪(93.6mg,1.08mmol)，N,N-二异丙基乙胺(467.6mg,3.60mmol)和无水N-甲基吡咯烷酮(3mL)一起加入10mL的微波反应管中,然后缓慢向微波管中鼓入氩气，密封后，将反应管放入微波反应器中，升至120℃并搅拌1h。LC-MS检测反应结束后，反应液经HPLC制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)。旋蒸除去乙腈，冻干后得目标化合物(SIAIS151024)(黄色固体,0.11g，收率36％)。 1H NMR(500MHz,DMSO)δ11.10(s,1H),9.01(s,1H),7.76(dd,J＝8.3,7.3Hz,1H),7.45(d,J＝7.0Hz,1H),7.42(d,J＝8.0Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),3.52–3.46(m,4H),3.29–3.25(m,4H),2.92–2.85(m,1H),2.65–2.54(m,2H),2.05–1.99(m,1H).HRMS(ESI)m/z:计算值C 17H 19N 4O 4 +[M+H] +,343.1401；实测值,343.1450.
布加替尼衍生物A、B、C通用制备方法：
Figure PCTCN2019081840-appb-000234
中间体制备例75：根据方案14合成布加替尼衍生物A(SIAIS1197135)：
步骤1：根据方案14制备叔丁基4-(3-甲氧基-4-硝基苯基)哌嗪-1-甲酸酯(SIAIS1197111):
敞口条件下，5-氟-2-硝基苯甲醚(7g,40.9mmol)溶于N,N-二甲基甲酰胺(60mL)中，依次加入碳酸钾(8.4g,60.8mmol)，N-叔丁氧羰基哌嗪(9.1g,48.9mmol)，室温搅拌过夜。反应结束后，水淬灭，乙酸乙酯萃取，有机相水洗，饱和食盐水洗涤，无水硫酸钠干燥，蒸发溶剂，采用石油醚:乙酸乙酯＝5:1的混合溶剂打浆，砂芯过滤得到化合物(SIAIS1197111)(黄色固体,11.1g,收率为80％)。 1H NMR(500MHz,DMSO)δ7.89(d,J＝9.3Hz,1H),6.57(d,J＝9.5Hz,1H),6.52(s,1H),3.90(s,3H),3.46(s,8H),1.42(s,9H).HRMS(ESI)计算值C 16H 24N 3O 5 +[M+H] +,338.1710；实测值,338.1610.
步骤2：根据方案14制备叔丁基4-(4-氨基-3-甲氧基苯基)哌嗪-1-甲酸酯(SIAIS1197129)：
室温敞口条件下，在蛋形瓶中，依次加入化合物SIAIS1197111(10g,29.6mmol)，乙醇(90mL)，水(30mL)，氯化铵(6.3g,118.6mmol)，铁粉(8.3g,148.2mmol)，随后抽换氩气80℃回流反应2h。TLC检测反应结束后，硅胶过滤，浓缩旋蒸除去乙醇，二氯甲烷萃取，无水硫酸钠干燥，旋蒸干得化合物(SIAIS1197129)(灰蓝色固体,7.7g,收率为85％)。 1H NMR(500MHz,MeOD)δ6.72(d,J＝8.3Hz,1H),6.63(d,J＝2.2Hz,1H),6.47(d,J＝7.0Hz,1H),3.86(s,3H),3.57(s,4H),2.99(s,4H),1.50(s,9H).HRMS(ESI)计算值C 16H 26N 3O 3 +[M+H] +,308.1969；实测值,308.1882.
步骤3：根据方案14制备化合物(SIAIS1197133)：
室温下，在标准微波反应管中，依次加入(2-((2,5-二氯嘧啶-4-基)氨基)苯基)二甲基氧化膦(2g,6.3mmol)，化合物SIAIS1197129(2.4g,7.8mmol)，醋酸钯(176mg,0.78mmol)，Xantphos(810mg,1.4mmol)，碳酸铯(6.4g,19.6mmol)，无水N,N-二甲基甲酰胺(30mL)，随后抽换氩气，110℃下微波反应1.5h。TLC检测反应结束后，硅胶过滤，水淬灭，乙酸乙酯萃取，水洗，无水硫酸钠干燥，反相C18柱分离，洗脱剂为甲醇和水，得化合物(SIAIS1197133)(红棕色固体,900mg)。
步骤4：根据方案14制备(2-((5-氯-2-((2-甲氧基-4-(哌嗪-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦(SIAIS1197135)：
室温敞口条件下，在蛋形瓶中，依次加入化合物SIAIS1197133(900mg)，二氯甲烷(6mL)，三氟乙酸(20mL)，随后室温反应2h。LC-MS检测反应结束后，减压旋蒸除去三氟乙酸，加入饱和碳酸氢钠溶液调节溶液pH值至碱性，二氯甲烷萃取，无水硫酸钠干燥，旋蒸干，反相C18柱分离，洗脱剂为甲醇和水，得目标化合物(SIAIS1197135)(红棕色固体,701mg，步骤3和4两步总收率为23％)。 1H NMR(500MHz,MeOD)δ8.32(dd,J＝8.2,4.4Hz,1H),8.04(s,1H),7.70(d,J＝8.7Hz,1H),7.61(dd,J＝14.1,7.7Hz,1H),7.52(t,J＝7.9Hz,1H),7.26(t,J＝7.5,1H),6.67(d,J＝2.5Hz,1H),6.45(dd,J＝8.8,2.5Hz,1H),3.86(s,3H),3.24 –3.17(m,4H),3.17–3.11(m,4H),1.83(d,J＝13.5Hz,6H).HRMS(ESI)计算值C 23H 29ClN 6O 2P +[M+H] +,487.1773；实测值,487.1773.
中间体制备例76：根据方案14制备布加替尼衍生物B(SIAIS151101)：
步骤1：根据方案14制备叔丁基(1-(3-甲氧基-4-硝基苯基)哌啶-4-基)氨基甲酸酯(SIAIS151054).
根据中间体制备例75的所述方案14的步骤1、在本领域可理解的适当条件下制备化合物SIAIS151054，不同之处在于采用的作为底物的胺是叔丁基哌啶-4-基氨基甲酸酯.化合物SIAIS151054为黄色固体,1.81g,收率88％。 1H NMR(500MHz,CDCl 3)δ7.99(t,J＝8.9Hz,1H),6.41(dd,J＝9.4,2.5Hz,1H),6.30(d,J＝2.5Hz,1H),4.49(s,1H),3.94(s,3H),3.86–3.82(m,2H),3.71(s,1H),3.09–3.00(m,2H),2.11–2.03(m,2H),1.89–1.75(m,2H),1.45(s,9H).
步骤2：根据方案14制备叔丁基(1-(4-氨基-3-甲氧基苯基)哌啶-4-基)氨基甲酸酯(SIAIS151062).
根据中间体制备例75的所述方案14的步骤2、在本领域可理解的适当条件下，从步骤1得到的产物SIAIS151054制备得到化合物SIAIS151062(灰紫色固体,411.6mg,收率90％)。 1H NMR(500MHz,DMSO)δ6.82(d,J＝7.6Hz,1H),6.50(d,J＝8.5Hz,1H),6.48(d,J＝2.5Hz,1H),6.28(dd,J＝8.4,2.4Hz,1H),4.20(s,2H),3.73(s,3H),3.33–3.26(m,3H),2.56–2.50(m,2H),1.77(d,J＝11.4Hz,2H),1.53–1.45(m,2H),1.39(s,9H).
步骤3：根据方案14制备(2-((2-((4-(4-氨基哌啶-1-基)-2-甲氧基苯基)氨基)-5-氯嘧啶-4-基)氨基)苯基)二甲基氧化膦(SIAIS151101)
根据所述方案14方法的步骤3和4、在本领域可理解的适当条件下，从步骤2得到的产物SIAIS151062制备得到目标化合物SIAIS151101(黄色固体,330mg,步骤3和4两步总收率33％)。 1H NMR(500MHz,DMSO)δ8.49(s,1H),8.08(s,1H),8.06(s,1H),7.53(ddd,J＝14.0,7.7,1.3Hz,1H),7.38–7.32(m,2H),7.10(t,J＝7.1Hz,1H),6.62(d,J＝2.5Hz,1H),6.46(dd,J＝8.7,2.5Hz,1H),3.75(s,3H),3.65–3.61(m,2H),2.78–2.67(m,3H),1.82–1.79(m,2H),1.78(s,3H),1.75(s,3H),1.42–1.34(m,2H).HRMS(ESI)计算值C 24H 31ClN 6O 2P[M+H] +:501.1913,实测值501.1900.
中间体制备例77：根据方案14制备布加替尼(Brigatinib)衍生物C(SIAIS164005)
步骤1：根据方案14制备叔丁基4-(1-(3-甲氧基-4-硝基苯基)哌啶-4-基)哌嗪-1-甲酸酯(SIAIS151059)
根据中间体制备例75的所述方案14的步骤1、在本领域可理解的适当条件下制备化合物SIAIS151059，不同之处在于采用的作为底物的胺是叔丁基4-(哌啶-4-基)哌嗪-1-甲酸酯。得到目标化合物SIAIS151059(黄色固体,1.02g,收率83％). 1H NMR(500MHz,MeOD)δ7.93(d,J＝9.4Hz,1H),6.55(dt,J＝13.4,6.7Hz,1H),6.50(d,J＝2.5Hz,1H),4.10(s,1H),4.07 (s,1H),3.94(d,J＝6.6Hz,3H),3.43(s,4H),3.02–2.93(m,2H),2.60–2.55(m,5H),2.02–1.95(m,2H),1.57(qd,J＝12.4,4.0Hz,2H),1.46(s,9H).HRMS(ESI)计算值C 21H 33N 4O 5[M+H] +:421.2445,实测值421.2442.
步骤2：根据方案14制备叔丁基4-(1-(4-氨基-3-甲氧基苯基)哌啶-4-基)哌嗪-1-甲酸酯(SIAIS164003)
根据中间体制备例75的所述方案14方法的步骤2、在本领域可理解的适当条件下，从步骤1得到的产物SIAIS151059制备得到化合物SIAIS164003(灰白色固体,745mg,收率79％). 1H NMR(500MHz,MeOD)δ6.59(t,J＝56.8Hz,3H),3.78(s,3H),3.46(s,6H),2.62(d,J＝4.3Hz,6H),2.42(s,1H),1.98(s,2H),1.69(d,J＝9.7Hz,2H),1.46(s,9H).HRMS(ESI)计算值C 21H 35N 4O 3[M+H] +:391.2704,实测值391.3048.
步骤3：根据方案14制备(2-((5-氯-2-((2-甲氧基-4-(4-(哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧化膦(SIAIS164005)
根据中间体制备例66的所述方案14方法的步骤3和4、在本领域可理解的适当条件下，从步骤2得到的产物SIAIS164003制备得到目标化合物SIAIS164005(黄色固体,350mg,两步总收率37％)。 1H NMR(500MHz,MeOD)δ8.33(dd,J＝8.2,4.4Hz,1H),8.03(s,1H),7.69–7.64(m,1H),7.60(ddd,J＝14.0,7.7,1.4Hz,1H),7.51(t,J＝7.9Hz,1H),7.26(td,J＝7.6,1.2Hz,1H),6.66(d,J＝2.4Hz,1H),6.45(dd,J＝8.8,2.5Hz,1H),3.85(s,3H),3.73–3.63(m,2H),3.11–3.02(m,4H),2.79–2.66(m,6H),2.48–2.43(m,1H),1.99(d,J＝12.5Hz,2H),1.84(d,J＝13.5Hz,6H),1.72–1.63(m,2H).HRMS(ESI)计算值C 28H 38ClN 7O 2P[M+H] +:570.2508,实测值570.2498.
中间体制备例78：中间体达沙替尼衍生物(SIAIS151055)的制备：
Figure PCTCN2019081840-appb-000235
根据方案15制备N-(2-氯-6-甲基苯基)-2-((2-甲基-6-(哌嗪-1-基)嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151055)：
将N-(2-氯-6-甲基苯基)-2-[(6-氯-2-甲基-4-嘧啶基)氨基]-5-噻唑甲酰胺(1.0g,2.54mmol)，无水哌嗪(1.31g,15.21mmol)，N,N-二异丙基乙胺(4.9g,38.0mmol)和无水正丁醇(8mL)一起加入30mL的微波反应管中,室温下搅拌10分钟，然后缓慢向微波管中鼓入氩气，密封后，将反应管放入微波反应器中，缓慢升至120℃，并搅拌1h。将反应液降至室温，放置过夜，有大量白色固体析出，抽滤，滤饼用无水正丁醇洗涤2次，减压除去溶剂得目 标化合物(SIAIS151055)(白色固体,0.9g，收率80％)。 1H NMR(500MHz,DMSO)δ9.88(s,1H),8.23(s,1H),7.43–7.38(m,1H),7.31–7.24(m,2H),6.04(s,1H),3.45(d,J＝4.6Hz,4H),2.79–2.71(m,4H),2.44–2.37(m,3H),2.25(s,3H).HRMS(ESI)C 20H 23ClN 7OS +[M+H] +,计算值444.1368；实测值,444.1301.
中间体制备例79：中间体伯舒替尼衍生物(SIAIS151151)的制备：
Figure PCTCN2019081840-appb-000236
根据方案16制备4-((2,4-二氯-5-甲氧基苯基)氨基)-6-甲氧基-7-(3-(哌嗪-1-基)丙氧基)喹啉-3-甲腈(SIAIS151151)：
将7-(3-氯丙氧基)-4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-3-氰基喹啉(1.0g,2.14mmol)，无水哌嗪(0.93g,10.7mmol)，碘化钠(0.4g,2.14mmol)和乙二醇二甲醚(8mL)一起加入30mL的微波反应管中,室温下搅拌10min，然后缓慢向微波管中鼓入氩气，将反应管放入微波反应器上，升至120℃并搅拌1h。将反应液降至室温，减压蒸去反应溶剂，随后加入20mL的饱和碳酸氢钠溶液，乙酸乙酯萃取(4x 50mL),合并有机相，饱和食盐水洗(20mL),无水硫酸钠干燥，减压蒸去溶剂，粗品经柱层析分离(洗脱剂(v/v)：二氯甲烷/甲醇＝10:1)纯化得目标化合物(SIAIS151151)(浅棕色固体,0.55g，收率50％)。 1H NMR(500MHz,DMSO)δ8.39(s,1H),7.82(s,1H),7.72(s,1H),7.30(s,1H),7.28(s,1H),5.75(s,1H),4.19(t,J＝6.4Hz,2H),3.94(s,3H),3.85(s,3H),2.76(t,J＝4.8Hz,4H),2.43(t,J＝7.1Hz,2H),2.39–2.32(m,4H),1.99–1.91(m,2H).HRMS(ESI)：计算值C 25H 28Cl 2N 5O 3 +[M+H] +,516.1564；实测值,516.1699.
中间体制备例80：中间体普纳替尼衍生物(SIAIS151190B)的制备方法：
Figure PCTCN2019081840-appb-000237
根据方案17制备1-(溴甲基)-4-硝基-2-(三氟甲基)苯(SIAIS151182)：
将化合物1-甲基-4-硝基-2-(三氟甲基)苯(2.0g,9.75mmol)加入一个100mL的蛋形瓶中，随后加入无水1,2-二氯乙烷(20mL),N-溴代丁二酰亚胺(1.74g,9.75mmol)和偶氮二异丁腈(160mg,0.98mmol)，加毕，缓慢升温至回流状态并搅拌过夜。冷却至室温，倾入水(100mL)，乙酸乙酯萃取(2x 50mL)，合并有机相，水洗(50mL)，饱和食盐水洗涤，无水硫酸钠干燥，减压除去溶剂，粗品经柱层析(洗脱剂(v/v)：石油醚/乙酸乙酯＝20:1)纯化，旋干得目标产物SIAIS151182.(黄色固体，1.8g,收率65％). 1HNMR(500MHz,CDCl 3)δ8.54(d,J＝2.2Hz,1H),8.42(dd,J＝8.5,2.3Hz,1H),7.84(d,J＝8.5Hz,1H),4.67(s,2H).
根据方案17制备4-(4-硝基-2-(三氟甲基)苄基)哌嗪-1-甲酸叔丁酯(SIAIS151186):
将化合物SIAIS151182(1.8g,6.33mmol)加入一个100mL的蛋形瓶中，随后加入无水二氯甲烷(30mL)，1-Boc-哌嗪(1.8g,7.59mmol)和三乙胺(1.28g,12.66mmol)，加完室温搅拌3h。原料反应完后，向反应混合物中倾入50mL的水，乙酸乙酯萃取(2x 50mL),合并有机相，水洗(30mL),饱和食盐水洗(50mL),无水硫酸钠干燥，减压蒸去溶剂，粗品经柱层析(洗脱剂(v/v)：石油醚/乙酸乙酯＝5:1)纯化旋干得到目标产物SIAIS151186.(黄色固体，2.0g,收率81％), 1H NMR(500MHz,CDCl 3)δ8.51(s,1H),8.45–8.36(m,1H),8.11(d,J＝8.6Hz,1H),3.75(s,2H),3.47(s,4H),2.45(s,4H),1.46(s,9H).
根据方案17制备4-(4-氨基-2-(三氟甲基)苄基)哌嗪-1-甲酸叔丁酯(SIAIS151189):
室温下，在蛋形瓶中，依次加入SIAIS151186(1.0g,2.57mmol)，乙醇(15mL)，水(5mL)，氯化铵(0.55g,10.28mmol)，铁粉(0.72g,12.85mmol)，随后氮气保护下缓慢升温至回流并搅拌1h。TLC检测反应结束后，趁热抽滤，旋去乙醇，加入水(50mL)，二氯甲烷萃取(3x 50mL)，饱和食盐水洗，无水硫酸钠干燥，减压蒸去溶剂，粗品经柱层析(洗脱剂(v/v)：二氯甲烷/甲醇＝20:1)纯化，旋干得到目标化合物SIAIS151189.(淡黄色固体,0.9g,收率97％), 1H NMR(500MHz,CDCl 3)δ7.47(d,J＝8.3Hz,1H),6.91(d,J＝2.2Hz,1H),6.85–6.72(m,1H),3.78(s,2H),3.52(s,2H),3.41(s,4H),2.38(s,4H),1.45(s,9H).
根据方案17制备4-(4-(3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰氨基)-2-(三氟甲基)苄基)哌嗪-1-甲酸叔丁酯(SIAIS151190A):
室温下，在反应瓶中，加入3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酸(300mg,1.08mmol)，SIAIS151189(420mg,1.19mmol),1-羟基-7-偶氮苯并三氮唑(73.5mg,0.54mmol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(414mg,2.16mmol),无水N,N-二甲基甲酰胺(10mL)，N-甲基吗啡啉(329mg,3.24mmol)，加完35℃下搅拌反应过夜。LC-MS检测反应结束后，向反应混合物中倾入50mL的水，乙酸乙酯萃取(3x 50mL),合并有机相，水洗(2x 20mL),饱和食盐水洗(20mL),无水硫酸钠干燥，减压蒸去溶剂，粗品经柱层析(洗脱剂(v/v)：石油醚/乙酸乙酯＝1:3)纯化,旋干得到目标产物SIAIS151190A.(黄色固体，450mg,收率67％), 1H NMR(500MHz,CDCl 3)δ8.56–8.46(m,1H), 8.29(s,1H),8.07(d,J＝15.2Hz,2H),8.02–7.90(m,3H),7.88–7.77(m,2H),7.39(d,J＝8.0Hz,1H),7.13(dd,J＝9.2,4.4Hz,1H),3.64(s,2H),3.45(s,4H),2.64(s,3H),2.43(s,4H),1.46(s,9H).HRMS(ESI)m/z:calcd for C 33H 34F 3N 6O 3 +[M+H] +,619.2639；found,619.3310.
根据方案17制备3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基-N-(4-(哌嗪-1-基甲基)-3-(三氟甲基)苯基)苯甲酰胺(SIAIS151190B):
将化合物(SIAIS151190A)加入50mL的蛋形瓶中，随后加入无水二氯甲烷(15mL)和三氟乙酸(5mL),室温搅拌3h。减压蒸去溶剂，加入二氯甲烷/甲醇(体积比:10:1)(22mL)，搅拌下缓慢加入饱和碳酸氢钠水溶液，调节溶液pH至8–9,10％的二氯甲烷/甲醇萃取(3x 30mL)，合并有机相，饱和食盐水洗涤(10mL)，无水硫酸钠干燥，减压蒸去溶剂得到目标化合物SIAIS151190B,粗品未进行进一步纯化，直接用于下步反应.(黄色固体，300mg,收率80％), 1H NMR(500MHz,DMSO)δ10.63(s,1H),8.80(s,1H),8.74(dd,J＝4.4,1.5Hz,1H),8.27(dd,J＝9.2,1.5Hz,1H),8.26–8.24(m,2H),8.22(d,J＝1.8Hz,1H),8.14(dd,J＝8.5,1.8Hz,1H),7.96(dd,J＝8.0,1.8Hz,1H),7.75(d,J＝8.6Hz,1H),7.56(d,J＝8.2Hz,1H),7.41(dd,J＝9.2,4.4Hz,1H),3.80(s,2H),3.17(s,4H),2.74(s,4H),2.61(s,3H).HRMS(ESI)m/z:calcd for C 28H 26F 3N 6O +[M+H] +,519.2115；found,519.2119.
中间体制备例81：中间体拖瑞米芬衍生物B的制备：
Figure PCTCN2019081840-appb-000238
步骤1：根据方案18制备4,4'-(4-氯-2-苯基丁-1-烯-1,1-二基)联苯酚(SIAIS208102)：
干燥的三口瓶中加入锌粉(6.5g,100mmol)，搭建回流装置，抽换气三次，然后在Ar气条件下加入THF(80mL)、0℃滴加TiCl 4(9.5g,50mmol)，撤去冰浴后升至室温并加热回流2h。冷至室温后加入1(2.14g,10mmol)和2(5.1g,30mmol)的THF(80mL)溶液，避光回流3h。反应结束后，冷却、旋去大部分溶剂，饱和氯化铵溶液淬灭，乙酸乙酯萃取，有机相合并后依次用水、饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离(洗脱剂为石油醚：乙酸乙酯＝2:1)，得到3g黄色固体产物，收率为86％。 1H NMR(500MHz,CDCl 3)δ7.21–7.10(m,7H),6.84–6.81(m,2H),6.75–6.72(m,2H),6.49–6.46(m,2H),4.99(s,1H),4.73(s,1H),3.45–3.36(m,2H),2.99–2.91(m,2H).HRMS(ESI)m/z:计算值C 22H 20ClO 2 +[M+H] +,351.1146；实测值,351.1138.
步骤2：根据方案18制备2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙腈(SIAIS208161)：
单口瓶中依次加入SIAIS208102(1.5g,4.28mmol)，丙酮(15mL)，K 2CO 3(592mg,4.28mmol)，溴乙腈(257mg,2.14mmol)，抽换气三次，Ar气条件下加热回流3.5h。反应结束后，冷至室温，旋干溶剂，硅胶柱层析分离(洗脱剂为纯二氯甲烷)，得到782mg淡黄色液体产物，收率为94％。 1H NMR(500MHz,CDCl 3)δ7.31–7.27(m,1H),7.21-7.18(m,2H),7.17–7.14(m,2H),7.13-7.10(m,2H),7.00–6.97(m,1H),6.86-6.83(m,2H),6.75–6.70(m,1H),6.65–6.61(m,1H),6.51–6.47(m,1H),4.95-4.70(m,1H),4.81(s,1H),4.70(s,1H),4.64(s,1H),3.45–3.39(m,2H),2.97-2.91(m,2H).HRMS(ESI)m/z:计算值C 24H 21ClNO 2 +[M+H]+,390.1255；实测值,390.1263.
步骤3：根据方案18制备4-(1-(4-(2-氨基乙氧基)苯基)-4-氯-2-苯基丁-1-烯-1-基)苯酚(SIAIS208164)
单口瓶中加入SIAIS208161(782mg,2mmol)，THF(25mL)，0℃下分批加入LiAlH 4(228mg,6mmol)，抽换气三次，Ar气条件下室温反应过夜。反应结束后，加入饱合氯化铵淬灭，旋干，过滤，甲醇洗涤，滤液浓缩后C18反相柱层析分离[洗脱剂为水(含0.05％HCl)和乙腈]，得到473mg淡黄色固体产物，收率为60％。 1H NMR(500MHz,DMSO)δ9.68–9.17(m,1H),8.12(d,J＝41.4Hz,3H),7.24–7.18(m,3H),7.16–7.12(m,3H),7.06(d,J＝8.5Hz,1H),7.00(d,J＝8.7Hz,1H),6.77(t,J＝8.4Hz,2H),6.65(d,J＝8.8Hz,1H),6.61(d,J＝8.6Hz,1H),6.42(d,J＝8.6Hz,1H),4.20(t,J＝4.9Hz,1H),4.03(t,J＝4.9Hz,1H),3.43(t,J＝7.3Hz,2H),3.23(s,1H),3.12(s,1H),2.93–2.83(m,2H).HRMS(ESI)m/z:计算值C 24H 25ClNO 2 +[M+H]+,394.1568；实测值,394.1561.
中间体制备例82：中间体JQ-1衍生物A(SIAIS171018)的制备：
Figure PCTCN2019081840-appb-000239
根据方案19制备(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚烷-6-基)乙酸(SIAIS171018)：
将化合物JQ-1(1.0g,2.14mmol)加入10mL的蛋形瓶中，随后加入88％的甲酸(5mL),室温搅拌12h。LC-MS检测反应结束后，减压蒸去溶剂，加水冻干得目标化合物 (SISIS171018)(白色固体,840mg，收率96％)。 1H NMR(500MHz,DMSO)δ12.46(s,1H),7.50(d,J＝8.6Hz,2H),7.44(d,J＝8.5Hz,2H),4.45(t,J＝7.1Hz,1H),3.43(dd,J＝16.7,6.8Hz,2H),2.61(d,J＝12.4Hz,3H),2.41(s,3H),1.63(s,3H).HRMS(ESI)：计算值C 19H 18ClN 4O 2S +[M+H] +,401.0834；实测值,401.1217.
中间体制备例83：中间体JQ-1衍生物B(SIAIS213113)的制备：
Figure PCTCN2019081840-appb-000240
根据方案20制备(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
Figure PCTCN2019081840-appb-000241
-6-基)-1-(哌嗪-1-基)乙-1-酮(SIAIS213113)：
室温下，在反应瓶中，加入SIAIS171018(200mg,0.5mmol)，哌嗪-1-甲酸叔丁酯(102mg,0.55mmol),HATU(285mg,0.75mmol),DIPEA(193.5mg,1.5mmol),无水N,N-二甲基甲酰胺(10mL)，室温下搅拌反应过夜。LC-MS检测反应结束后，反相柱制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)，旋去乙腈，冻干后得Boc保护的中间体。将该中间体(270mg，0.47mmol)溶于二氯甲烷(15mL)，然后加入三氟乙酸(2mL),室温搅拌2小时后，浓缩加水冻干得到目标化合物(SIAIS213113).(淡黄色固体,200mg，两步总收率89.9％)， 1H NMR(500MHz,MeOD)δ7.54–7.40(m,4H),4.78–4.72(m,1H),4.11(dt,J＝6.6,4.8Hz,1H),4.03–3.91(m,2H),3.85–3.77(m,1H),3.73(dd,J＝16.6,7.0Hz,1H),3.67–3.59(m,1H),3.43(ddt,J＝18.9,12.4,9.2Hz,2H),3.32–3.15(m,2H),2.77(s,3H),2.48(s,3H),1.72(s,3H).HRMS(ESI)：计算值C 23H 26ClN 6OS +[M+H] +,469.1572；实测值,469.1572.
中间体制备例84：中间体JQ-1衍生物C(SIAIS213130)的制备：
Figure PCTCN2019081840-appb-000242
根据方案21制备(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
Figure PCTCN2019081840-appb-000243
-6-基)-N-(2-(哌嗪-1-基)乙基)乙酰胺(SIAIS213130)：
室温下，在反应瓶中，加入SIAIS171018(100mg,0.25mmol)，tert-butyl 4-(2-氨基乙基)哌嗪-1-甲酸叔丁酯(69mg,0.3mmol),HATU(142.5mg,0.375mmol),DIPEA(97mg,0.75mmol),无水N,N-二甲基甲酰胺(3mL)，室温下搅拌反应过夜。LC-MS检测反应结束后，反相柱制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)，旋去乙腈，冻干后得Boc保护的中间体。将该中间体(120mg，0.20mmol)溶于二氯甲烷(6mL)，然后加入三氟乙酸(2mL),室温搅拌3小时后，浓缩加水冻干得到目标化合物(SIAIS213130).(淡黄色油状液体,100mg，两步总收率收率99％)， 1H NMR(500MHz,MeOD)δ7.46(dd,J＝20.9,8.6Hz,4H),4.67(t,J＝7.1Hz,1H),3.78(dt,J＝14.9,6.1Hz,1H),3.55–3.37(m,11H),3.19(dd,J＝13.2,7.2Hz,2H),2.74(s,3H),2.46(s,3H),1.71(s,3H).HRMS(ESI)：计算值C 25H 31ClN 7OS +[M+H] +,512.1994；实测值,512.1994.
降解剂制备实施例
CDK4/6靶点的一系列降解剂通用的合成方法:
Figure PCTCN2019081840-appb-000244
根据方案22，室温下，在反应瓶中，加入帕布昔利布抑制剂(1equiv)，相应的LIN-ULM(1equiv),1-羟基-7-偶氮苯并三氮唑(2equiv),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(2equiv),无水N,N-二甲基甲酰胺(2mL)，N-甲基吗啡啉(5equiv)，室温下搅拌反应过夜。LC-MS检测反应结束后，HPLC制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)。旋蒸除去乙腈，冻干后得相应的最终降解剂化合物。
实施例1：7-环戊基-2-((5-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219100)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS151045)制备得到目标化合物(SIAIS219100)(黄色固体,6.9mg,收率39％)。 1H NMR(500MHz,DMSO)δ11.13(s,1H),8.96(s,1H),8.03(s,1H),7.92(s,1H),7.85(d,J＝8.2Hz,1H),7.82–7.77(m,1H),7.65(d,J＝7.1Hz,2H),6.80(s,1H),5.13(dd,J＝12.8,5.5Hz,1H),4.84–4.74(m,1H),4.35(s,2H),3.80(s,2H),3.68(s,2H),3.28(s,4H),3.18(s,2H),3.06(s,6H),2.89-2.85(m,1H),2.64–2.55(m,1H),2.54(d,J＝4.6Hz,1H),2.35(d,J＝16.1Hz,2H),2.08-2.03(m,5H),1.65(d,J＝6.2Hz,2H).HRMS(ESI)m/z:计算值C 38H 41N 10O 6S +[M+H] +,765.2926；实测值,765.2922.
实施例2：7-环戊基-2-((5-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219101)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS151138B)制备得到目标化合物(SIAIS219101)(黄色固体,7.1mg,收率40％)。 1H NMR(500MHz,DMSO)δ11.33(s,1H),11.12(s,1H),8.97(s,1H),8.04(s,1H),7.89(d,J＝2.4Hz,1H),7.83–7.77(m,2H),7.68–7.59(m,2H),6.81(s,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.80(p,J＝8.7Hz,1H),3.68-3.59(m,4H),3.21–3.12(m,4H),3.06(s,6H),2.92–2.83(m,3H),2.64–2.54(m,1H),2.54–2.51(m,1H),2.38-2.32(m,2H),2.07–1.92(m,5H),1.69–1.60(m,2H).HRMS(ESI)m/z:计算值C 39H 43N 10O 6S +[M+H] +,779.3082；实测值,779.3077.
实施例3：7-环戊基-2-((5-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219102)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS151139B)制备得到目标化合物(SIAIS219102)(黄色固体,8.0mg,收率44％)。 1H NMR(500MHz,DMSO)δ11.38(s,1H),11.12(s,1H),8.98(s,1H),8.06(s,1H),7.92–7.84(m,2H),7.84–7.76(m,1H),7.62(dd,J＝18.1,8.2Hz,2H),6.82(s,1H),5.11(dd,J＝12.8,5.4Hz,1H),4.81(p,J＝8.8Hz,1H),3.65(s,4H),3.21-3.15(m,6H),3.06(s,6H),2.91-2.87(m,1H),2.59-2.55(m,3H),2.54–2.51(m,1H),2.32(d,J＝11.8Hz,2H),2.07–1.91(m,7H),1.70–1.62(m,2H).HRMS(ESI)m/z:计算值C 40H 45N 10O 6S +[M+H] +,793.3239；实测值,793.3231.
实施例4：7-环戊基-2-((5-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219103)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS151140B)制备得到目标化合物(SIAIS219103)(黄色固体,8.3mg,收率45％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),8.97(s,1H),8.02(s,1H),7.89(s,1H),7.81–7.74(m,2H),7.67–7.58(m,2H),6.80(s,1H),5.11(dd,J＝12.8,5.4Hz,1H),4.85–4.75(m,1H),3.64(s,4H),3.15(s,3H),3.14(s,3H),3.06(s,6H),2.92–2.84(m,1H),2.64–2.57(m,1H),2.45(s,1H),2.32(s,2H),2.05-1.98(m,5H),1.69-1.65(m,6H).HRMS(ESI)m/z:计算值C 41H 47N 10O 6S +[M+H] +,807.3395；实测值,807.3392.
实施例5：制备7-环戊基-2-((5-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219104)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS151141B)制备得到目标化合物(SIAIS219104)(黄色固体,8.2mg,收率43％)。 1H NMR(500MHz,DMSO)δ11.26(s,1H),11.12(s,1H),8.97(s,1H),8.03(s,1H),7.88(d,J＝2.5Hz,1H),7.79-7.75(m,2H),7.62(d,J＝6.6Hz,2H),6.81(s,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.79-4.76(m,1H),3.67–3.60(m,4H),3.17-3.12(m,6H),3.06(s,6H),2.93–2.84(m,1H),2.64–2.55(m,1H),2.38-2.34(m,3H),2.04-1.97(m,5H),1.74–1.64-1.58(m,4H),1.58(m,2H),1.51-1.46(m,2H).HRMS(ESI)m/z:计算值C 42H 49N 10O 6S +[M+H] +,821.3552；实测值,821.3548.
实施例6：制备7-环戊基-2-((5-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219105)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS151142B)制备得到目标化合物(SIAIS219105)(黄色固体,8.5mg,收率44％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),8.97(s,1H),8.04(s,1H),7.89(s,1H),7.82–7.71(m,2H),7.62(d,J＝6.9Hz,2H),6.81(s,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.86–4.75(m,1H),3.63(d,J＝5.4Hz,4H),3.17-3.11(m,6H),3.06(s,6H),2.93–2.84(m,1H),2.64–2.56(m,1H),2.37(d,J＝6.6Hz,1H),2.32(s,2H),2.05-2.00(m,5H),1.72–1.61(m,4H),1.51-1.47(m,4H),1.40–1.32(m,2H).HRMS(ESI)m/z:计算值C 43H 51N 10O 6S +[M+H] +,835.3708；实测值,835.3701.
实施例7：7-环戊基-2-((5-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219086)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS171090)制备得到目标化合物(SIAIS219086)(黄色固体,7.1mg,收率41％)。 1H NMR(500MHz,DMSO)δ11.36(s,1H),10.99(s,1H),8.98(s,1H),8.06(s,1H),7.90 (d,J＝2.6Hz,1H),7.75(d,J＝7.1Hz,1H),7.61(d,J＝7.1Hz,2H),7.54(t,J＝7.6Hz,1H),6.82(s,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.82-4.77(m,1H),4.37(d,J＝17.4Hz,1H),4.23(d,J＝17.4Hz,1H),4.22(s,2H),3.67-3.64(m,4H),3.19-3.16(m,4H),3.06(s,6H),2.95–2.87(m,1H),2.63-2.61(m,1H),2.48–2.40(m,1H),2.36-2.32(m,2H),2.08–1.92(m,5H),1.70–1.62(m,2H).HRMS(ESI)m/z:计算值C 38H 43N 10O 5S +[M+H] +,751.3133；实测值,751.3122.
实施例8：7-环戊基-2-((5-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219087)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS171086)制备得到目标化合物(SIAIS219087)(黄色固体,7.3mg,收率41％)。 1H NMR(500MHz,DMSO)δ11.32(s,1H),10.99(s,1H),8.97(s,1H),8.02(s,1H),7.88(d,J＝2.7Hz,1H),7.68(dd,J＝7.5,1.0Hz,1H),7.62–7.51(m,3H),6.81(s,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.80(p,J＝8.9Hz,1H),4.36(d,J＝17.4Hz,1H),4.22(d,J＝17.4Hz,1H),3.63-3.58(m,4H),3.28(s,2H),3.14(d,J＝4.4Hz,4H),3.06(s,6H),2.95–2.86(m,1H),2.77(t,J＝7.0Hz,2H),2.65–2.54(m,1H),2.48–2.40(m,1H),2.34(d,J＝21.5Hz,2H),2.07–1.91(m,5H),1.70–1.60(m,2H).HRMS(ESI)m/z:计算值C 39H 45N 10O 5S +[M+H] +,765.3290；实测值,765.3282.
实施例9：7-环戊基-2-((5-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219088)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS171089)制备得到目标化合物(SIAIS219088)(黄色固体,8.0mg,收率45％)。 1H NMR(500MHz,DMSO)δ11.50(s,1H),10.99(d,J＝5.5Hz,1H),9.00(s,1H),8.08(d,J＝7.3Hz,1H),7.89(d,J＝2.7Hz,1H),7.71-7.66(m,1H),7.67–7.59(m,1H),7.59–7.52(m,2H),6.82(s,1H),5.13(dd,J＝10.2,5.1Hz,1H),4.81-4.78(m,1H),4.40–4.35(m,1H),4.23(d,J＝17.4Hz,1H),3.64-3.61(m,4H),3.16-3.12(m,6H),3.06(s,6H),2.94-2.90(m,1H),2.62–2.52(m,3H),2.48-2.43(m,1H),2.33-2.29(m,2H),2.05–1.93(m,5H),1.89–1.82(m,2H),1.70–1.60(m,2H).HRMS(ESI)m/z:计算值C 40H 47N 10O 5S +[M+H] +,779.3446；实测值,779.3442.
实施例10：7-环戊基-2-((5-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219089)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS171079)制备得到目标化合物(SIAIS219089)(黄色固体,7.8mg,收率43％)。 1H NMR(500MHz,DMSO)δ11.50(s,1H),10.99(s,1H),9.00(s,1H),8.09(d,J＝7.4Hz,1H),7.88(d,J＝2.7Hz,1H),7.64(dt,J＝7.5,3.8Hz,1H),7.61–7.49(m,3H),6.83(s,1H),5.12 (dd,J＝13.3,5.1Hz,1H),4.82-477(m,1H),4.36(d,J＝17.4Hz,1H),4.22(d,J＝17.4Hz,1H),3.65–3.60(m,4H),3.18–3.10(m,6H),3.06(s,6H),2.92-2.87(m,1H),2.59-2.56(m,1H),2.48–2.44(m,1H),2.41(t,J＝6.8Hz,2H),2.32(d,J＝12.3Hz,2H),2.07–1.92(m,5H),1.65(d,J＝4.3Hz,6H).HRMS(ESI)m/z:计算值C 41H 49N 10O 5S +[M+H] +,793.3603；实测值,793.3601.
实施例11：制备7-环戊基-2-((5-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219090)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS171091)制备得到目标化合物(SIAIS219090)(黄色固体,5.8mg,收率31％)。 1H NMR(500MHz,DMSO)δ11.32(s,1H),10.99(s,1H),8.98(s,1H),8.03(s,1H),7.88(d,J＝2.7Hz,1H),7.63(dd,J＝7.4,1.1Hz,2H),7.53(dd,J＝15.1,7.6Hz,2H),6.81(s,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.80(p,J＝8.8Hz,1H),4.36(d,J＝17.4Hz,1H),4.22(d,J＝17.4Hz,1H),3.62(d,J＝4.1Hz,4H),3.18-3.12(m,4H),3.06(s,6H),2.94–2.87(m,1H),2.62-2.60(m,1H),2.48–2.42(m,1H),2.36-2.31(m,4H),2.04–1.93(m,5H),1.68–1.58(m,4H),1.55-1.51(m,2H),1.45-1.42(m,2H).HRMS(ESI)m/z:计算值C 42H 51N 10O 5S +[M+H] +,807.3759；实测值,807.3749.
实施例12：制备7-环戊基-2-((5-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219091)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS171092)制备得到目标化合物(SIAIS219091)(黄色固体,7.8mg,收率41％)。 1H NMR(500MHz,DMSO)δ11.42(s,1H),10.99(s,1H),8.99(s,1H),8.07(d,J＝8.7Hz,1H),7.89(d,J＝2.6Hz,1H),7.64–7.58(m,2H),7.58–7.50(m,2H),6.82(s,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.83-4.78(m,1H),4.35(d,J＝17.4Hz,1H),4.21(d,J＝17.4Hz,1H),3.62(s,4H),3.17-3.13(m,4H),3.06(d,J＝5.0Hz,6H),2.95–2.89(m,1H),2.61-2.56(m,1H),2.47-2.43(m,1H),2.36-2.32(m,4H),2.07–1.94(m,5H),1.64-1.59(m,4H),1.52-1.47(m,2H),1.44-1.39(m,2H),1.33-1.28(m,2H).HRMS(ESI)m/z:计算值C 43H 53N 10O 5S +[M+H] +,821.3916；实测值,821.3916.
实施例13：制备7-环戊基-2-((5-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219111)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS1204137)制备得到目标化合物(SIAIS219111)(黄色固体,8.2mg,收率44％)。 1H NMR(500MHz,DMSO)δ11.55(s,1H),11.11(s,1H),9.57(s,1H),9.01(d,J＝8.1Hz,1H),8.08(td,J＝9.3,2.6Hz,1H),7.84–7.74(m,2H),7.68–7.57(m,2H),6.83(d,J＝2.0Hz, 1H),5.11(dd,J＝12.7,5.3Hz,1H),4.81(p,J＝8.8Hz,1H),3.79-3.75(m,2H),3.60(d,J＝12.8Hz,4H),3.39-3.34(m,4H),3.27–3.14(m,4H),3.06(s,6H),2.92–2.83(m,1H),2.59-2.56(m,1H),2.54–2.51(m,1H),2.37–2.25(m,2H),2.05-1.98(m,5H),1.70–1.60(m,2H).HRMS(ESI)m/z:计算值C 40H 45N 10O 7S +[M+H] +,809.3188；实测值,809.3181.
实施例14：制备7-环戊基-2-((5-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219112)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS1204139)制备得到目标化合物(SIAIS219112)(黄色固体,9.2mg,收率47％)。 1H NMR(500MHz,DMSO)δ11.48(s,1H),11.12(s,1H),9.48(s,1H),8.99(d,J＝11.7Hz,1H),8.02(dd,J＝39.3,4.8Hz,1H),7.83–7.71(m,2H),7.69–7.53(m,2H),6.83(s,1H),5.11(dd,J＝13.1,5.5Hz,1H),4.85–4.76(m,1H),3.74-3.70(m,2H),3.62–3.58(m,6H),3.45(s,4H),3.29–3.14(m,6H),3.06(s,6H),2.89-2.85(m,1H),2.59(d,J＝15.7Hz,1H),2.54–2.51(m,1H),2.32(d,J＝9.0Hz,2H),2.08–1.93(m,5H),1.70–1.59(m,2H).HRMS(ESI)m/z:计算值C 42H 49N 10O 8S +[M+H] +,853.3450；实测值,853.3440.
实施例15：制备7-环戊基-2-((5-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219113)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS1204147)制备得到目标化合物(SIAIS219113)(黄色固体,9.2mg,收率45％)。 1H NMR(500MHz,DMSO)δ11.34(s,1H),11.12(s,1H),8.97(s,1H),8.00(d,J＝23.0Hz,1H),7.87(d,J＝2.6Hz,1H),7.81–7.72(m,2H),7.64–7.55(m,2H),6.80(d,J＝5.7Hz,1H),5.10(dd,J＝12.9,5.5Hz,1H),4.79(dd,J＝17.6,8.8Hz,1H),4.20(s,2H),3.71(t,J＝6.3Hz,2H),3.64–3.55(m,10H),3.41(s,4H),3.19-3.15(m,4H),3.06(s,6H),2.92–2.84(m,1H),2.65–2.53(m,2H),2.31(s,2H),2.07–1.94(m,5H),1.72–1.60(m,2H).HRMS(ESI)m/z:计算值C 44H 53N 10O 9S +[M+H] +,897.3712；实测值,897.3701.
实施例16：制备7-环戊基-2-((5-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十四碳酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219114)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS1204147)制备得到目标化合物(SIAIS219114)(黄色固体,9.7mg,收率45％)。 1H NMR(500MHz,DMSO)δ11.41(s,1H),11.12(s,1H),9.39(s,1H),9.02–8.95(m,1H),8.11–7.99(m,1H),7.81–7.73(m,2H),7.64-7.61(m,2H),6.82(d,J＝7.7Hz,1H),5.11(dd,J＝12.9,4.9Hz,1H),4.80(p,J＝8.7Hz,1H),3.70(q,J＝6.2Hz,2H),3.64–3.47(m,18H),3.28–3.13(m,6H),2.93–2.84(m,1H),2.59(d,J＝17.0Hz,1H),2.53(dd,J＝11.7,6.6Hz,1H),2.34- 2.31(m,2H),2.07–1.95(m,5H),1.65(d,J＝5.4Hz,2H).HRMS(ESI)m/z:计算值C 46H 57N 10O 10S +[M+H] +,941.3974；实测值,941.3966.
实施例17：制备7-环戊基-2-((5-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七碳酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219115)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS1204149)制备得到目标化合物(SIAIS219115)(黄色固体,10.1mg,收率45％)。 1H NMR(500MHz,DMSO)δ11.27(s,1H),11.12(s,1H),9.24(s,1H),8.96(d,J＝5.1Hz,1H),8.05–7.99(m,1H),7.79-7.74(m,2H),7.68–7.58(m,2H),6.79(d,J＝7.4Hz,1H),5.17–5.05(m,1H),4.86–4.74(m,1H),3.69(t,J＝6.7Hz,2H),3.59–3.48(m,22H),3.19-3.15(m,6H),2.94–2.83(m,1H),2.64–2.52(m,2H),2.36-2.33(m,2H),2.09–1.91(m,5H),1.65(d,J＝5.7Hz,2H).HRMS(ESI)m/z:计算值C 48H 61N 10O 11S +[M+H] +,985.4236；实测值,985.4231.
实施例18：制备7-环戊基-2-((5-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219106)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS1213129)制备得到目标化合物(SIAIS219106)(黄色固体,7.8mg,收率43％)。 1H NMR(500MHz,DMSO)δ10.99(s,1H),8.81(s,1H),8.03(s,1H),7.97(s,1H),7.70(d,J＝7.0Hz,1H),7.57(d,J＝6.8Hz,1H),7.52(t,J＝7.6Hz,1H),6.65(s,1H),6.52(s,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.79–4.69(m,1H),4.38(d,J＝17.4Hz,1H),4.25(d,J＝15.3Hz,3H),3.69(t,J＝6.4Hz,2H),3.59-3.55(m,4H),3.17–3.03(m,10H),2.95–2.85(m,1H),2.58(d,J＝16.6Hz,1H),2.48–2.37(m,3H),1.99-1.93(m,5H),1.64(d,J＝5.7Hz,2H),1.27–1.24(m,2H).HRMS(ESI)m/z:计算值C 40H 47N 10O 6S+[M+H] +,795.3395；实测值,795.3391.
实施例19：制备7-环戊基-2-((5-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219107)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS1213131)制备得到目标化合物(SIAIS219107)(黄色固体,7.5mg,收率39％)。 1H NMR(500MHz,DMSO)δ10.99(s,1H),9.70(s,1H),8.81(s,1H),8.03(s,1H),7.98(d,J＝2.7Hz,1H),7.67(dd,J＝7.7,0.9Hz,1H),7.60–7.54(m,2H),7.51(t,J＝7.6Hz,1H),6.64(s,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.74(dd,J＝17.5,8.7Hz,1H),4.36(d,J＝17.4Hz,1H),4.23(d,J＝17.4Hz,1H),4.19(s,2H),3.66–3.59(m,4H),3.56(s,6H),3.25(t,J＝6.3Hz,2H),3.15–3.09(m,4H),3.05(s,4H),2.95–2.85(m,1H),2.58(d,J＝17.4Hz,1H),2.47–2.35(m,3H),1.99-1.95(m,5H),1.68–1.58(m,2H),1.26(dt,J＝7.4,5.3Hz,2H).HRMS(ESI)m/z:计算值C 42H 51N 10O 7S+[M+H] +,839.3657；实测值,839.3651.
实施例20：制备7-环戊基-2-((5-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219108)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS1213133)制备得到目标化合物(SIAIS219108)(黄色固体,9.1mg,收率45％)。 1H NMR(500MHz,DMSO)δ10.99(s,1H),8.88(s,1H),7.92(s,1H),7.81(s,1H),7.65(d,J＝7.0Hz,1H),7.55(d,J＝6.8Hz,1H),7.50(t,J＝7.6Hz,1H),6.72(s,1H),5.11(dd,J＝13.2,5.1Hz,1H),4.78-4.73(m,1H),4.35(d,J＝17.4Hz,1H),4.22(d,J＝19.7Hz,3H),3.61–3.51(m,12H),3.23(d,J＝6.4Hz,2H),3.16-3.12(m,4H),3.06(s,6H),2.92-2.88(m,1H),2.58(d,J＝16.9Hz,1H),2.45(m,1H),2.36(s,2H),2.05–1.93(m,5H),1.64(d,J＝5.9Hz,2H),1.26(dd,J＝7.0,3.4Hz,2H).HRMS(ESI)m/z:计算值C 44H 55N 10O 8S +[M+H] +,883.3920；实测值,883.3912.
实施例21：制备7-环戊基-2-((5-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十四碳酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219109)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS1213135)制备得到目标化合物(SIAIS219109)(黄色固体,9.3mg,收率44％)。 1H NMR(500MHz,DMSO)δ10.99(s,1H),9.70(s,1H),8.80(s,1H),8.06(s,1H),7.99(d,J＝2.8Hz,1H),7.65(dd,J＝7.7,0.7Hz,1H),7.56(d,J＝6.9Hz,2H),7.51(td,J＝7.5,3.2Hz,1H),6.63(s,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.74(p,J＝8.8Hz,1H),4.39–4.33(m,1H),4.26–4.17(m,3H),3.62–3.55(m,8H),3.49(d,J＝6.6Hz,6H),3.16–3.03(m,10H),2.94–2.85(m,1H),2.58(d,J＝17.4Hz,1H),2.48–2.37(m,3H),2.00-1.95(m,5H),1.64(d,J＝5.5Hz,2H),1.26(dd,J＝7.0,3.7Hz,2H).HRMS(ESI)m/z:计算值C 46H 59N 10O 9S +[M+H] +,927.4182；实测值,927.4185.
实施例22：制备7-环戊基-2-((5-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七碳酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(SIAIS219110)
据方案22所述通用方法，在本领域可理解的适当条件下，采用瑞博西尼抑制剂和LIN-ULM(SIAIS1213137)制备得到目标化合物(SIAIS219110)(黄色固体,9.5mg,收率43％)。 1H NMR(500MHz,DMSO)δ11.01(s,1H),9.71(s,1H),8.81(s,1H),8.08(s,1H),7.99(d,J＝2.8Hz,1H),7.67(dd,J＝7.7,0.7Hz,1H),7.58(d,J＝6.9Hz,2H),7.55-7.50(m,1H),6.65(s,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.76(p,J＝8.8Hz,1H),4.41–4.33(m,1H),4.28–4.19(m,3H),3.65–3.56(m,12H),3.49(d,J＝6.6Hz,6H),3.18–3.03(m,10H),2.96–2.87(m,1H),2.59(d,J＝17.4Hz,1H),2.49–2.38(m,3H),2.01-1.97(m,5H),1.66(d,J＝5.5Hz,2H),1.27(dd,J＝7.0,3.7Hz,2H).HRMS(ESI)m/z:计算值C 48H 63N 10O 10S +[M+H] +,971.4444；实测值,971.4438.
实施例23：制备3-(4-((2-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-2-氧代乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS262164)
据方案22所述通用方法，在本领域可理解的适当条件下，采用Abemaciclib衍生物和LIN-ULM(SIAIS171090)制备得到目标化合物(SIAIS262164)(黄色固体,7.2mg,收率43％)。 1H NMR(500MHz,MeOD)δ8.88(s,1H),8.56(s,2H),8.39(d,J＝9.3Hz,1H),8.16(d,J＝11.2Hz,1H),7.81(d,J＝7.8Hz,1H),7.74(dt,J＝27.9,14.2Hz,2H),7.57(t,J＝7.7Hz,1H),5.15(ddd,J＝20.2,13.2,5.6Hz,2H),4.56(d,J＝17.5Hz,1H),4.50(d,J＝13.9Hz,1H),4.47(d,J＝7.6Hz,2H),3.99(dt,J＝18.8,9.3Hz,2H),3.30(s,8H),2.95(s,3H),2.93–2.87(m,1H),2.80(dd,J＝15.4,2.2Hz,1H),2.56(ddd,J＝25.9,13.2,4.5Hz,1H),2.24–2.15(m,1H),1.81(d,J＝6.9Hz,6H).HRMS(ESI)m/z:计算值C 40H 41F 2N 10O 4S +[M+H] +,795.2996；实测值,795.3002.
实施例24：制备3-(4-((3-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-3-氧代丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS262165)
据方案22所述通用方法，在本领域可理解的适当条件下，采用Abemaciclib衍生物和LIN-ULM(SIAIS171086)制备得到目标化合物(SIAIS262165)(黄色固体,6.9mg,收率41％)。 1H  1H NMR(500MHz,MeOD)δ8.88(d,J＝3.1Hz,1H),8.57(s,2H),8.41(d,J＝9.6Hz,1H),8.17(d,J＝11.2Hz,1H),7.77(d,J＝9.0Hz,1H),7.70(dd,J＝16.5,7.4Hz,2H),7.56(t,J＝7.7Hz,1H),5.21–5.11(m,2H),4.53–4.39(m,4H),3.40–3.32(m,6H),3.30–3.23(m,4H),2.96(s,3H),2.93–2.87(m,1H),2.83–2.75(m,3H),2.57-2.53(m,1H),2.24–2.14(m,1H),1.81(d,J＝6.9Hz,6H).HRMS(ESI)m/z:计算值C 41H 43F 2N 10O 4S +[M+H] +,809.3152；实测值,809.3134.
实施例25：制备3-(4-((4-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-4-氧代丁基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS262166)
据方案22所述通用方法，在本领域可理解的适当条件下，采用Abemaciclib衍生物和LIN-ULM(SIAIS171089)制备得到目标化合物(SIAIS262166)(黄色固体,7.4mg,收率43％)。 1H NMR(500MHz,MeOD)δ8.89(s,1H),8.57(s,2H),8.40(s,1H),8.17(d,J＝10.9Hz,1H),7.81(s,1H),7.72(d,J＝7.7Hz,1H),7.67(d,J＝7.4Hz,1H),7.55(t,J＝7.7Hz,1H),5.14(dd,J＝11.6,4.7Hz,2H),4.45(dt,J＝17.4,15.0Hz,4H),3.67–3.33(m,4H),3.30–3.01(m,6H),2.95(s,3H),2.92–2.86(m,1H),2.79(d,J＝17.8Hz,1H),2.62–2.50(m,3H),2.25–2.17(m,1H),2.00–1.92(m,2H),1.81(d,J＝6.9Hz,6H).HRMS(ESI)m/z:计算值C 42H 45F 2N 10O 4S +[M+H] +,823.3309；实测值,823.3294.
实施例26：制备3-(4-((5-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-5-氧代戊基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS262167)
据方案22所述通用方法，在本领域可理解的适当条件下，采用Abemaciclib衍生物和LIN-ULM(SIAIS171079)制备得到目标化合物(SIAIS262167)(黄色固体,7.8mg,收率44％)。 1H NMR(500MHz,MeOD)δ8.91(d,J＝3.1Hz,1H),8.64(d,J＝1.7Hz,1H),8.59(s,1H),8.49(dd,J＝9.1,1.9Hz,1H),8.19(d,J＝11.2Hz,1H),7.74(d,J＝9.1Hz,1H),7.66(t,J＝8.0Hz,2H),7.57–7.50(m,1H),5.21–5.13(m,2H),4.52(s,2H),4.48(d,J＝17.3Hz,1H),4.41(d,J＝17.4Hz,1H),3.32(s,6H),3.22–3.05(m,4H),2.97(s,3H),2.94–2.86(m,1H),2.82–2.76(m,1H),2.59-2.53(m,1H),2.45(t,J＝7.1Hz,2H),2.22–2.16(m,1H),1.82(d,J＝6.9Hz,6H),1.76-1.73(m,4H).HRMS(ESI)m/z:计算值C 43H 47F 2N 10O 4S +[M+H] +,837.3465；实测值,837.3450.
实施例27：制备3-(4-((6-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-6-氧代己基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS262168)
据方案22所述通用方法，在本领域可理解的适当条件下，采用Abemaciclib衍生物和LIN-ULM(SIAIS171091)制备得到目标化合物(SIAIS262168)(黄色固体,8.4mg,收率47％)。 1H NMR(500MHz,MeOD)δ8.88(d,J＝2.7Hz,1H),8.62(s,1H),8.57(s,1H),8.45(d,J＝8.6Hz,1H),8.16(d,J＝11.2Hz,1H),7.82(d,J＝8.7Hz,1H),7.66(dd,J＝7.7,4.6Hz,2H),7.53(t,J＝7.6Hz,1H),5.20–5.11(m,2H),4.45(dd,J＝29.1,17.4Hz,4H),3.73–3.32(m,6H),3.23–3.02(m,4H),2.94(d,J＝6.2Hz,3H),2.93–2.86(m,1H),2.82–2.75(m,1H),2.58-2.53(m,1H),2.39(t,J＝7.3Hz,2H),2.25–2.17(m,1H),1.81(d,J＝6.9Hz,6H),1.69-1.65(m,2H),1.64-1.61(m,2H),1.56–1.48(m,2H).HRMS(ESI)m/z:计算值C 44H 49F 2N 10O 4S +[M+H] +,851.3622；实测值,851.3614.
实施例28：制备3-(4-((7-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-7-氧代庚基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS262169)
据方案22所述通用方法，在本领域可理解的适当条件下，采用Abemaciclib衍生物和LIN-ULM(SIAIS171092)制备得到目标化合物(SIAIS262169)(黄色固体,8.3mg,收率46％)。 1H NMR(500MHz,MeOD)δ8.91(d,J＝3.1Hz,1H),8.66(s,1H),8.59(s,1H),8.50(d,J＝9.2Hz,1H),8.19(d,J＝10.9Hz,1H),7.77(d,J＝9.1Hz,1H),7.65(dd,J＝6.5,3.1Hz,1H),7.54(d,J＝7.7Hz,1H),7.32(d,J＝4.9Hz,1H),5.19–5.14(m,2H),4.53(s,2H),4.47(d,J＝17.3Hz,1H),4.40(d,J＝17.3Hz,1H),3.63–3.35(m,4H),3.19(d,J＝22.2Hz,4H),3.09-3.05(m,2H),2.97(s,3H),2.93–2.86(m,2H),2.82–2.77(m,1H),2.54(dd,J＝13.1,4.7Hz,1H),2.41(s,1H),2.22–2.17(m,1H),1.82(d,J＝6.9Hz,6H),1.71–1.67(m,2H),1.59-1.55(m,2H),1.51-1.47(m, 2H),1.39–1.35(m,2H).HRMS(ESI)m/z:计算值C 45H 51F 2N 10O 4S +[M+H] +,865.3778；实测值,865.3769.
实施例29：制备3-(4-((11-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-11-氧代十一烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS262170)
据方案22所述通用方法，在本领域可理解的适当条件下，采用Abemaciclib衍生物和LIN-ULM(SIAIS1220099)制备得到目标化合物(SIAIS262170)(黄色固体,10.2mg,收率53％)。 1H NMR(500MHz,MeOD)δ8.83(d,J＝3.2Hz,1H),8.55(d,J＝9.9Hz,2H),8.33(d,J＝7.2Hz,1H),8.13(d,J＝11.2Hz,1H),7.93(s,1H),7.62(d,J＝8.0Hz,2H),7.52(t,J＝7.7Hz,1H),5.18–5.09(m,2H),4.46-4.41(m,4H),3.40(d,J＝49.0Hz,4H),3.22(s,4H),3.05(t,J＝6.9Hz,2H),2.96–2.88(m,4H),2.80(dd,J＝10.1,7.8Hz,1H),2.56-2.52(m,1H),2.42(t,J＝7.5Hz,2H),2.19-2.16(m,1H),1.80(d,J＝6.9Hz,6H),1.69–1.55(m,4H),1.46-1.41(m,2H),1.30(s,10H).HRMS(ESI)m/z:计算值C 49H 59F 2N 10O 4S +[M+H] +,921.4404；实测值,921.4411.
实施例30：制备3-(4-((2-(2-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-2-氧代乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS262171)
据方案22所述通用方法，在本领域可理解的适当条件下，采用Abemaciclib衍生物和LIN-ULM(SIAIS1213129)制备得到目标化合物(SIAIS262171)(黄色固体,8.4mg,收率48％)。 1H NMR(500MHz,MeOD)δ8.85(s,1H),8.55(s,2H),8.36(s,1H),8.15(d,J＝10.9Hz,1H),7.83(s,1H),7.73(d,J＝7.7Hz,1H),7.69–7.65(m,1H),7.54(t,J＝7.6Hz,1H),5.15(dd,J＝18.3,5.3Hz,2H),4.49-4.46(m,4H),3.81–3.68(m,4H),3.50–3.34(m,4H),3.30–3.15(m,4H),2.98–2.85(m,6H),2.79-2.76(m,1H),2.60–2.51(m,1H),2.20(dd,J＝9.0,4.2Hz,1H),1.81(d,J＝6.9Hz,6H).HRMS(ESI)m/z:计算值C 42H 45F 2N 10O 5S +[M+H] +,839.3258；实测值,839.3257.
实施例31：制备4-((2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-2-氧代乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS151046)
根据方案22所述通用方法，在本领域可理解的适当条件下，采用帕布昔利布抑制剂和LIN-ULM(SIAIS151045)制备得到目标化合物(SIAIS151046)(黄色固体,20mg,收率59％)。 1H NMR(500MHz,MeOD)δ9.09(s,1H),8.16(dd,J＝9.6,2.7Hz,1H),7.90–7.86(m,2H),7.75(t,J＝7.7Hz,1H),7.67(d,J＝7.3Hz,1H),7.56(d,J＝9.6Hz,1H),6.04–5.98(m,1H),5.12(dd,J＝12.5,5.4Hz,1H),4.21(s,2H),3.92–3.76(m,4H),3.43–3.38(m,2H),3.28–3.26(m,2H),2.89–2.83(m,1H),2.79–2.64(m,2H),2.50(s,3H),2.43(s,3H),2.38–2.26(m,2H),2.15–2.07(m,3H),1.96–1.86(m,2H),1.72–1.68(m,2H).HRMS(ESI)计算值C 39H 40N 9O 7S +[M+H] +,778.2766；实测值,778.2209.
实施例32：制备4-((2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-2-氧代乙基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS151057)
根据方案22所述通用方法，在本领域可理解的适当条件下，采用帕布昔利布抑制剂和LIN-ULM(SIAIS151107)制备得到目标化合物(SIAIS151057)(黄色固体,26.5mg,收率72％)。 1H NMR(500MHz,MeOD)δ9.10(d,J＝2.3Hz,1H),8.31(dt,J＝7.6,1.1Hz,1H),8.17(d,J＝9.6Hz,1H),8.14–8.07(m,2H),7.88(d,J＝2.9Hz,1H),7.57(dd,J＝9.6,1.9Hz,1H),6.04–5.98(m,1H),5.21–5.16(m,1H),4.59(dd,J＝19.3,14.5Hz,1H),4.10(d,J＝14.5Hz,1H),3.93–3.86(m,2H),3.78–3.68(m,2H),3.46–3.23(m,4H),2.92–2.85(m,1H),2.80–2.68(m,2H),2.50(s,3H),2.43(s,3H),2.36–2.28(m,2H),2.21–2.15(m,1H),2.13–2.06(m,2H),1.94–1.88(m,2H),1.74–1.68(m,2H).HRMS(ESI)计算值C 39H 40N 9O 8S +[M+H] +,794.2715；实测值,794.2978.
实施例33：制备4-((2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-2-氧代乙基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS151056)
根据方案22所述通用方法，在本领域可理解的适当条件下，采用帕布昔利布抑制剂和LIN-ULM(SIAIS151106)制备得到目标化合物(SIAIS151056)(黄色固体,22.7mg,收率63％)。 1H NMR(500MHz,MeOD)δ9.10(s,1H),8.37(d,J＝7.9Hz,1H),8.25(d,J＝7.5Hz,1H),8.20(dd,J＝9.6,2.8Hz,1H),8.09(t,J＝7.7Hz,1H),7.87(d,J＝2.8Hz,1H),7.55(d,J＝9.6Hz,1H),6.04–5.98(m,1H),5.24(dd,J＝12.4,5.5Hz,1H),5.06(s,2H),4.21(s,2H),4.01–3.96(m,2H),3.46–3.42(m,2H),3.30–3.26(m,2H),2.93–2.86(m,1H),2.80–2.70(m,2H),2.50(s,3H),2.43(s,3H),2.35–2.28(m,2H),2.23–2.17(m,3H),1.94–1.87(m,2H),1.72–1.68(m,2H).HRMS(ESI)计算值C 39H 40N 9O 9S +[M+H] +,810.2664；实测值,810.2929.
实施例34：4-((3-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-3-氧代丙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS184086)
根据方案22所述通用方法，在本领域可理解的适当条件下，采用帕布昔利布抑制剂和LIN-ULM(SIAIS151138B)制备得到目标化合物(SIAIS184086)(黄色固体,11.1mg,收率42％)。 1H NMR(500MHz,MeOD)δ9.11(s,1H),8.18(dd,J＝9.7,2.9Hz,1H),7.84(d,J＝2.9Hz,1H),7.82–7.74(m,2H),7.63(dd,J＝6.7,1.4Hz,1H),7.53(d,J＝9.6Hz,1H),6.01(dd,J＝17.7,8.8Hz,1H),5.10(dd,J＝12.7,5.5Hz,1H),3.80(d,J＝5.1Hz,2H),3.77–3.70(m,2H),3.46(t,J＝6.8Hz,2H),3.30–3.23(m,6H),2.93(t,J＝6.9Hz,2H),2.89-2.84(m,1H),2.78–2.69(m,1H),2.51(s,3H),2.44(s,3H),2.35-2.28(m,2H),2.16-2.05(m,3H),1.95-1.88(m,2H),1.73-1.66(m,2H).HRMS(ESI)m/z:计算值C 40H 42N 9O 7S +[M+H] +,792.2922；实测值,792.2925.
实施例35：4-((4-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-4-氧代丁基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS184087)
根据方案22所述通用方法，在本领域可理解的适当条件下，采用帕布昔利布抑制剂和LIN-ULM(SIAIS151139B)制备得到目标化合物(SIAIS184087)(黄色固体,11.5mg,收率43％)。 1H NMR(500MHz,MeOD)δ9.11(s,1H),8.18(dd,J＝9.7,2.9Hz,1H),7.86–7.79(m,2H),7.77–7.71(m,1H),7.59(d,J＝7.2Hz,1H),7.52(d,J＝9.6Hz,1H),6.09–5.98(m,1H),5.14–5.10(m,1H),3.82–3.76(m,4H),3.29–3.21(m,6H),2.92–2.82(m,1H),2.79–2.66(m,4H),2.51(s,3H),2.44(s,3H),2.33(s,2H),2.16–2.07(m,5H),1.93(d,J＝7.8Hz,2H),1.70(d,J＝5.1Hz,2H).HRMS(ESI)m/z:计算值C 41H 44N 9O 7S +[M+H] +,806.3079；实测值,806.3082.
实施例36：4-((5-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-5-氧代戊基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS184088)
根据方案22所述通用方法，在本领域可理解的适当条件下，采用帕布昔利布抑制剂和LIN-ULM(SIAIS151140B)制备得到目标化合物(SIAIS184088)(黄色固体,10.8mg,收率39％)。 1H NMR(500MHz,MeOD)δ9.10(s,1H),8.17(dd,J＝9.6,2.9Hz,1H),7.83(d,J＝2.9Hz,1H),7.72(dd,J＝6.7,6.0Hz,2H),7.57-7.52(m,2H),6.02(p,J＝8.8Hz,1H),5.08(dd,J＝12.7,5.5Hz,1H),3.80–3.75(m,4H),3.29–3.18(m,6H),2.87-2.82(m,1H),2.77–2.66(m,2H),2.55(t,J＝6.7Hz,2H),2.51(s,3H),2.44(s,3H),2.35-2.31(m,2H),2.14–2.07(m,3H),1.95–1.83(m,6H),1.73-1.67(m,2H).HRMS(ESI)m/z:计算值C 42H 46N 9O 7S +[M+H] +,820.3235；实测值,820.3239.
实施例37：4-((6-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-6-氧代己基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS184089)
根据方案22所述通用方法，在本领域可理解的适当条件下，采用帕布昔利布抑制剂和LIN-ULM(SIAIS151141B)制备得到目标化合物(SIAIS184089)(黄色固体,11.6mg,收率42％)。 1H NMR(500MHz,MeOD)δ9.09(s,1H),8.09(t,J＝9.1Hz,1H),7.82(d,J＝2.8Hz,1H),7.76–7.67(m,2H),7.57–7.45(m,2H),6.01(p,J＝8.8Hz,1H),5.10(dd,J＝12.8,5.5Hz,1H),3.83–3.72(m,4H),3.30–3.23(m,4H),3.15(t,J＝7.1Hz,2H),2.89-2.83(m,1H),2.79–2.65(m,2H),2.53–2.48(m,5H),2.44(s,3H),2.37–2.29(m,2H),2.17–2.07(m,3H),1.95-1.90(m,2H),1.86–1.79(m,2H),1.76–1.68(m,4H),1.62–1.56(m,2H).HRMS(ESI)m/z:计算值C 43H 48N 9O 7S +[M+H] +,834.3392；实测值,834.3386.
实施例38：4-((7-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-7-氧代庚基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS184090)
根据方案22所述通用方法，在本领域可理解的适当条件下，采用帕布昔利布抑制剂和LIN-ULM(SIAIS151142B)制备得到目标化合物(SIAIS184090)(黄色固体,12.1mg,收率43％)。 1H NMR(500MHz,MeOD)δ9.10(s,1H),8.19(dd,J＝9.7,3.0Hz,1H),7.83(d,J＝2.9Hz,1H),7.74–7.67(m,2H),7.60–7.50(m,2H),6.02(p,J＝8.8Hz,1H),5.10(dd,J＝12.7,5.5Hz,1H),3.77(d,J＝10.4Hz,4H),3.26(t,J＝11.8Hz,2H),3.13(t,J＝7.1Hz,2H),2.89-2.83(m,1H),2.77–2.67(m,2H),2.53–2.46(m,5H),2.44(s,3H),2.34-2.31(m,2H),2.16–2.08(m,3H),1.95-1.90(m,2H),1.83–1.76(m,2H),1.75–1.65(m,4H),1.62–1.53(m,2H),1.48-1.42(m,2H).HRMS(ESI)m/z:计算值C 44H 50N 9O 7S +[M+H] +,848.3548；实测值,848.3540.
实施例39：3-(4-((2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-2-氧代乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS219051)
根据方案22所述通用方法，在本领域可理解的适当条件下，采用帕布昔利布抑制剂和LIN-ULM(SIAIS171090)制备得到目标化合物(SIAIS219051)(黄色固体,9.8mg,收率38％)。 1H NMR(500MHz,MeOD)δ9.12(s,1H),8.17(dd,J＝9.6,2.9Hz,1H),7.83(dd,J＝8.5,1.5Hz,2H),7.73(d,J＝7.5Hz,1H),7.56(t,J＝7.7Hz,1H),7.53(d,J＝9.6Hz,1H),6.02(p,J＝8.8Hz,1H),5.17(dd,J＝13.4,5.2Hz,1H),4.58(d,J＝17.4Hz,1H),4.51(d,J＝17.4Hz,1H),4.06–3.97(m,2H),3.79–3.70(m,4H),3.27–3.14(m,4H),2.95-2.87(m,1H),2.81-2.76(m,1H),2.57–2.53(m,1H),2.50(d,J＝3.4Hz,4H),2.44(s,3H),2.35-2.30(m,2H),2.23–2.16(m,1H),2.10(s,2H),1.94-1.88(m,2H),1.76–1.67(m,2H),1.31(d,J＝23.7Hz,2H).HRMS(ESI)m/z:计算值C 39H 42N 9O 6S +[M+H] +,764.2973；实测值,764.2970.
实施例40：3-(4-((3-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-3-氧代丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS219052)
根据方案22所述通用方法，在本领域可理解的适当条件下，采用帕布昔利布抑制剂和LIN-ULM(SIAIS171086)制备得到目标化合物(SIAIS219052)(黄色固体,10.2mg,收率39％)。 1H NMR(500MHz,MeOD)δ9.10(s,1H),8.11(d,J＝7.4Hz,1H),7.82(d,J＝2.7Hz,1H),7.77–7.70(m,1H),7.65(d,J＝6.9Hz,1H),7.55(t,J＝7.7Hz,2H),6.01(p,J＝8.9Hz,1H),5.15(dd,J＝13.4,5.2Hz,1H),4.48(d,J＝17.3Hz,1H),4.42(d,J＝17.3Hz,1H),3.75(s,2H),3.65(s,2H),3.45-3.38(m,1H),3.36-3.32(m,2H),3.25–3.13(m,4H),2.93-2.88(m,1H),2.86–2.76(m,3H),2.58–2.48(m,4H),2.43(s,3H),2.34-2.28(m,2H),2.19–2.14(m,1H),2.10(s,2H),1.95-1.87(m,2H),1.74-1.68(m,2H).HRMS(ESI)m/z:计算值C 40H 44N 9O 6S +[M+H] +,778.3130；实测值,778.3127.
实施例41：3-(4-((4-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-4-氧代丁基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS219053)
根据方案22所述通用方法，在本领域可理解的适当条件下，采用帕布昔利布抑制剂和LIN-ULM(SIAIS171089)制备得到目标化合物(SIAIS219053)(黄色固体,11.2mg,收率42％)。 1H NMR(500MHz,MeOD)δ9.11(s,1H),8.10(s,1H),7.80(s,1H),7.70(dd,J＝7.7,0.9Hz,1H),7.55(dt,J＝15.2,7.2Hz,3H),6.01(dd,J＝17.7,8.9Hz,1H),5.16(dd,J＝13.3,5.2Hz,1H),4.50(d,J＝17.4Hz,1H),4.44(d,J＝17.4Hz,1H),3.80–3.69(m,2H),3.66–3.63(m,2H),3.24–3.12(m,5H),3.09-3.05(m,1H),2.96-2.88(m,1H),2.83-2.79(m,1H),2.68–2.53(m,3H),2.51(s,3H),2.44(s,3H),2.35-2.30(m,2H),2.25–2.16(m,1H),2.10(s,2H),2.02–1.97(m,2H),1.96-1.89(m,2H),1.76–1.67(m,2H).HRMS(ESI)m/z:计算值C 41H 48N 9O 6S +[M+H] +,792.3286；实测值,792.3281.
实施例42：3-(4-((5-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-5-氧代戊基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS184092)
根据方案22所述通用方法，在本领域可理解的适当条件下，采用帕布昔利布抑制剂和LIN-ULM(SIAIS171079)制备得到目标化合物(SIAIS184092)(黄色固体,11.2mg,收率41％)。 1H NMR(500MHz,MeOD)δ9.11(d,J＝4.3Hz,1H),8.14(dd,J＝9.7,2.9Hz,1H),7.77(d,J＝2.9Hz,1H),7.65(dd,J＝7.3,1.3Hz,1H),7.59–7.41(m,3H),6.02(p,J＝8.8Hz,1H),5.11(dd,J＝13.4,5.2Hz,1H),4.46(d,J＝17.3Hz,1H),4.40(d,J＝17.3Hz,1H),3.88–3.63(m,4H),3.21-3.17(m,3H),3.13–3.00(m,3H),2.92-2.86(m,1H),2.81-2.77(m,1H),2.56–2.48(m,5H),2.44(s,3H),2.35-2.31(m,2H),2.19–2.08(m,3H),1.97–1.88(m,2H),1.87–1.65(m,6H).HRMS(ESI)m/z:计算值C 42H 50N 9O 6S +[M+H] +,806.3443；实测值,806.3433.
实施例43：3-(4-((6-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-6-氧代己基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS219054)
根据方案22所述通用方法，在本领域可理解的适当条件下，采用帕布昔利布抑制剂和LIN-ULM(SIAIS171091)制备得到目标化合物(SIAIS219054)(黄色固体,11.5mg,收率42％)。 1H NMR(500MHz,MeOD)δ9.12(s,1H),8.16(dd,J＝9.7,3.0Hz,1H),7.79(d,J＝2.9Hz,1H),7.62(dd,J＝7.6,0.9Hz,1H),7.57–7.47(m,3H),6.02(p,J＝8.9Hz,1H),5.14(dd,J＝13.3,5.2Hz,1H),4.45(d,J＝17.3Hz,1H),4.40(d,J＝17.3Hz,1H),3.80–3.66(m,4H),3.23(d,J＝4.6Hz,4H),3.15-3.07(m,2H),2.95-2.88(m,1H),2.81-2.76(m,1H),2.58–2.49(m,4H),2.47–2.41(m,5H),2.35-2.31(m,2H),2.21–2.16(m,1H),2.11(s,2H),1.96-1.91(m,2H),1.74–1.65(m,6H),1.59–1.49(m,2H).HRMS(ESI)m/z:计算值C 43H 52N 9O 6S +[M+H] +,820.3599；实测值,820.3591.
实施例44：3-(4-((7-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-7-氧代庚基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS219055)
根据方案22所述通用方法，在本领域可理解的适当条件下，采用帕布昔利布抑制剂和LIN-ULM(SIAIS171092)制备得到目标化合物(SIAIS219055)(黄色固体,12.1mg,收率43％)。 1H NMR(500MHz,MeOD)δ9.12(s,1H),8.19(dd,J＝9.7,2.9Hz,1H),7.84(d,J＝2.8Hz,1H),7.66–7.57(m,2H),7.57–7.46(m,2H),6.02(p,J＝8.8Hz,1H),5.14(dd,J＝13.3,5.2Hz,1H),4.45(d,J＝17.3Hz,1H),4.39(d,J＝17.3Hz,1H),3.81–3.70(m,4H),3.28-3.22(m,4H),3.10–3.03(m,2H),2.93-2.88(m,1H),2.81-2.77(m,1H),2.60–2.48(m,4H),2.48–2.42(m,5H),2.36–2.29(m,2H),2.18(m,1H),2.14-2.08(m,2H),1.94-1.90(m,2H),1.74–1.66(m,4H),1.66–1.59(m,2H),1.55–1.48(m,2H),1.41(dd,J＝14.7,7.4Hz,2H).HRMS(ESI)m/z:计算值C 44H 54N 9O 6S +[M+H] +,834.3756；实测值,834.3750.
实施例45：4-((2-(2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-2-氧代乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS184091)
根据方案22所述通用方法，在本领域可理解的适当条件下，采用帕布昔利布抑制剂和LIN-ULM(SIAIS1204137)制备得到目标化合物(SIAIS184091)(黄色固体,11.6mg,收率42％)。 1H NMR(500MHz,MeOD)δ9.09(d,J＝8.7Hz,1H),8.13(d,J＝9.4Hz,1H),7.80(d,J＝7.6Hz,1H),7.75–7.69(m,1H),7.54(dd,J＝12.6,8.4Hz,1H),6.09–5.99(m,1H),5.07(dd,J＝12.7,5.5Hz,1H),4.32–4.25(m,1H),3.88(t,J＝5.7Hz,2H),3.74(d,J＝3.9Hz,3H),3.52–3.37(m,4H),3.23(d,J＝23.4Hz,2H),2.86-2.81(m,1H),2.78–2.63(m,2H),2.51(d,J＝1.7Hz,3H),2.44(d,J＝1.2Hz,3H),2.31(d,J＝8.0Hz,2H),2.16–2.07(m,3H),1.93(d,J＝9.2Hz,2H),1.78–1.64(m,2H).HRMS(ESI)m/z:计算值C 41H 44N 9O 8S +[M+H] +,822.3028；实测值,822.3022.
实施例46：4-((2-(2-(2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-2-氧代乙氧基)乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS219059)
根据方案22所述通用方法，在本领域可理解的适当条件下，采用帕布昔利布抑制剂和LIN-ULM(SIAIS1204139)制备得到目标化合物(SIAIS219059)(黄色固体,9.1mg,收率47％)。 1H NMR(500MHz,MeOD)δ9.03(s,1H),8.13(dd,J＝9.7,3.0Hz,1H),7.73(d,J＝2.9Hz,1H),7.69–7.58(m,2H),7.46–7.35(m,2H),6.00(p,J＝9.1Hz,1H),5.11(dd,J＝12.7,5.5Hz,1H),4.29(s,2H),3.88–3.75(m,7H),3.70–3.64(m,9H),3.37(d,J＝5.3Hz,2H),2.93–2.81(m,1H),2.80–2.65(m,2H),2.52(s,3H),2.44(s,3H),2.33(dd,J＝11.7,7.7Hz,2H),2.17–2.09(m,3H),1.94(s,2H),1.75–1.68(m,2H).HRMS(ESI)m/z:计算值C 43H 48N 9O 9S +[M+H] +,866.3290；实测值,866.3281.
实施例47：制备4-((2-(2-(2-(2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-2-氧代乙氧基)乙氧基)乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS219060)
根据方案22所述通用方法，在本领域可理解的适当条件下，采用帕布昔利布抑制剂和LIN-ULM(SIAIS1204141)制备得到目标化合物(SIAIS219060)黄色固体,9.1mg,收率45％)。 1H NMR(500MHz,MeOD)δ9.02(s,1H),8.08(dd,J＝9.7,3.0Hz,1H),7.69(d,J＝2.9Hz,1H),7.67–7.59(m,2H),7.39–7.28(m,2H),6.02(p,J＝9.0Hz,1H),5.12(dd,J＝12.7,5.5Hz,1H),4.29(s,2H),3.89–3.76(m,6H),3.70(s,4H),3.45(d,J＝4.7Hz,2H),2.96–2.82(m,1H),2.78–2.64(m,2H),2.51(d,J＝4.4Hz,3H),2.45(s,3H),2.35-2.32(m,2H),2.11(d,J＝10.3Hz,3H),1.94(s,2H),1.76–1.69(m,2H).HRMS(ESI)m/z:计算值C 45H 52N 9O 10S +[M+H] +,910.3552；实测值,910.3545.
实施例48：制备4-((14-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-14-氧代-3,6,9,12-四氧杂十四烷基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS219061)
根据方案22所述通用方法，在本领域可理解的适当条件下，采用帕布昔利布抑制剂和LIN-ULM(SIAIS1204147)制备得到目标化合物(SIAIS219061)(黄色固体,9.3mg,收率44％)。 1H NMR(500MHz,MeOD)δ9.05(s,1H),8.17(d,J＝9.6Hz,1H),7.80(s,1H),7.68–7.63(m,2H),7.45(dd,J＝9.2,3.9Hz,2H),5.98(dd,J＝17.7,8.8Hz,1H),5.11(dd,J＝12.7,5.5Hz,1H),4.31(s,2H),3.81(dd,J＝16.9,10.9Hz,6H),3.72–3.61(m,14H),3.37(s,2H),2.93–2.82(m,1H),2.79–2.63(m,2H),2.51(s,3H),2.43(s,3H),2.36–2.28(m,2H),2.14-2.09(m,3H),1.93(d,J＝11.7Hz,2H),1.75–1.66(m,2H).HRMS(ESI)m/z:计算值C 47H 56N 9O 11S +[M+H] +,954.3815；实测值,954.3820.
实施例49：制备4-((17-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-17-氧代-3,6,9,12,15-五氧杂十七烷基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS219062)
根据方案22所述通用方法，在本领域可理解的适当条件下，采用帕布昔利布抑制剂和LIN-ULM(SIAIS1204149)制备得到目标化合物(SIAIS219062)(黄色固体,10.2mg,收率46％)。 1H NMR(500MHz,MeOD)δ9.04(s,1H),8.20(dd,J＝9.6,2.9Hz,1H),7.81(d,J＝2.9Hz,1H),7.73–7.60(m,2H),7.51–7.41(m,2H),5.99(p,J＝9.0Hz,1H),5.12(dd,J＝12.8,5.5Hz,1H),4.31(s,2H),3.85–3.75(m,7H),3.72–3.60(m,19H),3.38(s,2H),2.92–2.82(m,1H),2.79–2.63(m,2H),2.51(s,3H),2.43(s,3H),2.31(d,J＝7.6Hz,2H),2.18–2.06(m,3H),1.93(d,J＝16.4Hz,2H),1.76–1.66(m,2H).HRMS(ESI)m/z:计算值C 49H 60N 9O 12S +[M+H] +,998.4077；实测值,998.4071.
实施例50：CDK4/6靶点的特殊降解剂SIAIS219063的合成方法:
Figure PCTCN2019081840-appb-000245
Figure PCTCN2019081840-appb-000246
根据方案23制备4-((2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS219063)：
将帕布昔利布(50mg,0.11mmol)和NMP(2mL)加入15mL样品瓶中，搅拌下依次加入1-溴-2-氯乙烷(48.2mg,0.33mmol)，碘化钠(16.8mg,0.11mmol)，二异丙胺(43.4mg,0.33mmol)，90℃加热反应2h。过滤膜后制备级HPLC分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％-100％)，旋去乙腈，冻干后得中间体30mg，直接下一步。该中间体(10.2mg,0.02mmol)和DMF(2mL)加入15mL样品瓶中，搅拌下依次加入SIAIS151014(11.6mg,0.04mmol)，碳酸钾(8.3mg,0.06mmol)，碘化钠(6mg,0.04mmol)，50℃加热反应2h。过滤膜后制备级HPLC分离。(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％-100％)，旋去乙腈，冻干后得目标产物5.2mg，两步总收率18％。 1H NMR(500MHz,MeOD)δ9.12(s,1H),8.19(dd,J＝9.7,2.9Hz,1H),7.85(d,J＝2.9Hz,1H),7.84–7.75(m,2H),7.65(dd,J＝6.7,1.4Hz,1H),7.54(d,J＝9.6Hz,1H),6.05-5.98(m,1H),5.12(dd,J＝12.7,5.5Hz,1H),3.81(d,J＝5.1Hz,2H),3.79–3.70(m,2H),3.47(t,J＝6.8Hz,2H),3.31–3.23(m,6H),2.95(t,J＝6.9Hz,2H),2.89-2.85(m,1H),2.79–2.69(m,2H),2.52(s,3H),2.44(s,3H),2.36-2.31(m,2H),2.13-2.08(m,3H),1.93(dd,J＝12.0,7.0Hz,2H),1.75-1.68(m,2H).HRMS(ESI)m/z:计算值C 39H 42N 9O 6S +[M+H] +,764.2973；实测值,764.2971.
实施例51：CDK4/6靶点的特殊降解剂SIAIS262173的合成方法:
Figure PCTCN2019081840-appb-000247
根据方案24制备3-(4-((6-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)己基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS262173)：
将Abemaciclib衍生物(9.6mg,0.02mmol)和DMF(2mL)加入15mL样品瓶中，搅拌下依次加入SIAIS1216133(17.6mg,0.04mmol)，碳酸钾(8.3mg,0.06mmol)，碘化钠(6mg,0.04mmol)，50℃加热反应16h。过滤膜后制备级HPLC分离。(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％-100％)，旋去乙腈，冻干后得黄色固体产物8.9mg，收率34％。 1H NMR(500MHz,MeOD)δ8.92(d,J＝3.1Hz,1H),8.60(s,1H),8.56–8.45(m,2H),8.21(d,J＝11.2Hz,1H),7.65(dd,J＝8.9,5.5Hz,3H),7.53(t,J＝7.6Hz,1H),5.15(dd,J＝13.8,5.7Hz,2H),4.44(q,J＝17.3Hz,2H),4.15(s,2H),3.66(s,2H),3.38(d,J＝59.2Hz,4H),3.11-3.08(m,6H),2.98(s,3H),2.92-2.88(m,1H),2.79-2.75(m,1H),2.56-2.52(m,1H),2.25–2.16(m,1H),1.82(d, J＝6.9Hz,6H),1.77–1.65(m,4H),1.56–1.50(m,2H),1.43-1.38(m,2H).HRMS(ESI)m/z:计算值C 44H 51F 2N 10O 3S +[M+H] +,837.3829；实测值,837.3821.
ALK靶点的一系列降解剂通用的合成方法:
Figure PCTCN2019081840-appb-000248
根据方案25，室温下，在反应瓶中，加入相应的ALK抑制剂(1equiv)，相应的LIN-ULM(1equiv),1-羟基-7-偶氮苯并三氮唑(2equiv),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(2equiv),无水N,N-二甲基甲酰胺(2mL)，N-甲基吗啡啉(5equiv)，室温下搅拌反应过夜。LC-MS检测反应结束后，HPLC制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)。旋蒸除去乙腈，冻干后得相应的最终的降解剂化合物。
实施例52：制备4-((2-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)-2-氧代乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS1197113)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物A(SIAIS1197135)和LIN-ULM(SIAIS151045)制备得到目标化合物(SIAIS1197113)(黄色固体,13.4mg,收率49％)。 1H NMR(500MHz,DMSO)δ11.13(s,1H),8.44(s,1H),8.19(s,1H),7.85(d,J＝8.2Hz,1H),7.80(t,J＝8.7Hz,1H),7.65(d,J＝7.1Hz,1H),7.60(s,1H),7.40(s,2H),7.19(s,1H),6.76(s,1H),6.59(s,1H),5.13(dd,J＝12.9,5.4Hz,1H),4.35(s,2H),3.80(s,3H),3.67(s,4H),3.30(s,2H),3.21(s,2H),2.94-2.83(m,1H),2.66–2.56(m,2H),2.06(s,1H),1.79(d,J＝13.6Hz,6H).HRMS(ESI)计算值C 38H 39ClN 8O 7PS +[M+H] +,817.2083；实测值,817.1844.
实施例53：制备4-((3-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)-3-氧代丙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS1197115)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物A(SIAIS1197135)和LIN-ULM(SIAIS151138B)制备得到目标化合物(SIAIS1197115)(黄色固体,13.3mg,收率49％)。 1H NMR(500MHz,MeOD)δ8.35(s,1H),8.07(s,1H),7.81–7.74(m,2H),7.67(dd,J＝13.7,8.5Hz,1H),7.64(dd,J＝6.6,1.3Hz,1H),7.56(s,1H),7.39(t,J＝7.0Hz,1H),7.32(s,1H),6.81(s,1H),6.65(dd,J＝8.7,2.2Hz,1H),5.08(dd,J＝12.8,5.4Hz,1H),3.86(s,3H),3.82(s,2H),3.74(s,2H),3.46(t,J＝6.9Hz,2H),3.32(s,4H),2.93(t,J＝7.0Hz,2H),2.87-2.78(m,1H),2.74-2.60(m,2H),2.07(s,1H),1.88(d,J＝13.6Hz,6H).HRMS(ESI)计算值C 39H 41ClN 8O 7PS +[M+H] +,831.2240；实测值,831.2001.
实施例54：制备4-((4-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)-4-氧代丁基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS1197117)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物A(SIAIS1197135)和LIN-ULM(SIAIS151139B)制备得到目标化合物(SIAIS1197117)(黄色固体,14.6mg,收率54％)。 1H NMR(500MHz,MeOD)δ8.28(s,1H),8.13(s,1H),7.83(d,J＝7.9Hz,1H),7.78–7.72(m,1H),7.70(dd,J＝14.1,7.9Hz,1H),7.63-7.58(m,2H),7.42(t,J＝8.0Hz,2H),7.00(s,1H),6.81(d,J＝7.9Hz,1H),5.13–5.06(m,1H),3.90(s,3H),3.86(s,4H),3.48-3.38(m,4H),3.24(t,J＝7.0Hz,2H),2.89-2.79(m,1H),2.79–2.65(m,2H),2.69(t,J＝6.8Hz,2H),2.12–2.08(m,2H),2.06–1.97(m,1H),1.88(d,J＝13.6Hz,6H).HRMS(ESI)计算值C 40H 43ClN 8O 7PS +[M+H] +,845.2396；实测值,845.2171.
实施例55：制备4-((5-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)-5-氧代戊基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS1197119)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物A(SIAIS1197135)和LIN-ULM(SIAIS151140B)制备得到目标化合物(SIAIS1197119)(黄色固体,14.2mg,收率52％)。 1H NMR(500MHz,MeOD)δ8.32(s,1H),8.10(s,1H),7.76–7.69(m, 2H),7.68(dd,J＝13.3,8.0Hz,1H),7.61–7.56(m,2H),7.44–7.33(m,2H),6.90(s,1H),6.72(d,J＝8.6Hz,1H),5.07(dd,J＝12.6,5.5Hz,1H),3.88(s,3H),3.82(s,4H),3.38(s,2H),3.33(s,2H),3.19(t,J＝6.5Hz,2H),2.88-2.78(m,1H),2.78–2.62(m,2H),2.55(t,J＝6.7Hz,2H),2.16–2.05(m,1H),1.88(d,J＝13.6Hz,6H),1.87-1.83(m,2H),1.83-1.77(m,2H).HRMS(ESI)计算值C 41H 45ClN 8O 7PS +[M+H] +,859.2553；实测值,859.2326.
实施例56：制备4-((6-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)-6-氧代己基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS1197121)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物A(SIAIS1197135)和LIN-ULM(SIAIS151141B)制备得到目标化合物(SIAIS1197121)(黄色固体,13.8mg,收率51％)。 1H NMR(500MHz,MeOD)δ8.22(s,1H),8.18(s,1H),7.75–7.66(m,3H),7.62(t,J＝7.8Hz,1H),7.58(dd,J＝6.0,2.0Hz,1H),7.57–7.50(m,1H),7.45(t,J＝6.9Hz,1H),7.18(s,1H),6.95(dd,J＝8.5,1.9Hz,1H),5.09(dd,J＝12.7,5.5Hz,1H),3.95(s,4H),3.92(s,3H),3.55(s,2H),3.51(s,2H),3.16(t,J＝7.1Hz,2H),2.90–2.80(m,1H),2.77–2.64(m,2H),2.52(t,J＝7.3Hz,2H),2.15–2.07(m,1H),1.87(d,J＝13.6Hz,6H),1.84–1.76(m,2H),1.75–1.65(m,2H),1.64–1.56(m,2H).HRMS(ESI)计算值C 42H 47ClN 8O 7PS +[M+H] +,873.2709；实测值,873.0905.
实施例57：制备4-((7-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)-7-氧代庚基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS1197159)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物A(SIAIS1197135)和LIN-ULM(SIAIS151142B)制备得到目标化合物(SIAIS1197159)(黄色固体,12.5mg,收率46％)。 1H NMR(500MHz,MeOD)δ8.30(s,1H),8.10(s,1H),7.73–7.66(m,3H),7.58(dd,J＝6.3,1.6Hz,2H),7.45–7.35(m,2H),6.92(s,1H),6.74(dd,J＝8.9,1.8Hz,1H),5.09(dd,J＝12.6,5.5Hz,1H),3.88(s,3H),3.84(s,4H),3.40(s,2H),3.35(s,2H),3.13(t,J＝7.1Hz,2H),2.90–2.78(m,1H),2.76–2.64(m,2H),2.49(t,J＝7.4Hz,2H),2.11(dd,J＝8.8,3.7Hz,1H),1.88(d,J＝13.6Hz,6H),1.82–1.73(m,2H),1.72–1.62(m,2H),1.61–1.53(m,2H),1.50–1.40(m,2H).HRMS(ESI)计算值C 43H 49ClN 8O 7PS +[M+H] +,887.2866；实测值,887.1081.
实施例58：制备N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰胺(SIAIS164137)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物B(SIAIS151101)和LIN-ULM(SIAIS151045)制备得到目标化合物(SIAIS164137)(黄色固体,13.0mg,收率78％)。 1H NMR(500MHz,MeOD)δ8.20(s,2H),7.82(d,J＝8.0Hz,1H),7.78–7.70(m,3H),7.68–7.63(m,2H),7.46(t,J＝7.0Hz,1H),7.33(s,1H),7.08(s,1H),5.14(dd,J＝ 12.7,5.5Hz,1H),4.13–4.05(m,1H),3.96(s,3H),3.92(s,2H),3.76–3.73(m,2H),3.68–3.51(m,2H),2.91–2.83(m,1H),2.77–2.67(m,2H),2.22–2.11(m,3H),2.07–2.02(m,2H),1.88(s,3H),1.85(s,3H).HRMS(ESI)计算值C 39H 41ClN 8O 7PS +[M+H] +:831.2240,实测值831.1913.
实施例59：制备N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰胺(SIAIS164138)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物B(SIAIS151101)和LIN-ULM(SIAIS15138B)制备得到目标化合物(SIAIS164138)(黄色固体,11.8mg,收率70％)。 1H NMR(500MHz,MeOD)δ8.23(s,1H),8.17(s,1H),7.81–7.70(m,4H),7.68–7.62(m,2H),7.47(t,J＝7.6Hz,1H),7.41(s,1H),7.14(d,J＝7.7Hz,1H),5.09(dd,J＝12.8,5.3Hz,1H),4.15–4.10(m,1H),3.98(s,3H),3.83–3.73(m,2H),3.71–3.58(m,2H),3.44(t,J＝6.8Hz,2H),2.88–2.81(m,1H),2.75–2.62(m,4H),2.26–2.23(m,2H),2.14–2.02(m,3H),1.88(s,3H),1.85(s,3H).HRMS(ESI)计算值C 40H 43ClN 8O 7PS +[M+H] +:845.2396,实测值845.2034.
实施例60：制备N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰胺(SIAIS164139)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物B(SIAIS151101)和LIN-ULM(SIAIS151139B)制备得到目标化合物(SIAIS164139)(黄色固体,12.0mg,收率70％)。 1H NMR(500MHz,MeOD)δ8.24(s,1H),8.16(s,1H),7.80–7.71(m,4H),7.66(t,J＝7.9Hz,1H),7.61(dd,J＝6.3,1.7Hz,1H),7.49–7.44(m,2H),7.17(d,J＝8.1Hz,1H),5.11(dd,J＝12.7,5.5Hz,1H),4.16–4.09(m,1H),3.98(s,3H),3.79–3.65(m,4H),3.19(t,J＝7.1Hz,2H),2.90–2.83(m,1H),2.77–2.65(m,2H),2.47(t,J＝7.1Hz,2H),2.28–2.24(m,2H),2.16–2.04(m,5H),1.88(s,3H),1.85(s,3H).HRMS(ESI)计算值C 41H 45ClN 8O 7PS +[M+H] +:859.2553,实测值859.2198.
实施例61：制备N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰胺(SIAIS164140)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物B(SIAIS151101)和LIN-ULM(SIAIS151140B)制备得到目标化合物(SIAIS164140)(黄色固体,12.7mg,收率73％)。 1H NMR(500MHz,MeOD)δ8.24(s,1H),8.15(s,1H),7.78–7.65(m,5H),7.60(d,J＝6.4Hz,1H),7.53–7.44(m,2H),7.18(d,J＝8.2Hz,1H),5.11(dd,J＝12.7,5.3Hz,1H),4.14–4.08(m,1H),3.99(s,3H),3.80–3.66(m,4H),3.16(t,J＝6.9Hz,2H),2.90–2.83(m,1H),2.78–2.66(m,2H),2.34–2.31(m,2H),2.24–2.22(m,2H),2.15–2.04(m,3H),1.88(s,3H), 1.86(s,3H),1.82–1.79(m,4H).HRMS(ESI)计算值C 42H 47ClN 8O 7PS +[M+H] +:873.2709,实测值873.2339.
实施例62：制备N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰胺(SIAIS164141)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物B(SIAIS151101)和LIN-ULM(SIAIS151141B)制备得到目标化合物(SIAIS164141)(黄色固体,13.5mg,收率76％)。 1H NMR(500MHz,MeOD)δ8.26(s,1H),8.14(s,1H),7.79–7.66(m,5H),7.59(dd,J＝6.8,1.0Hz,1H),7.54–7.46(m,2H),7.22(dd,J＝8.8,2.1Hz,1H),5.07(dd,J＝12.5,5.5Hz,1H),4.17–4.11(m,1H),3.99(s,3H),3.81–3.70(m,4H),3.15(t,J＝7.0Hz,2H),2.85–2.76(m,1H),2.73–2.62(m,2H),2.29(t,J＝7.1Hz,4H),2.18–2.06(m,3H),1.89(s,3H),1.86(s,3H),1.84–1.78(m,2H),1.75–1.69(m,2H),1.60–1.54(m,2H).HRMS(ESI)计算值C 43H 49ClN 8O 7PS +[M+H] +:887.2866,实测值887.2421.
实施例63：制备N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰胺(SIAIS164142)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物B(SIAIS151101)和LIN-ULM(SIAIS151142B)制备得到目标化合物(SIAIS164142)(黄色固体,13.0mg,收率72％)。 1H NMR(500MHz,MeOD)δ8.24(s,1H),8.16(s,1H),7.78–7.69(m,4H),7.66(t,J＝7.9Hz,1H),7.61–7.58(m,1H),7.50–7.44(m,2H),7.16(d,J＝8.3Hz,1H),5.10(dd,J＝12.6,5.5Hz,1H),4.15–4.08(m,1H),3.98(s,3H),3.78–3.64(m,4H),3.14(t,J＝7.1Hz,2H),2.88–2.81(m,1H),2.75–2.68(m,2H),2.29–2.21(m,4H),2.14–2.04(m,3H),1.88(s,3H),1.85(s,3H),1.81–1.75(m,2H),1.71–1.64(m,2H),1.59–1.53(m,2H),1.45–1.40(m,2H).HRMS(ESI)计算值C 44H 51ClN 8O 7PS +[M+H] +:901.3022,实测值901.2544.
实施例64：制备N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰胺(SIAIS219133)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物B(SIAIS151101)和LIN-ULM(SIAIS171090)制备得到目标化合物(SIAIS219133)(黄色固体,7.2mg,收率44％)。 1H NMR(500MHz,MeOD)δ8.26(s,1H),8.09(s,1H),7.85–7.79(m,1H),7.75(dd,J＝14.3,5.4Hz,3H),7.67(t,J＝7.7Hz,1H),7.59–7.48(m,3H),7.23(d,J＝8.5Hz,1H),5.16(d,J＝11.3Hz,1H),4.59(d,J＝17.4Hz,1H),4.51(d,J＝17.5Hz,1H),4.06(s,1H),3.98(s,3H),3.77–3.67(m,6H),2.92(t,J＝15.4Hz,1H),2.80(d,J＝17.4Hz,1H),2.56(q,J＝12.9Hz,1H),2.22–1.97(m,5H),1.87(dd,J＝13.5,2.4Hz,6H).HRMS(ESI)m/z:计算值C 39H 43ClN 8O 6PS +[M+H] +,817.2447；实测值,817.2443.
实施例65：制备N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙酰胺(SIAIS219134)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物B(SIAIS151101)和LIN-ULM(SIAIS171086)制备得到目标化合物(SIAIS219134)(黄色固体,7.5mg,收率45％)。 1H NMR(500MHz,MeOD)δ8.22(s,1H),8.07(s,1H),7.74-7.69(m,3H),7.63(t,J＝6.7Hz,2H),7.54-7.45(m,3H),7.20(dd,J＝8.7,2.3Hz,1H),5.13(dd,J＝13.3,5.2Hz,1H),4.46(d,J＝17.3Hz,1H),4.39(d,J＝17.3Hz,1H),4.10–4.00(m,1H),3.95(s,3H),3.72(d,J＝5.4Hz,4H),3.36-3.33(m,2H),2.92-2.84(m,1H),2.78-2.73(m,1H),2.60–2.45(m,3H),2.19-2.15(m,3H),2.11–2.02(m,2H),1.83(d,J＝13.5Hz,6H).HRMS(ESI)m/z:计算值C 40H 45ClN 8O 6PS +[M+H] +,831.2603；实测值,831.2601.
实施例66：制备N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁酰胺(SIAIS219135)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物B(SIAIS151101)和LIN-ULM(SIAIS171089)制备得到目标化合物(SIAIS219135)(黄色固体,8.1mg,收率48％)。 1H NMR(500MHz,MeOD)δ8.26(s,1H),8.11(s,1H),7.78–7.72(m,2H),7.71–7.63(m,3H),7.57–7.49(m,3H),7.25(d,J＝8.6Hz,1H),5.17(dd,J＝13.3,5.1Hz,1H),4.49(d,J＝17.3Hz,1H),4.43(d,J＝17.3Hz,1H),4.17–4.09(m,1H),3.99(s,3H),3.77(s,4H),3.11(t,J＝7.3Hz,2H),2.96–2.87(m,1H),2.83–2.76(m,1H),2.61–2.50(m,1H),2.43(t,J＝7.2Hz,2H),2.28–2.11(m,5H),2.02–1.95(m,2H),1.87(d,J＝13.5Hz,6H).HRMS(ESI)m/z:计算值C 41H 47ClN 8O 6PS +[M+H] +,845.2760；实测值,845.2755.
实施例67：制备N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酰胺(SIAIS219136)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物B(SIAIS151101)和LIN-ULM(SIAIS171079)制备得到目标化合物(SIAIS219136)(黄色固体,8.4mg,收率49％)。 1H NMR(500MHz,MeOD)δ8.20(d,J＝11.3Hz,2H),7.79–7.71(m,2H),7.66(dd,J＝17.5,7.6Hz,3H),7.54(t,J＝7.6Hz,1H),7.47(t,J＝7.4Hz,1H),7.32(s,1H),7.07(d,J＝8.0Hz,1H),5.15(dd,J＝13.3,5.2Hz,1H),4.51(d,J＝17.3Hz,1H),4.44(d,J＝17.4Hz,1H),4.02-3.98(m,4H),3.66(t,J＝24.9Hz,4H),3.11-3.07(m,2H),2.99–2.87(m,1H),2.85–2.77(m,1H),2.58-2.54(m,1H),2.25-2.22(m,3H),2.03(d,J＝12.1Hz,2H),1.96-1.92(m,2H),1.87(d,J＝13.5Hz,6H),1.84–1.77(m,2H),1.69–1.61(m,2H).HRMS(ESI)m/z:计算值C 42H 49ClN 8O 6PS +[M+H] +,859.2916；实测值,859.2912.
实施例68：制备N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰胺(SIAIS219137)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物B(SIAIS151101)和LIN-ULM(SIAIS171091)制备得到目标化合物(SIAIS219137)(黄色固体,7.9mg,收率45％)。 1H NMR(500MHz,MeOD)δ8.24(s,1H),8.14(s,1H),7.79–7.71(m,2H),7.70–7.62(m,3H),7.53(t,J＝7.7Hz,1H),7.47(dd,J＝25.4,12.1Hz,2H),7.17(s,1H),5.16(dd,J＝13.3,5.2Hz,1H),4.47(d,J＝17.3Hz,1H),4.41(d,J＝17.3Hz,1H),4.08(s,1H),3.99(s,3H),3.73(s,4H),3.13–3.04(m,2H),2.95–2.87(m,1H),2.81-2.76(m,1H),2.61–2.50(m,1H),2.29–2.16(m,5H),2.05(s,2H),1.87(d,J＝13.6Hz,6H),1.72-1.63(m,4H),1.54-1.49(m,2H).HRMS(ESI)m/z:计算值C 43H 51ClN 8O 6PS +[M+H] +,873.3073；实测值,873.3066.
实施例69：制备N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)庚酰胺(SIAIS219138)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物B(SIAIS151101)和LIN-ULM(SIAIS171092)制备得到目标化合物(SIAIS219138)(黄色固体,8.3mg,收率47％)。 1H NMR(500MHz,MeOD)δ8.19(s,1H),7.72(dd,J＝13.8,7.8Hz,2H),7.67–7.61(m,4H),7.53(t,J＝7.6Hz,1H),7.45(t,J＝7.6Hz,1H),7.27(s,1H),7.03(s,1H),5.16(dd,J＝13.4,5.2Hz,1H),4.46(d,J＝17.3Hz,1H),4.40(d,J＝17.3Hz,1H),4.04(s,1H),3.96(s,3H),3.71(s,2H),3.56(s,2H),3.07(t,J＝7.0Hz,2H),2.91-2.87(m,1H),2.82-2.78(m,1H),2.60–2.49(m,1H),2.23-2.15(m,5H),1.97-1.94(m,2H),1.87(d,J＝13.5Hz,6H),1.72–1.66(m,2H),1.65–1.60(m,2H),1.54–1.48(m,2H),1.38–1.33(m,2H).HRMS(ESI)m/z:计算值C 44H 53ClN 8O 6PS +[M+H] +,887.3229；实测值,887.3223.
实施例70：制备N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙酰胺(SIAIS219144)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物B(SIAIS151101)和LIN-ULM(SIAIS1204137)制备得到目标化合物(SIAIS219144)(黄色固体,9.2mg,收率53％)。 1H NMR(500MHz,MeOD)δ8.27(s,1H),8.12(s,1H),7.83–7.74(m,4H),7.72–7.62(m,2H),7.56–7.48(m,2H),7.25(d,J＝8.7Hz,1H),5.11(dd,J＝12.8,5.4Hz,1H),4.24–4.18(m,1H),4.07(s,2H),3.99(s,3H),3.89(t,J＝6.0Hz,2H),3.84–3.73(m,4H),3.44(t,J＝6.0Hz,2H),2.93–2.80(m,1H),2.78–2.62(m,2H),2.23(t,J＝7.2Hz,4H),2.17–2.08(m,1H),1.87(d,J＝13.5Hz,6H).HRMS(ESI)m/z:计算值C 41H 45ClN 8O 8PS +[M+H] +,875.2502；实测值,875.2501.
实施例71：制备N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙酰胺(SIAIS219139)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物B(SIAIS151101)和LIN-ULM(SIAIS1213129)制备得到目标化合物(SIAIS219139)(黄色固体,8.5mg,收率49％)。 1H NMR(500MHz,MeOD)δ8.24(s,1H),8.15(s,1H),7.74(dd,J＝13.8,7.2Hz,3H),7.67(t,J＝7.5Hz,2H),7.56(t,J＝7.6Hz,1H),7.50(t,J＝7.3Hz,1H),7.43(s,1H),7.15(d,J＝8.6Hz,1H),5.18(dd,J＝13.3,5.2Hz,1H),4.54(d,J＝17.4Hz,1H),4.48(d,J＝17.4Hz,1H),4.15–4.07(m,1H),3.98(d,J＝4.6Hz,5H),3.79(t,J＝6.1Hz,2H),3.70(s,4H),3.36-3.31(m,2H),2.96–2.87(m,1H),2.79(d,J＝15.5Hz,1H),2.61–2.51(m,1H),2.25–2.17(m,1H),2.11(s,4H),1.87(d,J＝13.5Hz,6H).HRMS(ESI)m/z:计算值C 41H 47ClN 8O 7PS +[M+H] +,861.2709；实测值,861.2701.
实施例72：制备N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酰胺(SIAIS219140)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物B(SIAIS151101)和LIN-ULM(SIAIS1213131)制备得到目标化合物(SIAIS219140)(黄色固体,9.1mg,收率50％)。 1H NMR(500MHz,MeOD)δ8.26(s,1H),8.12(s,1H),7.78–7.71(m,3H),7.68(t,J＝7.9Hz,1H),7.63(d,J＝7.5Hz,1H),7.56–7.49(m,3H),7.25(dd,J＝8.8,2.1Hz,1H),5.16(dd,J＝13.3,5.2Hz,1H),4.51(d,J＝17.4Hz,1H),4.45(d,J＝17.4Hz,1H),4.22–4.15(m,1H),4.04(s,2H),3.99(s,3H),3.76(t,J＝6.1Hz,4H),3.68(d,J＝4.3Hz,6H),3.31-3.28(m,2H),2.95-2.88(m,1H),2.82-2.77(m,1H),2.62–2.50(m,1H),2.29–2.10(m,5H),1.87(d,J＝13.5Hz,6H).HRMS(ESI)m/z:计算值C 43H 51ClN 8O 8PS +[M+H] +,905.2971；实测值,905.2965.
实施例73：制备N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙酰胺(SIAIS219141)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物B(SIAIS151101)和LIN-ULM(SIAIS1213133)制备得到目标化合物(SIAIS219141)(黄色固体,9.0mg,收率47％)。 1H NMR(500MHz,MeOD)δ8.24(s,1H),8.15(s,1H),7.76–7.69(m,3H),7.68–7.61(m,2H),7.50(dd,J＝14.5,6.9Hz,2H),7.42(s,1H),7.14(s,1H),5.16(dd,J＝13.3,5.2Hz,2H),4.48(d,J＝17.4Hz,1H),4.42(d,J＝17.4Hz,1H),4.15(s,1H),4.03(s,2H),3.98(s,3H),3.75–3.63(m,12H),3.25(dd,J＝11.5,6.2Hz,4H),2.96–2.86(m,1H),2.81-2.79(m,1H),2.59-2.50(m,1H),2.20-2.17(m,5H),1.87(d,J＝13.6Hz,6H).HRMS(ESI)m/z:计算值C 45H 55ClN 8O 9PS +[M+H] +,949.3233；实测值,949.3223.
实施例74：制备N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十四烷-1-酰胺(SIAIS219142)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物B(SIAIS151101)和LIN-ULM(SIAIS1213135)制备得到目标化合物(SIAIS219142)(黄色固体,10.1mg,收率51％)。 1H NMR(500MHz,MeOD)δ8.26(s,1H),8.12(s,1H),7.75(dd,J＝14.2,8.6Hz,2H),7.71–7.61(m,3H),7.54–7.48(m,3H),7.23(dd,J＝8.7,2.2Hz,1H),5.16(dd,J＝13.3,5.1Hz,1H),4.48(d,J＝17.4Hz,1H),4.42(d,J＝17.4Hz,1H),4.23–4.16(m,1H),4.04(s,2H),3.99(s,3H),3.80–3.60(m,18H),3.24-3.21(m,2H),2.95-2.87(m,1H),2.82–2.76(m,1H),2.59–2.48(m,1H),2.26-2.21(m,5H),1.87(d,J＝13.5Hz,6H).HRMS(ESI)m/z:计算值C 47H 59ClN 8O 10PS +[M+H] +,993.3496；实测值,993.3491.
实施例75：制备N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷-1-酰胺(SIAIS219143)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物B(SIAIS151101)和LIN-ULM(SIAIS1213137)制备得到目标化合物(SIAIS219143)(黄色固体,9.9mg,收率48％)。 1H NMR(500MHz,MeOD)δ8.25(s,1H),8.14(s,1H),7.84–7.61(m,5H),7.50(dd,J＝16.6,8.4Hz,3H),7.20(s,1H),5.16(dd,J＝13.4,5.0Hz,1H),4.48(d,J＝17.4Hz,1H),4.42(d,J＝17.3Hz,1H),4.23–4.14(m,1H),4.03(s,2H),3.99(s,3H),3.85–3.52(m,22H),3.21(t,J＝6.3Hz,2H),2.97–2.85(m,1H),2.79(d,J＝16.3Hz,1H),2.58-2.50(m,1H),2.33–2.13(m,5H),1.87(d,J＝13.5Hz,6H).HRMS(ESI)m/z:计算值C 49H 63ClN 8O 11PS +[M+H] +,1037.3758；实测值,1037.3751.
实施例76：制备4-((2-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-2-氧代乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS164062)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物C(SIAIS164005)和LIN-ULM(SIAIS151045)制备得到目标化合物(SIAIS164062)(黄色固体,11.9mg,收率76％)。 1H NMR(500MHz,MeOD)δ8.37(s,1H),8.05(s,1H),7.89(s,1H),7.82–7.62(m,3H),7.56(s,1H),7.38(s,2H),6.75(s,1H),6.60(s,1H),5.15(dd,J＝13.5,7.3Hz,1H),4.23–4.14(m,3H),3.95(d,J＝10.9Hz,2H),3.86(s,3H),3.63–3.38(m,6H),2.87(d,J＝11.8Hz,4H),2.78–2.74(m,3H),2.26(s,2H),2.15(s,1H),1.94–1.87(m,8H).HRMS(ESI)计算值C 43H 48ClN 9O 7PS +[M+H] +:900.2818,实测值900.3216.
实施例77：制备4-((3-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-3-氧代丙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS164063)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物C(SIAIS164005)和LIN-ULM(SIAIS151138B)制备得到目标化合物(SIAIS164063)(黄色固体,9.6mg,收率60％)。 1H NMR(500MHz,MeOD)δ8.38(s,1H),8.06(s,1H),7.79–7.78(m,2H),7.71–7.64(m,2H),7.56(s,1H),7.36(dd,J＝15.4,8.0Hz,2H),6.73(s,1H),6.59(d,J＝8.3Hz,1H),5.11(dd,J＝12.3,5.4Hz,1H),3.94(s,2H),3.86(s,3H),3.65–3.32(m,10H),2.97–2.65(m,8H),2.23(s,2H),2.17–2.09(m,1H),1.89–1.87(m,8H).HRMS(ESI)计算值C 44H 50ClN 9O 7PS +[M+H] +:914.2975,实测值914.3368.
实施例78：制备4-((4-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-4-氧代丁基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS164064)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物C(SIAIS164005)和LIN-ULM(SIAIS151139B)制备得到目标化合物(SIAIS164064)(黄色固体,8mg,收率49％)。 1H NMR(500MHz,MeOD)δ8.30(s,1H),8.12(s,1H),7.83(d,J＝8.1Hz,1H),7.78–7.74(m,1H),7.71(dd,J＝13.6,8.2Hz,1H),7.64(d,J＝7.2Hz,1H),7.61(s,1H),7.44(t,J＝7.1Hz,2H),7.03(s,1H),6.83(s,1H),5.14(dd,J＝12.5,5.5Hz,1H),4.29(s,1H),3.95(d,J＝11.9Hz,2H),3.91(s,3H),3.62(s,4H),3.31–3.17(m,7H),2.92–2.84(m,1H),2.76–2.67(m,5H),2.36(s,2H),2.24–2.03(m,5H),1.88(d,J＝13.6Hz,6H).HRMS(ESI)计算值C 45H 52ClN 9O 7PS +[M+H] +:928.3131,实测值928.0598.
实施例79：制备4-((5-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-5-氧代戊基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS164066)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物C(SIAIS164005)和LIN-ULM(SIAIS151140B)制备得到目标化合物(SIAIS164066)(黄色固体,8.2mg,收率50％)。 1H NMR(500MHz,MeOD)δ8.28(s,1H),8.14(s,1H),7.80–7.67(m,3H),7.62(s,2H),7.45(s,2H),7.13(s,1H),6.91(s,1H),5.13(dd,J＝12.4,5.4Hz,1H),4.28(s,1H),3.96–3.91(m,5H),3.67(s,4H),3.31-3.25(m,8H),2.84(d,J＝17.8Hz,1H),2.80–2.66(m,2H),2.54(s,2H),2.41(s,2H),2.21–2.12(m,3H),1.98–1.74(m,10H).HRMS(ESI)计算值C 46H 54ClN 9O 7PS +[M+H] +:942.3288,实测值942.0592.
实施例80：制备4-((6-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-6-氧代己基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS164065)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物C(SIAIS164005)和LIN-ULM(SIAIS151141B)制备得到目标化合物(SIAIS164065)(黄色固体,11.2mg,收率67％)。 1H NMR(500MHz,MeOD)δ8.38(s,1H),8.05(s,1H),7.76–7.70(m,2H),7.67(dd,J＝14.4,8.1Hz,1H),7.61(d,J＝6.7Hz,1H),7.58–7.55(m,1H),7.37(t,J＝7.2Hz, 1H),7.33(d,J＝8.4Hz,1H),6.73(d,J＝2.3Hz,1H),6.58(d,J＝9.4Hz,1H),5.11(dd,J＝12.5,5.5Hz,1H),3.94(d,J＝12.1Hz,2H),3.85(s,3H),3.60–3.31(m,8H),3.16(t,J＝7.0Hz,3H),2.89–2.83(m,3H),2.76–2.66(m,2H),2.49(t,J＝7.1Hz,2H),2.26(d,J＝12.1Hz,2H),2.17–2.08(m,1H),1.97–1.83(m,8H),1.84–1.78(m,2H),1.71–1.57(m,2H),1.61–1.57(m,2H).HRMS(ESI)计算值C 47H 56ClN 9O 7PS +[M+H] +:956.3444,实测值956.3885.
实施例81：制备4-((7-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-7-氧代庚基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(SIAIS164067)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物C(SIAIS164005)和LIN-ULM(SIAIS151142B)制备得到目标化合物(SIAIS164067)(黄色固体,6.8mg,收率40％)。 1H NMR(500MHz,MeOD)δ8.30(s,1H),8.12(s,1H),7.76–7.68(m,3H),7.63-7.60(m,2H),7.44(t,J＝7.0Hz,2H),7.05(s,1H),6.84(s,1H),5.12(dd,J＝12.5,5.5Hz,1H),4.27(s,1H),3.96(d,J＝14.0Hz,2H),3.91(s,3H),3.69–3.62(m,5H),3.24(s,3H),3.15(t,J＝7.1Hz,4H),2.91–2.83(m,1H),2.79–2.66(m,2H),2.48(t,J＝7.3Hz,2H),2.39(d,J＝10.6Hz,2H),2.22–2.08(m,3H),1.88(d,J＝13.6Hz,6H),1.82–1.75(m,2H),1.69–1.63(m,2H),1.61–1.53(m,2H),1.48–1.43(m,2H).HRMS(ESI)计算值C 48H 58ClN 9O 7PS +[M+H] +:970.3601,实测值970.0767.
实施例82：制备3-(4-((2-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-2-氧代乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS219067)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物C(SIAIS164005)和LIN-ULM(SIAIS171090)制备得到目标化合物(SIAIS219067)(黄色固体,6.1mg,收率39％)。1H NMR(500MHz,MeOD)δ8.25(s,1H),8.15(s,1H),7.85(d,J＝7.7Hz,1H),7.79(d,J＝7.6Hz,1H),7.74–7.70(m,1H),7.65-7.58(m,2H),7.47(t,J＝7.5Hz,2H),7.14(s,1H),6.91(d,J＝7.2Hz,1H),5.19(dd,J＝13.7,4.9Hz,1H),4.59(d,J＝17.5Hz,1H),4.50(d,J＝15.8Hz,1H),4.06(s,2H),3.95(s,3H),3.93(s,4H),3.68-3.60(m,4H),3.35(s,2H),2.97–2.77(m,3H),2.62–2.51(m,1H),2.36(d,J＝11.7Hz,2H),2.25–2.14(m,4H),1.93-1.90(m,1H),1.89(s,3H),1.86(s,3H).HRMS(ESI)m/z:计算值C43H50ClN9O6PS+[M+H]+,886.3025；实测值,886.3021.
实施例83：制备3-(4-((3-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-3-氧代丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS219068)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物C(SIAIS164005)和LIN-ULM(SIAIS171086)制备得到目标化合物(SIAIS219068)(黄色固体,5.4mg,收率34％)。 1H NMR(500MHz,MeOD)δ8.20(s,2H),7.76–7.69(m,3H),7.66(t,J＝7.9 Hz,1H),7.59-7.55(m,2H),7.49(t,J＝7.5Hz,1H),7.34(s,1H),7.07(d,J＝6.4Hz,1H),5.18(dd,J＝13.4,5.2Hz,1H),4.50(d,J＝17.4Hz,1H),4.46–4.42(m,1H),3.96(s,3H),3.91(d,J＝12.3Hz,2H),3.72(s,2H),3.60(s,4H),3.42–3.33(m,3H),3.28(d,J＝6.9Hz,1H),3.17(s,2H),2.95-2.89(m,2H),2.86–2.77(m,3H),2.60–2.51(m,1H),2.46(d,J＝10.9Hz,2H),2.35(s,2H),2.24–2.17(m,1H),1.89(s,3H),1.86(s,3H).HRMS(ESI)m/z:计算值C 44H 52ClN 9O 6PS +[M+H] +,900.3182；实测值,900.3176.
实施例84：制备3-(4-((4-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-4-氧代丁基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS219069)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物C(SIAIS164005)和LIN-ULM(SIAIS171089)制备得到目标化合物(SIAIS219069)(黄色固体,5.1mg,收率32％)。 1H NMR(500MHz,MeOD)δ8.25(s,1H),8.15(s,1H),7.75–7.71(m,2H),7.68(d,J＝7.5Hz,1H),7.63(t,J＝7.5Hz,1H),7.56(t,J＝7.6Hz,1H),7.50(s,1H),7.47(t,J＝7.1Hz,1H),7.16(s,1H),6.93(d,J＝8.1Hz,1H),5.17(dd,J＝13.4,5.2Hz,1H),4.51(d,J＝17.4Hz,1H),4.44(d,J＝17.3Hz,1H),3.94(s,2H),3.93(s,3H),3.68-3.64(m,4H),3.38(s,2H),3.19-3.15(m,4H),2.96–2.89(m,1H),2.84-2.80(m,1H),2.59-2.53(m,4H),2.40(d,J＝11.6Hz,2H),2.27–2.17(m,4H),2.01-1.96(m,J＝6.9Hz,3H),1.89(s,3H),1.86(s,3H).HRMS(ESI)m/z:计算值C 45H 54ClN 9O 6PS +[M+H] +,914.3338；实测值,914.3334.
实施例85：制备3-(4-((5-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-5-氧代戊基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS219070)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物C(SIAIS164005)和LIN-ULM(SIAIS171079)制备得到目标化合物(SIAIS219070)(黄色固体,5.0mg,收率31％)。 1H NMR(500MHz,MeOD)δ8.19(s,2H),7.73(dd,J＝12.6,6.6Hz,1H),7.67(t,J＝7.8Hz,3H),7.59(s,1H),7.54(t,J＝7.8Hz,1H),7.49(t,J＝7.3Hz,1H),7.32(s,1H),7.06(d,J＝8.6Hz,1H),5.18–5.15(m,1H),4.49(d,J＝17.4Hz,1H),4.43(d,J＝17.4Hz,1H),3.95(s,3H),3.91(s,2H),3.71(s,4H),3.59(s,4H),3.13-3.07(m,4H),2.95–2.87(m,1H),2.79(d,J＝16.8Hz,1H),2.59–2.46(m,5H),2.38-2.33(m,3H),2.24–2.17(m,1H),1.89(s,3H),1.86(s,3H),1.80–1.71(m,4H).HRMS(ESI)m/z:计算值C 46H 56ClN 9O 6PS +[M+H] +,928.3495；实测值,928.3491.
实施例86：制备3-(4-((6-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-6-氧代己基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS219071)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物C(SIAIS164005)和LIN-ULM(SIAIS171091)制备得到目标化合物(SIAIS219071)(黄色固体, 6.2mg,收率38％)。 1H NMR(500MHz,MeOD)δ8.23(s,1H),8.16(s,1H),7.72(dd,J＝13.8,7.8Hz,1H),7.68–7.63(m,3H),7.54(t,J＝7.7Hz,2H),7.47(t,J＝7.4Hz,1H),7.19(s,1H),6.95(d,J＝7.6Hz,1H),5.17(dd,J＝13.1,4.8Hz,1H),4.48(d,J＝17.4Hz,1H),4.44–4.40(m,1H),3.93(s,3H),3.93–3.89(m,2H),3.69(s,4H),3.43-3.40(m,4H),3.13-3.08(m,4H),2.96–2.88(m,1H),2.84–2.77(m,1H),2.59-2.53(m,1H),2.42(t,J＝11.5Hz,4H),2.33–2.16(m,4H),1.89(s,3H),1.86(s,3H),1.71–1.61(m,4H),1.57–1.50(m,2H).HRMS(ESI)m/z:计算值C 47H 58ClN 9O 6PS +[M+H] +,942.3651；实测值,942.3644.
实施例87：制备3-(4-((7-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-7-氧代庚基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS219072)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物C(SIAIS164005)和LIN-ULM(SIAIS171092)制备得到目标化合物(SIAIS219072)(黄色固体,6.3mg,收率38％)。 1H NMR(500MHz,MeOD)δ8.31(s,1H),8.11(s,1H),7.71(dd,J＝14.0,7.7Hz,1H),7.65(dd,J＝7.6,2.0Hz,2H),7.60(s,1H),7.54(t,J＝7.7Hz,1H),7.43(t,J＝7.6Hz,2H),6.97(s,1H),6.78(d,J＝8.1Hz,1H),5.17(dd,J＝13.3,5.2Hz,1H),4.47(d,J＝17.4Hz,1H),4.41(d,J＝17.3Hz,1H),3.96(d,J＝12.6Hz,2H),3.90(s,3H),3.68-3.60(m,4H),3.36-3.32(m,2H),3.25–3.02(m,7H),2.97–2.87(m,1H),2.81-2.77(m,1H),2.60–2.50(m,1H),2.42(t,J＝7.5Hz,2H),2.36(d,J＝11.4Hz,2H),2.21-2.17(m,1H),2.08(d,J＝12.1Hz,2H),1.89(d,J＝8.4Hz,3H),1.87(s,3H),1.71-1.65(m,2H),1.62-1.56(m,2H),1.54–1.47(m,2H),1.41-1.35(m,2H).HRMS(ESI)m/z:计算值C 48H 60ClN 9O 6PS +[M+H] +,956.3808；实测值,956.3805.
实施例88：制备3-(4-((2-(2-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-2-氧代乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS219092)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用布加替尼衍生物C(SIAIS164005)和LIN-ULM(SIAIS1213129)制备得到目标化合物(SIAIS219092)(黄色固体,6.7mg,收率41％)。 1H NMR(500MHz,MeOD)δ8.32(d,J＝18.7Hz,1H),8.13(s,1H),7.71(ddd,J＝21.8,14.5,7.9Hz,4H),7.62(t,J＝7.5Hz,1H),7.55(dd,J＝14.4,6.9Hz,1H),7.45(t,J＝6.9Hz,2H),7.05(s,1H),6.85(d,J＝7.3Hz,1H),5.17(dd,J＝13.3,5.0Hz,1H),4.53(d,J＝17.4Hz,1H),4.48(d,J＝14.5Hz,1H),4.25(s,2H),3.93(d,J＝12.7Hz,7H),3.76(d,J＝13.8Hz,2H),3.69–3.52(m,4H),3.29–2.99(m,6H),2.92-2.88(m,1H),2.82–2.76(m,1H),2.58-2.54(m,1H),2.32(s,2H),2.23–2.18(m,1H),2.12(s,2H),1.89-1.85(m,6H).HRMS(ESI)m/z:计算值C 45H 54ClN 9O 7PS +[M+H] +,930.3288；实测值,930.3282.
实施例89：制备8-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS164068)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物A和LIN-ULM(SIAIS151045)制备得到目标化合物(SIAIS164068)(黄色固体,11.7mg,收率47％)。 1H NMR(500MHz,DMSO)δ12.71(s,1H),11.13(s,1H),8.32(d,J＝8.2Hz,1H),8.08(s,1H),8.00(s,1H),7.86(d,J＝8.1Hz,1H),7.83–7.78(m,1H),7.66(d,J＝7.1Hz,1H),7.61(dd,J＝8.1,1.4Hz,1H),7.41(s,1H),5.14(dd,J＝12.8,5.4Hz,1H),4.35(s,2H),3.75(d,J＝54.1Hz,4H),3.02(d,J＝31.7Hz,4H),2.96–2.83(m,1H),2.77(q,J＝7.4Hz,2H),2.66–2.53(m,2H),2.09–2.04(m,1H),1.76(s,6H),1.30(t,J＝7.5Hz,3H).HRMS(ESI)计算值C 40H 37N 6O 6S +[M+H] +:729.2490,实测值729.2846.
实施例90：制备8-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS164069)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物A和LIN-ULM(SIAIS151138B)制备得到目标化合物(SIAIS164069)(黄色固体,13.6mg,收率53％)。 1H NMR(500MHz,DMSO)δ12.70(s,1H),11.12(s,1H),8.32(d,J＝8.1Hz,1H),8.06(s,1H),8.00(s,1H),7.87–7.76(m,2H),7.65(d,J＝6.0Hz,1H),7.61(d,J＝9.1Hz,1H),7.39(s,1H),5.12(dd,J＝12.9,5.4Hz,1H),3.69(s,2H),3.62(s,2H),3.40–3.36(m,2H),2.94(s,4H),2.87–2.85(m,3H),2.75(q,J＝7.4Hz,2H),2.61–2.58(m,2H),2.07–2.04(m,1H),1.75(s,6H),1.28(t,J＝7.5Hz,3H).HRMS(ESI)计算值C 41H 39N 6O 6S +[M+H] +:743.2646,实测值743.3002.
实施例91：制备8-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS164070)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物A和LIN-ULM(SIAIS151139B)制备得目标化合物(SIAIS164070)(黄色固体,19.5mg,收率75％)。 1H NMR(500MHz,DMSO)δ12.71(s,1H),11.12(s,1H),8.32(d,J＝8.1Hz,1H),8.07(s,1H),8.00(s,1H),7.90(d,J＝8.3Hz,1H),7.84–7.78(m,1H),7.64(d,J＝7.2Hz,1H),7.61(dd,J＝8.1,1.3Hz,1H),7.39(s,1H),5.12(dd,J＝12.8,5.4Hz,1H),3.66(d,J＝10.5Hz,2H),3.64(s,2H),3.20(t,J＝7.4Hz,2H),2.98(s,2H),2.93(s,2H),2.91–2.83(m,1H),2.76(q,J＝7.5Hz,2H),2.66–2.52(m,4H),2.06(dd,J＝10.2,4.9Hz,1H),2.00–1.90(m,2H),1.75(s,6H),1.29(t,J＝7.5Hz,3H).HRMS(ESI)计算值C 42H 41N 6O 6S +[M+H] +:757.2803,实测值757.3013.
实施例92：制备8-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS164072)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物A和LIN-ULM(SIAIS151140B)制备得目标化合物(SIAIS164072)(黄色固体,16.6mg,收率62％)。 1H NMR(500MHz,DMSO)δ12.70(s,1H),11.12(s,1H),8.32(d,J＝8.2Hz,1H),8.07(s, 1H),8.00(s,1H),7.82–7.76(m,2H),7.63(d,J＝4.6Hz,1H),7.62–7.59(m,1H),7.39(s,1H),5.11(dd,J＝12.9,5.4Hz,1H),3.65(s,4H),3.18(s,2H),2.98(s,2H),2.93(s,2H),2.90–2.84(m,1H),2.75(q,J＝7.4Hz,2H),2.66–2.55(m,2H),2.45(s,2H),2.04(s,1H),1.75(s,10H),1.28(t,J＝7.5Hz,3H).HRMS(ESI)计算值C 43H 43N 6O 6S +[M+H] +:771.2959,实测值771.3153.
实施例93：制备8-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS164071)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物A和LIN-ULM(SIAIS151141B)制备得目标化合物(SIAIS164071)(黄色固体,20.7mg,收率75％)。 1H NMR(500MHz,DMSO)δ12.70(s,1H),11.12(s,1H),8.32(d,J＝8.1Hz,1H),8.07(s,1H),8.00(s,1H),7.82–7.73(m,2H),7.63(d,J＝6.9Hz,1H),7.61(dd,J＝8.2,1.3Hz,1H),7.39(s,1H),5.11(dd,J＝12.9,5.4Hz,1H),3.64(s,4H),3.15(t,J＝7.3Hz,2H),2.97(s,2H),2.93(s,2H),2.90–2.84(m,1H),2.75(q,J＝7.5Hz,2H),2.66–2.55(m,2H),2.41–2.36(m,2H),2.07–2.04(m,1H),1.75(s,6H),1.72–1.70(m,2H),1.64–1.55(m,2H),1.51–1.50(m,2H),1.29(t,J＝7.5Hz,3H).HRMS(ESI)计算值C 44H 45N 6O 6S +[M+H] +:785.3116,实测值785.3486.
实施例94：制备8-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS164073)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物A和LIN-ULM(SIAIS151142B)制备得目标化合物(SIAIS164073)(黄色固体,19.7mg,收率71％)。 1H NMR(500MHz,DMSO)δ12.71(s,1H),11.12(s,1H),8.32(d,J＝8.2Hz,1H),8.06(s,1H),8.00(s,1H),7.82–7.73(m,2H),7.61(t,J＝8.4Hz,2H),7.39(s,1H),5.10(s,1H),3.64(s,4H),3.14(s,2H),2.97(s,2H),2.93(s,2H),2.89–2.84(m,1H),2.75(d,J＝7.7Hz,2H),2.61(s,2H),2.37(s,2H),2.07–2.03(m,1H),1.75(s,6H),1.69(s,2H),1.55(s,2H),1.48(s,2H),1.37(s,2H),1.28(t,J＝7.4Hz,3H).HRMS(ESI)计算值C 45H 47N 6O 6S +[M+H] +:799.3272,实测值799.3473.
实施例95：制备N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰胺(SIAIS219012)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物B和LIN-ULM(SIAIS151045)制备得目标化合物(SIAIS219012)(黄色固体,6.7mg,收率37％)。 1H NMR(500MHz,DMSO)δ12.76(s,1H),11.13(s,1H),8.38(d,J＝7.6Hz,1H),8.32(d,J＝8.2Hz,1H),8.02(d,J＝21.8Hz,2H),7.90–7.76(m,2H),7.73–7.55(m,2H),7.36(s,1H),5.14(dd,J＝12.8,5.4Hz,1H),3.90(s,2H),3.79(s,1H),3.44(s,4H),3.16(d,J＝11.6Hz,2H),2.89-2.85(m,3H),2.71(q,J＝7.5Hz,2H),2.61(d,J＝19.0Hz,2H),2.11–2.02(m,1H),1.90(d, J＝10.2Hz,2H),1.75(s,6H),1.68–1.61(m,2H),1.28(t,J＝7.5Hz,3H).HRMS(ESI)m/z:计算值C 41H 39N 6O 6S +[M+H] +,743.2646；实测值,743.2674.
实施例96：制备N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰胺(SIAIS219013)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物B和LIN-ULM(SIAIS151139B)制备得目标化合物(SIAIS219013)(黄色固体,9.2mg,收率49％)。 1H NMR(500MHz,DMSO)δ12.71(s,1H),11.12(s,1H),8.32(d,J＝8.2Hz,1H),8.02(d,J＝19.9Hz,2H),7.95(d,J＝7.7Hz,1H),7.81(dd,J＝7.1,5.0Hz,2H),7.64-7.61(m,2H),7.36(s,1H),5.12(dd,J＝12.9,5.4Hz,1H),3.78(s,1H),3.22–3.11(m,4H),2.87-2.82(m,3H),2.70(q,J＝7.5Hz,2H),2.66–2.56(m,2H),2.30(t,J＝7.1Hz,2H),2.10–2.00(m,1H),1.93-1.90(m,4H),1.75(s,6H),1.59(d,J＝9.3Hz,2H),1.28(d,J＝7.5Hz,3H).HRMS(ESI)m/z:计算值C 43H 43N 6O 6S +[M+H] +,771.2959；实测值,771.2979.
实施例97：制备N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰胺(SIAIS219014)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物B和LIN-ULM(SIAIS151141B)制备得目标化合物(SIAIS219014)(黄色固体,9.3mg,收率48％)。 1H NMR(500MHz,DMSO)δ12.71(s,1H),11.12(s,1H),8.32(d,J＝8.1Hz,1H),8.03-7.98(m,2H),7.78(dd,J＝15.1,8.1Hz,2H),7.64–7.59(m,2H),7.36(s,1H),5.11(dd,J＝12.8,5.5Hz,1H),3.75(s,1H),3.15(d,J＝7.5Hz,4H),2.83(t,J＝10.9Hz,3H),2.70(q,J＝7.6Hz,2H),2.62(d,J＝18.3Hz,1H),2.11-2.08(m,3H),1.87(d,J＝10.1Hz,2H),1.75(s,6H),1.72–1.67(m,2H),1.59-1.55(m,4H),1.45(d,J＝6.4Hz,2H),1.27(t,J＝7.5Hz,3H).HRMS(ESI)m/z:计算值C 45H 47N 6O 6S +[M+H] +,799.3272；实测值,799.3274.
实施例98：制备N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰胺(SIAIS262161)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物B和LIN-ULM(SIAIS171090)制备得目标化合物(SIAIS262161)(黄色固体,7.5mg,收率43％)。 1H NMR(500MHz,DMSO)δ12.72(s,1H),11.00(s,1H),8.32(d,J＝8.2Hz,1H),8.20(d,J＝7.7Hz,1H),8.04(s,1H),8.00(s,1H),7.70(d,J＝7.6Hz,1H),7.60(dd,J＝7.3,2.0Hz,2H),7.55(t,J＝7.6Hz,1H),7.34(s,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.42(d,J＝17.4Hz,1H),4.28(d,J＝17.4Hz,1H),3.74(d,J＝14.8Hz,3H),3.13(d,J＝12.0Hz,2H),2.95–2.87(m,1H),2.83(s,1H),2.69(q,J＝7.5Hz,2H),2.60(d,J＝16.9Hz,1H),2.44(dd,J＝13.4,4.4Hz,1H),2.00(dd, J＝16.4,8.8Hz,2H),1.84(d,J＝12.4Hz,2H),1.75(s,6H),1.56(d,J＝12.0Hz,2H),1.27(t,J＝7.4Hz,3H).HRMS(ESI)m/z:计算值C 41H 41N 6O 5S +[M+H] +,729.2854；实测值,729.2839.
实施例99：制备N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰胺(SIAIS262162)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物B和LIN-ULM(SIAIS171091)制备得目标化合物(SIAIS262162)(黄色固体,9.2mg,收率48％)。 1H NMR(500MHz,DMSO)δ12.72(s,1H),10.99(s,1H),8.32(d,J＝8.2Hz,1H),8.04(s,1H),8.00(s,1H),7.80(d,J＝7.6Hz,1H),7.62(dd,J＝16.8,7.9Hz,2H),7.59–7.51(m,2H),7.36(s,1H),5.13(dd,J＝13.3,5.2Hz,1H),4.36(d,J＝17.5Hz,1H),4.22(d,J＝17.4Hz,1H),3.73(s,1H),3.14(d,J＝12.1Hz,2H),3.09(t,J＝7.2Hz,2H),2.94–2.80(m,3H),2.70(q,J＝7.5Hz,2H),2.62(d,J＝18.9Hz,1H),2.45(d,J＝4.4Hz,1H),2.10–2.05(m,2H),2.04–1.97(m,1H),1.86(d,J＝9.8Hz,2H),1.75(s,6H),1.65–1.52(m,6H),1.41(d,J＝7.0Hz,2H),1.27(t,J＝7.5Hz,3H).HRMS(ESI)m/z:计算值C 45H 49N 6O 5S +[M+H] +,785.3480；实测值,785.3470.
实施例100：制备N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酰胺(SIAIS219022)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物B和LIN-ULM(SIAIS1204139)制备得目标化合物(SIAIS219022)(黄色固体,9.7mg,收率48％)。 1H NMR(500MHz,DMSO)δ12.72(s,1H),11.13(s,1H),8.33(d,J＝8.1Hz,1H),8.04-8.01(m,2H),7.79(dd,J＝15.1,8.1Hz,2H),7.65–7.59(m,2H),7.37(s,1H),5.12(dd,J＝12.8,5.5Hz,1H),3.88-3.81(m,6H),3.77(s,1H),3.16(d,J＝7.5Hz,4H),2.84(t,J＝10.9Hz,3H),2.71(q,J＝7.6Hz,2H),2.63(d,J＝18.3Hz,1H),2.09-2.04(m,3H),1.89(d,J＝10.1Hz,2H),1.76(s,6H),1.73–1.67(m,2H),1.46(d,J＝6.4Hz,2H),1.29(t,J＝7.5Hz,3H).HRMS(ESI)m/z:计算值C 45H 47N 6O 8S +[M+H] +,831.3171；实测值,831.3170.
实施例101：制备N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙酰胺(SIAIS262163)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物B和LIN-ULM(SIAIS1213129)制备得目标化合物(SIAIS262163)(黄色固体,8.9mg,收率48％)。 1H NMR(500MHz,DMSO)δ12.72(s,1H),10.99(s,1H),8.32(d,J＝8.2Hz,1H),8.04(s,1H),8.00(s,1H),7.73(d,J＝7.4Hz,1H),7.65(d,J＝8.1Hz,1H),7.62–7.58(m,2H),7.55(t,J＝7.6Hz,1H),7.36(s,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.39(d,J＝17.5Hz,1H),4.25(d,J＝17.4Hz,1H),3.91(s,2H),3.81(s,1H),3.69(t,J＝6.5Hz,2H),3.15(d,J＝11.6Hz,2H),2.88(ddd,J＝30.9,21.8,8.6Hz,3H),2.71(q,J＝7.5Hz,2H),2.57(d,J＝17.1Hz,1H),2.49–2.40(m,2H),2.04 –1.94(m,2H),1.81(s,2H),1.75(s,6H),1.68(d,J＝11.6Hz,2H),1.28(t,J＝7.5Hz,3H).HRMS(ESI)m/z:计算值C 43H 45N 6O 6S +[M+H] +,773.3116；实测值,773.3105.
实施例102：制备8-(4-(1-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰基)哌啶-4-基)哌嗪-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS219005)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物C和LIN-ULM(SIAIS151045)制备得目标化合物(SIAIS219005)(黄色固体,6.8mg,收率40％)。 1H NMR(500MHz,DMSO)δ12.70(s,1H),11.13(s,1H),8.32(d,J＝8.3Hz,1H),8.02(d,J＝22.0Hz,2H),7.82-7.76(m,2H),7.65-7.61(m,2H),7.34(s,1H),5.13(dd,J＝12.9,5.4Hz,1H),4.28(s,2H),3.58-3.54(m,6H),3.24(s,2H),2.88(d,J＝12.0Hz,1H),2.78(s,2H),2.74–2.69(m,2H),2.61(d,J＝20.0Hz,4H),2.06(s,1H),2.00(d,J＝7.5Hz,1H),1.89(s,1H),1.75(s,6H),1.65(s,1H),1.27(d,J＝7.4Hz,3H).HRMS(ESI)m/z:计算值C 45H 46N 7O 6S +[M+H] +,812.3225；实测值,812.3222.
实施例103：制备8-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS219006)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物C和LIN-ULM(SIAIS151139B)制备得目标化合物(SIAIS219006)(黄色固体,7.5mg,收率43％)。1H NMR(500MHz,DMSO)δ12.71(s,1H),11.14(s,1H),8.32(d,J＝8.3Hz,1H),8.05-8.01(m,2H),7.82-7.79(m,2H),7.66-7.62(m,2H),7.35(s,1H),5.12(dd,J＝12.9,5.4Hz,1H),4.29(s,2H),3.59-3.54(m,6H),3.24(s,2H),2.89(d,J＝12.0Hz,1H),2.78(s,2H),2.76–2.69(m,2H),2.65-2.60(m,6H),2.07(s,1H),2.01(d,J＝7.5Hz,1H),1.89-1.81(m,3H),1.76(s,1H),1.67(s,1H),1.28(d,J＝7.4Hz,3H).HRMS(ESI)m/z:计算值C47H50N7O6S+[M+H]+,840.3538；实测值,840.3550.
实施例104：制备8-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS219007)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物C和LIN-ULM(SIAIS151141B)制备得目标化合物(SIAIS219007)(黄色固体,6.9mg,收率38％)。 1H NMR(500MHz,DMSO)δ12.84(s,1H),11.14(s,1H),8.31(d,J＝8.2Hz,1H),8.06(s,1H),8.01(s,1H),7.86–7.72(m,2H),7.70–7.59(m,2H),7.36(s,1H),5.12(dd,J＝12.9,5.4Hz,1H),4.51(d,J＝13.1Hz,1H),4.10(d,J＝13.5Hz,1H),3.59-3.54(m,4H),3.31(d,J＝11.3Hz,4H),3.21–3.06(m,4H),2.94–2.78(m,3H),2.71(q,J＝7.4Hz,2H),2.63-2.56(m,1H),2.39-2.33(m,2H),2.21(d,J＝10.7Hz,2H),2.07–2.03(m,1H),1.92(t,J＝19.9Hz,2H),1.76(s,6H), 1.73–1.68(m,2H),1.59–1.54(m,2H),1.50–1.45(m,2H),1.28(t,J＝7.2Hz,3H).HRMS(ESI)m/z:计算值C 49H 54N 7O 6S +[M+H] +,868.3851；实测值,868.3856.
实施例105：制备8-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS262096)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物C和LIN-ULM(SIAIS171090)制备得目标化合物(SIAIS262096)(黄色固体,10.4mg,收率42％)。 1H NMR(500MHz,DMSO)δ12.83(s,1H),11.03(s,1H),8.31(d,J＝8.2Hz,1H),8.04(d,J＝23.8Hz,2H),7.72(d,J＝7.2Hz,1H),7.63–7.60(m,2H),7.59–7.52(m,1H),7.36(s,1H),5.15(dd,J＝13.3,5.1Hz,1H),4.49–4.40(m,2H),4.32–4.19(m,4H),3.67–3.52(m,4H),3.32(d,J＝11.1Hz,6H),3.17(t,J＝12.3Hz,2H),2.98–2.89(m,1H),2.82(d,J＝5.2Hz,2H),2.71(q,J＝7.4Hz,2H),2.62-2.55(m,1H),2.22(s,2H),2.05–1.99(m,1H),1.76(s,6H),1.29(t,J＝7.5Hz,3H).HRMS(ESI)m/z:计算值C 45H 48N 7O 5S +[M+H] +,798.3432；实测值,798.2945.
实施例106：制备8-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS262097)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物C和LIN-ULM(SIAIS171086)制备得目标化合物(SIAIS219007)(黄色固体,9.8mg,收率39％)。 1H NMR(500MHz,DMSO)δ12.83(s,1H),11.02(d,J＝7.3Hz,1H),8.31(d,J＝8.2Hz,1H),8.06(s,1H),8.01(s,1H),7.68(d,J＝6.8Hz,1H),7.64–7.53(m,3H),7.36(s,1H),5.15(dd,J＝13.3,5.2Hz,1H),4.51(d,J＝13.6Hz,1H),4.40–4.34(m,1H),4.24-4.21(m,1H),4.03(d,J＝13.1Hz,1H),3.37–3.23(m,6H),3.11(s,2H),3.04–2.87(m,3H),2.79(t,J＝7.1Hz,4H),2.71(q,J＝7.4Hz,2H),2.63-2.56(m,1H),2.19(s,2H),2.03-1.99(m,1H),1.90(d,J＝10.4Hz,2H),1.76(s,6H),1.28(t,J＝7.5Hz,3H).HRMS(ESI)m/z:计算值C 46H 50N 7O 5S +[M+H] +,812.3589；实测值,8123110.
实施例107：制备8-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS262098)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物C和LIN-ULM(SIAIS171089)制备得目标化合物(SIAIS262098)(黄色固体,10.9mg,收率43％)。 1H NMR(500MHz,DMSO)δ12.83(s,1H),11.02(s,1H),8.31(d,J＝8.2Hz,1H),8.06(s,1H),8.01(s,1H),7.70(dd,J＝7.4,1.2Hz,1H),7.65–7.51(m,3H),7.36(s,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.51(d,J＝12.6Hz,1H),4.37(d,J＝17.4Hz,1H),4.22(d,J＝17.4Hz,1H),4.06(d,J＝13.5Hz,1H),3.58-3.55(m,4H),3.43–3.27(m,5H),3.14–3.05(m,4H),3.01–2.88(m,2H),2.81(s,2H),2.71(q,J＝7.4Hz,2H),2.59-2.55(m,2H),2.49–2.44(m,1H),2.19(s,2H),2.04- 1.99(m,1H),1.93–1.81(m,4H),1.76(s,6H),1.28(t,J＝7.5Hz,3H).HRMS(ESI)m/z:计算值C 47H 52N 7O 5S +[M+H] +,826.3745；实测值,826.3243.
实施例108：制备8-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS262099)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物C和LIN-ULM(SIAIS171079)制备得目标化合物(SIAIS262099)(黄色固体,11.3mg,收率43％)。 1H NMR(500MHz,DMSO)δ12.89(s,1H),11.01(s,1H),8.31(d,J＝8.2Hz,1H),8.05(s,1H),8.01(s,1H),7.67–7.52(m,4H),7.36(s,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.50(d,J＝13.0Hz,1H),4.37(d,J＝17.4Hz,1H),4.22(d,J＝17.4Hz,1H),4.08(d,J＝13.3Hz,1H),3.61–3.49(m,4H),3.31(d,J＝11.3Hz,4H),3.14(d,J＝21.2Hz,4H),2.93-2.91(m,2H),2.81(s,2H),2.71(q,J＝7.4Hz,2H),2.61(t,J＝15.4Hz,1H),2.47–2.40(m,2H),2.22(d,J＝10.0Hz,2H),2.01(dd,J＝9.0,3.6Hz,1H),1.91(d,J＝11.9Hz,2H),1.76(s,6H),1.64(s,4H),1.28(t,J＝7.5Hz,3H).HRMS(ESI)m/z:计算值C 48H 54N 7O 5S +[M+H] +,840.3902；实测值,840.3387.
实施例109：制备8-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS262100)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物C和LIN-ULM(SIAIS171091)制备得目标化合物(SIAIS262100)(黄色固体,11.8mg,收率45％)。1H NMR(500MHz,DMSO)δ12.86(s,1H),11.01(s,1H),8.31(d,J＝8.1Hz,1H),8.06(s,1H),8.01(s,1H),7.68–7.51(m,4H),7.36(s,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.50(d,J＝13.1Hz,1H),4.36(d,J＝17.4Hz,1H),4.22(d,J＝17.4Hz,1H),4.07(d,J＝13.1Hz,1H),3.56(t,J＝21.2Hz,4H),3.31(d,J＝11.2Hz,4H),3.16–3.05(m,4H),3.02–2.87(m,2H),2.82(s,2H),2.71(q,J＝7.4Hz,2H),2.59(d,J＝17.1Hz,1H),2.46-2.41(m,1H),2.36(t,J＝7.1Hz,2H),2.22(d,J＝9.9Hz,2H),2.06–1.98(m,1H),1.90(d,J＝11.3Hz,2H),1.76(s,6H),1.65-1.60(m,2H),1.51(d,J＝5.2Hz,2H),1.46-1.42(m,2H),1.28(t,J＝7.5Hz,3H).HRMS(ESI)m/z:计算值C49H56N7O5S+[M+H]+,854.4058；实测值,854.3545.
实施例110：制备8-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS262101)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物C和LIN-ULM(SIAIS171092)制备得目标化合物(SIAIS262101)(黄色固体,11.2mg,收率42％)。 1H NMR(500MHz,DMSO)δ12.89(s,1H),11.01(s,1H),8.31(d,J＝8.2Hz,1H),8.06(s,1H),8.01(s,1H),7.59-7.53(m,4H),7.36(s,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.50(d,J＝13.3Hz,1H),4.36(d,J＝17.4Hz,1H),4.21(d,J＝17.4Hz,1H),4.07(d,J＝13.3Hz,1H),3.41–3.26 (m,4H),3.13-3.08(m,4H),3.03–2.86(m,2H),2.86–2.78(m,2H),2.71(q,J＝7.4Hz,2H),2.59(d,J＝17.6Hz,1H),2.49–2.42(m,1H),2.35(t,J＝7.3Hz,2H),2.22(d,J＝10.8Hz,2H),2.02-1.98(m,1H),1.96–1.85(m,2H),1.76(s,6H),1.66–1.56(m,2H),1.51–1.41(m,4H),1.33–1.27(m,5H).HRMS(ESI)m/z:计算值C 50H 58N 7O 5S +[M+H] +,868.4215；实测值,868.3679.
实施例111：制备8-(4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS249066)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物C和LIN-ULM(SIAIS1213129)制备得目标化合物(SIAIS249066)(黄色固体,11.8mg,收率45％)。 1H NMR(500MHz,DMSO)δ12.87(s,1H),11.02(s,1H),8.31(d,J＝8.2Hz,1H),8.05(s,1H),8.01(s,1H),7.71(d,J＝7.0Hz,1H),7.63–7.50(m,3H),7.36(s,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.47–4.35(m,2H),4.25(t,J＝8.7Hz,3H),3.97(d,J＝13.2Hz,1H),3.77–3.65(m,3H),3.32(d,J＝6.0Hz,6H),3.17-3.11(m,2H),3.04–2.88(m,2H),2.80(s,2H),2.70(q,J＝7.4Hz,2H),2.59-2.55(m,1H),2.47-2.44(m,1H),2.20(s,2H),2.02-1.98(m,1H),1.90(d,J＝8.9Hz,2H),1.76(s,6H),1.28(t,J＝6.6Hz,3H).HRMS(ESI)m/z:计算值C 47H 52N 7O 6S +[M+H] +,842.3694；实测值,842.3691.
实施例112：制备8-(4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS249067)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物C和LIN-ULM(SIAIS1213131)制备得目标化合物(SIAIS249067)(黄色固体,12.2mg,收率44％)。 1H NMR(500MHz,DMSO)δ12.89(s,1H),11.01(s,1H),8.31(d,J＝8.2Hz,1H),8.05(s,1H),8.01(s,1H),7.70(d,J＝7.6Hz,1H),7.59-7.54(m,3H),7.35(s,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.44(d,J＝12.4Hz,1H),4.39(d,J＝17.6Hz,1H),4.25(d,J＝17.6Hz,1H),4.01(d,J＝12.8Hz,1H),3.81–3.62(m,8H),3.39–3.25(m,6H),3.14–2.97(m,2H),2.94–2.86(m,1H),2.79(s,2H),2.70(q,J＝7.5Hz,2H),2.59(d,J＝17.7Hz,1H),2.21(d,J＝8.6Hz,2H),2.03–1.96(m,2H),1.93(d,J＝26.9Hz,2H),1.76(s,6H),1.28(d,J＝7.5Hz,3H).HRMS(ESI)m/z:计算值C 49H 56N 7O 7S +[M+H] +,886.3956；实测值,886.3952.
实施例113：制备8-(4-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS249068)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物C和LIN-ULM(SIAIS1213133)制备得目标化合物(SIAIS249068)(黄色固体,12.5mg,收率43％)。 1H NMR(500MHz,DMSO)δ12.89(s,1H),11.01(s,1H),8.31(d,J＝8.1Hz,1H),8.05(s,1H),8.01(s,1H),7.69(d,J＝7.3Hz,1H),7.62–7.49(m,3H),7.36(s,1H),5.13(dd,J＝13.3,5.1 Hz,1H),4.44(d,J＝13.7Hz,1H),4.38(d,J＝17.5Hz,1H),4.24-4.21(m,2H),4.02(d,J＝13.2Hz,1H),3.65-3.61(m,8H),3.44–3.23(m,8H),3.12-3,07(m,3H),2.89-2.84(m,4H),2.70(q,J＝7.4Hz,2H),2.59(d,J＝17.5Hz,1H),2.21(s,2H),2.03–1.96(m,2H),1.91(s,2H),1.76(s,6H),1.27(d,J＝7.5Hz,3H).HRMS(ESI)m/z:计算值C 51H 60N 7O 8S +[M+H] +,930.4219；实测值,930.4214.
实施例114：制备8-(4-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十四碳酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS249069)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物C和LIN-ULM(SIAIS1213135)制备得目标化合物(SIAIS249069)(黄色固体,12.4mg,收率41％)。 1H NMR(500MHz,DMSO)δ12.89(s,1H),11.01(s,1H),8.31(d,J＝8.1Hz,1H),8.06(s,1H),8.01(s,1H),7.69(d,J＝6.8Hz,1H),7.65–7.50(m,3H),7.36(s,1H),5.13(dd,J＝13.3,5.0Hz,1H),4.45(d,J＝14.0Hz,1H),4.37(d,J＝17.4Hz,1H),4.24-4.18(m,2H),4.03(d,J＝17.0Hz,1H),3.65-3.58(m,8H),3.39–3.22(m,8H),3.14-3.11(m,4H),2.96–2.86(m,1H),2.81(t,J＝11.0Hz,2H),2.77–2.69(m,2H),2.59(d,J＝16.8Hz,1H),2.47–2.41(m,1H),2.21(s,2H),2.02-1.98(m,2H),1.95-1.91(m,2H),1.76(s,6H),1.27(d,J＝7.5Hz,3H).HRMS(ESI)m/z:计算值C 53H 64N 7O 9S +[M+H] +,974.4481；实测值,974.4477.
实施例115：制备8-(4-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七碳酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS249070)
根据方案25所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物C和LIN-ULM(SIAIS1213137)制备得目标化合物(SIAIS249070)(黄色固体,14.3mg,收率45％)。 1H NMR(500MHz,DMSO)δ12.97(s,1H),11.01(s,1H),8.31(d,J＝8.2Hz,1H),8.05(s,1H),8.01(s,1H),7.67(dt,J＝9.0,4.5Hz,1H),7.63–7.49(m,3H),7.36(d,J＝8.7Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.44(d,J＝12.8Hz,1H),4.37(d,J＝17.4Hz,1H),4.27–4.19(m,2H),4.05-4.01(m,1H),3.60–3.48(m,22H),3.40–3.20(m,7H),3.15–2.98(m,2H),2.92-2.88(m,1H),2.82(t,J＝11.5Hz,2H),2.70(q,J＝7.4Hz,2H),2.59(d,J＝16.9Hz,1H),2.49–2.41(m,2H),2.23(d,J＝9.8Hz,2H),2.04–1.88(m,4H),1.76(s,6H),1.28(t,J＝6.7Hz,3H).HRMS(ESI)m/z:计算值C 55H 68N 7O 10S +[M+H] +,1018.4743；实测值,1018.4733.
实施例116：ALK靶点的特殊降解剂SIAIS219098的合成方法:
Figure PCTCN2019081840-appb-000249
根据方案26制备3-(4-((6-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)己基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS219098)：
将布加替尼衍生物C(20mg,0.035mmol)和DMF(2mL)加入15mL样品瓶中，搅拌下依次加入1-bromo-6-chlorohexane(20.9mg,0.105mmol)，碘化钠(5.2mg,0.035mmol)，碳酸钾(9.7mg,0.07mmol)，45℃加热反应6h。过滤膜后制备级HPLC分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％-100％)，旋去乙腈，冻干后得中间体18mg，直接下一步。该中间体(10mg,0.0145mmol)和DMF(2mL)加入15mL样品瓶中，搅拌下依次加入SIAIS151014(9.6mg,0.0348mmol)，碳酸钾(6mg,0.0435mmol)，碘化钠(4.3mg,0.029mmol)，50℃加热反应12h。过滤膜后制备级HPLC分离。(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％-100％)，旋去乙腈，冻干后得目标产物5.8mg，黄色固体，两步总收率35％。 1H NMR(500MHz,MeOD)δ8.24(s,1H),8.17(s,1H),7.73(dd,J＝13.8,7.8Hz,1H),7.69–7.63(m,3H),7.55(t,J＝7.7Hz,2H),7.48(t,J＝7.4Hz,1H),7.19(s,1H),6.96(d,J＝7.6Hz,1H),5.18(dd,J＝13.1,4.8Hz,1H),4.49(d,J＝17.4Hz,1H),4.45–4.40(m,1H),3.95(s,3H),3.95–3.89(m,4H),3.71(s,4H),3.44-3.40(m,4H),3.15-3.08(m,4H),2.98–2.89(m,1H),2.85–2.77(m,1H),2.59-2.53(m,1H),2.43(t,J＝11.5Hz,4H),2.35–2.16(m,4H),1.91(s,3H),1.87(s,3H),1.72–1.61(m,4H),1.58–1.50(m,2H).HRMS(ESI)m/z:计算值C 47H 60ClN 9O 5PS +[M+H] +,928.3859；实测值,928.3851.
实施例117：ALK靶点的特殊降解剂SIAIS262158和SIAIS262159的合成方法:
Figure PCTCN2019081840-appb-000250
根据方案27制备8-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS262158)：
将艾乐替尼衍生物C(20mg,0.042mmol)和DMF(2mL)加入15mL样品瓶中，搅拌下依次加入SIAIS213137(48.3mg,0.126mmol)，碘化钠(6.3mg,0.042mmol)，碳酸钾(11.6mg,0.084mmol)，50℃加热反应2h。过滤膜后制备级HPLC分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％-100％)，旋去乙腈，冻干后得目标产物12.4mg，黄色固体，收率37％。 1H NMR(500MHz,DMSO)δ12.83(s,1H),11.14(s,1H),8.32(d,J＝8.2Hz,1H),8.07(s,1H),8.01(s,1H),7.90(s,1H),7.83(t,J＝7.7Hz,1H),7.69(d,J＝7.3Hz,1H),7.64–7.57(m,1H),7.37(s,1H),5.13(dd,J＝12.8,5.5Hz,1H),3.66(d,J＝58.3Hz,4H),3.32(d,J＝ 11.2Hz,8H),3.19–3.08(m,2H),2.89-2.84(m,4H),2.72(q,J＝7.4Hz,2H),2.61(d,J＝17.4Hz,1H),2.57–2.52(m,1H),2.23(s,2H),2.10–2.04(m,1H),1.91(s,2H),1.77(s,6H),1.29(t,J＝7.5Hz,3H).HRMS(ESI)m/z:计算值C 45H 48N 7O 5S +[M+H] +,798.3432；实测值,798.3435.
实施例118：制备8-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(SIAIS262159)
根据方案27所述通用方法，在本领域可理解的适当条件下，采用艾乐替尼衍生物C和LIN-ULM(SIAIS1216133)制备得目标化合物(SIAIS262159)(黄色固体,7.3mg,收率29％)。(黄色固体,9.3mg,收率36％)。 1H NMR(500MHz,MeOD)δ8.41(d,J＝8.1Hz,1H),8.21(s,1H),7.87(s,1H),7.67(dd,J＝7.5,3.7Hz,2H),7.57–7.54(m,2H),7.43(s,1H),5.18(dd,J＝13.4,5.2Hz,1H),4.48(d,J＝17.3Hz,1H),4.45–4.40(m,1H),3.93(s,4H),3.59(s,2H),3.43(d,J＝12.7Hz,2H),3.29–3.23(m,2H),3.14–3.05(m,2H),3.00–2.91(m,3H),2.82(q,J＝7.7Hz,3H),2.59–2.51(m,1H),2.35(s,1H),2.23–2.16(m,1H),2.10–2.02(m,2H),1.80(d,J＝13.6Hz,8H),1.77–1.64(m,4H),1.63–1.49(m,4H),1.47–1.41(m,2H),1.35(d,J＝6.6Hz,3H).HRMS(ESI)m/z:计算值C 49H 58N 7O 4S +[M+H] +,840.4266；实测值,840.4261.
BCR-ABL靶点的一系列降解剂通用的合成方法:
Figure PCTCN2019081840-appb-000251
根据方案28，室温下，在反应瓶中，加入相应的BCR-ABL抑制剂(1equiv)，相应的LIN-ULM(1equiv),1-羟基-7-偶氮苯并三氮唑(2equiv),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(2equiv),无水N,N-二甲基甲酰胺(2mL)，N-甲基吗啡啉(5equiv)，室温下搅拌反应过夜。LC-MS检测反应结束后，HPLC制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)。旋蒸除去乙腈，冻干后得相应的最终降解剂化合物。
实施例119：制备4-((4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺(SIAIS1197107)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用去甲基伊马替尼和LIN-ULM(SIAIS151045)制备得目标化合物(SIAIS1197107)(黄色固体,7.3mg,收率29％)。 1H NMR(500MHz,DMSO)δ11.13(s,1H),10.30(s,1H),9.33(s,1H),9.05(s,1H),8.75(d,J＝4.5Hz,1H),8.62(s,1H),8.55(d,J＝5.1Hz,1H),8.11(s,1H),8.06(d,J＝8.1Hz,2H),7.79(d,J＝3.1Hz,2H),7.74(d,J＝8.0Hz,2H),7.68–7.62(m,2H),7.48(t,J＝5.5Hz,2H),7.23(d,J＝8.4Hz,1H),5.13(dd,J＝12.9,5.4Hz,1H),4.50–4.22(m,6H),3.3–3.30(m,2H),3.20-2.95(m,4H),2.95-2.84(m,1H),2.64(s,1H),2.36(s,1H),2.23(s,3H),2.10-2.02(m,1H).HRMS(ESI)m/z:计算值C 43H 40N 9O 6S +[M+H] +,810.2817；实测值,810.2351.
实施例120：制备4-((4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺(SIAIS1197097)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用去甲基伊马替尼和LIN-ULM(SIAIS151138B)制备得目标化合物(SIAIS1197097)(黄色固体,6.1mg,收率23％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),10.30(s,1H),9.34(s,1H),9.06(s,1H),8.77(s,1H),8.67(s,1H),8.55(s,1H),8.11(s,1H),8.05(d,J＝8.1Hz,2H),7.83-7.61(m,6H),7.48(d,J＝6.4Hz,2H),7.23(d,J＝8.5Hz,1H),5.12(dd,J＝12.9,5.2Hz,1H),4.52-4.38(m,2H),4.41(s,2H),4.10-3.98(m,2H),3.33(s,2H),3.14-2.90(m,4H),2.94-2.87(m 1H),2.87-2.78(m,2H),2.65-2.60(m,1H),2.36(s,1H),2.23(s,3H),2.08-2.01(m,1H).HRMS(ESI)m/z:计算值C 44H 42N 9O 6S +[M+H] +,824.2973；实测值,824.2485.
实施例121：制备4-((4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺(SIAIS1197099)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用去甲基伊马替尼和LIN-ULM(SIAIS151139B)制备得目标化合物(SIAIS1197099)(黄色固体,7.4mg,收率29％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),10.31(s,1H),9.37(s,1H),9.09(s,1H),8.80(s,1H),8.74(s,1H),8.57(d,J＝5.1Hz,1H),8.12(s,1H),8.05(d,J＝8.2Hz,2H),7.85(d,J＝8.3Hz,1H),7.83–7.70(m,4H),7.64(d,J＝6.9Hz,1H),7.52-7.45(m,2H),7.23(d,J＝8.4Hz,1H), 5.12(dd,J＝12.8,5.4Hz,1H),4.52-4.40(m,2H),4.41(s,2H),4.10-4.00(m,2H),3.31(s,2H),3.19-3.13(m,2H),3.12–2.88(m,4H),2.93–2.84(m,1H),2.63–2.56(m,1H),2.46-2.40(m,1H),2.23(s,3H),2.09-2.01(m,1H),1.95-1.84(m,2H).HRMS(ESI)m/z:计算值C 45H 44N 9O 6S +[M+H] +,838.3130；实测值,838.2631.
实施例122：制备4-((4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺(SIAIS1197101)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用去甲基伊马替尼和LIN-ULM(SIAIS151140B)制备得目标化合物(SIAIS1197101)(黄色固体,7.8mg,收率29％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),10.32(s,1H),9.40(s,1H),9.12(s,1H),8.83(dd,J＝12.5,6.7Hz,2H),8.58(d,J＝5.1Hz,1H),8.13(s,1H),8.05(d,J＝8.2Hz,2H),7.87–7.71(m,5H),7.63(d,J＝6.8Hz,1H),7.52(d,J＝5.2Hz,1H),7.48(dd,J＝8.2,1.8Hz,1H),7.23(d,J＝8.5Hz,1H),5.11(dd,J＝12.8,5.4Hz,1H),4.50–4.35(m,4H),4.11-3.99(m,2H),3.30(s,2H),3.16(s,2H),3.12–2.88(m,4H),2.92-2.83(m,1H),2.63–2.56(m,1H),2.42(d,J＝7.1Hz,1H),2.21(s,3H),2.09–2.00(m,1H),1.68(s,4H). .HRMS(ESI)m/z:计算值C 46H 46N 9O 6S +[M+H] +,852.3286；实测值,852.2785.
实施例123：制备4-((4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺(SIAIS1197103)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用去甲基伊马替尼和LIN-ULM(SIAIS151141B)制备得目标化合物(SIAIS1197103)(黄色固体,6.6mg,收率26％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),10.34(s,1H),9.38(s,1H),9.10(s,1H),8.79(d,J＝27.6Hz,2H),8.57(d,J＝5.0Hz,1H),8.13(s,1H),8.05(d,J＝8.2Hz,2H),7.86–7.70(m,5H),7.63(d,J＝7.1Hz,1H),7.53–7.45(m,2H),7.23(d,J＝8.5Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.40(s,4H),4.04(s,2H),3.58(s,2H),3.27(s,2H),3.13(t,J＝7.1Hz,2H),3.12–2.96(m,2H),2.93-2.83(m,1H),2.63–2.56(m,1H),2.36(s,1H),2.23(s,3H),2.09–2.01(m,1H),1.72–1.64(m,2H),1.58-1.50(m,2H),1.50-1.41(m,2H).HRMS(ESI)m/z:计算值C 47H 48N 9O 6S +[M+H] +,866.3443；实测值,866.2928.
实施例124：制备4-((4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺(SIAIS1197105)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用去甲基伊马替尼和LIN-ULM(SIAIS151142B)制备得目标化合物(SIAIS1197105)(黄色固体,6.0mg,收率23％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),10.32(s,1H),9.37(s,1H),9.09(s,1H),8.84–8.74(m,2H),8.57(d,J＝5.1Hz,1H),8.12(s,1H),8.05(d,J＝8.3Hz,2H),7.77(dt,J＝19.6,7.8 Hz,5H),7.66–7.64(m,1H),7.53–7.45(m,2H),7.23(d,J＝8.5Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.41(s,4H),4.05(s,2H),3.30(d,J＝10.6Hz,2H),3.13(t,J＝7.3Hz,2H),3.08–2.83(m,5H),2.63(d,J＝11.9Hz,1H),2.37(s,1H),2.23(s,3H),2.09–2.00(m,1H),1.73–1.64(m,2H),1.60-1.50(m,2H),1.50-1.42(m,2H),1.42-1.30(m,2H).HRMS(ESI)m/z:计算值C 48H 50N 9O 6S +[M+H] +,880.3599；实测值,880.3105.
实施例125：制备N-(2-氯-6-甲基苯基)-2-((6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151110)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物(SIAIS151055)和LIN-ULM(SIAIS151045)制备得目标化合物(SIAIS151110)(黄色固体,26.6mg,收率56％)。 1H NMR(500MHz,DMSO)δ11.56(s,1H),11.15(s,1H),9.91(s,1H),8.23(s,1H),7.85–7.75(m,2H),7.64(d,J＝6.4Hz,1H),7.40(d,J＝7.2Hz,1H),7.34–7.21(m,2H),6.09(s,1H),5.13(dd,J＝12.9,5.4Hz,1H),4.34(s,2H),3.75–3.59(m,8H),2.94–2.84(m,1H),2.64–2.53(m,2H),2.44(s,3H),2.24(s,3H),2.10–2.02(m,1H).HRMS(ESI)m/z:计算值C 35H 33ClN 9O 6S 2 +[M+H] +,774.1678；实测值,774.1688.
实施例126：制备N-(2-氯-6-甲基苯基)-2-((6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151152)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物(SIAIS151055)和LIN-ULM(SIAIS151138B)制备得目标化合物(SIAIS151152)(黄色固体,15.2mg,收率43％)。 1H NMR(500MHz,DMSO)δ11.55(s,1H),11.12(s,1H),9.92(s,1H),8.24(s,1H),7.83-7.78(m,2H),7.64(d,J＝6.3Hz,1H),7.40(d,J＝7.2Hz,1H),7.32–7.23(m,2H),6.08(s,1H),5.12(dd,J＝12.8,5.4Hz,1H),3.63–3.47(m,8H),3.36(t,J＝6.9Hz,2H),2.92–2.86(m,1H),2.84(t,J＝7.5Hz,2H),2.66–2.53(m,2H),2.43(s,3H),2.24(s,3H),2.07–2.01(m,1H).HRMS(ESI)m/z:计算值C 36H 35N 9O 6S 2 +[M+H] +,788.1835；实测值,788.2066.
实施例127：制备N-(2-氯-6-甲基苯基)-2-((6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151153)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物(SIAIS151055)和LIN-ULM(SIAIS151139B)制备得目标化合物(SIAIS151153)(黄色固体,14.5mg,收率40％)。 1H NMR(500MHz,DMSO)δ11.53(s,1H),11.12(s,1H),9.89(s,1H),8.23(s,1H),7.88(d,J＝8.2Hz,1H),7.80(t,J＝7.7Hz,1H),7.63(d,J＝7.2Hz,1H),7.40(d,J＝7.1Hz,1H),7.33–7.22(m,2H),6.08(s,1H),5.12(dd,J＝12.8,5.4Hz,1H),3.56(s,8H),3.21–3.15(m,2H),2.93–2.84(m,1H),2.63–2.53(m,4H),2.42(s,3H),2.24(s,3H),2.09–2.01(m,1H), 1.95–1.88(m,2H).HRMS(ESI)m/z:计算值C 37H 37N 9O 6S 2 +[M+H] +,802.1991；实测值,802.2222.
实施例128：制备N-(2-氯-6-甲基苯基)-2-((6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151154)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物(SIAIS151055)和LIN-ULM(SIAIS151140B)制备得目标化合物(SIAIS151154)(黄色固体,17.3mg,收率47％)。 1H NMR(500MHz,DMSO)δ11.53(s,1H),11.12(s,1H),9.90(s,1H),8.23(s,1H),7.81–7.73(m,2H),7.63(d,J＝6.5Hz,1H),7.40(d,J＝6.8Hz,1H),7.32–7.22(m,2H),6.08(s,1H),5.11(dd,J＝12.8,5.4Hz,1H),3.54-3.42(m,8H),3.17(t,J＝7.5Hz,2H),2.92–2.84(m,1H),2.65–2.52(m,2H),2.43(s,3H),2.48–2.36(m,2H),2.24(s,3H),2.08–2.01(m,1H),1.75–1.66(m,4H).HRMS(ESI)m/z:计算值C 38H 39N 9O 6S 2 +[M+H] +,816.2148；实测值,816.2373.
实施例129：制备N-(2-氯-6-甲基苯基)-2-((6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151155)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物(SIAIS151055)和LIN-ULM(SIAIS151141B)制备得目标化合物(SIAIS151155)(黄色固体,13.7mg,收率37％)。 1H NMR(500MHz,DMSO)δ11.55(s,1H),11.12(s,1H),9.90(s,1H),8.23(s,1H),7.80–7.74(m,2H),7.62(d,J＝6.9Hz,1H),7.40(d,J＝6.7Hz,1H),7.34–7.23(m,2H),6.08(s,1H),5.11(dd,J＝12.8,5.4Hz,1H),3.57(s,8H),3.14(t,J＝7.2Hz,2H),2.92–2.84(m,1H),2.63–2.52(m,2H),2.43(s,3H),2.37(t,J＝7.2Hz,2H),2.24(s,3H),2.08–2.02(m,1H),1.73–1.66(m,2H),1.60–1.54(m,2H),1.52–1.44(m,2H).HRMS(ESI)m/z:计算值C 39H 41N 9O 6S 2 +[M+H] +,830.2304；实测值,830.2543.
实施例130：制备N-(2-氯-6-甲基苯基)-2-((6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151156)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物(SIAIS151055)和LIN-ULM(SIAIS151142B)制备得目标化合物(SIAIS151156)(黄色固体,10.6mg,收率28％)。 1H NMR(500MHz,MeOD)δ8.21(s,1H),7.73–7.66(m,2H),7.57(d,J＝6.7Hz,1H),7.35(d,J＝7.4Hz,1H),7.29–7.22(m,2H),6.29(s,1H),5.09(dd,J＝12.5,5.4Hz,1H),3.91–3.70(m,8H),3.12(t,J＝7.1Hz,2H),2.90–2.80(m,1H),2.77–2.67(m,2H),2.61(s,3H),2.46(t,J＝7.4Hz,2H),2.31(s,3H),2.16–2.08(m,1H),1.82–1.73(m,2H),1.69–1.62(m,2H),1.58–1.52(m,2H),1.47–1.39(m,2H).HRMS(ESI)m/z:计算值C 40H 43N 9O 6S 2 +[M+H] +,844.2461；实测值,844.2696.
实施例131：制备N-(2-氯-6-甲基苯基)-2-((6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS171105)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物(SIAIS151055)和LIN-ULM(SIAIS171090)制备得目标化合物(SIAIS171105)(白色固体,10mg,收率39％)。 1H NMR(500MHz,DMSO)δ11.55(s,1H),10.99(s,1H),9.90(s,1H),8.23(s,1H),7.76–7.71(m,1H),7.60(d,J＝6.8Hz,1H),7.53(t,J＝7.6Hz,1H),7.40(d,J＝6.4Hz,1H),7.32–7.18(m,2H),6.09(s,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.42(d,J＝17.4Hz,1H),4.28(d,J＝17.4Hz,1H),4.20(s,2H),3.58–3.32(m,8H),2.95–2.85(m,1H),2.64–2.57(m,1H),2.52–2.42(m,4H),2.24(s,3H),2.04–1.94(m,1H).HRMS(ESI)m/z:计算值C 35H 35ClN 9O 5S 2 +[M+H] +,760.1886；实测值,760.1930.
实施例132：制备N-(2-氯-6-甲基苯基)-2-((6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS171106)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物(SIAIS151055)和LIN-ULM(SIAIS171086)制备得目标化合物(SIAIS171106)(白色固体,9mg,收率34％)。 1H NMR(500MHz,DMSO)δ11.58(s,1H),11.00(s,1H),9.92(s,1H),8.25(s,1H),7.69(dd,J＝7.5,1.0Hz,1H),7.62–7.53(m,2H),7.40(d,J＝7.7Hz,1H),7.33–7.23(m,2H),6.09(s,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.37(d,J＝17.4Hz,1H),4.23(d,J＝17.4Hz,1H),3.60–3.54(m,8H),3.30(t,J＝7.1Hz,2H),2.95–2.86(m,1H),2.76(t,J＝7.0Hz,2H),2.65–2.58(m,1H),2.49–2.46(m,1H),2.44(s,3H),2.24(s,3H),2.05–1.97(m,1H).HRMS(ESI)m/z:计算值C 36H 37ClN 9O 5S 2 +[M+H] +,774.2024；实测值,774.2075.
实施例133：制备N-(2-氯-6-甲基苯基)-2-((6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS171107)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物(SIAIS151055)和LIN-ULM(SIAIS171089)制备得目标化合物(SIAIS171107)(白色固体,11mg,收率42％)。 1H NMR(500MHz,DMSO)δ11.58(s,1H),11.00(s,1H),9.92(s,1H),8.25(s,1H),7.70(dd,J＝7.4,1.2Hz,1H),7.59–7.53(m,2H),7.41(d,J＝7.4Hz,1H),7.35–7.23(m,2H),6.10(s,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.38(d,J＝17.4Hz,1H),4.24(d,J＝17.4Hz,1H),3.58–3.54(m,8H),3.14(t,J＝7.3Hz,2H),2.96–2.88(m,1H),2.66–2.53(m,4H),2.45(s,3H),2.25(s,3H),2.05–1.98(m,1H),1.89–1.83(m,2H).HRMS(ESI)m/z:计算值C 37H 39ClN 9O 5S 2 +[M+H] +,788.2199；实测值,788.2216.
实施例134：制备N-(2-氯-6-甲基苯基)-2-((6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS171108)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物(SIAIS151055)和LIN-ULM(SIAIS171079)制备得目标化合物(SIAIS171108)(白色固体,10mg,收率37％)。 1H NMR(500MHz,DMSO)δ11.58(s,1H),10.99(s,1H),9.92(s,1H),8.25(s,1H),7.64(dd,J＝12.9,6.7Hz,1H),7.55–7.45(m,2H),7.41(d,J＝7.5Hz,1H),7.32–7.25(m,2H),6.10(s,1H),5.13(dd,J＝13.3,5.0Hz,1H),4.43–4.17(m,2H),3.57–3.52(m,8H),3.15–3.11(m,2H),2.96–2.85(m,1H),2.66–2.57(m,1H),2.47–2.36(m,6H),2.22(s,3H),2.06–1.96(m,1H),1.69–1.58(m,4H).HRMS(ESI)m/z:计算值C 38H 41ClN 9O 5S 2 +[M+H] +,802.2355；实测值,802.2364.
实施例135：制备N-(2-氯-6-甲基苯基)-2-((6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS171109)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物(SIAIS151055)和LIN-ULM(SIAIS171091)制备得目标化合物(SIAIS171109)(白色固体,10mg,收率36％)。 1H NMR(500MHz,DMSO)δ11.59(s,1H),11.00(s,1H),9.92(s,1H),8.25(s,1H),7.64(dd,J＝7.5,1.1Hz,1H),7.57–7.54(m,2H),7.41(d,J＝7.7Hz,1H),7.34–7.23(m,2H),6.10(s,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.30(dd,J＝68.7,17.4Hz,2H),3.57–3.53(m,8H),3.09(t,J＝7.2Hz,2H),2.92–2.88(m,1H),2.66–2.57(m,1H),2.49–2.44(m,4H),2.34(t,J＝7.2Hz,2H),2.25(s,3H),2.04–1.99(m,1H),1.67–1.62(m,2H),1.60–1.50(m,2H),1.48–1.41(m,2H).HRMS(ESI)m/z:计算值C 39H 43ClN 9O 5S 2 +[M+H] +,816.2512；实测值,816.2520.
实施例136：制备N-(2-氯-6-甲基苯基)-2-((6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS171110)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物(SIAIS151055)和LIN-ULM(SIAIS171092)制备得目标化合物(SIAIS171110)(白色固体,10mg,收率37％)。 1H NMR(500MHz,DMSO)δ11.56(s,1H),10.99(s,1H),9.91(s,1H),8.24(s,1H),7.64(dd,J＝7.5,1.2Hz,1H),7.58–7.53(m,2H),7.41(d,J＝7.8Hz,1H),7.32–7.23(m,2H),6.09(s,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.29(dd,J＝69.8,17.4Hz,2H),3.58–3.53(m,8H),3.09(t,J＝7.2Hz,2H),2.95–2.86(m,1H),2.65–2.58(m,1H),2.47–2.44(m,4H),2.34(t,J＝7.4Hz,2H),2.25(s,3H),2.05–1.98(m,1H),1.67–1.63(m,2H),1.61–1.58(m,2H),1.55–1.52(m,2H),1.50–1.30(m,2H).HRMS(ESI)m/z:计算值C 40H 45ClN 9O 5S 2 +[M+H] +,830.2668；实测值,830.2665.
实施例137：制备N-(2-氯-6-甲基苯基)-2-((6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)乙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151109)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物(SIAIS151055)和LIN-ULM(SIAIS151107)制备得目标化合物(SIAIS151109)(黄色固体,17.2mg,收率48％)。 1H NMR(500MHz,MeOD)δ8.32(dd,J＝7.6,1.1Hz,1H),8.20(s,1H),8.13–8.06(m,2H),7.41–7.33(m,1H),7.29–7.22(m,2H),6.24(s,1H),5.21–5.16(m,1H),4.59(dd,J＝22.9,14.6Hz,1H),4.10(dd,J＝14.6,7.6Hz,1H),3.95–3.77(m,5H),3.74–3.62(m,3H),2.93–2.84(m,1H),2.79–2.68(m,2H),2.57(s,3H),2.32(s,3H),2.20–2.13(m,1H).HRMS(ESI)m/z:计算值C 35H 33ClN 9O 7S 2 +[M+H] +,790.1672；实测值,790.1645.
实施例138：制备N-(2-氯-6-甲基苯基)-2-((6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)乙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS151108)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用达沙替尼衍生物(SIAIS151055)和LIN-ULM(SIAIS151106)制备得目标化合物(SIAIS151108)(黄色固体,25.2mg,收率69％)。 1H NMR(500MHz,MeOD)δ8.38(dd,J＝7.9,0.9Hz,1H),8.25(dd,J＝7.5,0.9Hz,1H),8.20(s,1H),8.09(t,J＝7.7Hz,1H),7.37(dd,J＝7.4,1.8Hz,1H),7.31–7.19(m,2H),6.24(s,1H),5.25(dd,J＝12.6,5.5Hz,1H),5.06(dd,J＝22.0,14.0Hz,2H),3.95–3.86(m,4H),3.80–3.66(m,4H),2.94–2.85(m,1H),2.82–2.70(m,2H),2.58(s,3H),2.32(s,3H),2.25–2.16(m,1H).HRMS(ESI)m/z:计算值C 35H 33ClN 9O 8S 2 +[M+H] +,806.1577；实测值,806.1602.
实施例139：制备4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈(SIAIS151168)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物(SIAIS151151)和LIN-ULM(SIAIS151045)制备得到目标化合物(SIAIS151168)(黄色固体,9.3mg,收率38％)。 1H NMR(500MHz,DMSO)δ11.30(s,1H),11.13(s,1H),8.85(s,1H),8.18(s,1H),7.85–7.77(m,3H),7.65(d,J＝6.6Hz,1H),7.52(s,1H),7.47(s,1H),5.13(dd,J＝12.9,5.4Hz,1H),4.45(d,J＝13.2Hz,1H),4.37(s,2H),4.35–4.28(m,3H),4.01(s,3H),3.88(s,3H),3.71–3.57(m,4H),3.25–3.15(m,3H),3.08–2.98(m,1H),2.94–2.83(m,1H),2.67–2.52(m,2H),2.40–2.33(s,2H),2.11–2.00(m,1H).HRMS(ESI)m/z:计算值C 40H 38Cl 2N 7O 8S +[M+H] +,846.1874；实测值,846.1415.
实施例140：制备4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈(SIAIS151169)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物(SIAIS151151)和LIN-ULM(SIAIS151138B)制备得目标化合物(SIAIS151169)(黄色固体,10.5mg,收率42％)。 1H NMR(500MHz,DMSO)δ11.12(s,2H),8.87(s,1H),8.17(s,1H),7.85–7.75(m,3H),7.65(d,J＝6.3Hz,1H),7.51(s,1H),7.48(s,1H),5.16–5.07(m,1H),4.49(d,J＝13.6Hz,1H),4.35–4.28(m,2H),4.10-4.03(s,1H),4.00(s,3H),3.8 8(s,3H),3.43–3.24(m,5H),3.20–3.03(m,3H),3.01–2.81(m,5H),2.66–2.55(m,2H),2.38–2.30(m,2H),2.08–2.02(m,1H).HRMS(ESI)m/z:计算值C 41H 40Cl 2N 7O 8S +[M+H] +,860.2031；实测值,860.1564.
实施例141：制备4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈(SIAIS151170)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物(SIAIS151151)和LIN-ULM(SIAIS151139B)制备得目标化合物(SIAIS151170)(黄色固体,12.3mg,收率48％)。 1H NMR(500MHz,MeOD)δ8.84(s,1H),8.00(s,1H),7.81(d,J＝8.1Hz,1H),7.74(t,2H),7.66(s,1H),7.61(d,J＝7.2Hz,1H),7.40(d,J＝2.2Hz,2H),5.12(dd,J＝12.7,5.5Hz,1H),4.79–4.63(m,1H),4.45(t,J＝5.5Hz,2H),4.39–4.16(m,1H),4.08(s,3H),3.94(s,3H),3.87–3.54(m,3H),3.49(t,J＝7.3Hz,2H),3.25–3.06(m,4H),2.90–2.81(m,1H),2.75–2.58(m,4H),2.52–2.44(m,2H),2.18–2.05(m,3H).HRMS(ESI)m/z:计算值C 42H 42Cl 2N 7O 8S +[M+H] +,874.2187；实测值,874.1729.
实施例142：制备4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈(SIAIS151171)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物(SIAIS151151)和LIN-ULM(SIAIS151140B)制备得目标化合物(SIAIS151171)(黄色固体,10.6mg,收率42％)。 1H NMR(500MHz,MeOD)δ8.86(s,1H),8.01(s,1H),7.75–7.69(m,2H),7.66(s,1H),7.59(d,J＝6.3Hz,1H),7.41(s,2H),5.11(dd,J＝12.5,5.4Hz,1H),4.74–4.61(m,1H),4.46(t,J＝5.4Hz,2H),4.33–4.17(m,1H),4.08(s,3H),3.94(s,3H),3.85–3.57(m,3H),3.49(t,J＝7.0Hz,2H),3.25–3.00(m,5H),2.89–2.81(m,1H),2.76–2.65(m,2H),2.55(s,2H),2.50–2.43(m,2H),2.17–2.09(m,1H),1.87–1.79(m,4H).HRMS(ESI)m/z:计算值C 43H 44Cl 2N 7O 8S +[M+H] +,888.2344；实测值,888.1851.
实施例143：制备4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈(SIAIS151172)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物(SIAIS151151)和LIN-ULM(SIAIS151141B)制备得目标化合物(SIAIS151172)(黄色固体,11.3mg,收率43％)。 1H NMR(500MHz,MeOD)δ8.84(s,1H),7.99(s,1H),7.74–7.68(m,2H), 7.66(s,1H),7.58(d,J＝6.5Hz,1H),7.40(d,J＝1.7Hz,2H),5.11(dd,J＝12.7,5.5Hz,1H),4.78–4.61(m,1H),4.45(t,J＝5.5Hz,2H),4.35–4.16(m,1H),4.08(s,3H),3.94(s,3H),3.86–3.56(m,3H),3.49(t,J＝7.2Hz,2H),3.25–2.95(m,3H),3.13(t,J＝7.5Hz,2H),2.91–2.81(m,1H),2.78–2.65(m,2H),2.53–2.43(m,4H),2.18–2.10(m,1H),1.83–1.77(m,2H),1.74–1.66(m,2H),1.62–1.55(m,2H).HRMS(ESI)m/z:计算值C 44H 46Cl 2N 7O 8S +[M+H] +,902.2500；实测值,902.1993.
实施例144：制备4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈(SIAIS151173)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用伯舒替尼衍生物(SIAIS151151)和LIN-ULM(SIAIS151142B)制备得目标化合物(SIAIS151173)(黄色固体,14.0mg,收率52％)。 1H NMR(500MHz,MeOD)δ8.83(s,1H),7.99(s,1H),7.75–7.68(m,2H),7.66(s,1H),7.59(d,J＝6.3Hz,1H),7.40(d,J＝3.6Hz,2H),5.11(dd,J＝12.6,5.5Hz,1H),4.78–4.61(m,1H),4.45(t,J＝5.5Hz,2H),4.33–4.16(m,1H),4.08(s,3H),3.94(s,3H),3.85–3.56(m,3H),3.49(t,J＝7.2Hz,2H),3.26–2.97(m,3H),3.14(t,J＝7.5Hz,2H),2.90–2.83(m,1H),2.79–2.65(m,2H),2.53–2.42(m,4H),2.16–2.10(m,1H),1.81–1.75(m,2H),1.71–1.62(m,2H),1.59–1.53(m,2H),1.50–1.41(m,2H).HRMS(ESI)m/z:计算值C 45H 48Cl 2N 7O 8S +[M+H] +,916.2657；实测值,916.2110.
实施例145：制备N-(4-((4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺(SIAIS220046)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用普纳替尼衍生物(SIAIS151190B)和LIN-ULM(SIAIS151138B)制备得目标化合物(SIAIS220046)(淡黄色固体,9.2mg,收率55％), 1H NMR(500MHz,DMSO)δ11.12(s,1H),10.82(s,1H),8.76(dd,J＝4.4,1.4Hz,1H),8.38(d,J＝1.9Hz,1H),8.33(d,J＝8.4Hz,1H),8.31–8.26(m,2H),8.22(d,J＝8.6Hz,2H),7.99(dd,J＝8.0,1.8Hz,1H),7.83–7.75(m,2H),7.64(d,J＝6.8Hz,1H),7.57(d,J＝8.3Hz,1H),7.43(dd,J＝9.2,4.4Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.48–4.40(m,2H),4.09–3.97(m,1H),3.75–3.64(m,4H),3.34(t,J＝6.9Hz,2H),3.28–3.16(m,2H),3.12–2.99(m,1H),2.93–2.80(m,3H),2.62(s,3H),2.61–2.51(m,2H),2.08–2.02(m,1H).HRMS(ESI)m/z:计算值C 44H 38F 3N 8O 6S +[M+H] +,863.2582；实测值,863.2589.
实施例146：制备N-(4-((4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺(SIAIS220047)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用普纳替尼衍生物(SIAIS151190B)和LIN-ULM(SIAIS151139B)制备得目标化合物(SIAIS220047)(淡黄色固体, 8.6mg,收率51％), 1H NMR(500MHz,DMSO)δ11.12(s,1H),10.80(s,1H),8.75(dd,J＝4.4,1.5Hz,1H),8.37(s,1H),8.30–8.22(m,4H),7.99(dd,J＝8.0,1.8Hz,1H),7.86(d,J＝8.1Hz,1H),7.82–7.77(m,1H),7.63(d,J＝7.1Hz,1H),7.58(d,J＝8.2Hz,1H),7.42(dd,J＝9.2,4.4Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.50–4.40(m,2H),3.76–3.66(m,4H),3.31–3.13(m,4H),3.08–3.02(m,2H),2.91–2.85(m,1H),2.63–2.55(m,5H),2.11–2.01(m,1H),1.94–1.86(m,2H).`HRMS(ESI)m/z:计算值C 45H 40F 3N 8O 6S +[M+H] +,877.2738；实测值,877.2733.
实施例147：N-(4-((4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺(SIAIS220048)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用普纳替尼衍生物(SIAIS151190B)和LIN-ULM(SIAIS151140B)制备得目标化合物(SIAIS220048)(淡黄色固体,7.9mg,收率46％), 1H NMR(500MHz,DMSO)δ11.12(s,1H),10.82(s,1H),8.77(dd,J＝4.4,1.4Hz,1H),8.38(t,J＝5.4Hz,1H),8.35(d,J＝8.7Hz,1H),8.30(dd,J＝9.2,1.5Hz,2H),8.22(dd,J＝10.2,1.7Hz,2H),8.00(dd,J＝8.0,1.8Hz,1H),7.82–7.74(m,2H),7.63(d,J＝6.8Hz,1H),7.57(d,J＝8.3Hz,1H),7.45(dd,J＝9.2,4.5Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.46(d,J＝14.8Hz,2H),4.07–4.02(m,4H),3.74–3.62(m,1H),3.38–3.32(m,1H),3.24–3.19(m,1H),3.16(t,J＝6.3Hz,2H),3.07–2.97(m,1H),2.93–2.85(m,1H),2.62(s,3H),2.60–2.50(m,2H),2.42(t,J＝6.3Hz,2H),2.08–2.02(m,1H),1.74–1.64(m,1H).HRMS(ESI)m/z:计算值C 46H 42F 3N 8O 6S +[M+H] +,891.2895；实测值,891.2889.
实施例148：制备N-(4-((4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺(SIAIS220049)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用普纳替尼衍生物(SIAIS151190B)和LIN-ULM(SIAIS151141B)制备得目标化合物(SIAIS220049)(淡黄色固体,8.2mg,收率47％), 1H NMR(500MHz,DMSO)δ11.12(s,1H),10.81(s,1H),8.75(dd,J＝4.4,1.4Hz,1H),8.38(s,1H),8.36–8.26(m,3H),8.23(t,J＝4.8Hz,2H),7.99(dd,J＝8.0,1.7Hz,1H),7.83–7.71(m,2H),7.63(d,J＝6.8Hz,1H),7.58(d,J＝8.3Hz,1H),7.43(dd,J＝9.2,4.4Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.50–4.40(m,2H),4.12–3.98(m,1H),3.68–3.56(m,4H),3.38–3.30(m,1H),3.16–3.09(m,4H),2.94–2.84(m,1H),2.62(s,3H),2.61–2.51(m,2H),2.37(t,J＝7.1Hz,2H),2.08–2.02(m,1H),1.72–1.66(m,2H),1.59–1.42(m,4H).HRMS(ESI)m/z:计算值C 47H 44F 3N 8O 6S +[M+H] +,905.3051；实测值,905.3058.
实施例149：N-(4-((4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺(SIAIS220050)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用普纳替尼衍生物(SIAIS151190B)和LIN-ULM(SIAIS15142B)制备得目标化合物(SIAIS220050)(淡黄色固体,10.2mg,收率57％), 1H NMR(500MHz,DMSO)δ11.12(s,1H),10.79(s,1H),8.75(dd,J＝4.4,1.5Hz,1H),8.37(s,1H),8.29(dd,J＝9.2,1.6Hz,1H),8.27(s,1H),8.23(d,J＝1.8Hz,2H),7.98(dd,J＝8.0,1.9Hz,1H),7.81–7.76(m,2H),7.74(d,J＝7.5Hz,2H),7.62(s,1H),7.58(d,J＝8.2Hz,1H),7.43(dd,J＝9.2,4.4Hz,1H),5.11(dd,J＝12.9,5.4Hz,2H),4.50-4.40(m,2H),3.72–3.60(m,4H),3.40–3.30(m,2H),3.26–3.16(m,1H),3.16–3.12(t,J＝7.0Hz,2H),3.10–3.00(m,1H),2.92–2.84(m,1H),2.62(s,3H),2.56–2.51(m,2H),2.38–2.32(m,2H),2.29(t,J＝7.4Hz,2H),2.08–2.02(m,2H),1.71–1.63(m,2H),1.54–1.42(m,4H),1.36–1.29(m,2H).HRMS(ESI)m/z:计算值C 48H 46F 3N 8O 6S +[M+H] +,919.3208；实测值,919.3209.
实施例150：N-(4-((4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺(SIAIS220051)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用普纳替尼衍生物(SIAIS151190B)和LIN-ULM(SIAIS171090)制备得目标化合物(SIAIS220051)(淡黄色固体,10.3mg,收率64％), 1H NMR(500MHz,DMSO)δ11.00(s,1H),10.79(s,1H),8.74(dd,J＝4.4,1.5Hz,1H),8.37(s,1H),8.28(dd,J＝9.2,1.6Hz,1H),8.26(s,1H),8.23(d,J＝1.8Hz,2H),7.98(dd,J＝8.0,1.9Hz,1H),7.70(d,J＝7.2Hz,1H),7.59(dd,J＝11.7,7.5Hz,2H),7.53(t,J＝7.6Hz,1H),7.42(dd,J＝9.2,4.4Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.44(s,2H),4.40(s,1H),4.27(d,J＝17.4Hz,1H),4.23(s,2H),3.57–3.05(m,8H),2.97–2.87(m,1H),2.62(s,3H),2.49–2.42(m,2H),2.07–1.98(m,1H).HRMS(ESI)m/z:计算值C 43H 38F 3N 8O 5S +[M+H] +,835.2632；实测值,835.2635.
实施例151：制备N-(4-((4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺(SIAIS220052)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用普纳替尼衍生物(SIAIS151190B)和LIN-ULM(SIAIS171086)制备得目标化合物(SIAIS220052)(淡黄色固体,9.1mg,收率55％), 1H NMR(500MHz,DMSO)δ10.99(s,1H),10.79(s,1H),8.75(dd,J＝4.4,1.5Hz,1H),8.37(s,1H),8.28(dd,J＝9.2,1.6Hz,1H),8.27(s,1H),8.23(t,J＝4.4Hz,2H),7.98(dd,J＝8.0,1.8Hz,1H),7.66(dd,J＝7.6,1.1Hz,1H),7.60–7.52(m,3H),7.43(dd,J＝9.2,4.4Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.50-4.40(m,2H),4.35(d,J＝17.4Hz,1H),4.22(d,J＝17.4Hz,1H),3.73–3.55(m,4H),3.37–3.31(m,1H),3.28(dd,J＝15.2,6.8Hz,2H),3.22–3.00(m,3H),2.96–2.86(m,1H),2.76(t,J＝6.4Hz,2H),2.62(s,3H),2.49–2.41(m,2H),2.04–1.97(m,1H).HRMS(ESI)m/z:计算值C 44H 40F 3N 8O 5S +[M+H] +,849.2789；实测值,849.2783.
实施例152：制备N-(4-((4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺(SIAIS220053)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用普纳替尼衍生物(SIAIS151190B)和LIN-ULM(SIAIS171089)制备得目标化合物(SIAIS220053)(淡黄色固体,7.2mg,收率43％), 1H NMR(500MHz,DMSO)δ11.00(s,1H),10.82(s,1H),8.76(d,J＝3.1Hz,1H),8.39(d,J＝1.5Hz,1H),8.34(d,J＝7.9Hz,1H),8.31–8.28(m,2H),8.23(d,J＝8.4Hz,2H),8.00(dd,J＝8.0,1.5Hz,1H),7.69(d,J＝6.7Hz,1H),7.60–7.52(m,3H),7.44(dd,J＝9.2,4.4Hz,1H),5.14(dd,J＝13.3,5.0Hz,1H),4.50–4.42(m,2H),4.37(d,J＝17.4Hz,1H),4.23(d,J＝17.4Hz,1H),4.12–3.92(d,J＝37.5Hz,4H),3.39–3.31(m,1H),3.20-3.00(m,5H),2.97–2.86(m,1H),2.62(s,3H),2.50–2.42(m,2H),2.05–1.97(m,1H),1.89–1.79(m,2H).HRMS(ESI)m/z:计算值C 45H 42F 3N 8O 5S +[M+H] +,863.2945；实测值,863.2952.
实施例153：N-(4-((4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺(SIAIS220054)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用普纳替尼衍生物(SIAIS151190B)和LIN-ULM(SIAIS171079)制备得目标化合物(SIAIS220054)(淡黄色固体,7.5mg,收率44％), 1H NMR(500MHz,DMSO)δ10.99(s,1H),10.79(s,1H),8.75(dd,J＝4.4,1.5Hz,1H),8.37(s,1H),8.28(dd,J＝9.2,1.5Hz,1H),8.26(s,1H),8.23(d,J＝1.7Hz,2H),7.98(dd,J＝8.0,1.8Hz,1H),7.64(dd,J＝7.5,1.1Hz,1H),7.59–7.56(m,2H),7.53(t,J＝7.5Hz,1H),7.42(dd,J＝9.2,4.4Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.44(s,2H),4.36(d,J＝17.4Hz,1H),4.22(d,J＝17.4Hz,1H),3.67–3.58(m,4H),3.38–3.32(m,1H),3.20–2.98(m,5H),2.95–2.87(m,1H),2.62(s,3H),2.49–2.45(m,2H),2.39(s,2H),2.04–1.97(m,1H),1.69–1.57(m,4H).HRMS(ESI)m/z:计算值C 46H 44F 3N 8O 5S +[M+H] +,877.3102；实测值,877.3110.
实施例154：制备N-(4-((4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺(SIAIS220055)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用普纳替尼衍生物(SIAIS151190B)和LIN-ULM(SIAIS171091)制备得目标化合物(SIAIS220055)(淡黄色固体,8.2mg,收率48％), 1H NMR(500MHz,DMSO)δ10.99(s,1H),10.80(s,1H),8.75(dd,J＝4.4,1.5Hz,1H),8.37(s,1H),8.28(dd,J＝9.2,1.5Hz,1H),8.27(s,1H),8.25–8.21(m,2H),7.98(dd,J＝8.0,1.9Hz,1H),7.63(dd,J＝7.5,1.1Hz,1H),7.59–7.55(m,2H),7.53(t,J＝7.5Hz,1H),7.42(dd,J＝9.2,4.4Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.49-4.41(m,2H),4.35(d,J＝17.4Hz,1H),4.22(d,J＝17.4Hz,1H),4.07–3.97(m,1H),3.68–3.57(m,4H),3.36–3.32(m,1H),3.23–3.11(m,2H),3.08(t,J＝7.2Hz,2H),2.95–2.85(m,1H),2.62(s,3H),2.49–2.41(m,2H),2.33(t, J＝7.0Hz,2H),2.04–1.97(m,1H),1.65–1.58(m,2H),1.54–1.48(m,2H),1.45–1.39(m,2H).HRMS(ESI)m/z:计算值C 47H 46F 3N 8O 5S +[M+H] +,891.3258；实测值,891.3255.
实施例155：制备N-(4-((4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺(SIAIS220056)
根据方案28所述通用方法，在本领域可理解的适当条件下，采用普纳替尼衍生物(SIAIS151190B)和LIN-ULM(SIAIS171092)制备得目标化合物(SIAIS220056)(淡黄色固体,9.2mg,收率52％), 1H NMR(500MHz,DMSO)δ10.99(s,1H),10.80(s,1H),8.75(dd,J＝4.4,1.5Hz,1H),8.37(d,J＝1.8Hz,1H),8.29(dd,J＝9.2,1.6Hz,1H),8.27(s,1H),8.23(t,J＝4.0Hz,2H),7.99(dd,J＝8.0,1.9Hz,1H),7.62(dd,J＝7.5,1.2Hz,1H),7.59–7.55(m,2H),7.53(t,J＝7.5Hz,1H),7.43(dd,J＝9.2,4.4Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.49–4.41(m,2H),4.35(d,J＝17.4Hz,1H),4.21(d,J＝17.4Hz,1H),4.08–3.96(m,1H),3.73–3.57(m,4H),3.37–3.33(m,1H),3.23–3.11(m,2H),3.08(t,J＝7.2Hz,2H),2.95–2.87(m,1H),2.62(s,3H),2.49–2.41(m,2H),2.32(t,J＝7.3Hz,2H),2.04–1.97(m,1H),1.65–1.56(m,2H),1.51–1.39(m,4H),1.32–1.26(m,2H).HRMS(ESI)m/z:计算值C 48H 48F 3N 8O 5S +[M+H] +,905.3415；实测值,905.3421.
BCR-ABL靶点的特殊降解剂SIAIS172056和SIAIS172106的通用合成方法:
Figure PCTCN2019081840-appb-000252
根据方案29制备N-(2-氯-6-甲基苯基)-2-((6-(4-(2-氯乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS172051)：
将SIAIS151055(1000mg,2.25mmol)，1-溴-2-氯乙烷(968mg,6.75mmol)，N,N-二异丙基乙胺(1450mg,11.25mmol)和N-甲基吡咯烷酮(15mL)一起加入100mL的蛋形瓶中，随后缓慢升温至100℃，并搅拌2h。反应完毕后，降至室温，随后向反应液中加入水(100mL)，乙酸乙酯萃取(3x 50mL)，合并有机相，水洗(30mL)，饱和食盐水洗涤，无水硫酸钠干燥，减压蒸去溶剂，硅胶拌样，粗品经柱层析(洗脱剂梯度：0-3％MeOH/DCM)，旋干得目标化合物SIAIS172051(黄色固体,650mg,收率57％), 1H NMR(500MHz,DMSO)δ11.47(s,1H),9.87(s,1H),8.22(s,1H),7.40(d,J＝6.6Hz,1H),7.30–7.23(m,2H),6.06(s,1H),3.72(t,J＝6.4Hz,2H),3.57–3.47(m,4H),2.69(t,J＝6.3Hz,2H),2.51–2.55 (m,4H),2.41(s,3H),2.24(s,3H).HRMS(ESI)m/z:计算值C 22H 26Cl 2N 7OS +[M+H] +,506.1291；实测值,505.7968.
实施例156：根据方案29制备N-(2-氯-6-甲基苯基)-2-((6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS172056)：
将化合物SIAIS172051(20mg,0.04mmol),SIAIS151014(13mg,0.044mmol),无水碳酸钾(27.6mg,0.2mmol)及碘化钠(30mg,0.2mmol)加入一个10mL的蛋形瓶中，随后加入无水N,N-二甲基甲酰胺(3mL),缓慢升温至50℃并搅拌2h.LC-MS检测反应结束后，将反应混合物过滤，滤液经HPLC制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)得目标化合物(SIAIS172056)。(淡黄色固体,20.2mg,收率68％), 1H NMR(500MHz,DMSO)δ11.50(s,1H),11.13(s,1H),9.93(s,1H),8.26(s,1H),7.97(d,J＝8.3Hz,1H),7.84(t,J＝7.7Hz,1H),7.71(d,J＝7.3Hz,1H),7.40(d,J＝7.6Hz,1H),7.32–7.23(m,2H),6.18(s,1H),5.13(dd,J＝12.9,5.4Hz,1H),4.39–4.37(m,2H),3.73–3.66(m,4H),3.44–3.35(m,4H),3.18–3.07(m,2H),2.93–2.85(m,1H),2.64–2.52(m,2H),2.46(s,3H),2.24(s,3H),2.08–2.01(m,1H).HRMS(ESI)m/z:计算值C 35H 35ClN 9O 5S 2 +[M+H] +,760.1886；实测值,760.1882.
根据方案29制备N-(2-氯-6-甲基苯基)-2-((6-(4-(3-氯丙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS172104)：
根据方案29所述通用方法，采用1-溴-3-氯丙烷制备得目标化合物(SIAIS172104)(黄色固体,50mg,收率76％), 1H NMR(500MHz,DMSO)δ11.64(s,1H),10.83(d,J＝43.8Hz,1H),9.93(s,1H),8.25(s,1H),7.40(d,J＝7.4Hz,1H),7.31–7.23(m,2H),6.16(s,1H),4.35(d,J＝10.8Hz,2H),3.76(t,J＝6.3Hz,2H),3.62–3.56(m,2H),3.34(d,J＝12.7Hz,2H),3.26–3.18(m,2H),3.13–3.01(m,2H),2.45(s,3H),2.24(s,3H),2.23–2.18(m,2H).HRMS(ESI)m/z:计算值C 23H 28Cl 2N 7OS +[M+H] +,520.1448；实测值,520.1443.
实施例157：根据方案29制备N-(2-氯-6-甲基苯基)-2-((6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS172106)：
根据方案29所述通用方法，采用SIAIS172104和SIAIS151014制备得目标化合物(SIAIS172106)(淡黄色固体,18.6mg,收率66％), 1H NMR(500MHz,DMSO)δ11.63(s,1H),11.13(s,1H),9.92(s,1H),8.25(s,1H),7.85–7.80(m,2H),7.67(dd,J＝5.0,3.0Hz,1H),7.40(d,J＝7.8Hz,1H),7.33–7.23(m,2H),6.15(s,1H),5.12(dd,J＝12.9,5.4Hz,1H),4.34(d,J＝12.3Hz,2H),3.59(d,J＝11.4Hz,2H),3.31–3.25(m,6H),3.12–3.02(m,2H),2.93–2.84(m,1H),2.65–2.52(m,2H),2.44(s,3H),2.24(s,3H),2.18–2.10(m,2H),2.08–2.03(m,1H).HRMS(ESI)m/z:计算值C 36H 39ClN 9O 5S 2 +[M+H] +,774.2042；实测值,774.2042.
BCR-ABL靶点的特殊降解剂SIAIS171166和SIAIS171181的通用合成方法:
Figure PCTCN2019081840-appb-000253
实施例158：根据方案30制备N-(2-氯-6-甲基苯基)-2-((6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS171166)：
将化合物SIAIS172051(15mg,0.03mmol),SIAIS171095(8.2mg,0.03mmol),无水碳酸钾(8.2mg,0.06mmol)及碘化钠(9.0mg,0.06mmol)加入一个10mL的蛋形瓶中，随后加入无水N,N-二甲基甲酰胺(2mL),缓慢升温至50℃并搅拌2h.LC-MS检测反应结束后，将反应混合物过滤，滤液经HPLC制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)得目标化合物(SIAIS171166)。(白色固体,6.0mg,收率27％), 1H NMR(500MHz,MeOD)δ8.22(s,1H),7.79(ddd,J＝24.9,11.2,3.9Hz,2H),7.60(dd,J＝17.9,10.2Hz,1H),7.36(dd,J＝7.2,2.0Hz,1H),7.32–7.15(m,2H),6.42(d,J＝29.7Hz,1H),5.18(dd,J＝13.3,5.2Hz,1H),4.58–4.46(m,2H),4.18–3.31(m,12H),2.95–2.88(m,1H),2.79(ddd,J＝17.5,4.5,2.3Hz,1H),2.64–2.46(m,4H),2.31(s,3H),2.19(ddd,J＝10.4,5.2,2.6Hz,1H).HRMS(ESI)m/z:计算值C 35H 37ClN 9O 4S 2 +[M+H] +,746.2093；实测值,746.2660.
实施例159：根据方案30制备N-(2-氯-6-甲基苯基)-2-((6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(SIAIS171181)：
根据方案30所述通用方法，采用SIAIS172104和SIAIS171095制备得目标化合物(SIAIS171181)。(白色固体,10.0mg,收率34％), 1H NMR(500MHz,MeOD)δ8.24(s,1H),7.79–7.66(m,2H),7.58(t,J＝7.7Hz,1H),7.36(dt,J＝9.2,4.5Hz,1H),7.31–7.20(m,2H),6.50(d,J＝11.0Hz,1H),5.19(dd,J＝13.4,5.2Hz,1H),4.49(q,J＝17.4Hz,2H),3.84–3.35(m,8H),3.19(ddt,J＝36.4,13.9,7.0Hz,4H),2.91(ddd,J＝18.8,13.6,5.4Hz,1H),2.81–2.75(m,1H),2.67–2.60(m,3H),2.58–2.48(m,1H),2.33(d,J＝19.5Hz,4H),2.19–2.10(m,2H).HRMS(ESI)m/z:计算值C 36H 39ClN 9O 4S 2 +[M+H] +,760.2249；实测值,746.2399.
PARP靶点的一系列降解剂通用的合成方法:
Figure PCTCN2019081840-appb-000254
根据方案31，室温下，在反应瓶中，加入相应的PARP抑制剂(1equiv)，相应的LIN-ULM(1equiv),1-羟基-7-偶氮苯并三氮唑(2equiv),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(2equiv),无水N,N-二甲基甲酰胺(2mL)，N-甲基吗啡啉(5equiv)，室温下搅拌反应过夜。LC-MS检测反应结束后，HPLC制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)。旋蒸除去乙腈，冻干后得相应的最终降解剂化合物。
实施例160：制备2-(2,6-二氧代哌啶-3-基)-4-((2-(4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)哌嗪-1-基)-2-氧代乙基)硫基)异吲哚啉-1,3-二酮(SIAIS180063)
根据方案31所述通用方法，在本领域可理解的适当条件下，采用奥拉帕尼抑制剂和LIN-ULM(SIAIS151045)制备得目标化合物(SIAIS180063)(黄色固体,10.5mg,收率55％)。 1H NMR(500MHz,DMSO)δ12.59(s,1H),11.13(s,1H),8.26(dd,J＝7.7,2.3Hz,1H),7.97(t,J＝7.6Hz,1H),7.90(dd,J＝15.8,8.0Hz,1H),7.83(t,J＝7.8Hz,1H),7.79–7.76(m,2H),7.64(d,J＝6.8Hz,1H),7.47–7.43(m,1H),7.39(dd,J＝20.3,6.3Hz,1H),7.27–7.22(m,1H),5.13(dd,J＝12.8,5.3Hz,1H),4.33(s,3H),4.26(s,1H),3.71–3.69(m,2H),3.62(s,1H),3.59–3.51(m,2H),3.42(s,1H),3.27(s,1H),3.19(s,1H),2.95–2.83(m,1H),2.66–2.53(m,2H),2.10–2.02(m,1H).HRMS(ESI)m/z:计算值C 35H 30FN 6O 7S +[M+H] +,697.1875；实测值,696.9606.
实施例161：制备2-(2,6-二氧代哌啶-3-基)-4-((3-(4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)哌嗪-1-基)-3-氧代丙基)硫基)异吲哚啉-1,3-二酮(SIAIS180064)
根据方案31所述通用方法，在本领域可理解的适当条件下，采用奥拉帕尼抑制剂和LIN-ULM(SIAIS151138B)制备得目标化合物(SIAIS180064)(黄色固体,9.9mg,收率51％)。 1H NMR(500MHz,DMSO)δ12.59(d,J＝4.4Hz,1H),11.12(s,1H),8.30–8.22(m,1H),7.96(d,J＝7.5Hz,1H),7.89(t,J＝7.5Hz,1H),7.85–7.74(m,3H),7.63(dd,J＝6.7,2.7Hz,1H),7.45–7.42(m,1H),7.37–7.35(m,1H),7.23(t,J＝8.8Hz,1H),5.11(dd,J＝12.7,3.3Hz,1H),4.33(s,2H),3.63–3.50(m,4H),3.40(s,1H),3.34(s,2H),3.18–3.16(m,2H),2.92–2.81(m,2H),2.75(t,J＝6.8Hz,1H),2.65–2.51(m,3H),2.07–2.03(m,1H).HRMS(ESI)m/z:计算值C 36H 32FN 6O 7S +[M+H] +,711.2032；实测值,710.9738.
实施例162：制备2-(2,6-二氧代哌啶-3-基)-4-((4-(4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)哌嗪-1-基)-4-氧代丁基)硫基)异吲哚啉-1,3-二酮(SIAIS180065)
根据方案31所述通用方法，在本领域可理解的适当条件下，采用奥拉帕尼抑制剂和LIN-ULM(SIAIS151139B)制备得目标化合物(SIAIS180065)(黄色固体,9.7mg,收率49％)。 1H NMR(500MHz,DMSO)δ12.59(s,1H),11.12(s,1H),8.26(d,J＝7.9Hz,1H),7.96(d,J＝7.8Hz,1H),7.93–7.76(m,4H),7.63(d,J＝7.1Hz,1H),7.46–7.43(m,1H),7.37–7.35(m,1H),7.24(t,J＝8.9Hz,1H),5.11(dd,J＝12.1,4.6Hz,1H),4.33(s,2H),3.69–3.48(m,4H),3.40–3.33(m,3H),3.19–3.15(m,4H),2.95–2.82(m,1H),2.66–2.53(m,3H),2.06–2.03(m,1H),1.96–1.85(m,2H).HRMS(ESI)m/z:计算值C 37H 34FN 6O 7S +[M+H] +,725.2188；实测值,724.9790.
实施例163：制备2-(2,6-二氧代哌啶-3-基)-4-((5-(4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)哌嗪-1-基)-5-氧代戊基)硫基)异吲哚啉-1,3-二酮(SIAIS180066)
根据方案31所述通用方法，在本领域可理解的适当条件下，采用奥拉帕尼抑制剂和LIN-ULM(SIAIS151140B)制备得目标化合物(SIAIS180066)(黄色固体,9.1mg,收率45％)。 1H NMR(500MHz,DMSO)δ12.59(s,1H),11.12(s,1H),8.26(dd,J＝7.9,1.0Hz,1H),7.96(d,J＝8.0Hz,1H),7.89(t,J＝7.2Hz,1H),7.83(t,J＝7.5Hz,1H),7.80–7.72(m,2H),7.62(d,J＝6.7Hz,1H),7.45–7.43(m,1H),7.37–7.35(m,1H),7.23(t,J＝9.0Hz,1H),5.11(dd,J＝12.7,5.4Hz,1H),4.33(s,2H),3.67–3.49(m,4H),3.36(s,2H),3.17-3.14(m,4H),2.92–2.85(m,1H),2.68–2.52(m,2H),2.43–2.42(m,1H),2.36(d,J＝5.6Hz,1H),2.07–1.99(m,1H),1.68(s,4H).HRMS(ESI)m/z:计算值C 38H 36FN 6O 7S +[M+H] +,739.2345；实测值,738.9875.
实施例164：制备2-(2,6-二氧代哌啶-3-基)-4-((6-(4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)哌嗪-1-基)-6-氧代己基)硫基)异吲哚啉-1,3-二酮(SIAIS180067)
根据方案31所述通用方法，在本领域可理解的适当条件下，采用奥拉帕尼抑制剂和LIN-ULM(SIAIS151141B)制备得目标化合物(SIAIS180067)(黄色固体,10.4mg,收率51％)。 1H NMR(500MHz,DMSO)δ12.59(s,1H),11.12(s,1H),8.26(d,J＝7.3Hz,1H),7.96(d,J＝8.0Hz,1H),7.89(t,J＝7.6Hz,1H),7.83(t,J＝7.5Hz,1H),7.80–7.71(m,2H),7.63–7.61(m,1H),7.45–7.44(m,1H),7.36–7.35(m,1H),7.23(t,J＝9.0Hz,1H),5.11(dd,J＝12.8,5.4Hz,1H),4.33(s,2H),3.68–3.47(m,4H),3.36(s,2H),3.22–3.08(m,4H),2.92–2.85(m,1H),2.65–2.51(m,2H),2.37–2.34(m,1H),2.29(t,J＝6.8Hz,1H),2.07–1.99(m,1H),1.70-1.66(m,2H),1.56–1.52(m,2H),1.47–1.43(m,2H).HRMS(ESI)m/z:计算值C 39H 38FN 6O 7S +[M+H] +,753.2501；实测值,752.9993.
实施例165：制备2-(2,6-二氧代哌啶-3-基)-4-((7-(4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)哌嗪-1-基)-7-氧代庚基)硫基)异吲哚啉-1,3-二酮(SIAIS180068)
根据方案31所述通用方法，在本领域可理解的适当条件下，采用奥拉帕尼抑制剂和LIN-ULM(SIAIS151142B)制备得目标化合物(SIAIS180068)(黄色固体,10.1mg,收率48％)。 1H NMR(500MHz,DMSO)δ12.59(s,1H),11.12(s,1H),8.26(dd,J＝7.9,1.0Hz,1H),7.96(d,J＝7.9Hz,1H),7.89(t,J＝7.4Hz,1H),7.83(t,J＝7.2Hz,1H),7.81–7.72(m,2H),7.62 (d,J＝6.6Hz,1H),7.45–7.43(m,1H),7.37–7.35(m,1H),7.23(t,J＝9.0Hz,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.33(s,2H),3.67–3.46(m,4H),3.37(s,1H),3.17–3.12(m,4H),2.92–2.85(m,1H),2.66–2.51(m,3H),2.34(t,J＝7.2Hz,1H),2.27(t,J＝7.3Hz,1H),2.07–1.98(m,1H),1.66(s,2H),1.56–1.39(m,4H),1.34–1.31(m,2H).HRMS(ESI)m/z:计算值C 40H 40FN 6O 7S +[M+H] +,767.2658；实测值,767.0053.
实施例166：制备2-(4-((3S)-1-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰基)哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺(SIAIS164165)
根据方案31所述通用方法，在本领域可理解的适当条件下，采用尼拉帕尼抑制剂和LIN-ULM(SIAIS151045)制备得目标化合物(SIAIS164165)(淡黄色固体,12.6mg,收率62％)。 1H NMR(500MHz,DMSO)δ11.13(s,1H),9.30(d,J＝5.0Hz,1H),8.57(s,1H),8.16–7.99(m,4H),7.91–7.73(m,3H),7.63(dd,J＝14.1,7.2Hz,2H),7.54(d,J＝8.5Hz,1H),7.31–7.23(m,1H),5.13(dd,J＝12.8,5.4Hz,1H),4.52–4.24(m,3H),4.11(d,J＝13.4Hz,1H),3.28–3.19(m,1H),2.95–2.84(m,2H),2.79–2.53(m,3H),2.12–2.03(m,1H),2.01–1.97(m,1H),1.90–1.75(m,2H),1.74–1.37(m,1H).HRMS(ESI)m/z:计算值C 34H 31N 6O 6S +[M+H] +,651.2020；实测值,651.1876.
实施例167：制备2-(4-((3S)-1-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰基)哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺(SIAIS164166)
根据方案31所述通用方法，在本领域可理解的适当条件下，采用尼拉帕尼抑制剂和LIN-ULM(SIAIS151138B)制备得目标化合物(SIAIS164166)(淡黄色固体,13.3mg,收率64％)。 1H NMR(500MHz,DMSO)δ11.12(d,J＝5.6Hz,1H),9.28(d,J＝9.3Hz,1H),8.57(s,1H),8.12–8.05(m,3H),8.02(d,J＝8.4Hz,1H),7.88(s,1H),7.83–7.77(m,2H),7.67–7.58(m,1H),7.54–7.51(m,2H),7.27(dd,J＝8.2,7.2Hz,1H),5.12(dt,J＝12.5,6.2Hz,1H),4.50(d,J＝11.8Hz,1H),3.88(t,J＝12.5Hz,1H),3.11(dt,J＝37.9,12.0Hz,1H),2.96–2.52(m,9H),2.10–2.00(m,1H),1.96(d,J＝9.5Hz,1H),1.80–1.72(m,2H),1.58–1.43(m,1H).HRMS(ESI)m/z:计算值C 35H 33N 6O 6S +[M+H] +,665.2177；实测值,665.2068.
实施例168：制备2-(4-((3S)-1-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰基)哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺(SIAIS164167)
根据方案31所述通用方法，在本领域可理解的适当条件下，采用尼拉帕尼抑制剂和LIN-ULM(SIAIS151139B)制备得目标化合物(SIAIS164167)(淡黄色固体,13.1mg,收率62％)。 1H NMR(500MHz,DMSO)δ11.12(d,J＝6.0Hz,1H),9.29(s,1H),8.57(s,1H),8.08(dd,J＝16.8,7.6Hz,3H),8.10–8.05(m,1H),7.93–7.85(m,2H),7.81–7.76(m,1H),7.62(t,J＝6.9Hz,1H),7.53(t,J＝9.0Hz,2H),7.32–7.23(m,1H),5.11(dt,J＝12.7,6.5Hz,1H),4.50(d,J＝10.3Hz,1H),3.91(d,J＝11.9Hz,1H),3.24–3.03(m,3H),2.96–2.66(m,3H),2.66–2.52(m,4H),2.12–2.00(m,1H),1.97–1.90(m,3H),1.78–1.76(m,2H),1.61–1.38(m,1H).HRMS(ESI)m/z:计算值C 36H 35N 6O 6S +[M+H] +,679.2333；实测值,679.2221.
实施例169：制备2-(4-((3S)-1-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰基)哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺(SIAIS164168)
根据方案31所述通用方法，在本领域可理解的适当条件下，采用尼拉帕尼抑制剂和LIN-ULM(SIAIS151140B)制备得目标化合物(SIAIS164168)(淡黄色固体,15.1mg,收率70％)。 1H NMR(500MHz,DMSO)δ11.12(d,J＝5.0Hz,1H),9.29(d,J＝5.0Hz,1H),8.57(s,1H),8.13–8.04(m,3H),8.02(d,J＝8.2Hz,1H),7.88(s,1H),7.82–7.73(m,2H),7.62(dd,J＝9.2,6.6Hz,1H),7.56(d,J＝8.2Hz,1H),7.51(d,J＝8.4Hz,1H),7.30–7.24(m,1H),5.11(dt,J＝12.7,6.5Hz,1H),4.47(d,J＝8.0Hz,1H),3.93(d,J＝12.3Hz,1H),3.23–3.03(m,3H),2.96–2.52(m,5H),2.47–2.31(m,2H),2.07–2.01(m,1H),1.95(d,J＝11.6Hz,1H),1.77–1.71(m,6H),1.60–1.32(m,1H).HRMS(ESI)m/z:计算值C 37H 37N 6O 6S +[M+H] +,693.2490；实测值,693.2381.
实施例170：制备2-(4-((3S)-1-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺(SIAIS164169)
根据方案31所述通用方法，在本领域可理解的适当条件下，采用尼拉帕尼抑制剂和LIN-ULM(SIAIS151141B)制备得目标化合物(SIAIS164169)(淡黄色固体，15.0mg,收率68％)。 1H NMR(500MHz,DMSO)δ11.11(d,J＝5.1Hz,1H),9.29(d,J＝2.9Hz,1H),8.56(s,1H),8.10–8.05(m,3H),8.02(d,J＝8.4Hz,1H),7.88(s,1H),7.82–7.71(m,2H),7.63–7.59(m,1H),7.58–7.49(m,2H),7.27(t,J＝7.7Hz,1H),5.10(dt,J＝12.5,6.2Hz,1H),4.48(d,J＝11.5Hz,1H),3.94–3.89(m,1H),3.19–3.03(m,3H),2.96–2.52(m,5H),2.42–2.33(m,2H),2.06–1.99(m,1H),1.96(d,J＝11.1Hz,1H),1.84–1.64(m,4H),1.62–1.37(m,5H).HRMS(ESI)m/z:计算值C 38H 39N 6O 6S +[M+H] +,707.2646；实测值,707.2537.
实施例171：制备2-(4-((3S)-1-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺(SIAIS164170)
根据方案31所述通用方法，在本领域可理解的适当条件下，采用尼拉帕尼抑制剂和LIN-ULM(SIAIS151142B)制备得目标化合物(SIAIS164170)(淡黄色固体,12.9mg,收率57％)。 1H NMR(500MHz,DMSO)δ11.11(d,J＝4.1Hz,1H),9.29(d,J＝5.6Hz,1H),8.57(s,1H),8.14–8.04(m,3H),8.02(dd,J＝8.4,1.0Hz,1H),7.80-7.71(m,1H),7.80–7.71(m,2H),7.61(dd,J＝13.0,7.0Hz,1H),7.56(d,J＝8.5Hz,1H),7.51(d,J＝8.5Hz,1H),7.30–7.24(m,1H),5.11(dt,J＝12.4,6.2Hz,1H),4.47(d,J＝10.5Hz,1H),3.92–3.88(s,1H),3.21–3.02(m,3H),2.96–2.53(m,5H),2.41–2.26(m,2H),2.07–2.02(m,1H),1.96(d,J＝10.4Hz,1H),1.79–1.75(m,2H),1.70–1.65(m,2H),1.59–1.40(m,5H),1.40–1.29(m,2H).HRMS(ESI)m/z:计算值C 39H 41N 6O 6S +[M+H] +,721.2803；实测值,721.2695.
实施例172：制备2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-(4-(8-氟-1-氧代-2,3,4,6-四氢-1H-氮杂卓并[5,4,3-cd]吲哚-5-基)苄基)-N-甲基乙酰胺(SIAIS180043)
根据方案31所述通用方法，在本领域可理解的适当条件下，采用瑞卡帕布抑制剂和LIN-ULM(SIAIS151045)制备得目标化合物(SIAIS180043)(淡黄色固体,9.7mg,收率48％)。 1H NMR(500MHz,DMSO)δ11.75–11.67(m,1H),11.13(s,1H),8.25(t,J＝5.7Hz,1H),7.82–7.73(m,2H),7.68–7.57(m,3H),7.47–7.30(m,4H),5.16–5.10(m,1H),4.71(d,J＝104.0Hz,2H),4.38(d,J＝19.0Hz,2H),3.43–3.37(m,2H),3.13(s,2H),3.06–3.00(m,2H),2.93–2.84(m,1H),2.87(s,1H),2.65–2.51(m,2H),2.08–2.02(m,1H).HRMS(ESI)m/z:计算值C 34H 29FN 5O 6S +[M+H] +,654.1817；实测值,654.0244.
实施例173：制备3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-(4-(8-氟-1-氧代-2,3,4,6-四氢-1H-氮杂卓并[5,4,3-cd]吲哚-5-基)苄基)-N-甲基丙酰胺(SIAIS180044)
根据方案31所述通用方法，在本领域可理解的适当条件下，采用瑞卡帕布抑制剂和LIN-ULM(SIAIS151138B)制备得目标化合物(SIAIS180044)(淡黄色固体,8.5mg,收率41％)。 1H NMR(500MHz,DMSO)δ11.66(d,J＝11.5Hz,1H),11.12(d,J＝3.3Hz,1H),8.24(t,J＝5.7Hz,1H),7.82–7.70(m,2H),7.67–7.55(m,3H),7.44–7.30(m,4H),5.14–5.08(m,1H),4.62(d,J＝14.3Hz,2H),3.42–3.36(m,4H),3.06–2.98(m,2H),2.95(s,2H),2.90(s,1H),2.91–2.82(m,3H),2.63–2.52(m,2H),2.06–1.98(m,1H).HRMS(ESI)m/z:计算值C 35H 31FN 5O 6S +[M+H] +,668.1974；实测值,668.0385.
实施例174：制备4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-(4-(8-氟-1-氧代-2,3,4,6-四氢-1H-氮杂卓并[5,4,3-cd]吲哚-5-基)苄基)-N-甲基丁酰胺(SIAIS180045)
根据方案31所述通用方法，在本领域可理解的适当条件下，采用瑞卡帕布抑制剂和LIN-ULM(SIAIS151139B)制备得目标化合物(SIAIS180045)(淡黄色固体,10.0mg,收率48％)。 1H NMR(500MHz,DMSO)δ11.68(d,J＝11.9Hz,1H),11.11(d,J＝5.1Hz,1H),8.24(t,J＝5.6Hz,1H),7.88(t,J＝8.7Hz,1H),7.81–7.76(m,1H),7.65–7.57(m,3H),7.43–7.41(m,1H),7.38–7.35(m,2H),7.33–7.31(m,1H),5.14–5.08(m,1H),4.62(d,J＝30.7Hz,2H),3.41–3.36(m,2H),3.22–3.13(m,2H),3.06–3.00(m,2H),2.97(s,2H),2.87(s,1H),2.90–2.83(m,1H),2.66–2.52(m,4H),2.09–2.01(m,1H),1.97–1.91(m,2H).HRMS(ESI)m/z:计算值C 36H 33FN 5O 6S +[M+H] +,682.2130；实测值,682.0486.
实施例175：制备5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-(4-(8-氟-1-氧代-2,3,4,6-四氢-1H-氮杂卓并[5,4,3-cd]吲哚-5-基)苄基)-N-甲基戊酰胺(SIAIS180046)
根据方案31所述通用方法，在本领域可理解的适当条件下，采用瑞卡帕布抑制剂和LIN-ULM(SIAIS151140B)制备得目标化合物(SIAIS180046)(淡黄色固体,9.3mg,收率43％)。 1H NMR(500MHz,DMSO)δ11.67(d,J＝7.1Hz,1H),11.12(s,1H),8.24(t,J＝5.7Hz,1H),7.80–7.71(m,2H),7.65–7.57(m,3H),7.42(dd,J＝11.0,2.3Hz,1H),7.37–7.30(m,3H), 5.13–5.09(m,1H),4.61(d,J＝42.5Hz,2H),3.41–3.35(m,2H),3.20–3.09(m,2H),3.06–3.00(m,2H),2.96(s,2H),2.93–2.86(m,1H),2.85(s,1H),2.65–2.52(m,2H),2.49–2.42(m,2H),2.07–2.01(m,1H),1.77–1.67(m,4H).HRMS(ESI)m/z:计算值C 37H 35FN 5O 6S +[M+H] +,696.2287；实测值,696.0577.
实施例176：制备6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-(4-(8-氟-1-氧代-2,3,4,6-四氢-1H-氮杂卓并[5,4,3-cd]吲哚-5-基)苄基)-N-甲基己酰胺(SIAIS180047)
根据方案31所述通用方法，在本领域可理解的适当条件下，采用瑞卡帕布抑制剂和LIN-ULM(SIAIS151141B)制备得目标化合物(SIAIS180047)(淡黄色固体,10.5mg,收率48％)。 1H NMR(500MHz,DMSO)δ11.67(d,J＝9.0Hz,1H),11.12(s,1H),8.24(t,J＝5.8Hz,1H),7.80–7.69(m,2H),7.65–7.57(m,3H),7.42(dd,J＝11.0,2.4Hz,1H),7.37–7.29(m,3H),5.12–5.08(m,1H),4.60(d,J＝41.2Hz,2H),3.42–3.35(m,2H),3.17–3.07(m,2H),3.03(s,2H),2.96(s,2H),2.86(s,1H),2.92–2.83(m,1H),2.62–2.51(m,2H),2.44–2.35(m,2H),2.06–2.00(m,1H),1.73–1.42(m,6H).HRMS(ESI)m/z:计算值C 38H 37FN 5O 6S +[M+H] +,710.2443；实测值,710.0702.
实施例177：制备7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-(4-(8-氟-1-氧代-2,3,4,6-四氢-1H-氮杂卓并[5,4,3-cd]吲哚-5-基)苄基)-N-甲基庚酰胺(SIAIS180048)
根据方案31所述通用方法，在本领域可理解的适当条件下，采用瑞卡帕布抑制剂和LIN-ULM(SIAIS151142B)制备得目标化合物(SIAIS180048)(淡黄色固体,10.2mg,收率45％)。 1H NMR(500MHz,DMSO)δ11.67(d,J＝9.3Hz,1H),11.12(s,1H),8.24(t,J＝5.7Hz,1H),7.80–7.68(m,2H),7.65–7.57(m,3H),7.43–7.40(m,1H),7.32(ddd,J＝9.9,9.1,5.5Hz,3H),5.13–5.08(m,1H),4.60(d,J＝40.3Hz,2H),3.41–3.35(m,2H),3.14–3.06(m,2H),3.06–3.00(m,2H),2.96(s,2H),2.92–2.87(m,1H),2.85(s,1H),2.63–2.51(m,2H),2.42–2.34(m,2H),2.07–2.01(m,1H),1.72–1.34(m,8H).HRMS(ESI)m/z:计算值C 39H 39FN 5O 6S +[M+H] +,724.2600；实测值,724.0825.
ER靶点的一系列降解剂通用的合成方法:
Figure PCTCN2019081840-appb-000255
根据方案32，室温下，在反应瓶中，加入相应的雌激素受体调节剂(1equiv)，相应的LIN-ULM(1equiv),1-羟基-7-偶氮苯并三氮唑(2equiv),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(2equiv),无水N,N-二甲基甲酰胺(2mL)，N-甲基吗啡啉(5equiv)，室温下搅拌反应过夜。LC-MS检测反应结束后，HPLC制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)。旋蒸除去乙腈，冻干后得相应的最终降解剂化合物。
实施例178：制备(Z)-N-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-甲基乙酰胺(SIAIS180014)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用拖瑞米芬衍生物A和LIN-ULM(SIAIS151045)制备得目标化合物(SIAIS180014)(淡黄色固体,16.9mg,收率50％). 1H NMR(500MHz,DMSO)δ11.13(s,1H),7.74–7.63(m,2H),7.63–7.57(m,1H),7.40(dt,J＝7.6,3.7Hz,2H),7.32–7.27(m,3H),7.25–7.20(m,2H),7.19–7.13(m,3H),6.79–6.73(m,2H),6.63(dd,J＝13.3,8.8Hz,2H),5.12(dd,J＝12.8,5.4Hz,1H),4.30(s,1H),4.24(s,1H),4.08(t,J＝5.2Hz,1H),3.93(t,J＝5.5Hz,1H),3.79(t,J＝5.1Hz,1H),3.60(t,J＝5.6Hz,1H),3.43(t,J＝7.2Hz,2H),3.15(s,1.5H,N-CH 3),2.97–2.80(m,4.5H),2.65–2.51(m,2H),2.07–1.99(m,1H).HRMS(ESI)m/z:计算值C 40H 37ClN 3O 6S +[M+H] +,722.2086；实测值,722.1727.
实施例179：制备(Z)-N-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-甲基丙酰胺(SIAIS180015)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用拖瑞米芬衍生物A和LIN-ULM(SIAIS151138B)制备得目标化合物(SIAIS180015)(黄色固体,15.7mg,收率46％)。 1H NMR(500MHz,DMSO)δ11.12(d,J＝5.6Hz,1H),7.79–7.70(m,2H),7.60(dd,J＝19.5,6.7Hz,1H),7.40(t,J＝6.9Hz,2H),7.32–7.26(m,3H),7.23–7.20(m,2H),7.18–7.13(m,3H),6.77–6.73(m,1H),6.70(d,J＝8.7Hz,1H),6.63–6.61(m,1H),6.51(d,J＝8.8Hz,1H),5.13-5.09(m,1H),3.94(dd,J＝10.3,5.1Hz,2H),3.64–3.48(m,2H),3.43(t,J＝7.2Hz,2H),3.31–3.25(m,2H),2.95(s,1.5H,N-CH 3),2.92–2.80(m,5.5H),2.71(t,J＝7.1Hz,1H),2.65–2.52(m,2H),2.05-2.01(m,1H).HRMS(ESI)m/z:计算值C 41H 39ClN 3O 6S +[M+H] +,736.2243；实测值,736.1855.
实施例180：制备(Z)-N-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-甲基丁酰胺(SIAIS180016)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用拖瑞米芬衍生物A和LIN-ULM(SIAIS151139B)制备得到目标化合物(SIAIS180016)(黄色固体,17.3mg,收率49％)。 1H NMR(500MHz,DMSO)δ11.12(d,J＝5.5Hz,1H),7.84(dd,J＝8.2,2.6Hz,1H),7.75(td,J＝7.7,4.8Hz,1H),7.61(d,J＝7.4Hz,1H),7.39(dt,J＝7.7,3.7Hz,2H),7.34–7.25(m,3H),7.22(t,J＝7.7Hz,2H),7.18–7.12(m,3H),6.74(d,J＝8.7Hz,2H),6.62(dd,J＝8.7,5.0Hz,2H),5.11(dd,J＝12.8,5.4Hz,1H),3.98(t,J＝5.2Hz,1H),3.93(t,J＝5.7Hz,1H),3.62(t,J＝5.2Hz,1H),3.56(t,J＝5.7Hz,1H),3.43(t,J＝7.1Hz,2H),3.16–3.05(m,2H),2.98(s,1.5H,N-CH 3),2.94–2.80(m,4.5H),2.65–2.52(m,3H),2.45(t,J＝6.9Hz,1H),2.07–1.98(m,1H),1.88–1.84(m,2H).HRMS(ESI)m/z:计算值C 42H 41ClN 3O 6S +[M+H] +,750.2399；实测值,750.2025.
实施例181：制备(Z)-N-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-甲基戊酰胺(SIAIS180017)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用拖瑞米芬衍生物A和LIN-ULM(SIAIS151140B)制备得目标化合物(SIAIS180017)(黄色固体,11.5mg,收率32％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),7.79–7.69(m,2H),7.63–7.58(m,1H),7.39(td,J＝7.5,1.4Hz,2H),7.33–7.25(m,3H),7.23–7.19(m,2H),7.18–7.11(m,3H),6.75–6.72(m,2H),6.65–6.56(m,2H),5.11(dd,J＝12.8,5.4Hz,1H),3.98(t,J＝5.2Hz,1H),3.90(t,J＝5.7Hz,1H),3.60(t,J＝5.2Hz,1H),3.54(t,J＝5.7Hz,1H),3.46–3.37(m,2H),3.18–3.07(m,2H),2.97(s,1.5H,N-CH 3),2.93–2.75(m,4.5H),2.65–2.52(m,2H),2.39–2.36(m,1H),2.31(t,J＝6.8Hz,1H),2.07–1.99(m,1H),1.69–1.64(m,4H).HRMS(ESI)m/z:计算值C 43H 43ClN 3O 6S +[M+H] +,764.2556；实测值,764.2167.
实施例182：制备(Z)-N-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-甲基己酰胺(SIAIS180018)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用拖瑞米芬衍生物A和LIN-ULM(SIAIS151141B)制备得目标化合物(SIAIS180018)(黄色固体,21.7mg,收率60％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),7.75(dt,J＝22.5,7.9Hz,2H),7.62(d,J＝7.2Hz,1H),7.39(t,J＝7.5Hz,2H),7.31–7.27(m,3H),7.25–7.18(m,2H),7.18–7.11(m,3H),6.74(dd,J＝8.7,5.1Hz,2H),6.61(d,J＝8.7Hz,2H),5.18–5.04(m,1H),3.97(t,J＝5.2Hz,1H),3.91(t,J＝5.7Hz,1H),3.60(t,J＝5.2Hz,1H),3.53(t,J＝5.7Hz,1H),3.42(t,J＝7.2Hz,2H),3.15–3.05(m,2H),2.97(s,1.5H,N-CH 3),2.93–2.77(m,4.5H),2.66–2.51(m,2H),2.32(t,J＝7.2Hz,1H),2.25(t,J＝7.2Hz,1H),2.06–1.99(m,1H),1.69–1.62(m,2H),1.57–1.47(m,2H),1.45–1.39(m,2H).HRMS(ESI)m/z:计算值C 44H 45ClN 3O 6S +[M+H] +,778.2712；实测值,778.2304.
实施例183：制备(Z)-N-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-甲基庚酰胺(SIAIS180019)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用拖瑞米芬衍生物A和LIN-ULM(SIAIS151142B)制备得目标化合物(SIAIS180019)(黄色固体,21.7mg,收率59％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),7.81–7.69(m,2H),7.62(dd,J＝6.9,3.0Hz,1H),7.39(t,J＝7.1Hz,2H),7.33–7.25(m,3H),7.25–7.18(m,2H),7.18–7.12(m,3H),6.74(dd,J＝8.5,5.7Hz,2H),6.61(d,J＝8.5Hz,2H),5.11(dd,J＝12.8,5.4Hz,1H),3.97(t,J＝5.2Hz,1H),3.90(t,J＝5.8Hz,1H),3.59(t,J＝5.2Hz,1H),3.53(t,J＝5.7Hz,1H),3.42(t,J＝7.2Hz,2H),3.11–3.06(m,2H),2.96(s,1.5H,N-CH 3),2.93–2.75(m,4.5H),2.66–2.51(m,2H),2.30(t,J＝7.3Hz,1H),2.23(t,J＝7.3Hz,1H),2.07–2.00(m,1H),1.71–1.57(m,2H),1.52–1.41(m,4H),1.35–1.20(m,2H).HRMS(ESI)m/z:计算值C 45H 47ClN 3O 6S +[M+H] +,792.2869；实测值,792.2457.
实施例184：制备N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰胺(SIAIS208146)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用拖瑞米芬衍生物B和LIN-ULM(SIAIS151045)制备得目标化合物(SIAIS208146)(淡黄色固体,10.8mg,收率59％)。 1H NMR(500MHz,DMSO)δ11.11(d,J＝17.0Hz,1H),9.44(d,J＝113.9,1H),8.60–8.45(m,1H),7.73–7.51(m,3H),7.23–7.16(m,3H),7.15-7.10(m,3H),7.06(d,J＝8.5Hz,1H),6.91(d,J＝8.7Hz,1H),6.77(d,J＝8.5Hz,1H),6.71(d,J＝8.8Hz,1H),6.62-6.59(m,1H),6.55(d,J＝8.8Hz,1H),6.43–6.37(m,1H),5.14–5.04(m,1H),3.98(t,J＝5.3Hz,1H),3.88(d,J＝25.7Hz,2H),3.81(t,J＝5.3Hz,1H),3.48–3.45(m,1H),3.42-3.35(m,3H),2.89–2.81(m,3H),2.64–2.51(m,2H),2.04-2.02(m,1H).HRMS(ESI)m/z:计算值C39H35ClN3O7S+[M+H] +,724.1879；实测值,724.1871.
实施例185：制备N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰胺(SIAIS208147)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用拖瑞米芬衍生物B和LIN-ULM(SIAIS151138B)制备得目标化合物(SIAIS208147)(淡黄色固体,9.8mg,收率52％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),9.41(d,J＝111.3Hz,1H),8.33–8.18(m,1H),7.82–7.70(m,2H),7.65–7.58(m,1H),7.23–7.09(m,6H),7.07–7.02(m,1H),6.94(d,J＝8.7Hz,1H),6.78–6.74(m,1H),6.71(d,J＝8.8Hz,1H),6.62–6.55(m,2H),6.42–6.37(m,1H),5.15–5.04(m,1H),4.00(t,J＝5.5Hz,1H),3.83(t,J＝5.5Hz,1H),3.47–3.39(m,4H),3.36-3.27(m,4H),2.92–2.80(m,3H),2.62–2.54(m,2H),2.08–1.98(m,1H).HRMS(ESI)m/z:计算值C40H37ClN3O7S+[M+H] +,738.2035；实测值,738.2031.
实施例186：制备N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰胺(SIAIS208148)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用拖瑞米芬衍生物B和LIN-ULM(SIAIS151139B)制备得目标化合物(SIAIS208148)(淡黄色固体,9.1mg,收率48％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),9.33(d,J＝126.8Hz,1H),8.24–8.02(m,1H),7.81–7.72(m,2H),7.61(d,J＝6.6Hz,1H),7.24–7.10(m,6H),7.05(d,J＝8.5Hz,1H),6.94(d,J＝8.7Hz,1H),6.76(d,J＝8.6Hz,1H),6.71(d,J＝8.8Hz,1H),6.60(dd,J＝8.7,5.7Hz,2H),6.40(d,J＝8.7Hz,1H),5.11(dd,J＝12.8,5.4Hz,1H),4.02(t,J＝5.6Hz,1H),3.84(t,J＝5.6Hz,1H),3.43(dd,J＝12.6,6.4Hz,3H),3.35(s,1H),3.17–3.05(m,2H),2.93–2.82(m,3H),2.63-2.57(m,2H),2.31(t,J＝7.2Hz,1H),2.26(t,J＝7.1Hz,1H),2.07-2.03(m,1H),1.94–1.82(m,2H).HRMS(ESI)m/z:计算值C41H39ClN3O7S+[M+H] +,752.2192；实测值,752.2197.
实施例187：制备N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰胺(SIAIS208152)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用拖瑞米芬衍生物B和LIN-ULM(SIAIS151140B)制备得目标化合物(SIAIS208152)(淡黄色固体,10.6mg,收率54％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),9.52–9.18(m,1H),8.04(dd,J＝36.1,5.4Hz,1H),7.81–7.68(m,2H),7.61(dd,J＝6.6,3.0Hz,1H),7.24–7.08(m,6H),7.05(d,J＝8.5Hz,1H),6.94(d,J＝8.7Hz,1H),6.76(d,J＝8.5Hz,1H),6.72(d,J＝8.8Hz,1H),6.60(dd,J＝8.7,5.2Hz,2H),6.40(d,J＝8.6Hz,1H),5.11(dd,J＝12.9,5.5Hz,1H),4.00(t,J＝5.6Hz,1H),3.82(t,J＝5.6Hz,1H),3.43(dd,J＝9.0,5.9Hz,3H),3.12(dd,J＝13.7,7.0Hz,2H),2.93–2.80(m,3H),2.63–2.51(m,3H),2.16(d,J＝6.7Hz,1H),2.11(d,J＝6.7Hz,1H),2.08–2.01(m,1H),1.65(d,J＝13.2Hz,4H).HRMS(ESI)m/z:计算值C42H41ClN3O7S+[M+H] +,766.2348；实测值,766.2341.
实施例188：制备N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰胺(SIAIS208153)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用拖瑞米芬衍生物B和LIN-ULM(SIAIS151141B)制备得目标化合物(SIAIS208153)(淡黄色固体,9.6mg,收率 48％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),9.33(d,J＝126.6Hz,1H),8.02(d,J＝41.0Hz,1H),7.79–7.74(m,1H),7.73–7.69(m,1H),7.62(d,J＝7.0Hz,1H),7.15(ddd,J＝45.8,24.1,18.2Hz,6H),7.05(d,J＝8.6Hz,1H),6.95(d,J＝8.7Hz,1H),6.76(d,J＝8.5Hz,1H),6.71(d,J＝8.8Hz,1H),6.59(dd,J＝8.7,2.0Hz,2H),6.40(d,J＝8.7Hz,1H),5.11(dd,J＝12.8,5.3Hz,1H),4.00(t,J＝5.7Hz,1H),3.82(t,J＝5.6Hz,1H),3.42(d,J＝3.1Hz,3H),3.08(dd,J＝17.7,7.7Hz,2H),2.87(dd,J＝12.8,6.3Hz,3H),2.56(dd,J＝31.2,14.1Hz,3H),2.18(t,J＝8.1Hz,1H),2.11(t,J＝7.3Hz,1H),2.05(d,J＝7.2Hz,1H),1.65(d,J＝6.4Hz,2H),1.52(d,J＝12.9Hz,2H),1.42(s,2H).HRMS(ESI)m/z:计算值C43H43ClN3O7S+[M+H] +,780.2505；实测值,780.2501.
实施例189：制备N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰胺(SIAIS208154)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用拖瑞米芬衍生物B和LIN-ULM(SIAIS151142B)制备得目标化合物(SIAIS208154)(淡黄色固体,10.2mg,收率51％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),9.49–9.18(m,1H),8.08–7.92(m,1H),7.80–7.69(m,2H),7.62(d,J＝6.9Hz,1H),7.25–7.07(m,6H),7.05(d,J＝8.6Hz,1H),6.94(d,J＝8.7Hz,1H),6.76(d,J＝8.6Hz,1H),6.71(d,J＝8.8Hz,1H),6.62–6.57(m,2H),6.42–6.38(m,1H),5.11(dd,J＝12.9,5.4Hz,1H),3.99(t,J＝5.6Hz,1H),3.82(t,J＝5.6Hz,1H),3.42(t,J＝6.0Hz,3H),3.09(dd,J＝14.5,7.2Hz,2H),2.93–2.82(m,3H),2.62–2.52(m,3H),2.10(t,J＝7.4Hz,1H),2.05(t,J＝7.4Hz,2H),1.69–1.58(m,2H),1.55–1.37(m,4H),1.33–1.21(m,2H).HRMS(ESI)m/z:计算值C44H45ClN3O7S+[M+H] +,794.2661；实测值,794.2667.
实施例190：制备N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰胺(SIAIS208155)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用拖瑞米芬衍生物B和LIN-ULM(SIAIS171090)制备得目标化合物(SIAIS208155)(淡黄色固体,7.0mg,收率39％)。 1H NMR(500MHz,DMSO)δ10.99(s,1H),9.34(d,J＝125.8Hz,2H),8.40(d,J＝41.7Hz,1H),7.57(ddd,J＝20.3,19.2,7.0Hz,2H),7.38(dt,J＝26.5,7.6Hz,1H),7.24–7.10(m,6H),7.07(d,J＝8.5Hz,1H),6.93(d,J＝8.8Hz,1H),6.77(d,J＝8.6Hz,1H),6.73(d,J＝8.8Hz,1H),6.62(d,J＝8.6Hz,1H),6.58(d,J＝8.9Hz,1H),6.41(d,J＝8.7Hz,1H),5.17–5.08(m,1H),4.39(dd,J＝17.5,12.0Hz,1H),4.25(dd,J＝17.5,12.1Hz,1H),3.95(d,J＝5.2Hz,1H),3.79(s,2H),3.74(s,1H),3.44(t,J＝7.4Hz,3H),3.30–3.24(m,2H),2.88(dd,J＝16.5,7.4Hz,3H),2.59(d,J＝18.2Hz,1H),1.98(s,1H).HRMS(ESI)m/z:计算值C39H37ClN3O6S+[M+H] +,710.2086；实测值,710.2082.
实施例191：制备N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙酰胺(SIAIS208156)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用拖瑞米芬衍生物B和LIN-ULM(SIAIS171086)制备得目标化合物(SIAIS208156)(淡黄色固体,7.3mg,收率 40％)。 1H NMR(500MHz,DMSO)δ10.98(s,1H),9.34(d,J＝126.0Hz,2H),8.17(d,J＝42.5Hz,1H),7.68–7.49(m,3H),7.16(ddd,J＝11.6,10.0,5.9Hz,6H),7.05(d,J＝8.5Hz,1H),6.94(d,J＝8.7Hz,1H),6.76(d,J＝8.5Hz,1H),6.72(d,J＝8.8Hz,1H),6.59(dd,J＝8.7,6.4Hz,2H),6.40(d,J＝8.7Hz,1H),5.11(d,J＝13.4Hz,1H),4.34(dd,J＝17.4,11.0Hz,1H),4.21(dd,J＝17.5,10.5Hz,1H),3.99(s,1H),3.82(s,1H),3.42(s,3H),3.24(dd,J＝19.7,6.9Hz,4H),2.93–2.82(m,3H),2.56(d,J＝25.5Hz,3H),1.99(s,1H).HRMS(ESI)m/z:计算值C40H39ClN3O6S+[M+H] +,724.2243；实测值,724.2242.
实施例192：制备N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁酰胺(SIAIS208157)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用拖瑞米芬衍生物B和LIN-ULM(SIAIS171089)制备得目标化合物(SIAIS208157)(淡黄色固体,8.4mg,收率45％)。 1H NMR(500MHz,DMSO)δ10.99(s,1H),9.33(d,J＝126.5Hz,2H),8.08(d,J＝42.4Hz,1H),7.56(ddt,J＝36.6,16.5,7.7Hz,3H),7.25–7.08(m,6H),7.06(d,J＝8.5Hz,1H),6.94(d,J＝8.7Hz,1H),6.76(d,J＝8.6Hz,1H),6.71(d,J＝8.8Hz,1H),6.59(t,J＝8.8Hz,2H),6.40(d,J＝8.7Hz,1H),5.12(dd,J＝13.1,5.6Hz,1H),4.35(dd,J＝17.5,6.3Hz,1H),4.21(dd,J＝17.4,6.4Hz,1H),4.00(t,J＝5.5Hz,1H),3.83(t,J＝5.6Hz,1H),3.46–3.39(m,3H),3.10–3.01(m,2H),2.95–2.82(m,3H),2.58(d,J＝17.0Hz,1H),2.44(s,2H),2.27(t,J＝7.2Hz,1H),2.22(t,J＝7.2Hz,1H),1.99(s,1H),1.87–1.74(m,2H).HRMS(ESI)m/z:计算值C41H41ClN3O6S+[M+H] +,738.2399；实测值,738.2389.
实施例193：制备N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酰胺(SIAIS208158)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用拖瑞米芬衍生物B和LIN-ULM(SIAIS171079)制备得目标化合物(SIAIS208158)(淡黄色固体,7.6mg,收率40％)。 1H NMR(500MHz,DMSO)δ10.98(s,1H),9.34(d,J＝126.4Hz,2H),8.02(d,J＝41.5Hz,1H),7.64–7.47(m,3H),7.17(ddd,J＝18.7,10.8,5.7Hz,6H),7.06(d,J＝8.5Hz,1H),6.94(d,J＝8.7Hz,1H),6.76(d,J＝8.5Hz,1H),6.72(d,J＝8.8Hz,1H),6.59(t,J＝8.9Hz,2H),6.40(d,J＝8.7Hz,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.35(dd,J＝17.6,4.9Hz,1H),4.21(dd,J＝17.5,4.8Hz,1H),3.98(t,J＝5.6Hz,1H),3.81(t,J＝5.6Hz,1H),3.45–3.38(m,3H),3.06(dt,J＝13.8,7.0Hz,2H),2.88(dt,J＝13.1,12.2Hz,3H),2.58(d,J＝18.7Hz,1H),2.45(s,2H),2.13(t,J＝7.1Hz,1H),2.08(t,J＝7.2Hz,1H),2.01(s,1H),1.70–1.50(m,4H).HRMS(ESI)m/z:计算值C42H43ClN3O6S+[M+H] +,752.2556；实测值,752.2566.
实施例194：制备N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰胺(SIAIS208159)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用拖瑞米芬衍生物B和LIN-ULM(SIAIS171091)制备得目标化合物(SIAIS208159)(淡黄色固体,8.7mg,收率 45％)。 1H NMR(500MHz,DMSO)δ10.98(s,1H),9.33(d,J＝126.4Hz,1H),8.02(dd,J＝26.4,20.6Hz,1H),7.63–7.47(m,3H),7.24–7.07(m,6H),7.05(d,J＝8.5Hz,1H),6.94(d,J＝8.7Hz,1H),6.76(d,J＝8.6Hz,1H),6.71(d,J＝8.8Hz,1H),6.59(dd,J＝8.7,5.5Hz,2H),6.40(d,J＝8.7Hz,1H),5.12(dd,J＝13.4,5.1Hz,1H),4.34(dd,J＝17.4,3.6Hz,1H),4.20(dd,J＝17.5,3.6Hz,1H),3.99(t,J＝5.5Hz,1H),3.82(t,J＝5.7Hz,1H),3.42(dd,J＝11.3,7.1Hz,3H),3.04(dd,J＝17.1,7.3Hz,2H),2.94–2.81(m,3H),2.58(d,J＝16.9Hz,1H),2.49–2.39(m,2H),2.09(t,J＝7.2Hz,1H),2.06–1.96(m,2H),1.62–1.43(m,4H),1.37(dd,J＝16.9,8.4Hz,2H).HRMS(ESI)m/z:计算值C43H45ClN3O6S+[M+H] +,766.2712；实测值,766.2712.
实施例195：制备N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)庚酰胺(SIAIS208160)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用拖瑞米芬衍生物B和LIN-ULM(SIAIS171092)制备得目标化合物(SIAIS208160)(淡黄色固体,9.3mg,收率47％)。 1H NMR(500MHz,DMSO)δ10.98(s,1H),9.48–9.18(m,1H),7.98(dt,J＝41.9,5.5Hz,1H),7.63–7.48(m,3H),7.24–7.08(m,6H),7.05(d,J＝8.5Hz,1H),6.94(d,J＝8.7Hz,1H),6.76(d,J＝8.6Hz,1H),6.71(d,J＝8.8Hz,1H),6.59(t,J＝8.5Hz,2H),6.42–6.38(m,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.34(d,J＝17.4Hz,1H),4.21(d,J＝17.2Hz,1H),3.99(t,J＝5.6Hz,1H),3.81(t,J＝5.6Hz,1H),3.47–3.38(m,3H),3.04(dd,J＝14.4,7.2Hz,2H),2.95–2.81(m,3H),2.58(d,J＝18.3Hz,1H),2.49–2.39(m,2H),2.08(t,J＝7.4Hz,1H),2.05–1.97(m,2H),1.62–1.52(m,2H),1.51–1.42(m,2H),1.37(dt,J＝14.7,7.8Hz,2H),1.29–1.17(m,2H).HRMS(ESI)m/z:计算值C44H47ClN3O6S+[M+H] +,780.2869；实测值,780.2869.
实施例196：制备N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰胺(SIAIS251128)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用他莫昔芬衍生物A和LIN-ULM(SIAIS151045)制备得目标化合物(SIAIS251128)(淡黄色固体,8.7mg,收率46％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),9.36-9.13(m,2H),8.22(dt,J＝34.2,5.4Hz,1H),7.83–7.72(m,2H),7.68–7.60(m,1H),7.05(d,J＝8.6Hz,1H),6.92(dd,J＝11.3,8.6Hz,2H),6.87(dd,J＝8.4,1.4Hz,2H),6.71(dd,J＝11.8,8.7Hz,2H),6.63–6.52(m,4H),6.41(d,J＝8.6Hz,1H),5.11(ddd,J＝12.8,5.4,2.2Hz,1H),3.99(t,J＝5.5Hz,1H),3.85(t,J＝5.5Hz,1H),3.44(dt,J＝16.1,7.9Hz,1H),2.94–2.82(m,1H),2.64–2.53(m,4H),2.33(td,J＝14.3,6.9Hz,2H),2.04(dd,J＝14.8,9.3Hz,1H),0.83(td,J＝7.3,3.0Hz,3H).HRMS(ESI)m/z:计算值C39H36N3O8S+[M+H] +,706.2218；实测值,706.2216.
实施例197：制备N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰胺(SIAIS251129)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用他莫昔芬衍生物A和LIN-ULM(SIAIS151138B)制备得目标化合物(SIAIS251129)(淡黄色固体,9.0mg,收率 47％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),9.37-9.13(m,2H),8.51(dt,J＝35.6,5.5Hz,1H),7.76–7.60(m,2H),7.57(dd,J＝6.9,3.3Hz,1H),7.05(d,J＝8.6Hz,1H),6.94(d,J＝8.5Hz,1H),6.89(t,J＝8.3Hz,3H),6.72(dd,J＝12.2,8.7Hz,2H),6.63–6.53(m,4H),6.44–6.39(m,1H),5.12(ddd,J＝12.8,5.4,2.0Hz,1H),3.99(t,J＝5.3Hz,1H),3.90(d,J＝17.5Hz,2H),3.85(t,J＝5.3Hz,1H),3.47(dd,J＝10.6,5.2Hz,1H),3.42–3.36(m,2H),2.96–2.83(m,1H),2.66–2.51(m,3H),2.41–2.29(m,2H),2.05(dd,J＝13.7,6.6Hz,1H),0.92–0.79(m,3H).HRMS(ESI)m/z:计算值C40H38N3O8S+[M+H] +,720.2374；实测值,720.2371.
实施例198：制备N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰胺(SIAIS251130)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用他莫昔芬衍生物A和LIN-ULM(SIAIS151139B)制备得目标化合物(SIAIS251130)(淡黄色固体,8.9mg,收率46％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),9.36-9.13(m,2H),8.13(dt,J＝36.3,5.4Hz,1H),7.80–7.71(m,2H),7.61(d,J＝6.5Hz,1H),7.04(d,J＝8.5Hz,1H),6.96–6.84(m,4H),6.71(dd,J＝15.5,8.6Hz,2H),6.61–6.52(m,4H),6.41(d,J＝8.6Hz,1H),5.11(dd,J＝12.8,5.4Hz,1H),4.00(t,J＝5.5Hz,1H),3.85(t,J＝5.5Hz,1H),3.44(dd,J＝10.8,5.4Hz,1H),3.17–3.05(m,2H),2.93-2.85(m,1H),2.65–2.51(m,3H),2.39–2.23(m,4H),2.05(dd,J＝13.6,8.1Hz,1H),1.95–1.82(m,2H),0.85-0.81(m,3H).HRMS(ESI)m/z:计算值C41H40N3O8S+[M+H] +,734.2531；实测值,734.2535.
实施例199：制备N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰胺(SIAIS251131)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用他莫昔芬衍生物A和LIN-ULM(SIAIS151140B)制备得目标化合物(SIAIS251131)(淡黄色固体,9.8mg,收率49％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),9.36-9.13(m,2H),8.04(dt,J＝35.4,5.5Hz,1H),7.79–7.69(m,2H),7.61(dd,J＝6.9,2.2Hz,1H),7.04(d,J＝8.5Hz,1H),6.96–6.84(m,4H),6.71(dd,J＝12.4,8.6Hz,2H),6.60-6.54(m,4H),6.40(d,J＝8.5Hz,1H),5.11(dd,J＝12.8,5.4Hz,1H),3.98(t,J＝5.5Hz,1H),3.83(t,J＝5.6Hz,1H),3.42(dd,J＝11.0,5.5Hz,1H),3.17–3.06(m,2H),2.94–2.82(m,1H),2.65–2.51(m,3H),2.36-2.30(m,2H),2.14(dt,J＝17.9,6.7Hz,2H),2.05(dd,J＝14.9,7.8Hz,1H),1.73–1.58(m,4H),0.85-0.81(m,3H).HRMS(ESI)m/z:计算值C42H42N3O8S+[M+H] +,748.2687；实测值,748.2690.
实施例200：制备N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰胺(SIAIS251132)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用他莫昔芬衍生物A和LIN-ULM(SIAIS151141B)制备得目标化合物(SIAIS251132)(淡黄色固体,10.5mg,收率52％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),9.36-9.13(m,2H),8.02(dt,J＝34.7,5.5Hz,1H),7.80–7.74(m,1H),7.71(dd,J＝7.7,4.4Hz,1H),7.61(d,J＝7.2Hz,1H),7.03(d,J＝8.7Hz, 1H),6.91(dd,J＝10.4,8.6Hz,2H),6.86(d,J＝8.5Hz,2H),6.75–6.66(m,2H),6.60-6.53(m,4H),6.43–6.38(m,1H),5.11(dd,J＝12.8,5.4Hz,1H),3.98(t,J＝5.5Hz,1H),3.83(t,J＝5.6Hz,1H),3.41(dd,J＝11.1,5.6Hz,1H),3.08(dd,J＝14.3,7.0Hz,2H),2.94–2.82(m,1H),2.66–2.51(m,3H),2.33(td,J＝14.2,6.9Hz,2H),2.12-2.02(m,3H),1.71–1.60(m,2H),1.58-1.49(m,2H),1.46–1.35(m,2H),0.85-0.81(m,3H).HRMS(ESI)m/z:计算值C43H44N3O8S+[M+H] +,762.2844；实测值,762.2843.
实施例201：制备N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰胺(SIAIS208170)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用他莫昔芬衍生物A和LIN-ULM(SIAIS151142B)制备得目标化合物(SIAIS208170)(淡黄色固体,10.1mg,收率49％)。 1H NMR(500MHz,DMSO)δ11.12(s,1H),9.36-9.12(m,2H),8.00(dt,J＝35.5,5.5Hz,1H),7.80–7.74(m,1H),7.72(dd,J＝7.8,3.0Hz,1H),7.61(d,J＝7.0Hz,1H),7.04(d,J＝8.6Hz,1H),6.96–6.89(m,2H),6.86(d,J＝8.5Hz,2H),6.75–6.66(m,2H),6.62–6.52(m,4H),6.43–6.38(m,1H),5.11(dd,J＝12.8,5.4Hz,1H),3.97(t,J＝5.6Hz,1H),3.83(t,J＝5.6Hz,1H),3.44–3.40(m,1H),3.31(d,J＝5.6Hz,1H),3.09(dd,J＝11.9,7.2Hz,2H),2.95–2.80(m,1H),2.63–2.55(m,1H),2.53–2.51(m,1H),2.38–2.27(m,2H),2.14–1.99(m,3H),1.67-1.60(m,2H),1.55–1.37(m,4H),1.31-1.24(m,2H),0.83(td,J＝7.4,3.9Hz,3H).HRMS(ESI)m/z:计算值C44H46N3O8S+[M+H] +,776.3000；实测值,776.3003.
实施例202：制备N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰胺(SIAIS251133)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用他莫昔芬衍生物A和LIN-ULM(SIAIS171090)制备得目标化合物(SIAIS251133)(淡黄色固体,7.8mg,收率42％)。 1H NMR(500MHz,DMSO)δ10.99(s,1H),9.37-9.14(m,2H),8.40(dt,J＝35.2,5.4Hz,1H),7.61(dd,J＝19.5,7.8Hz,1H),7.53(dd,J＝7.5,3.3Hz,1H),7.38(dt,J＝18.5,7.7Hz,1H),7.06(d,J＝8.5Hz,1H),6.95(d,J＝8.3Hz,1H),6.88(dd,J＝8.6,2.2Hz,3H),6.76–6.69(m,2H),6.62–6.52(m,4H),6.41(d,J＝8.5Hz,1H),5.12(ddd,J＝13.3,4.9,2.6Hz,1H),4.39(dd,J＝17.4,8.1Hz,1H),4.25(dd,J＝17.4,8.7Hz,1H),3.94(t,J＝5.3Hz,1H),3.84–3.72(m,3H),3.44(dd,J＝10.7,5.3Hz,1H),3.36(dd,J＝10.4,4.9Hz,1H),2.95–2.85(m,1H),2.59(d,J＝17.4Hz,1H),2.48–2.39(m,1H),2.39–2.29(m,2H),2.00-1.98(m,1H),0.84(t,J＝7.3Hz,3H).HRMS(ESI)m/z:计算值C39H38N3O7S+[M+H] +,692.2425；实测值,692.2424.
实施例203：制备N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙酰胺(SIAIS251134)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用他莫昔芬衍生物A和LIN-ULM(SIAIS171086)制备得目标化合物(SIAIS251134)(淡黄色固体,9.0mg,收率48％)。 1H NMR(500MHz,DMSO)δ10.98(s,1H),9.36-9.13(m,2H),8.17(dt,J＝34.8,5.3Hz, 1H),7.65(dd,J＝10.4,7.7Hz,1H),7.58(dd,J＝7.4,3.9Hz,1H),7.52(dd,J＝15.2,7.6Hz,1H),7.04(d,J＝8.6Hz,1H),6.94-6.86(m,4H),6.71(dd,J＝12.9,8.7Hz,2H),6.62–6.51(m,4H),6.41(d,J＝8.6Hz,1H),5.21–4.99(m,1H),4.34(dd,J＝17.4,6.6Hz,1H),4.21(dd,J＝17.4,7.2Hz,1H),3.97(t,J＝5.4Hz,1H),3.83(t,J＝5.4Hz,1H),3.47–3.39(m,1H),3.25(dt,J＝14.5,7.1Hz,2H),2.96–2.84(m,1H),2.58(d,J＝17.5Hz,1H),2.45(dt,J＝18.3,7.2Hz,4H),2.38–2.28(m,2H),2.00-1.98(m,1H),0.83(td,J＝7.3,3.0Hz,3H).HRMS(ESI)m/z:计算值C40H40N3O7S+[M+H] +,706.2581；实测值,706.2581.
实施例204：制备N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁酰胺(SIAIS251135)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用他莫昔芬衍生物A和LIN-ULM(SIAIS171089)制备得目标化合物(SIAIS251135)(淡黄色固体,8.6mg,收率45％)。 1H NMR(500MHz,DMSO)δ10.99(s,1H),9.36-9.13(m,2H),8.08(dt,J＝36.1,5.5Hz,1H),7.62(td,J＝7.6,0.9Hz,1H),7.55(dd,J＝6.3,1.3Hz,1H),7.50(dd,J＝14.4,7.4Hz,1H),7.08–7.01(m,1H),6.96–6.84(m,4H),6.75–6.67(m,2H),6.61–6.57(m,2H),6.56–6.52(m,2H),6.44–6.37(m,1H),5.12(dd,J＝13.3,5.0Hz,1H),4.35(dd,J＝17.4,4.1Hz,1H),4.21(dd,J＝17.4,4.4Hz,1H),3.98(t,J＝5.6Hz,1H),3.84(t,J＝5.6Hz,1H),3.42(q,J＝5.5Hz,1H),3.10–3.01(m,2H),2.96–2.84(m,1H),2.58(d,J＝17.7Hz,1H),2.48–2.40(m,1H),2.38–2.30(m,2H),2.25(dt,J＝18.3,7.2Hz,2H),2.05–1.94(m,1H),1.88–1.72(m,2H),0.83(td,J＝7.4,3.0Hz,3H).HRMS(ESI)m/z:计算值C41H42N3O7S+[M+H] +,720.2738；实测值,720.2735.
实施例205：制备N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰胺(SIAIS251137)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用他莫昔芬衍生物A和LIN-ULM(SIAIS171091)制备得目标化合物(SIAIS251137)(淡黄色固体,9.9mg,收率50％)。 1H NMR(500MHz,DMSO)δ10.98(s,1H),9.40–9.08(m,2H),8.00(dt,J＝35.1,5.5Hz,1H),7.60(ddd,J＝7.6,3.4,1.0Hz,1H),7.56(d,J＝6.7Hz,1H),7.51(td,J＝7.5,1.8Hz,1H),7.04(d,J＝8.7Hz,1H),6.91(dd,J＝13.7,8.6Hz,2H),6.86(dd,J＝8.5,1.4Hz,2H),6.71(dd,J＝15.8,8.7Hz,2H),6.62–6.52(m,4H),6.43–6.37(m,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.34(dd,J＝17.4,1.5Hz,1H),4.20(dd,J＝17.4,2.0Hz,1H),3.97(t,J＝5.6Hz,1H),3.83(t,J＝5.6Hz,1H),3.40(q,J＝5.6Hz,1H),3.04(dd,J＝14.0,6.9Hz,2H),2.96–2.84(m,1H),2.64–2.53(m,1H),2.48–2.39(m,1H),2.36-2.29(m,2H),2.13–2.02(m,2H),2.02–1.94(m,1H),1.61-1.45(m,4H),1.41-1.32(m,2H),0.83(td,J＝7.4,4.5Hz,3H).HRMS(ESI)m/z:计算值C43H46N3O7S+[M+H] +,748.3051；实测值,748.3050.
实施例206：制备N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)庚酰胺(SIAIS208171)
根据方案32所述通用方法，在本领域可理解的适当条件下，采用他莫昔芬衍生物A和LIN-ULM(SIAIS171092)制备得目标化合物(SIAIS208171)(淡黄色固体,8.9mg,收率44％)。 1H NMR(500MHz,DMSO)δ10.98(s,1H),9.36-9.13(m,2H),7.98(dt,J＝35.4,5.4Hz,1H),7.63–7.58(m,1H),7.55(d,J＝6.6Hz,1H),7.51(dt,J＝8.9,4.4Hz,1H),7.04(d,J＝8.6Hz,1H),6.96–6.84(m,4H),6.76–6.67(m,2H),6.59-6.54(m,4H),6.41(d,J＝8.6Hz,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.34(d,J＝17.4Hz,1H),4.21(d,J＝17.4Hz,1H),3.97(t,J＝5.5Hz,1H),3.83(t,J＝5.6Hz,1H),3.40(dd,J＝11.1,5.5Hz,1H),3.04(dd,J＝11.8,7.2Hz,2H),2.97–2.83(m,1H),2.58(d,J＝17.5Hz,1H),2.48–2.39(m,1H),2.36-2.30(m,2H),2.12–1.95(m,3H),1.62–1.52(m,2H),1.52–1.32(m,4H),1.28-1.21(m,2H),0.83(td,J＝7.3,3.5Hz,3H).HRMS(ESI)m/z:计算值C44H48N3O7S+[M+H] +,762.3207；实测值,762.3202.
BRD4靶点的一系列降解剂通用的合成方法:
Figure PCTCN2019081840-appb-000256
根据方案33，室温下，在反应瓶中，加入相应的JQ-1衍生物A(1equiv)，相应的LIN-ULM(1equiv),1-羟基-7-偶氮苯并三氮唑(2equiv),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(2equiv),无水N,N-二甲基甲酰胺(2mL)，N-甲基吗啡啉(5equiv)，室温下搅拌反应过夜。LC-MS检测反应结束后，HPLC制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)。旋蒸除去乙腈，冻干后得相应的最终降解剂化合物。
实施例207：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚烷-6-基)-N-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙基)乙酰胺(SIAIS171036)
根据方案33所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物A(SIAIS171018)和LIN-ULM(SIAIS171026)制备得目标化合物(SIAIS171036)(淡黄色固体,11.0mg,收率41％)。 1H NMR(500MHz,MeOD)δ7.82(d,J＝8.1Hz,1H),7.73(t,J＝7.7Hz,1H),7.62(d,J＝7.2Hz,1H),7.53(dd,J＝8.4,5.0Hz,2H),7.41(d,J＝8.7Hz,2H),5.14–5.03(m,1H),4.88–4.86(m,1H),3.61(t,J＝6.5Hz,2H),3.45–3.40(m,1H),3.38–3.35(m,1H),3.33(t,J＝6.4Hz,2H),2.92(s,3H),2.88–2.80(m,1H),2.78–2.59(m,2H),2.46(s,3H),2.13–2.06(m,1H),1.73(s,3H).HRMS(ESI)m/z:计算值C 34H 31ClN 7O 5S 2 +[M+H] +,716.1511；实测值,716.1228.
实施例208：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚烷-6-基)-N-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙基)乙酰胺(SIAIS171013)
根据方案33所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物A(SIAIS171018)和LIN-ULM(SIAIS171025)制备得目标化合物(SIAIS171013)(淡黄色固体,5.2mg,收率25％)。 1H NMR(500MHz,MeOD)δ7.71–7.66(m,2H),7.62–7.56(m,1H),7.47(d,J＝8.4Hz,2H),7.40(dd,J＝8.8,2.3Hz,2H),5.13–5.08(m,1H),4.82–4.78(m,1H),3.51–3.40(m,3H),3.38–3.34(m,1H),3.21–3.18(m,2H),2.91–2.83(m,1H),2.81(s,3H),2.78–2.67(m,2H),2.47(s,3H),2.16–2.08(m,1H),2.05–1.96(m,2H),1.69(s,3H).HRMS(ESI)m/z:计算值C 35H 33ClN 7O 5S 2 +[M+H] +,730.1668；实测值,730.2598.
实施例209：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚烷-6-基)-N-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁基)乙酰胺(SIAIS171037)
根据方案33所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物A(SIAIS171018)和LIN-ULM(SIAIS171023)制备得目标化合物(SIAIS171037)(淡黄色固体,13.0mg,收率47％)。 1H NMR(500MHz,MeOD)δ7.74–7.66(m,2H),7.62–7.55(m,1H),7.51(d,J＝8.2Hz,2H),7.45(d,J＝8.7Hz,2H),5.12–5.08(m,1H),4.93–4.90(m,1H),3.46(dd,J＝15.3,8.7Hz,1H),3.40–3.32(m,3H),3.15(t,J＝6.9Hz,2H),2.91–2.81(m,4H),2.78–2.64(m,2H),2.48(s,3H),2.17–2.06(m,1H),1.85–1.75(m,4H),1.70(s,3H).HRMS(ESI)m/z:计算值C 36H 35ClN 7O 5S 2 +[M+H] +,744.1824；实测值,744.1507.
实施例210：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚烷-6-基)-N-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊基)乙酰胺(SIAIS171038)
根据方案33所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物A(SIAIS171018)和LIN-ULM(SIAIS171027)制备得目标化合物(SIAIS171038)(淡黄色固体,5.3mg,收率19％)。 1H NMR(500MHz,MeOD)δ7.72–7.68(m,2H),7.58(d,J＝7.0Hz,1H),7.51–7.45(m,4H),5.11–5.03(m,1H),4.82–4.80(m,1H),3.48–3.41(m,1H),3.36–3.31(m,3H),3.14–3.09(m,2H),2.86–2.82(m,4H),2.77–2.62(m,2H),2.47(s,3H),2.15–2.08(m,1H),1.85–1.78(m,2H),1.70(s,3H),1.67–1.54(m,4H).HRMS(ESI)m/z:计算值C 37H 37ClN 7O 5S 2 +[M+H] +,758.1981；实测值,758.1658.
实施例211：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚烷-6-基)-N-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己基)乙酰胺(SIAIS171039)
根据方案33所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物A(SIAIS171018)和LIN-ULM(SIAIS171028)制备得目标化合物(SIAIS171039)(淡黄色固体,9.0 mg,收率31％)。 1H NMR(500MHz,MeOD)δ7.71–7.61(m,2H),7.57(d,J＝7.0Hz,1H),7.43(dd,J＝24.3,8.6Hz,4H),5.13–5.08(m,1H),4.70–4.68(m,1H),3.45–3.38(m,1H),3.30–3.25(m,3H),3.09(t,J＝7.3Hz,2H),2.88–2.82(m,1H),2.79–2.65(m,5H),2.44(s,3H),2.15–2.08(m,1H),1.78–1.67(m,5H),1.62–1.55(m,4H),1.48–1.40(m,2H).HRMS(ESI)m/z:计算值C 38H 39ClN 7O 5S 2 +[M+H] +,772.2137；实测值,772.1789.
实施例212：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚烷-6-基)-N-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚基)乙酰胺(SIAIS171040)
根据方案33所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物A(SIAIS171018)和LIN-ULM(SIAIS171033)制备得目标化合物(SIAIS171040)(淡黄色固体,15.0mg,收率51％)。 1H NMR(500MHz,MeOD)δ7.75–7.63(m,2H),7.58(d,J＝6.8Hz,1H),7.51–7.45(m,4H),5.13–5.06(m,1H),4.92–4.90(m,1H),3.49–3.41(m,1H),3.38–3.33(m,1H),3.30–3.24(m,2H),3.09(t,J＝7.1Hz,2H),2.96–2.80(m,4H),2.78–2.64(m,2H),2.47(s,3H),2.13–2.10(m,1H),1.80–1.68(m,5H),1.60–1.48(m,4H),1.45–1.35(m,4H).HRMS(ESI)m/z:计算值C 39H 41ClN 7O 5S 2 +[M+H] +,786.2294；实测值,786.1950.
实施例213：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚烷-6-基)-N-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)辛基)乙酰胺(SIAIS171049)
根据方案33所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物A(SIAIS171018)和LIN-ULM(SIAIS171047)制备得目标化合物(SIAIS171049)(淡黄色固体,10.0mg,收率33％)。 1H NMR(500MHz,MeOD)δ7.73–7.63(m,2H),7.58–7.54(m,1H),7.46–7.38(m,4H),5.14–5.08(m,1H),4.65–4.62(m,1H),3.45–3.37(m,1H),3.29–3.18(m,3H),3.09(t,J＝7.3Hz,2H),2.90–2.81(m,1H),2.78–2.66(m,5H),2.43(s,3H),2.16–2.08(m,1H),1.77–1.65(m,5H),1.55–1.45(m,4H),1.40–1.32(m,6H).HRMS(ESI)m/z:计算值C 40H 43ClN 7O 5S 2 +[M+H] +,800.2450；实测值,800.0319.
实施例214：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚烷-6-基)-N-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙基)乙酰胺(SIAIS171138)
根据方案33所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物A(SIAIS171018)和LIN-ULM(SIAIS171123)制备得目标化合物(SIAIS171138)(淡黄色固体,10.0mg,收率38％)。 1H NMR(500MHz,MeOD)δ7.78–7.76(m,1H),7.66(dd,J＝7.7,7.0Hz,1H),7.55–7.52(m,3H),7.44(dd,J＝8.9,1.6Hz,2H),5.15–5.12(m,1H),4.83–4.80(m,1H),4.44(q,J＝17.3Hz,2H),3.57–3.49(m,2H),3.45–3.33(m,2H),3.29–3.20(m,2H),2.94–2.83(m,4H),2.79–2.71(m,1H),2.54–2.38(m,4H),2.20–2.09(m,1H),1.72(s,3H).HRMS(ESI)m/z:计算值C 34H 33ClN 7O 4S 2 +[M+H] +,702.1718；实测值,701.9827.
实施例215：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚烷-6-基)-N-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙基)乙酰胺(SIAIS171139)
根据方案33所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物A(SIAIS171018)和LIN-ULM(SIAIS171124)制备得目标化合物(SIAIS171139)(淡黄色固体,8.0mg,收率30％)。 1H NMR(500MHz,MeOD)δ7.69–7.61(m,2H),7.54–7.38(m,5H),5.16–5.13(m,1H),4.82–4.77(m,1H),4.44–4.40(m,2H),3.77–3.64(m,1H),3.49–3.37(m,3H),3.18–3.08(m,2H),2.91–2.81(m,4H),2.79–2.68(m,1H),2.56–2.42(m,4H),2.17–2.13(m,1H),1.97–1.85(m,2H),1.71(s,3H).HRMS(ESI)m/z:计算值C 35H 35ClN 7O 4S 2 +[M+H] +,716.1875；实测值,715.9937.
实施例216：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚烷-6-基)-N-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)乙酰胺(SIAIS171141)
根据方案33所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物A(SIAIS171018)和LIN-ULM(SIAIS171131)制备得目标化合物(SIAIS171141)(淡黄色固体,10.0mg,收率37％)。 1H NMR(500MHz,MeOD)δ7.72–7.60(m,2H),7.52–7.46(m,5H),5.17–5.04(m,1H),4.81–4.75(m,1H),4.42–4.36(m,2H),3.73–3.69(m,1H),3.47–3.34(m,1H),3.26–3.22(m,2H),3.17–3.02(m,2H),2.91–2.82(m,4H),2.78–2.68(m,1H),2.52–2.40(m,4H),2.20–2.09(m,1H),1.73–1.71(m,7H).HRMS(ESI)m/z:计算值C 36H 37ClN 7O 4S 2 +[M+H] +,730.2031；实测值,730.1548.
实施例217：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚烷-6-基)-N-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊基)乙酰胺(SIAIS171142)
根据方案33所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物A(SIAIS171018)和LIN-ULM(SIAIS171132)制备得目标化合物(SIAIS171142)(淡黄色固体,14.0mg,收率50％)。 1H NMR(500MHz,MeOD)δ7.61(dd,J＝7.8,3.9Hz,2H),7.48–7.42(m,5H),5.15–5.11(m,1H),4.76–4.72(m,1H),4.42–4.38(m,2H),3.46–3.34(m,2H),3.28–3.21(m,2H),3.07(t,J＝7.1Hz,2H),2.91–2.87(m,1H),2.79–2.62(m,4H),2.50–2.42(m,4H),2.18–2.10(m,1H),1.72–1.65(m,5H),1.60–1.51(m,4H).HRMS(ESI)m/z:计算值C 37H 39ClN 7O 4S 2 +[M+H] +,744.2188；实测值,744.1699.
实施例218：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚烷-6-基)-N-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己基)乙酰胺(SIAIS171143)
根据方案33所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物A(SIAIS171018)和LIN-ULM(SIAIS171134)制备得目标化合物(SIAIS171143)(淡黄色固体, 16.0mg,收率56％)。 1H NMR(500MHz,MeOD)δ7.61(dd,J＝6.9,5.7Hz,2H),7.53–7.42(m,5H),5.14(dd,J＝13.2,5.2Hz,1H),4.74(dd,J＝8.3,5.0Hz,1H),4.40(qd,J＝17.2,4.0Hz,2H),3.47–3.37(m,1H),3.29–3.17(m,3H),3.05(t,J＝7.2Hz,2H),2.92–2.83(m,1H),2.80–2.72(m,4H),2.54–2.42(m,4H),2.20–2.10(m,1H),1.72–1.64(m,5H),1.60–1.49(m,4H),1.44–1.38(m,2H).HRMS(ESI)m/z:计算值C 38H 41ClN 7O 4S 2 +[M+H] +,758.2344；实测值,758.2989.
实施例219：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚烷-6-基)-N-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)庚基)乙酰胺(SIAIS171144)
根据方案33所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物A(SIAIS171018)和LIN-ULM(SIAIS171135)制备得目标化合物(SIAIS171144)(淡黄色固体,15.0mg,收率52％)。 1H NMR(500MHz,MeOD)δ7.65–7.58(m,2H),7.56–7.42(m,5H),5.17–5.11(m,1H),4.80–4.78(m,1H),4.39(qd,J＝17.2,7.2Hz,2H),3.49–3.41(m,1H),3.29–3.18(m,3H),3.04(td,J＝7.2,3.5Hz,2H),2.93–2.81(m,4H),2.80–2.70(m,1H),2.55–2.43(m,4H),2.20–2.10(m,1H),1.75–1.62(m,5H),1.60–1.52(m,2H),1.50–1.46(m,2H),1.44–1.35(m,4H).HRMS(ESI)m/z:计算值C 39H 43ClN 7O 4S 2 +[M+H] +,772.2501；实测值,772.3154.
实施例220：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂环庚烷-6-基)-N-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)辛基)乙酰胺(SIAIS171145)
根据方案33所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物A(SIAIS171018)和LIN-ULM(SIAIS171136)制备得目标化合物(SIAIS171145)(淡黄色固体,15.0mg,收率51％)。 1H NMR(500MHz,MeOD)δ7.62(t,J＝7.2Hz,2H),7.50–7.44(m,5H),5.14(dd,J＝13.3,5.1Hz,1H),4.75(dd,J＝8.9,5.3Hz,1H),4.40(qd,J＝17.3,3.4Hz,2H),3.44(dd,J＝15.2,8.9Hz,1H),3.27–3.22(m,3H),3.03(t,J＝7.2Hz,2H),2.93–2.84(m,1H),2.81–2.70(m,4H),2.56–2.43(m,4H),2.20–2.15(m,1H),1.72–1.60(m,5H),1.56–1.51(m,2H),1.49–1.42(m,2H),1.40–1.30(m,6H).HRMS(ESI)m/z:计算值C 40H 45ClN 7O 4S 2 +[M+H] +,786.2657；实测值,786.3335.
实施例221：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
Figure PCTCN2019081840-appb-000257
-6-基)-N-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙基)乙酰胺(SIAIS213070)
根据方案33所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物A(SIAIS171018)和LIN-ULM(SIAIS213066)制备得目标化合物(SIAIS213070)(白色固体,8.0mg,收率39.8％), 1H NMR(500MHz,MeOD)δ7.69(tdd,J＝15.0,7.7,2.0Hz,2H),7.55(d,J＝6.9Hz,1H),7.44(ddd,J＝14.5,8.7,4.9Hz,4H),5.12–4.95(m,1H),4.71(ddd,J＝8.9,5.2,1.3Hz,1H),3.87–3.75(m,2H),3.72–3.57(m,6H),3.53–3.39(m,3H),3.33(dd,J＝9.8,6.5Hz,3H), 2.87–2.61(m,6H),2.46(d,J＝8.9Hz,3H),2.14–2.01(m,1H),1.69(s,3H).HRMS(ESI)m/z:计算值C 38H 39ClN 7O 7S 2 +[M+H] +,804.2035；实测值,804.2036.
实施例222：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
Figure PCTCN2019081840-appb-000258
-6-基)-N-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙基)乙酰胺(SIAIS213100)
根据方案33所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物A(SIAIS171018)和LIN-ULM(SIAIS213096)制备得目标化合物(SIAIS213100)(淡黄色固体,12.0mg,收率64.2％), 1H NMR(500MHz,MeOD)δ7.69(d,J＝7.8Hz,1H),7.61(t,J＝8.8Hz,1H),7.53–7.37(m,5H),5.06(ddd,J＝24.5,13.3,5.2Hz,1H),4.74–4.66(m,1H),4.46–4.27(m,2H),3.78–3.68(m,2H),3.62–3.54(m,2H),3.50–3.35(m,3H),3.29–3.20(m,3H),2.85(ddt,J＝19.1,13.5,5.6Hz,1H),2.79–2.68(m,4H),2.51–2.35(m,4H),2.15–2.13(m,1H),1.68(s,3H).HRMS(ESI)m/z:计算值C 36H 37ClN 7O 5S 2 +[M+H] +,746.1981；实测值,746.1984.
实施例223：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
Figure PCTCN2019081840-appb-000259
-6-基)-N-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙基)乙酰胺(SIAIS213072)
根据方案33所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物A(SIAIS171018)和LIN-ULM(SIAIS213068)制备得目标化合物(SIAIS213072)(淡黄色固体,5.0mg,收率25.3％), 1H NMR(500MHz,MeOD)δ7.72–7.68(m,1H),7.64(dd,J＝6.8,5.3Hz,1H),7.55–7.48(m,5H),5.11(dd,J＝13.4,5.2Hz,1H),4.99(dd,J＝13.3,5.2Hz,1H),4.49–4.27(m,2H),3.74–3.69(m,2H),3.63–3.57(m,6H),3.51–3.41(m,3H),3.36(dd,J＝10.5,5.3Hz,1H),3.27–3.19(m,2H),2.90–2.79(m,4H),2.73(ddd,J＝15.0,4.6,2.3Hz,1H),2.53–2.43(m,4H),2.16–2.13(m,1H),1.72(s,3H).HRMS(ESI)m/z:计算值C 38H 41ClN 7O 6S 2 +[M+H] +,790.2243；实测值,790.2238.
实施例224：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
Figure PCTCN2019081840-appb-000260
-6-基)-N-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙基)乙酰胺(SIAIS213112)
根据方案33所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物A(SIAIS171018)和LIN-ULM(SIAIS213111)制备得目标化合物(SIAIS213112)(淡黄色固体,12.0mg,收率57.5％), 1H NMR(500MHz,MeOD)δ7.72(t,J＝7.0Hz,1H),7.65(dt,J＝14.7,7.4Hz,1H),7.52(ddd,J＝22.6,20.6,8.7Hz,5H),5.21–5.03(m,1H),4.77(s,1H),4.44(qd,J＝17.3,9.1Hz,2H),3.70(dd,J＝13.2,6.9Hz,2H),3.63(dt,J＝6.6,3.5Hz,10H),3.57–3.40(m,4H),3.25(dd,J＝11.6,5.4Hz,2H),2.94–2.85(m,4H),2.81–2.74(m,1H),2.55–2.46(m,4H),2.20–2.16(m,1H),1.73(s,3H).HRMS(ESI)m/z:计算值C 40H 45ClN 7O 7S 2 +[M+H] +,834.2505；实测值,834.2507.
实施例225：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
Figure PCTCN2019081840-appb-000261
-6-基)-N-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰氨基)丁基)乙酰胺(SIAIS213075)
根据方案33所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物A(SIAIS171018)和LIN-ULM(SIAIS213073)制备得目标化合物(SIAIS213075)(淡黄色固体,14.0mg,收率70.0％), 1H NMR(500MHz,MeOD)δ7.75–7.67(m,2H),7.64–7.59(m,1H),7.48(q,J＝8.8Hz,4H),5.07(ddd,J＝24.4,12.7,5.4Hz,1H),4.81(ddd,J＝8.7,5.9,3.1Hz,1H),3.85(d,J＝1.5Hz,2H),3.45–3.34(m,2H),3.26–3.15(m,4H),2.89–2.78(m,4H),2.69(dddd,J＝17.6,12.8,6.2,3.3Hz,2H),2.47(s,3H),2.11(ddd,J＝13.1,5.8,2.6Hz,1H),1.71(s,3H),1.53–1.50(m,4H).HRMS(ESI)m/z:计算值C 38H 38ClN 8O 6S 2 +[M+H] +,801.2039；实测值,801.2037.
实施例226：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
Figure PCTCN2019081840-appb-000262
-6-基)-N-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰氨基)丁基)乙酰胺(SIAIS213094)
根据方案33所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物A(SIAIS171018)和LIN-ULM(SIAIS213092)制备得目标化合物(SIAIS213094)(淡黄色固体,9.0mg,收率45.9％), 1H NMR(500MHz,MeOD)δ7.70(dd,J＝7.6,6.6Hz,2H),7.59–7.38(m,5H),5.17–5.06(m,1H),4.84–4.79(m,1H),4.48(qd,J＝17.3,7.1Hz,2H),3.68–3.63(m,2H),3.45–3.40(m,1H),3.37(d,J＝5.9Hz,1H),3.26–3.10(m,4H),2.93–2.81(m,4H),2.77(ddd,J＝20.0,10.0,7.6Hz,1H),2.56–2.43(m,4H),2.23–2.11(m,1H),1.71(s,3H),1.45–1.31(m,4H).HRMS(ESI)m/z:计算值C 38H 40ClN 8O 5S 2 +[M+H] +,787.2246；实测值,787.2249.
BRD4靶点的一些特殊降解剂通用的合成方法:
Figure PCTCN2019081840-appb-000263
根据方案34，室温下，在反应瓶中，加入JQ-1衍生物B(SIAIS213113)或JQ-1衍生物C(SIAIS213130)(1equiv)，LIN-ULM(1equiv),二异丙基乙胺(3equiv),碘化钠(1equiv),NMP(1.5mL)，55℃搅拌反应过夜。LC-MS检测反应结束后，HPLC制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)，旋去乙腈，冻干后得最终化合物。
实施例227：制备3-(4-((2-(4-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
Figure PCTCN2019081840-appb-000264
-6-基)乙酰基)哌嗪-1-基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS213140)
根据方案34所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物B(SIAIS213113)和LIN-ULM(SIAIS213137)制备得目标化合物(SIAIS213140)(淡黄色固体,7.0mg,收率42.7％), 1H NMR(500MHz,MeOD)δ7.85–7.72(m,2H),7.67–7.59(m,1H),7.49(q,J＝8.8Hz,4H),5.24–5.14(m,1H),4.80(s,1H),4.59–4.48(m,2H),3.80–3.32(m,14H),2.95–2.86(m,1H),2.86–2.75(m,4H),2.56–2.46(m,4H),2.25–2.15(m,1H),1.71(s,3H).HRMS(ESI)m/z:计算值C 38H 40ClN 8O 4S 2 +[M+H] +,771.2297；实测值,771.2298.
实施例228：制备3-(4-((3-(4-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
Figure PCTCN2019081840-appb-000265
-6-基)乙酰基)哌嗪-1-基)丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS213117)
根据方案34所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物B(SIAIS213113)和LIN-ULM(SIAIS213132)制备得目标化合物(SIAIS213117)(淡黄色固体,1.5mg,收率13.0％), 1H NMR(500MHz,MeOD)δ7.82–7.78(m,1H),7.75(dd,J＝7.4,1.8Hz,1H),7.62(t,J＝7.7Hz,1H),7.58–7.42(m,4H),5.45–5.31(m,1H),5.20(dd,J＝13.4,4.9Hz,1H),4.57–4.46(m,2H),3.64(d,J＝23.4Hz,4H),3.42–3.35(m,2H),3.27–3.08(m,4H),2.95–2.87(m,1H),2.79(d,J＝18.7Hz,4H),2.59–2.46(m,4H),2.27–2.17(m,2H),2.09(d,J＝36.9Hz,3H),1.73(s,3H),1.37–1.35(s,2H).HRMS(ESI)m/z:计算值C 39H 42ClN 8O 4S 2 +[M+H] +,785.2453；实测值,785.2457.
实施例229：制备3-(4-((4-(4-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
Figure PCTCN2019081840-appb-000266
-6-基)乙酰基)哌嗪-1-基)丁基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS213138)
根据方案34所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物B(SIAIS213113)和LIN-ULM(SIAIS213134)制备得目标化合物(SIAIS213138)(淡黄色固体,7.0mg,收率41.2％), 1H NMR(500MHz,MeOD)δ7.70(dd,J＝15.2,7.7Hz,2H),7.58–7.47(m,5H),5.18(d,J＝8.6Hz,1H),4.84–4.58(m,2H),4.47(q,J＝17.4Hz,3H),3.70(d,J＝55.4Hz,6H),3.26–3.09(m,6H),2.93–2.76(m,5H),2.56–2.44(m,4H),2.19(dd,J＝9.0,3.7Hz,1H),2.00–1.89(m,2H),1.78–1.73(m,5H).HRMS(ESI)m/z:计算值C 40H 44ClN 8O 4S 2 +[M+H] +,799.2610；实测值,799.2616.
实施例230：制备3-(4-((5-(4-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
Figure PCTCN2019081840-appb-000267
-6-基)乙酰基)哌嗪-1-基)戊基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(SIAIS213131)
根据方案34所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物B(SIAIS213113)和LIN-ULM(SIAIS213129)制备得目标化合物(SIAIS213131)(淡黄色固体,6.0mg,收率34.7％), 1H NMR(500MHz,MeOD)δ7.68–7.64(m,2H),7.62–7.50(m,5H),5.16(dt,J＝13.0,6.5Hz,1H),4.95(d,J＝15.9Hz,1H),4.68(d,J＝14.2Hz,1H),4.45(q,J＝17.3Hz,3H),3.87–3.59(m,5H),3.29–3.00(m,7H),2.94–2.85(m,4H),2.80(dd,J＝18.6,16.5Hz,1H),2.59–2.47(m,4H),2.22–2.15(m,1H),1.88–1.79(m,2H),1.77–1.66(m,5H),1.57–1.51(m,2H).HRMS(ESI)m/z:计算值C 41H 46ClN 8O 4S 2 +[M+H] +,813.2766；实测值,813.2767.
实施例231：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
Figure PCTCN2019081840-appb-000268
-6-基)-N-(2-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙基)哌嗪-1-基)乙基)乙酰胺(SIAIS213141)
根据方案34所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物C(SIAIS213130)和LIN-ULM(SIAIS213137)制备得目标化合物(SIAIS213141)(白色固体,5.0mg,收率31.4％), 1H NMR(500MHz,MeOD)δ7.67(dt,J＝21.4,10.7Hz,2H),7.53(t,J＝7.5Hz,1H),7.49–7.35(m,4H),5.16(dd,J＝13.3,5.0Hz,1H),4.63–4.55(m,2H),4.46(qd,J＝17.6,4.5Hz,2H),3.62(dd,J＝32.0,17.1Hz,2H),3.46–3.34(m,4H),3.16(dd,J＝17.7,16.0Hz,4H),2.96–2.83(m,1H),2.83–2.73(m,1H),2.68(s,3H),2.62(s,2H),2.52(dd,J＝15.9,6.5Hz,6H),2.44(s,3H),2.19(s,1H),1.69(s,3H).HRMS(ESI)m/z:计算值C 40H 45ClN 9O 4S 2 +[M+H] +,814.2719；实测值,814.2716.
实施例232：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
Figure PCTCN2019081840-appb-000269
-6-基)-N-(2-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙基)哌嗪-1-基)乙基)乙酰胺(SIAIS213136)
根据方案34所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物C(SIAIS213130)和LIN-ULM(SIAIS213132)制备得目标化合物(SIAIS213136)(淡黄色固体,6.0mg,收率37.0％), 1H NMR(500MHz,MeOD)δ7.77(d,J＝7.8Hz,1H),7.72(d,J＝8.3Hz,1H),7.62–7.46(m,5H),5.16(dd,J＝13.4,5.1Hz,1H),4.83–4.78(m,1H),4.49(q,J＝17.5Hz,2H),3.87–3.49(m,12H),3.40(dt,J＝17.7,5.9Hz,4H),3.24–3.07(m,2H),2.97–2.70(m,5H),2.60–2.43(m,4H),2.18(dd,J＝8.8,3.9Hz,1H),2.04(dd,J＝33.1,25.9Hz,2H),1.71(s,3H).HRMS(ESI)m/z:计算值C 41H 47ClN 9O 4S 2 +[M+H] +,828.2875；实测值,828.2874.
实施例233：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
Figure PCTCN2019081840-appb-000270
-6-基)-N-(2-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)乙基)乙酰胺(SIAIS213139)
根据方案34所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物C(SIAIS213130)和LIN-ULM(SIAIS213134)制备得目标化合物(SIAIS213139)(淡黄色固体,5.0mg,收率30.3％), 1H NMR(500MHz,MeOD)δ7.78–7.65(m,2H),7.61–7.44(m,5H),5.16(ddd,J＝22.9,13.4,5.1Hz,1H),4.84–4.79(m,1H),4.54–4.39(m,2H),3.96–3.44(m,12H),3.39(t,J＝5.3Hz,2H),3.19(ddd,J＝8.5,4.9,3.0Hz,3H),3.09(ddd,J＝17.5,13.7,7.0Hz,1H),2.94–2.71(m,5H),2.59–2.42(m,4H),2.17(dd,J＝7.5,5.3Hz,1H),2.06–1.88(m,2H),1.80–1.53(m,5H).HRMS(ESI)m/z:计算值C 42H 49ClN 9O 4S 2 +[M+H] +,842.3032；实测值,842.3036.
实施例234：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
Figure PCTCN2019081840-appb-000271
-6-基)-N-(2-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊基)哌嗪-1-基)乙基)乙酰胺(SIAIS213133)
根据方案34所述通用方法，在本领域可理解的适当条件下，采用JQ-1衍生物C(SIAIS213130)和LIN-ULM(SIAIS213129)制备得目标化合物(SIAIS213133)(白色固体,5.0mg,收率29.9％), 1H NMR(500MHz,MeOD)δ7.65(dd,J＝7.7,1.2Hz,2H),7.53(t,J＝7.6Hz,1H),7.48–7.37(m,4H),5.16(dd,J＝13.3,5.1Hz,1H),4.63(t,J＝7.1Hz,1H),4.58(s,1H),4.43(q,J＝17.3Hz,2H),3.53–3.43(m,1H),3.41–3.32(m,4H),3.17–2.70(m,12H),2.69(s,3H),2.63(t,J＝6.3Hz,2H),2.52(dt,J＝12.2,7.8Hz,1H),2.44(s,3H),2.20–2.14(m,1H),1.75–1.67(m,5H),1.63(dd,J＝15.8,7.7Hz,2H),1.56–1.46(m,2H).HRMS(ESI)m/z:计算值C 43H 51ClN 9O 4S 2 +[M+H] +,856.3188；实测值,856.3189.
比较实施例1：制备N-(2-氯-6-甲基苯基)-2-((6-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基乙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺(参照化合物SIAIS151072)
室温下，在反应瓶中，依次加入N-(2-氯-6-甲基苯基)-2-((2-甲基-6-(哌嗪-1-基)嘧啶-4-基)氨基)噻唑-5-甲酰胺(即达沙替尼衍生物SIAIS151055；1equiv)，(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基乙酸(即HO 2C-LIN-ULM中间体SIAIS151025；1equiv),HOAt(2equiv),EDCI(2equiv),无水DMF(2mL)，NMM(5equiv)，室温下搅拌反应过夜。LC-MS检测反应结束后，HPLC制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)，旋去乙腈，冻干后得目标化合物(SIAIS151072)，为黄色固体,19.1mg,收率56％, 1H NMR(500MHz,MeOD)δ8.11(s,1H),7.51–7.46(m,1H),7.27(d,J＝7.9Hz,1H),7.19–7.12(m,2H),7.01(d,J＝7.0Hz,1H),6.94(d,J＝8.5Hz,1H),6.19(s,1H),4.98(dd,J＝12.6,5.3Hz,1H),4.19(s,2H),3.83–3.63(m,8H),2.82–2.73(m,1H),2.69–2.61(m,2H),2.50(s,3H),2.22(s,3H),2.06–1.99(m,1H).HRMS(ESI)m/z:计算值C 35H 34ClN 10O 6S +[M+H] +,757.2067；实测值,757.1286.
比较实施例2：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
Figure PCTCN2019081840-appb-000272
-6-基)-N-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)戊基)乙酰胺(参照化合物SIAIS213110)
室温下，在反应瓶中，依次加入(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
Figure PCTCN2019081840-appb-000273
-6-基)乙酸(即JQ-1衍生物A：SIAIS171018；1equiv)，3-(4-((5-氨基戊基)氨基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(即HO 2C-LIN-ULM中间体SIAIS1204075；1equiv),HOAt(2equiv),EDCI(2equiv),无水DMF(2mL)，NMM(5equiv)，室温下搅拌反应过夜。LC-MS检测反应结束后，HPLC制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)，旋去乙腈，冻干后得目标化合物(SIAIS213110)，为黄色固体,21.4mg,收率59％, 1H NMR(500MHz,MeOD)δ7.45–7.27(m,5H),7.06(dd,J＝7.4,3.0Hz,1H),6.79(dd,J＝8.0,5.0Hz,1H),5.07(ddd,J＝30.3,13.3,5.2Hz,1H),4.67–4.59(m,1H),4.31–4.19(m,2H),3.45–3.32(m,2H),3.29–3.23(m,2H),3.18(dt,J＝6.7,5.3Hz,2H),2.86(dtd,J＝18.9,13.6,5.4Hz,1H),2.75–2.64(m,4H),2.45–2.33(m,4H),2.09(ddtd,J＝18.1,12.7,5.2,2.3Hz,1H),1.72(ddd,J＝21.0,13.9,6.7Hz,2H),1.62(t,J＝11.2Hz,5H),1.56–1.47(m,2H).HRMS(ESI)m/z:计算值C 37H 40ClN 8O 4S +[M+H] +,727.2576；实测值,727.2573.
比较实施例3：制备2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
Figure PCTCN2019081840-appb-000274
-6-基)-N-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)戊基)乙酰胺(参照化合物SIAIS271066)
室温下，在反应瓶中，依次加入(S)-2-(4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
Figure PCTCN2019081840-appb-000275
-6-基)乙酸(即JQ-1衍生物A：SIAIS171018；1equiv)，3-(4-((5-氨基戊基)氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(即HO 2C-LIN-ULM中间体SIAIS271064；1equiv),HOAt(2equiv),EDCI(2equiv),无水DMF(2mL)，NMM(5equiv)，室温下搅拌反应过夜。LC-MS检测反应结束后，HPLC制备分离(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)，旋去乙腈，冻干后得目标化合物(SIAIS271066)，为淡黄色固体,9.0mg,收率50％， 1H NMR(500MHz,DMSO)δ10.94(d,J＝14.8Hz,1H),8.22(s,1H),7.53–7.36(m,5H),7.33–7.25(m,1H),7.25–7.17(m,1H),5.08(dt,J＝13.3,4.8Hz,1H),4.58–4.48(m,1H),4.36(dd,J＝17.4,9.7Hz,1H),4.23–4.13(m,1H),4.10(dd,J＝10.3,6.1Hz,2H),3.17(qdd,J＝18.8,13.9,7.3Hz,4H),2.95–2.80(m,1H),2.59(t,J＝9.6Hz,3H),2.50–2.35(m,5H),2.01–1.89(m,1H),1.76(d,J＝5.1Hz,2H),1.64–1.56(m,3H),1.55–1.42(m,4H).HRMS(ESI)m/z:计算值C 37H 39ClN 7O 5S +[M+H] +,728.2416；实测值,728.2411.
生物活性检测实验
基于泊马度胺/来那度胺的式(IV)含硫化合物生物活性检测实验
实验试剂
Figure PCTCN2019081840-appb-000276
Figure PCTCN2019081840-appb-000277
实验细胞
所使用的多发性骨髓瘤细胞株为：MM1S(骨髓瘤(免疫球蛋白A lambda)，B淋巴母细胞)，购买自ATCC。培养基为添加有10％FBS和1％Penicillin-Streptomycin(青霉素和链霉素)的RPMI1640。所使用细胞经过STR细胞鉴定为正确细胞，并通过常规检查为支原体阴性。
实验方法
细胞培养
本公开使用的细胞培养在含5％CO 2的37℃培养箱中。细胞完全培养基为RPMI l640培养基中加入10％胎牛血清，青霉素、链霉素终浓度为100U/mL。
化合物肿瘤细胞半抑制浓度(IC 50)测定
将MM1S细胞以15000个细胞/每孔的数量接种在含有100μL RPMI1640完全培养基中。将待测化学物从最高浓度10μM/1μM进行5倍梯度稀释，从高到低共设置10个浓度，然后取稀释好的本公开实施例式(IV)含硫化合物0.5μL加入接种好的100μL细胞中，药物处理细胞72h后，按照CCK-8的试剂操作说明书进行细胞活性测定，阴性对照为DMSO，阳性对照为商品化的抑制剂。CCK-8处理2h后，使用酶标仪测定O.D.450的值。本公开式(IV)含硫化合物对细胞的生长抑制率计算公式为细胞抑制率％＝(对照组O.D.值-实验组O.D.值)/对照组O.D.值*100％，进一步通过Prism Graphpad软件进行绘制抑制曲线和统计本公开化合物的IC 50。
结果显示设计的本公开基于泊马度胺/来那度胺的式(IV)含硫化合物均可以抑制多发性骨髓瘤细胞MM1S的增殖。值得一提的是原药泊马度胺(Pomalidomide)的IC 50为9.38nM，来那度胺(Lenalidomide)的IC 50为19.59nM，我们设计合成的式(IV)含硫化合物的IC 50最低达到了1.98nM，对肿瘤细胞生长抑制的效果比母本药物更好。
表4：本公开式(IV)含硫化合物对MM1S细胞增殖抑制活性的IC 50值
化合物 IC 50(nM)/MM1S细胞系
泊马度胺(Pomalidomide) 9.38±1.33
来那度胺(Lenalidomide) 19.59±3.30
SIAIS171075 18.51±0.64
SIAIS1216049 1.27±0.62
SIAIS1216133 1.27±0.13
SIAIS1216135 1.23±0.42
SIAIS1216137 1.58±0.71
SIAIS1220013 1.98
SIAIS1220015 3.45
SIAIS171123 71.43
SIAIS171124 56.93
SIAIS171131 6.61
SIAIS171132 8.27
SIAIS171134 4.77
SIAIS171135 4.31
SIAIS171136 4.22
SIAIS1210065 63.87
SIAIS1210067 39.47
SIAIS1210069 57.97
SIAIS1216107 327.8
SIAIS1210079 388
SIAIS1210077 71.85
CDK4/6靶点化合物生物活性检测实验
实验试剂
Figure PCTCN2019081840-appb-000278
实验细胞
CDK4/6阳性细胞T-47D细胞(人乳腺癌细胞)购自中国科学院细胞库；Jurkat(T细胞白血病)细胞购自美国模式培养物保藏所American Type Culture Collection(ATCC)。
实验方法
细胞培养
本公开使用的细胞培养在含5％CO 2的37℃培养箱中。细胞完全培养基为RPMI l640培养基中加入10％胎牛血清，青霉素、链霉素终浓度为100U/mL。所有细胞实验前用支原体检测试剂盒检测为支原体阴性。
PROTAD化合物蛋白质免疫印迹Western-blot测定
(1)细胞种板：T-47D细胞加入24孔板中，细胞密度1.5×10 5/mL，总体积为1mL；本公开实施例PROTAD化合物分别设置1nM、10nM、500nM、100nM、500nM或0.04nM、0.2nM、1nM、10nM、50nM5个浓度梯度，同时设置DMSO和商品化母本抑制剂组(瑞博西尼(Ribociclib)、帕布昔利布(Palbociclib))作为阴性对照和阳性对照，药物处理24h，PBS洗2次，每孔加入50μLSDS裂解液冰上裂解5min，收集裂解液于1.5mL EP管中，金属浴100℃，加热8min，然后冰上放置5min，10000rpm离心5min，吸取上清为提取的细胞总蛋白。用Bradford法测定蛋白浓度，每个样品等浓度后，加入溴酚蓝作为上样指示剂；
(2)电泳：在Bio Rad电泳仪中开始时，电压80V电泳，当染料进入分离胶后，电压调成120V；
(3)转膜：裁剪相应大小的滤纸和硝酸纤维素膜(NC膜)；滤纸和NC膜均在转移电泳缓冲液中浸透。按“滤纸-凝胶-NC膜-滤纸”的顺序装置好放入电泳槽中转膜；恒流400mA，1h；之后抗体孵育和显影等操作按照Cell Signaling Technology的抗体说明书进行。
结果显示设计的本公开PROTAD化合物均可以降解CDK4/6蛋白(如表5所示)。采用Western-blot检测了本公开PROTAD化合物处理后的T-47D细胞24h后的CDK4/6蛋白的表达，免疫蛋白印记实验表明本公开的PROTAD化合物(即所述降解剂)能够促进CDK4/6蛋白的降解，并且这种降解作用呈剂量依赖性。
表5 本公开CDK4/6靶点实施例PROTAD化合物对CDK4/6蛋白降解结果
化合物 DC 50(nM)/T-47D细胞系 DC 50(nM)/Jurkat细胞系
SIAIS151046 1～10 1～10
SIAIS219063 <1  
SIAIS184086 >500  
SIAIS184087 1～10  
SIAIS184088 1～10  
SIAIS184089 1～10  
SIAIS184090 1～10 1～10
SIAIS151056 100～500  
SIAIS151057 100～500  
SIAIS184091 1～10 1～10
SIAIS219059 10～50  
SIAIS219060 1～10  
SIAIS219061 1～10  
SIAIS219062 1～10  
SIAIS219051 <1  
SIAIS219052 <1  
SIAIS219053 <1  
SIAIS184092 <0.1 <1
SIAIS219054 <1  
SIAIS219055 <1  
SIAIS219100 <0.04  
SIAIS219101 >100  
SIAIS219102 1～10  
SIAIS219103 <1  
SIAIS219104 1～10  
SIAIS219105 0.04～0.2  
SIAIS219111 <1  
SIAIS219112 0.04～0.2  
SIAIS219113 <1  
SIAIS219114 1～10  
SIAIS219115    
SIAIS219086 <1  
SIAIS219087 <1  
SIAIS219088 1～10  
SIAIS219089 1～10  
SIAIS219090 0.2～1  
SIAIS219091 <1  
SIAIS219106 0.04～0.2  
SIAIS219107 0.04～0.2  
SIAIS219108 0.04～0.2  
SIAIS219109 1～10  
SIAIS219110 0.04～0.2  
SIAIS262164 0.5～5  
SIAIS262165 5  
SIAIS262166 0.5～5  
SIAIS262167 0.5～5  
SIAIS262168 0.05～0.5  
SIAIS262173 0.05～0.5  
SIAIS262169 5  
SIAIS262170 50  
SIAIS262171 0.5  
ALK靶点化合物生物活性检测实验
实验试剂
Figure PCTCN2019081840-appb-000279
Figure PCTCN2019081840-appb-000280
实验细胞
ALK阳性细胞SR细胞(人大细胞免疫母细胞淋巴瘤)购自美国模式培养物保藏所American Type Culture Collection(ATCC)；H3122细胞(人非小细胞肺癌)源于上海科技大学林海帆课题组友情赠送。
实验方法
细胞培养
本公开使用的细胞培养在含5％CO 2的37℃培养箱中。细胞完全培养基为RPMI l640培养基中加入10％胎牛血清，青霉素、链霉素终浓度为100U/mL。所有细胞实验前用支原体检测试剂盒检测为支原体阴性。
PROTAD化合物肿瘤细胞半抑制浓度(IC 50)测定
将SR细胞以10000个细胞/每孔的数量接种在含有100μL RPMI1640完全培养基中。将待测化学物从最高浓度10μM进行5倍梯度稀释，从高到低共设置10个浓度，然后取稀释好的本公开实施例PROTAD化合物0.5μL加入接种好的100μL细胞中，药物处理细胞72h后，按照CCK-8的试剂操作说明书进行细胞活性测定，阴性对照为DMSO，阳性对照为商品 化的抑制剂。CCK-8处理2h后，使用酶标仪测定O.D.450的值。本公开PROTAD化合物对细胞的生长抑制率计算公式为细胞抑制率％＝(对照组O.D.值-实验组O.D.值)/对照组O.D.值*100％，进一步通过Prism Graphpad软件进行绘制抑制曲线和统计本公开化合物的IC 50。
结果显示设计的本公开PROTAD化合物均可以抑制ALK阳性细胞SR的增殖(如表6所示)。所有的实施例化合物的IC 50都低于150nM。值得一提的是抑制剂布加替尼(Brigatinib)的IC 50为10.6nM，我们设计合成的PROTAD化合物的IC 50最低达到了0.17nM，对肿瘤细胞生长抑制的效果比母本药物布加替尼提高了60倍以上。
蛋白质免疫印迹Western-blot测定PROTAD化合物对靶蛋白的半数降解浓度(DC 50)
(1)细胞种板：SR细胞或H3122细胞加入24孔板中，细胞密度3/1.5×10 5/mL，总体积为1mL；本公开实施例PROTAD化合物和参照化合物SIAIS151072分别设置1nM、10nM、50nM、100nM、500nM或0.01nM、0.1nM、1nM、10nM、50nM5个浓度梯度，同时设置DMSO和商品化母本抑制剂组(布加替尼(Brigatinib)、艾乐替尼(Alectinib))作为阴性对照和阳性对照，药物的处理24h后收集细胞于1.5mL EP管中，3000rpm离心3min，收集细胞沉淀后加入30μL PBS悬细胞后再加入30μL的2×SDS裂解液，金属浴100℃，加热8min，然后冰上放置5min，10000rpm离心5min，吸取上清为提取的细胞总蛋白。用Bradford法测定蛋白浓度，每个样品等浓度后，加入溴酚蓝作为上样指示剂；
(2)电泳：在Bio Rad电泳仪中开始时，电压80V电泳，当染料进入分离胶后，电压调成120V；
(3)转膜：裁剪相应大小的滤纸和硝酸纤维素膜(NC膜)；滤纸和NC膜均在转移电泳缓冲液中浸透。按“滤纸-凝胶-NC膜-滤纸”的顺序装置好放入电泳槽中转膜；恒流400mA，1h；之后抗体孵育和显影等操作按照Cell Signaling Technology的抗体说明书进行。
DC 50(蛋白降解至50％所对应的药物浓度)计算：根据药物处理后对应Western blotting条带的灰度值,拟合药物浓度与灰度值之间的关系曲线推算对应灰度值一半的药物浓度范围。结果如表6所示。
表6 本公开ALK靶点实施例PROTAD化合物对ALK阳性肿瘤细胞增殖抑制活性的IC 50值及ALK蛋白降解结果(DC 50值)
Figure PCTCN2019081840-appb-000281
Figure PCTCN2019081840-appb-000282
Figure PCTCN2019081840-appb-000283
BCR-ABL靶点化合物生物活性检测实验
实验试剂
Figure PCTCN2019081840-appb-000284
实验细胞
BCR-ABL阳性细胞K562细胞(人慢性髓系白血病细胞)购自美国模式培养物保藏所American Type Culture Collection(ATCC)；
BCR-ABL阴性细胞：
U937细胞人单核细胞白血病细胞系购自美国模式培养物保藏所American Type Culture Collection(ATCC)
HEK293细胞(人胚肾细胞)购自美国模式培养物保藏所American Type Culture Collection(ATCC)。
实验方法
细胞培养
本公开使用的细胞培养在含5％CO 2的37℃培养箱中。细胞完全培养基为RPMI l640培养基中加入10％胎牛血清，青霉素、链霉素终浓度为100U/mL。所有细胞实验前用支原体检测试剂盒检测为支原体阴性。
PROTAD化合物肿瘤细胞半抑制浓度(IC 50)测定
K562细胞以20000个细胞/每孔的数量接种在含有100μL RPMI1640完全培养基中。将待测化学物从最高浓度10μM进行3倍梯度稀释，从高到低共设置9个浓度，然后取稀释好的本公开实施例PROTAD化合物100μL加入接种好的100μL细胞中，药物处理细胞48h后，按照CCK-8的试剂操作说明书进行细胞活性测定，阴性对照为DMSO，阳性对照为商品化的抑制剂。CCK-8处理2h后，使用酶标仪测定O.D.450的值。本公开PROTAD化合物对细胞的生长抑制率计算公式为细胞抑制率％＝(对照组O.D.值-实验组O.D.值)/对照组O.D.值*100％，进一步通过Prism Graphpad软件进行绘制抑制曲线和统计本公开化合物的IC 50值。
结果显示设计的本公开PROTAD化合物均可以抑制BCR-ABL阳性细胞K562的增殖(如表6所示)。值得一提的是抑制剂达沙替尼(Dasatinib)的IC 50为0.9nM，我们设计合成的PROTAD化合物的IC 50最低达到了0.09nM，对肿瘤细胞生长抑制的效果比母本药物Dasatinib提高了10倍。并且本公开这些PROTAD小分子只对BCR-ABL阳性的细胞株如K562具有很强的增殖抑制作用，对其他非BCR-ABL阳性的细胞株，如U937细胞或HEK293细胞没有增殖抑制作用，说明本公开PROTAD化合物的确是具有选择性。
蛋白质免疫印迹Western-blot测定PROTAD化合物对靶蛋白的半数降解浓度(DC 50)
(1)细胞种板：K562细胞加入24孔板中，细胞密度3×10 5/mL，总体积为1.5mL；本公开实施例PROTAD化合物和参照化合物SIAIS151072分别设置1nM、10nM、100nM、1μM、10μM 5个浓度梯度的，同时设置DMSO和商品化母本抑制剂组(达沙替尼(Dasatinib)、伯舒替尼(Bosutinib)、普纳替尼(Ponatinib))作为阴性对照和阳性对照，药物的处理24h后收集细胞于1.5mL EP管中，3000rpm离心3min，收集细胞沉淀后加入30μL PBS悬细胞后再加入30μL的2×SDS裂解液，金属浴100℃，加热8min，然后冰上放置 5min，10000rpm离心5min，吸取上清为提取的细胞总蛋白。用Bradford法测定蛋白浓度，每个样品等浓度后，加入溴酚蓝作为上样指示剂；
(2)电泳：在Bio Rad电泳仪中开始时，电压80V电泳，当染料进入分离胶后，电压调成120V；
(3)转膜：裁剪相应大小的滤纸和硝酸纤维素膜(NC膜)；滤纸和NC膜均在转移电泳缓冲液中浸透。按“滤纸-凝胶-NC膜-滤纸”的顺序装置好放入电泳槽中转膜；恒压100V，1.5h；之后抗体孵育和显影等操作按照Cell Signaling Technology的抗体说明书进行。
结果如表7、图1-图15b所示。采用Western-blot检测了本公开PROTAD化合物处理后的K562细胞24h后的BCR-ABL以及c-ABL蛋白的表达，免疫蛋白印记实验表明本公开的PROTAD化合物(即所述降解剂)能够促进BCR-ABL和c-ABL蛋白的降解，并且这种降解作用呈剂量依赖性，在100nM浓度时可降解超过90％。而商品化母本抑制剂达沙替尼在100nM浓度下仅是抑制了BCR-ABL的酪氨酸激酶的活性，而不像本公开的降解剂那样可以将靶蛋白BCR-ABL降解。图1、2、4、5、6、13、15a、15b显示实验采用(Bio-Rad)伯乐TGX预制胶(4-15％梯度分离胶)，图3、7、8、9、10、11、12、14显示实验采用(Bio-Rad)伯乐TGX预制胶(10％分离胶)，其中，图1中达沙替尼针对的BCR-ABL目的条带与例如图3、7、8、9、10、11、12的达沙替尼针对的BCR-ABL目的条带略有差异，原因是在电泳实验中采用所述两种SDS-PAGE凝胶梯度不同所导致，其不影响测试结果的分析。
图15a和图15b显示了采用Western-blot检测本公开PROTAD系列化合物，相比于碳氮键共价结合的参照PROTAD化合物(SIAIS151072)来说，本公开碳硫键共价结合PROTAD化合物可以有效降解BCR-ABL和c-ABL蛋白，而碳氮键共价结合的参照PROTAD化合物降解BCR-ABL和c-ABL蛋白能力明显更弱，进而说明碳硫键共价结合PROTAD化合物更具有优势。
表7 本公开BCR-ABL靶点实施例PROTAD化合物对BCR-ABL阳性肿瘤细胞增殖抑制活性的IC 50值及BCR-ABL蛋白降解结果
Figure PCTCN2019081840-appb-000285
Figure PCTCN2019081840-appb-000286
注：NA：表示最高浓度10μM处理时未见有明显的增殖抑制作用。
PARP靶点化合物生物活性检测实验
实验试剂
Figure PCTCN2019081840-appb-000287
Figure PCTCN2019081840-appb-000288
实验细胞
PARP阳性细胞MDA-MB-436细胞(人乳腺癌细胞)购自美国模式培养物保藏所American Type Culture Collection(ATCC)。
实验方法
细胞培养
本公开使用的细胞培养在含5％CO 2的37℃培养箱中。细胞完全培养基为DMEM培养基中加入10％胎牛血清，青霉素、链霉素终浓度为100U/mL。所有细胞实验前用支原体检测试剂盒检测为支原体阴性。
PROTAD化合物肿瘤细胞半抑制浓度(IC 50)测定
MDA-MB-436细胞以3500个细胞/每孔的数量接种在含有100μLDMEM完全培养基中。将待测化学物从最高浓度50μM进行3倍梯度稀释，从高到低共设置10个浓度，然后取稀释好的本公开实施例PROTAD化合物0.5μL加入接种好的100μL细胞中，药物处理细胞72h后，按照CCK-8的试剂操作说明书进行细胞活性测定，阴性对照为DMSO，阳性对照为商品化的抑制剂。CCK-8处理2h后，使用酶标仪测定O.D.450的值。本公开PROTAD化合物对细胞的生长抑制率计算公式为细胞抑制率％＝(对照组O.D.值-实验组O.D.值)/对照组O.D.值*100％，进一步通过Prism Graphpad软件进行绘制抑制曲线和统计本公开化合物的IC 50。
结果显示设计的本公开部分PROTAD化合物可以抑制PARP阳性细胞MDA-MB-436的增殖(如表8所示)。值得一提的是抑制剂奥拉帕利(Olaparib)的IC 50为2.31μM，我们设计合成的PROTAD化合物的IC 50最低达到了2.09μM，对肿瘤细胞生长抑制的效果与母本药物Olaparib相当。
表8 本公开PARP靶点实施例PROTAD化合物对PARP阳性肿瘤细胞增殖抑制活性的IC 50值
化合物 IC 50(μM)/MDA-MB-436细胞系
奥拉帕利(Olaparib) 2.31
芦卡帕利(Rucaparib) 1.12
尼拉帕尼(Niraparib) 1.0
SIAIS180063 6.45
SIAIS180064 5.78
SIAIS180065 3.82
SIAIS180066 3.57
SIAIS180067 2.90
SIAIS180068 2.09
ER靶点化合物生物活性检测实验
实验试剂
Figure PCTCN2019081840-appb-000289
实验细胞
ER阳性细胞T-47D细胞(人乳腺癌细胞)购自中国科学院细胞库；
实验方法
细胞培养
本公开使用的细胞培养在含5％CO 2的37℃培养箱中。细胞完全培养基为RPMI l640培养基中加入10％胎牛血清，青霉素、链霉素终浓度为100U/mL。所有细胞实验前用支原体检测试剂盒检测为支原体阴性。
蛋白质免疫印迹Western-blot测定PROTAD化合物对靶蛋白的半数降解浓度(DC 50)
(1)细胞种板：T-47D细胞加入24孔板中，细胞密度1.5×10 5/mL，总体积为1mL；本公开实施例PROTAD化合物分别设置1nM、10nM、50nM、100nM、500nM或0.04nM、0.2nM、1nM、10nM、50nM5个浓度梯度，同时设置DMSO和商品化母本抑制剂组(他莫昔芬(tamoxifen)、拖瑞米芬(toremifene))作为阴性对照和阳性对照，药物处理24h，PBS洗2次，每孔加入50μL SDS裂解液冰上裂解5min，收集裂解液于1.5mL EP管中，金属浴100℃，加热8min，然后冰上放置5min，10000rpm离心5min，吸取上清为提取的细胞总蛋白。用Bradford法测定蛋白浓度，每个样品等浓度后，加入溴酚蓝作为上样指示剂；
(2)电泳：在Bio Rad电泳仪中开始时，电压80V电泳，当染料进入分离胶后，电压调成120V；
(3)转膜：裁剪相应大小的滤纸和硝酸纤维素膜(NC膜)；滤纸和NC膜均在转移电泳缓冲液中浸透。按“滤纸-凝胶-NC膜-滤纸”的顺序装置好放入电泳槽中转膜；恒流400mA，1h；之后抗体孵育和显影等操作按照Cell Signaling Technology的抗体说明书进行。
结果显示设计的本公开部分PROTAD化合物可以降解ER蛋白(如表9所示)。采用Western-blot检测了本公开PROTAD化合物处理后的T-47D细胞24h后的ER蛋白的表达，免疫蛋白印记实验表明本公开的部分PROTAD化合物(即所述降解剂)能够促进ER蛋白的降解，并且这种降解作用呈剂量依赖性。
表9 本公开ER靶点实施例PROTAD化合物对ER蛋白降解结果
化合物 DC 50(nM)/T-47D细胞系
SIAIS251132 50～100
SIAIS208170 10
SIAIS208171 10
BET靶点化合物生物活性检测实验
实验试剂
Figure PCTCN2019081840-appb-000290
实验细胞
表达BET的细胞MV-4-11细胞(人B粒细胞白血病细胞)、MDA-MB-231细胞(人乳腺癌细胞)、MDA-MB-468细胞(人乳腺癌细胞)、MDA-MB-453细胞(人乳腺癌细胞)、MM1S细胞(骨髓瘤(免疫球蛋白A lambda)，B淋巴母细胞)和SR细胞(人大细胞免疫母细胞淋巴瘤)购自美国模式培养物保藏所American Type Culture Collection(ATCC)。
实验方法
细胞培养
本公开使用的细胞培养在含5％CO 2的37℃培养箱中。细胞完全培养基为RPMI l640/IMDM/DMEM培养基中加入10％胎牛血清，青霉素、链霉素终浓度为100U/mL。所有细胞实验前用支原体检测试剂盒检测为支原体阴性。
PROTAD化合物对肿瘤细胞的半抑制浓度(IC 50)测定
MV-4-11细胞、MM1S细胞和SR细胞以15000/10000个细胞/每孔的数量；MDA-MB-231细胞、MDA-MB-468细胞、MDA-MB-453细胞以3000/5000个细胞/每孔的数量接种在含有100μLIMDM/RPMI1640/DMEM完全培养基中。将待测化学物从最高浓度10μM进行5倍梯度稀释，从高到低共设置10个浓度，然后取稀释好的本公开实施例PROTAD化合物0.5μL加入接种好的100μL细胞中，药物处理细胞48/72h后，按照CCK-8的试剂操作说明书进行细胞活性测定，阴性对照为DMSO，阳性对照为商品化的抑制剂。CCK-8处理2h后，使用酶标仪测定O.D.450的值。本公开PROTAD化合物对细胞的生长抑制率计算公式为细胞抑制率％＝(对照组O.D.值-实验组O.D.值)/对照组O.D.值*100％，进一步通过Prism Graphpad软件进行绘制抑制曲线和统计本公开化合物的IC 50。
结果显示设计的本公开PROTAD化合物均可以抑制表达BET细胞的增殖(如表10、11所示)。值得一提的是在MV-4-11细胞系中抑制剂JQ-1的IC 50值为9.0nM，我们设计合成的PROTAD化合物的IC 50则最低达到了0.08nM，对肿瘤细胞生长抑制的效果比母本药物JQ-1提高了100多倍。
蛋白质免疫印迹Western-blot测定PROTAD化合物对靶蛋白的半数降解浓度(DC 50)
(1)细胞种板：MV-4-11细胞加入24孔板中，细胞密度3×10 5/mL，总体积为1mL；本公开实施例PROTAD化合物设置1nM、10nM、50nM、100nM、500nM或0.001nM、0.05nM、0.1nM、1nM、20nM5个浓度梯度，同时设置DMSO和商品化母本抑制剂组JQ-1作为阴性对照和阳性对照，药物的处理24h后收集细胞于1.5mL EP管中，3000rpm离心3min，收集细胞沉淀后加入30μL PBS悬细胞后再加入30μL的2×SDS裂解液，金属浴100℃，加热8min，然后冰上放置5min，10000rpm离心5min，吸取上清为提取的细胞总蛋白。用Bradford法测定蛋白浓度，每个样品等浓度后，加入溴酚蓝作为上样指示剂；
(2)电泳：在Bio Rad电泳仪中开始时，电压80V电泳，当染料进入分离胶后，电压调成120V；
(3)转膜：裁剪相应大小的滤纸和硝酸纤维素膜(NC膜)；滤纸和NC膜均在转移电泳缓冲液中浸透。按“滤纸-凝胶-NC膜-滤纸”的顺序装置好放入电泳槽中转膜；恒压100V，1.5h；之后抗体孵育和显影等操作按照Cell Signaling Technology的抗体说明书进行。结果如表11所示。
图16a-c显示了采用MV-4-11细胞系参照上述Western-blot方法检测到本公开PROTAD系列化合物，相比于碳氮键、碳氧键共价结合的参照PROTAD化合物(SIAIS213110、SIAIS271066)来说，本公开碳硫键共价结合PROTAD化合物可以有效降解BRD2和BRD4蛋白，而碳氮键、碳氧键共价结合的参照PROTAD化合物降解BRD2和BRD4蛋白能力明显更弱，进而说明碳硫键共价结合PROTAD化合物更具有优势。
表10 本公开BET靶点实施例PROTAD化合物对表达BET的肿瘤细胞增殖抑制活性的IC 50值
Figure PCTCN2019081840-appb-000291
Figure PCTCN2019081840-appb-000292
表11 本公开BET靶点实施例PROTAD化合物对表达BET的肿瘤细胞增殖抑制活性的IC 50值及BET蛋白降解结果(DC 50值)
Figure PCTCN2019081840-appb-000293
本发明不受上面所显示和描述的实施例的限制，而是在权利要求的范围内可以改变。

Claims (96)

  1. 式(I)化合物：
    Figure PCTCN2019081840-appb-100001
    其中SMBP通过连接基团LIN共价连接ULM；
    其中SMBP表示能够结合蛋白的小分子化合物或其衍生物；
    LIN-ULM表示以下式(II)的化学结构：
    Figure PCTCN2019081840-appb-100002
    其中
    环原子A表示CH 2或CO，环原子B、X、Y、Z相同或不同且分别独立地表示CH或N，R表示S、SO、SO 2或哌嗪亚基；以及
    LIN是连接基团，表示-U-亚烷基-，其中
    所述亚烷基是可选地被一或多个选自以下的基团中断一或多次的直链或支链的亚烷基：O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基、亚杂芳基或它们的任意组合，其中所述直链或支链的亚烷基可选地被一或多个取代基取代，且
    基团U表示CO或NH，或基团U不存在；
    或其盐、对映异构体、立体异构体、溶剂化物、多晶型物。
  2. 如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述SMBP是靶向CDK4/6小分子药物、靶向ALK靶点小分子药物、靶向Bcr-abl靶点的小分子药物、靶向PARP靶点的小分子药物、靶向ER靶点的小分子药物或靶向BET靶点的小分子药物。
  3. 如权利要求2所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述SMBP表示：
    Figure PCTCN2019081840-appb-100003
    Figure PCTCN2019081840-appb-100004
    其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30、R 31、R 32、R 34、R 35、R 36、R 37、R 38、R 39、R 40、R 41、R 42、R 43、R 44、R 45、R 50、R 51、R 52、R 53、R 54、R 55、R 56、R 57、R 58、R 59、R 60、R 61、R 62、R 63、R 64、R 65、R 66各自独立地为H或甲基，R 33和R 67各自独立地表示H、甲基或乙基；以及
    其中在式(If)中，环原子Q是N或CH，其中CH进一步通过NH或哌嗪亚基连接至基团LIN；
    其中在式(Is)中，X 1是Cl或H，Y 1是H或OH，Z 1是H或甲基，以及W 1是H。
  4. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中在式(Is)中，X 1是Cl或H，Y 1是H或OH，Z 1是H或甲基，以及W 1是OH。
  5. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶 型物，其中所述式(I)化合物亦是式(Ia-2)化合物：
    Figure PCTCN2019081840-appb-100005
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义，以及基团R 1、R 2、R 3、R 4如在权利要求3中所定义。
  6. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(Ib-2)化合物：
    Figure PCTCN2019081840-appb-100006
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义，以及基团R 5、R 6、R 7、R 8如在权利要求3中所定义。
  7. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(Ic-2)化合物：
    Figure PCTCN2019081840-appb-100007
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义，以及基团R 9、R 10、R 11、R 12如在权利要求3中所定义。
  8. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(Id-2)化合物：
    Figure PCTCN2019081840-appb-100008
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义，以及基团R 13、R 14、R 15、R 16如在权利要求3中所定义。
  9. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(Ie-2)化合物：
    Figure PCTCN2019081840-appb-100009
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义，以及基团R 17、R 18、R 19、R 20如在权利要求3中所定义。
  10. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(If-2)化合物：
    Figure PCTCN2019081840-appb-100010
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义，以及环原子Q、基团R 21、R 22、R 23、R 24如在权利要求3中所定义。
  11. 如权利要求2所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(If-3)化合物：
    Figure PCTCN2019081840-appb-100011
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义，以及基团R 21、R 22、R 23、R 24各自独立地为H或甲基，且环原子Q是CH，其中CH进一步通过N(CH 3)连接至基团LIN。
  12. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(Ig-2)化合物：
    Figure PCTCN2019081840-appb-100012
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义，以及基团R 25、R 26、R 27、R 28如在权利要求3中所定义。
  13. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(Ih-2)化合物：
    Figure PCTCN2019081840-appb-100013
    其中，基团LIN、R、A、B、X、Y、Z如在权利要求1中所定义，以及基团R 29、R 30、R 31、R 32、R 33如在权利要求3中所定义。
  14. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(Ii-2)化合物：
    Figure PCTCN2019081840-appb-100014
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义，以及基团R 34、R 35、R 36、R 37、R 38、R 39、R 40、R 41如在权利要求3中所定义。
  15. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(Ij-2)化合物：
    Figure PCTCN2019081840-appb-100015
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义，以及基团R 42、R 43、R 44、R 45如在权利要求3中所定义。
  16. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(Il-2)化合物：
    Figure PCTCN2019081840-appb-100016
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义，以及基团R 50、R 51、R 52、R 53如在权利要求3中所定义。
  17. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶 型物，其中所述式(I)化合物亦是式(Im-2)化合物：
    Figure PCTCN2019081840-appb-100017
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义，以及基团R 54、R 55、R 56、R 57如在权利要求3中所定义。
  18. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(In-2)化合物：
    Figure PCTCN2019081840-appb-100018
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义，以及基团R 58、R 59、R 60、R 61如在权利要求3中所定义。
  19. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(Io-2)化合物：
    Figure PCTCN2019081840-appb-100019
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义，以及基团R 62、R 63、R 64、R 65如在权利要求3中所定义。
  20. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(Ip-2)化合物：
    Figure PCTCN2019081840-appb-100020
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义。
  21. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(Iq-2)化合物：
    Figure PCTCN2019081840-appb-100021
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义。
  22. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(Ir-2)化合物：
    Figure PCTCN2019081840-appb-100022
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义，以及基团R 66如在权利要求3中所定义。
  23. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(Is-2)化合物：
    Figure PCTCN2019081840-appb-100023
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义，以及基团X 1、Y 1、Z 1如在权利要求3中所定义。
  24. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(It-2)化合物：
    Figure PCTCN2019081840-appb-100024
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义。
  25. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(Iu-2)化合物：
    Figure PCTCN2019081840-appb-100025
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义。
  26. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(Iv-2)化合物：
    Figure PCTCN2019081840-appb-100026
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义。
  27. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(Iw-2)化合物：
    Figure PCTCN2019081840-appb-100027
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义。
  28. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(Ix-2)化合物：
    Figure PCTCN2019081840-appb-100028
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义，以及基团R 67如在权利要求3中所定义。
  29. 如权利要求3所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(Iy-2)化合物：
    Figure PCTCN2019081840-appb-100029
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义。
  30. 如权利要求2所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述SMBP表示由式(It-3)所表示的化学部分：
    Figure PCTCN2019081840-appb-100030
  31. 如权利要求30所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(It-3-1)化合物：
    Figure PCTCN2019081840-appb-100031
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义。
  32. 如权利要求2所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述SMBP表示由式(It-4)所表示的化学部分：
    Figure PCTCN2019081840-appb-100032
  33. 如权利要求32所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(It-4-1)化合物：
    Figure PCTCN2019081840-appb-100033
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义。
  34. 如权利要求2所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述SMBP表示由式(It-5)所表示的化学部分：
    Figure PCTCN2019081840-appb-100034
  35. 如权利要求34所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述式(I)化合物亦是式(It-5-1)化合物：
    Figure PCTCN2019081840-appb-100035
    其中，基团LIN、R、环原子A、B、X、Y、Z如在权利要求1中所定义。
  36. 如权利要求1-29、30、31、32、33、34、或35中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中在式(II)中，环原子A表示CH 2或CO，环原子B、X、Y、Z相同且均表示CH，以及R表示S、SO、SO 2或哌嗪亚基。
  37. 如权利要求1-29、30、31、32、33、34、35、或36中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示： -U-C 1-30亚烷基-，-U-(CH 2) n1-(O(CH 2) n2) m1-，-U-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-，-U-(CR a1R a2) n1-(O(CR a3R a4) n2) m1-，-U-(CR a5R a6) n1-(O(CR a7R a8) n2) m1-(O(CR a9R a10) n3) m2-，-U-(CH 2) n1-(CONH-(CH 2) n2) m1-，-U-(CH 2) n1-(CONH-(CH 2) n2) m1-(O(CH 2) n3) m2-，-U-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-CONH-(CH 2) n4-(O(CH 2) n5) m2-O-(CH 2) n6-，-U-(CR a11R a12) n1-(O(CR a13R a14) n2) m1-O-(CR a15R a16) n3-CONH-(CR a17R a18) n4-(O(CR a19R a20) n5) m2-O-(CR a21R a22) n6-，-U-(CR a23R a24) n1-CONH-(O(CR a25R a26) n2) m1-，-U-(CH 2) n1-(NHCO-(CH 2) n2) m1-，-U-(CH 2) n1-(NHCO-(CH 2) n2) m1-(O(CH 2) n3) m2-，由一或多个亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次的直链或支链的-U-亚烷基链-，或其碳链被一或多个亚芳基或亚杂环基或亚杂芳基或它们的任意组合中断一或多次的-U-(CH 2) n1-(O(CH 2) n2) m1-；
    R a1、R a2、R a3、R a4、R a5、R a6、R a7、R a8、R a9、R a10、R a11、R a12、R a13、R a14、R a15、R a16、R a17、R a18、R a19、R a20、R a21、R a22、R a23、R a24、R a25、R a26分别独立地表示H、直链或支链的C 1-C 10烷基或C 3-C 10环烷基，其中在相同的所述LIN中时，R a1、R a2、R a3、R a4，R a5、R a6、R a7、R a8、R a9、R a10，R a11、R a12、R a13、R a14、R a15、R a16、R a17、R a18、R a19、R a20、R a21、R a22，或R a23、R a24、R a25、R a26不同时为H；
    n1、n2、n3、n4、n5、n6、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。
  38. 如权利要求37所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示：
    -U-CH 2-；-U-(CH 2) 2-；-U-(CH 2) 3-；-U-(CH 2) 4-；-U-(CH 2) 5-；-U-(CH 2) 6-；-U-(CH 2) 7-；-U-(CH 2) 8-；-U-(CH 2) 9-；-U-(CH 2) 10-；-U-(CH 2) 11-；-U-(CH 2) 12-；-U-(CH 2) 13-；-U-(CH 2) 14-；-U-(CH 2) 15-；-U-(CH 2) 16-；-U-(CH 2) 17-；-U-(CH 2) 18-；-U-(CH 2) 19-；-U-(CH 2) 20-；-U-(CH 2) 21-；-U-(CH 2) 22-；-U-(CH 2) 23-；-U-(CH 2) 24-；-U-(CH 2) 25-；-U-(CH 2) 26-；-U-(CH 2) 27-；-U-(CH 2) 28-；-U-(CH 2) 29-；或-U-(CH 2) 30-。
  39. 如权利要求37所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示：
    -U-CH 2-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 2) 6-、-U-CH 2-(O(CH 2) 2) 7-、-U-CH 2-(O(CH 2) 2) 8-、-U-CH 2-(O(CH 2) 2) 9-、-U-CH 2-(O(CH 2) 2) 10-、-U-(CH 2) 2-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-、-U- (CH 2) 2-(O(CH 2) 2) 7-、-U-(CH 2) 2-(O(CH 2) 2) 8-、-U-(CH 2) 2-(O(CH 2) 2) 9-、-U-(CH 2) 2-(O(CH 2) 2) 10-、-U-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-、-U-(CH 2) 3-(O(CH 2) 2) 7-、-U-(CH 2) 3-(O(CH 2) 2) 8-、-U-(CH 2) 3-(O(CH 2) 2) 9-、-U-(CH 2) 3-(O(CH 2) 2) 10-、-U-(CH 2) 4-O-(CH 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 2-、-U-(CH 2) 4-(O(CH 2) 2) 3-、-U-(CH 2) 4-(O(CH 2) 2) 4-、-U-(CH 2) 4-(O(CH 2) 2) 5-、-U-(CH 2) 4-(O(CH 2) 2) 6-、-U-(CH 2) 4-(O(CH 2) 2) 7-、-U-(CH 2) 4-(O(CH 2) 2) 8-、-U-(CH 2) 4-(O(CH 2) 2) 9-、-U-(CH 2) 4-(O(CH 2) 2) 10-、-U-CH 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 3) 6-、-U-CH 2-(O(CH 2) 3) 7-、-U-CH 2-(O(CH 2) 3) 8-、-U-CH 2-(O(CH 2) 3) 9-、-U-CH 2-(O(CH 2) 3) 10-、-U-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-、-U-(CH 2) 2-(O(CH 2) 3) 7-、-U-(CH 2) 2-(O(CH 2) 3) 8-、-U-(CH 2) 2-(O(CH 2) 3) 9-、-U-(CH 2) 2-(O(CH 2) 3) 10-、-U-(CH 2) 3-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-、-U-(CH 2) 3-(O(CH 2) 3) 7-、-U-(CH 2) 3-(O(CH 2) 3) 8-、-U-(CH 2) 3-(O(CH 2) 3) 9-、-U-(CH 2) 3-(O(CH 2) 3) 10-、-U-CH 2-O-(CH 2) 2-O-(CH 2) 3-、-U-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、-U-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、-U-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、-U-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、-U-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、-U-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、-U-CH 2-O-(CH 2) 3-O-(CH 2) 2-、-U-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、-U-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、-U-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、-U-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、-U-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、-U-CH 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-O-(CH 2) 2-O-CH 2-、-U-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、-U-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、-U-(CH 2) 5- (O(CH 2) 2) 2-O-(CH 2) 5-、或-U-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-。
  40. 如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述取代基选自羟基、氨基、巯基、卤素或其组合。
  41. 如权利要求40所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示-U-C 1-30亚烷基链-，所述C 1-30亚烷基链是由一或多个选自羟基、氨基、巯基、卤素或其组合的取代基取代的直链或支链的C 1-30亚烷基链-。
  42. 如权利要求37所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示：-U-(CH 2) n11-亚三唑基-(CH 2) n12-、-U-(CH 2) n11-亚三唑基-(CH 2) n12-(O(CH 2) n13) m11-、-U-(CH 2) n11-(O(CH 2) n12) m11-O-(CH 2) n13-亚三唑基-(CH 2) n14-(O(CH 2) n15) m12-O-(CH 2) n16-、-U-(CH 2) n11-亚三唑基-(CH 2) n12-(O(CH 2) n13) m11-O-(CH 2) n14-或-U-(CH 2) n11-(O(CH 2) n12) m11-O-(CH 2) n13-亚三唑基-(CH 2) n14-；以及
    n11、n12、n13、n14、n15、n16、m11、m12分别独立地表示1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数。
  43. 如权利要求42所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示：-U-(CH 2) 3-亚三唑基-(CH 2) 5-、-U-(CH 2) 2-亚三唑基-(CH 2) 5-、-U-CH 2-亚三唑基-(CH 2) 5-、-U-(CH 2) 2-亚三唑基-(CH 2) 4-、-U-(CH 2) 3-亚三唑基-(CH 2) 2-O(CH 2) 2-、-U-(CH 2) 2-亚三唑基-(CH 2) 2-O(CH 2) 2-或-U-CH 2-亚三唑基-(CH 2) 2-O(CH 2) 2-。
  44. 权利要求42所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示：
    Figure PCTCN2019081840-appb-100036
    Figure PCTCN2019081840-appb-100037
  45. 如权利要求37所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示：
    -U-CH 2CONHCH 2-、-U-(CH 2) 2CONH(CH 2) 2-、-U-(CH 2) 3CONH(CH 2) 3-、-U-(CH 2) 3CONH(CH 2) 4-、-U-(CH 2) 4CONH(CH 2) 4-、-U-(CH 2) 5CONH(CH 2) 5-、-U-(CH 2) 6CONH(CH 2) 7-、-U-(CH 2) 6CONH(CH 2) 6-、-U-(CH 2) 7CONH(CH 2) 7-、-U-(CH 2) 8CONH(CH 2) 8、-U-(CH 2) 9CONH(CH 2) 9-、-U-(CH 2) 10CONH(CH 2) 10-、-U-(CH 2) 2CONH(CH 2) 5-、-U-(CH 2) 2CONH(CH 2) 3-、-U-(CH 2) 2CONH(CH 2) 4-、或-U-(CH 2) 2CONH(CH 2) 2-O-(CH 2) 2-。
  46. 如权利要求37所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示：-U-CH 2NHCOCH 2-、-U-(CH 2) 2NHCO(CH 2) 2-、-U-(CH 2) 3NHCO(CH 2) 3-、-U-(CH 2) 3NHCO(CH 2) 4-、-U-(CH 2) 4NHCO(CH 2) 4-、-U-(CH 2) 5NHCO(CH 2) 5-、-U-(CH 2) 6NHCO(CH 2) 7-、-U-(CH 2) 6NHCO(CH 2) 6-、-U-(CH 2) 7NHCO(CH 2) 7-、-U-(CH 2) 8NHCO(CH 2) 8、-U-(CH 2) 9NHCO(CH 2) 9-、-U-(CH 2) 10NHCO(CH 2) 10-、-U-(CH 2) 2NHCO(CH 2) 5-、-U-(CH 2) 2NHCO(CH 2) 3-、-U-(CH 2) 2NHCO(CH 2) 4-、-U-(CH 2) 4NHCO(CH 2) 8-或-U-(CH 2) 2NHCO(CH 2) 2-O-(CH 2) 2-。
  47. 如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其选自：
    7-环戊基-2-((5-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(11-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)十一烷酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)丙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)丙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    2-(2,6-二氧代哌啶-3-基)-4-((2-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-2-氧代乙基)硫基)异吲哚啉-1,3-二酮；
    3-(4-((6-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-6-氧代己基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((6-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)己基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((8-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-8-氧代辛基)硫基)异吲哚啉-1,3-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((8-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)辛基)硫基)异吲哚啉-1,3-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((12-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-12-氧代十二烷基)硫基)异吲哚啉-1,3-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((2-(3-(3-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-3-氧代丙氧基)丙氧基)乙基)硫基)异吲哚啉-1,3-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((2-(3-(3-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)丙氧基)丙氧基)乙基)硫基)异吲哚啉-1,3-二 酮；
    2-(2,6-二氧代哌啶-3-基)-4-((2-(2-(2-(3-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-3-氧代丙氧基)乙氧基)乙氧基)乙基)硫基)异吲哚啉-1,3-二酮；
    3-(4-((2-(2-(2-(3-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-3-氧代丙氧基)乙氧基)乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(2-(2-(3-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)丙氧基)乙氧基)乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((15-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-15-氧代-3,6,9,12-四氧杂十五烷基)硫基)异吲哚啉-1,3-二酮；
    4-((2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-2-氧代乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-2-氧代乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-2-氧代乙基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-2-氧代乙基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((3-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-3-氧代丙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((3-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-3-氧代丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((3-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)丙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((3-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((4-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-4-氧代丁基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((4-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-4-氧代丁基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((4-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)丁基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((5-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-5-氧代戊基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((5-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-5-氧代戊基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((5-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)戊基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((5-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)戊基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((6-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-6-氧代己基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((6-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-6-氧代己基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((6-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶- 3-基)哌嗪-1-基)己基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((7-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-7-氧代庚基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((7-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-7-氧代庚基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((7-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)庚基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-2-氧代乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((2-(2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-2-氧代乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((2-(2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(3-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-3-氧代丙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((2-(3-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-3-氧代丙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((2-(3-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)丙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-(3-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-3-氧代丙氧基)乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((2-(2-(3-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-3-氧代丙氧基)乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((2-(2-(3-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)丙氧基)乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-(2-(3-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-3-氧代丙氧基)乙氧基)乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异 吲哚啉-1,3-二酮；
    3-(4-((2-(2-(2-(3-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-3-氧代丙氧基)乙氧基)乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((15-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-15-氧代-3,6,9,12-四氧杂十五烷基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((15-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-3,6,9,12-四氧杂十五烷基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((18-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-18-氧代-3,6,9,12,15-五氧杂十八烷基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((18-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-18-氧代-3,6,9,12,15-五氧杂十八烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((18-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-3,6,9,12,15-五氧杂十八烷基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((18-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-3,6,9,12,15-五氧杂十八烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((6-(4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-基)-6-氧代己基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(3-(4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-基)-3-氧代丙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((6-(4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-基)-6-氧代己基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(3-(4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-基)-3-氧代丙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((2-(3-(4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-基)丙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((2-(3-(4-(4-(6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)吡啶-3-基)-1H-吡唑-1-基)哌啶-1-基)丙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((6-(4-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-6-氧代己基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((6-(4-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)己基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((6-(4-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-6-氧代己基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((6-(4-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)己基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((2-(3-(4-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-3-氧代丙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((9-(4-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-9-氧代壬基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-(3-(4-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-3-氧代丙氧基)乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-(3-(4-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)丙氧基)乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((2-(2-(3-(4-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-3-氧代丙氧基)乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((2-(2-(2-(3-(4-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-3-氧代丙氧基)乙氧基)乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((2-(2-(2-(3-(4-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-异丙氧基-2-甲基苯基)哌啶-1-基)-3-氧代丙氧基)乙氧基)乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((2-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)-2-氧代乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((2-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)-2-氧代乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((3-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)-3-氧代丙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((3-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)丙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((4-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)-4-氧代丁基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((4-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)-4-氧代丁基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((5-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)-5-氧代戊基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((5-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)戊基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((6-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)-6-氧代己基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((6-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)-6-氧代己基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((7-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)-7-氧代庚基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((7-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)庚基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((7-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)庚基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((11-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)-11-氧代十一烷基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-(2-(2-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基) 哌嗪-1-基)-2-氧代乙氧基)乙氧基)乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-(2-(2-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)乙氧基)乙氧基)乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((11-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十一烷基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((11-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)-11-氧代十一烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(2-(2-(2-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)-2-氧代乙氧基)乙氧基)乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((11-(4-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十一烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰胺；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-甲基乙酰胺；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰胺；
    4-((2-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)(甲基)氨基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰胺；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙酰胺；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-甲基丙酰胺；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-N-甲基丙酰胺；
    4-((3-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4- 基)(甲基)氨基)丙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((3-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)(甲基)氨基)丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰胺；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁酰胺；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-甲基丁酰胺；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-N-甲基丁酰胺；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰胺；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-甲基戊酰胺；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酰胺；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰胺；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰胺；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰胺；
    4-((7-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)氨基)庚基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((3-(3-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)氨基)丙氧基)丙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((3-(3-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)(甲基)氨基)丙氧基)丙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((7-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)(甲基)氨基)庚基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((7-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)氨基)庚基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((7-((1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)(甲基)氨基)庚基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((2-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-2-氧代乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((2-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-2-氧代乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((3-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-3-氧代丙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((3-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)丙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((4-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-4-氧代丁基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((4-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-4-氧代丁基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((4-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)丁基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((5-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-5-氧代戊基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((5-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-5-氧代戊基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((5-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)戊基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((6-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-6-氧代己基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((6-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌 啶-4-基)哌嗪-1-基)-6-氧代己基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((7-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-7-氧代庚基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((3-(3-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-3-氧代丙氧基)丙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((3-(3-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)丙氧基)丙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(4-((3-(3-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-3-氧代丙氧基)丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((7-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-7-氧代庚基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((7-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)庚基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    8-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(3-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙氧基)丙酰基)哌嗪-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己基)哌嗪-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(3-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙氧基)丙基)哌嗪-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-10-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)癸酰胺；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-3-(2-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙氧基)乙氧基)丙酰胺；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-10-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-甲基癸酰胺；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-3-(2-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙氧基)乙氧基)-N-甲基丙酰胺；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-10-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)癸酰胺；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-3-(2-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙氧基)乙氧基)丙酰胺；
    8-(4-(4-(9-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)壬酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(4-(9-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)壬基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)丙基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(4-(9-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)壬酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)丙酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(4-(9-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)壬基)哌嗪-1-基)哌啶-1- 基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(4-(3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)丙基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-N-(4-((3R,5S)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰基)-3,5-二甲基哌嗪-1-羰基)苯基)哒嗪-3-甲酰胺；
    6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-N-(4-((3R,5S)-4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)-3,5-二甲基哌嗪-1-羰基)苯基)哒嗪-3-甲酰胺；
    6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-N-(4-((3R,5S)-4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己基)-3,5-二甲基哌嗪-1-羰基)苯基)哒嗪-3-甲酰胺；
    6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-N-(4-((3R,5S)-4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰基)-3,5-二甲基哌嗪-1-羰基)苯基)哒嗪-3-甲酰胺；
    6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-N-(4-((3R,5S)-4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己基)-3,5-二甲基哌嗪-1-羰基)苯基)哒嗪-3-甲酰胺；
    6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-N-(4-((3R,5S)-4-(12-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)十二烷酰基)-3,5-二甲基哌嗪-1-羰基)苯基)哒嗪-3-甲酰胺；
    6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-N-(4-((3R,5S)-4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)丙酰基)-3,5-二甲基哌嗪-1-羰基)苯基)哒嗪-3-甲酰胺；
    6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-N-(4-((3R,5S)-4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)丙基)-3,5-二甲基哌嗪-1-羰基)苯基)哒嗪-3-甲酰胺；
    6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-N-(4-((3R,5S)-4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)丙酰基)-3,5-二甲基哌嗪-1-羰基)苯基)哒嗪-3-甲酰胺；
    6-氨基-5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-N-(4-((3R,5S)-4-(3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)丙基)-3,5-二甲基哌嗪-1-羰基)苯基)哒嗪-3-甲酰胺；
    4-((4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    4-((4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)乙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)乙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基) 乙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(3-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)丙氧基)丙酰基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)丙酰基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙氧基)丙基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    4-((2,4-二氯-5-甲氧基苯基)氨基)-7-(3-(4-(3-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙氧基)丙基)哌嗪-1-基)丙氧基)-6-甲氧基喹啉-3-甲腈；
    N-(4-((4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺；
    N-(4-((4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺；
    N-(4-((4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺；
    N-(4-((4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺；
    N-(4-((4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺；
    N-(4-((4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺；
    N-(4-((4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧 基)乙氧基)乙酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺；
    N-(4-((4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺；
    N-(4-((4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺；
    N-(4-((4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺；
    2-(2,6-二氧代哌啶-3-基)-4-((2-(4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)哌嗪-1-基)-2-氧代乙基)硫基)异吲哚啉-1,3-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((3-(4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)哌嗪-1-基)-3-氧代丙基)硫基)异吲哚啉-1,3-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((4-(4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)哌嗪-1-基)-4-氧代丁基)硫基)异吲哚啉-1,3-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((5-(4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)哌嗪-1-基)-5-氧代戊基)硫基)异吲哚啉-1,3-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((6-(4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)哌嗪-1-基)-6-氧代己基)硫基)异吲哚啉-1,3-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((7-(4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)哌嗪-1-基)-7-氧代庚基)硫基)异吲哚啉-1,3-二酮；
    3-(4-((2-(4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)哌嗪-1-基)-2-氧代乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((3-(4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)哌嗪-1-基)丙基)硫基)异吲哚啉-1,3-二酮；
    3-(4-((4-(4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)哌嗪-1-基)丁基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((2-(2-(4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)哌嗪-1-基)-2-氧代乙氧基)乙基)硫基)异吲哚啉-1,3-二酮；
    3-(4-((2-(3-(4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)哌嗪-1-基)-3-氧代丙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((2-(2-(2-(2-(4-(2-氟-5-((4-氧代-3,4-二氢酞嗪-1-基)甲基)苯甲酰基)哌嗪-1-基)-2-氧代乙氧基)乙氧基)乙氧基)乙基)硫基)异吲哚啉-1,3-二酮；
    2-(4-((3S)-1-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰基)哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺；
    2-(4-((3S)-1-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰基)哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺；
    2-(4-((3S)-1-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰基)哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺；
    2-(4-((3S)-1-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰基)哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺；
    2-(4-((3S)-1-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺；
    2-(4-((3S)-1-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺；
    2-(4-((3S)-1-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰基)哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺；
    2-(4-((3S)-1-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙基)哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺；
    2-(4-((3S)-1-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺；
    2-(4-((3S)-1-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺；
    2-(4-((3S)-1-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)丙基)哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺；
    2-(4-((3S)-1-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)丙基)哌啶- 3-基)苯基)-2H-吲唑-7-甲酰胺；
    2-(4-((3S)-1-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺；
    2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-(4-(8-氟-1-氧代-2,3,4,6-四氢-1H-氮杂
    Figure PCTCN2019081840-appb-100038
    并[5,4,3-cd]吲哚-5-基)苄基)-N-甲基乙酰胺；
    3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-(4-(8-氟-1-氧代-2,3,4,6-四氢-1H-氮杂
    Figure PCTCN2019081840-appb-100039
    并[5,4,3-cd]吲哚-5-基)苄基)-N-甲基丙酰胺；
    4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-(4-(8-氟-1-氧代-2,3,4,6-四氢-1H-氮杂
    Figure PCTCN2019081840-appb-100040
    并[5,4,3-cd]吲哚-5-基)苄基)-N-甲基丁酰胺；
    5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-(4-(8-氟-1-氧代-2,3,4,6-四氢-1H-氮杂
    Figure PCTCN2019081840-appb-100041
    并[5,4,3-cd]吲哚-5-基)苄基)-N-甲基戊酰胺；
    6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-(4-(8-氟-1-氧代-2,3,4,6-四氢-1H-氮杂
    Figure PCTCN2019081840-appb-100042
    并[5,4,3-cd]吲哚-5-基)苄基)-N-甲基己酰胺；
    7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-(4-(8-氟-1-氧代-2,3,4,6-四氢-1H-氮杂
    Figure PCTCN2019081840-appb-100043
    并[5,4,3-cd]吲哚-5-基)苄基)-N-甲基庚酰胺；
    2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-N-(4-(8-氟-1-氧代-2,3,4,6-四氢-1H-氮杂
    Figure PCTCN2019081840-appb-100044
    并[5,4,3-cd]吲哚-5-基)苄基)-N-甲基乙酰胺；
    3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-N-(4-(8-氟-1-氧代-2,3,4,6-四氢-1H-氮杂
    Figure PCTCN2019081840-appb-100045
    并[5,4,3-cd]吲哚-5-基)苄基)-N-甲基丙酰胺；
    4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-N-(4-(8-氟-1-氧代-2,3,4,6-四氢-1H-氮杂
    Figure PCTCN2019081840-appb-100046
    并[5,4,3-cd]吲哚-5-基)苄基)-N-甲基丁酰胺；
    2-(2,6-二氧代哌啶-3-基)-4-((5-((4-(8-氟-1-氧代-2,3,4,6-四氢-1H-氮杂
    Figure PCTCN2019081840-appb-100047
    并[5,4,3-cd]吲哚-5-基)苄基)(甲基)氨基)戊基)硫基)异吲哚啉-1,3-二酮；
    3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)-N-(4-(8-氟-1-氧代-2,3,4,6-四氢-1H-氮杂
    Figure PCTCN2019081840-appb-100048
    并[5,4,3-cd]吲哚-5-基)苄基)-N-甲基丙酰胺；
    3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)-N-(4-(8-氟-1-氧代-2,3,4,6-四氢-1H-氮杂
    Figure PCTCN2019081840-appb-100049
    并[5,4,3-cd]吲哚-5-基)苄基)-N-甲基丙酰胺；
    3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)-N-(4-(8-氟-1-氧代-2,3,4,6-四氢-1H-氮杂
    Figure PCTCN2019081840-appb-100050
    并[5,4,3-cd]吲哚-5-基)苄基)-N-甲基丙酰胺；
    3-(4-((2-(2-(3-((4-(8-氟-1-氧代-2,3,4,6-四氢-1H-氮杂
    Figure PCTCN2019081840-appb-100051
    并[5,4,3-cd]吲哚-5-基)苄基)(甲基)氨基)丙氧基)乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    (Z)-N-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-甲基乙酰胺；
    (Z)-N-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-甲基丙酰胺；
    (Z)-N-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-甲基丁酰胺；
    (Z)-N-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-甲基戊酰胺；
    (Z)-N-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-甲基己酰胺；
    (Z)-N-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-甲基庚酰胺；
    (Z)-N-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)-N-甲基丙酰胺；
    (Z)-N-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)-N-甲基丙酰胺；
    (Z)-N-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)-N-甲基丙酰胺；
    (Z)-N-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-甲基-3,6,9,12-四氧杂十五烷-15-酰胺；
    (Z)-N-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-甲基-3,6,9,12,15-五氧杂十八烷-18-酰胺；
    (Z)-N-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-N-甲基己酰胺；
    (Z)-N-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)-N-甲基丙酰胺；
    (Z)-N-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-12-((2-(2,6-二氧代哌啶-3-基)-1-氧 代异吲哚啉-4-基)硫基)-N-甲基十二烷酰胺；
    (Z)-N-(2-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-1-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-N-甲基-3,6,9,12-四氧杂十五烷-15-酰胺；
    (Z)-4-((21-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)-19-甲基-3,6,9,12,15-五氧杂-19-氮杂二十一烷基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    (Z)-3-(4-((21-(4-(4-氯-1,2-二苯基丁-1-烯-1-基)苯氧基)-19-甲基-3,6,9,12,15-五氧杂-19-氮杂二十一烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    (Z)-6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-N-甲基己酰胺；
    (Z)-9-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-N-甲基壬酰胺；
    (Z)-3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)-N-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-N-甲基丙酰胺；
    (Z)-1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-N-甲基-3,6,9,12-四氧杂十五烷-15-酰胺；
    (Z)-1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-N-甲基-3,6,9,12,15-五氧杂十八烷-18-酰胺；
    (Z)-6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-N-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-N-甲基己酰胺；
    (Z)-9-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-N-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-N-甲基壬酰胺；
    (Z)-3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)-N-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-N-甲基丙酰胺；
    (Z)-1-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-N-(2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)-N-甲基-3,6,9,12-四氧杂十五烷-15-酰胺；
    (Z)-3-(4-((18-((2-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)乙基)(甲基)氨基)十八烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    (Z)-3-(4-((21-(4-(1,2-二苯基丁-1-烯-1-基)苯氧基)-19-甲基-3,6,9,12,15-五氧杂-19-氮杂二十一烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    (Z)-3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)-N-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-N-甲基丙酰胺；
    (Z)-3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)-N-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-N-甲基丙酰胺；
    (Z)-3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)-N-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-N-甲基丙酰胺；
    (Z)-1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-N-甲基-3,6,9,12-四氧杂十五烷-15-酰胺；
    (Z)-2-(2,6-二氧代哌啶-3-基)-4-((21-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)-19-甲基-3,6,9,12,15-五氧杂-19-氮杂二十一烷基)硫基)异吲哚啉-1,3-二酮；
    (Z)-12-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-N-甲基十二烷酰胺；
    (Z)-2-(2,6-二氧代哌啶-3-基)-4-((12-((2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)(甲基)氨基)十二烷基)硫基)异吲哚啉-1,3-二酮；
    (Z)-15-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-N-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-N-甲基十五烷酰胺；
    (Z)-3-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)-N-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-N-甲基丙酰胺；
    (Z)-9-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-N-(2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-N-甲基壬酰胺；
    (Z)-3-(4-((9-((2-(4-(1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)(甲基)氨基)壬基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100052
    -6-基)-N-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100053
    -6-基)-N-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100054
    -6-基)-N-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100055
    -6-基)- N-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100056
    -6-基)-N-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100057
    -6-基)-N-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100058
    -6-基)-N-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)辛基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100059
    -6-基)-N-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100060
    -6-基)-N-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100061
    -6-基)-N-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十五烷-15-基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100062
    -6-基)-N-(1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12,15,18-六氧杂二十一烷-21-基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100063
    -6-基)-N-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100064
    -6-基)-N-(1-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十五烷-15-基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100065
    -6-基)-N-(1-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12,15,18-六氧杂二十一烷-21-基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100066
    -6-基)-N-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100067
    -6-基)-N-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100068
    -6-基)-N-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100069
    -6-基)-N-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100070
    -6-基)-N-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100071
    -6-基)-N-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)庚基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100072
    -6-基)-N-(8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)辛基)乙酰胺；
    2-((S)-6-(4-氯苯基)-8-甲氧基-1-甲基-4H-苯并[f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100073
    -4-基)-N-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙基)乙酰胺；
    2-((S)-6-(4-氯苯基)-8-甲氧基-1-甲基-4H-苯并[f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100074
    -4-基)-N-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁基)乙酰胺；
    2-((S)-6-(4-氯苯基)-8-甲氧基-1-甲基-4H-苯并[f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100075
    -4-基)-N-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)乙酰胺；
    2-((S)-6-(4-氯苯基)-8-甲氧基-1-甲基-4H-苯并[f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100076
    -4-基)-N-(10-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)癸基)乙酰胺；
    2-((S)-6-(4-氯苯基)-8-甲氧基-1-甲基-4H-苯并[f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100077
    -4-基)-N-(3-(2-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙氧基)乙氧基)丙基)乙酰胺；或
    2-((S)-6-(4-氯苯基)-8-甲氧基-1-甲基-4H-苯并[f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100078
    -4-基)-N-(3-(2-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙氧基)乙氧基)丙基)乙酰胺。
  48. 如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其选自：
    7-环戊基-2-((5-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十四碳酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七碳酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰 胺；
    7-环戊基-2-((5-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十四碳酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    7-环戊基-2-((5-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七碳酰基)哌嗪-1-基)吡啶-2-基)氨基)-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺；
    2-(2,6-二氧代哌啶-3-基)-4-((3-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-3-氧代丙基)硫基)异吲哚啉-1,3-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((4-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-4-氧代丁基)硫基)异吲哚啉-1,3-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((5-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-5-氧代戊基)硫基)异吲哚啉-1,3-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((6-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-6-氧代己基)硫基)异吲哚啉-1,3-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((7-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-7-氧代庚基)硫基)异吲哚啉-1,3-二酮；
    3-(4-((2-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-2-氧代乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((3-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-3-氧代丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((4-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-4-氧代丁基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((5-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-5-氧代戊基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((6-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)己基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((7-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-7-氧代庚基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((11-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-11-氧代十一烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((2-(2-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-2-氧代乙氧基)乙基)硫基)异吲哚啉-1,3-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((2-(2-(2-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-2-氧代乙氧基)乙氧基)乙基)硫基)异吲哚啉-1,3-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((2-(2-(2-(2-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-2-氧代乙氧基)乙氧基)乙氧基)乙基)硫基)异吲哚啉-1,3-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((14-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-14-氧代-3,6,9,12-四氧杂十四烷基)硫基)异吲哚啉-1,3-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-((17-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-17-氧代-3,6,9,12,15-五氧杂十七烷基)硫基)异吲哚啉-1,3-二酮；
    3-(4-((2-(2-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-2-氧代乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(2-(2-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-2-氧代乙氧基)乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(2-(2-(2-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-2-氧代乙氧基)乙氧基)乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((14-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-14-氧代-3,6,9,12-四氧杂十四烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((17-(4-((6-((5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)嘧啶-2-基)氨基)吡啶-3-基)甲基)哌嗪-1-基)-17-氧代-3,6,9,12,15-五氧杂十七烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶- 2,6-二酮；
    4-((2-(2-(2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-2-氧代乙氧基)乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-(2-(2-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-2-氧代乙氧基)乙氧基)乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((14-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-14-氧代-3,6,9,12-四氧杂十四烷基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((17-(4-(6-((6-乙酰基-8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)-17-氧代-3,6,9,12,15-五氧杂十七烷基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙酰胺；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙酰胺；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酰胺；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙酰胺；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十四烷-1-酰胺；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷-1-酰胺；
    3-(4-((2-(2-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-2-氧代乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰胺；
    8-(4-((2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙基)氨基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰胺；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰胺；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰胺；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰胺；
    8-(4-((6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己基)氨基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰胺；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰胺；
    8-(4-((2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙基)氨基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙酰胺；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁酰胺；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酰胺；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰胺；
    8-(4-((6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己基)氨基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-7-((2- (2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)庚酰胺；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙酰胺；
    8-(4-((2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙基)氨基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酰胺；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙酰胺；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十四烷酰胺；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-17-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酰胺；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙酰胺；
    8-(4-((2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙基)氨基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酰胺；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙酰胺；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十四烷酰胺；
    N-(1-(3-氰基-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-8-基)哌啶-4-基)-17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酰胺；
    8-(4-(1-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰基)哌啶-4-基)哌嗪-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)哌啶 -1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(4-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(4-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(4-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(4-(14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十四碳酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    8-(4-(4-(17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七碳酰基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙基) 哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(2-氯-6-甲基苯基)-2-((6-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙基)哌嗪-1-基)-2-甲基嘧啶-4-基)氨基)噻唑-5-甲酰胺；
    N-(4-((4-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺；
    N-(4-((4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺；
    N-(4-((4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺；
    N-(4-((4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺；
    N-(4-((4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺；
    N-(4-((4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺；
    N-(4-((4-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)庚酰基)哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯甲酰胺；
    2-(4-((3S)-1-(3-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙氧基)丙酰基)哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺；
    N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰胺；
    N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰胺；
    N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰胺；
    N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰胺；
    N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰胺；
    N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰胺；
    N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰胺；
    N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙酰胺；
    N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁酰胺；
    N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酰胺；
    N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰胺；
    N-(2-(4-(4-氯-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)苯氧基)乙基)-7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)庚酰胺；
    N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰胺；
    N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酰胺；
    N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酰胺；
    N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酰胺；
    N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰胺；
    N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酰胺；
    N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰胺；
    N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-3-((2-(2,6-二氧代哌啶-3-基)-1-氧代 异吲哚啉-4-基)硫基)丙酰胺；
    N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁酰胺；
    N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰胺；
    N-(2-(4-(1,2-二(4-羟基苯基)丁-1-烯-1-基)苯氧基)乙基)-7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)庚酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100079
    -6-基)-N-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100080
    -6-基)-N-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100081
    -6-基)-N-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100082
    -6-基)-N-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰氨基)丁基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100083
    -6-基)-N-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰氨基)丁基)乙酰胺；
    3-(4-((2-(4-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100084
    -6-基)乙酰基)哌嗪-1-基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((3-(4-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100085
    -6-基)乙酰基)哌嗪-1-基)丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((4-(4-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100086
    -6-基)乙酰基)哌嗪-1-基)丁基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((5-(4-(2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100087
    -6-基)乙酰基)哌嗪-1-基)戊基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100088
    -6-基)-N-(2-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙基)哌嗪-1-基)乙基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100089
    -6-基)-N-(2-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙基)哌嗪-1-基)乙基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100090
    -6-基)-N-(2-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁基)哌嗪-1-基)乙基)乙酰胺；
    2-((S)-4-(4-氯苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
    Figure PCTCN2019081840-appb-100091
    -6-基)-N-(2-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊基)哌嗪-1-基)乙基)乙酰胺；
    N-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)-7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)庚酰胺；
    3-(4-((3-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)-3-氧代丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((6-(4-(1-(4-((5-氯-4-((2-(二甲基膦酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-基)哌嗪-1-基)己基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    8-(4-(4-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈；或
    8-(4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己基)哌嗪-1-基)哌啶-1-基)-9-乙基-6,6-二甲基-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈。
  49. 医药组合物，其包含如权利要求1至48中任一项所述的式(I)化合物或其医药学上可接受的盐，及至少一种医药学上可接受的载体。
  50. 如权利要求49所述的医药组合物，进一步包括至少一种额外的治疗或预防癌症的药物。
  51. 如权利要求1至48中任一项所述的式(I)化合物，或其医药学上可接受的盐，其是用作药剂。
  52. 如权利要求1至48中任一项所述的式(I)化合物，或其医药学上可接受的盐，其用于预防及/或治疗癌症。
  53. 如权利要求52所述的式(I)化合物，或其医药学上可接受的盐，其中所述癌症选自：与细胞周期蛋白依赖性激酶(CDK4/6)相关的肿瘤；与间变性淋巴瘤激酶(ALK)相关的肿 瘤；与Bcr-abl靶点相关的肿瘤；与聚腺苷二磷酸-核糖聚合酶(PARP)相关的肿瘤；与雌激素受体(ER)相关的肿瘤；或与BET溴结构域蛋白相关的肿瘤。
  54. 如权利要求53所述的式(I)化合物，或其医药学上可接受的盐，其中所述癌症选自：绝经妇女晚期乳腺癌，乳腺癌，晚期乳腺癌，转移性乳腺癌，中枢神经肿瘤，非小细胞肺癌，ROS1阳性非小细胞肺癌，间变性淋巴瘤激酶(ALK)阳性非小细胞肺癌，转移性非小细胞肺癌，骨髓增生异常综合征，骨髓及外骨髓增殖，胃肠道间质瘤，侵略性系统性肥大细胞增多症，嗜酸性粒细胞增多症，隆凸性皮肤纤维肉瘤，慢性嗜酸性白血病，急性淋巴细胞白血病，慢性髓细胞性白血病，BRCA突变/HER-2阴性转移性乳腺癌，原发性腹膜癌，输卵管癌，上皮性卵巢癌，晚期卵巢癌，BRCA突变的晚期卵巢癌，胰腺癌，实体瘤，乳腺癌，转移性乳腺癌，复发性胶质瘤，实体瘤，血液系统恶性肿瘤，或乳腺癌。
  55. 一种如权利要求1至48中任一项所述的式(I)化合物或其医药学上可接受的盐或如权利要求49或50所述的药物组合物的用途，其用于制备用以预防及/或治疗癌症的药剂。
  56. 如权利要求55所述的用途，所述癌症选自由以下组成的群：与细胞周期蛋白依赖性激酶(CDK4/6)相关的肿瘤；与间变性淋巴瘤激酶(ALK)相关的肿瘤；与Bcr-abl靶点相关的肿瘤；与聚腺苷二磷酸-核糖聚合酶(PARP)相关的肿瘤；与雌激素受体(ER)相关的肿瘤；或与BET溴结构域蛋白相关的肿瘤。
  57. 如权利要求56所述的用途，其中所述癌症选自：绝经妇女晚期乳腺癌，乳腺癌，晚期乳腺癌，转移性乳腺癌，中枢神经肿瘤，非小细胞肺癌，ROS1阳性非小细胞肺癌，间变性淋巴瘤激酶(ALK)阳性非小细胞肺癌，转移性非小细胞肺癌，骨髓增生异常综合征，骨髓及外骨髓增殖，胃肠道间质瘤，侵略性系统性肥大细胞增多症，嗜酸性粒细胞增多症，隆凸性皮肤纤维肉瘤，慢性嗜酸性白血病，急性淋巴细胞白血病，慢性髓细胞性白血病，BRCA突变/HER-2阴性转移性乳腺癌，原发性腹膜癌，输卵管癌，上皮性卵巢癌，晚期卵巢癌，BRCA突变的晚期卵巢癌，胰腺癌，实体瘤，乳腺癌，转移性乳腺癌，复发性胶质瘤，实体瘤，血液系统恶性肿瘤，或乳腺癌。
  58. 治疗或预防癌症的方法，其包括向受试者施用治疗有效量的如权利要求1至48中任一项所述的式(I)化合物，或其医药学上可接受的盐，或如权利要求49或50所述的药物组合物。
  59. 如权利要求58所述的方法，其中所述癌症选自：与细胞周期蛋白依赖性激酶(CDK4/6)相关的肿瘤；与间变性淋巴瘤激酶(ALK)相关的肿瘤；与Bcr-abl靶点相关的肿瘤；与聚腺 苷二磷酸-核糖聚合酶(PARP)相关的肿瘤；与雌激素受体(ER)相关的肿瘤；或与BET溴结构域蛋白相关的肿瘤。
  60. 如权利要求58所述的方法，其中所述癌症选自：绝经妇女晚期乳腺癌，乳腺癌，晚期乳腺癌，转移性乳腺癌，中枢神经肿瘤，非小细胞肺癌，ROS1阳性非小细胞肺癌，间变性淋巴瘤激酶(ALK)阳性非小细胞肺癌，转移性非小细胞肺癌，骨髓增生异常综合征，骨髓及外骨髓增殖，胃肠道间质瘤，侵略性系统性肥大细胞增多症，嗜酸性粒细胞增多症，隆凸性皮肤纤维肉瘤，慢性嗜酸性白血病，急性淋巴细胞白血病，慢性髓细胞性白血病，BRCA突变/HER-2阴性转移性乳腺癌，原发性腹膜癌，输卵管癌，上皮性卵巢癌，晚期卵巢癌，BRCA突变的晚期卵巢癌，胰腺癌，实体瘤，乳腺癌，转移性乳腺癌，复发性胶质瘤，实体瘤，血液系统恶性肿瘤，或乳腺癌。
  61. 如权利要求59或60所述的方法，其中通过至少一种选自鼻腔给药、吸入给药、局部给药、口服给药、口腔粘膜给药、直肠给药、胸膜腔给药、腹膜给药、阴道给药、肌内给药、皮下给药、经皮给药、硬膜外腔给药、鞘内给药和静脉给药的给药方式施用至所述受试者。
  62. 式(III)化合物：
    Figure PCTCN2019081840-appb-100092
    其中A表示CH 2或CO，B、X、Y、Z相同或不同且分别独立地表示CH或N，R表示SH、S(O)-烷基、SO 2-烷基或哌嗪基；
    或其盐、对映异构体、立体异构体、溶剂化物、多晶型物。
  63. 如权利要求62所述的式(III)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其选自：
    2-(2,6-二氧代哌啶-3-基)-4-巯基异吲哚啉-1,3-二酮；
    3-(4-巯基-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-(哌嗪-1-基)异吲哚啉-1,3-二酮；
    3-(1-氧代-4-(哌嗪-1-基)异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-(甲基亚磺酰基)异吲哚啉-1,3-二酮；
    3-(4-(甲基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2,6-二氧代哌啶-3-基)-4-(甲基磺酰基)异吲哚啉-1,3-二酮；或
    3-(4-(甲基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮。
  64. 式(IV)化合物：
    Figure PCTCN2019081840-appb-100093
    其中A表示CH 2或CO，B、X、Y、Z相同或不同且分别独立地表示CH或N，R表示S、SO、SO 2或哌嗪亚基；
    LIN是连接基团，表示W-亚烷基-，其中
    所述亚烷基是可选地被一或多个选自以下的基团中断一或多次的直链或支链的亚烷基：O、CONH、NHCO、NH、亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基、亚杂芳基或它们的任意组合，其中所述直链或支链的亚烷基可选地被一或多个取代基取代，且
    W表示氢、离去基团、CHO、COOH或NH 2，其能通过反应将式(IV)化合物的LIN共价连接至能够结合蛋白的小分子化合物SMBP；
    或其盐、对映异构体、立体异构体、溶剂化物、多晶型物。
  65. 如权利要求64所述的式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述能够结合蛋白的小分子化合物SMBP是靶向CDK4/6小分子药物、靶向ALK靶点小分子药物、靶向Bcr-abl靶点的小分子药物、靶向PARP靶点的小分子药物、靶向ER靶点的小分子药物或靶向BET靶点的小分子药物。
  66. 如权利要求65所述的式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述能够结合蛋白的小分子化合物SMBP是：
    Figure PCTCN2019081840-appb-100094
    Figure PCTCN2019081840-appb-100095
    其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、R 15、R 16、R 17、R 18、R 19、R 20、R 21、R 22、R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30、R 31、R 32、R 34、R 35、R 36、R 37、R 38、R 39、R 40、R 41、R 42、R 43、R 44、R 45、R 50、R 51、R 52、R 53、R 54、R 55、R 56、R 57、R 58、R 59、R 60、R 61、R 62、R 63、R 64、R 65、R 66各自独立地为H或甲基，R 33和R 67各自独立地表示H、甲基或乙基；以及
    其中在式(If1)中，环原子Q 1是NH或CH，其中CH被NH 2或哌嗪基取代；
    其中在式(Is1)中，X 1是Cl或H，Y 1是H或OH，Z 1是H或甲基，以及W 1是H。
  67. 如权利要求66所述的式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中在式(Is1)中，X 1是Cl或H，Y 1是H或OH，Z 1是H或甲基，以及W 1是OH。
  68. 如权利要求64所述的式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中环原子A表示CH 2或CO，环原子B、X、Y、Z相同且均表示CH，以及R表示S、SO、SO 2或哌嗪亚基。
  69. 如权利要求65所述的式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多 晶型物，其中所述能够结合蛋白的小分子化合物SMBP是式(It-31)的化合物：
    Figure PCTCN2019081840-appb-100096
  70. 如权利要求65所述的式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述能够结合蛋白的小分子化合物SMBP是式(It-41)的化合物：
    Figure PCTCN2019081840-appb-100097
  71. 如权利要求64-66、67、68、69或70中任一项所述的式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述W表示COOH、NH 2、N 3、CHO、卤素、甲磺酰氧基、三氟甲磺酰氧基或对甲苯磺酰氧基。
  72. 如权利要求71所述的式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示：W-C 1-30亚烷基-、W-(CH 2) n1-(O(CH 2) n2) m1-、W-(CH 2) n1-(O(CH 2) n2) m1-(O(CH 2) n3) m2-、W-(CR a1R a2) n1-(O(CR a3R a4) n2) m1-、W-(CR a5R a6) n1-(O(CR a7R a8) n2) m1-(O(CR a9R a10) n3) m2-、W-(CH 2) n1-(CONH-(CH 2) n2) m1-、W-(CH 2) n1-(CONH-(CH 2) n2) m1-(O(CH 2) n3) m2-、W-(CH 2) n1-(O(CH 2) n2) m1-O-(CH 2) n3-CONH-(CH 2) n4-(O(CH 2) n5) m2-O-(CH 2) n6-、W-(CR a11R a12) n1-(O(CR a13R a14) n2) m1-O-(CR a15R a16) n3-CONH-(CR a17R a18) n4-(O(CR a19R a20) n5) m2-O-(CR a21R a22) n6-、W-(CR a23R a24) n1-CONH-(O(CR a25R a26) n2) m1-、W-(CH 2) n1-(NHCO-(CH 2) n2) m1-、W-(CH 2) n1-(NHCO-(CH 2) n2) m1-(O(CH 2) n3) m2-、由一或多个亚炔基、亚烯基、亚环烷基、亚芳基、亚杂环基或亚杂芳基或它们的任意组合中断一或多次的直链或支链的W-亚烷基链-、和其碳链被一或多个亚芳基或亚杂环基或亚杂芳基或它们的任意组合中断一或多次的W-(CH 2) n1-(O(CH 2) n2) m1-；
    R a1、R a2、R a3、R a4、R a5、R a6、R a7、R a8、R a9、R a10、R a11、R a12、R a13、R a14、R a15、R a16、R a17、R a18、R a19、R a20、R a21、R a22、R a23、R a24、R a25、R a26分别独立地表示H、直链或 支链的C 1-C 10烷基或C 3-C 10环烷基，其中在相同的所述LIN中时，R a1、R a2、R a3、R a4，R a5、R a6、R a7、R a8、R a9、R a10，R a11、R a12、R a13、R a14、R a15、R a16、R a17、R a18、R a19、R a20、R a21、R a22，或R a23、R a24、R a25、R a26不同时为H；
    n1、n2、n3、n4、n5、n6、m1、m2分别独立地表示整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。
  73. 如权利要求72所述的式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示：
    W-CH 2-；W-(CH 2) 2-；W-(CH 2) 3-；W-(CH 2) 4-；W-(CH 2) 5-；W-(CH 2) 6-；W-(CH 2) 7-；W-(CH 2) 8-；W-(CH 2) 9-；W-(CH 2) 10-；W-(CH 2) 11-；W-(CH 2) 12-；W-(CH 2) 13-；W-(CH 2) 14-；W-(CH 2) 15-；W-(CH 2) 16-；W-(CH 2) 17-；W-(CH 2) 18-；W-(CH 2) 19-；W-(CH 2) 20-；W-(CH 2) 21-；W-(CH 2) 22-；W-(CH 2) 23-；W-(CH 2) 24-；W-(CH 2) 25-；W-(CH 2) 26-；W-(CH 2) 27-；W-(CH 2) 28-；W-(CH 2) 29-；或W-(CH 2) 30-。
  74. 如权利要求72所述的式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示：
    W-CH 2-O-(CH 2) 2-、W-CH 2-(O(CH 2) 2) 2-、W-CH 2-(O(CH 2) 2) 3-、W-CH 2-(O(CH 2) 2) 4-、W-CH 2-(O(CH 2) 2) 5-、W-CH 2-(O(CH 2) 2) 6-、W-CH 2-(O(CH 2) 2) 7-、W-CH 2-(O(CH 2) 2) 8-、W-CH 2-(O(CH 2) 2) 9-、W-CH 2-(O(CH 2) 2) 10-、W-(CH 2) 2-O-(CH 2) 2-、W-(CH 2) 2-(O(CH 2) 2) 2-、W-(CH 2) 2-(O(CH 2) 2) 3-、W-(CH 2) 2-(O(CH 2) 2) 4-、W-(CH 2) 2-(O(CH 2) 2) 5-、W-(CH 2) 2-(O(CH 2) 2) 6-、W-(CH 2) 2-(O(CH 2) 2) 7-、W-(CH 2) 2-(O(CH 2) 2) 8-、W-(CH 2) 2-(O(CH 2) 2) 9-、W-(CH 2) 2-(O(CH 2) 2) 10-、W-(CH 2) 3-O-(CH 2) 2-、W-(CH 2) 3-(O(CH 2) 2) 2-、W-(CH 2) 3-(O(CH 2) 2) 3-、W-(CH 2) 3-(O(CH 2) 2) 4-、W-(CH 2) 3-(O(CH 2) 2) 5-、W-(CH 2) 3-(O(CH 2) 2) 6-、W-(CH 2) 3-(O(CH 2) 2) 7-、W-(CH 2) 3-(O(CH 2) 2) 8-、W-(CH 2) 3-(O(CH 2) 2) 9-、W-(CH 2) 3-(O(CH 2) 2) 10-、W-(CH 2) 4-O-(CH 2) 2-、W-(CH 2) 4-(O(CH 2) 2) 2-、W-(CH 2) 4-(O(CH 2) 2) 3-、W-(CH 2) 4-(O(CH 2) 2) 4-、W-(CH 2) 4-(O(CH 2) 2) 5-、W-(CH 2) 4-(O(CH 2) 2) 6-、W-(CH 2) 4-(O(CH 2) 2) 7-、W-(CH 2) 4-(O(CH 2) 2) 8-、W-(CH 2) 4-(O(CH 2) 2) 9-、W-(CH 2) 4-(O(CH 2) 2) 10-、W-CH 2-O-(CH 2) 3-、W-CH 2-(O(CH 2) 3) 2-、W-CH 2-(O(CH 2) 3) 3-、W-CH 2-(O(CH 2) 3) 4-、W-CH 2-(O(CH 2) 3) 5-、W-CH 2-(O(CH 2) 3) 6-、W-CH 2-(O(CH 2) 3) 7-、W-CH 2-(O(CH 2) 3) 8-、W-CH 2-(O(CH 2) 3) 9-、W-CH 2-(O(CH 2) 3) 10-、W-(CH 2) 2-O-(CH 2) 3-、W-(CH 2) 2-(O(CH 2) 3) 2-、W-(CH 2) 2-(O(CH 2) 3) 3-、W-(CH 2) 2-(O(CH 2) 3) 4-、W-(CH 2) 2-(O(CH 2) 3) 5-、W-(CH 2) 2-(O(CH 2) 3) 6-、W-(CH 2) 2-(O(CH 2) 3) 7-、W-(CH 2) 2-(O(CH 2) 3) 8-、W-(CH 2) 2-(O(CH 2) 3) 9-、W-(CH 2) 2-(O(CH 2) 3) 10-、W- (CH 2) 3-O-(CH 2) 3-、W-(CH 2) 3-(O(CH 2) 3) 2-、W-(CH 2) 3-(O(CH 2) 3) 3-、W-(CH 2) 3-(O(CH 2) 3) 4-、W-(CH 2) 3-(O(CH 2) 3) 5-、W-(CH 2) 3-(O(CH 2) 3) 6-、W-(CH 2) 3-(O(CH 2) 3) 7-、W-(CH 2) 3-(O(CH 2) 3) 8-、W-(CH 2) 3-(O(CH 2) 3) 9-、W-(CH 2) 3-(O(CH 2) 3) 10-、W-CH 2-O-(CH 2) 2-O-(CH 2) 3-、W-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、W-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、W-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、W-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、W-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、W-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、W-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、W-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、W-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、W-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、W-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、W-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、W-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、W-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、W-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、W-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、W-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、W-CH 2-O-(CH 2) 3-O-(CH 2) 2-、W-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、W-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、W-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、W-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、W-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、W-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、W-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、W-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、W-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、W-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、W-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、W-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、W-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、W-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、W-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、W-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、W-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、W-CH 2-O-(CH 2) 2-O-CH 2-、W-(CH 2) 2-O-(CH 2) 2-O-CH 2-、W-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、W-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、W-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、W-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、或W-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-。
  75. 如权利要求64所述的式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述取代基选自羟基、氨基、巯基和卤素。
  76. 如权利要求75所述的式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示W-C 1-30亚烷基链，所述C 1-30亚烷基链是由一或多个选自羟基、氨基、巯基、卤素或其组合的取代基取代的直链或支链的C 1-30亚烷基链。
  77. 如权利要求72所述的式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示：W-(CH 2) n11-亚三唑基-(CH 2) n12-、W-(CH 2) n11-亚三唑基-(CH 2) n12-(O(CH 2) n13) m11-、W-(CH 2) n11-(O(CH 2) n12) m11-O-(CH 2) n13-亚三唑基-(CH 2) n14-(O(CH 2) n15) m12-O-(CH 2) n16-、W-(CH 2) n11-亚三唑基-(CH 2) n12-(O(CH 2) n13) m11-O-(CH 2) n14-或W-(CH 2) n11-(O(CH 2) n12) m11-O-(CH 2) n13-亚三唑基-(CH 2) n14-；以及
    n11、n12、n13、n14、n15、n16、m11、m12分别独立地表示1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的整数。
  78. 如权利要求77所述的式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示：W-(CH 2) 3-亚三唑基-(CH 2) 5-、W-(CH 2) 2-亚三唑基-(CH 2) 5-、W-CH 2-亚三唑基-(CH 2) 5-、W-(CH 2) 2-亚三唑基-(CH 2) 4-、W-(CH 2) 3-亚三唑基-(CH 2) 2-O(CH 2) 2-、W-(CH 2) 2-亚三唑基-(CH 2) 2-O(CH 2) 2-或W-CH 2-亚三唑基-(CH 2) 2-O(CH 2) 2-。
  79. 如权利要求72所述的式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示：
    W-CH 2CONHCH 2-、W-(CH 2) 2CONH(CH 2) 2-、W-(CH 2) 3CONH(CH 2) 3-、W-(CH 2) 3CONH(CH 2) 4-、W-(CH 2) 4CONH(CH 2) 4-、W-(CH 2) 5CONH(CH 2) 5-、W-(CH 2) 6CONH(CH 2) 7-、W-(CH 2) 6CONH(CH 2) 6-、W-(CH 2) 7CONH(CH 2) 7-、W-(CH 2) 8CONH(CH 2) 8、W-(CH 2) 9CONH(CH 2) 9-、W-(CH 2) 10CONH(CH 2) 10-、W-(CH 2) 2CONH(CH 2) 5-、W-(CH 2) 2CONH(CH 2) 3-、W-(CH 2) 2CONH(CH 2) 4-、或W-(CH 2) 2CONH(CH 2) 2-O-(CH 2) 2-。
  80. 如权利要求72所述的式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示：W-CH 2NHCOCH 2-、W-(CH 2) 2NHCO(CH 2) 2-、W-(CH 2) 3NHCO(CH 2) 3-、W-(CH 2) 3NHCO(CH 2) 4-、W-(CH 2) 4NHCO(CH 2) 4-、W-(CH 2) 5NHCO(CH 2) 5-、W-(CH 2) 6NHCO(CH 2) 7-、W-(CH 2) 6NHCO(CH 2) 6-、W-(CH 2) 7NHCO(CH 2) 7-、W-(CH 2) 8NHCO(CH 2) 8、W-(CH 2) 9NHCO(CH 2) 9-、W-(CH 2) 10NHCO(CH 2) 10-、W-(CH 2) 2NHCO(CH 2) 5-、W-(CH 2) 2NHCO(CH 2) 3-、W-(CH 2) 2NHCO(CH 2) 4-、W-(CH 2) 4NHCO(CH 2) 8-或W-(CH 2) 2NHCO(CH 2) 2-O-(CH 2) 2-。
  81. 如权利要求72所述的式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其中所述LIN表示：W-(CH 2) 4NHCOCH 2-、W-(CH 2) 2-O-CH 2-亚苯基-CH 2-O-(CH 2) 2-、W-CH 2-亚苯基-CH 2-、W-(CH 2) 3-亚苯基-(CH 2) 3-、W-(CH 2) 2-O-CH 2-亚哌嗪基-CH 2-O-(CH 2) 2-、或W-(CH 2) 3-亚哌嗪基-(CH 2) 3-。
  82. 如权利要求64所述的式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其选自：
    2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙酸；
    3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)丙酸；
    2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酸；
    3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)丙酸；
    2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙酸；
    3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)丙酸；
    14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十四烷酸；
    1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十五烷-15-酸；
    17-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酸；
    1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十八烷-18-酸；
    3-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙氧基)丙酸；
    3-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)丙氧基)丙酸；
    3-(2-(3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙氧基)乙氧基)丙酸；
    3-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)丙酰氨基)丙酸；
    2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酸；
    3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丙酸；
    4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)丁酸；
    5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊酸；
    6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酸；
    7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)庚酸；
    8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)辛酸；
    9-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)壬酸；
    10-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)癸酸；
    11-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)十一烷酸；
    12-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)十二烷酸；
    13-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)十三烷酸；
    14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)十四烷酸；
    15-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)十五烷酸；
    3-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)己酰氨基)丙酸；
    4-((2-(2-氨基乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-(2-氨基乙氧基)乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((3-(2-(3-氨基丙氧基)乙氧基)丙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((14-氨基-3,6,9,12-四氧杂十四烷基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((17-氨基-3,6,9,12,15-五氧杂十七烷基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙基)氨基)-4-氧代丁酸；
    4-((2-氨基乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((3-氨基丙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((4-氨基丁基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((5-氨基戊基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((6-氨基己基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((7-氨基庚基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((8-氨基辛基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊基)氨基)-4-氧代丁酸；
    4-((2-(2-叠氮基乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-(2-叠氮基乙氧基)乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-(2-(2-叠氮基乙氧基)乙氧基)乙氧基)乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((14-叠氮基-3,6,9,12-四氧杂十四烷基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((17-叠氮基-3,6,9,12,15-五氧杂十七烷基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-(1-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙氧基)乙基)-1H-1,2,3-三唑-4-基)丁酸；
    4-((2-叠氮基乙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((3-叠氮基丙基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((4-叠氮基丁基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((5-叠氮基戊基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((6-叠氮基己基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((7-叠氮基庚基)硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-(1-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)戊基)-1H-1,2,3-三唑-4-基)丁酸；
    2-(2,6-二氧代哌啶-3-基)-4-(2-(2-碘乙氧基)乙基硫基)异吲哚啉-1,3-二酮；
    4-(2-(2-溴乙氧基)乙基硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    2-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基硫基)乙氧基)乙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(2-(2-(2-碘乙氧基)乙氧基)乙基硫基)异吲哚啉-1,3-二酮；
    4-(2-(2-(2-溴乙氧基)乙氧基)乙基硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基硫基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙基硫基)异吲哚啉-1,3-二酮；
    4-(2-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)乙基硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    2-(2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基硫基)乙氧基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(2-(2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙氧基)乙基硫基)异吲哚啉-1,3-二酮；
    4-(2-(2-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)乙氧基)乙基硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    2-(2-(2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基硫基)乙氧基)乙氧基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(2-(2-(2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙基 硫基)异吲哚啉-1,3-二酮；
    4-(2-(2-(2-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙基硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    2-(2-(2-(2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基硫基)乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(3-(3-碘丙氧基)丙基硫基)异吲哚啉-1,3-二酮；
    4-(3-(3-溴丙氧基)丙基硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基硫基)丙氧基)丙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(2-(3-(3-碘丙氧基)丙氧基)乙基硫基)异吲哚啉-1,3-二酮；
    4-(2-(3-(3-溴丙氧基)丙氧基)乙基硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(3-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基硫基)乙氧基)丙氧基)丙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(2-碘乙基硫基)异吲哚啉-1,3-二酮；
    4-(2-溴乙基硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基硫基)乙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(3-碘丙基硫基)异吲哚啉-1,3-二酮；
    4-(3-溴丙基硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基硫基)丙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(4-碘丁基硫基)异吲哚啉-1,3-二酮；
    4-(4-溴丁基硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基硫基)丁基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(5-碘戊基硫基)异吲哚啉-1,3-二酮；
    4-(5-溴戊基硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基硫基)戊基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(6-碘己基硫基)异吲哚啉-1,3-二酮；
    4-(6-溴己基硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基硫基)己基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(7-碘庚基硫基)异吲哚啉-1,3-二酮；
    4-(7-溴庚基硫基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基硫基)庚基4-甲基苯磺酸酯；
    2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)乙氧基)乙酸；
    3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)乙氧基)丙酸；
    2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)乙氧基)乙氧基)乙酸；
    3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)乙氧基)乙氧基)丙酸；
    2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)乙氧基)乙氧基)乙氧基)乙酸；
    3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)乙氧基)乙氧基)乙氧基)丙酸；
    14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)-3,6,9,12-四氧杂十四烷酸；
    1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)-3,6,9,12-四氧杂十五烷-15-酸；
    17-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)-3,6,9,12,15-五氧杂十七烷酸；
    1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)-3,6,9,12,15-五氧杂十八烷-18-酸；
    3-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)乙氧基)丙酰氨基)丙酸；
    2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)乙酸；
    3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)丙酸；
    4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)丁酸；
    5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)戊酸；
    6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)己酸；
    7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)庚酸；
    8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)辛酸；
    9-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)壬酸；
    10-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)癸酸；
    11-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)十一烷酸；
    12-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)十二烷酸；
    13-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)十三烷酸；
    14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)十四烷酸；
    15-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)十五烷酸；
    3-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)己酰氨基)丙酸；
    4-((2-(2-氨基乙氧基)乙基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-(2-氨基乙氧基)乙氧基)乙基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)乙基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((14-氨基-3,6,9,12-四氧杂十四烷基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((17-氨基-3,6,9,12,15-五氧杂十七烷基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)乙氧基)乙基)氨基)-4-氧代丁酸；
    4-((2-氨基乙基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((3-氨基丙基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((4-氨基丁基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((5-氨基戊基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((6-氨基己基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((7-氨基庚基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((8-氨基辛基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)戊基)氨基)-4-氧代丁酸；
    4-((2-(2-叠氮基乙氧基)乙基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-(2-叠氮基乙氧基)乙氧基)乙基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-(2-(2-叠氮基乙氧基)乙氧基)乙氧基)乙基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((14-叠氮基-3,6,9,12-四氧杂十四烷基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((17-叠氮基-3,6,9,12,15-五氧杂十七烷基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-(1-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)乙氧基)乙基)-1H-1,2,3-三唑-4-基)丁酸；
    4-((2-叠氮基乙基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((3-叠氮基丙基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((4-叠氮基丁基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((5-叠氮基戊基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((6-叠氮基己基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((7-叠氮基庚基)亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-(1-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)亚磺酰基)戊基)-1H-1,2,3-三唑-4-基)丁酸；
    2-(2,6-二氧代哌啶-3-基)-4-(2-(2-碘乙氧基)乙基亚磺酰基)异吲哚啉-1,3-二酮；
    4-(2-(2-溴乙氧基)乙基亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    2-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基亚磺酰基)乙氧基)乙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(2-(2-(2-碘乙氧基)乙氧基)乙基亚磺酰基)异吲哚啉-1,3-二酮；
    4-(2-(2-(2-溴乙氧基)乙氧基)乙基亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基亚磺酰基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙基亚磺酰基)异吲哚啉-1,3-二酮；
    4-(2-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)乙基亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉- 1,3-二酮；
    2-(2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基亚磺酰基)乙氧基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(2-(2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙氧基)乙基亚磺酰基)异吲哚啉-1,3-二酮；
    4-(2-(2-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)乙氧基)乙基亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    2-(2-(2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基亚磺酰基)乙氧基)乙氧基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(2-(2-(2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙基亚磺酰基)异吲哚啉-1,3-二酮；
    4-(2-(2-(2-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙基亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    2-(2-(2-(2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基亚磺酰基)乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(2-碘乙基亚磺酰基)异吲哚啉-1,3-二酮；
    4-(2-溴乙基亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基亚磺酰基)乙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(3-碘丙基亚磺酰基)异吲哚啉-1,3-二酮；
    4-(3-溴丙基亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基亚磺酰基)丙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(4-碘丁基亚磺酰基)异吲哚啉-1,3-二酮；
    4-(4-溴丁基亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基亚磺酰基)丁基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(5-碘戊基亚磺酰基)异吲哚啉-1,3-二酮；
    4-(5-溴戊基亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基亚磺酰基)戊基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(6-碘己基亚磺酰基)异吲哚啉-1,3-二酮；
    4-(6-溴己基亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基亚磺酰基)己基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(7-碘庚基亚磺酰基)异吲哚啉-1,3-二酮；
    4-(7-溴庚基亚磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基亚磺酰基)庚基4-甲基苯磺酸酯；
    2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)乙氧基)乙酸；
    3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)乙氧基)丙酸；
    2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)乙氧基)乙氧基)乙酸；
    3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)乙氧基)乙氧基)丙酸；
    2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)乙氧基)乙氧基)乙氧基)乙酸；
    3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)乙氧基)乙氧基)乙氧基)丙酸；
    14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)-3,6,9,12-四氧杂十四烷酸；
    1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)-3,6,9,12-四氧杂十五烷-15-酸；
    17-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)-3,6,9,12,15-五氧杂十七烷酸；
    1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)-3,6,9,12,15-五氧杂十八烷-18-酸；
    3-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)乙氧基)丙酰氨基)丙酸；
    2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)乙酸；
    3-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)丙酸；
    4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)丁酸；
    5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)戊酸；
    6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)己酸；
    7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)庚酸；
    8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)辛酸；
    9-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)壬酸；
    10-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)癸酸；
    11-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)十一烷酸；
    12-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)十二烷酸；
    13-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)十三烷酸；
    14-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)十四烷酸；
    15-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)十五烷酸；
    3-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)己酰氨基)丙酸；
    4-((2-(2-氨基乙氧基)乙基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-(2-氨基乙氧基)乙氧基)乙基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)乙基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((14-氨基-3,6,9,12-四氧杂十四烷基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((17-氨基-3,6,9,12,15-五氧杂十七烷基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)乙氧基)乙基)氨基)-4-氧代丁酸；
    4-((2-氨基乙基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((3-氨基丙基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((4-氨基丁基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((5-氨基戊基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((6-氨基己基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((7-氨基庚基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((8-氨基辛基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)戊基)氨基)-4-氧代丁酸；
    4-((2-(2-叠氮基乙氧基)乙基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-(2-叠氮基乙氧基)乙氧基)乙基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((2-(2-(2-(2-叠氮基乙氧基)乙氧基)乙氧基)乙基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((14-叠氮基-3,6,9,12-四氧杂十四烷基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((17-叠氮基-3,6,9,12,15-五氧杂十七烷基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-(1-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)乙氧基)乙基)-1H-1,2,3-三唑-4-基)丁酸；
    4-((2-叠氮基乙基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((3-叠氮基丙基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((4-叠氮基丁基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((5-叠氮基戊基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((6-叠氮基己基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-((7-叠氮基庚基)磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-(1-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)磺酰基)戊基)-1H-1,2,3-三唑-4-基)丁酸；
    2-(2,6-二氧代哌啶-3-基)-4-(2-(2-碘乙氧基)乙基磺酰基)异吲哚啉-1,3-二酮；
    4-(2-(2-溴乙氧基)乙基磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    2-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基磺酰基)乙氧基)乙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(2-(2-(2-碘乙氧基)乙氧基)乙基磺酰基)异吲哚啉-1,3-二酮；
    4-(2-(2-(2-溴乙氧基)乙氧基)乙基磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基磺酰基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙基磺酰基)异吲哚啉-1,3-二酮；
    4-(2-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)乙基磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    2-(2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基磺酰基)乙氧基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(2-(2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙氧基)乙基磺酰基)异吲 哚啉-1,3-二酮；
    4-(2-(2-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)乙氧基)乙基磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    2-(2-(2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基磺酰基)乙氧基)乙氧基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(2-(2-(2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙基磺酰基)异吲哚啉-1,3-二酮；
    4-(2-(2-(2-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙基磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    2-(2-(2-(2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基磺酰基)乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(2-碘乙基磺酰基)异吲哚啉-1,3-二酮；
    4-(2-溴乙基磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    2-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基磺酰基)乙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(3-碘丙基磺酰基)异吲哚啉-1,3-二酮；
    4-(3-溴丙基磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    3-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基磺酰基)丙基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(4-碘丁基磺酰基)异吲哚啉-1,3-二酮；
    4-(4-溴丁基磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基磺酰基)丁基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(5-碘戊基磺酰基)异吲哚啉-1,3-二酮；
    4-(5-溴戊基磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    5-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基磺酰基)戊基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(6-碘己基磺酰基)异吲哚啉-1,3-二酮；
    4-(6-溴己基磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    6-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基磺酰基)己基4-甲基苯磺酸酯；
    2-(2,6-二氧代哌啶-3-基)-4-(7-碘庚基磺酰基)异吲哚啉-1,3-二酮；
    4-(7-溴庚基磺酰基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮；
    7-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基磺酰基)庚基4-甲基苯磺酸酯；
    2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙酸；
    3-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)丙酸；
    2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙酸；
    3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)丙酸；
    2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)乙酸；
    3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙氧基)乙氧基)丙酸；
    14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十四烷酸；
    1-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12-四氧杂十五烷-15-酸；
    17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十七烷酸；
    1-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)-3,6,9,12,15-五氧杂十八烷-18-酸；
    3-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙氧基)丙酸；
    3-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)丙酰氨基)丙酸；
    2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酸；
    3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙酸；
    4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丁酸；
    5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊酸；
    6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酸；
    7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)庚酸；
    8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)辛酸；
    9-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)壬酸；
    10-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)癸酸；
    11-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)十一烷酸
    12-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)十二烷酸；
    13-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)十三烷酸；
    14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)十四烷酸；
    15-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)十五烷酸；
    3-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)己酰氨基)丙酸；
    3-(4-((2-(2-氨基乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(2-(2-氨基乙氧基)乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((3-(2-(3-氨基丙氧基)乙氧基)丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((14-氨基-3,6,9,12-四氧杂十四烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((17-氨基-3,6,9,12,15-五氧杂十七烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙基)氨基)-4-氧代丁酸；
    3-(4-((2-氨基乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((3-氨基丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((4-氨基丁基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((5-氨基戊基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((6-氨基己基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((7-氨基庚基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((8-氨基辛基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊基)氨基)-4-氧代丁酸；
    3-(4-((2-(2-叠氮基乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(2-(2-叠氮基乙氧基)乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(2-(2-(2-叠氮基乙氧基)乙氧基)乙氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((14-叠氮基-3,6,9,12-四氧杂十四烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((17-叠氮基-3,6,9,12,15-五氧杂十七烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-(1-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)乙基)-1H-1,2,3-三唑-4-基)丁酸；
    3-(4-((2-叠氮基乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((3-叠氮基丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((4-叠氮基丁基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((5-叠氮基戊基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((6-叠氮基己基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((8-叠氮基辛基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-(1-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)戊基)-1H-1,2,3-三唑-4-基)丁酸；
    3-(4-(2-(2-碘乙氧基)乙基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(2-(2-溴乙氧基)乙基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基硫基)乙氧基)乙基4-甲基苯磺酸酯；
    3-(4-(3-(3-碘丙氧基)丙基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(3-(3-溴丙氧基)丙基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基硫基)丙氧基)丙基4-甲基苯磺酸酯；
    3-(4-(2-(2-(2-碘乙氧基)乙氧基)乙基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(2-(2-(2-溴乙氧基)乙氧基)乙基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基硫基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    3-(4-(2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(2-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)乙基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基硫基)乙氧基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    3-(4-(2-(2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙氧基)乙基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(2-(2-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)乙氧基)乙基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2-(2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基硫基)乙氧基)乙氧基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    3-(4-(2-(2-(2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(2-(2-(2-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2-(2-(2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基硫基)乙氧基)乙氧基)乙氧基) 乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    3-(4-(2-碘乙基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(2-溴乙基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基硫基)乙基4-甲基苯磺酸酯；
    3-(4-(3-碘丙基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(3-溴丙基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基硫基)丙基4-甲基苯磺酸酯；
    3-(4-(4-碘丁基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(4-溴丁基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基硫基)丁基4-甲基苯磺酸酯；
    3-(4-(5-碘戊基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(5-溴戊基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基硫基)戊基4-甲基苯磺酸酯；
    3-(4-(6-碘己基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(6-溴己基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基硫基)己基4-甲基苯磺酸酯；
    3-(4-(7-碘庚基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(7-溴庚基硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基硫基)庚基4-甲基苯磺酸酯；
    2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)乙氧基)乙酸；
    3-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)乙氧基)丙酸；
    2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)乙氧基)乙氧基)乙酸；
    3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)乙氧基)乙氧基)丙酸；
    2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)乙氧基)乙氧基)乙氧基)乙酸；
    3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)乙氧基)乙氧基)乙氧基)丙酸；
    14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)-3,6,9,12-四氧杂十四烷酸；
    1-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)-3,6,9,12-四氧杂十五烷-15- 酸；
    17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)-3,6,9,12,15-五氧杂十七烷酸；
    1-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)-3,6,9,12,15-五氧杂十八烷-18-酸；
    3-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)乙氧基)丙酰氨基)丙酸；
    2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)乙酸；
    3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)丙酸；
    4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)丁酸；
    5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)戊酸；
    6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)己酸；
    7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)庚酸；
    8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)辛酸；
    9-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)壬酸；
    10-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)癸酸；
    11-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)十一烷酸；
    12-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)十二烷酸；
    13-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)十三烷酸；
    14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)十四烷酸；
    15-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)十五烷酸；
    3-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)己酰氨基)丙酸；
    3-(4-((2-(2-氨基乙氧基)乙基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(2-(2-氨基乙氧基)乙氧基)乙基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)乙基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((14-氨基-3,6,9,12-四氧杂十四烷基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((17-氨基-3,6,9,12,15-五氧杂十七烷基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)乙氧基)乙基)氨基)-4-氧 代丁酸；
    3-(4-((2-氨基乙基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((3-氨基丙基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((4-氨基丁基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((5-氨基戊基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((6-氨基己基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((7-氨基庚基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((8-氨基辛基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)戊基)氨基)-4-氧代丁酸；
    3-(4-((2-(2-叠氮基乙氧基)乙基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(2-(2-叠氮基乙氧基)乙氧基)乙基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(2-(2-(2-叠氮基乙氧基)乙氧基)乙氧基)乙基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((14-叠氮基-3,6,9,12-四氧杂十四烷基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((17-叠氮基-3,6,9,12,15-五氧杂十七烷基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-(1-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)乙氧基)乙基)-1H-1,2,3-三唑-4-基)丁酸；
    3-(4-((2-叠氮基乙基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((3-叠氮基丙基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((4-叠氮基丁基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((5-叠氮基戊基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮
    3-(4-((6-叠氮基己基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((7-叠氮基庚基)亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-(1-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)亚磺酰基)戊基)-1H-1,2,3-三唑-4-基)丁酸；
    3-(4-(2-(2-碘乙氧基)乙基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(2-(2-溴乙氧基)乙基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基亚磺酰基)乙氧基)乙基4-甲基苯磺酸酯；
    3-(4-(2-(2-(2-碘乙氧基)乙氧基)乙基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(2-(2-(2-溴乙氧基)乙氧基)乙基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基亚磺酰基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    3-(4-(2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(2-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)乙基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基亚磺酰基)乙氧基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    3-(4-(2-(2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙氧基)乙基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(2-(2-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)乙氧基)乙基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2-(2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基亚磺酰基)乙氧基)乙氧基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    3-(4-(2-(2-(2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(2-(2-(2-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2-(2-(2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基亚磺酰基)乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    3-(4-(2-碘乙基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(2-溴乙基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基亚磺酰基)乙基4-甲基苯磺酸酯；
    3-(4-(3-碘丙基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(3-溴丙基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基亚磺酰基)丙基4-甲基苯磺酸酯；
    3-(4-(4-碘丁基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(4-溴丁基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基亚磺酰基)丁基4-甲基苯磺酸酯；
    3-(4-(5-碘戊基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(5-溴戊基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基亚磺酰基)戊基4-甲基苯磺酸酯；
    3-(4-(6-碘己基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(6-溴己基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基亚磺酰基)己基4-甲基苯磺酸酯；
    3-(4-(7-碘庚基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(7-溴庚基亚磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基亚磺酰基)庚基4-甲基苯磺酸酯；
    2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)乙氧基)乙酸；
    3-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)乙氧基)丙酸；
    2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)乙氧基)乙氧基)乙酸；
    3-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)乙氧基)乙氧基)丙酸；
    2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)乙氧基)乙氧基)乙氧基)乙酸；
    3-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)乙氧基)乙氧基)乙氧基)丙酸；
    14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)-3,6,9,12-四氧杂十四烷酸；
    1-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)-3,6,9,12-四氧杂十五烷-15-酸；
    17-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)-3,6,9,12,15-五氧杂十七烷酸；
    1-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)-3,6,9,12,15-五氧杂十八烷-18-酸；
    3-(3-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)乙氧基)丙酰氨基)丙酸；
    2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)乙酸；
    3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)丙酸；
    4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)丁酸；
    5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)戊酸；
    6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)己酸；
    7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)庚酸；
    8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)辛酸；
    9-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)壬酸；
    10-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)癸酸；
    11-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)十一烷酸；
    12-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)十二烷酸；
    13-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)十三烷酸；
    14-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)十四烷酸；
    15-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)十五烷酸；
    3-(6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)己酰氨基)丙酸；
    3-(4-((2-(2-氨基乙氧基)乙基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(2-(2-氨基乙氧基)乙氧基)乙基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)乙基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((14-氨基-3,6,9,12-四氧杂十四烷基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((17-氨基-3,6,9,12,15-五氧杂十七烷基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)乙氧基)乙基)氨基)-4-氧代丁酸；
    3-(4-((2-氨基乙基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((3-氨基丙基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((4-氨基丁基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((5-氨基戊基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((6-氨基己基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((7-氨基庚基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((8-氨基辛基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-((5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)戊基)氨基)-4-氧代丁酸；
    3-(4-((2-(2-叠氮基乙氧基)乙基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(2-(2-叠氮基乙氧基)乙氧基)乙基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-(2-(2-(2-叠氮基乙氧基)乙氧基)乙氧基)乙基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((14-叠氮基-3,6,9,12-四氧杂十四烷基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((17-叠氮基-3,6,9,12,15-五氧杂十七烷基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-(1-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)乙氧基)乙基)-1H-1,2,3-三唑-4-基)丁酸；
    3-(4-((2-叠氮基乙基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((3-叠氮基丙基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((4-叠氮基丁基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((5-叠氮基戊基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((6-叠氮基己基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((7-叠氮基庚基)磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-(1-(5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)磺酰基)戊基)-1H-1,2,3-三唑-4-基)丁酸；
    3-(4-(2-(2-碘乙氧基)乙基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(2-(2-溴乙氧基)乙基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基磺酰基)乙氧基)乙基4-甲基苯磺酸酯；
    3-(4-(2-(2-(2-碘乙氧基)乙氧基)乙基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(2-(2-(2-溴乙氧基)乙氧基)乙基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基磺酰基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    3-(4-(2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(2-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)乙基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基磺酰基)乙氧基)乙氧基)乙氧基)乙 基4-甲基苯磺酸酯；
    3-(4-(2-(2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙氧基)乙基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(2-(2-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)乙氧基)乙基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2-(2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基磺酰基)乙氧基)乙氧基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    3-(4-(2-(2-(2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(2-(2-(2-(2-(2-(2-溴乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2-(2-(2-(2-(2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基磺酰基)乙氧基)乙氧基)乙氧基)乙氧基)乙氧基)乙基4-甲基苯磺酸酯；
    3-(4-(2-碘乙基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(2-溴乙基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基磺酰基)乙基4-甲基苯磺酸酯；
    3-(4-(3-碘丙基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(3-溴丙基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基磺酰基)丙基4-甲基苯磺酸酯；
    3-(4-(4-碘丁基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(4-溴丁基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基磺酰基)丁基4-甲基苯磺酸酯；
    3-(4-(5-碘戊基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(5-溴戊基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基磺酰基)戊基4-甲基苯磺酸酯；
    3-(4-(6-碘己基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(6-溴己基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基磺酰基)己基4-甲基苯磺酸酯；
    3-(4-(7-碘庚基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-(7-溴庚基磺酰基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；或
    7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基磺酰基)庚基4-甲基苯磺酸酯。
  83. 如权利要求64所述的式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其选自：
    N-(4-氨基丁基)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)硫基)乙酰胺；
    N-(4-氨基丁基)-2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙酰胺；
    3-((4-((2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)甲基)苄基)氧基)丙酸；
    3-((4-((2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)甲基)哌嗪-1-基)甲氧基)丙酸；
    4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙基)苯基)丁酸；
    4-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙基)哌嗪-1-基)丁酸；
    3-(4-((2-((4-((2-氨基乙氧基)甲基)苄基)氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-((4-((2-氨基乙氧基)甲基)哌嗪-1-基)甲氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((3-(4-(3-氨基丙基)苯基)丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((3-(4-(3-氨基丙基)哌嗪-1-基)丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-((4-((2-叠氮基乙氧基)甲基)苄基)氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-((4-((2-叠氮基乙氧基)甲基)哌嗪-1-基)甲氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((3-(4-(3-叠氮基丙基)苯基)丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((3-(4-(3-叠氮基丙基)哌嗪-1-基)丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-((4-((2-碘乙氧基)甲基)苄基)氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-((4-((2-碘乙氧基)甲基)哌嗪-1-基)甲氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((3-(4-(3-碘丙基)苯基)丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((3-(4-(3-碘丙基)哌嗪-1-基)丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-((4-((2-溴乙氧基)甲基)苄基)氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((2-((4-((2-溴乙氧基)甲基)哌嗪-1-基)甲氧基)乙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((8-溴辛基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((9-溴壬基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((10-溴癸基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((11-溴十一烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((12-溴十二烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((4-(溴甲基)苄基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((3-(4-(3-溴丙基)苯基)丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((3-(4-(3-溴丙基)哌嗪-1-基)丙基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    2-((4-((2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)甲基)苄基)氧基)乙基4-甲基苯磺酸酯；
    2-((4-((2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)乙氧基)甲基)哌嗪-1-基)甲氧基)乙基4-甲基苯磺酸酯；
    3-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙基)苯基)丙基4-甲基苯磺酸酯；
    3-(4-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)硫基)丙基)哌嗪-1-基)丙基4-甲基苯磺酸酯；
    3-(4-((9-叠氮基壬基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((10-叠氮基癸基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；
    3-(4-((11-叠氮基十一烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮；或
    3-(4-((12-叠氮基十二烷基)硫基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮。
  84. 如权利要求62或63所述式(III)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物用于制备如权利要求1所述的式(I)化合物的用途。
  85. 如权利要求64-83中任一项所述式(IV)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物用于制备如权利要求1所述的式(I)化合物的用途。
  86. 一种药物组合物，其包含如权利要求64-83中任一项所述的式(IV)化合物或其医药学上可接受的盐，及至少一种医药学上可接受的载体。
  87. 如权利要求86所述的药物组合物，进一步包括至少一种额外的治疗剂。
  88. 如权利要求87所述的药物组合物，所述至少一种额外的治疗剂用于治疗或预防癌症。
  89. 如权利要求64-83中任一项所述的式(I)化合物，或其医药学上可接受的盐，其是用作药物。
  90. 如权利要求64-83中任一项所述的式(I)化合物，或其医药学上可接受的盐，其用于预防及/或治疗癌症。
  91. 如权利要求90所述的式(I)化合物，或其医药学上可接受的盐，其中所述癌症选自由以下组成的群组：多发性骨髓瘤、骨髓增生异常综合征(MDS)、既往治疗的骨髓增生异常综合征、浆细胞骨髓瘤、移植相关的癌症、骨髓纤维化、浆细胞骨髓瘤、骨髓疾病、中性粒细胞减少；白血病、急性髓细胞白血病、贫血、慢性粒细胞白血病、B细胞慢性淋巴细胞白血病、急性髓性白血病(AML)、CD20阳性、原发性淋巴瘤、B细胞淋巴瘤、复发性B细胞非霍奇金淋巴瘤、复发性弥漫性大B细胞淋巴瘤、复发性原发性纵隔(胸腺)大B细胞、复发性转化非霍奇金淋巴瘤、难治性B细胞非霍奇金淋巴瘤、难治性弥漫性大B细胞淋巴瘤、难治性原发性纵隔(胸腺)大B细胞、难治性转化的非霍奇金淋巴瘤、阴燃骨髓瘤、闷烧多发性骨髓瘤、或里希特综合症。
  92. 一种如权利要求64-83中任一项所述的式(IV)化合物或其医药学上可接受的盐的用途，其用于制备用以预防及/或治疗癌症的药物。
  93. 如权利要求92所述的用途，其中所述癌症选自由以下组成的群组：多发性骨髓瘤、骨髓增生异常综合征(MDS)、既往治疗的骨髓增生异常综合征、浆细胞骨髓瘤、移植相关的癌症、骨髓纤维化、浆细胞骨髓瘤、骨髓疾病、中性粒细胞减少；白血病、急性髓细胞白血病、贫血、慢性粒细胞白血病、B细胞慢性淋巴细胞白血病、急性髓性白血病(AML)、CD20阳性、原发性淋巴瘤、B细胞淋巴瘤、复发性B细胞非霍奇金淋巴瘤、复发性弥漫性大B细胞淋巴瘤、复发性原发性纵隔(胸腺)大B细胞、复发性转化非霍奇金淋巴瘤、难治性B细胞非霍奇金淋巴瘤、难治性弥漫性大B细胞淋巴瘤、难治性原发性纵隔(胸腺)大B细胞、难治性转化的非霍奇金淋巴瘤、阴燃骨髓瘤、闷烧多发性骨髓瘤、或里希特综合症。
  94. 治疗或预防癌症的方法，其包括向受试者施用治疗有效量的如权利要求64-83中任一 项所述的式(IV)化合物，或其医药学上可接受的盐，或如权利要求86至88中任一项所述的药物组合物。
  95. 如权利要求94所述的方法，其中所述癌症选自由以下组成的群组：多发性骨髓瘤、骨髓增生异常综合征(MDS)、既往治疗的骨髓增生异常综合征、浆细胞骨髓瘤、移植相关的癌症、骨髓纤维化、浆细胞骨髓瘤、骨髓疾病、中性粒细胞减少；白血病、急性髓细胞白血病、贫血、慢性粒细胞白血病、B细胞慢性淋巴细胞白血病、急性髓性白血病(AML)、CD20阳性、原发性淋巴瘤、B细胞淋巴瘤、复发性B细胞非霍奇金淋巴瘤、复发性弥漫性大B细胞淋巴瘤、复发性原发性纵隔(胸腺)大B细胞、复发性转化非霍奇金淋巴瘤、难治性B细胞非霍奇金淋巴瘤、难治性弥漫性大B细胞淋巴瘤、难治性原发性纵隔(胸腺)大B细胞、难治性转化的非霍奇金淋巴瘤、阴燃骨髓瘤、闷烧多发性骨髓瘤、或里希特综合症。
  96. 如权利要求94或95所述的方法，其中通过至少一种选自鼻腔给药、吸入给药、局部给药、口服给药、口腔粘膜给药、直肠给药、胸膜腔给药、腹膜给药、阴道给药、肌内给药、皮下给药、经皮给药、硬膜外腔给药、鞘内给药和静脉给药的给药方式施用至所述受试者。
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KR102548191B1 (ko) 2023-06-28
CA3096790A1 (en) 2019-10-17
KR20210006364A (ko) 2021-01-18
AU2019251151A1 (en) 2020-11-26
CN110357889A (zh) 2019-10-22

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