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WO2025119380A1 - Estrogen receptor modulator and use thereof - Google Patents

Estrogen receptor modulator and use thereof Download PDF

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Publication number
WO2025119380A1
WO2025119380A1 PCT/CN2024/137621 CN2024137621W WO2025119380A1 WO 2025119380 A1 WO2025119380 A1 WO 2025119380A1 CN 2024137621 W CN2024137621 W CN 2024137621W WO 2025119380 A1 WO2025119380 A1 WO 2025119380A1
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Prior art keywords
alkyl
membered
methyl
alkoxy
phenyl
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French (fr)
Chinese (zh)
Inventor
吴勇
龚彦春
刘永强
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Jiangsu Vcare Pharmatech Co Ltd
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Jiangsu Vcare Pharmatech Co Ltd
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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    • C07B2200/07—Optical isomers

Definitions

  • the present invention belongs to the field of medical technology and relates to an estrogen receptor modulator represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof and uses thereof.
  • Anti-estrogen (hormone) therapy is the first choice for the treatment of estrogen-positive breast cancer.
  • Anti-estrogen therapy is mainly divided into three categories, including aromatase inhibitors (such as letrozole, anastrozole); estrogen antagonists (such as tamoxifen, raloxifene); and selective estrogen receptor degraders (such as fulvestrant). These types of anti-estrogen therapy work through different mechanisms to block estrogen and inhibit tumor growth.
  • Targeted protein degradation chimera is a new therapeutic technology that blocks signaling pathways by degrading target proteins, thereby exerting a therapeutic effect.
  • PROTAC molecules usually consist of three parts: target protein binding ligand, E3 ubiquitin ligase (E3 ubiquitin ligase) ligand and linker.
  • E3 ubiquitin ligase E3 ubiquitin ligase
  • linker E3 ubiquitin ligase
  • PROTAC molecules tightly bind to the target protein through one end of the chimera and bind to the E3 ubiquitin ligase at the other end to form a target protein-PROTAC-E3 ubiquitin ligase ternary complex.
  • the target protein is ubiquitinated and "tagged" through E3 ubiquitin ligase-mediated ubiquitination; the ubiquitinated "tagged” target protein is then transported to the proteasome and degraded by the proteasome.
  • PROTAC technology Compared with traditional small molecule inhibitors, PROTAC technology has the following advantages: 1. A smaller dosage may be required. The target protein degradation process is similar to a catalytic reaction. PROTAC molecules can be reused, and only a catalytic amount of drugs is needed to inhibit the target protein. 2. Feedback upregulation of target protein expression due to inhibition of the target protein can be avoided. 3. Expanding the drug targeting range, PROTAC technology makes proteins such as transcription factors, regulatory proteins and other non-enzyme proteins that traditional small molecule inhibitors cannot directly act on become regulatable proteins, turning the target from "non-drugable" to "drugable”.
  • ER-PROTAC drugs that target the degradation of estrogen receptors have preliminarily demonstrated efficacy and excellent safety in clinical studies and are expected to become a new type of hormone therapy, an important supplement to traditional therapies that are resistant, intolerant, and ineffective.
  • One object of the invention is to provide a class of ER-PROTAC compounds, isomers thereof or pharmaceutically acceptable salts thereof that target the degradation of estrogen receptors.
  • X is selected from N or CH
  • Cy1 is selected from (For example ), Said (For example ), unsubstituted or each independently substituted by 1-3 R a1 ;
  • G is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R a1 : C 6-10 aryl or 5-10 membered heteroaryl, such as phenyl, pyridyl, pyrimidinyl;
  • Each Ra1 is independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxyl C1-6 alkyl, C1-6 alkylamino, (C1-6 alkyl ) 2amino , C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl) 2aminocarbonyl ;
  • B is -L2-Cy2-L3-Cy3-L4-Cy4-L5-; A is connected to L2; C is connected to L5;
  • L1, L2, L3, L4, L5, and L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, -S-, -NR 2 , -CR 31 R 32 -, -C(O)-, -C(O)O-, -C(O)NR 4 -, -NR 5 -C(O)-, -S(O)-, -S(O) 2 -, -P(O)(R 6 )-, C 2-8 alkenyl, and C 2-8 alkynyl;
  • n and m are independently any integer from zero to six; for example, 0, 1, 2, 3, 4, 5 or 6;
  • R 2 , R 31 , R 32 , R 4 , R 5 and R 6 are each independently selected from hydrogen, deuterium, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, wherein the C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8
  • Cy2 is selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclyl, 3-13 membered cycloalkenyl, 3-13 membered cycloalkyl substituted by 1-3 R a2 , 3-13 membered heterocyclyl substituted by 1-3 R a2 , 3-13 membered cycloalkenyl substituted by 1-3 R a2 , Cy21-Cy22, wherein the heteroatom of the 3-13 membered heterocyclyl is selected from O, N or S; Cy21 and Cy22 are the same or different and are independently selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclyl, 3-13 membered cycloalkenyl;
  • Cy3 is selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclyl, 6-13 membered bicyclic condensed cyclic group or 8-21 membered polycyclic condensed cyclic group, wherein the 3-13 membered cycloalkyl, 3-13 membered heterocyclyl, 6-13 membered bicyclic condensed cyclic group or 8-21 membered polycyclic condensed cyclic group is unsubstituted or each independently substituted by 1-5 R a3 , and the heteroatom of the 5-6 membered heterocyclyl is N, O, S or Si;
  • Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclyl, 3-8 membered cycloalkyl substituted by 1-3 R a4 , 3-8 membered heterocyclyl substituted by 1-3 R a4 , 3-8 membered cycloalkenyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring cycloalkyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring alkenyl substituted by 1-3 R a4 , and the heteroatoms of the 3-8 membered heterocyclyl or 6-13 membered bicyclic condensed ring heterocyclyl are
  • Each of Ra2 , Ra3 and Ra4 when present, is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, silanol, selenohydroxyl, carboxyl, amino, cyano, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 alkyl -C(O)O-, C1-6 alkylthio, C1-6 alkylseleno, hydroxyC1-6 alkyl, C1-6 alkyl-C(O)NH-, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C2-8alkenyl , C2-8alkynyl , C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl)2aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membere
  • X1 is N or CR b1 ;
  • X2 is N or CR b2 ;
  • X3 is N or CR b3 ;
  • X4 is N or CR b4 ;
  • X5 is N or CR b5 ;
  • R b1 , R b2 , R b3 , R b4 and R b5 are each independently selected from hydrogen, deuterium, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl;
  • Cy5 is selected from a 6-13 membered bicyclic fused ring group and an 8-21 membered polycyclic fused ring group; the 6-13 membered bicyclic fused ring group or the 8-21 membered polycyclic fused ring group is unsubstituted or substituted with 1-3 R a5 ;
  • Each Ra5 is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl)2amino, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, (C1-6 alkyl)2aminocarbonyl, 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl)2amino,
  • the condition is that when Cy3 is hour, Not for
  • X is selected from N or CH
  • Cy1 is selected from and phenyl, the and phenyl are unsubstituted or are each independently substituted with 1-3 R a1 ;
  • Each Ra1 is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxy C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl ) 2aminocarbonyl ;
  • B is -L2-Cy2-L3-Cy3-L4-Cy4-L5-;
  • L1, L2, L3, L4, L5, L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, -S-, -NR 2 , -CR 31 R 32 -, -C(O)-, -C(O)O-, -C(O)NR 4 -, -NR 5 -C(O)-, -CH 2 NR 4 -, -NR 5 -CH 2 -, C 2-8 alkenyl and C 2-8 alkynyl;
  • n and m are each independently any integer from zero to six;
  • R 2 , R 31 , R 32 , R 4 and R 5 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, wherein the C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C
  • Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl, 4-6 membered cycloalkyl substituted by 1-3 R a2 , 4-6 membered heterocyclyl substituted by 1-3 R a2 , 4-6 membered cycloalkenyl substituted by 1-3 R a2 , wherein the heteroatom of the 4-6 membered heterocyclyl is selected from O, N or S;
  • Cy3 is selected from 5-6 membered cycloalkyl or 5-6 membered heterocyclyl, wherein the 5-6 membered cycloalkyl or 5-6 membered heterocyclyl is unsubstituted or each independently substituted by 1-3 R a3 , wherein the heteroatom of the 5-6 membered heterocyclyl is N;
  • Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclyl, 3-8 membered cycloalkyl substituted by 1-3 R a4 , 3-8 membered heterocyclyl substituted by 1-3 R a4 , 3-8 membered cycloalkenyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring cycloalkyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring alkenyl substituted by 1-3 R a4 , and the heteroatom of the 3-8 membered heterocyclyl or 6-13 membered bicyclic condensed ring heterocyclyl is selected
  • Each of Ra2 , Ra3 and Ra4 when present, is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halo- C1-6 alkyl, C1-6 alkoxy, halo- C1-6 alkoxy, hydroxy- C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl)2amino, C2-8alkenyl , C2-8alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl)2aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, wherein said C1-6 alkyl, halo- C1-6 alkyl, C1-6 alkoxy, halo -C1-6 alkoxy, hydroxy- C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl
  • X1 is N or CR b1 ;
  • X2 is N or CR b2 ;
  • X3 is N or CR b3 ;
  • X4 is N or CR b4 ;
  • X5 is N or CR b5 ;
  • R b1 , R b2 , R b3 , R b4 and R b5 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl;
  • Cy5 is selected from a 6-13 membered bicyclic fused ring group and an 8-21 membered polycyclic fused ring group; the 6-13 membered bicyclic fused ring group or the 8-21 membered polycyclic fused ring group is unsubstituted or substituted with 1-3 R a5 ;
  • Each Ra5 is independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl) 2aminocarbonyl , 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated
  • the condition is that when Cy3 is hour, Not for
  • Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof,
  • X is selected from N or CH
  • Cy1 is selected from and phenyl, the and phenyl are unsubstituted or are each independently substituted with 1-3 R a1 ;
  • Each Ra1 is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxy C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl ) 2aminocarbonyl ;
  • B is -L2-Cy2-L3-Cy3-L4-Cy4-L5-;
  • L1, L2, L3, L4, L5, L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, -S-, -NR 2 , -CR 31 R 32 -, -C(O)-, -C(O)O-, -C(O)NR 4 -, -NR 5 -C(O)-, C 2-8 alkenyl, and C 2-8 alkynyl;
  • n and m are each independently any integer from zero to six;
  • R 2 , R 31 , R 32 , R 4 and R 5 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, wherein the C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C
  • Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl, 4-6 membered cycloalkyl substituted by 1-3 R a2 , 4-6 membered heterocyclyl substituted by 1-3 R a2 , 4-6 membered cycloalkenyl substituted by 1-3 R a2 , wherein the heteroatom of the 4-6 membered heterocyclyl is selected from O, N or S;
  • Cy3 is selected from 5-6 membered cycloalkyl or 5-6 membered heterocyclyl, wherein the 5-6 membered cycloalkyl or 5-6 membered heterocyclyl is unsubstituted or each independently substituted by 1-3 R a3 , wherein the heteroatom of the 5-6 membered heterocyclyl is N;
  • Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclyl, 3-8 membered cycloalkyl substituted by 1-3 R a4 , 3-8 membered heterocyclyl substituted by 1-3 R a4 , 3-8 membered cycloalkenyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring cycloalkyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring alkenyl substituted by 1-3 R a4 , and the heteroatom of the 3-8 membered heterocyclyl or 6-13 membered bicyclic condensed ring heterocyclyl is selected
  • Each of Ra2 , Ra3 and Ra4 when present, is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halo- C1-6 alkyl, C1-6 alkoxy, halo- C1-6 alkoxy, hydroxy- C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C2-8alkenyl, C2-8alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl) 2aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, wherein said C1-6 alkyl, halo-C1-6 alkyl, C1-6 alkoxy, halo- C1-6 alkoxy, hydroxy -C1-6 alkyl, C1-6 alkylamino, (C1-6 alkyl
  • X1 is N or CR b1 ;
  • X2 is N or CR b2 ;
  • X4 is N or CR b4 ;
  • X5 is N or CR b5 ;
  • R b1 , R b2 , R b3 , R b4 and R b5 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl;
  • Cy5 is selected from a 6-13 membered bicyclic fused ring group and an 8-21 membered polycyclic fused ring group; the 6-13 membered bicyclic fused ring group or the 8-21 membered polycyclic fused ring group is unsubstituted or substituted with 1-3 R a5 ;
  • Each Ra5 is independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl) 2aminocarbonyl , 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated
  • the condition is that when Cy3 is hour, Not for
  • Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof,
  • X is selected from N or CH
  • Cy1 is selected from and phenyl, the and phenyl are unsubstituted or are each independently substituted with 1-3 R a1 ;
  • Each Ra1 is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxy C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl ) 2aminocarbonyl ;
  • B is -L2-Cy2-L3-Cy3-L4-Cy4-L5-;
  • L1, L2, L3, L4, L5, L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, -S-, -NR 2 , -CR 31 R 32 -, -C(O)-, -C(O)O-, -C(O)NR 4 -, -NR 5 -C(O)-, C 2-8 alkenyl, and C 2-8 alkynyl;
  • n and m are each independently any integer from zero to six;
  • R 2 , R 31 , R 32 , R 4 and R 5 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, wherein the C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C
  • Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl, 4-6 membered cycloalkyl substituted by 1-3 R a2 , 4-6 membered heterocyclyl substituted by 1-3 R a2 , 4-6 membered cycloalkenyl substituted by 1-3 R a2 , wherein the heteroatom of the 4-6 membered heterocyclyl is selected from O, N or S;
  • Cy3 is selected from Said unsubstituted or each independently substituted with 1-3 Ra3 ;
  • Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclyl, 3-8 membered cycloalkyl substituted by 1-3 R a4 , 3-8 membered heterocyclyl substituted by 1-3 R a4 , 3-8 membered cycloalkenyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring cycloalkyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring alkenyl substituted by 1-3 R a4 , and the heteroatom of the 3-8 membered heterocyclyl or 6-13 membered bicyclic condensed ring heterocyclyl is selected
  • Each of Ra2 , Ra3 and Ra4 when present, is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halo- C1-6 alkyl, C1-6 alkoxy, halo- C1-6 alkoxy, hydroxy- C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl)2amino, C2-8alkenyl , C2-8alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl)2aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, wherein said C1-6 alkyl, halo- C1-6 alkyl, C1-6 alkoxy, halo -C1-6 alkoxy, hydroxy- C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl
  • X1 is N or CR b1 ;
  • X2 is N or CR b2 ;
  • X3 is N or CR b3 ;
  • X4 is N or CR b4 ;
  • X5 is N or CR b5 ;
  • R b1 , R b2 , R b3 , R b4 and R b5 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl;
  • Cy5 is selected from 6-13 membered bicyclic condensed ring groups and 8-21 membered polycyclic condensed ring groups; the 6-13 membered bicyclic condensed ring groups and 8-21 membered polycyclic condensed ring groups are unsubstituted or optionally substituted with 1-3 R a5 ;
  • Each Ra5 is independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl) 2aminocarbonyl , 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated
  • the condition is that when Cy3 is hour, Not for
  • Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof,
  • X is selected from N or CH
  • Cy1 is selected from and phenyl, the and phenyl are unsubstituted or are each independently substituted with 1-3 R a1 ;
  • Each R a1 is independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl;
  • B is -L2-Cy2-L3-Cy3-L4-Cy4-L5-;
  • L1, L2, L3, L4, L5, and L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, and -C(O)-;
  • n and m are independently 0, 1 or 2;
  • Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl, 4-6 membered cycloalkyl substituted by 1-3 R a2 , 4-6 membered heterocyclyl substituted by 1-3 R a2 , 4-6 membered cycloalkenyl substituted by 1-3 R a2 , wherein the heteroatom of the 4-6 membered heterocyclyl is selected from O, N or S;
  • Cy3 is selected from Said unsubstituted or each independently substituted with 1-3 Ra3 ;
  • Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclyl, 3-8 membered cycloalkyl substituted by 1-3 R a4 , 3-8 membered heterocyclyl substituted by 1-3 R a4 , 3-8 membered cycloalkenyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring cycloalkyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring alkenyl substituted by 1-3 R a4 , and the heteroatom of the 3-8 membered heterocyclyl or 6-13 membered bicyclic condensed ring heterocyclyl is selected
  • X1 is N or CR b1 ;
  • X2 is N or CR b2 ;
  • X4 is N or CR b4 ;
  • X5 is N or CR b5 ;
  • R b1 , R b2 , R b3 , R b4 and R b5 are independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino;
  • Cy5 is selected from 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heterocyclyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl, 8-21 membered polycyclic heteroaryl; the 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heterocyclyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl, 8-21 membered polycyclic heteroaryl are unsubstituted or optionally substituted with 1-3 R a5 ;
  • each Ra5 is independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, wherein said C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl is unsubstituted or optionally substituted by one or more substituted or substituted
  • Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof, having a structure represented by formula (ii),
  • X is selected from N or CH
  • Cycle Cy1 is selected from and phenyl, the and phenyl are unsubstituted or are each independently substituted with 1-3 R a1 ;
  • Each R a1 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy;
  • L1, L2, L3, L4, L5, and L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, and -C(O)-;
  • n and m are independently 0, 1 or 2;
  • Cy2 is selected from a 4-6 membered nitrogen-containing heterocyclic group or a 4-6 membered nitrogen-containing heterocyclic group substituted by 1-3 R a2 ;
  • Cy4 is selected from 3-8 membered heterocyclyl, 3-8 membered heterocyclyl substituted by 1-3 R a4 , 6-13 membered bicyclic spiro heterocyclyl or 6-13 membered bicyclic spiro heterocyclyl substituted by 1-3 R a4 , wherein the heteroatom of the 3-8 membered heterocyclyl or 6-13 membered bicyclic spiro heterocyclyl is selected from O, N or S;
  • Each Ra2 and Ra4 when present, is independently selected from hydrogen, C1-6 alkyl, 3-8 membered heterocyclyl, said C1-6 alkyl or 3-8 membered heterocyclyl being unsubstituted or substituted with one or more C1-6 alkyl or 3-8 membered heterocyclyl;
  • X1 is N or CR b1 ;
  • X2 is N or CR b2 ;
  • X4 is N or CR b4 ;
  • X5 is N or CR b5 ;
  • R b1 , R b2 , R b3 , R b4 and R b5 are independently selected from hydrogen and halogen;
  • Cy5 is selected from 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl, wherein the 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl is unsubstituted or optionally substituted with 1-3 R a5 ;
  • Each R a5 is independently selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, and phenyl, wherein the phenyl is unsubstituted or substituted with one or more halogens, halogenated C 1-6 alkyl, and C 1-6 alkoxy.
  • Another embodiment of the present invention relates to a compound represented by formula (ii), an isomer thereof or a pharmaceutically acceptable salt thereof,
  • X is selected from N or CH
  • Cy1 is selected from and phenyl, the and phenyl are unsubstituted or are each independently substituted with 1-3 R a1 ;
  • Each R a1 is independently selected from hydrogen, methoxy, methyl, and ethyl;
  • L1 is selected from a bond, -NH-;
  • L2 is selected from a bond, -NH-;
  • Cy2 is selected from
  • L3 is selected from -CH 2 -, -C(O)-, -NH-CH 2 -;
  • Cy3 is selected from
  • L4 is selected from -CH 2 -, -NH-CH 2 -, -C(O)-;
  • Cy4 is selected from
  • L5 is selected from a bond
  • L6 is selected from a bond, -O-;
  • Cy5 is selected from Said unsubstituted or optionally substituted with 1-3 Ra5 ;
  • Each R a5 is independently selected from hydroxyl, methyl, methoxy, phenyl,
  • the phenyl group is unsubstituted or substituted with one or more fluorine, methoxy, trifluoromethyl, replace.
  • Cy1 is selected from *Terminal is connected to L1.
  • each Ra1 is each independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkoxy, hydroxy C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl ) 2amino , C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl) 2aminocarbonyl ; still more preferably, each Ra1 is each independently substituted by 1-3 halogen (such as F) or C1-6 alkyl (such as methyl).
  • Cy1 is selected from *Terminal is connected to L1.
  • L1, L2, L3, L4, L5, L6 are the same or different, and are independently selected from a bond, -O-, -NH-, C 1-6 alkylene, -NHC(O)-, NH(C 1-6 alkylene), -C(O)-.
  • L1 is selected from a bond, -NHC(O)-; preferably, when L1 is -NHC(O)-, the C(O) terminus is connected to Cy1.
  • L2 is selected from a bond, NH or NH(C 1-3 alkylene).
  • L2 is selected from a bond, -NH- or -NHCH2- ; preferably a bond.
  • L3 is selected from C 1-3 alkylene, -C(O), -CH 2 NR 4 -, -NR 5 -CH 2 -- or NHC 1-3 alkylene, and R 4 and R 5 are independently selected from C 3-6 cycloalkyl.
  • L3 is selected from methylene, -C(O)- or NHCH 2- ; preferably methylene.
  • L4 is selected from a bond, C 1-3 alkylene or -C(O)-.
  • L4 is selected from a bond, a methylene group or -C(O)-; preferably a methylene group.
  • L5 is selected from a bond or a C 1-3 alkylene group.
  • L5 is selected from a bond or a methylene group; preferably a bond.
  • L6 is selected from a bond or -O-; preferably a bond.
  • Cy2 is selected from 4-10 membered cycloalkyl, 4-10 membered heterocyclyl, 4-10 membered cycloalkenyl, 4-10 membered cycloalkyl substituted by 1-3 Ra2, 4-10 membered heterocyclyl substituted by 1-3 Ra2, 4-10 membered cycloalkenyl substituted by 1-3 Ra2, Cy21-Cy22, the heteroatom of the 4-10 membered heterocyclyl is selected from O, N or S; Cy21 and Cy22 are the same or different and are independently selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl.
  • Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl, 4-6 membered cycloalkyl substituted by 1-3 Ra2 , 4-6 membered heterocyclyl substituted by 1-3 Ra2 , 4-6 membered cycloalkenyl substituted by 1-3 Ra2 , and the heteroatom of the 4-6 membered heterocyclyl is selected from O, N or S.
  • Cy2 is selected from 6-9 membered heterocyclic group which is unsubstituted or substituted with 1-3 R a2 , Cy21-Cy22; Cy21 and Cy22 are the same or different and are independently selected from cyclohexyl, piperazinyl and piperidinyl.
  • Cy2 is selected from piperazinyl and piperidinyl which are unsubstituted or substituted with 1-3 H or F groups.
  • Cy2 is selected from piperazinyl , piperidinyl,
  • Cy2 is selected from (For example ), (For example ), (For example ), *The end is connected to Cy1.
  • Cy3 is selected from 5-10 membered cycloalkyl, 5-10 membered heterocyclyl, 6-13 membered bicyclic condensed cycloalkyl, 6-13 membered bicyclic condensed cycloalkenyl, 6-13 membered bicyclic condensed heterocyclyl, 8-13 membered bicyclic condensed heteroaryl, 8-13 membered bicyclic condensed aryl, 8-21 membered polycyclic condensed cycloalkyl, 8-21 polycyclic condensed cycloalkenyl, 8-21 membered polycyclic condensed heterocyclyl, 8-21 membered polycyclic condensed heteroaryl, 8-21 membered polycyclic condensed aryl.
  • Cy3 is selected from a 5-6 membered cycloalkyl or a 5-6 membered heterocyclyl, wherein the 5-6 membered cycloalkyl or the 5-6 membered heterocyclyl is unsubstituted or each is independently substituted with 1-3 Ra3, and the heteroatom of the 5-6 membered heterocyclyl is N, O, S, or Si.
  • Cy3 is selected from 5-6 membered cycloalkyl or 5-6 membered heterocyclyl; the 5-6 membered cycloalkyl or 5-6 membered heterocyclyl is unsubstituted or each is independently substituted with 1-3 Ra3 .
  • Cy3 is selected from cyclohexyl, piperidinyl, tetrahydropyranyl, dioxanyl, tetrahydropyrrolyl; the cyclohexyl, piperidinyl, tetrahydropyranyl, dioxanyl, tetrahydropyrrolyl are unsubstituted or are each independently substituted with 1-3 R a3 ; preferably cyclohexyl.
  • Cy3 is selected from Said are unsubstituted or are each independently substituted with 1 to 3 Ra3 .
  • Cy4 is selected from a 5-6 membered heterocyclic group which is unsubstituted or optionally substituted with one, two or more C 1-6 alkyl or C 1-6 alkoxy groups.
  • Cy4 is selected from piperazinyl, For example *End is connected to L5.
  • Cy5 is selected from the following groups which are unsubstituted or substituted with 1-3 Ra5 : 6-13 membered bicyclic cycloalkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl.
  • Cy5 is selected from unsubstituted or substituted with 1-3 OH or phenyl groups.
  • Cy5 is For example
  • R a1 is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy.
  • R a1 is selected from F, methyl, ethyl, methoxy.
  • each Ra2 , Ra3 and Ra4 are the same or different and are independently selected from H, OH, amino, thiol, silanol, selenohydroxy, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl -NH-, C3-6 cycloalkyl, C1-6 alkyl-C(O)NH-, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, hydroxyl C1-6 alkyl.
  • Ra2 is selected from H, OH, amino, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl-NH-, C3-6 cycloalkyl, C1-6 alkyl-C(O)NH-.
  • Ra2 is selected from H, F, OH, amino, methylamino, acetamido, methyl, methoxy, and cyclopropyl.
  • Ra3 and Ra4 are the same or different and are independently selected from H and halogen.
  • Ra3 and Ra4 are the same or different and are independently selected from H and F.
  • Ra5 is selected from hydroxyl or C6-10 aryl.
  • Ra5 is selected from hydroxyl or phenyl.
  • Ra5 is selected from hydroxyl, C6-10 aryl, and halogen-substituted C6-10 aryl.
  • Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof, having a structure represented by formula (iii):
  • X is selected from N or CH
  • R a1 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy;
  • L2, L3, L4, L5, and L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, and -C(O)-;
  • n and m are independently 0, 1 or 2;
  • Cy2 is selected from a 4-6 membered nitrogen-containing heterocyclic group or a 4-6 membered nitrogen-containing heterocyclic group substituted by 1-3 R a2 ;
  • Cy4 is selected from 3-8 membered heterocyclyl, 3-8 membered heterocyclyl substituted by 1-3 R a4 , 6-13 membered bicyclic spiro heterocyclyl or 6-13 membered bicyclic spiro heterocyclyl substituted by 1-3 R a4 , wherein the heteroatom of the 3-8 membered heterocyclyl or 6-13 membered bicyclic spiro heterocyclyl is selected from O, N or S;
  • Each Ra2 and Ra4 when present, is independently selected from hydrogen, C1-6 alkyl, 3-8 membered heterocyclyl, said C1-6 alkyl or 3-8 membered heterocyclyl being unsubstituted or substituted with one or more C1-6 alkyl or 3-8 membered heterocyclyl;
  • X1 is N or CR b1 ;
  • X2 is N or CR b2 ;
  • X4 is N or CR b4 ;
  • X5 is N or CR b5 ;
  • R b1 , R b2 , R b3 , R b4 and R b5 are independently selected from hydrogen and halogen;
  • Cy5 is selected from 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl, wherein the 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl is unsubstituted or optionally substituted with 1-3 R a5 ;
  • Each R a5 is independently selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, and phenyl, wherein the phenyl is unsubstituted or substituted with one or more halogens, halogenated C 1-6 alkyl, and C 1-6 alkoxy.
  • Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof, having a structure represented by formula (iv):
  • X is selected from N or CH
  • Each Ra1 is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxy C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl ) 2aminocarbonyl ;
  • L2, L3, L4, L5, and L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, and -C(O)-;
  • n and m are independently 0, 1 or 2;
  • Cy2 is selected from a 4-6 membered nitrogen-containing heterocyclic group or a 4-6 membered nitrogen-containing heterocyclic group substituted by 1-3 R a2 ;
  • Cy4 is selected from 3-8 membered heterocyclyl, 3-8 membered heterocyclyl substituted by 1-3 R a4 , 6-13 membered bicyclic spiro heterocyclyl or 6-13 membered bicyclic spiro heterocyclyl substituted by 1-3 R a4 , wherein the heteroatom of the 3-8 membered heterocyclyl or 6-13 membered bicyclic spiro heterocyclyl is selected from O, N or S;
  • Each Ra2 and Ra4 when present, is independently selected from hydrogen, C1-6 alkyl, 3-8 membered heterocyclyl, said C1-6 alkyl or 3-8 membered heterocyclyl being unsubstituted or substituted with one or more C1-6 alkyl or 3-8 membered heterocyclyl;
  • X1 is N or CR b1 ;
  • X2 is N or CR b2 ;
  • X4 is N or CR b4 ;
  • X5 is N or CR b5 ;
  • R b1 , R b2 , R b3 , R b4 and R b5 are independently selected from hydrogen and halogen;
  • Cy5 is selected from 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl, wherein the 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl is unsubstituted or optionally substituted with 1-3 R a5 ;
  • Each R a5 is independently selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, and phenyl, wherein the phenyl is unsubstituted or substituted with one or more halogens, halogenated C 1-6 alkyl, and C 1-6 alkoxy.
  • Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof, having a structure represented by formula (v):
  • X is selected from N or CH
  • Cy1 is selected from and phenyl, the and phenyl are unsubstituted or are each independently substituted with 1-3 R a1 ;
  • Each Ra1 is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxy C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl ) 2aminocarbonyl ;
  • L1, L2, L3, L4, L5, L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, -S-, -NR 2 , -CR 31 R 32 -, -C(O)-, -C(O)O-, -C(O)NR 4 -, -NR 5 -C(O)-, C 2-8 alkenyl, and C 2-8 alkynyl;
  • n and m are each independently any integer from zero to six;
  • R 2 , R 31 , R 32 , R 4 and R 5 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, wherein the C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C
  • Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl, 4-6 membered cycloalkyl substituted by 1-3 R a2 , 4-6 membered heterocyclyl substituted by 1-3 R a2 , 4-6 membered cycloalkenyl substituted by 1-3 R a2 , wherein the heteroatom of the 4-6 membered heterocyclyl is selected from O, N or S;
  • Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclyl, 3-8 membered cycloalkyl substituted by 1-3 R a4 , 3-8 membered heterocyclyl substituted by 1-3 R a4 , 3-8 membered cycloalkenyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring cycloalkyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring alkenyl substituted by 1-3 R a4 , and the heteroatom of the 3-8 membered heterocyclyl or 6-13 membered bicyclic condensed ring heterocyclyl is selected
  • Each of Ra2 and Ra4 when present, is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halo -C1-6 alkyl, C1-6 alkoxy, halo -C1-6 alkoxy, hydroxy- C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C2-8alkenyl , C2-8alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl)2aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, wherein said C1-6 alkyl, halo -C1-6 alkyl, C1-6 alkoxy, halo -C1-6 alkoxy, hydroxy -C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl
  • X1 is N or CR b1 ;
  • X2 is N or CR b2 ;
  • X4 is N or CR b4 ;
  • X5 is N or CR b5 ;
  • R b1 , R b2 , R b3 , R b4 and R b5 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 116 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl;
  • Cy5 is selected from a 6-13 membered bicyclic fused ring group and an 8-21 membered polycyclic fused ring group; the 6-13 membered bicyclic fused ring group or the 8-21 membered polycyclic fused ring group is unsubstituted or substituted with 1-3 R a5 ;
  • Each Ra5 is independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl) 2aminocarbonyl , 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated
  • Cy1 is selected from and phenyl, the and phenyl are unsubstituted or each independently substituted with 1 to 3 Ra1 .
  • Cy1 is unsubstituted or substituted with 1-3 R a1
  • Cy1 is unsubstituted or substituted with 1-3 R a1
  • Cy1 is unsubstituted or substituted with 1-3 R a1
  • Cy1 is unsubstituted or substituted with 1-3 R a1
  • Cy1 is unsubstituted or substituted with 1-3 R a1
  • the compound represented by formula (i) has the structure shown below:
  • Y is selected from N or CR a2 ;
  • X, L 1 , Cy1 and Ra2 have the definitions given above.
  • the compound represented by formula (i-1) has the structure shown below:
  • Y is selected from N or CR a2 ;
  • X, L 1 , Cy1 and Ra2 have the definitions given above.
  • the compound represented by formula (i) has the structure shown below:
  • Z1 and Z2 are the same or different and are independently selected from C(R a3 )(R a3 ), O, N(R a3 ), S, Si(R a3 )(R a3 );
  • X, G, L 2 , L 3 , L 4 , L 5 , Cy2, Cy4, Cy5, R a1 , R a33 , X 1 , X 2 , X 4 , X 5 have the definitions described above.
  • the compound represented by formula (i-2) has the structure shown below:
  • Z 3 is selected from N, C or CR a4 ; represents a single bond or a double bond; G, Y, Z 1 , Z 2 , R b1 , R b2 , R b4 , R b5 , Ra1 and Ra5 have the meanings described above.
  • the compound of the aforementioned formula (i), its isomer or its pharmaceutically acceptable salt is shown in the following table:
  • the present invention also provides a pharmaceutical composition, which comprises the compound of formula (i), its isomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention also provides use of the compound of formula (i), its isomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of a drug for treating and/or preventing a disease or condition by degrading a target protein.
  • the disease or disorder is selected from abnormal cell proliferation, tumors, immune diseases, diabetes, cardiovascular diseases, infectious diseases and inflammatory diseases; preferably tumors and infectious diseases.
  • the tumor is cancer; preferably selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube tumors, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, colorectal cancer, esophageal cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, pancreatic cancer, gastric cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelioma, glioma, astrocytoma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, medulloblastoma, pineal cell tumor, meningioma, neurofibroma, neurilemoma, thyroid cancer, Wilms' tumor and teratoma; more preferably selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer,
  • the infectious disease is selected from viral pneumonia, influenza, avian influenza, meningitis, gonorrhea, or infection with HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, flavivirus, rotavirus, coronavirus, EBV, drug-resistant virus, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, togavirus, orthomyxovirus, retrovirus, hepadnavirus, Gram-negative bacteria, Gram-positive bacteria, atypical bacteria, Staphylococcus, Streptococcus, Escherichia coli, Salmonella, Helicobacter pylori, Chlamydiaceae, Mycoplasmaceae, fungi, protozoa, intestinal worms, worms, prions or parasites.
  • the present invention also provides the use of the compound of formula (i), its isomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of a drug for treating and/or preventing estrogen receptor-mediated or dependent diseases or conditions, wherein the estrogen receptor-mediated or dependent diseases or conditions are tumors, preferably cancer, more preferably selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer and fallopian tube tumors, and most preferably breast cancer.
  • the estrogen receptor-mediated or dependent diseases or conditions are tumors, preferably cancer, more preferably selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer and fallopian tube tumors, and most preferably breast cancer.
  • the present invention also provides a method for treating and/or preventing a disease or condition by degrading a target protein, comprising administering to a patient a therapeutically effective amount of a compound of formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method for treating and/or preventing estrogen receptor-mediated or dependent diseases or conditions, comprising administering to a patient a therapeutically effective amount of a compound of formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof, which can be used as an estrogen receptor degrader for preparing a drug for treating and/or preventing estrogen receptor-mediated or dependent diseases or conditions.
  • Figure 1 shows the effect of compound IV-9 on ER protein degradation in MCF-7 cells
  • FIG2 shows the effect of compound VI-20 on ER protein degradation in MCF-7 cells
  • FIG3 shows the effect of compound VI-23 on ER protein degradation in MCF-7 cells
  • FIG4 shows the effect of compound VI-24 on ER protein degradation in MCF-7 cells
  • FIG5 shows the effect of compound VI-29 on ER protein degradation in MCF-7 cells
  • FIG6 shows the ER protein degradation effect of compound VI-28 on MCF-7 cells.
  • halogen refers to fluorine, chlorine, bromine, iodine, etc., preferably fluorine and chlorine.
  • halogenated means that any hydrogen atom in the substituent may be replaced by one or more halogen atoms which are the same or different. "Halogen” is as defined above.
  • C 1-6 alkyl refers to a straight or branched alkyl derived from a hydrocarbon portion containing 1 to 6 carbon atoms by removing a hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl and 1-methyl-2-methyl
  • C2-8 alkenyl refers to a straight chain, branched or cyclic olefin group derived from an olefin portion of 2 to 8 carbon atoms containing a carbon-carbon double bond by removing a hydrogen atom, such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, and 1,4-hexadienyl.
  • C 2-8 alkynyl refers to a straight-chain or branched alkynyl derived from an alkyne moiety of 2 to 8 carbon atoms containing a carbon-carbon triple bond by removing a hydrogen atom, such as ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl, etc.
  • the "C 2-8 alkynyl” is preferably C 2-4 alkynyl or C 2-3 alkynyl.
  • the "C 1-6 alkoxy” of the present invention refers to a group in which the "C 1-6 alkyl” defined above is connected to the parent molecule through an oxygen atom, i.e., a "C 1-6 alkyl-O-” group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy, neopentoxy and n-hexoxy, etc.
  • the "C 1-6 alkoxy” is preferably a C 1-4 alkoxy or a C 1-3 alkoxy.
  • C 1-6 alkylamino refers to C 1-6 alkyl-NH-, (C 1-6 alkyl)(C 1-6 alkyl)N-, C 1-6 alkyl-C(O)-NH-, C 1-6 alkyl-S(O) 2 -NH 2 -, C 1-6 alkyl -NH-C(O)-, (C 1-6 alkyl)(C 1-6 alkyl)NC(O)-, C
  • the "condensed ring” described in the present invention refers to a multi-ring structure formed by two or more cyclic structures in the form of parallel, spiro, or bridge connection.
  • Each cyclic structure refers to any monocyclic alkyl, monoheterocyclic, monocyclic alkenyl, phenyl, or monoheteroaryl.
  • the parallel ring refers to a condensed ring structure formed by two or more cyclic structures sharing two adjacent ring atoms (i.e., sharing a bond).
  • the bridged ring refers to a condensed ring structure formed by two or more cyclic structures sharing two non-adjacent ring atoms.
  • the spiro ring refers to a condensed ring structure formed by two or more cyclic structures sharing one ring atom. Multiple cyclic structures are optionally connected in parallel, spiro, or bridge mode.
  • bicyclic fused ring groups such as 6-13 membered bicyclic fused ring groups.
  • 6-13 membered bicyclic fused ring groups include 6-13 membered bicyclic fused cycloalkyl, 6-13 membered bicyclic fused cycloalkenyl, 6-13 membered bicyclic fused heterocyclic group, 8-13 membered bicyclic fused heteroaryl, 8-13 membered bicyclic fused aryl.
  • a polycyclic fused ring group is a group in which two or more cyclic structures are connected in parallel, spiro or bridge mode, such as a monocyclic ring structure connected to a 6-13-membered bicyclic fused ring group in parallel, spiro or bridge mode, such as an 8-21-membered polycyclic fused ring group.
  • the 8-21-membered polycyclic fused ring group further includes an 8-21-membered polycyclic fused cycloalkyl, an 8-21-membered polycyclic fused cycloalkenyl, an 8-21-membered polycyclic fused heterocyclic group, an 8-21-membered polycyclic fused heteroaryl, and an 8-21-membered polycyclic fused aryl.
  • the 8-21-membered polycyclic fused heterocyclic group includes an 8-21-membered polycyclic bridged heterocyclic group, an 8-21-membered polycyclic fused heterocyclic group and an 8-21-membered polycyclic spiro heterocyclic group.
  • Examples of 8-21 membered polycyclic heterocyclic groups include, but are not limited to
  • the 3-8 membered monocyclic group of the present invention includes monocyclic alkyl, monoheterocyclic, monocyclic alkenyl, monoheteroaryl and phenyl.
  • Monocycloalkyl is a cycloalkyl group containing 3-13 carbon atoms, including 3-13-membered cycloalkyl, 3-8-membered cycloalkyl, 4-7-membered cycloalkyl, 4-6-membered cycloalkyl, 5-6-membered cycloalkyl.
  • 3-8-membered cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.
  • the monoheterocyclic group refers to a non-aromatic cyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, and N, preferably 1 to 3 heteroatoms.
  • the monoheterocyclic group may be saturated or partially saturated, including 3-13 membered heterocyclic groups, 3-8 membered heterocyclic groups, 3-6 membered heterocyclic groups, 4-6 membered heterocyclic groups, 4-7 membered heterocyclic groups, 5-7 membered heterocyclic groups, 5-6 membered heterocyclic groups, 4-6 membered nitrogen-containing heterocyclic groups, 5-6 membered oxygen-containing heterocyclic groups, 3-8 membered nitrogen-containing heterocyclic groups, 5-6 membered nitrogen-containing heterocyclic groups, 5-6 membered saturated heterocyclic groups, and the like.
  • the monocycloalkenyl group refers to a partially saturated carbon ring group, including 3-13 membered cycloalkenyl, 3-8 membered cycloalkenyl, 4-7 membered cycloalkenyl, and 5-6 membered cycloalkenyl.
  • the heteroaryl group of the present invention refers to an aromatic cyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, and N.
  • the monoheteroaryl group may be a 5-7-membered heteroaryl group or a 5-6-membered heteroaryl group, and examples thereof include but are not limited to furanyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thienyl, triazolyl, and triazinyl.
  • bicyclic condensed cycloalkyl includes cycloalkyl, bridged cycloalkyl, spirocycloalkyl. It can be saturated, partially saturated or unsaturated, but not aromatic.
  • Cycloalkyl can be 6-11-membered cycloalkyl, 7-10-membered cycloalkyl, and its representative examples include but are not limited to bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane and bicyclo[4.2.1]nonane.
  • the spirocyclyl can be 7-12-membered spirocyclyl, 7-11-membered spirocyclyl, 10-11-membered spirocyclyl, and its examples include but are not limited to:
  • the bridged ring group may be a 6-11-membered bridged ring group or a 7-10-membered bridged ring group, examples of which include but are not limited to:
  • the 6-13-membered bicyclic fused cycloalkenyl group includes cycloalkenyl, bridged cycloalkenyl, and spirocycloalkenyl.
  • Representative examples of 6-13-membered bicyclic cycloalkenyl groups include, but are not limited to
  • 6-13 membered bicyclic fused heterocyclic groups include heterocyclic groups, spiro heterocyclic groups, and bridged heterocyclic groups, which may be saturated, partially saturated, or unsaturated, but not aromatic.
  • the fused heterocyclic group is a 5-6 membered monocyclic heterocyclic group fused to a benzene ring, a 5-6 membered monocyclic cycloalkyl group, a 5-6 membered monocyclic cycloalkenyl group, a 5-6 membered monocyclic heterocyclic group, or a 5-6 membered monocyclic heteroaryl group.
  • the heterocyclic group may be a 6-12 membered heterocyclic group, a 7-10 membered heterocyclic group, a 6-10 membered heterocyclic group, an 8-10 membered bicyclic heterocyclic group, or a 6-12 membered saturated heterocyclic group, representative examples of which include, but are not limited to, 3-azabicyclo[3.1.0]hexane, 3,6-diazabicyclo[3.2.0]heptane, 3,8-diazabicyclo[4.2.0]octanyl, 3,7-diazabicyclo[4.2.0]octanyl, octahydropyrrolo[ 3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,4-b][1,4]oxazinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, 2,3-dihydro
  • the spiro heterocyclic group may be a 6-12-membered spiro heterocyclic group, a 7-11-membered spiro heterocyclic group, a 6-12-membered saturated spirocyclic group, or a 10-11-membered bicyclic spiro heterocyclic group, examples of which include, but are not limited to:
  • the bridged heterocyclic group may be a 6-12-membered bridged heterocyclic group, a 7-11-membered bridged heterocyclic group, or a 6-12-membered saturated bridged ring group, examples of which include but are not limited to:
  • 8-13 membered bicyclic fused heteroaryl refers to a group formed by a monocyclic heteroaryl ring fused to a phenyl group or a monoheteroaryl group.
  • the fused heteroaryl group may be an 8-13 membered fused heteroaryl group, a 9-10 membered fused heteroaryl group, or an 8-10 membered bicyclic fused heteroaryl group, and examples thereof include but are not limited to
  • the 8-13 membered bicyclic fused aryl group refers to a group formed by condensing a single aromatic ring to a single aromatic group, including naphthalene, phenanthrene and the like.
  • the "pharmaceutically acceptable salt” of the present invention refers to a pharmaceutically acceptable acid and base addition salt or a solvate thereof.
  • Such pharmaceutically acceptable salts include salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, alkanoic acid (such as acetic acid, HOOC-(CH 2 )n-COOH (wherein n is 0 to 4)), etc.
  • Alkaline salts sodium salts, potassium salts, calcium salts, ammonium salts, etc.
  • a variety of non-toxic pharmaceutically acceptable addition salts are known to those skilled in the art.
  • Stereoisomers refer to enantiomers produced when a compound has an asymmetric atom; cis-trans isomers produced when a compound has a double bond or a ring structure; all enantiomers, diastereomers, racemates, cis-trans isomers, geometric isomers, epimers and mixtures thereof of compounds of formula (I) are included in the scope of the present invention.
  • Tautomers refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions. Tautomers are a special type of functional group isomers. For example, the tautomerism of carbonyl compounds containing ⁇ -H, specifically Such as other proton migration tautomerism, specifically phenol-keto tautomerism, nitroso-oxime tautomerism, imine-enamine tautomerism.
  • T, T1, and T2 are each independently any group that conforms to the bonding rules of the compound.
  • Ra2 and Ra4 described in the present invention can be optionally connected to L2, L3, L4 or L5 when complying with the bonding rules.
  • Step 1 Using the aldehyde compound int-1 and the amino compound int-2 as starting materials, reductive amination is performed to obtain the intermediate int-3.
  • Step 2 The intermediate int-3 is further hydrogenated and reduced to obtain the final product compound.
  • X is selected from N or CH;
  • Y 1 , Y 2 and Y 3 are selected from N, NR a1 , CR a1 , C(R a1 ) 2 or C(O);
  • Example 1 Synthesis of 1-(5-fluoro-6-(4-((1R, 2R)-2-((4-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound IV-5)
  • toluene 750ml
  • potassium tert-butoxide 75.60g, 673.73mmol
  • palladium acetate 7.8g, 34.74mmol
  • 1,1′-binaphthyl-2,2′-bisdiphenylphosphine 25.8g, 41.43mmol
  • 6-methoxy-1-naphthalene ketone 60g, 340.5mmol
  • bromobenzene 53.4g, 340.5mmol
  • Step 4 Synthesis of 4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenol
  • Step 5 Preparation of 4-((1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenol
  • A is CO2
  • B is IPA
  • Step 6 Synthesis of 4-((1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl 1,1,2,2,3,3,4,4,4-perfluorobutyl-1-sulfonate
  • Step 7 Synthesis of tert-butyl 4-(4-((1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-carboxylate
  • Step 8 Synthesis of (5R,6S)-6-phenyl-5-(4-(piperazin-1-yl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol
  • tert-butyl 4-(4-((1R, 2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-carboxylate (3.0 g, 6.0 mmol) was dissolved in 100 mL of dichloromethane, and 30 mL of 1.0 N boron tribromide n-heptane solution was added dropwise at -60 °C. After addition, the mixture was naturally warmed up overnight. The mixture was cooled and methanol was added dropwise to quench the mixture. The mixture was concentrated and chromatographed on a silica gel column to obtain 1.7 g of a yellow solid with a yield of 73%. MS (ESI) m/z: 385.2 [M+H] + .
  • Step 10 Synthesis of tert-butyl 4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-carboxylate
  • tert-butyl 4-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-carboxylate 220.00 g, 0.45 mol
  • potassium carbonate 94.11 g, 0.68 mol
  • 18 crown 6 2.2 g, 1% w/w
  • acetonitrile (2 L) were added sequentially into the reaction bottle, and BnBr (89.28 g, 0.52 mol) was added dropwise.
  • the mixture was reacted at 60°C for 18 h, cooled to room temperature, the reaction solution was added to water, the mixture was crystallized and filtered, the filter cake was slurried with methanol and filtered to obtain 247.90 g of the product with a yield of 95%.
  • Step 11 Synthesis of 1-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine hydrochloride
  • Step 12 Synthesis of 1-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-4-(((1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)methyl)piperazine
  • Step 13 Synthesis of ((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methanol
  • Step 14 Synthesis of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde
  • Step 15 Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate
  • Step 16 Synthesis of 1-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.14 g, 0.32 mmol) and dichloromethane (10 ml) were added to the reaction bottle in sequence, and hydrochloric acid/dioxane (4 ml) was added after dissolving, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed to obtain 0.11 g of a crude product, which was directly used in the next step.
  • Step 17 Synthesis of 1-(6-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • Step 18 1-(5-Fluoro-6-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • Step 2 Synthesis of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione
  • Step 3 Synthesis of tert-butyl 4-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperazine-1-carboxylate
  • Step 4 Synthesis of 3-(3-methyl-2-oxo-4-(piperazin-1-yl)-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione
  • tert-butyl 4-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperazine-1-carboxylate (0.41 g, 0.73 mmol), trifluoroacetic acid (3 ml) and TfOH (0.5 ml) were added to the reaction bottle in sequence, and the temperature was raised to 65°C and stirred for 2 hours. After the reaction was completed, the solvent was removed and the column chromatography was performed using a reverse column chromatography (acetonitrile/water) system to obtain 0.10 g of a crude product, which was directly used in the next step.
  • Step 5 Synthesis of 3-(4-(4-(((1R,2R)-2-((4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione
  • Step 6 Synthesis of 3-(4-(4-(((1R,2R)-2-((4-(4-(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione
  • the reaction was stirred at 30°C for 16 h. After the reaction was completed, the mixture was filtered through a pad of diatomaceous earth, the filter cake was eluted with tetrahydrofuran, and the filtrate was desolvated. The product was purified by column chromatography using a DCM/MeOH system to obtain 0.030 g (0.026 g in storage), with a yield of 29%.
  • Step 1 Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Step 2 Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate
  • Step 3 Synthesis of 1-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate (0.25 g, 0.56 mmol) and dichloromethane (10 ml) were added to the reaction bottle in sequence, and hydrochloric acid/dioxane (9 ml) was added after dissolving, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed to obtain 0.19 g of a crude product, which was directly used in the next step.
  • Step 4 Synthesis of 1-(6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • Step 5 Synthesis of 1-(5-fluoro-6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • the reaction was stirred at room temperature for 24 hours. After the reaction was completed, diatomaceous earth was used for filtration, and the filter cake was eluted with tetrahydrofuran and the filtrate was desolvated.
  • the product was chromatographed on a DCM/MeOH system to obtain 0.135 g of the product (0.130 g in storage), with a yield of 54%.
  • Step 1 Synthesis of tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate
  • tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (2.50 g, 7.78 mmol), NaOH (1.24 g, 31.11 mmol), MeOH (30 ml) and H 2 O (10 ml) were added to the reaction bottle in sequence, and the temperature was raised to 50°C for 4 hours. After the reaction was completed, the solvent was removed, and HCl aqueous solution was added to adjust the acidity. The product precipitated and filtered to obtain 2.20 g of a white solid with a yield of 92%.
  • Step 3 Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazine-1-carboxylate
  • tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazine-1-carboxylate (0.27 g, 0.65 mmol) and dichloromethane (2 mL) were added to the reaction bottle in sequence, and hydrochloric acid/dioxane (2 mL) was added after dissolving, and the mixture was stirred at room temperature for 3 h. After the reaction was completed, the solvent was removed to obtain 0.26 g of a crude product, which was directly carried out to the next step.
  • Step 5 Synthesis of 4-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide
  • N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazine-1-yl)benzamide (0.15 g, 0.47 mmol)
  • (1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-yl)methyl)cyclohexane-1-carbaldehyde (0.28 g, 0.47 mmol) and dichloromethane (5 mL) were added to the reaction bottle in sequence, and TIPT (0.5 mL) was added.
  • Step 6 Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)benzamide
  • Step 1 Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole
  • 6-bromo-3-iodo-1-methyl-1H-indazole (1.00 g, 2.97 mmol)
  • 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridine (1.24 g, 2.97 mmol)
  • sodium carbonate (0.94 g, 8.90 mmol
  • tetrakistriphenylphosphine palladium (0.34 g, 0.30 mmol
  • water (1 mL) and dioxane (10 ml) were added to the reaction bottle in sequence, and the mixture was reacted for 5 h at 90° C. in a nitrogen atmosphere.
  • Step 2 Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate
  • Step 3 Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate
  • tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.20 g, 0.33 mmol), 10% Pd/C (0.02 g), tetrahydrofuran (5 mL) and ethanol (5 ml) were added to the reaction bottle in sequence and reacted at room temperature for 24 h. After the reaction was completed, the mixture was filtered and dried to obtain 0.13 g of a crude product, which was directly used in the next step.
  • tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.13 g, 0.30 mmol) and HCl dioxane solution (5 ml) were added to the reaction bottle in sequence and reacted at room temperature for 2 h. After the reaction was completed, the mixture was spin-dried to obtain 0.11 g of a crude product, which was directly used for the next step.
  • Step 5 Synthesis of 3-(6-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperazine-2,6-dione
  • Step 6 Synthesis of 3-(6-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione
  • Step 1 Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate
  • Step 2 Synthesis of 3-(3-methyl-2-oxo-5-piperazin-1-yl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperazine-2,6-dione
  • tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate (0.45 mg, 1.01 mmol) and dichloromethane (2 ml) were added to the reaction bottle in sequence, and hydrochloric acid/dioxane (2 ml) was added after dissolving, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed to obtain 0.30 g of a crude product, which was directly carried out to the next step.
  • Step 3 Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperazine-2,6-dione
  • Step 4 Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione
  • Step 1 Synthesis of tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylic acid methyl ester
  • tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylic acid methyl ester (2.50 g, 7.78 mmol), NaOH (1.24 g, 31.11 mmol), MeOH (30 ml) and H 2 O (10 ml) were added to the reaction bottle in sequence, and the temperature was raised to 50°C for 4 h. After the reaction was completed, the solvent was removed, HCl aqueous solution was added to adjust to acidity, and DCM was extracted three times to obtain 2.20 g of a yellow solid with a yield of 92%.
  • Step 3 Synthesis of tert-butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
  • tert-butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate (0.27 mg, 0.65 mmol) and dichloromethane (2 ml) were added to the reaction bottle in sequence, and hydrochloric acid/dioxane (2 ml) was added after dissolving, and the mixture was stirred at room temperature for 3 h. After the reaction was completed, the solvent was removed to obtain 0.26 g of a crude product, which was directly carried out to the next step.
  • Step 5 Synthesis of 5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridine-3-carboxamide
  • N-(2,6-dioxopiperidin-3-yl)-5-(piperazine-1-yl)pyridine-3-carboxamide (0.15 g, 0.47 mmol)
  • (1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-yl)methyl)cyclohexane-1-carboxaldehyde (0.28 g, 0.47 mmol) and dichloromethane (5 ml) were added to the reaction bottle in sequence, and TIPT (0.45 ml) was added.
  • Step 6 Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)picolinamide
  • Example 8 Synthesis of 3-(4-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound VII-3)
  • Step 1 Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Step 2 Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-1-carboxylate
  • Step 3 Synthesis of 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione
  • tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-1-carboxylate (0.20 mg, 0.45 mmol) and dichloromethane (2 ml) were added to the reaction bottle in sequence, and hydrochloric acid/dioxane (2 ml) was added after dissolving, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed to obtain 0.11 g of a crude product, which was directly carried out to the next step.
  • Step 4 Synthesis of 3-(4-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione
  • Step 5 Synthesis of 3-(4-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione
  • Step 1 Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate
  • Step 2 Synthesis of tert-butyl 4-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1H-indazol-5-yl)piperazine-1-carboxylate
  • tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.47 g, 1.09 mmol), 1-Boc-piperazine (0.20 g, 1.09 mmol), PEPPSI IHept-Cl (0.11 g, 0.11 mmol), cesium carbonate (1.07 g, 3.28 mmol), 4A molecular sieves (0.11 g) and 1,4-dioxane (15 ml) were added to the reaction bottle in sequence, nitrogen was replaced 3-4 times, and the temperature was raised to 100°C for reaction for 15 hours.
  • tert-butyl 4-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1H-indazol-5-yl)piperazine-1-carboxylate (0.13 g, 0.23 mmol), trifluoroacetic acid (3 ml) and TfOH (0.5 ml) were added to the reaction bottle in sequence, and the temperature was raised to 65°C and stirred for 2 hours. After the reaction was completed, the solvent was removed and column chromatography was performed using a reverse column chromatography (acetonitrile/water) system to obtain 0.06 g of a crude product, which was directly used in the next step.
  • Step 4 Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-(1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)yl)cyclohexyl)methyl)piperazin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione
  • Step 5 Synthesis of 3-(5-(4-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione
  • Step 1 Synthesis of tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Step 2 Synthesis of 4-(1-(tert-butyloxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzoic acid
  • tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (2.50 g, 7.78 mmol), NaOH (1.24 g, 31.11 mmol), MeOH (30 ml) and H 2 O (10 ml) were added to the reaction bottle in sequence, and the temperature was raised to 50°C for 4 h. After the reaction was completed, the solvent was removed, and HCl aqueous solution was added to adjust the acidity. The product precipitated and filtered to obtain 2.20 g of a white solid with a yield of 92%.
  • Step 3 Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Step 4 Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide
  • tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (0.27 g, 0.65 mmol) and dichloromethane (2 mL) were added to the reaction bottle in sequence, and hydrochloric acid/dioxane (2 mL) was added after dissolving, and the reaction was stirred at room temperature for 3 h. After the reaction was completed, the solvent was removed to obtain 0.26 g of a crude product, which was directly carried out to the next step.
  • Step 5 Synthesis of 4-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide
  • N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.15 g, 0.47 mmol)
  • (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.28 g, 0.47 mmol) and dichloromethane (5 mL) were added to the reaction bottle in sequence, and TIPT (0.5 mL) was added.
  • Step 6 Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)benzamide
  • Step 1 Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole
  • 6-bromo-5-fluoro-3-iodo-1-methyl-1H-indazole (1.00 g, 2.97 mmol)
  • 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridine (1.24 g, 2.97 mmol)
  • sodium carbonate (0.94 g, 8.90 mmol
  • tetrakistriphenylphosphine palladium (0.34 g, 0.30 mmol
  • water (1 mL) and dioxane (10 ml) were added to the reaction bottle in sequence, and the mixture was reacted for 5 h at 90° C. in a nitrogen atmosphere.
  • Step 2 Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate
  • Step 3 Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate
  • tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.20 g, 0.33 mmol), 10% Pd/C (0.02 g), tetrahydrofuran (5 mL) and ethanol (5 ml) were added to the reaction bottle in sequence and reacted at room temperature for 24 h. After the reaction was completed, the mixture was filtered and dried to obtain 0.13 g of a crude product, which was directly used in the next step.
  • tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.13 g, 0.30 mmol) and HCl dioxane solution (5 ml) were added to the reaction bottle in sequence and reacted at room temperature for 2 h. After the reaction was completed, the mixture was spin-dried to obtain 0.11 g of a crude product, which was directly used for the next step.
  • Step 5 Synthesis of 3-(6-(4-(((1R,2R)-2-((4-(4-(1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione
  • Step 6 Synthesis of 3-(5-fluoro-6-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperazine-2,6-dione
  • Example 12 Synthesis of 3-(6-fluoro-5-(4-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperazine-2,6-dione (Compound VI-5)
  • Step 1 Synthesis of 3-(5-bromo-6-fluoro-1H-indazol-1-yl)-1-(4-methoxyphenylmethyl)piperazine-2,6-dione
  • Step 2 Synthesis of tert-butyl 4-(6-fluoro-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1H-indazole-5-yl)piperazine-1-carboxylate
  • Step 5 Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-(1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-6-fluoro-1H-indazol-1-yl)piperidine-2,6-dione
  • Step 6 Synthesis of 3-(6-fluoro-5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperazine-2,6-dione
  • Example 13 Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)picolinamide (Compound III-3)
  • Step 1 Synthesis of 1′-(tert-butyl)6-methyl 3′,6′-dihydro-[3,4′-bipyridine]-1′,6(2′H)-dicarboxylate
  • Step 2 Synthesis of 1′-(tert-butyloxycarbonyl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carboxylic acid
  • tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylic acid methyl ester (1.25 g, 3.93 mmol), NaOH (0.63 g, 15.72 mmol), MeOH (15 ml) and H 2 O (5 ml) were added to the reaction bottle in sequence, and the temperature was raised to 50°C for 4 h. After the reaction was completed, the solvent was removed, HCl aqueous solution was added to adjust to acidity, and DCM was extracted three times to obtain 1.10 g of a yellow solid with a yield of 92%.
  • Step 3 Synthesis of tert-butyl 6-((2,6-dioxopiperidin-3-yl)carbamoyl)-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate
  • Step 4 Synthesis of N-(2,6-dioxopiperidin-3-yl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carboxamide
  • tert-butyl 6-((2,6-dioxopiperidin-3-yl)carbamoyl)-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate (0.27 mg, 0.65 mmol) and dichloromethane (2 ml) were added to the reaction bottle in sequence, and hydrochloric acid/dioxane (2 ml) was added after dissolving, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed to obtain 0.26 g of a crude product, which was directly carried out to the next step.
  • Step 5 Synthesis of 1′-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-N-(2,6-dioxopiperidin-3-yl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carboxamide
  • N-(2,6-dioxopiperidin-3-yl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carboxamide (0.15 g, 0.47 mmol)
  • (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carboxaldehyde (0.28 g, 0.47 mmol) and dichloromethane (5 ml) were added to the reaction bottle in sequence, and TIPT (0.45 ml) was added.
  • Step 6 Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)pyridine-2-carboxamide
  • the reaction was stirred at room temperature for 24 h. After the reaction was completed, diatomaceous earth was used for filtration, the filter cake was eluted with THF, the filtrate was desolvated, and DCM/MeOH system column chromatography was used to obtain 0.033 g of product, 0.028 g was put into storage, and the yield was 22.9%.
  • Example 14 Synthesis of 3-(5-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (Compound VI-8)
  • Step 1 Synthesis of 5-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridine-3-carboxamide
  • Step 2 Synthesis of 3-(3-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione
  • Step 3 Synthesis of 3-(5-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione
  • Step 4 Synthesis of 3-(5-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione
  • Step 1 Synthesis of 3-(5-bromo-6-fluoro-3-methyl-1h-indazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione
  • Step 2 Synthesis of tert-butyl 4-(6-fluoro-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Step 3 Synthesis of tert-butyl 4-(6-fluoro-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-5-yl)piperidine-1-carboxylate
  • Step 4 Synthesis of 3-(6-fluoro-3-methyl-5-(piperidin-4-yl)-1h-indazol-1-yl)piperidine-2,6-dione
  • tert-butyl 4-(6-fluoro-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-5-yl)piperidine-1-carboxylate (0.50 g, 0.89 mmol)
  • trifluoroacetic acid 3 ml
  • TfOH 0.5 ml
  • the solvent was removed and the mixture was chromatographed using a reverse column chromatography (acetonitrile/water) system to obtain 0.20 g of a crude product, which was directly used in the next step.
  • Step 5 Synthesis of 3-(5-(1-(((1R,2R)-2-((4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-6-fluoro-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione
  • Step 6 Synthesis of 3-(6-fluoro-5-(1-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione
  • the reaction was stirred at room temperature for 24 hours. After the reaction was completed, diatomaceous earth was used for filtration, and the filter cake was eluted with tetrahydrofuran and the filtrate was desolvated. The product was chromatographed on a DCM/MeOH system to obtain 0.05 g of the product with a yield of 37%.
  • Example 16 Synthesis of 3-(5-fluoro-6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (Compound IV-9)
  • Step 1 Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole
  • 6-bromo-5-fluoro-3-iodo-1-methyl-1H-indazole (1.00 g, 2.97 mmol)
  • 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridine (1.24 g, 2.97 mmol)
  • sodium carbonate (0.94 g, 8.90 mmol
  • tetrakistriphenylphosphine palladium (0.34 g, 0.30 mmol
  • water (1 mL) and dioxane (10 ml) were added to the reaction bottle in sequence, and the mixture was reacted for 5 h at 90° C. in a nitrogen atmosphere.
  • Step 2 Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • the reaction was carried out at 90° C. in a nitrogen atmosphere for 5 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, the liquids were separated, and the organic phase was dried and then chromatographed using a PE/EA system column to obtain 0.47 g of the product with a yield of 66%.
  • Step 3 Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indol-6-yl)piperidine-1-carboxylate
  • Step 4 Synthesis of 3-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indol-3-yl)piperidine-2,6-dione
  • tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indol-6-yl)piperidine-1-carboxylate (0.26 g, 0.60 mmol) and HCl dioxane solution (5 ml) were added to the reaction bottle in sequence, and the mixture was reacted at room temperature for 2 h. After the reaction was completed, the mixture was spin-dried to obtain 0.22 g of a crude product, which was directly used for the next step.
  • Step 5 Synthesis of 3-(6-(1-(((1R,2R)-2-((4-(4-(((2R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione
  • Step 6 Synthesis of 3-(5-fluoro-6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione
  • Example 17 Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)picolinamide (Compound III-2)
  • Step 1 Synthesis of 5-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridine-3-carboxamide
  • N-(2,6-dioxopiperidin-3-yl)-5-(piperazine-1-yl)pyridine-3-carboxamide (0.09 g, 0.28 mmol)
  • (1S, 2S)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-yl)methyl)cyclohexane-1-carboxaldehyde (0.17 g, 0.28 mmol) and dichloromethane (5 ml) were added to the reaction bottle in sequence, and TIPT (0.3 ml) was added.
  • Step 2 Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)picolinamide
  • Example 18 Synthesis of 3-(6-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (Compound IV-4)
  • Step 1 Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole
  • 6-bromo-3-iodo-1-methyl-1H-indazole (1.00 g, 2.97 mmol)
  • 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridine (1.24 g, 2.97 mmol)
  • sodium carbonate (0.94 g, 8.90 mmol
  • tetrakistriphenylphosphine palladium (0.34 g, 0.30 mmol
  • water (1 mL) and dioxane (10 ml) were added to the reaction bottle in sequence, and the mixture was reacted for 5 h at 90° C. in a nitrogen atmosphere.
  • Step 2 Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate
  • Step 3 Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate
  • tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.20 g, 0.33 mmol), 10% Pd/C (0.02 g), tetrahydrofuran (5 mL) and ethanol (5 ml) were added to the reaction bottle in sequence and reacted at room temperature for 24 h. After the reaction was completed, the mixture was filtered and dried to obtain 0.13 g of a crude product, which was directly used in the next step.
  • tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.13 g, 0.30 mmol) and HCl dioxane solution (5 ml) were added to the reaction bottle in sequence and reacted at room temperature for 2 h. After the reaction was completed, the mixture was spin-dried to obtain 0.11 g of a crude product, which was directly used for the next step.
  • Step 5 Synthesis of 3-(6-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperazine-2,6-dione
  • Step 6 Synthesis of 3-(6-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione
  • Step 4 Synthesis of N 1 -(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-5-fluorobenzene-1,2-diamine
  • N 1 -(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-5-fluorobenzene-1,2-diamine (3.25 g, 6.57 mmol) was dissolved in toluene (30 mL), trimethyl orthoformate (1.74 g, 16.44 mmol) and TsOH (0.23 g, 1.31 mmol) were added, and the mixture was reacted at 120° C. for 1 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated by column chromatography (EA/PE), and 3.00 g of brown oil was obtained, with a yield of 90.5%.
  • EA/PE column chromatography
  • Step 6 Synthesis of tert-butyl 4-(1-(2,6-bisbenzyloxy)pyridin-3-yl)-6-fluoro-1H-benzimidazol-5-yl)piperazine-1-carboxylate
  • Step 7 Synthesis of tert-butyl 4-(1-(2,6-dioxapiperidin-3-yl)-6-fluoro-1H-benzimidazol-5-yl)piperazine-1-carboxylate
  • Step 8 Synthesis of 3-(6-fluoro-5-(piperazin-1-yl)-1H-benzimidazol-1-yl)piperidine-2,6-dione
  • tert-butyl 4-(1-(2,6-dioxapiperidin-3-yl)-6-fluoro-1H-benzimidazol-5-yl)piperazine-1-carboxylate (0.30 g, 0.70 mmol), DCM (3 mL) and HCl in Do (5 mL) were added to the reaction bottle in sequence, and the temperature was raised to 35°C for 30 min. After the reaction was completed, the crude product was concentrated to obtain 0.25 g, which was directly carried out to the next step.
  • Step 9 Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-6-fluoro-1H-benzimidazol-1-yl)piperidine-2,6-dione
  • Step 4 Synthesis of 3-(6-fluoro-5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-benzimidazol-1-yl)piperidine-2,6-dione
  • Example 20 Synthesis of 3-(6-fluoro-5-(1-(((1R,2R)-2-((4-(4-(((2R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound V-5)
  • Step 4 Synthesis of N 1 -(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-5-fluorobenzene-1,2-diamine
  • N 1 -(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-5-fluorobenzene-1,2-diamine (3.25 g, 6.57 mmol) was dissolved in toluene (30 mL), trimethyl orthoformate (1.74 g, 16.44 mmol) and TsOH (0.23 g, 1.31 mmol) were added, and the mixture was reacted at 120° C. for 1 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated by column chromatography (EA/PE), and 3.00 g of brown oil was obtained, with a yield of 90.5%.
  • EA/PE column chromatography
  • Step 6 Synthesis of tert-butyl 4-(1-(2,6-di(benzyloxy)pyridin-3-yl)-6-fluoro-1H-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Step 7 Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate
  • Step 8 Synthesis of 3-(6-fluoro-5-(piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione
  • tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate (0.30 g, 0.70 mmol), DCM (3 mL) and HCl in Do (5 mL) were added to the reaction bottle in sequence, and the temperature was raised to 35°C for 30 min. After the reaction was completed, the crude product was concentrated to obtain 0.25 g, which was directly carried out to the next step.
  • Step 9 Synthesis of 3-(5-(1-(((1R,2R)-2-((4-(4-(((2R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-6-fluoro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione
  • Step 10 3-(6-fluoro-5-(1-(((1R,2R)-2-((4-(4-(((2R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione
  • Example 21 Synthesis of 3-(5-(1-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound V-7)
  • Step 5 Synthesis of tert-butyl 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-1H-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Step 6 Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate
  • Step 8 Synthesis of 3-(5-(1-(((1R,2R)-2-((4-(((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione
  • Step 9 Synthesis of 3-(5-(1-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione
  • the reaction was stirred at room temperature for 90 hours. After the reaction was completed, diatomaceous earth was used for filtration, and the filter cake was eluted with tetrahydrofuran and the filtrate was desolvated.
  • the product was chromatographed on a DCM/MeOH system to obtain 0.006 g of the product with a yield of 5%, and 0.003 g was put into storage.
  • Step 1 Synthesis of tert-butyl 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate
  • Step 2 Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate
  • Step 4 Synthesis of 3-(5-(4-(((1R,2R)-2-((4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione
  • Step 5 3-(5-(4-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione
  • Step 1 Synthesis of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-2-methyl-1H-benzo[d]imidazole
  • Acetic acid (10 ml), N1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromobenzene-1,2-diamine (0.84 g, 1.77 mmol), and triethyl orthoformate (0.32 g, 2.65 mmol) were added to the reaction bottle in sequence, and the temperature was raised to 120°C for reaction for 3 hours. After the reaction was completed, the temperature was lowered to room temperature, the solvent was removed until there were no obvious droplets, sand was made, and PE/EA system column chromatography was used to obtain 0.92 g of the product (a small amount of acetic acid remained, which did not affect the next step).
  • Step 2 Synthesis of tert-butyl 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-2-methyl-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate
  • Step 3 Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-2-methyl-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate
  • Step 5 Synthesis of 3-(5-(4-(((1R,2R)-2-((4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-2-methyl-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione
  • Step 6 Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-2-methyl-1H-benzimidazol-1-yl)piperidine-2,6-dione
  • Example 24 Synthesis of 3-(5-fluoro-6-(1-(((1S,2S)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (Compound IV-10)
  • Step 1 Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole
  • 6-bromo-5-fluoro-3-iodo-1-methyl-1H-indazole (1.00 g, 2.97 mmol)
  • 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridine (1.24 g, 2.97 mmol)
  • sodium carbonate (0.94 g, 8.90 mmol
  • tetrakistriphenylphosphine palladium (0.34 g, 0.30 mmol
  • water (1 mL) and dioxane (10 ml) were added to the reaction bottle in sequence, and the mixture was reacted for 5 h at 90° C. in a nitrogen atmosphere.
  • Step 2 Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • the reaction was carried out at 90° C. in a nitrogen atmosphere for 5 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, the liquids were separated, and the organic phase was dried and then chromatographed using a PE/EA system column to obtain 0.47 g of the product with a yield of 66%.
  • Step 3 Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indol-6-yl)piperidine-1-carboxylate
  • Step 4 Synthesis of 3-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indol-3-yl)piperidine-2,6-dione
  • tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indol-6-yl)piperidine-1-carboxylate (0.26 g, 0.60 mmol) and HCl dioxane solution (5 ml) were added to the reaction bottle in sequence, and the mixture was reacted at room temperature for 2 h. After the reaction was completed, the mixture was spin-dried to obtain 0.22 g of a crude product, which was directly used for the next step.
  • Step 5 Synthesis of 3-(6-(1-(((1S,2S)-2-((4-(4-(((2R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione
  • Step 6 Synthesis of 3-(5-fluoro-6-(1-(((1S,2S)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione
  • Example 25 Synthesis of 1-(5-fluoro-6-(8-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-17)
  • Step 1 Synthesis of tert-butyl 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-8-azabicyclo-4-oct-2-ene-8-carboxylate
  • Step 2 Synthesis of 1-(6-(8-azabicyclo[3.2.1]oct-2-en-3-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • tert-butyl 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indol-6-yl)-8-azabicyclo-4-oct-2-ene-8-carboxylate (0.10 mg, 0.21 mmol) and dichloromethane (2 ml) were added to the reaction bottle in sequence, and hydrochloric acid/dioxane (5 ml) was added after dissolving, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed to obtain 0.10 g of a white solid crude product, which was directly carried out to the next step.
  • Step 3 Synthesis of 1-(6-(8-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)-8-azabicyclo[3.2.1]oct-2-en-3-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • Step 4 Synthesis of 1-(5-fluoro-6-(8-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • Step 1 Synthesis of tert-butyl 7-(((trifluoromethyl)sulfonyl)oxy)-4-azaspiro[2.5]oct-6-ene-4-carboxylate
  • tert-butyl 7-oxo-4-azaspiro[2.5]octane-4-carboxylate (1 g, 4.44 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (2.38 g, 6.66 mmol) were dissolved in THF (20 mL), cooled to -78 ° C, and LiHMDS (7 mL, 7.00 mmol) was added. After the addition was completed, the reaction was reacted at room temperature for 8 h. After the reaction was completed, water (3 mL) was added to the reaction solution, and the solution was directly concentrated by column chromatography (EA/PE) to obtain 1.2 g of a yellow solid with a yield of 75%.
  • EA/PE column chromatography
  • Step 2 Synthesis of tert-butyl 7-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-azaspiro[2.5]oct-6-ene-4-carboxylate
  • Step 3 Synthesis of 1-(5-fluoro-1-methyl-6-(4-azaspiro[2.5]oct-6-en-7-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indol-6-yl)-3,3-difluoro-3,6-dihydropyridine-1(2H)-carboxylate (0.20 mg, 0.42 mmol) and dichloromethane (2 ml) were added to the reaction bottle in sequence. After dissolving, hydrochloric acid/dioxane (3 ml) was added and stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed to obtain 0.20 g of a white solid crude product, which was directly carried out to the next step.
  • Step 4 Synthesis of 1-(6-(4-(((1R,2R)-2-((4-(4-(2R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-azaspiro[2.5]oct-6-en-7-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • Step 5 Synthesis of 1-(5-fluoro-6-(4-((1R,2R)-2-((4-(4-(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-azaspiro[2.5]octan-7-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • the mixture was filtered through a diatomaceous earth pad, the filter cake was rinsed with THF, the filtrate was desolventized, and column chromatography using a DCM/MeOH system was performed to obtain 0.012 g of the product with a yield of 22.0%.
  • Example 27 Synthesis of 1-(6-(3,3-difluoro-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound IV-12)
  • Step 1 Synthesis of tert-butyl 3,3-difluoro-4-(((trifluoromethyl)sulfonyloxy)-3,6-dihydropyridine-1(2H)-carboxylate
  • tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate 5 g, 21.26 mmol was dissolved in DCM (50 mL), cooled to -15 ° C, TEA (6.45 g, 63.77 mmol) was added, trifluoromethanesulfonic anhydride (9.00 g, 31.88 mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 8 h.
  • Step 2 Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,3-difluoro-3,6-dihydropyridine-1(2H)-carboxylate
  • Step 3 Synthesis of 1-(6-(3,3-difluoro-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indol-6-yl)-3,3-difluoro-3,6-dihydropyridine-1(2H)-carboxylate (0.20 mg, 0.42 mmol) and dichloromethane (2 ml) were added to the reaction bottle in sequence. After dissolving, hydrochloric acid/dioxane (3 ml) was added and stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed to obtain 0.20 g of a white solid crude product, which was directly carried out to the next step.
  • Step 4 Synthesis of 1-(6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)-3,3-difluoro-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • Step 5 Synthesis of 1-(6-(3,3-difluoro-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • Example 28 Synthesis of 1-(5-fluoro-6-(1′-((1R, 2R)-2-((4-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-[1,4′-bipiperidinyl]-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-19)
  • Step 1 Synthesis of tert-butyl 4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-[1,4′-bipiperidine]-1′-carboxylate
  • Step 2 Synthesis of 1-(6-([1,4′-bipiperidinyl]-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • Step 3 Synthesis of 1-(6-(1′-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-[1,4′-bipiperidinyl]-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • Step 4 1-(5-Fluoro-6-(1′-((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-[1,4′-bipiperidinyl]-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • Example 29 Synthesis of 1-(5-fluoro-6-((2R)-1-(((1R,2R)-2-((4-(4-(((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-20)
  • Step 1 Synthesis of tert-butyl (R)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate.
  • Step 2 Synthesis of (R)-tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate.
  • Step 3 Synthesis of (R)-1-(5-fluoro-1-methyl-6-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
  • Step 4 Synthesis of 1-(6-((R)-1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
  • Step 5 Synthesis of 1-(5-fluoro-6-((2R)-1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
  • oxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.14 g, 0.15 mmol)
  • Pd/C (0.20 g, 10%)
  • MeOH 20 mL
  • react at room temperature for 16 h under a hydrogen balloon atmosphere filter on diatomaceous earth, concentrate the filtrate and perform column chromatography (MeOH/DCM system) to obtain 0.50 g of a white solid.
  • Example 30 Synthesis of 1-(5-fluoro-6-((2S)-1-(((1R, 2R)-2-((4-(4-(((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-21)
  • Step 1 Synthesis of (S)-tert-butyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate.
  • Step 2 Synthesis of (S)-tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate.
  • Step 3 Synthesis of (S)-1-(5-fluoro-1-methyl-6-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
  • Step 4 Synthesis of 1-(6-((S)-1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
  • Step 5 Synthesis of 1-(5-fluoro-6-((2S)-1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
  • oxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.14 g, 0.15 mmol)
  • Pd/C (0.20 g, 10%)
  • MeOH 20 mL
  • react at room temperature for 16 h under a hydrogen balloon atmosphere filter on diatomaceous earth, concentrate the filtrate and perform column chromatography (MeOH/DCM system) to obtain 0.50 g of a white solid.
  • Example 31 Synthesis of 1-(5-fluoro-6-((2S,6R)-1-(((1R,2R)-2-((4-(4-(((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,6-dimethylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-22)
  • Step 1 Synthesis of (2S,6R)-1-(4-methoxybenzyl)-2,6-dimethylpiperidin-4-one.
  • Step 2 Synthesis of (2S,6R)-2,6-dimethylpiperidin-4-one.
  • Step 3 Synthesis of tert-butyl (2S,6R)-2,6-dimethyl-4-oxopiperidine-1-carboxylate.
  • di-tert-butyl dicarbonate (3.14 g, 14.40 mmol) and DIEA (3.10 g, 24.0 mmol) were added to a solution of cis-1-(4-methoxybenzyl)-2,6-dimethylpiperidin-4-one (1.54 g, 12.0 mmol) in dichloromethane (30 mL), and the mixture was stirred at room temperature for 16 h.
  • the reaction solution was concentrated and subjected to column chromatography (EA/PE) to obtain 2.0 g of a white solid.
  • Step 4 Synthesis of tert-butyl (2S,6R)-2,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate.
  • Step 5 Synthesis of tert-butyl (2S,6R)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2,6-dimethyl-3,6-dihydropyridine-1(2H)-carboxylate.
  • Step 6 Synthesis of 1-(6-((2S,6R)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
  • (2S,6R)-4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2,6-dimethyl-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.20 g, 0.42 mmol), DCM (10 mL), and dioxane hydrochloride solution (10 mL) were added to a single-mouth bottle in sequence, and the reaction was terminated at room temperature for 3 h. The reaction was concentrated to obtain 0.20 g of a yellow solid crude product.
  • Step 7 Synthesis of 1-(6-((2S,6R)-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
  • Step 8 Synthesis of 1-(5-fluoro-6-((2S,6R)-1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,6-dimethylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
  • Example 32 Synthesis of 1-(5-fluoro-6-(4-hydroxy-1-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-23)
  • Step 1 tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Step 2 tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidine-1-carboxylate
  • reaction was carried out under an oxygen ball atmosphere for 2 hours, and the reaction was completed by TLC and LC-MS.
  • the reaction solution was concentrated, water was added, and ethyl acetate was extracted.
  • the organic phase was concentrated, sand was made, and column chromatography (PE/EA/DCM/MeOH) was performed to obtain a crude product, and ethyl acetate was used to beat the product to obtain 3.6 g of an off-white solid product.
  • Step 4 1-(6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-hydroxypiperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • Step 5 1-(5-Fluoro-6-(4-hydroxy-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • Example 33 Synthesis of 1-(5-fluoro-6-(4-(4-(((1R, 2R)-2-((4-(-4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)cyclohexyl-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-24)
  • Step 1 Synthesis of 1-(5-fluoro-1-methyl-6-(1,4-dioxaspirino[4.5]dec-7-en-8-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
  • Step 2 Synthesis of 1-(5-fluoro-1-methyl-6-(1,4-dioxaspirino[4.5]dec-8-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
  • Step 3 Synthesis of 1-(5-fluoro-1-methyl-6-(4-oxocyclohexyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
  • Step 4 Synthesis of tert-butyl 4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)cyclohexyl)piperazine-1-carboxylate.
  • Step 5 Synthesis of 1-(5-fluoro-1-methyl-6-(4-(piperazin-1-yl)cyclohexyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
  • Step 6 Synthesis of 1-(6-(4-(4-(((1R,2R)-2-)(4-(-4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
  • Step 7 Synthesis of 1-(5-fluoro-6-(4-(4-((1R,2R)-2-((4-(-4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)cyclohexyl-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
  • the mixture was reacted at room temperature for 16 h under a hydrogen balloon atmosphere, filtered through a pad of diatomaceous earth, and the filtrate was concentrated and subjected to column chromatography (MeOH/DCM system) to obtain 0.02 g of a white solid.
  • Example 34 Synthesis of 1-(6-(4-(cyclopropyl(((1R,2R)-2-((4-(4-(((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)amino)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-25)
  • Step 1 Synthesis of 1-(6-(4-(cyclopropylamino)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
  • Step 2 Synthesis of 1-(6-(4-((((1R,2R)-2-((4-(4-(2R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)(cyclopropyl)amino)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
  • Step 3 1-(6-(4-(cyclopropyl(((1R,2R)-2-((4-(4-(((3R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)amino)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
  • Step 1 Synthesis of tert-butyl 6-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate.
  • Step 2 Synthesis of 1-(5-fluoro-1-methyl-6-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
  • Step 3 Synthesis of 1-(6-(6-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,6-diazaspiro[3.3]heptane-2-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
  • Step 4 Synthesis of 1-(5-fluoro-6-(6-(((1R,2R)-2-((4-(4-(((3R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,6-diazaspiro[3.3]heptane-2-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
  • Example 36 Synthesis of 1-(5-fluoro-6-(7-(((1R,2R)-2-((4-(4-(((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-27)
  • Step 1 Synthesis of tert-butyl 2-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate.

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Abstract

The present invention relates to the technical field of medicine. Provided are an estrogen receptor modulator and a use thereof, particularly a compound as represented by general formula (i) or an isomer or pharmaceutically acceptable salt thereof and a use thereof, particularly a use thereof as an estrogen receptor degrading agent, a use thereof in the preparation of a medicament for treating and/or preventing an estrogen receptor-mediated or dependent disease or condition, and a use thereof in the preparation of a medicament for treating and/or preventing a disease or condition by degrading a target protein.

Description

雌激素受体调节剂及其用途Estrogen receptor modulators and uses thereof

本发明要求享有：The present invention claims:

于2023年12月8日向中国国家知识产权局提交的，专利申请号为202311681737.X，名称为“雌激素受体调节剂及其用途”的在先申请的优先权；Priority to the prior application for patent application number 202311681737.X, entitled “Estrogen receptor modulators and uses thereof”, filed with the State Intellectual Property Office of China on December 8, 2023;

于2023年12月12日向中国国家知识产权局提交的，专利申请号为202311700571.1，名称为“雌激素受体调节剂及其用途”的在先申请的优先权；Priority to the prior application for patent application number 202311700571.1, entitled “Estrogen receptor modulators and uses thereof”, filed with the State Intellectual Property Office of China on December 12, 2023;

于2023年12月13日向中国国家知识产权局提交的，专利申请号为202311711928.6，名称为“雌激素受体调节剂及其用途”的在先申请的优先权；Priority to the prior application for patent application number 202311711928.6, entitled “Estrogen receptor modulators and uses thereof”, filed with the State Intellectual Property Office of China on December 13, 2023;

于2023年12月26日向中国国家知识产权局提交的，专利申请号为202311808960.6，名称为“雌激素受体调节剂及其用途”的在先申请的优先权；Priority to the prior application for patent application number 202311808960.6, entitled “Estrogen receptor modulators and their uses”, filed with the State Intellectual Property Office of China on December 26, 2023;

于2024年1月25日向中国国家知识产权局提交的，专利申请号为202410106933.2，名称为“雌激素受体调节剂及其用途”的在先申请的优先权；Priority to the prior application for patent application number 202410106933.2, entitled “Estrogen receptor modulators and their uses”, filed with the State Intellectual Property Office of China on January 25, 2024;

于2024年2月27日向中国国家知识产权局提交的，专利申请号为202410214069.8，名称为“雌激素受体调节剂及其用途”的在先申请的优先权；Priority to the prior application for patent application number 202410214069.8, entitled “Estrogen receptor modulators and uses thereof”, filed with the State Intellectual Property Office of China on February 27, 2024;

于2024年6月29日向中国国家知识产权局提交的，专利申请号为202410863924.8，名称为“雌激素受体调节剂及其用途”的在先申请的优先权；Priority to the prior application for patent application number 202410863924.8, entitled “Estrogen receptor modulators and uses thereof”, filed with the State Intellectual Property Office of China on June 29, 2024;

所述在先申请的全文通过引用的方式结合于本发明中。The entirety of said prior application is incorporated herein by reference.

技术领域Technical Field

本发明属于医药技术领域，涉及式(I)所示雌激素受体调节剂，其异构体或其药学上可接受的盐及其用途。The present invention belongs to the field of medical technology and relates to an estrogen receptor modulator represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof and uses thereof.

背景技术Background Art

抗雌激素(激素)疗法是治疗雌激素阳性乳腺癌的首选疗法。抗雌激素疗法主要分为三大类，包括芳香酶抑制剂(如来曲唑、阿那曲唑)；雌激素拮抗剂(如他莫昔芬、雷洛昔芬)；和选择性雌激素受体降解剂(如氟维司群)。这些类别的抗雌激素疗法通过不同的作用机制发挥作用，起到阻断雌激素，抑制肿瘤生长的作用。Anti-estrogen (hormone) therapy is the first choice for the treatment of estrogen-positive breast cancer. Anti-estrogen therapy is mainly divided into three categories, including aromatase inhibitors (such as letrozole, anastrozole); estrogen antagonists (such as tamoxifen, raloxifene); and selective estrogen receptor degraders (such as fulvestrant). These types of anti-estrogen therapy work through different mechanisms to block estrogen and inhibit tumor growth.

靶向蛋白降解嵌合体(PROTAC)是一种全新的治疗技术，通过降解靶蛋白来阻断信号通路，从而发挥治疗作用。PROTAC分子通常由三部分组成：靶蛋白结合配体、E3泛素连接酶(E3 ubiquitin ligase)配体和连接子(Linker)。PROTAC分子通过嵌合体的一端与靶蛋白紧密结合，另一端与E3泛素连接酶结合，形成靶蛋白-PROTAC-E3泛素连接酶三元复合体，通过E3泛素连接酶介导泛素化，使得靶蛋白被泛素化“标记”；随后泛素化“标记”的靶蛋白被转运至蛋白酶体，进而被蛋白酶体降解。Targeted protein degradation chimera (PROTAC) is a new therapeutic technology that blocks signaling pathways by degrading target proteins, thereby exerting a therapeutic effect. PROTAC molecules usually consist of three parts: target protein binding ligand, E3 ubiquitin ligase (E3 ubiquitin ligase) ligand and linker. PROTAC molecules tightly bind to the target protein through one end of the chimera and bind to the E3 ubiquitin ligase at the other end to form a target protein-PROTAC-E3 ubiquitin ligase ternary complex. The target protein is ubiquitinated and "tagged" through E3 ubiquitin ligase-mediated ubiquitination; the ubiquitinated "tagged" target protein is then transported to the proteasome and degraded by the proteasome.

相对于传统的小分子抑制剂，PROTAC技术具有如下优势：1.可能需要较少的给药剂量。靶蛋白降解过程类似于催化反应，PROTAC分子可以重复利用，抑制靶蛋白只需要催化量的药物。2.可以避免因抑制靶蛋白而导致靶蛋白表达量的反馈性上调。3.扩大药物靶向范围，PROTAC技术使得转录因子、调节蛋白及其他非酶类蛋白等传统小分子抑制剂无法直接作用的蛋白成为可以调控的蛋白，使靶点从“无成药性”变为“有成药性”。Compared with traditional small molecule inhibitors, PROTAC technology has the following advantages: 1. A smaller dosage may be required. The target protein degradation process is similar to a catalytic reaction. PROTAC molecules can be reused, and only a catalytic amount of drugs is needed to inhibit the target protein. 2. Feedback upregulation of target protein expression due to inhibition of the target protein can be avoided. 3. Expanding the drug targeting range, PROTAC technology makes proteins such as transcription factors, regulatory proteins and other non-enzyme proteins that traditional small molecule inhibitors cannot directly act on become regulatable proteins, turning the target from "non-drugable" to "drugable".

靶向降解雌激素受体的ER-PROTAC药物已经在临床研究中初步证明了疗效和出色的安全性，有望成为全新类型的激素疗法，是对传统疗法耐药、不耐受、疗效不佳的重要补充。ER-PROTAC drugs that target the degradation of estrogen receptors have preliminarily demonstrated efficacy and excellent safety in clinical studies and are expected to become a new type of hormone therapy, an important supplement to traditional therapies that are resistant, intolerant, and ineffective.

发明内容Summary of the invention

发明的一个目的是提供一类靶向降解雌激素受体的ER-PROTAC的化合物，其异构体或其药学上可接受的盐。One object of the invention is to provide a class of ER-PROTAC compounds, isomers thereof or pharmaceutically acceptable salts thereof that target the degradation of estrogen receptors.

本发明的技术方案如下：The technical solution of the present invention is as follows:

式(i)所示化合物、其异构体或其药学上可接受的盐：The compound represented by formula (i), its isomer or its pharmaceutically acceptable salt:

A-B-CA-B-C

(i)(i)

其中，in,

A为 A is

X选自N或CH；X is selected from N or CH;

Cy1选自(例如)、所述(例如 )、未被取代，或各自分别独立地被1-3个Ra1取代；G选自无取代或任选被一个、两个或更多个Ra1取代的下列基团：C6-10芳基或5-10元杂芳基，例如苯基、吡啶基、嘧啶基；Cy1 is selected from (For example ), Said (For example ), unsubstituted or each independently substituted by 1-3 R a1 ; G is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R a1 : C 6-10 aryl or 5-10 membered heteroaryl, such as phenyl, pyridyl, pyrimidinyl;

每个Ra1分别独立地选自氢、氘、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基；Each Ra1 is independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxyl C1-6 alkyl, C1-6 alkylamino, (C1-6 alkyl ) 2amino , C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl) 2aminocarbonyl ;

B为-L2-Cy2-L3-Cy3-L4-Cy4-L5-；A与L2相连接；C与L5相连接；B is -L2-Cy2-L3-Cy3-L4-Cy4-L5-; A is connected to L2; C is connected to L5;

L1、L2、L3、L4、L5、L6分别独立地选自键、-(CH2)n-(NH)m-、-O-，-S-，-NR2、-CR31R32-、-C(O)-、-C(O)O-、-C(O)NR4-、-NR5-C(O)-、-S(O)-、-S(O)2-、-P(O)(R6)-、C2-8烯基和C2-8炔基；L1, L2, L3, L4, L5, and L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, -S-, -NR 2 , -CR 31 R 32 -, -C(O)-, -C(O)O-, -C(O)NR 4 -, -NR 5 -C(O)-, -S(O)-, -S(O) 2 -, -P(O)(R 6 )-, C 2-8 alkenyl, and C 2-8 alkynyl;

n和m分别独立地为零至六的任意整数；例如0、1、2、3、4、5或6；n and m are independently any integer from zero to six; for example, 0, 1, 2, 3, 4, 5 or 6;

R2、R31、R32、R4和R5和R6分别独立地选自氢、氘、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基，其中所述C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷基羰基氨基、C1-6烷基磺酰氨基、C1-6烷羰氧基、C3-6环烷基、C3-6环烷基羰氧基、C2-8炔基、卤代C1-6烷基、C2-8烯基、卤代C1-6烷氧基的基团取代；R 2 , R 31 , R 32 , R 4 , R 5 and R 6 are each independently selected from hydrogen, deuterium, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, wherein the C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2aminocarbonyl are unsubstituted or optionally substituted by one or more groups independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl ) 2amino , C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonyloxy, C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonyloxy, C 2-8 alkynyl, halo-substituted C 1-6 alkyl, C 2-8 alkenyl, halo-substituted C 1-6 alkoxy;

Cy2选自3-13元环烷基、3-13元杂环基、3-13元环烯基、被1-3个Ra2取代的3-13元环烷基、被1-3个Ra2取代的3-13元杂环基、被1-3个Ra2取代的3-13元环烯基、Cy21-Cy22，所述3-13元杂环基的杂原子选自O、N或S；Cy21和Cy22相同或不同，彼此独立地选自3-13元环烷基、3-13元杂环基、3-13元环烯基；Cy2 is selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclyl, 3-13 membered cycloalkenyl, 3-13 membered cycloalkyl substituted by 1-3 R a2 , 3-13 membered heterocyclyl substituted by 1-3 R a2 , 3-13 membered cycloalkenyl substituted by 1-3 R a2 , Cy21-Cy22, wherein the heteroatom of the 3-13 membered heterocyclyl is selected from O, N or S; Cy21 and Cy22 are the same or different and are independently selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclyl, 3-13 membered cycloalkenyl;

Cy3选自3-13元环烷基、3-13元杂环基、6-13元双环稠环基或8-21元多环稠环基，所述3-13元环烷基、3-13元杂环基、6-13元双环稠环基或8-21元多环稠环基未被取代或各自分别独立地被1-5个Ra3取代，所述5-6元杂环基的杂原子为N、O、S、Si；Cy3 is selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclyl, 6-13 membered bicyclic condensed cyclic group or 8-21 membered polycyclic condensed cyclic group, wherein the 3-13 membered cycloalkyl, 3-13 membered heterocyclyl, 6-13 membered bicyclic condensed cyclic group or 8-21 membered polycyclic condensed cyclic group is unsubstituted or each independently substituted by 1-5 R a3 , and the heteroatom of the 5-6 membered heterocyclyl is N, O, S or Si;

Cy4选自3-8元环烷基、3-8元杂环基、3-8元环烯基、6-13元双环稠环环烷基、6-13元双环稠环烯基、6-13元双环稠环杂环基、被1-3个Ra4取代的3-8元环烷基、被1-3个Ra4取代的3-8元杂环基、被1-3个Ra4取代的3-8元环烯基、被1-3个Ra4取代的6-13双环稠环环烷基、被1-3个Ra4取代的6-13元双环稠环烯基、被1-3个Ra4取代的6-13元双环稠环杂环基，所述3-8元杂环基或6-13元双环稠环杂环基的杂原子选自O、N或S；Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclyl, 3-8 membered cycloalkyl substituted by 1-3 R a4 , 3-8 membered heterocyclyl substituted by 1-3 R a4 , 3-8 membered cycloalkenyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring cycloalkyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring alkenyl substituted by 1-3 R a4 , and the heteroatoms of the 3-8 membered heterocyclyl or 6-13 membered bicyclic condensed ring heterocyclyl are selected from O, N or S ;

每个Ra2、Ra3和Ra4在出现时，分别独立地选自氢、氘、卤素、羟基、巯基、硅羟基、硒羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷基-C(O)O-、C1-6烷硫基、C1-6烷硒基、羟基C1-6烷基、C1-6烷基-C(O)NH-、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、3-8元环烷基、3-8元杂环基、3-8元环烯基，其中所述C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、3-8元环烷基、3-8元杂环基、3-8元环烯基未被取代或任选被一至多个选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷基羰基氨基、C1-6烷基磺酰氨基、C1-6烷羰氧基、C3-6环烷基、C3-6环烷基羰氧基、C2-8炔基、卤代C1-6烷基、C2-8烯基、卤代C1-6烷氧基、3-8元环烷基、3-8元杂环基、3-8元环烯基的基团取代；Each of Ra2 , Ra3 and Ra4 , when present, is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, silanol, selenohydroxyl, carboxyl, amino, cyano, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 alkyl -C(O)O-, C1-6 alkylthio, C1-6 alkylseleno, hydroxyC1-6 alkyl, C1-6 alkyl-C(O)NH-, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C2-8alkenyl , C2-8alkynyl , C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl)2aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, wherein said C1-6 C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted by one or more selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonyloxy, C substituted with a C 3-6 cycloalkyl, a C 3-6 cycloalkylcarbonyloxy, a C 2-8 alkynyl, a halogenated C 1-6 alkyl, a C 2-8 alkenyl, a halogenated C 1-6 alkoxy, a 3-8 membered cycloalkyl, a 3-8 membered heterocyclyl, or a 3-8 membered cycloalkenyl;

C为 C is

X1为N或CRb1； X1 is N or CR b1 ;

X2为N或CRb2； X2 is N or CR b2 ;

X3为N或CRb3； X3 is N or CR b3 ;

X4为N或CRb4； X4 is N or CR b4 ;

X5为N或CRb5； X5 is N or CR b5 ;

Rb1、Rb2、Rb3、Rb4和Rb5分别独立地选自氢、氘、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基；R b1 , R b2 , R b3 , R b4 and R b5 are each independently selected from hydrogen, deuterium, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl;

Cy5选自6-13元双环稠环基和8-21元多环稠环基；所述6-13元双环稠环基或8-21元多环稠环基未被取代或被1-3个Ra5取代；Cy5 is selected from a 6-13 membered bicyclic fused ring group and an 8-21 membered polycyclic fused ring group; the 6-13 membered bicyclic fused ring group or the 8-21 membered polycyclic fused ring group is unsubstituted or substituted with 1-3 R a5 ;

每个Ra5分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C1-6烷基磺酰基、C1-6烷基硫基、C3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基，其中所述C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C1-6烷基磺酰基、C1-6烷基硫基、C3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷基羰基氨基、C1-6烷基磺酰氨基、C1-6烷羰氧基、C3-6环烷基、C3-6环烷基羰氧基、C2-8炔基、卤代C1-6烷基、C2-8烯基、卤代C1-6烷氧基的基团取代；Each Ra5 is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl)2amino, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, (C1-6 alkyl)2aminocarbonyl, 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl)2amino, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl)2aminocarbonyl, 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2aminocarbonyl , 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy are unsubstituted or optionally substituted by one or more independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2amino , C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonyloxy, C substituted with C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 alkyl, C 2-8 alkenyl, or halogenated C 1-6 alkoxy;

条件是当Cy3为时，不为 The condition is that when Cy3 is hour, Not for

在一个实施方式中，式(i)所示化合物、其异构体或其药学上可接受的盐：In one embodiment, the compound represented by formula (i), its isomer or a pharmaceutically acceptable salt thereof:

其中，in,

A为 A is

X选自N或CH；X is selected from N or CH;

Cy1选自和苯基，所述 和苯基未被取代，或各自分别独立地被1-3个Ra1取代；Cy1 is selected from and phenyl, the and phenyl are unsubstituted or are each independently substituted with 1-3 R a1 ;

每个Ra1分别独立地选自氢、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基；Each Ra1 is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxy C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl ) 2aminocarbonyl ;

B为-L2-Cy2-L3-Cy3-L4-Cy4-L5-；B is -L2-Cy2-L3-Cy3-L4-Cy4-L5-;

L1、L2、L3、L4、L5、L6分别独立地选自键、-(CH2)n-(NH)m-、-O-，-S-，-NR2、-CR31R32-、-C(O)-、-C(O)O-、-C(O)NR4-、-NR5-C(O)-、-CH2NR4-、-NR5-CH2-、C2-8烯基和C2-8炔基；L1, L2, L3, L4, L5, L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, -S-, -NR 2 , -CR 31 R 32 -, -C(O)-, -C(O)O-, -C(O)NR 4 -, -NR 5 -C(O)-, -CH 2 NR 4 -, -NR 5 -CH 2 -, C 2-8 alkenyl and C 2-8 alkynyl;

n和m分别独立地为零至六的任意整数；n and m are each independently any integer from zero to six;

R2、R31、R32、R4和R5分别独立地选自氢、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基，其中所述C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷基羰基氨基、C1-6烷基磺酰氨基、C1-6烷羰氧基、C3-6环烷基、C3-6环烷基羰氧基、C2-8炔基、卤代C1-6烷基、C2-8烯基、卤代C1-6烷氧基的基团取代；R 2 , R 31 , R 32 , R 4 and R 5 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, wherein the C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2aminocarbonyl are unsubstituted or optionally substituted by one or more groups independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2amino , C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonyloxy, C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 alkyl, C 2-8 alkenyl, halogenated C 1-6 alkoxy;

Cy2选自4-6元环烷基、4-6元杂环基、4-6元环烯基、被1-3个Ra2取代的4-6元环烷基、被1-3个Ra2取代的4-6元杂环基、被1-3个Ra2取代的4-6元环烯基，所述4-6元杂环基的杂原子选自O、N或S；Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl, 4-6 membered cycloalkyl substituted by 1-3 R a2 , 4-6 membered heterocyclyl substituted by 1-3 R a2 , 4-6 membered cycloalkenyl substituted by 1-3 R a2 , wherein the heteroatom of the 4-6 membered heterocyclyl is selected from O, N or S;

Cy3选自5-6元环烷基或5-6元杂环基，所述5-6元环烷基或5-6元杂环基未被取代或各自分别独立地被1-3个Ra3取代，所述5-6元杂环基的杂原子为N；Cy3 is selected from 5-6 membered cycloalkyl or 5-6 membered heterocyclyl, wherein the 5-6 membered cycloalkyl or 5-6 membered heterocyclyl is unsubstituted or each independently substituted by 1-3 R a3 , wherein the heteroatom of the 5-6 membered heterocyclyl is N;

Cy4选自3-8元环烷基、3-8元杂环基、3-8元环烯基、6-13双环稠环环烷基、6-13元双环稠环烯基、6-13元双环稠环杂环基、被1-3个Ra4取代的3-8元环烷基、被1-3个Ra4取代的3-8元杂环基、被1-3个Ra4取代的3-8元环烯基、被1-3个Ra4取代的6-13双环稠环环烷基、被1-3个Ra4取代的6-13元双环稠环烯基、被1-3个Ra4取代的6-13元双环稠环杂环基，所述3-8元杂环基或6-13元双环稠环杂环基的杂原子选自O、N或S；Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclyl, 3-8 membered cycloalkyl substituted by 1-3 R a4 , 3-8 membered heterocyclyl substituted by 1-3 R a4 , 3-8 membered cycloalkenyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring cycloalkyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring alkenyl substituted by 1-3 R a4 , and the heteroatom of the 3-8 membered heterocyclyl or 6-13 membered bicyclic condensed ring heterocyclyl is selected from O, N or S ;

每个Ra2、Ra3和Ra4在出现时，分别独立地选自氢、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、3-8元环烷基、3-8元杂环基、3-8元环烯基，其中所述C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、3-8元环烷基、3-8元杂环基、3-8元环烯基未被取代或任选被一至多个选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷基羰基氨基、C1-6烷基磺酰氨基、C1-6烷羰氧基、C3-6环烷基、C3-6环烷基羰氧基、C2-8炔基、卤代C1-6烷基、C2-8烯基、卤代C1-6烷氧基、3-8元环烷基、3-8元杂环基、3-8元环烯基的基团取代；Each of Ra2 , Ra3 and Ra4 , when present, is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halo- C1-6 alkyl, C1-6 alkoxy, halo- C1-6 alkoxy, hydroxy- C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl)2amino, C2-8alkenyl , C2-8alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl)2aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, wherein said C1-6 alkyl, halo- C1-6 alkyl, C1-6 alkoxy, halo -C1-6 alkoxy, hydroxy- C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl)2amino, C2-8alkenyl, C2-8alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl)2aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl The present invention comprises a C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, which are unsubstituted or optionally substituted by one or more selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonyloxy, C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonyloxy , C 2-8 alkynyl, halogenated C 1-6 alkyl, C 2-8 alkenyl, halogenated C 1-6 membered alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl;

C为 C is

X1为N或CRb1； X1 is N or CR b1 ;

X2为N或CRb2； X2 is N or CR b2 ;

X3为N或CRb3； X3 is N or CR b3 ;

X4为N或CRb4； X4 is N or CR b4 ;

X5为N或CRb5； X5 is N or CR b5 ;

Rb1、Rb2、Rb3、Rb4和Rb5分别独立地选自氢、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基；R b1 , R b2 , R b3 , R b4 and R b5 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl;

Cy5选自6-13元双环稠环基和8-21元多环稠环基；所述6-13元双环稠环基或8-21元多环稠环基未被取代或被1-3个Ra5取代；Cy5 is selected from a 6-13 membered bicyclic fused ring group and an 8-21 membered polycyclic fused ring group; the 6-13 membered bicyclic fused ring group or the 8-21 membered polycyclic fused ring group is unsubstituted or substituted with 1-3 R a5 ;

每个Ra5分别独立地选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C1-6烷基磺酰基、C1-6烷基硫基、C3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基，其中所述C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C1-6烷基磺酰基、C1-6烷基硫基、C3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷基羰基氨基、C1-6烷基磺酰氨基、C1-6烷羰氧基、C3-6环烷基、C3-6环烷基羰氧基、C2-8炔基、卤代C1-6烷基、C2-8烯基、卤代C1-6烷氧基的基团取代；Each Ra5 is independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl) 2aminocarbonyl , 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2aminocarbonyl , 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy are unsubstituted or optionally substituted by one or more independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2amino , C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonyloxy, C 3-6 cycloalkyl, C substituted with a C3-6 cycloalkylcarbonyloxy group, a C2-8 alkynyl group, a halogenated C1-6 alkyl group, a C2-8 alkenyl group, or a halogenated C1-6 alkoxy group;

条件是当Cy3为时，不为 The condition is that when Cy3 is hour, Not for

本发明另一个实施方案涉及式(i)所示的化合物、其异构体或其药学上可接受盐，Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof,

其中，in,

A为 A is

X选自N或CH；X is selected from N or CH;

Cy1选自和苯基，所述 和苯基未被取代，或各自分别独立地被1-3个Ra1取代；Cy1 is selected from and phenyl, the and phenyl are unsubstituted or are each independently substituted with 1-3 R a1 ;

每个Ra1分别独立地选自氢、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基；Each Ra1 is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxy C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl ) 2aminocarbonyl ;

B为-L2-Cy2-L3-Cy3-L4-Cy4-L5-；B is -L2-Cy2-L3-Cy3-L4-Cy4-L5-;

L1、L2、L3、L4、L5、L6分别独立地选自键、-(CH2)n-(NH)m-、-O-，-S-，-NR2、-CR31R32-、-C(O)-、-C(O)O-、-C(O)NR4-、-NR5-C(O)-、C2-8烯基和C2-8炔基；L1, L2, L3, L4, L5, L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, -S-, -NR 2 , -CR 31 R 32 -, -C(O)-, -C(O)O-, -C(O)NR 4 -, -NR 5 -C(O)-, C 2-8 alkenyl, and C 2-8 alkynyl;

n和m分别独立地为零至六的任意整数；n and m are each independently any integer from zero to six;

R2、R31、R32、R4和R5分别独立地选自氢、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基，其中所述C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷基羰基氨基、C1-6烷基磺酰氨基、C1-6烷羰氧基、C3-6环烷基、C3-6环烷基羰氧基、C2-8炔基、卤代C1-6烷基、C2-8烯基、卤代C1-6烷氧基的基团取代；R 2 , R 31 , R 32 , R 4 and R 5 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, wherein the C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2aminocarbonyl are unsubstituted or optionally substituted by one or more groups independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2amino , C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonyloxy, C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 alkyl, C 2-8 alkenyl, halogenated C 1-6 alkoxy;

Cy2选自4-6元环烷基、4-6元杂环基、4-6元环烯基、被1-3个Ra2取代的4-6元环烷基、被1-3个Ra2取代的4-6元杂环基、被1-3个Ra2取代的4-6元环烯基，所述4-6元杂环基的杂原子选自O、N或S；Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl, 4-6 membered cycloalkyl substituted by 1-3 R a2 , 4-6 membered heterocyclyl substituted by 1-3 R a2 , 4-6 membered cycloalkenyl substituted by 1-3 R a2 , wherein the heteroatom of the 4-6 membered heterocyclyl is selected from O, N or S;

Cy3选自5-6元环烷基或5-6元杂环基，所述5-6元环烷基或5-6元杂环基未被取代或各自分别独立地被1-3个Ra3取代，所述5-6元杂环基的杂原子为N；Cy3 is selected from 5-6 membered cycloalkyl or 5-6 membered heterocyclyl, wherein the 5-6 membered cycloalkyl or 5-6 membered heterocyclyl is unsubstituted or each independently substituted by 1-3 R a3 , wherein the heteroatom of the 5-6 membered heterocyclyl is N;

Cy4选自3-8元环烷基、3-8元杂环基、3-8元环烯基、6-13双环稠环环烷基、6-13元双环稠环烯基、6-13元双环稠环杂环基、被1-3个Ra4取代的3-8元环烷基、被1-3个Ra4取代的3-8元杂环基、被1-3个Ra4取代的3-8元环烯基、被1-3个Ra4取代的6-13双环稠环环烷基、被1-3个Ra4取代的6-13元双环稠环烯基、被1-3个Ra4取代的6-13元双环稠环杂环基，所述3-8元杂环基或6-13元双环稠环杂环基的杂原子选自O、N或S；Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclyl, 3-8 membered cycloalkyl substituted by 1-3 R a4 , 3-8 membered heterocyclyl substituted by 1-3 R a4 , 3-8 membered cycloalkenyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring cycloalkyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring alkenyl substituted by 1-3 R a4 , and the heteroatom of the 3-8 membered heterocyclyl or 6-13 membered bicyclic condensed ring heterocyclyl is selected from O, N or S ;

每个Ra2、Ra3和Ra4在出现时，分别独立地选自氢、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、3-8元环烷基、3-8元杂环基、3-8元环烯基，其中所述C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、3-8元环烷基、3-8元杂环基、3-8元环烯基未被取代或任选被一至多个选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷基羰基氨基、C1-6烷基磺酰氨基、C1-6烷羰氧基、C3-6环烷基、C3-6环烷基羰氧基、C2-8炔基、卤代C1-6烷基、C2-8烯基、卤代C1-6烷氧基、3-8元环烷基、3-8元杂环基、3-8元环烯基的基团取代；Each of Ra2 , Ra3 and Ra4 , when present, is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halo- C1-6 alkyl, C1-6 alkoxy, halo- C1-6 alkoxy, hydroxy- C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C2-8alkenyl, C2-8alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl) 2aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, wherein said C1-6 alkyl, halo-C1-6 alkyl, C1-6 alkoxy, halo- C1-6 alkoxy, hydroxy -C1-6 alkyl, C1-6 alkylamino, (C1-6 alkyl)2amino, C2-8alkenyl, C2-8alkynyl , C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl)2aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl The present invention comprises a C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, which are unsubstituted or optionally substituted by one or more selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonyloxy, C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonyloxy , C 2-8 alkynyl, halogenated C 1-6 alkyl, C 2-8 alkenyl, halogenated C 1-6 membered alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl;

C为 C is

X1为N或CRb1； X1 is N or CR b1 ;

X2为N或CRb2； X2 is N or CR b2 ;

X3为N或CRb3； X3 is N or CR b3 ;

X4为N或CRb4； X4 is N or CR b4 ;

X5为N或CRb5； X5 is N or CR b5 ;

Rb1、Rb2、Rb3、Rb4和Rb5分别独立地选自氢、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基；R b1 , R b2 , R b3 , R b4 and R b5 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl;

Cy5选自6-13元双环稠环基和8-21元多环稠环基；所述6-13元双环稠环基或8-21元多环稠环基未被取代或被1-3个Ra5取代；Cy5 is selected from a 6-13 membered bicyclic fused ring group and an 8-21 membered polycyclic fused ring group; the 6-13 membered bicyclic fused ring group or the 8-21 membered polycyclic fused ring group is unsubstituted or substituted with 1-3 R a5 ;

每个Ra5分别独立地选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C1-6烷基磺酰基、C1-6烷基硫基、C3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基，其中所述C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C1-6烷基磺酰基、C1-6烷基硫基、C3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷基羰基氨基、C1-6烷基磺酰氨基、C1-6烷羰氧基、C3-6环烷基、C3-6环烷基羰氧基、C2-8炔基、卤代C1-6烷基、C2-8烯基、卤代C1-6烷氧基的基团取代；Each Ra5 is independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl) 2aminocarbonyl , 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2aminocarbonyl , 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy are unsubstituted or optionally substituted by one or more independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2amino , C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonyloxy, C 3-6 cycloalkyl, C substituted with a C3-6 cycloalkylcarbonyloxy group, a C2-8 alkynyl group, a halogenated C1-6 alkyl group, a C2-8 alkenyl group, or a halogenated C1-6 alkoxy group;

条件是当Cy3为时，不为 The condition is that when Cy3 is hour, Not for

本发明另一个实施方案涉及式(i)所示的化合物、其异构体或其药学上可接受盐，Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof,

其中，in,

A为 A is

X选自N或CH；X is selected from N or CH;

Cy1选自和苯基，所述 和苯基未被取代，或各自分别独立地被1-3个Ra1取代；Cy1 is selected from and phenyl, the and phenyl are unsubstituted or are each independently substituted with 1-3 R a1 ;

每个Ra1分别独立地选自氢、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基；Each Ra1 is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxy C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl ) 2aminocarbonyl ;

B为-L2-Cy2-L3-Cy3-L4-Cy4-L5-；B is -L2-Cy2-L3-Cy3-L4-Cy4-L5-;

L1、L2、L3、L4、L5、L6分别独立地选自键、-(CH2)n-(NH)m-、-O-、-S-、-NR2、-CR31R32-、-C(O)-、-C(O)O-、-C(O)NR4-、-NR5-C(O)-、C2-8烯基和C2-8炔基；L1, L2, L3, L4, L5, L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, -S-, -NR 2 , -CR 31 R 32 -, -C(O)-, -C(O)O-, -C(O)NR 4 -, -NR 5 -C(O)-, C 2-8 alkenyl, and C 2-8 alkynyl;

n和m分别独立地为零至六的任意整数；n and m are each independently any integer from zero to six;

R2、R31、R32、R4和R5分别独立地选自氢、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基，其中所述C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷基羰基氨基、C1-6烷基磺酰氨基、C1-6烷羰氧基、C3-6环烷基、C3-6环烷基羰氧基、C2-8炔基、卤代C1-6烷基、C2-8烯基、卤代C1-6烷氧基的基团取代；R 2 , R 31 , R 32 , R 4 and R 5 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, wherein the C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2aminocarbonyl are unsubstituted or optionally substituted by one or more groups independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2amino , C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonyloxy, C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 alkyl, C 2-8 alkenyl, halogenated C 1-6 alkoxy;

Cy2选自4-6元环烷基、4-6元杂环基、4-6元环烯基、被1-3个Ra2取代的4-6元环烷基、被1-3个Ra2取代的4-6元杂环基、被1-3个Ra2取代的4-6元环烯基，所述4-6元杂环基的杂原子选自O、N或S；Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl, 4-6 membered cycloalkyl substituted by 1-3 R a2 , 4-6 membered heterocyclyl substituted by 1-3 R a2 , 4-6 membered cycloalkenyl substituted by 1-3 R a2 , wherein the heteroatom of the 4-6 membered heterocyclyl is selected from O, N or S;

Cy3选自所述未被取代或各自分别独立地被1-3个Ra3取代；Cy3 is selected from Said unsubstituted or each independently substituted with 1-3 Ra3 ;

Cy4选自3-8元环烷基、3-8元杂环基、3-8元环烯基、6-13双环稠环环烷基、6-13元双环稠环烯基、6-13元双环稠环杂环基、被1-3个Ra4取代的3-8元环烷基、被1-3个Ra4取代的3-8元杂环基、被1-3个Ra4取代的3-8元环烯基、被1-3个Ra4取代的6-13双环稠环环烷基、被1-3个Ra4取代的6-13元双环稠环烯基、被1-3个Ra4取代的6-13元双环稠环杂环基，所述3-8元杂环基或6-13元双环稠环杂环基的杂原子选自O、N或S；Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclyl, 3-8 membered cycloalkyl substituted by 1-3 R a4 , 3-8 membered heterocyclyl substituted by 1-3 R a4 , 3-8 membered cycloalkenyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring cycloalkyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring alkenyl substituted by 1-3 R a4 , and the heteroatom of the 3-8 membered heterocyclyl or 6-13 membered bicyclic condensed ring heterocyclyl is selected from O, N or S ;

每个Ra2、Ra3和Ra4在出现时，分别独立地选自氢、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、3-8元环烷基、3-8元杂环基、3-8元环烯基，其中所述C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、3-8元环烷基、3-8元杂环基、3-8元环烯基未被取代或任选被一至多个选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷基羰基氨基、C1-6烷基磺酰氨基、C1-6烷羰氧基、C3-6环烷基、C3-6环烷基羰氧基、C2-8炔基、卤代C1-6烷基、C2-8烯基、卤代C1-6烷氧基、3-8元环烷基、3-8元杂环基、3-8元环烯基的基团取代；Each of Ra2 , Ra3 and Ra4 , when present, is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halo- C1-6 alkyl, C1-6 alkoxy, halo- C1-6 alkoxy, hydroxy- C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl)2amino, C2-8alkenyl , C2-8alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl)2aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, wherein said C1-6 alkyl, halo- C1-6 alkyl, C1-6 alkoxy, halo -C1-6 alkoxy, hydroxy- C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl)2amino, C2-8alkenyl, C2-8alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl)2aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl The present invention comprises a C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, which are unsubstituted or optionally substituted by one or more selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonyloxy, C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonyloxy , C 2-8 alkynyl, halogenated C 1-6 alkyl, C 2-8 alkenyl, halogenated C 1-6 membered alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl;

C为 C is

X1为N或CRb1； X1 is N or CR b1 ;

X2为N或CRb2； X2 is N or CR b2 ;

X3为N或CRb3； X3 is N or CR b3 ;

X4为N或CRb4； X4 is N or CR b4 ;

X5为N或CRb5； X5 is N or CR b5 ;

Rb1、Rb2、Rb3、Rb4和Rb5分别独立地选自氢、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基；R b1 , R b2 , R b3 , R b4 and R b5 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl;

Cy5选自6-13元双环稠环基和8-21元多环稠环基；所述6-13元双环稠环基和8-21元多环稠环基未被取代或任选被1-3个Ra5取代；Cy5 is selected from 6-13 membered bicyclic condensed ring groups and 8-21 membered polycyclic condensed ring groups; the 6-13 membered bicyclic condensed ring groups and 8-21 membered polycyclic condensed ring groups are unsubstituted or optionally substituted with 1-3 R a5 ;

每个Ra5分别独立地选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C1-6烷基磺酰基、C1-6烷基硫基、C3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基，其中所述C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C1-6烷基磺酰基、C1-6烷基硫基、C3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷基羰基氨基、C1-6烷基磺酰氨基、C1-6烷羰氧基、C3-6环烷基、C3-6环烷基羰氧基、C2-8炔基、卤代C1-6烷基、C2-8烯基、卤代C1-6烷氧基的基团取代；Each Ra5 is independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl) 2aminocarbonyl , 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2aminocarbonyl , 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy are unsubstituted or optionally substituted by one or more independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2amino , C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonyloxy, C 3-6 cycloalkyl, C substituted with a C3-6 cycloalkylcarbonyloxy group, a C2-8 alkynyl group, a halogenated C1-6 alkyl group, a C2-8 alkenyl group, or a halogenated C1-6 alkoxy group;

条件是当Cy3为时，不为 The condition is that when Cy3 is hour, Not for

本发明另一个实施方案涉及式(i)所示的化合物、其异构体或其药学上可接受盐，Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof,

A为 A is

X选自N或CH；X is selected from N or CH;

Cy1选自和苯基，所述 和苯基未被取代，或各自分别独立地被1-3个Ra1取代；Cy1 is selected from and phenyl, the and phenyl are unsubstituted or are each independently substituted with 1-3 R a1 ;

每个Ra1分别独立地选自氢、卤素、羟基、氨基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基；Each R a1 is independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl;

B为-L2-Cy2-L3-Cy3-L4-Cy4-L5-；B is -L2-Cy2-L3-Cy3-L4-Cy4-L5-;

L1、L2、L3、L4、L5、L6分别独立地选自键、-(CH2)n-(NH)m-、-O-、-C(O)-；L1, L2, L3, L4, L5, and L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, and -C(O)-;

n和m分别独立地为0、1或2；n and m are independently 0, 1 or 2;

Cy2选自4-6元环烷基、4-6元杂环基、4-6元环烯基、被1-3个Ra2取代的4-6元环烷基、被1-3个Ra2取代的4-6元杂环基、被1-3个Ra2取代的4-6元环烯基，所述4-6元杂环基的杂原子选自O、N或S；Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl, 4-6 membered cycloalkyl substituted by 1-3 R a2 , 4-6 membered heterocyclyl substituted by 1-3 R a2 , 4-6 membered cycloalkenyl substituted by 1-3 R a2 , wherein the heteroatom of the 4-6 membered heterocyclyl is selected from O, N or S;

Cy3选自所述未被取代或各自分别独立地被1-3个Ra3取代；Cy3 is selected from Said unsubstituted or each independently substituted with 1-3 Ra3 ;

Cy4选自3-8元环烷基、3-8元杂环基、3-8元环烯基、6-13双环稠环环烷基、6-13元双环稠环烯基、6-13元双环稠环杂环基、被1-3个Ra4取代的3-8元环烷基、被1-3个Ra4取代的3-8元杂环基、被1-3个Ra4取代的3-8元环烯基、被1-3个Ra4取代的6-13双环稠环环烷基、被1-3个Ra4取代的6-13元双环稠环烯基、被1-3个Ra4取代的6-13元双环稠环杂环基，所述3-8元杂环基或6-13元双环稠环杂环基的杂原子选自O、N或S；Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclyl, 3-8 membered cycloalkyl substituted by 1-3 R a4 , 3-8 membered heterocyclyl substituted by 1-3 R a4 , 3-8 membered cycloalkenyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring cycloalkyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring alkenyl substituted by 1-3 R a4 , and the heteroatom of the 3-8 membered heterocyclyl or 6-13 membered bicyclic condensed ring heterocyclyl is selected from O, N or S ;

每个Ra2、Ra3和Ra4在出现时，分别独立地选自氢、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、3-8元环烷基、3-8元杂环基、3-8元环烯基，其中所述C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、3-8元环烷基、3-8元杂环基、3-8元环烯基未被取代或任选被一至多个选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、3-8元环烷基、3-8元杂环基、3-8元环烯基的基团取代；Each of Ra2 , Ra3 and Ra4 , when present, is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxyC1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2 amino, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, wherein said C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxyC1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2 amino, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl is unsubstituted or optionally substituted with one or more substituted or substituted radicals selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl)2 amino, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl substituted with C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2amino , halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl;

C为 C is

X1为N或CRb1； X1 is N or CR b1 ;

X2为N或CRb2； X2 is N or CR b2 ;

X4为N或CRb4； X4 is N or CR b4 ;

X5为N或CRb5； X5 is N or CR b5 ;

Rb1、Rb2、Rb3、Rb4和Rb5分别独立地选自氢、卤素、羟基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基；R b1 , R b2 , R b3 , R b4 and R b5 are independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino;

Cy5选自6-13元双环并环烯基、6-13元双环并杂环基、6-13元双环并杂芳基、8-21元多环并杂环基、8-21元多环并杂芳基；所述6-13元双环并环烯基、6-13元双环并杂环基、6-13元双环并杂芳基、8-21元多环并杂环基、8-21元多环并杂芳基未被取代或任选被1-3个Ra5取代；Cy5 is selected from 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heterocyclyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl, 8-21 membered polycyclic heteroaryl; the 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heterocyclyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl, 8-21 membered polycyclic heteroaryl are unsubstituted or optionally substituted with 1-3 R a5 ;

每个Ra5分别独立地选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基，其中所述C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、C3-6环烷基、C3-6环烷基羰氧基、C2-8炔基、卤代C1-6烷基、C2-8烯基、卤代C1-6烷氧基的基团取代。each Ra5 is independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, wherein said C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl is unsubstituted or optionally substituted by one or more substituted or substituted radicals independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 The group may be substituted with a C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 alkyl, C 2-8 alkenyl, or halogenated C 1-6 alkoxy group.

本发明另一个实施方案涉及式(i)所示的化合物、其异构体或其药学上可接受盐，具有式(ii)所示结构，
Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof, having a structure represented by formula (ii),

X选自N或CH；X is selected from N or CH;

环Cy1选自和苯基，所述 和苯基未被取代，或各自分别独立地被1-3个Ra1取代；Cycle Cy1 is selected from and phenyl, the and phenyl are unsubstituted or are each independently substituted with 1-3 R a1 ;

每个Ra1分别独立地选自氢、C1-6烷基、C1-6烷氧基；Each R a1 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy;

L1、L2、L3、L4、L5、L6分别独立地选自键、-(CH2)n-(NH)m-、-O-、-C(O)-；L1, L2, L3, L4, L5, and L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, and -C(O)-;

n和m分别独立地为0、1或2；n and m are independently 0, 1 or 2;

Cy2选自4-6元含氮杂环基或被1-3个Ra2取代的4-6元含氮杂环基；Cy2 is selected from a 4-6 membered nitrogen-containing heterocyclic group or a 4-6 membered nitrogen-containing heterocyclic group substituted by 1-3 R a2 ;

Cy4选自3-8元杂环基、被1-3个Ra4取代的3-8元杂环基、6-13元双环螺杂环基或被1-3个Ra4取代的6-13元双环螺杂环基，所述3-8元杂环基或6-13元双环螺杂环基的杂原子选自O、N或S；Cy4 is selected from 3-8 membered heterocyclyl, 3-8 membered heterocyclyl substituted by 1-3 R a4 , 6-13 membered bicyclic spiro heterocyclyl or 6-13 membered bicyclic spiro heterocyclyl substituted by 1-3 R a4 , wherein the heteroatom of the 3-8 membered heterocyclyl or 6-13 membered bicyclic spiro heterocyclyl is selected from O, N or S;

每个Ra2和Ra4在出现时，分别独立地选自氢、C1-6烷基、3-8元杂环基，所述C1-6烷基或3-8元杂环基未被取代或被一至多个C1-6烷基或3-8元杂环基取代；Each Ra2 and Ra4 , when present, is independently selected from hydrogen, C1-6 alkyl, 3-8 membered heterocyclyl, said C1-6 alkyl or 3-8 membered heterocyclyl being unsubstituted or substituted with one or more C1-6 alkyl or 3-8 membered heterocyclyl;

X1为N或CRb1； X1 is N or CR b1 ;

X2为N或CRb2； X2 is N or CR b2 ;

X4为N或CRb4； X4 is N or CR b4 ;

X5为N或CRb5； X5 is N or CR b5 ;

Rb1、Rb2、Rb3、Rb4和Rb5分别独立地选自氢、卤素；R b1 , R b2 , R b3 , R b4 and R b5 are independently selected from hydrogen and halogen;

Cy5选自6-13元双环并环烯基、6-13元双环并杂芳基、8-21元多环并杂环基，所述6-13元双环并环烯基、6-13元双环并杂芳基、8-21元多环并杂环基未被取代或任选被1-3个Ra5取代；Cy5 is selected from 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl, wherein the 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl is unsubstituted or optionally substituted with 1-3 R a5 ;

每个Ra5分别独立地选自氢、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、苯基，所述苯基未被取代或被一至多个卤素、卤代C1-6烷基、C1-6烷氧基取代。Each R a5 is independently selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, and phenyl, wherein the phenyl is unsubstituted or substituted with one or more halogens, halogenated C 1-6 alkyl, and C 1-6 alkoxy.

本发明另一个实施方案涉及式(ii)所示的化合物、其异构体或其药学上可接受盐，Another embodiment of the present invention relates to a compound represented by formula (ii), an isomer thereof or a pharmaceutically acceptable salt thereof,

X选自N或CH；X is selected from N or CH;

Cy1选自和苯基，所述 和苯基未被取代，或各自分别独立地被1-3个Ra1取代；Cy1 is selected from and phenyl, the and phenyl are unsubstituted or are each independently substituted with 1-3 R a1 ;

每个Ra1分别独立地选自氢、甲氧基、甲基、乙基；Each R a1 is independently selected from hydrogen, methoxy, methyl, and ethyl;

L1选自键、-NH-；L1 is selected from a bond, -NH-;

L2选自键、-NH-；L2 is selected from a bond, -NH-;

Cy2选自 Cy2 is selected from

L3选自-CH2-、-C(O)-、-NH-CH2-；L3 is selected from -CH 2 -, -C(O)-, -NH-CH 2 -;

Cy3选自 Cy3 is selected from

L4选自-CH2-、-NH-CH2-、-C(O)-；L4 is selected from -CH 2 -, -NH-CH 2 -, -C(O)-;

Cy4选自 Cy4 is selected from

L5选自键；L5 is selected from a bond;

选自 Selected from

L6选自键、-O-；L6 is selected from a bond, -O-;

Cy5选自所述 未被取代或任选被1-3个Ra5取代；Cy5 is selected from Said unsubstituted or optionally substituted with 1-3 Ra5 ;

每个Ra5分别独立地选自羟基、甲基、甲氧基、苯基、所述苯基未被取代或被一至多个氟、甲氧基、三氟甲基、取代。Each R a5 is independently selected from hydroxyl, methyl, methoxy, phenyl, The phenyl group is unsubstituted or substituted with one or more fluorine, methoxy, trifluoromethyl, replace.

在本发明另一个实施方式中，Cy1选自 *端与L1连接。In another embodiment of the present invention, Cy1 is selected from *Terminal is connected to L1.

在本发明另一个实施方式中，所述 未被取代，或各自分别独立地被1-3个Ra1取代；更优选地，所述每个Ra1各自分别独立地选自氢、卤素、羟基、羧基、氨基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基；还更优选地，所述每个Ra1各自分别独立地被1-3个卤素(如F)或C1-6烷基(如甲基)取代。In another embodiment of the present invention, is unsubstituted or is each independently substituted by 1-3 Ra1 ; more preferably, each Ra1 is each independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkoxy, hydroxy C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl ) 2amino , C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl) 2aminocarbonyl ; still more preferably, each Ra1 is each independently substituted by 1-3 halogen (such as F) or C1-6 alkyl (such as methyl).

在本发明另一个实施方式中，Cy1选自 *端与L1连接。In another embodiment of the present invention, Cy1 is selected from *Terminal is connected to L1.

在本发明另一个实施方式中，L1、L2、L3、L4、L5、L6相同或不同，彼此独立地选自键、-O-、-NH-、C1-6亚烷基、-NHC(O)-、NH(C1-6亚烷基)、-C(O)-。In another embodiment of the present invention, L1, L2, L3, L4, L5, L6 are the same or different, and are independently selected from a bond, -O-, -NH-, C 1-6 alkylene, -NHC(O)-, NH(C 1-6 alkylene), -C(O)-.

在本发明另一个实施方式中，L1选自键、-NHC(O)-；优选地，当L1为-NHC(O)-时，C(O)端与Cy1连接。In another embodiment of the present invention, L1 is selected from a bond, -NHC(O)-; preferably, when L1 is -NHC(O)-, the C(O) terminus is connected to Cy1.

在本发明另一个实施方式中，L2选自键、NH或NH(C1-3亚烷基)。In another embodiment of the present invention, L2 is selected from a bond, NH or NH(C 1-3 alkylene).

在本发明另一个实施方式中，L2选自键、-NH-或-NHCH2-；优选为键。In another embodiment of the present invention, L2 is selected from a bond, -NH- or -NHCH2- ; preferably a bond.

在本发明另一个实施方式中，L3选自C1-3亚烷基、-C(O)、-CH2NR4-、-NR5-CH2--或NHC1-3亚烷基，R4、R5彼此独立地选自C3-6环烷基。In another embodiment of the present invention, L3 is selected from C 1-3 alkylene, -C(O), -CH 2 NR 4 -, -NR 5 -CH 2 -- or NHC 1-3 alkylene, and R 4 and R 5 are independently selected from C 3-6 cycloalkyl.

在本发明另一个实施方式中，L3选自亚甲基、-C(O)-或NHCH2-；优选为亚甲基。In another embodiment of the present invention, L3 is selected from methylene, -C(O)- or NHCH 2- ; preferably methylene.

在本发明另一个实施方式中，L4选自键、C1-3亚烷基或-C(O)-。In another embodiment of the present invention, L4 is selected from a bond, C 1-3 alkylene or -C(O)-.

在本发明另一个实施方式中，L4选自键、亚甲基或-C(O)-；优选为亚甲基。In another embodiment of the present invention, L4 is selected from a bond, a methylene group or -C(O)-; preferably a methylene group.

在本发明另一个实施方式中，L5选自键或C1-3亚烷基。In another embodiment of the present invention, L5 is selected from a bond or a C 1-3 alkylene group.

在本发明另一个实施方式中，L5选自键或亚甲基；优选为键。In another embodiment of the present invention, L5 is selected from a bond or a methylene group; preferably a bond.

在本发明另一个实施方式中，L6选自键或-O-；优选为键。In another embodiment of the present invention, L6 is selected from a bond or -O-; preferably a bond.

在本发明另一个实施方式中，Cy2选自4-10元环烷基、4-10元杂环基、4-10元环烯基、被1-3个Ra2取代的4-10元环烷基、被1-3个Ra2取代的4-10元杂环基、被1-3个Ra2取代的4-10元环烯基、Cy21-Cy22，所述4-10元杂环基的杂原子选自O、N或S；Cy21和Cy22相同或不同，彼此独立地选自4-6元环烷基、4-6元杂环基、4-6元环烯基。In another embodiment of the present invention, Cy2 is selected from 4-10 membered cycloalkyl, 4-10 membered heterocyclyl, 4-10 membered cycloalkenyl, 4-10 membered cycloalkyl substituted by 1-3 Ra2, 4-10 membered heterocyclyl substituted by 1-3 Ra2, 4-10 membered cycloalkenyl substituted by 1-3 Ra2, Cy21-Cy22, the heteroatom of the 4-10 membered heterocyclyl is selected from O, N or S; Cy21 and Cy22 are the same or different and are independently selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl.

在本发明另一个实施方式中，Cy2选自4-6元环烷基、4-6元杂环基、4-6元环烯基、被1-3个Ra2取代的4-6元环烷基、被1-3个Ra2取代的4-6元杂环基、被1-3个Ra2取代的4-6元环烯基，所述4-6元杂环基的杂原子选自O、N或S。In another embodiment of the present invention, Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl, 4-6 membered cycloalkyl substituted by 1-3 Ra2 , 4-6 membered heterocyclyl substituted by 1-3 Ra2 , 4-6 membered cycloalkenyl substituted by 1-3 Ra2 , and the heteroatom of the 4-6 membered heterocyclyl is selected from O, N or S.

在本发明另一个实施方式中，Cy2选自无取代或被1-3个Ra2取代的6-9元杂环基、Cy21-Cy22；Cy21和Cy22相同或不同，彼此独立地选自环己基、哌嗪基、哌啶基。In another embodiment of the present invention, Cy2 is selected from 6-9 membered heterocyclic group which is unsubstituted or substituted with 1-3 R a2 , Cy21-Cy22; Cy21 and Cy22 are the same or different and are independently selected from cyclohexyl, piperazinyl and piperidinyl.

在本发明另一个实施方式中，Cy2选自无取代或被1-3个H或F取代的哌嗪基、哌啶基。In another embodiment of the present invention, Cy2 is selected from piperazinyl and piperidinyl which are unsubstituted or substituted with 1-3 H or F groups.

在本发明另一个实施方式中，Cy2选自无取代或被1-3个Ra2取代的哌嗪基、哌啶基、 In another embodiment of the present invention, Cy2 is selected from piperazinyl , piperidinyl,

在本发明另一个实施方式中，Cy2选自 (例如)、(例如)、(例如)、*端与Cy1连接。In another embodiment of the present invention, Cy2 is selected from (For example ), (For example ), (For example ), *The end is connected to Cy1.

在本发明另一个实施方式中，Cy3选自5-10元环烷基、5-10元杂环基、6-13元双环稠环烷基、6-13双环稠环烯基、6-13元双环稠杂环基、8-13元双环稠杂芳基、8-13元双环稠芳基、8-21元多环稠环烷基、8-21多环稠环烯基、8-21元多环稠杂环基、8-21元多环稠杂芳基、8-21元多环稠芳基。In another embodiment of the present invention, Cy3 is selected from 5-10 membered cycloalkyl, 5-10 membered heterocyclyl, 6-13 membered bicyclic condensed cycloalkyl, 6-13 membered bicyclic condensed cycloalkenyl, 6-13 membered bicyclic condensed heterocyclyl, 8-13 membered bicyclic condensed heteroaryl, 8-13 membered bicyclic condensed aryl, 8-21 membered polycyclic condensed cycloalkyl, 8-21 polycyclic condensed cycloalkenyl, 8-21 membered polycyclic condensed heterocyclyl, 8-21 membered polycyclic condensed heteroaryl, 8-21 membered polycyclic condensed aryl.

在本发明另一个实施方式中，Cy3选自5-6元环烷基或5-6元杂环基，所述5-6元环烷基或5-6元杂环基未被取代或各自分别独立地被1-3个Ra3取代，所述5-6元杂环基的杂原子为N、O、S、Si。In another embodiment of the present invention, Cy3 is selected from a 5-6 membered cycloalkyl or a 5-6 membered heterocyclyl, wherein the 5-6 membered cycloalkyl or the 5-6 membered heterocyclyl is unsubstituted or each is independently substituted with 1-3 Ra3, and the heteroatom of the 5-6 membered heterocyclyl is N, O, S, or Si.

在本发明另一个实施方式中，Cy3选自5-6元环烷基或5-6元杂环基；所述5-6元环烷基或5-6元杂环基未被取代或各自分别独立地被1-3个Ra3取代。In another embodiment of the present invention, Cy3 is selected from 5-6 membered cycloalkyl or 5-6 membered heterocyclyl; the 5-6 membered cycloalkyl or 5-6 membered heterocyclyl is unsubstituted or each is independently substituted with 1-3 Ra3 .

在本发明另一个实施方式中，Cy3选自环己基、哌啶基、四氢吡喃基、二氧六环基、四氢吡咯基；所述环己基、哌啶基、四氢吡喃基、二氧六环基、四氢吡咯基未被取代或各自分别独立地被1-3个Ra3取代；优选为环己基。In another embodiment of the present invention, Cy3 is selected from cyclohexyl, piperidinyl, tetrahydropyranyl, dioxanyl, tetrahydropyrrolyl; the cyclohexyl, piperidinyl, tetrahydropyranyl, dioxanyl, tetrahydropyrrolyl are unsubstituted or are each independently substituted with 1-3 R a3 ; preferably cyclohexyl.

在本发明另一个实施方式中，Cy3选自所述未被取代或各自分别独立地被1-3个Ra3取代。In another embodiment of the present invention, Cy3 is selected from Said are unsubstituted or are each independently substituted with 1 to 3 Ra3 .

在本发明另一个实施方式中，Cy4选自无取代或任选被一个、两个或更多个C1-6烷基或C1-6烷氧基取代的5-6元杂环基。In another embodiment of the present invention, Cy4 is selected from a 5-6 membered heterocyclic group which is unsubstituted or optionally substituted with one, two or more C 1-6 alkyl or C 1-6 alkoxy groups.

在本发明另一个实施方式中，Cy4选自哌嗪基、例如*端与L5连接。In another embodiment of the present invention, Cy4 is selected from piperazinyl, For example *End is connected to L5.

在本发明另一个实施方式中，Cy5选自未被取代或被1-3个Ra5取代的下列基团：6-13元双环并环烯基、6-13元双环并杂芳基、8-21元多环并杂环基。In another embodiment of the present invention, Cy5 is selected from the following groups which are unsubstituted or substituted with 1-3 Ra5 : 6-13 membered bicyclic cycloalkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl.

在本发明另一个实施方式中，Cy5选自未被取代或被1-3个OH或苯基取代的例如 In another embodiment of the present invention, Cy5 is selected from unsubstituted or substituted with 1-3 OH or phenyl groups. For example

在本发明另一个实施方式中，Cy5为例如 In another embodiment of the present invention, Cy5 is For example

在本发明另一个实施方式中，Ra1选自卤素、C1-6烷基、C1-6烷氧基。In another embodiment of the present invention, R a1 is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy.

在本发明另一个实施方式中，Ra1选自F、甲基、乙基、甲氧基。In another embodiment of the present invention, R a1 is selected from F, methyl, ethyl, methoxy.

在本发明另一个实施方式中，每个Ra2、Ra3和Ra4相同或不同分别独立地选自H、OH、氨基、巯基、硅羟基、硒羟基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷基-NH-、C3-6环烷基、C1-6烷基-C(O)NH-、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基。In another embodiment of the present invention, each Ra2 , Ra3 and Ra4 are the same or different and are independently selected from H, OH, amino, thiol, silanol, selenohydroxy, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl -NH-, C3-6 cycloalkyl, C1-6 alkyl-C(O)NH-, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, hydroxyl C1-6 alkyl.

在本发明另一个实施方式中，Ra2选自H、OH、氨基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷基-NH-、C3-6环烷基、C1-6烷基-C(O)NH-。In another embodiment of the present invention, Ra2 is selected from H, OH, amino, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl-NH-, C3-6 cycloalkyl, C1-6 alkyl-C(O)NH-.

在本发明另一个实施方式中，Ra2选自H、F、OH、氨基、甲氨基、乙酰胺基、甲基、甲氧基、环丙基。In another embodiment of the present invention, Ra2 is selected from H, F, OH, amino, methylamino, acetamido, methyl, methoxy, and cyclopropyl.

在本发明另一个实施方式中，Ra3和Ra4相同或不同，彼此独立地选自H、卤素。In another embodiment of the present invention, Ra3 and Ra4 are the same or different and are independently selected from H and halogen.

在本发明另一个实施方式中，Ra3和Ra4相同或不同，彼此独立地选自H、F。In another embodiment of the present invention, Ra3 and Ra4 are the same or different and are independently selected from H and F.

在本发明另一个实施方式中，Ra5选自羟基或C6-10芳基。In another embodiment of the present invention, Ra5 is selected from hydroxyl or C6-10 aryl.

在本发明另一个实施方式中，Ra5选自羟基或苯基。In another embodiment of the present invention, Ra5 is selected from hydroxyl or phenyl.

在本发明另一个实施方式中，Ra5选自羟基或C6-10芳基、卤素取代的C6-10芳基。In another embodiment of the present invention, Ra5 is selected from hydroxyl, C6-10 aryl, and halogen-substituted C6-10 aryl.

在本发明另一个实施方式中，选自无取代或任选被Rb1、Rb2、Rb3、Rb4、Rb5中的1至4个取代基所取代的下列基团：苯基、含1个或2个杂原子的的6元杂芳基，例如 In another embodiment of the present invention, Selected from the following groups which are unsubstituted or optionally substituted by 1 to 4 substituents selected from R b1 , R b2 , R b3 , R b4 , and R b5 : phenyl, 6-membered heteroaryl containing 1 or 2 heteroatoms, for example

本发明另一个实施方案涉及式(i)所示的化合物、其异构体或其药学上可接受盐，具有式(iii)所示结构：
Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof, having a structure represented by formula (iii):

X选自N或CH；X is selected from N or CH;

Ra1选自氢、C1-6烷基、C1-6烷氧基；R a1 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy;

L2、L3、L4、L5、L6分别独立地选自键、-(CH2)n-(NH)m-、-O-、-C(O)-；L2, L3, L4, L5, and L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, and -C(O)-;

n和m分别独立地为0、1或2；n and m are independently 0, 1 or 2;

Cy2选自4-6元含氮杂环基或被1-3个Ra2取代的4-6元含氮杂环基；Cy2 is selected from a 4-6 membered nitrogen-containing heterocyclic group or a 4-6 membered nitrogen-containing heterocyclic group substituted by 1-3 R a2 ;

Cy4选自3-8元杂环基、被1-3个Ra4取代的3-8元杂环基、6-13元双环螺杂环基或被1-3个Ra4取代的6-13元双环螺杂环基，所述3-8元杂环基或6-13元双环螺杂环基的杂原子选自O、N或S；Cy4 is selected from 3-8 membered heterocyclyl, 3-8 membered heterocyclyl substituted by 1-3 R a4 , 6-13 membered bicyclic spiro heterocyclyl or 6-13 membered bicyclic spiro heterocyclyl substituted by 1-3 R a4 , wherein the heteroatom of the 3-8 membered heterocyclyl or 6-13 membered bicyclic spiro heterocyclyl is selected from O, N or S;

每个Ra2和Ra4在出现时，分别独立地选自氢、C1-6烷基、3-8元杂环基，所述C1-6烷基或3-8元杂环基未被取代或被一至多个C1-6烷基或3-8元杂环基取代；Each Ra2 and Ra4 , when present, is independently selected from hydrogen, C1-6 alkyl, 3-8 membered heterocyclyl, said C1-6 alkyl or 3-8 membered heterocyclyl being unsubstituted or substituted with one or more C1-6 alkyl or 3-8 membered heterocyclyl;

X1为N或CRb1； X1 is N or CR b1 ;

X2为N或CRb2； X2 is N or CR b2 ;

X4为N或CRb4； X4 is N or CR b4 ;

X5为N或CRb5； X5 is N or CR b5 ;

Rb1、Rb2、Rb3、Rb4和Rb5分别独立地选自氢、卤素；R b1 , R b2 , R b3 , R b4 and R b5 are independently selected from hydrogen and halogen;

Cy5选自6-13元双环并环烯基、6-13元双环并杂芳基、8-21元多环并杂环基，所述6-13元双环并环烯基、6-13元双环并杂芳基、8-21元多环并杂环基未被取代或任选被1-3个Ra5取代；Cy5 is selected from 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl, wherein the 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl is unsubstituted or optionally substituted with 1-3 R a5 ;

每个Ra5分别独立地选自氢、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、苯基，所述苯基未被取代或被一至多个卤素、卤代C1-6烷基、C1-6烷氧基取代。Each R a5 is independently selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, and phenyl, wherein the phenyl is unsubstituted or substituted with one or more halogens, halogenated C 1-6 alkyl, and C 1-6 alkoxy.

本发明另一个实施方案涉及式(i)所示的化合物、其异构体或其药学上可接受盐，具有式(iv)所示结构：
Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof, having a structure represented by formula (iv):

X选自N或CH；X is selected from N or CH;

每个Ra1分别独立地选自氢、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基；Each Ra1 is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxy C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl ) 2aminocarbonyl ;

L2、L3、L4、L5、L6分别独立地选自键、-(CH2)n-(NH)m-、-O-、-C(O)-；L2, L3, L4, L5, and L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, and -C(O)-;

n和m分别独立地为0、1或2；n and m are independently 0, 1 or 2;

Cy2选自4-6元含氮杂环基或被1-3个Ra2取代的4-6元含氮杂环基；Cy2 is selected from a 4-6 membered nitrogen-containing heterocyclic group or a 4-6 membered nitrogen-containing heterocyclic group substituted by 1-3 R a2 ;

Cy4选自3-8元杂环基、被1-3个Ra4取代的3-8元杂环基、6-13元双环螺杂环基或被1-3个Ra4取代的6-13元双环螺杂环基，所述3-8元杂环基或6-13元双环螺杂环基的杂原子选自O、N或S；Cy4 is selected from 3-8 membered heterocyclyl, 3-8 membered heterocyclyl substituted by 1-3 R a4 , 6-13 membered bicyclic spiro heterocyclyl or 6-13 membered bicyclic spiro heterocyclyl substituted by 1-3 R a4 , wherein the heteroatom of the 3-8 membered heterocyclyl or 6-13 membered bicyclic spiro heterocyclyl is selected from O, N or S;

每个Ra2和Ra4在出现时，分别独立地选自氢、C1-6烷基、3-8元杂环基，所述C1-6烷基或3-8元杂环基未被取代或被一至多个C1-6烷基或3-8元杂环基取代；Each Ra2 and Ra4 , when present, is independently selected from hydrogen, C1-6 alkyl, 3-8 membered heterocyclyl, said C1-6 alkyl or 3-8 membered heterocyclyl being unsubstituted or substituted with one or more C1-6 alkyl or 3-8 membered heterocyclyl;

X1为N或CRb1； X1 is N or CR b1 ;

X2为N或CRb2； X2 is N or CR b2 ;

X4为N或CRb4； X4 is N or CR b4 ;

X5为N或CRb5； X5 is N or CR b5 ;

Rb1、Rb2、Rb3、Rb4和Rb5分别独立地选自氢、卤素；R b1 , R b2 , R b3 , R b4 and R b5 are independently selected from hydrogen and halogen;

Cy5选自6-13元双环并环烯基、6-13元双环并杂芳基、8-21元多环并杂环基，所述6-13元双环并环烯基、6-13元双环并杂芳基、8-21元多环并杂环基未被取代或任选被1-3个Ra5取代；Cy5 is selected from 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl, wherein the 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl is unsubstituted or optionally substituted with 1-3 R a5 ;

每个Ra5分别独立地选自氢、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、苯基，所述苯基未被取代或被一至多个卤素、卤代C1-6烷基、C1-6烷氧基取代。Each R a5 is independently selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, and phenyl, wherein the phenyl is unsubstituted or substituted with one or more halogens, halogenated C 1-6 alkyl, and C 1-6 alkoxy.

本发明另一个实施方案涉及式(i)所示的化合物、其异构体或其药学上可接受盐，具有式(v)所示结构：
Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof, having a structure represented by formula (v):

A为 A is

X选自N或CH；X is selected from N or CH;

Cy1选自和苯基，所述和苯基未被取代，或各自分别独立地被1-3个Ra1取代；Cy1 is selected from and phenyl, the and phenyl are unsubstituted or are each independently substituted with 1-3 R a1 ;

每个Ra1分别独立地选自氢、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基；Each Ra1 is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxy C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl ) 2aminocarbonyl ;

L1、L2、L3、L4、L5、L6分别独立地选自键、-(CH2)n-(NH)m-、-O-，-S-，-NR2、-CR31R32-、-C(O)-、-C(O)O-、-C(O)NR4-、-NR5-C(O)-、C2-8烯基和C2-8炔基；L1, L2, L3, L4, L5, L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, -S-, -NR 2 , -CR 31 R 32 -, -C(O)-, -C(O)O-, -C(O)NR 4 -, -NR 5 -C(O)-, C 2-8 alkenyl, and C 2-8 alkynyl;

n和m分别独立地为零至六的任意整数；n and m are each independently any integer from zero to six;

R2、R31、R32、R4和R5分别独立地选自氢、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基，其中所述C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷基羰基氨基、C1-6烷基磺酰氨基、C1-6烷羰氧基、C3-6环烷基、C3-6环烷基羰氧基、C2-8炔基、卤代C1-6烷基、C2-8烯基、卤代C1-6烷氧基的基团取代；R 2 , R 31 , R 32 , R 4 and R 5 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, wherein the C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2aminocarbonyl are unsubstituted or optionally substituted by one or more groups independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2amino , C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonyloxy, C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 alkyl, C 2-8 alkenyl, halogenated C 1-6 alkoxy;

Cy2选自4-6元环烷基、4-6元杂环基、4-6元环烯基、被1-3个Ra2取代的4-6元环烷基、被1-3个Ra2取代的4-6元杂环基、被1-3个Ra2取代的4-6元环烯基，所述4-6元杂环基的杂原子选自O、N或S；Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl, 4-6 membered cycloalkyl substituted by 1-3 R a2 , 4-6 membered heterocyclyl substituted by 1-3 R a2 , 4-6 membered cycloalkenyl substituted by 1-3 R a2 , wherein the heteroatom of the 4-6 membered heterocyclyl is selected from O, N or S;

Cy4选自3-8元环烷基、3-8元杂环基、3-8元环烯基、6-13双环稠环环烷基、6-13元双环稠环烯基、6-13元双环稠环杂环基、被1-3个Ra4取代的3-8元环烷基、被1-3个Ra4取代的3-8元杂环基、被1-3个Ra4取代的3-8元环烯基、被1-3个Ra4取代的6-13双环稠环环烷基、被1-3个Ra4取代的6-13元双环稠环烯基、被1-3个Ra4取代的6-13元双环稠环杂环基，所述3-8元杂环基或6-13元双环稠环杂环基的杂原子选自O、N或S；Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclyl, 3-8 membered cycloalkyl substituted by 1-3 R a4 , 3-8 membered heterocyclyl substituted by 1-3 R a4 , 3-8 membered cycloalkenyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring cycloalkyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring alkenyl substituted by 1-3 R a4 , and the heteroatom of the 3-8 membered heterocyclyl or 6-13 membered bicyclic condensed ring heterocyclyl is selected from O, N or S ;

每个Ra2和Ra4在出现时，分别独立地选自氢、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、3-8元环烷基、3-8元杂环基、3-8元环烯基，其中所述C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、3-8元环烷基、3-8元杂环基、3-8元环烯基未被取代或任选被一至多个选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷基羰基氨基、C1-6烷基磺酰氨基、C1-6烷羰氧基、C3-6环烷基、C3-6环烷基羰氧基、C2-8炔基、卤代C1-6烷基、C2-8烯基、卤代C1-6烷氧基、3-8元环烷基、3-8元杂环基、3-8元环烯基的基团取代；Each of Ra2 and Ra4 , when present, is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C1-6 alkyl, halo -C1-6 alkyl, C1-6 alkoxy, halo -C1-6 alkoxy, hydroxy- C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C2-8alkenyl , C2-8alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl)2aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, wherein said C1-6 alkyl, halo -C1-6 alkyl, C1-6 alkoxy, halo -C1-6 alkoxy, hydroxy -C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C2-8alkenyl , C2-8alkynyl, The present invention may be substituted with one or more alkyl radicals selected from the group consisting of hydroxy , amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, or a alkyl radical selected from the group consisting of hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonyloxy, C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 alkyl, C 2-8 alkenyl, halogenated C 1-6 membered alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl;

X1为N或CRb1； X1 is N or CR b1 ;

X2为N或CRb2； X2 is N or CR b2 ;

X4为N或CRb4； X4 is N or CR b4 ;

X5为N或CRb5； X5 is N or CR b5 ;

Rb1、Rb2、Rb3、Rb4和Rb5分别独立地选自氢、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C116烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基；R b1 , R b2 , R b3 , R b4 and R b5 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 116 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl;

Cy5选自6-13元双环稠环基和8-21元多环稠环基；所述6-13元双环稠环基或8-21元多环稠环基未被取代或被1-3个Ra5取代；Cy5 is selected from a 6-13 membered bicyclic fused ring group and an 8-21 membered polycyclic fused ring group; the 6-13 membered bicyclic fused ring group or the 8-21 membered polycyclic fused ring group is unsubstituted or substituted with 1-3 R a5 ;

每个Ra5分别独立地选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C1-6烷基磺酰基、C1-6烷基硫基、C3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基，其中所述C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C1-6烷基磺酰基、C1-6烷基硫基、C3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷基羰基氨基、C1-6烷基磺酰氨基、C1-6烷羰氧基、C3-6环烷基、C3-6环烷基羰氧基、C2-8炔基、卤代C1-6烷基、C2-8烯基、卤代C1-6烷氧基的基团取代。Each Ra5 is independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl) 2aminocarbonyl , 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl) 2amino , halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2aminocarbonyl , 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy are unsubstituted or optionally substituted by one or more independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2amino , C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonyloxy, C 3-6 cycloalkyl, C The group may be substituted with a C 3-6 cycloalkylcarbonyloxy group, a C 2-8 alkynyl group, a halogenated C 1-6 alkyl group, a C 2-8 alkenyl group, or a halogenated C 1-6 alkoxy group.

任一实施方式所述的化合物、其异构体或其药学上可接受盐，The compound described in any embodiment, its isomer or a pharmaceutically acceptable salt thereof,

Cy1选自和苯基，所述 和苯基未被取代，或各自分别独立地被1-3个Ra1取代。Cy1 is selected from and phenyl, the and phenyl are unsubstituted or each independently substituted with 1 to 3 Ra1 .

任一实施方式所述的化合物、其异构体或其药学上可接受盐，The compound described in any embodiment, its isomer or a pharmaceutically acceptable salt thereof,

Cy1为未被取代，或被1-3个Ra1取代的 Cy1 is unsubstituted or substituted with 1-3 R a1

任一实施方式所述的化合物、其异构体或其药学上可接受盐，The compound described in any embodiment, its isomer or a pharmaceutically acceptable salt thereof,

Cy1为未被取代，或被1-3个Ra1取代的 Cy1 is unsubstituted or substituted with 1-3 R a1

任一实施方式所述的化合物、其异构体或其药学上可接受盐，The compound described in any embodiment, its isomer or a pharmaceutically acceptable salt thereof,

Cy1为未被取代，或被1-3个Ra1取代的 Cy1 is unsubstituted or substituted with 1-3 R a1

任一实施方式所述的化合物、其异构体或其药学上可接受盐，The compound described in any embodiment, its isomer or a pharmaceutically acceptable salt thereof,

Cy1为未被取代，或被1-3个Ra1取代的 Cy1 is unsubstituted or substituted with 1-3 R a1

任一实施方式所述的化合物、其异构体或其药学上可接受盐，The compound described in any embodiment, its isomer or a pharmaceutically acceptable salt thereof,

Cy1为未被取代，或被1-3个Ra1取代的 Cy1 is unsubstituted or substituted with 1-3 R a1

在本发明另一个实施方式中，式(i)所示化合物具有如下所示的结构：
In another embodiment of the present invention, the compound represented by formula (i) has the structure shown below:

其中，Y选自N或CRa2；X、L1、Cy1、Ra2具有上文所述的定义。wherein Y is selected from N or CR a2 ; X, L 1 , Cy1 and Ra2 have the definitions given above.

在本发明另一个实施方式中，式(i-1)所示化合物具有如下所示的结构：
In another embodiment of the present invention, the compound represented by formula (i-1) has the structure shown below:

其中，Y选自N或CRa2；X、L1、Cy1、Ra2具有上文所述的定义。wherein Y is selected from N or CR a2 ; X, L 1 , Cy1 and Ra2 have the definitions given above.

在本发明另一个实施方式中，式(i)所示化合物具有如下所示的结构：
In another embodiment of the present invention, the compound represented by formula (i) has the structure shown below:

其中，Z1和Z2相同或不同，彼此独立地选自C(Ra3)(Ra3)、O、N(Ra3)、S、Si(Ra3)(Ra3)；X、G、L2、L3、L4、L5、Cy2、Cy4、Cy5、Ra1、Ra33、X1、X2、X4、X5具有上文所述的定义。wherein Z1 and Z2 are the same or different and are independently selected from C(R a3 )(R a3 ), O, N(R a3 ), S, Si(R a3 )(R a3 ); X, G, L 2 , L 3 , L 4 , L 5 , Cy2, Cy4, Cy5, R a1 , R a33 , X 1 , X 2 , X 4 , X 5 have the definitions described above.

在本发明另一个实施方式中，式(i-2)所示化合物具有如下所示的结构：
In another embodiment of the present invention, the compound represented by formula (i-2) has the structure shown below:

其中，Z3选自N、C或CRa4；表示单键或双键；G、Y、Z1、Z2、Rb1、Rb2、Rb4、Rb5、Ra1、Ra5具有上文所述的定义。Wherein, Z 3 is selected from N, C or CR a4 ; represents a single bond or a double bond; G, Y, Z 1 , Z 2 , R b1 , R b2 , R b4 , R b5 , Ra1 and Ra5 have the meanings described above.

在本发明的一些实施方式中，如前述式(i)所述化合物、其异构体或其药学上可接受的盐见下表：In some embodiments of the present invention, the compound of the aforementioned formula (i), its isomer or its pharmaceutically acceptable salt is shown in the following table:

表1








Table 1








表2


Table 2


表3

Table 3

表4


Table 4


表5

Table 5

表6




Table 6




表7
Table 7

本发明还提供一种药物组合物，所述药物组合物包含式(i)所述的化合物、其异构体或其药学上可接受的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。The present invention also provides a pharmaceutical composition, which comprises the compound of formula (i), its isomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

本发明还提供式(i)所述的化合物、其异构体或其药学上可接受的盐，或所述药物组合物在制备通过降解靶蛋白治疗和/或预防疾病或病症的药物中的用途。The present invention also provides use of the compound of formula (i), its isomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of a drug for treating and/or preventing a disease or condition by degrading a target protein.

根据本发明的实施方案，所述疾病或病症选自异常细胞增殖、肿瘤、免疫疾病、糖尿病、心血管疾病、传染性疾病和炎性疾病；优选为肿瘤和传染性疾病。According to an embodiment of the present invention, the disease or disorder is selected from abnormal cell proliferation, tumors, immune diseases, diabetes, cardiovascular diseases, infectious diseases and inflammatory diseases; preferably tumors and infectious diseases.

根据本发明的实施方案，所述的肿瘤为癌症；优选选自乳腺癌、子宫内膜癌、睾丸癌、宫颈癌、前列腺癌、卵巢癌、输卵管肿瘤、白血病、皮肤癌、鳞状细胞癌、基底细胞癌、膀胱癌、结直肠癌、食管癌、头颈癌、肾癌、肝癌、肺癌、胰腺癌、胃癌、淋巴瘤、黑色素瘤、肉瘤、外周神经上皮瘤、神经胶质瘤、星形细胞瘤、室管膜瘤、成胶质细胞瘤、成神经细胞瘤、神经节细胞瘤、成神经管细胞瘤、松果体细胞肿瘤、脑膜瘤、神经纤维瘤、神经鞘瘤、甲状腺癌、维尔姆斯瘤和畸胎癌；更优选选自乳腺癌、子宫内膜癌、睾丸癌、宫颈癌、前列腺癌、卵巢癌和输卵管肿瘤。According to an embodiment of the present invention, the tumor is cancer; preferably selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube tumors, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, colorectal cancer, esophageal cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, pancreatic cancer, gastric cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelioma, glioma, astrocytoma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, medulloblastoma, pineal cell tumor, meningioma, neurofibroma, neurilemoma, thyroid cancer, Wilms' tumor and teratoma; more preferably selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer and fallopian tube tumors.

根据本发明的实施方案，其中所述的传染性疾病选自病毒性肺炎、流感、禽流感、脑膜炎、淋病或是感染HIV、HBV、HCV、HSV、HPV、RSV、CMV、埃博拉病毒、黄病毒、痕病毒、轮状病毒、冠状病毒、EBV、耐药病毒、RNA病毒、DNA病毒、腺病毒、痘病毒、小核糖核酸病毒、披膜病毒、正粘病毒、逆转录病毒、嗜肝DNA病毒、革兰氏阴性菌、革兰氏阳性菌、非典型菌、葡萄球菌、链球菌、大肠杆菌、沙门氏菌、幽门螺旋杆菌、衣原体科、支原体科、真菌、原生动物、肠虫、蠕虫、朊病毒或寄生虫的疾病。According to an embodiment of the present invention, the infectious disease is selected from viral pneumonia, influenza, avian influenza, meningitis, gonorrhea, or infection with HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, flavivirus, rotavirus, coronavirus, EBV, drug-resistant virus, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, togavirus, orthomyxovirus, retrovirus, hepadnavirus, Gram-negative bacteria, Gram-positive bacteria, atypical bacteria, Staphylococcus, Streptococcus, Escherichia coli, Salmonella, Helicobacter pylori, Chlamydiaceae, Mycoplasmaceae, fungi, protozoa, intestinal worms, worms, prions or parasites.

本发明还提供式(i)所述的化合物、其异构体或其药学上可接受的盐，或所述药物组合物在制备用于治疗和/或预防雌激素受体介导的或依赖性的疾病或病症的药物中的用途，所述的雌激素受体介导的或依赖性的疾病或病症为肿瘤，优选为癌症，更优选选自乳腺癌、子宫内膜癌、睾丸癌、宫颈癌、前列腺癌、卵巢癌和输卵管肿瘤，最优选为乳腺癌。The present invention also provides the use of the compound of formula (i), its isomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of a drug for treating and/or preventing estrogen receptor-mediated or dependent diseases or conditions, wherein the estrogen receptor-mediated or dependent diseases or conditions are tumors, preferably cancer, more preferably selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer and fallopian tube tumors, and most preferably breast cancer.

本发明还提供一种通过降解靶蛋白治疗和/或预防疾病或病症的方法，包括给予患者治疗有效量的式(i)所述的化合物、其异构体或其药学上可接受的盐。The present invention also provides a method for treating and/or preventing a disease or condition by degrading a target protein, comprising administering to a patient a therapeutically effective amount of a compound of formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof.

本发明还提供一种治疗和/或预防雌激素受体介导的或依赖性的疾病或病症的方法，包括给予患者治疗有效量的式(i)所述的化合物、其异构体或其药学上可接受的盐。The present invention also provides a method for treating and/or preventing estrogen receptor-mediated or dependent diseases or conditions, comprising administering to a patient a therapeutically effective amount of a compound of formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof.

有益效果Beneficial Effects

本发明提供了一种式(i)所示的化合物，其异构体或其药学上可接受的盐，可作为雌激素受体降解剂，用于制备治疗和/或预防雌激素受体介导的或依赖性的疾病或病症的药物。The present invention provides a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof, which can be used as an estrogen receptor degrader for preparing a drug for treating and/or preventing estrogen receptor-mediated or dependent diseases or conditions.

附图说明BRIEF DESCRIPTION OF THE DRAWINGS

图1为化合物IV-9对MCF-7细胞的ER蛋白降解作用；Figure 1 shows the effect of compound IV-9 on ER protein degradation in MCF-7 cells;

图2为化合物VI-20对MCF-7细胞的ER蛋白降解作用；FIG2 shows the effect of compound VI-20 on ER protein degradation in MCF-7 cells;

图3为化合物VI-23对MCF-7细胞的ER蛋白降解作用；FIG3 shows the effect of compound VI-23 on ER protein degradation in MCF-7 cells;

图4为化合物VI-24对MCF-7细胞的ER蛋白降解作用；FIG4 shows the effect of compound VI-24 on ER protein degradation in MCF-7 cells;

图5为化合物VI-29对MCF-7细胞的ER蛋白降解作用；FIG5 shows the effect of compound VI-29 on ER protein degradation in MCF-7 cells;

图6为化合物VI-28对MCF-7细胞的ER蛋白降解作用。FIG6 shows the ER protein degradation effect of compound VI-28 on MCF-7 cells.

术语定义与说明Definition and explanation of terms

除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当被理解为本申请说明书和/或权利要求书记载的范围内。Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The definitions of groups and compound structures after such combinations and combinations should be understood to be within the scope of the specification and/or claims of this application.

本发明所述的“卤素”是指氟、氯、溴、碘等，优选氟，氯。The "halogen" described in the present invention refers to fluorine, chlorine, bromine, iodine, etc., preferably fluorine and chlorine.

本发明所述的“卤代”是指取代基中的任一氢原子可被一个或多个相同或不同的卤素原子取代。“卤素”如前文所定义。The term "halogenated" as used herein means that any hydrogen atom in the substituent may be replaced by one or more halogen atoms which are the same or different. "Halogen" is as defined above.

本发明所述的“C1-6烷基”指含有1-6个碳原子的烃部分去除一个氢原子衍生的直链或支链的烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3，3-二甲基丁基、2，2-二甲基丁基、1，1-二甲基丁基、1，2-二甲基丁基、1，3-二甲基丁基、2，3-二甲基丁基、2-乙基丁基和1-甲基-2-甲基丙基等。所述“C1-6烷基”优选为C1-4烷基、C1-3烷基。The "C 1-6 alkyl" of the present invention refers to a straight or branched alkyl derived from a hydrocarbon portion containing 1 to 6 carbon atoms by removing a hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl and 1-methyl-2-methylpropyl, etc. The "C 1-6 alkyl" is preferably a C 1-4 alkyl or a C 1-3 alkyl.

本发明所述的“C2-8烯基”指含有碳碳双键的2～8个碳原子的烯烃部分去除一个氢原子衍生的直链或支链或环状的烯烃基，如乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、1，3-丁二烯基、1-戊烯基、2-戊烯基、3-戊烯基、1，3-戊二烯基、1，4-戊二烯基、1-己烯基、1，4-己二烯基。The " C2-8 alkenyl" mentioned in the present invention refers to a straight chain, branched or cyclic olefin group derived from an olefin portion of 2 to 8 carbon atoms containing a carbon-carbon double bond by removing a hydrogen atom, such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, and 1,4-hexadienyl.

本发明所述的“C2-8炔基”指含有碳碳叁键的2～8个碳原子的炔烃部分去除一个氢原子衍生的直链或支链的炔烃基，如乙炔基、丙炔基、2-丁炔基、2-戊炔基、3-戊炔基、4-甲基-2-戊炔基、2-己炔基、3-己炔基等。所述“C2-8炔基”优选为C2-4炔基、C2-3炔基。The "C 2-8 alkynyl" of the present invention refers to a straight-chain or branched alkynyl derived from an alkyne moiety of 2 to 8 carbon atoms containing a carbon-carbon triple bond by removing a hydrogen atom, such as ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl, etc. The "C 2-8 alkynyl" is preferably C 2-4 alkynyl or C 2-3 alkynyl.

本发明所述的“C1-6烷氧基”是指前文所定义的“C1-6烷基”通过氧原子与母体分子连接的基团，即“C1-6烷基-O-”基团，如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、正戊氧基、新戊氧基和正己氧基等。所述“C1-6烷氧基”优选为C1-4烷氧基、C1-3烷氧基。The "C 1-6 alkoxy" of the present invention refers to a group in which the "C 1-6 alkyl" defined above is connected to the parent molecule through an oxygen atom, i.e., a "C 1-6 alkyl-O-" group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy, neopentoxy and n-hexoxy, etc. The "C 1-6 alkoxy" is preferably a C 1-4 alkoxy or a C 1-3 alkoxy.

本发明所述的“C1-6烷基氨基”、“(C1-6烷基)2氨基”、“C1-6烷基羰基氨基”、“C1-6烷基磺酰氨基”、“C1-6烷基氨基羰基”、“(C1-6烷基)2氨基-羰基”、“C1-6烷氧基-羰基”、“C1-6烷基磺酰基”、“C1-6烷基硫基”、“C1-6烷基羰基”、“氨基羰基”、“羟基C1-6烷基”分别指C1-6烷基-NH-、(C1-6烷基)(C1-6烷基)N-、C1-6烷基-C(O)-NH-、C1-6烷基-S(O)2-NH2-、C1-6烷基-NH-C(O)-、(C1-6烷基)(C1-6烷基)N-C(O)-、C1-6烷基-O-C(O)-、C1-6烷基-S(O)2-、C1-6烷基-S-、C1-6烷基-C(O)-、NH2-C(O)-、OH-C1-6烷基-；所述“C1-6烷基”如前文所定义，优选为“C1-4烷基、C1-3烷基”。The "C 1-6 alkylamino", "(C 1-6 alkyl) 2 amino", "C 1-6 alkylcarbonylamino", "C 1-6 alkylsulfonylamino", "C 1-6 alkylaminocarbonyl", "(C 1-6 alkyl) 2 amino-carbonyl", "C 1-6 alkoxy-carbonyl", "C 1-6 alkylsulfonyl", "C 1-6 alkylthio", "C 1-6 alkylcarbonyl", "aminocarbonyl" and "hydroxyC 1-6 alkyl" mentioned in the present invention refer to C 1-6 alkyl-NH-, (C 1-6 alkyl)(C 1-6 alkyl)N-, C 1-6 alkyl-C(O)-NH-, C 1-6 alkyl-S(O) 2 -NH 2 -, C 1-6 alkyl -NH-C(O)-, (C 1-6 alkyl)(C 1-6 alkyl)NC(O)-, C 1-6 alkyl-OC(O)-, C 1-6 alkyl-S(O) 2 -, C 1-6 alkyl-S-, C 1-6 alkyl-C(O)-, NH 2- C(O)-, OH-C 1-6 alkyl-; the "C 1-6 alkyl" is as defined above, preferably "C 1-4 alkyl, C 1-3 alkyl".

本发明所述的“稠环”是指由两个或两个以上环状结构以并、螺、桥的连接方式所形成的多环系结构。每个环状结构是指任意单环烷基、单杂环基、单环烯基、苯基、单杂芳基。所述的并环是指由两个或两个以上环状结构彼此公用两个相邻的环原子(即共用一个键)所形成的稠环结构。所述的桥环是指有两个或两个以上环装结构彼此共用两个非相邻的环原子所形成的稠环结构。所述的螺环是指由两个或两个以上环状结构彼此共用一个环原子所形成的稠环结构。多个环状结构任选通过并、螺和桥方式连接。The "condensed ring" described in the present invention refers to a multi-ring structure formed by two or more cyclic structures in the form of parallel, spiro, or bridge connection. Each cyclic structure refers to any monocyclic alkyl, monoheterocyclic, monocyclic alkenyl, phenyl, or monoheteroaryl. The parallel ring refers to a condensed ring structure formed by two or more cyclic structures sharing two adjacent ring atoms (i.e., sharing a bond). The bridged ring refers to a condensed ring structure formed by two or more cyclic structures sharing two non-adjacent ring atoms. The spiro ring refers to a condensed ring structure formed by two or more cyclic structures sharing one ring atom. Multiple cyclic structures are optionally connected in parallel, spiro, or bridge mode.

两个环状结构以并、螺、桥的连接方式连接的为双环稠环基，如6-13元双环稠环基。6-13元双环稠环基又包括6-13元双环稠环烷基、6-13双环稠环烯基、6-13元双环稠杂环基、8-13元双环稠杂芳基、8-13元双环稠芳基。Two ring structures connected by parallel, spiro or bridge connection are bicyclic fused ring groups, such as 6-13 membered bicyclic fused ring groups. 6-13 membered bicyclic fused ring groups include 6-13 membered bicyclic fused cycloalkyl, 6-13 membered bicyclic fused cycloalkenyl, 6-13 membered bicyclic fused heterocyclic group, 8-13 membered bicyclic fused heteroaryl, 8-13 membered bicyclic fused aryl.

两个以上环状结构以并、螺、桥的连接方式连接的为多环稠环基，如单环环状结构以并、螺、桥的方式与6-13元双环稠环基连接，如8-21元多环稠环基。8-21元多环稠环基又包括8-21元多环稠环烷基、8-21多环稠环烯基、8-21元多环稠杂环基、8-21元多环稠杂芳基、8-21元多环稠芳基。A polycyclic fused ring group is a group in which two or more cyclic structures are connected in parallel, spiro or bridge mode, such as a monocyclic ring structure connected to a 6-13-membered bicyclic fused ring group in parallel, spiro or bridge mode, such as an 8-21-membered polycyclic fused ring group. The 8-21-membered polycyclic fused ring group further includes an 8-21-membered polycyclic fused cycloalkyl, an 8-21-membered polycyclic fused cycloalkenyl, an 8-21-membered polycyclic fused heterocyclic group, an 8-21-membered polycyclic fused heteroaryl, and an 8-21-membered polycyclic fused aryl.

8-21元多环稠杂环基包括8-21元多环桥杂环基、8-21元多环并杂环基和8-21元多环螺杂环基。The 8-21-membered polycyclic fused heterocyclic group includes an 8-21-membered polycyclic bridged heterocyclic group, an 8-21-membered polycyclic fused heterocyclic group and an 8-21-membered polycyclic spiro heterocyclic group.

8-21元多环并环杂环基实例包括但不限于 Examples of 8-21 membered polycyclic heterocyclic groups include, but are not limited to

本发明所述3-8元单环基包括单环烷基、单杂环基、单环烯基、单杂芳基和苯基。The 3-8 membered monocyclic group of the present invention includes monocyclic alkyl, monoheterocyclic, monocyclic alkenyl, monoheteroaryl and phenyl.

单环烷基是含3-13个碳原子的环烃基基团，包括3-13元环烷基、3-8元环烷基、4-7元环烷基、4-6元环烷基、5-6元环烷基。3-8元环烷基，实例包括但不限于：环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基、环辛烷基等。Monocycloalkyl is a cycloalkyl group containing 3-13 carbon atoms, including 3-13-membered cycloalkyl, 3-8-membered cycloalkyl, 4-7-membered cycloalkyl, 4-6-membered cycloalkyl, 5-6-membered cycloalkyl. Examples of 3-8-membered cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

单杂环基是指至少一个环碳原子被选自O、S、N的杂原子替代的非芳香性的环状基团，优选1-3个杂原子。单杂环基可以是饱和的，也可以是部分饱和的，包括3-13元杂环基、3-8元杂环基、3-6元杂环基、4-6元杂环基、4-7元元杂环基、5-7元杂环基、5-6元杂环基、4-6元含氮杂环基、5-6元含氧杂环基、3-8元含氮杂环基、5-6元含氮杂环基、5-6元饱和杂环基等。“3-8”元饱和杂环基”，其实例包括但不限于氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、四氢呋喃基、吡咯烷基、四氢噻吩基、咪唑烷基、吡唑烷基、1，2-噁唑烷基、1，3-噁唑烷基、1，2-噻唑烷基、1，3-噻唑烷基、四氢-2H-吡喃基、四氢-2H-噻喃基、哌啶基、哌嗪基、吗啉基、1，4-二氧杂环己烷基、1，4-氧硫杂环己烷基；“3-8元部分饱和杂环基”，其实例包括但不限于4，5-二氢异噁唑基、4，5-二氢噁唑基、2，5-二氢噁唑基、2，3-二氢噁唑基、3，4-二氢-2H-吡咯基、2，3-二氢-1H-吡咯基、2，5-二氢-1H-咪唑基、4，5-二氢-1H-咪唑基、4，5-二氢-1H-吡唑基、4，5-二氢-3H-吡唑基、4，5-二氢噻唑基、2，5-二氢噻唑基、2H-吡喃基、4H-吡喃基、2H-噻喃基、4H-噻喃基、2，3，4，5-四氢吡啶基、1，2-异噁嗪基、1，4-异噁嗪基或6H-1，3-噁嗪基等。The monoheterocyclic group refers to a non-aromatic cyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, and N, preferably 1 to 3 heteroatoms. The monoheterocyclic group may be saturated or partially saturated, including 3-13 membered heterocyclic groups, 3-8 membered heterocyclic groups, 3-6 membered heterocyclic groups, 4-6 membered heterocyclic groups, 4-7 membered heterocyclic groups, 5-7 membered heterocyclic groups, 5-6 membered heterocyclic groups, 4-6 membered nitrogen-containing heterocyclic groups, 5-6 membered oxygen-containing heterocyclic groups, 3-8 membered nitrogen-containing heterocyclic groups, 5-6 membered nitrogen-containing heterocyclic groups, 5-6 membered saturated heterocyclic groups, and the like. “3-8 membered saturated heterocyclic group”, examples of which include but are not limited to aziridine, oxirane, thiirane, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2-thiazolidinyl, 1,3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanyl, 1,4-oxathiinyl; “3-8 membered partially saturated heterocyclic group”, examples of which include but are not limited to 4,5-dioxanyl, 1,4-oxathiinyl 4,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-3H-pyrazolyl, 4,5-dihydrothiazolyl, 2,5-dihydrothiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 2,3,4,5-tetrahydropyridinyl, 1,2-isoxazinyl, 1,4-isoxazinyl or 6H-1,3-oxazinyl, etc.

单环烯基是指部分饱和的碳环基团，包括3-13元环烯基、3-8元环烯基、4-7元环烯基、5-6元环烯基。The monocycloalkenyl group refers to a partially saturated carbon ring group, including 3-13 membered cycloalkenyl, 3-8 membered cycloalkenyl, 4-7 membered cycloalkenyl, and 5-6 membered cycloalkenyl.

本发明所述的杂芳基是指至少一个环碳原子被选自O、S、N的杂原子替代的芳香性的环状基团。单杂芳基可以为5-7元杂芳基、5-6元杂芳基，其实例包括但不仅限于呋喃基、咪唑基、异噁唑基、噻唑基、异噻唑基、噁二唑基、噁唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡唑基、吡咯基、四唑基、噻二唑基、噻吩基、三唑基和三嗪基。The heteroaryl group of the present invention refers to an aromatic cyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, and N. The monoheteroaryl group may be a 5-7-membered heteroaryl group or a 5-6-membered heteroaryl group, and examples thereof include but are not limited to furanyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thienyl, triazolyl, and triazinyl.

6-13双环稠环烷基包括并环烷基、桥环烷基、螺环烷基。可以是饱和的、部分饱和的或不饱和的，但不是芳香性的。并环环烷基可以为6-11元并环环烷基、7-10元并环环烷基，其的代表性例子包括但不限于双环[3.1.1]庚烷、双环[2.2.1]庚烷、双环[2.2.2]辛烷、双环[3.2.2]壬烷、双环[3.3.1]壬烷和双环[4.2.1]壬烷。所述的螺环基可以为7-12元螺环基、7-11元螺环基、10-11元螺环基，其实例包括但不限于： 所述的桥环基可以为6-11元桥环基、7-10元桥环基，其实例包括但不限于： 6-13 bicyclic condensed cycloalkyl includes cycloalkyl, bridged cycloalkyl, spirocycloalkyl. It can be saturated, partially saturated or unsaturated, but not aromatic. Cycloalkyl can be 6-11-membered cycloalkyl, 7-10-membered cycloalkyl, and its representative examples include but are not limited to bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane and bicyclo[4.2.1]nonane. The spirocyclyl can be 7-12-membered spirocyclyl, 7-11-membered spirocyclyl, 10-11-membered spirocyclyl, and its examples include but are not limited to: The bridged ring group may be a 6-11-membered bridged ring group or a 7-10-membered bridged ring group, examples of which include but are not limited to:

6-13双环稠环烯基包括并环烯基、桥环烯基、螺环烯基。6-13元双环并环烯基的代表性例子包括但不限于 The 6-13-membered bicyclic fused cycloalkenyl group includes cycloalkenyl, bridged cycloalkenyl, and spirocycloalkenyl. Representative examples of 6-13-membered bicyclic cycloalkenyl groups include, but are not limited to

6-13元双环稠杂环基包括并杂环基、螺杂环基、桥杂环基，可以是饱和的、部分饱和的或不饱和的，但不是芳香性的。稠杂环基是稠合到苯环、5-6元的单环环烷基、5-6元单环环烯基、5-6元单环杂环基或5-6元单环杂芳基的5-6元单环杂环基。所述的并杂环基可以为6-12元并环基、7-10元并环基、6-10元并环基、8-10元双环并杂环基、6-12元饱和并环基，代表性实例包括但不限于：3-氮杂双环[3.1.0]己烷基、3，6-二氮杂双环[3.2.0]庚烷基、3，8-二氮杂双环[4.2.0]辛烷基、3，7-二氮杂双环[4.2.0]辛烷基、八氢吡咯并[3，4-c]吡咯基、八氢吡咯并[3，4-b]吡咯基、八氢吡咯并[3，4-b][1，4]噁嗪基、八氢-1H-吡咯并[3，4-c]吡啶基、2，3-二氢苯并呋喃-2-基、2，3-二氢苯并呋喃-3-基、二氢吲哚-1-基、二氢吲哚-2-基、二氢吲哚3-基、2，3-二氢苯并噻吩-2基、八氢-1H-吲哚基、八氢苯并呋喃基。所述的螺杂环基可以为6-12元螺杂环基、7-11元螺杂环基、6-12元饱和螺环基、10-11元双环螺杂环基，其实例包括但不限于： 6-13 membered bicyclic fused heterocyclic groups include heterocyclic groups, spiro heterocyclic groups, and bridged heterocyclic groups, which may be saturated, partially saturated, or unsaturated, but not aromatic. The fused heterocyclic group is a 5-6 membered monocyclic heterocyclic group fused to a benzene ring, a 5-6 membered monocyclic cycloalkyl group, a 5-6 membered monocyclic cycloalkenyl group, a 5-6 membered monocyclic heterocyclic group, or a 5-6 membered monocyclic heteroaryl group. The heterocyclic group may be a 6-12 membered heterocyclic group, a 7-10 membered heterocyclic group, a 6-10 membered heterocyclic group, an 8-10 membered bicyclic heterocyclic group, or a 6-12 membered saturated heterocyclic group, representative examples of which include, but are not limited to, 3-azabicyclo[3.1.0]hexane, 3,6-diazabicyclo[3.2.0]heptane, 3,8-diazabicyclo[4.2.0]octanyl, 3,7-diazabicyclo[4.2.0]octanyl, octahydropyrrolo[ 3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,4-b][1,4]oxazinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indole-1-yl, indole-2-yl, indole-3-yl, 2,3-dihydrobenzothiophene-2-yl, octahydro-1H-indolyl, octahydrobenzofuranyl. The spiro heterocyclic group may be a 6-12-membered spiro heterocyclic group, a 7-11-membered spiro heterocyclic group, a 6-12-membered saturated spirocyclic group, or a 10-11-membered bicyclic spiro heterocyclic group, examples of which include, but are not limited to:

所述的桥杂环基可以为6-12元桥杂环基、7-11元桥杂环基、6-12元饱和桥环基，其实例包括但不限于： The bridged heterocyclic group may be a 6-12-membered bridged heterocyclic group, a 7-11-membered bridged heterocyclic group, or a 6-12-membered saturated bridged ring group, examples of which include but are not limited to:

8-13元双环稠杂芳基是指单环杂芳环稠合到苯基、单杂芳基所形成的基团，稠杂芳基可以为8-13元并杂芳基、9-10元并杂芳基、8-10元双环并杂芳基，其实例包括但不限于 8-13 membered bicyclic fused heteroaryl refers to a group formed by a monocyclic heteroaryl ring fused to a phenyl group or a monoheteroaryl group. The fused heteroaryl group may be an 8-13 membered fused heteroaryl group, a 9-10 membered fused heteroaryl group, or an 8-10 membered bicyclic fused heteroaryl group, and examples thereof include but are not limited to

8-13元双环稠芳基是指单芳环稠合到单芳基所形成的基团，包括萘、菲等。The 8-13 membered bicyclic fused aryl group refers to a group formed by condensing a single aromatic ring to a single aromatic group, including naphthalene, phenanthrene and the like.

本发明所述的“药学上可接受的盐”是指可药用的酸和碱的加成盐或其溶剂化物。这样的可药用盐包括诸如以下的酸的盐：盐酸、磷酸、氢溴酸、硫酸、亚硫酸、甲酸、甲苯磺酸、甲磺酸、硝酸、苯甲酸、柠檬酸、酒石酸、马来酸、氢碘酸、链烷酸(诸如乙酸、HOOC-(CH2)n-COOH(其中n是0～4))等。碱的盐：钠盐、钾盐、钙盐、铵盐等。本领域技术人员知晓多种无毒的可药用加成盐。The "pharmaceutically acceptable salt" of the present invention refers to a pharmaceutically acceptable acid and base addition salt or a solvate thereof. Such pharmaceutically acceptable salts include salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, alkanoic acid (such as acetic acid, HOOC-(CH 2 )n-COOH (wherein n is 0 to 4)), etc. Alkaline salts: sodium salts, potassium salts, calcium salts, ammonium salts, etc. A variety of non-toxic pharmaceutically acceptable addition salts are known to those skilled in the art.

本发明所述“异构体”是指立体异构体和互变异构体。The "isomers" mentioned in the present invention refer to stereoisomers and tautomers.

立体异构体是指当化合物存在不对称原子时，会产生对映异构体；当化合物存在双键或环状结构时，会产生顺反异构体；所有式(I)化合物的对映异构体、非对映异构体、消旋异构体、顺反异构体、几何异构体、差向异构体及其混合物，均包括在本发明范围中。Stereoisomers refer to enantiomers produced when a compound has an asymmetric atom; cis-trans isomers produced when a compound has a double bond or a ring structure; all enantiomers, diastereomers, racemates, cis-trans isomers, geometric isomers, epimers and mixtures thereof of compounds of formula (I) are included in the scope of the present invention.

“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体，互变异构体是一种特殊的官能团异构体。如含有α-H的羰基化合物的互变异构，具体如如其他质子迁移互变异构，具体如酚-酮互变异构、亚硝基-肟互变异构、亚胺-烯胺互变异构。"Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions. Tautomers are a special type of functional group isomers. For example, the tautomerism of carbonyl compounds containing α-H, specifically Such as other proton migration tautomerism, specifically phenol-keto tautomerism, nitroso-oxime tautomerism, imine-enamine tautomerism.

T、T1、T2分别独立地为任意符合化合物成键规律的基团。T, T1, and T2 are each independently any group that conforms to the bonding rules of the compound.

本发明所述Ra2和Ra4，在符合成键规律时，可任选与L2、L3、L4或L5相连。 Ra2 and Ra4 described in the present invention can be optionally connected to L2, L3, L4 or L5 when complying with the bonding rules.

具体实施方式DETAILED DESCRIPTION

下文将结合具体实施例对本公开的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本公开，而不应被解释为对本公开保护范围的限制。凡基于本公开上述内容所实现的技术均涵盖在本公开旨在保护的范围内。The technical solution of the present disclosure will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary illustrations and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included in the scope of protection intended by the present disclosure.

除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

部分试剂的缩写Abbreviations of some reagents

BnBr，溴化苄BnBr, benzyl bromide

TIPT，钛酸四异丙酯TIPT, Tetraisopropyl Titanate

STAB，三乙酰氧基硼氢化钠STAB, sodium triacetoxyborohydride

TBAF，四丁基氟化铵TBAF, Tetrabutylammonium fluoride

NMO，N-甲基氧化吗啉NMO, N-methylmorpholine oxide

TPAP，四正丙基高钌酸铵TPAP, Tetra-n-propylammonium perruthenate

Pd-PEPPSI IHept-Cl，(SP-4-1)-[1，3-双[2，6-双(1-丙基丁基)苯基]-4，5-二氯-1，3-二氢-2H-咪唑-2-基亚基]二氯(3-氯吡啶-KN)钯Pd-PEPPSI IHept-Cl, (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-KN)palladium

Xphos-Pd-G2，氯(2-二环己基膦基-2′，4′，6′-三异丙基-1，1′-联苯基)[2-(2′-氨基-1，1′-联苯)]钯(II)Xphos-Pd-G2, Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

Pd(dppf)Cl2，1，1′-二(二苯膦基)二茂铁二氯化钯(II)Pd(dppf)Cl2, 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride

Mn(TMHD)3，三(2，2，6，6-四甲基-3，5-庚烯酸)锰Mn(TMHD)3, tris(2,2,6,6-tetramethyl-3,5-heptenoate)manganese

PhSiH3，苯基硅烷PhSiH3, phenylsilane

PMBCl，甲氧基氯苄PMBCl, methoxybenzyl chloride

本发明式(i)化合物中所包含的各个独立的具体化合物结构相似，其合成方法或机理类似。为了方便本领域技术人员理解，举例来说，其一般合成方法如下：
The structures of the individual specific compounds contained in the compound of formula (i) of the present invention are similar, and their synthesis methods or mechanisms are similar. For the convenience of those skilled in the art to understand, for example, the general synthesis method is as follows:

Step1：以醛基化合物int-1、氨基化合物int-2为起始原料，经还原胺化，得到中间体int-3。Step 1: Using the aldehyde compound int-1 and the amino compound int-2 as starting materials, reductive amination is performed to obtain the intermediate int-3.

Step2：中间体int-3再经一步氢化还原得到终产物compound。Step 2: The intermediate int-3 is further hydrogenated and reduced to obtain the final product compound.

上述通式所述X选自N或CH；In the above general formula, X is selected from N or CH;

Y1、Y2和Y3选自N、NRa1、CRa1、C(Ra1)2或C(O)；Y 1 , Y 2 and Y 3 are selected from N, NR a1 , CR a1 , C(R a1 ) 2 or C(O);

M选自N或CRa2；M is selected from N or CR a2 ;

是指符合成键规律的单键或双键。 Refers to single bonds or double bonds that conform to the bonding rules.

上述通式int-1、int-2、int-3和compound可进一步被取代基取代，取代基范围同说明书所述任意实施方式。The above general formulas int-1, int-2, int-3 and compound may be further substituted by substituents, and the scope of the substituents is the same as any embodiment described in the specification.

实施例1：1-(5-氟-6-(4-((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成(化合物IV-5)
Example 1: Synthesis of 1-(5-fluoro-6-(4-((1R, 2R)-2-((4-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound IV-5)

步骤1：6-甲氧基-2-苯基-3，4-二氢萘-1(2氢)-酮的合成
Step 1: Synthesis of 6-methoxy-2-phenyl-3,4-dihydronaphthalen-1(2H)-one

室温下，依次向单口瓶中加入甲苯(750ml)，叔丁醇钾(75.60g，673.73mmol)，醋酸钯(7.8g，34.74mmol)，1，1′-联萘-2，2′-双二苯膦(25.8g，41.43mmol)，搅拌均匀。再一次加入6-甲氧基-1-奈满酮(60g，340.5mmol)，溴苯(53.4g，340.5mmol)，加热至100℃反应3h。降温至室温，用饱和氯化铵溶液(500mL)淬灭反应，甲基叔丁基醚(500mL x3)萃取。合并有机相，依次用饱和食盐水，水洗涤。无水硫酸钠干燥，浓缩，柱层析提纯(洗脱剂：乙酸乙酯/石油醚＝0～15％)，得到白色固体51g，收率59.3％。1H NMR(400MHz，DMSO-d6)δ7.92-7.85(m，1H)，7.32(t，J＝7.6Hz，2H)，7.28-7.22(m，1H)，7.21-7.15(m，2H)，6.93(d，J＝7.2Hz，2H)，3.85(s，4H)，3.11(ddd，J＝16.0，10.8，4.6Hz，1H)，2.96(dt，J＝16.8，4.4Hz，1H)，2.31(dddt，J＝35.2，17.7，9.3，4.4Hz，2H).MS(ESI)m/z：253.4[M+H]+.At room temperature, toluene (750ml), potassium tert-butoxide (75.60g, 673.73mmol), palladium acetate (7.8g, 34.74mmol), 1,1′-binaphthyl-2,2′-bisdiphenylphosphine (25.8g, 41.43mmol) were added to the single-mouth bottle in sequence and stirred evenly. 6-methoxy-1-naphthalene ketone (60g, 340.5mmol) and bromobenzene (53.4g, 340.5mmol) were added again, and the mixture was heated to 100°C for 3h. The mixture was cooled to room temperature, quenched with saturated ammonium chloride solution (500mL), and extracted with methyl tert-butyl ether (500mL x3). The organic phases were combined and washed with saturated brine and water in sequence. The mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: ethyl acetate/petroleum ether = 0-15%) to obtain 51g of a white solid with a yield of 59.3%. 1 H NMR (400MHz, DMSO-d 6 )δ7.92-7.85 (m, 1H), 7.32 (t, J=7.6Hz, 2H), 7.28-7.22 (m, 1H), 7.21-7.15 (m, 2H), 6.93 (d, J=7.2Hz, 2H), 3.85 (s, 4H), 3.11 (dd d, J=16.0, 10.8, 4.6Hz, 1H), 2.96 (dt, J=16.8, 4.4Hz, 1H), 2.31 (dddt, J=35.2, 17.7, 9.3, 4.4Hz, 2H). MS (ESI) m/z: 253.4[M+H] + .

步骤2：4-溴-7-甲氧基-3-苯基-1，2-二氢萘的合成
Step 2: Synthesis of 4-bromo-7-methoxy-3-phenyl-1,2-dihydronaphthalene

于500mL烧瓶中加入6-甲氧基-2-苯基-3，4-二氢萘-1(2氢)-酮(51g，202.2mmol)，甲苯(800mL)，搅拌至完全溶解。缓慢加入三溴化磷(108g，398.9mmol)的甲苯(400mL)溶液，加热至回流，反应24小时后，蒸去大部分甲苯。冷却后再加入1000mL二氯’甲烷，用500ml饱和亚硫酸氢钠洗涤一次，水洗一次。无水硫酸钠干燥，浓缩，柱层析提纯(洗脱剂：二氯甲烷/石油醚＝0～30％)，得到白色固体42g，收率66％。Add 6-methoxy-2-phenyl-3,4-dihydronaphthalene-1(2-hydrogen)-one (51 g, 202.2 mmol) and toluene (800 mL) into a 500 mL flask and stir until completely dissolved. Slowly add a toluene (400 mL) solution of phosphorus tribromide (108 g, 398.9 mmol), heat to reflux, react for 24 hours, and evaporate most of the toluene. After cooling, add 1000 mL of dichloromethane, wash once with 500 ml of saturated sodium bisulfite, and wash once with water. Dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (eluent: dichloromethane/petroleum ether = 0-30%) to obtain 42 g of a white solid with a yield of 66%.

步骤3：4-(6-甲氧基-2-苯基-3，4-二氢萘-1-基)苯酚的合成
Step 3: Synthesis of 4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenol

将化合物4-溴-7-甲氧基-3-苯基-1，2-二氢萘(42g，133.2mmol)，4-羟基苯硼酸(23.85g，172.9mmol)，四三苯基磷钯(5.13g，4.4mmol)和四氢呋喃(600ml)加入2L三口瓶中，加入碳酸钠(42.34g，399.4mmol)的水(200mL)溶液，搅拌，并升温回流，搅拌18h。冷却，稀盐酸调节至明显分层，分液，水层用乙酸乙酯萃取(500mL x2)，合并有机相，依次用饱和碳酸钠溶液，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析提纯(洗脱剂：二氯甲烷/石油醚＝0～30％)，得到白色固体30.4g，收率69％。1H NMR(400MHz，DMSO-d6)δ9.31(s，1H)，7.12(t，J＝7.5Hz，2H)，7.06-6.99(m，3H)，6.84(d，J＝2.6Hz，1H)，6.80-6.75(m，2H)，6.67-6.57(m，4H)，3.75(s，3H)，2.89(dd，J＝9.2，6.5Hz，2H)，2.68(dd，J＝9.2，6.4Hz，2H).Compound 4-bromo-7-methoxy-3-phenyl-1,2-dihydronaphthalene (42g, 133.2mmol), 4-hydroxyphenylboronic acid (23.85g, 172.9mmol), tetrakistriphenylphosphine palladium (5.13g, 4.4mmol) and tetrahydrofuran (600ml) were added to a 2L three-necked flask, and a solution of sodium carbonate (42.34g, 399.4mmol) in water (200mL) was added, stirred, and the temperature was raised to reflux, and stirred for 18h. Cooling, dilute hydrochloric acid was adjusted to obvious stratification, and the liquid was separated. The water layer was extracted with ethyl acetate (500mL x2), and the organic phases were combined, washed with saturated sodium carbonate solution and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: dichloromethane/petroleum ether = 0-30%) to obtain 30.4g of white solid, with a yield of 69%. 1 H NMR (400MHz, DMSO-d 6 )δ9.31 (s, 1H), 7.12 (t, J=7.5Hz, 2H), 7.06-6.99 (m, 3H), 6.84 (d, J=2.6Hz, 1H), 6.80-6.75 (m, 2H), 6.67-6.57 (m, 4H), 3.75 (s, 3H), 2.89 (dd, J=9.2, 6.5Hz, 2H), 2.68 (dd, J=9.2, 6.4Hz, 2H).

步骤4：4-(6-甲氧基-2-苯基-1，2，3，4-四氢萘-1-基)苯酚的合成
Step 4: Synthesis of 4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenol

室温下，依次向1L高压釜中加入甲醇(250ml)，四氢呋喃(250ml)，20％氢氧化钯/碳(13g)，4-(6-甲氧基-2-苯基-3，4-二氢萘-1-基)苯酚(26.94g，82.03mmol)，密闭高压釜。置换氮气一次，氢气三次，最后控制氢气下压力为3MPa，室温搅拌48h。反应液经硅藻土过滤，滤液浓缩得到灰白色固18.9g，收率100％。1H NMR(400MHz，DMSO-d6)δ9.00(s，1H)，7.19-7.11(m，3H)，6.86-6.81(m，2H)，6.81-6.75(m，2H)，6.66(dd，J＝8.5，2.6Hz，1H)，6.37(d，J＝8.1Hz，2H)，6.17(d，J＝8.3Hz，2H)，4.18(d，J＝5.0Hz，1H)，3.74(s，3H)，3.30(ddd，J＝13.1，5.2，2.1Hz，1H)，3.12-2.91(m，2H)，2.12(qd，J＝12.6，6.1Hz，1H)，1.73(dd，J＝13.0，6.1Hz，1H).At room temperature, methanol (250 ml), tetrahydrofuran (250 ml), 20% palladium hydroxide/carbon (13 g), 4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenol (26.94 g, 82.03 mmol) were added to a 1L autoclave in sequence, and the autoclave was sealed. Nitrogen was replaced once, hydrogen was replaced three times, and finally the hydrogen pressure was controlled to 3 MPa, and the mixture was stirred at room temperature for 48 h. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain 18.9 g of off-white solid, with a yield of 100%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.00(s, 1H), 7.19-7.11(m, 3H), 6.86-6.81(m, 2H), 6.81-6.75(m, 2H), 6 .66 (dd, J=8.5, 2.6Hz, 1H), 6.37 (d, J=8.1Hz, 2H), 6.17 (d, J=8.3Hz, 2H), 4 .18 (d, J=5.0Hz, 1H), 3.74 (s, 3H), 3.30 (ddd, J=13.1, 5.2, 2.1Hz, 1H), 3.1 2-2.91 (m, 2H), 2.12 (qd, J=12.6, 6.1Hz, 1H), 1.73 (dd, J=13.0, 6.1Hz, 1H).

步骤5：4-((1R，2S)-6-甲氧基-2-苯基-1，2，3，4-四氢萘基-1-基)苯酚的制备
Step 5: Preparation of 4-((1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenol

将4-(6-甲氧基-2-苯基-1，2，3，4-四氢萘-1-基)苯酚(0.14g，0.25mmol)进行手性柱拆分制备，得产物绝对构型B峰，白色固体0.05g，收率35％。4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenol (0.14 g, 0.25 mmol) was prepared by chiral column separation to obtain the product with absolute configuration B peak, 0.05 g of white solid, with a yield of 35%.

分离制备方法：Separation and preparation method:

仪器：WATERS SFC-350Instrument: WATERS SFC-350

色谱柱：CHIRALPAK IA 5cm×25cm，5umChromatographic column: CHIRALPAK IA 5cm×25cm, 5um

流动相：A为CO2，B为IPAMobile phase: A is CO2, B is IPA

波长：220nmWavelength: 220nm

流速：200ml/minFlow rate: 200ml/min

溶剂：MeOH，DCMSolvent: MeOH, DCM

梯度条件：B：50％Gradient conditions: B: 50%

循环时间：11minCycle time: 11min

柱温：35℃Column temperature: 35°C

分离检测方法：Separation detection method:

仪器：WATERS ACQUITY UPC2Instrument: WATERS ACQUITY UPC2

色谱柱：Lux 3u-Cellulose-3 4.6×50mm，3umColumn: Lux 3u-Cellulose-3 4.6×50mm, 3um

流动相：A为CO2，B为MeOH(0.1％DEA)Mobile phase: A is CO2, B is MeOH (0.1% DEA)

波长：220nmWavelength: 220nm

柱温：35℃Column temperature: 35°C

流速：4ml/minFlow rate: 4ml/min

进样量：1uLInjection volume: 1uL

进样浓度：1mg/mlInjection concentration: 1mg/ml

溶剂：MeOHSolvent: MeOH

梯度条件：B：10％to 50％in 2min，hold 1min at 50％Gradient conditions: B: 10% to 50% in 2 min, hold 1 min at 50%

运行时间：3minRun time: 3 minutes

保留时间：0.972min，1.095minRetention time: 0.972min, 1.095min

步骤6：4-((1R，2S)-6-甲氧基-2-苯基-1，2，3，4-四氢化萘-1-基)苯基1，1，2，2，3，3，4，4，4-全氟丁基-1-磺酸酯的合成
Step 6: Synthesis of 4-((1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl 1,1,2,2,3,3,4,4,4-perfluorobutyl-1-sulfonate

室温下，依次向单口瓶中加入4-((1R，2S)-6-甲氧基-2-苯基-1，2，3，4-四氢化萘-1-基)苯酚(22.00g，66.58mmol)，全氟丁基磺酰氟(26.14g，86.55mmol)，K2CO3(18.40g，133.16mmol)，CH3CN(120mL)和THF(120mL)。氮气保护，室温反应20h终止。反应液过滤，洗涤滤饼，收集母液，浓缩，柱层析纯化(EA/PE体系)得白色固体27.14g，收率67％。At room temperature, 4-((1R, 2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenol (22.00 g, 66.58 mmol), perfluorobutylsulfonyl fluoride (26.14 g, 86.55 mmol), K 2 CO 3 (18.40 g, 133.16 mmol), CH 3 CN (120 mL) and THF (120 mL) were added to a single-mouth bottle in sequence. The reaction was terminated at room temperature for 20 h under nitrogen protection. The reaction solution was filtered, the filter cake was washed, the mother liquor was collected, concentrated, and purified by column chromatography (EA/PE system) to obtain 27.14 g of a white solid with a yield of 67%.

步骤7：4-(4-((1R，2S)-6-甲氧基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-甲酸叔丁酯的合成
Step 7: Synthesis of tert-butyl 4-(4-((1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-carboxylate

室温下，将4-((1R，2S)-6-甲氧基-2-苯基-1，2，3，4-四氢萘-1-基)苯基1，1，2，2，3，3，4，4，4-九氟丁烷-1-磺酸酯(7.4g，12.1mmol)、N-Boc哌嗪(6.7g，36.2mmol)、醋酸钯(542mg，2.42mmol)、2-二环己基膦-2′，4′，6′-三异丙基联苯(1.7g，3.63mmol)和叔丁醇钠(4.6g，48.4mmol)置于甲苯(200mL)中，氮气保护95℃反应4小时，TLC检测反应结束。冷却至室温，倒入冰水中，EA萃取，有机相浓缩，制砂，柱层析PE/EA(0～8％)得棕色油状物4.7g，收率78％。At room temperature, 4-((1R, 2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (7.4 g, 12.1 mmol), N-Boc piperazine (6.7 g, 36.2 mmol), palladium acetate (542 mg, 2.42 mmol), 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (1.7 g, 3.63 mmol) and sodium tert-butoxide (4.6 g, 48.4 mmol) were placed in toluene (200 mL), and reacted at 95° C. under nitrogen protection for 4 hours. The reaction was completed by TLC detection. The mixture was cooled to room temperature, poured into ice water, extracted with EA, the organic phase was concentrated, sanded, and column chromatography with PE/EA (0-8%) was performed to obtain 4.7 g of brown oil with a yield of 78%.

步骤8：(5R，6S)-6-苯基-5-(4-(哌嗪-1-基)苯基)-5，6，7，8-四氢萘-2-醇的合成
Step 8: Synthesis of (5R,6S)-6-phenyl-5-(4-(piperazin-1-yl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol

室温下，将4-(4-((1R，2S)-6-甲氧基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-甲酸叔丁酯(3.0g，6.0mmol)置于溶于100mL二氯甲烷，-60℃滴加30mL 1.0N三溴化硼正庚烷溶液，加毕，自然回温过夜。降温滴加甲醇淬灭，浓缩，硅胶柱层析，得黄色固体1.7g，收率73％。MS(ESI)m/z：385.2[M+H]+.At room temperature, tert-butyl 4-(4-((1R, 2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-carboxylate (3.0 g, 6.0 mmol) was dissolved in 100 mL of dichloromethane, and 30 mL of 1.0 N boron tribromide n-heptane solution was added dropwise at -60 °C. After addition, the mixture was naturally warmed up overnight. The mixture was cooled and methanol was added dropwise to quench the mixture. The mixture was concentrated and chromatographed on a silica gel column to obtain 1.7 g of a yellow solid with a yield of 73%. MS (ESI) m/z: 385.2 [M+H] + .

步骤9：4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-甲酸叔丁酯的合成
Step 9: Synthesis of tert-butyl 4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-carboxylate

室温下，将(5R，6S)-6-苯基-5-(4-(哌嗪-1-基)苯基)-5，6，7，8-四氢萘-2-醇(0.38g，1.0mmol)置于甲醇(10mL)，10℃下加入Boc酸酐(0.26g，1.2mmol)。搅拌反应2小时，将反应液旋干，加入EA/NaHCO3水溶液，调pH 8，分液，有机相浓缩得到白色固体0.36g，收率75％。MS(ESI)m/z：485.2[M+H]+.At room temperature, (5R, 6S)-6-phenyl-5-(4-(piperazin-1-yl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (0.38 g, 1.0 mmol) was placed in methanol (10 mL), and Boc anhydride (0.26 g, 1.2 mmol) was added at 10°C. The reaction was stirred for 2 hours, the reaction solution was spin-dried, EA/NaHCO 3 aqueous solution was added, pH was adjusted to 8, the liquid was separated, and the organic phase was concentrated to obtain 0.36 g of white solid, with a yield of 75%. MS (ESI) m/z: 485.2 [M+H] + .

步骤10：4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-羧酸叔丁酯的合成
Step 10: Synthesis of tert-butyl 4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-羧酸叔丁酯(220.00g，0.45mol)，碳酸钾(94.11g，0.68mol)，18冠6(2.2g，1％w/w)，乙腈(2L)，滴加BnBr(89.28g，0.52mol)，60℃下，反应18h，降至室温，将反应液加入水中，析晶过滤，滤饼用甲醇打浆，过滤，得产物247.90g，收率95％。At room temperature, tert-butyl 4-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-carboxylate (220.00 g, 0.45 mol), potassium carbonate (94.11 g, 0.68 mol), 18 crown 6 (2.2 g, 1% w/w), acetonitrile (2 L) were added sequentially into the reaction bottle, and BnBr (89.28 g, 0.52 mol) was added dropwise. The mixture was reacted at 60°C for 18 h, cooled to room temperature, the reaction solution was added to water, the mixture was crystallized and filtered, the filter cake was slurried with methanol and filtered to obtain 247.90 g of the product with a yield of 95%.

步骤11：1-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪盐酸盐的合成
Step 11: Synthesis of 1-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine hydrochloride

室温下，依次向反应瓶中加入HCl乙酸乙酯溶液(1L)和4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-羧酸叔丁酯(265.00g，0.46mol)，室温反应2h。反应完成后，过滤，得到产物235.65g，收率100％。At room temperature, HCl ethyl acetate solution (1 L) and tert-butyl 4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-carboxylate (265.00 g, 0.46 mol) were added to the reaction bottle in sequence and reacted at room temperature for 2 h. After the reaction was completed, the product was filtered to obtain 235.65 g of product with a yield of 100%.

步骤12：1-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)-4-(((1R，2R)-2-(((叔丁基二苯基甲硅烷基)氧基)甲基)环己基)甲基)哌嗪的合成
Step 12: Synthesis of 1-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-4-(((1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)methyl)piperazine

室温下，依次向反应瓶中加入1-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪盐酸盐(50.00g，97.83mmol)，(1R，2R)-2-(((叔丁基二苯基甲硅烷基)氧基)甲基)环己烷-1-甲醛(48.40g，127.17mmol)和二氯甲烷(500mL)，加入TIPT(50mL)，室温搅拌16小时，再加入STAB(31.00g，146.74mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，甲醇打浆，得到产物74.00g，收率：90％。At room temperature, 1-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine hydrochloride (50.00 g, 97.83 mmol), (1R, 2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexane-1-carbaldehyde (48.40 g, 127.17 mmol) and dichloromethane (500 mL) were added to the reaction bottle in sequence, TIPT (50 mL) was added, and the mixture was stirred at room temperature for 16 hours. STAB (31.00 g, 146.74 mmol) was then added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and slurried with methanol to obtain 74.00 g of the product with a yield of 90%.

步骤13：((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲醇的合成
Step 13: Synthesis of ((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methanol

室温下，依次向反应瓶中加入1-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)-4-(((1R，2R)-2-(((叔丁基二苯基甲硅烷基)氧基)甲基)环己基)甲基)哌嗪(74.00g，88.17mmol)，TBAF(23.00g，88.17mmol)和四氢呋喃(300mL)，50℃搅拌反应4h。反应完成后，旋干，加入二氯甲烷和水分液，有机相干燥旋干，加入甲醇打浆，得到产物45.00g，收率：85％。At room temperature, 1-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-4-(((1R, 2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)methyl)piperazine (74.00 g, 88.17 mmol), TBAF (23.00 g, 88.17 mmol) and tetrahydrofuran (300 mL) were added to the reaction bottle in sequence, and the mixture was stirred at 50° C. for 4 h. After the reaction was completed, the mixture was dried by spin drying, and dichloromethane and water were added to separate the mixture. The organic phase was dried by spin drying, and methanol was added to make a pulp to obtain 45.00 g of the product with a yield of 85%.

步骤14：(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成
Step 14: Synthesis of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde

室温下，依次向反应瓶中加入((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲醇(45.00g，74.89mmol)，分子筛(45g，100％w/w)，NMO(13.16g，112.34mmol)和DCM(450mL)，再加入TPAP(2.63g，7.49mmol)室温反应12h。反应完成后，过滤，加水分液，有机相干燥旋干，柱层析(MeOH/DCM体系)，得到产物40.00g，收率：89％。At room temperature, ((1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methanol (45.00 g, 74.89 mmol) were added to the reaction bottle in sequence, Molecular sieves (45 g, 100% w/w), NMO (13.16 g, 112.34 mmol) and DCM (450 mL), then TPAP (2.63 g, 7.49 mmol) were added and reacted at room temperature for 12 h. After the reaction was completed, the mixture was filtered, separated by adding water, the organic phase was dried and spin-dried, and column chromatography (MeOH/DCM system) was performed to obtain 40.00 g of the product with a yield of 89%.

步骤15：4-(3-(2，4-二氧代四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)哌嗪-1-甲酸叔丁酯的合成
Step 15: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入1-(6-溴-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.25g，0.73mmol)，1-Boc-哌嗪(0.14g，0.73mmol)，Pd-PEPPSI IHept-Cl(0.07g，0.07mmol)，碳酸铯(0.72g，2.20mmol)，4A分子筛(0.70g)和1，4-一二氧六环(15ml)，置换氮气3-4次，升温至100℃反应15h。反应完成后，降温至室温，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物0.14g，收率44％。At room temperature, 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.25 g, 0.73 mmol), 1-Boc-piperazine (0.14 g, 0.73 mmol), Pd-PEPPSI IHept-Cl (0.07 g, 0.07 mmol), cesium carbonate (0.72 g, 2.20 mmol), 4A molecular sieve (0.70 g) and 1,4-dioxane (15 ml) were added to the reaction bottle in sequence, nitrogen was replaced 3-4 times, and the temperature was raised to 100°C for 15 hours. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, the liquids were separated, and the organic phase was dried and chromatographed using a PE/EA system column to obtain 0.14 g of the product with a yield of 44%.

步骤16：1-(5-氟-1-甲基-6-(哌嗪-1-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成
Step 16: Synthesis of 1-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

室温下，依次向反应瓶中加入4-(3-(2，4-二氧代四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)哌嗪-1-甲酸叔丁酯(0.14g，0.32mmol)和二氯甲烷(10ml)，溶清后加入盐酸/二氧六环(4ml)，室温搅拌反应3h。反应完成后，脱溶，得到粗品0.11g，直接下一步。At room temperature, tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.14 g, 0.32 mmol) and dichloromethane (10 ml) were added to the reaction bottle in sequence, and hydrochloric acid/dioxane (4 ml) was added after dissolving, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed to obtain 0.11 g of a crude product, which was directly used in the next step.

步骤17：1-(6-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成
Step 17: Synthesis of 1-(6-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

室温下，依次向反应瓶中加入1-(5-氟-1-甲基-6-(哌嗪-1-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.11g，0.34mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.19g，0.31mmol)和二氯甲烷(10ml)，再加入TIPT(0.5ml)，室温搅拌16小时，再加入STAB(0.13g，0.62mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.20g，收率：63％。At room temperature, 1-(5-fluoro-1-methyl-6-(piperazine-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.11 g, 0.34 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-yl)methyl)cyclohexane-1-carbaldehyde (0.19 g, 0.31 mmol) and dichloromethane (10 ml) were added to the reaction bottle in sequence, and TIPT (0.5 ml) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.13 g, 0.62 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.20 g of the product with a yield of 63%.

步骤18：1-(5-氟-6-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮
Step 18: 1-(5-Fluoro-6-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

室温下，依次向反应瓶中加入1-(6-(4-(((1R，2R)-2-((4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.20g，0.22mmol)，10％钯碳(0.02g)和四氢呋喃(10ml)，再加入置换氢气3-4次，室温搅拌反应24h。反应完成后，垫硅藻土过滤，滤饼使用四氢呋喃淋洗滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.07g，收率：39％。At room temperature, 1-(6-(4-(((1R, 2R)-2-((4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.20 g, 0.22 mmol), 10% palladium on carbon (0.02 g) and tetrahydrofuran (10 ml) were added to the reaction bottle in sequence, and then hydrogen was added for 3-4 times, and the reaction was stirred at room temperature for 24 hours. After the reaction was completed, diatomaceous earth was used for filtration, and the filter cake was eluted with tetrahydrofuran and the filtrate was desolvated. The product was chromatographed on a DCM/MeOH system to obtain 0.07 g of the product with a yield of 39%.

1H NMR(400MHz，DMSO-d6)δ10.55(s，1H)，9.13(s，1H)，7.36(d，J＝12.8Hz，1H)，7.19-7.04(m，4H)，6.83(d，J＝7.2Hz，2H)，6.67-6.59(m，2H)，6.54(d，J＝8.3Hz，2H)，6.48(dd，J＝8.3，2.5Hz，1H)，6.21(d，J＝8.2Hz，2H)，4.14(d，J＝4.9Hz，1H)，3.95-3.90(m，3H)，3.90-3.86(m，2H)，3.31-3.21(m，2H)，3.12-3.04(m，4H)，3.02-2.88(m，5H)，2.74(t，J＝6.7Hz，2H)，2.68-2.51(m，4H)，2.29-2.00(m，8H)，1.88-1.81(m，2H)，1.74-1.66(m，2H)，1.62-1.55(m，2H)，1.52-1.39(m，2H)，1.30-1.12(m，2H)，1.07-0.89(m，2H).MS(ESI)m/z：839.5[M+H]+. 1 H NMR (400MHz, DMSO-d 6 )δ10.55 (s, 1H), 9.13 (s, 1H), 7.36 (d, J=12.8Hz, 1H), 7.19-7.04 (m, 4H), 6.83 (d, J=7.2Hz, 2H), 6.67-6.59 (m, 2H), 6.54 (d, J=8 .3Hz, 2H), 6.48 (dd, J=8.3, 2.5Hz, 1H), 6.21 (d, J=8.2Hz, 2H), 4.14 (d, J=4.9Hz, 1H), 3.95-3.90 (m, 3H), 3.90-3.86 (m, 2H), 3.3 1-3.21(m, 2H), 3.12-3.04(m, 4H), 3.02-2.88(m, 5H), 2.74(t, J=6.7Hz, 2H), 2.68-2.51(m, 4H), 2.29-2.00(m, 8H), 1.88-1.81( m, 2H), 1.74-1.66 (m, 2H), 1.62-1.55 (m, 2H), 1.52-1.39 (m, 2H), 1.30-1.12 (m, 2H), 1.07-0.89 (m, 2H). MS (ESI) m/z: 839.5 [M+H] + .

实施例2：3-(4-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-3-甲基-2-氧代-2，3-二氢-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮的合成(化合物VII-1)
Example 2: Synthesis of 3-(4-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound VII-1)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：1-(4-甲氧基苄基)-2，6-二氧代哌啶-3-基三氟甲磺酸酯的合成
Step 1: Synthesis of 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate

室温下，依次向反应瓶中加入3-羟基-1-(4-甲氧基苄基)哌啶-2，6-二酮(4.00g，16.05mmol)和二氯甲烷(50ml)，溶清后降温至-10℃，控温缓慢加入三氟甲磺酸酐(6.80g，24.07mmol)，加完后控温0℃反应2小时。反应完成后，直接脱溶，使用PE/EA体系柱层析，得到产物4.41g，收率：72％。At room temperature, 3-hydroxy-1-(4-methoxybenzyl)piperidine-2,6-dione (4.00 g, 16.05 mmol) and dichloromethane (50 ml) were added to the reaction bottle in sequence, and the temperature was lowered to -10°C after the solution was dissolved, and trifluoromethanesulfonic anhydride (6.80 g, 24.07 mmol) was slowly added under temperature control, and the temperature was controlled at 0°C for 2 hours after the addition. After the reaction was completed, the solvent was directly removed, and PE/EA system column chromatography was used to obtain 4.41 g of the product, with a yield of 72%.

步骤2：3-(4-溴-3-甲基-2-氧代-2，3-二氢-1H-苯并咪唑-1-基)-1-(4-甲氧基苄基)哌啶-2，6-二酮的合成
Step 2: Synthesis of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

室温下，依次向反应瓶中加入7-溴-1-甲基-1，3-二氢-2H-苯并咪唑-2-酮(1.00g，3.61mmol)，叔丁醇钾(0.49g，4.33mmol)和四氢呋喃(20ml)，降温至0℃搅拌30分钟，再加入1-(4-甲氧基苄基)-2，6-二氧代哌啶-3-基三氟甲磺酸酯(1.38g，3.61mmol)，加完后恢复室温反应3h。反应完成后，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物1.48g，收率90％。At room temperature, 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (1.00 g, 3.61 mmol), potassium tert-butoxide (0.49 g, 4.33 mmol) and tetrahydrofuran (20 ml) were added to the reaction bottle in sequence, the temperature was lowered to 0°C and stirred for 30 minutes, and then 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (1.38 g, 3.61 mmol) was added, and the reaction was restored to room temperature for 3 hours after the addition. After the reaction was completed, ethyl acetate and water were added, the liquids were separated, and the organic phase was dried and chromatographed using a PE/EA system column to obtain 1.48 g of the product with a yield of 90%.

步骤3：4-(1-(1-(4-甲氧基苄基)-2，6-二氧代哌啶-3-基)-3-甲基-2-氧代-2，3-二氢-1H-苯并[d]咪唑-4-基)哌嗪-1-甲酸叔丁酯的合成
Step 3: Synthesis of tert-butyl 4-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入3-(4-溴-3-甲基-2-氧代-2，3-二氢-1H-苯并咪唑-1-基)-1-(4-甲氧基苄基)哌啶-2，6-一二酮(0.74g，1.62mmol)，1-Boc-哌嗪(0.30g，1.62mmol)，Pd-PEPPSI IHept-Cl(0.16g，0.16mmol)，碳酸铯(1.58g，4.85mmol)，4A分子筛(0.16g)和1，4-二氧六环(9ml)，置换氮气3-4次，升温至100℃反应15h。反应完成后，降温至室温，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物0.41g，收率45％。At room temperature, 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-(4-methoxybenzyl)piperidin-2,6-one (0.74 g, 1.62 mmol), 1-Boc-piperazine (0.30 g, 1.62 mmol), Pd-PEPPSI IHept-Cl (0.16 g, 0.16 mmol), cesium carbonate (1.58 g, 4.85 mmol), 4A molecular sieve (0.16 g) and 1,4-dioxane (9 ml) were added to the reaction bottle in sequence, nitrogen was replaced 3-4 times, and the temperature was raised to 100°C for reaction for 15 hours. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, the liquids were separated, and the organic phase was dried and chromatographed using a PE/EA system column to obtain 0.41 g of the product with a yield of 45%.

步骤4：3-(3-甲基-2-氧代-4-(哌嗪-1-基)-2，3-二氢-1H-苯并咪唑-1-基)哌啶-2，6-二酮的合成
Step 4: Synthesis of 3-(3-methyl-2-oxo-4-(piperazin-1-yl)-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入4-(1-(1-(4-甲氧基苄基)-2，6-二氧代哌啶-3-基)-3-甲基-2-氧代-2，3-二氢-1H-苯并[d]咪唑-4-基)哌嗪-1-甲酸叔丁酯(0.41g，0.73mmol)，三氟乙酸(3ml)和TfOH(0.5ml)，升温65℃搅拌反应2h。反应完成后，脱溶，使用反向柱层析(乙腈/水)体系柱层析，得到粗品0.10g，直接下一步。At room temperature, tert-butyl 4-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperazine-1-carboxylate (0.41 g, 0.73 mmol), trifluoroacetic acid (3 ml) and TfOH (0.5 ml) were added to the reaction bottle in sequence, and the temperature was raised to 65°C and stirred for 2 hours. After the reaction was completed, the solvent was removed and the column chromatography was performed using a reverse column chromatography (acetonitrile/water) system to obtain 0.10 g of a crude product, which was directly used in the next step.

步骤5：3-(4-(4-(((1R，2R)-2-((4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-3-甲基-2-氧代-2，3-二氢-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮的合成
Step 5: Synthesis of 3-(4-(4-(((1R,2R)-2-((4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(3-甲基-2-氧代-4-(哌嗪-1-基)-2，3-二氢-1H-苯并咪唑-1-基)哌啶-2，6-二酮(0.10g，0.21mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.13g，0.21mmol)和二氯甲烷(10ml)，再加入TIPT(0.5ml)，室温搅拌16小时，再加入STAB(0.09g，0.42mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.11g，收率58％。At room temperature, 3-(3-methyl-2-oxo-4-(piperazine-1-yl)-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (0.10 g, 0.21 mmol), (1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-yl)methyl)cyclohexane-1-carbaldehyde (0.13 g, 0.21 mmol) and dichloromethane (10 ml) were added to the reaction bottle in sequence, and TIPT (0.5 ml) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.09 g, 0.42 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.11 g of the product with a yield of 58%.

步骤6：3-(4-(4-(((1R，2R)-2-((4-(4-(1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-3-甲基-2-氧代-2，3-二氢-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮的合成
Step 6: Synthesis of 3-(4-(4-(((1R,2R)-2-((4-(4-(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(4-(4-(((1R，2R)-2-((4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-3-甲基-2-氧代-2，3-二氢-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮(0.11g，0.12mmol)，10％钯碳(0.01g)和四氢呋喃(10ml)，再加入置换氢气3-4次，30℃搅拌反应16h。反应完成后，垫硅藻土过滤，滤饼使用四氢呋喃淋洗滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.030g(入库0.026g)，收率：29％。At room temperature, 3-(4-(4-(((1R, 2R)-2-((4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.11 g, 0.12 mmol), 10% palladium on carbon (0.01 g) and tetrahydrofuran (10 ml) were added into the reaction bottle in sequence, and hydrogen was added for replacement 3-4 times. The reaction was stirred at 30°C for 16 h. After the reaction was completed, the mixture was filtered through a pad of diatomaceous earth, the filter cake was eluted with tetrahydrofuran, and the filtrate was desolvated. The product was purified by column chromatography using a DCM/MeOH system to obtain 0.030 g (0.026 g in storage), with a yield of 29%.

1H NMR(400MHz，DMSO-d6)δ11.10(s，1H)，9.12(s，1H)，7.12(d，J＝8.9Hz，3H)，7.05-6.87(m，3H)，6.83(d，J＝7.1Hz，2H)，6.69-6.54(m，3H)，6.48(d，J＝8.3Hz，1H)，6.24(s，2H)，5.60-4.99(m，1H)，4.15(d，J＝4.7Hz，1H)，3.61(s，3H)，3.43-3.20(m，10H)，3.12-2.82(m，10H)，2.81-2.54(m，4H)，2.20-1.98(m，4H)，1.83-1.59(m，5H)，1.49-1.39(m，2H)，1.29-1.17(m，3H)，1.07-0.92(m，2H).MS(ESI)m/z：836.5[M+H]+. 1 H NMR (400MHz, DMSO-d 6 )δ11.10 (s, 1H), 9.12 (s, 1H), 7.12 (d, J = 8.9Hz, 3H), 7.05-6.87 (m, 3H), 6.83 (d, J = 7.1Hz, 2H), 6 .69-6.54 (m, 3H), 6.48 (d, J = 8.3Hz, 1H), 6.24 (s, 2H), 5.60-4.99 (m, 1H), 4.15 (d, J = 4.7Hz, 1H), 3 .61(s, 3H), 3.43-3.20(m, 10H), 3.12-2.82(m, 10H), 2.81-2.54(m, 4H), 2.20-1.98(m, 4H), 1.83 -1.59(m, 5H), 1.49-1.39(m, 2H), 1.29-1.17(m, 3H), 1.07-0.92(m, 2H).MS(ESI)m/z: 836.5[M+H] + .

实施例3：1-(5-氟-6-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成(化合物IV-9)
Example 3: Synthesis of 1-(5-fluoro-6-(1-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound IV-9)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：4-(3-(2，4-二氧代四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-3，6-二氢吡啶-1(2H)-甲酸叔丁酯的合成
Step 1: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate

室温下，依次向反应瓶中加入1-(6-溴-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.25g，0.73mmol)，4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸叔丁酯(0.34g，1.10mmol)，Xphos-Pd-G2(0.06g，0.07mmol)，磷酸钾(0.31g，1.47mmol)，水(3ml)和1，4-二氧六环(10ml)，置换氮气3-4次，升温至80℃反应4h。反应完成后，降温至室温，脱溶，加入乙酸乙酯稀释，垫硅藻土过滤，滤液干燥后，脱溶，使用PE/EA体系柱层析，得到产物0.25g，收率78％。At room temperature, 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.25 g, 0.73 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.34 g, 1.10 mmol), Xphos-Pd-G2 (0.06 g, 0.07 mmol), potassium phosphate (0.31 g, 1.47 mmol), water (3 ml) and 1,4-dioxane (10 ml) were added to the reaction bottle in sequence, nitrogen was replaced 3-4 times, and the temperature was raised to 80°C for 4 h. After the reaction was completed, the temperature was lowered to room temperature, the solvent was removed, ethyl acetate was added to dilute, and diatomaceous earth was used for filtration. After the filtrate was dried, the solvent was removed, and PE/EA system column chromatography was used to obtain 0.25 g of the product with a yield of 78%.

步骤2：4-(3-(2，4-二氧代四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)哌啶-1-甲酸叔丁酯的合成
Step 2: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate

室温下，依次向反应瓶中加入4-(3-(2，4-二氧代四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-3，6-二氢吡啶-1(2H)-甲酸叔丁酯(0.25g，0.57mmol)和四氢呋喃(15ml)，加入10％钯碳(0.03g)，置换氢气3-4次，室温搅拌反应16h。反应完成后，垫硅藻土过滤，脱溶，得到产物0.25g，直接下一步。At room temperature, 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.25 g, 0.57 mmol) and tetrahydrofuran (15 ml) were added to the reaction bottle in sequence, and 10% palladium carbon (0.03 g) was added, and hydrogen was replaced 3-4 times. The reaction was stirred at room temperature for 16 hours. After the reaction was completed, diatomaceous earth was used for filtration and solvent removal to obtain 0.25 g of the product, which was directly used for the next step.

步骤3：1-(5-氟-1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成
Step 3: Synthesis of 1-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

室温下，依次向反应瓶中加入4-(3-(2，4-二氧代四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)哌啶-1-甲酸叔丁酯(0.25g，0.56mmol)和二氯甲烷(10ml)，溶清后加入盐酸/二氧六环(9ml)，室温搅拌反应3h。反应完成后，脱溶，得到粗品0.19g，直接下一步。At room temperature, tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate (0.25 g, 0.56 mmol) and dichloromethane (10 ml) were added to the reaction bottle in sequence, and hydrochloric acid/dioxane (9 ml) was added after dissolving, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed to obtain 0.19 g of a crude product, which was directly used in the next step.

步骤4：1-(6-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成
Step 4: Synthesis of 1-(6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

室温下，依次向反应瓶中加入1-(5-氟-1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.19g，0.50mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.27g，0.45mmol)和二氯甲烷(10ml)，再加入TIPT(0.5ml)，室温搅拌16小时，再加入STAB(0.19g，0.91mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.27g，收率：58％。At room temperature, 1-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.19 g, 0.50 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.27 g, 0.45 mmol) and dichloromethane (10 ml) were added to the reaction bottle in sequence, and TIPT (0.5 ml) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.19 g, 0.91 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.27 g of the product with a yield of 58%.

步骤5：1-(5-氟-6-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成
Step 5: Synthesis of 1-(5-fluoro-6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

室温下，依次向反应瓶中加入1-(6-(1-(((1R，2R)-2-((4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.27g，0.29mmol)，10％钯碳(0.03g)和四氢呋喃(10ml)，再加入置换氢气3-4次，室温搅拌反应24h。反应完成后，垫硅藻土过滤，滤饼使用四氢呋喃淋洗滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.135g(入库0.130g)，收率：54％。At room temperature, 1-(6-(1-(((1R, 2R)-2-((4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.27 g, 0.29 mmol), 10% palladium on carbon (0.03 g) and tetrahydrofuran (10 ml) were added to the reaction bottle in sequence, and then hydrogen was replaced 3-4 times. The reaction was stirred at room temperature for 24 hours. After the reaction was completed, diatomaceous earth was used for filtration, and the filter cake was eluted with tetrahydrofuran and the filtrate was desolvated. The product was chromatographed on a DCM/MeOH system to obtain 0.135 g of the product (0.130 g in storage), with a yield of 54%.

1H NMR(400MHz，DMSO-d6)δ10.57(s，1H)，9.15(s，1H)，7.58(d，J＝6.0Hz，1H)，7.36(d，J＝10.8Hz，1H)，7.13(dd，J＝10.3，6.9Hz，3H)，6.83(d，J＝7.2Hz，2H)，6.69-6.31(m，5H)，6.21(d，J＝8.2Hz，2H)，4.13(d，J＝4.9Hz，1H)，3.99(s，3H)，3.90(t，J＝6.7Hz，2H)，3.10-2.81(m，9H)，2.75(t，J＝6.7Hz，2H)，2.48-2.24(m，6H)，2.19-2.03(m，3H)，1.96-1.86(m，4H)，1.83-1.75(m，4H)，1.73-1.64(m，2H)，1.60-1.50(m，2H)，1.46-1.31(m，2H)，1.27-1.12(m，2H)，1.03-0.85(m，2H).MS(ESI)m/z：838.5[M+H]+. 1 H NMR (400MHz, DMSO-d 6 ) δ10.57 (s, 1H), 9.15 (s, 1H), 7.58 (d, J = 6.0Hz, 1H), 7.36 (d, J = 10.8Hz, 1H), 7.13 (dd, J = 10.3, 6.9Hz, 3H), 6.83 (d, J = 7.2Hz, 2H), 6.69-6.31 (m, 5H), 6.21 (d, J=8.2Hz, 2H), 4.13 (d, J=4.9Hz, 1H), 3.99 (s, 3H), 3.90 (t, J=6.7Hz, 2H), 3.10 -2.81 (m, 9H), 2.75 (t, J=6.7Hz, 2H), 2.48-2.24 (m, 6H), 2.19-2.03 (m, 3H), 1.96-1.86 (m, 4H), 1.83-1.75 (m, 4H), 1.7 3-1.64(m, 2H), 1.60-1.50(m, 2H), 1.46-1.31(m, 2H), 1.27-1.12(m, 2H), 1.03-0.85(m, 2H).MS(ESI)m/z: 838.5[M+H] + .

实施例4：N-(2，6-二氧代哌啶-3-基)-2-氟-4-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)苯甲酰胺的合成(化合物I-69)
Example 4: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)benzamide (Compound I-69)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：4-(3-氟-4-(甲氧羰基)苯基)哌嗪-1-羧酸叔丁酯的合成
Step 1: Synthesis of tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入甲基4-溴-2-氟苯甲酸酯(2.00g，9.26mmol)，N-Boc-哌嗪(3.45g，18.52mmol)，Pd(OAc)2(0.10g，0.46mmol)，BINAP(0.58g，0.93mmol)，Cs2CO3(9.05g，27.77mmol)和Toluene(20ml)，置换氮气3-4次，升温至100℃反应16h。反应完成后，降温至室温，过滤，滤液浓缩，使用PE/EA体系柱层析，得到产物棕色油状物2.50g，收率83％。At room temperature, methyl 4-bromo-2-fluorobenzoate (2.00 g, 9.26 mmol), N-Boc-piperazine (3.45 g, 18.52 mmol), Pd(OAc) 2 (0.10 g, 0.46 mmol), BINAP (0.58 g, 0.93 mmol), Cs 2 CO 3 (9.05 g, 27.77 mmol) and Toluene (20 ml) were added to the reaction bottle in sequence, and nitrogen was replaced 3-4 times, and the temperature was raised to 100° C. for reaction for 16 h. After the reaction was completed, the temperature was lowered to room temperature, filtered, and the filtrate was concentrated and chromatographed using a PE/EA system column to obtain 2.50 g of a brown oily product with a yield of 83%.

步骤2：4-(4-(叔丁氧羰基)哌嗪-1-基)-2-氟苯甲酸的合成
Step 2: Synthesis of 4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid

室温下，依次向反应瓶中加入4-(3-氟-4-(甲氧羰基)苯基)哌嗪-1-羧酸叔丁酯(2.50g，7.78mmol)，NaOH(1.24g，31.11mmol)，MeOH(30ml)和H2O(10ml)，升温至50℃反应4h。反应完成后，脱溶，加HCl水溶液调至酸性，产物析出，过滤得到白色固体2.20g，收率92％。At room temperature, tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (2.50 g, 7.78 mmol), NaOH (1.24 g, 31.11 mmol), MeOH (30 ml) and H 2 O (10 ml) were added to the reaction bottle in sequence, and the temperature was raised to 50°C for 4 hours. After the reaction was completed, the solvent was removed, and HCl aqueous solution was added to adjust the acidity. The product precipitated and filtered to obtain 2.20 g of a white solid with a yield of 92%.

步骤3：4-(4-((2，6-二氧代哌啶-3-基)氨甲酰基)-3-氟苯基)哌嗪-1-甲酸叔丁酯的合成
Step 3: Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入4-(4-(叔丁氧羰基)哌嗪-1-基)-2-氟苯甲酸(0.20g，0.65mmol)，3-氨基哌啶-2，6-二酮盐酸盐(0.13g，0.78mmol)，HATU(0.37g，0.98mmol)，DIEA(0.25g，1.95mmol)和DMF(3ml)，室温搅拌反应2h。反应完成后，向反应液加入水(3mL)和饱和食盐水(3mL)，析出大量固体，过滤，滤饼溶于DCM，用无水硫酸镁干燥后直接进行下一步。At room temperature, 4-(4-(tert-butyloxycarbonyl)piperazine-1-yl)-2-fluorobenzoic acid (0.20 g, 0.65 mmol), 3-aminopiperidine-2,6-dione hydrochloride (0.13 g, 0.78 mmol), HATU (0.37 g, 0.98 mmol), DIEA (0.25 g, 1.95 mmol) and DMF (3 ml) were added to the reaction bottle in sequence, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, water (3 mL) and saturated brine (3 mL) were added to the reaction solution, and a large amount of solid was precipitated, which was filtered, and the filter cake was dissolved in DCM, dried over anhydrous magnesium sulfate, and then directly proceeded to the next step.

步骤4：N-(2，6-二氧代哌啶-3-基)-2-氟-4-(哌嗪-1-基)苯甲酰胺的合成
Step 4: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide

室温下，依次向反应瓶中加入4-(4-((2，6-二氧代哌啶-3-基)氨甲酰基)-3-氟苯基)哌嗪-1-甲酸叔丁酯(0.27g，0.65mmol)和二氯甲烷(2mL)，溶清后加入盐酸/二氧六环(2mL)，室温搅拌反应3h。反应完成后，脱溶，得到粗品0.26g，直接进行下一步。At room temperature, tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazine-1-carboxylate (0.27 g, 0.65 mmol) and dichloromethane (2 mL) were added to the reaction bottle in sequence, and hydrochloric acid/dioxane (2 mL) was added after dissolving, and the mixture was stirred at room temperature for 3 h. After the reaction was completed, the solvent was removed to obtain 0.26 g of a crude product, which was directly carried out to the next step.

步骤5：4-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-N-(2，6-二氧代哌啶-3-基)-2-氟苯甲酰胺的合成
Step 5: Synthesis of 4-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide

室温下，依次向反应瓶中加入N-(2，6-二氧代哌啶-3-基)-2-氟-4-(哌嗪-1-基)苯甲酰胺(0.15g，0.47mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.28g，0.47mmol)和二氯甲烷(5mL)，再加入TIPT(0.5mL)，室温搅拌16小时，再加入STAB(0.15g，0.71mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.21g，三步收率：62％。At room temperature, N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazine-1-yl)benzamide (0.15 g, 0.47 mmol), (1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-yl)methyl)cyclohexane-1-carbaldehyde (0.28 g, 0.47 mmol) and dichloromethane (5 mL) were added to the reaction bottle in sequence, and TIPT (0.5 mL) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.15 g, 0.71 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.21 g of the product with a three-step yield of 62%.

步骤6：N-(2，6-二氧代哌啶-3-基)-2-氟-4-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)苯甲酰胺的合成
Step 6: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)benzamide

室温下，依次向反应瓶中加入4-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-N-(2，6-二氧代哌啶-3-基)-2-氟苯甲酰胺(0.21g，0.23mmol)，10％钯碳(0.10g)和THF(3mL)，置换氢气3-4次，室温搅拌反应24h。反应完成后，垫硅藻土过滤，滤饼使用THF淋洗，滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.07g，收率：37％。At room temperature, 4-(4-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (0.21 g, 0.23 mmol), 10% palladium on carbon (0.10 g) and THF (3 mL) were added to the reaction bottle in sequence, hydrogen was replaced 3-4 times, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, diatomaceous earth was used for filtration, the filter cake was rinsed with THF, the filtrate was desolvated, and DCM/MeOH system column chromatography was used to obtain 0.07 g of the product, with a yield of 37%.

1H NMR(400MHz，DMSO-d6)δ10.86(s，1H)，9.12(s，1H)，8.05(t，J＝7.2Hz，1H)，7.62(t，J＝9.0Hz，1H)，7.17-7.10(m，3H)，6.85-6.74(m，4H)，6.66-6.59(m，2H)，6.55-6.46(m，3H)，6.21(d，J＝8.3Hz，2H)，4.73(dt，J＝12.9，6.8Hz，1H)，4.14(d，J＝4.9Hz，1H)，3.29-3.20(m，6H)，3.00-2.93(m，5H)，2.83-2.68(m，1H)，2.48-2.29(m，10H)，2.16-1.99(m，5H)，1.90-1.81(m，2H)，1.73-1.68(m，1H)，1.60-1.52(m，2H)，1.45-1.40(m，2H)，1.23-1.15(m，2H)，1.02-0.93(m，2H)，0.87-0.81(m，1H).MS(ESI)m/z：827.4[M+H]+. 1 H NMR (400MHz, DMSO-d 6 )δ10.86 (s, 1H), 9.12 (s, 1H), 8.05 (t, J=7.2Hz, 1H), 7.62 (t, J=9.0Hz, 1H), 7.17-7.10 (m, 3H), 6.85-6.74 (m, 4H), 6.66-6 .59 (m, 2H), 6.55-6.46 (m, 3H), 6.21 (d, J = 8.3Hz, 2H), 4.73 (dt, J = 12.9, 6.8Hz, 1H), 4.14 (d, J = 4.9Hz, 1H), 3.29-3.20 (m, 6H), 3.00-2.93(m, 5H), 2.83-2.68(m, 1H), 2.48-2.29(m, 10H), 2.16-1.99(m, 5H), 1.90-1.81(m, 2H), 1.73-1.68(m, 1H), 1.60-1.52(m, 2H), 1.45-1.40(m, 2H), 1.23-1.15(m, 2H), 1.02-0.93(m, 2H), 0.87-0.81(m, 1H).MS(ESI)m/z: 827.4[M+H] + .

实施例5：3-(6-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1-甲基-1H-吲唑-3-基)哌啶-2，6-二酮的合成(化合物IV-3)
Example 5: Synthesis of 3-(6-(4-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (Compound IV-3)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：3-(2，6-双(苄氧)吡啶-3-基)-6-溴-1-甲基-1H-吲唑的合成
Step 1: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole

室温下，依次向反应瓶中加入6-溴-3-碘-1-甲基-1H-吲唑(1.00g，2.97mmol)，2，6-双(苄氧)-3-(4，4，5，5-四甲基-1，3，2-二氧杂环戊烷-2-基)吡啶(1.24g，2.97mmol)，碳酸钠(0.94g，8.90mmol)，四三苯基膦钯(0.34g，0.30mmol)，水(1mL)和二氧六环(10ml)，90℃下，氮气氛围，反应5h。反应完成后，降至室温，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物1.20g，收率81％。At room temperature, 6-bromo-3-iodo-1-methyl-1H-indazole (1.00 g, 2.97 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridine (1.24 g, 2.97 mmol), sodium carbonate (0.94 g, 8.90 mmol), tetrakistriphenylphosphine palladium (0.34 g, 0.30 mmol), water (1 mL) and dioxane (10 ml) were added to the reaction bottle in sequence, and the mixture was reacted for 5 h at 90° C. in a nitrogen atmosphere. After the reaction was completed, the mixture was cooled to room temperature, ethyl acetate and water were added, and the liquid was separated. After the organic phase was dried, PE/EA system column chromatography was used to obtain 1.20 g of the product with a yield of 81%.

步骤2：4-(3-(2，6-双(苄氧)吡啶-3-基)-1-甲基-1H-吲唑-6-基)哌嗪-1-甲酸叔丁酯的合成
Step 2: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入3-(2，6-双(苄氧)吡啶-3-基)-6-溴-1-甲基-1H-吲唑(0.25g，0.50mmol)，1-Boc-哌嗪(0.28g，1.50mmol)，Pd2(dba)3(0.05g，0.05mmol)，10％三叔丁基膦甲苯溶液(200mg，0.10mmol)，叔丁醇钠(0.10g，1.00mmol)和甲苯(10ml)。100℃下，氮气氛围，反应5h。反应完成后，降温至室温，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物0.20g，收率66％。At room temperature, 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (0.25 g, 0.50 mmol), 1-Boc-piperazine (0.28 g, 1.50 mmol), Pd 2 (dba) 3 (0.05 g, 0.05 mmol), 10% tri-tert-butylphosphine toluene solution (200 mg, 0.10 mmol), sodium tert-butoxide (0.10 g, 1.00 mmol) and toluene (10 ml) were added to the reaction bottle in sequence. The reaction was carried out at 100° C. in a nitrogen atmosphere for 5 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, the liquid was separated, and the organic phase was dried and chromatographed on a PE/EA system column to obtain 0.20 g of the product with a yield of 66%.

步骤3：4-(3-(2，6-二氧代哌啶-3-基)-1-甲基-1H-吲唑-6-基)哌嗪-1-甲酸叔丁基酯的合成
Step 3: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入4-(3-(2，6-双(苄氧)吡啶-3-基)-1-甲基-1H-吲唑-6-基)哌嗪-1-甲酸叔丁酯(0.20g，0.33mmol)，10％Pd/C(0.02g)，四氢呋喃(5mL)和乙醇(5ml)，室温反应24h。反应完成后，过滤旋干，得到粗品0.13g，直接下一步。At room temperature, tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.20 g, 0.33 mmol), 10% Pd/C (0.02 g), tetrahydrofuran (5 mL) and ethanol (5 ml) were added to the reaction bottle in sequence and reacted at room temperature for 24 h. After the reaction was completed, the mixture was filtered and dried to obtain 0.13 g of a crude product, which was directly used in the next step.

步骤4：3-(1-甲基-6-(哌嗪-1-基)-1H-吲唑-3-基)哌嗪-2，6-二酮的合成
Step 4: Synthesis of 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperazine-2,6-dione

室温下，依次向反应瓶中加入4-(3-(2，6-二氧代哌啶-3-基)-1-甲基-1H-吲唑-6-基)哌嗪-1-甲酸叔丁基酯(0.13g，0.30mmol)和HCl二氧六环溶液(5ml)，室温反应2h。反应完成后，旋干，得到粗品0.11g，直接下一步。At room temperature, tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.13 g, 0.30 mmol) and HCl dioxane solution (5 ml) were added to the reaction bottle in sequence and reacted at room temperature for 2 h. After the reaction was completed, the mixture was spin-dried to obtain 0.11 g of a crude product, which was directly used for the next step.

步骤5：3-(6-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1-甲基-1H-吲唑-3-基)哌嗪-2，6-二酮的合成
Step 5: Synthesis of 3-(6-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperazine-2,6-dione

室温下，依次向反应瓶中加入3-(1-甲基-6-(哌嗪-1-基)-1H-吲唑-3-基)哌嗪-2，6-二酮(0.06g，0.18mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.11g，0.18mmol)和二氯甲烷(10ml)，再加入TIPT(0.5ml)，室温搅拌16小时，再加入STAB(0.08g，0.36mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.03g，收率：27％。At room temperature, 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperazine-2,6-dione (0.06 g, 0.18 mmol), (1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.11 g, 0.18 mmol) and dichloromethane (10 ml) were added to the reaction bottle in sequence, and TIPT (0.5 ml) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.08 g, 0.36 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring evenly to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.03 g of the product with a yield of 27%.

步骤6：3-(6-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1-甲基-1H-吲唑-3-基)哌啶-2，6-二酮的合成
Step 6: Synthesis of 3-(6-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(6-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1-甲基-1H-吲唑-3-基)哌嗪-2，6-二酮(0.03g，0.03mmol)，10％钯碳(0.01g)和四氢呋喃(5ml)，再加入置换氢气3-4次，30℃搅拌反应16h。反应完成后，垫硅藻土过滤，滤饼使用四氢呋喃淋洗滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.01g，收率：37％。At room temperature, 3-(6-(4-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperazine-2,6-dione (0.03 g, 0.03 mmol), 10% palladium on carbon (0.01 g) and tetrahydrofuran (5 ml) were added to the reaction bottle in sequence, and hydrogen was replaced 3-4 times. The reaction was stirred at 30° C. for 16 h. After the reaction was completed, diatomaceous earth was used for filtration, and the filter cake was eluted with tetrahydrofuran and the filtrate was desolvated. The product was chromatographed on a DCM/MeOH system to obtain 0.01 g of the product with a yield of 37%.

1H NMR(400MHz，DMSO-d6)δ10.87(s，1H)，9.15(s，1H)，7.51(d，J＝9.0Hz，1H)，7.11(dt，J＝11.5，7.1Hz，3H)，6.93(d，J＝9.1Hz，1H)，6.82(d，J＝8.5Hz，3H)，6.65-6.60(m，2H)，6.55(d，J＝8.3Hz，2H)，6.48(dd，J＝8.2，2.6Hz，1H)，6.22(d，J＝8.2Hz，2H)，4.27(dd，J＝9.3，5.1Hz，1H)，4.14(d，J＝5.0Hz，1H)，3.85(s，3H)，3.14-2.86(m，10H)，2.72-2.55(m，6H)，2.35-1.97(m，7H)，1.83-1.46(m，9H)，1.03-0.96(m，2H)，0.87-0.81(m，1H).MS(ESI)m/z：820.8[M+H]+. 1 H NMR (400MHz, DMSO-d 6 ) δ10.87 (s, 1H), 9.15 (s, 1H), 7.51 (d, J = 9.0Hz, 1H), 7.11 (dt, J = 11.5, 7.1Hz, 3H), 6.93 (d, J = 9.1Hz, 1H), 6 .82 (d, J=8.5Hz, 3H), 6.65-6.60 (m, 2H), 6.55 (d, J=8.3Hz, 2H), 6.48 (dd, J=8.2, 2.6Hz, 1H), 6.22 (d, J=8.2 Hz, 2H), 4.27 (dd, J=9.3, 5.1Hz, 1H), 4.14 (d, J=5.0Hz, 1H), 3.85 (s, 3H), 3.14-2.86 (m, 10H), 2.72-2.55 (m , 6H), 2.35-1.97(m, 7H), 1.83-1.46(m, 9H), 1.03-0.96(m, 2H), 0.87-0.81(m, 1H).MS(ESI)m/z: 820.8[M+H] + .

实施例6：3-(5-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-3-甲基-2-氧代-2，3-二氢-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮的合成(化合物VII-2)
Example 6: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound VII-2)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：叔丁基4-(1-(2，6-二氧代哌啶-3-基)-3-甲基-2-氧代-2，3-二氢-1H-苯并[d]咪唑-5-基)哌嗪-1-甲酸酯的合成
Step 1: Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入3-(5-溴-3-甲基-2-氧代-2，3-二氢-1H-苯并[D]咪唑-1-基)哌啶-2，6-二酮(0.50g，1.48mmol)，N-Boc-哌嗪(0.55g，2.96mmol)，RuPhos-Pd-G3(0.25g，0.30mmol)，RuPhos(0.14g，0.30mmol)，1M LiHMDS(6mL)，4AMS和Toluene(5ml)，置换氮气3-4次，升温至100℃反应5h。反应完成后，降温至室温，浓缩，使用PE/EA体系柱层析，得到棕色油状物0.45g，收率68％。At room temperature, 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidine-2,6-dione (0.50 g, 1.48 mmol), N-Boc-piperazine (0.55 g, 2.96 mmol), RuPhos-Pd-G3 (0.25 g, 0.30 mmol), RuPhos (0.14 g, 0.30 mmol), 1M LiHMDS (6 mL), 4AMS and Toluene (5 ml) were added to the reaction bottle in sequence, nitrogen was replaced 3-4 times, and the temperature was raised to 100 ° C for 5 h. After the reaction was completed, the temperature was lowered to room temperature, concentrated, and PE/EA system column chromatography was used to obtain 0.45 g of brown oil with a yield of 68%.

步骤2：3-(3-甲基-2-氧代-5-哌嗪-1-基-2，3-二氢-1H-苯并[d]咪唑-1-基)哌嗪-2，6-二酮的合成
Step 2: Synthesis of 3-(3-methyl-2-oxo-5-piperazin-1-yl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperazine-2,6-dione

室温下，依次向反应瓶中加入叔丁基4-(1-(2，6-二氧代哌啶-3-基)-3-甲基-2-氧代-2，3-二氢-1H-苯并[d]咪唑-5-基)哌嗪-1-甲酸酯(0.45mg，1.01mmol)和二氯甲烷(2ml)，溶清后加入盐酸/二氧六环(2ml)，室温搅拌反应3h。反应完成后，脱溶，得到粗品0.30g，直接进行下一步。At room temperature, tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate (0.45 mg, 1.01 mmol) and dichloromethane (2 ml) were added to the reaction bottle in sequence, and hydrochloric acid/dioxane (2 ml) was added after dissolving, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed to obtain 0.30 g of a crude product, which was directly carried out to the next step.

步骤3：3-(5-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧)-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-3-甲基-2-氧代-2，3-二氢-1H-苯并[d]咪唑-1-基)哌嗪-2，6-二酮的合成
Step 3: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperazine-2,6-dione

室温下，依次向反应瓶中加入3-(3-甲基-2-氧代-5-哌嗪-1-基-2，3-二氢-1H-苯并[d]咪唑-1-基)哌嗪-2，6-二酮(0.15g，0.44mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.26g，0.44mmol)和二氯甲烷(5ml)，再加入TIPT(0.45ml)，室温搅拌16小时，再加入STAB(0.14g，0.66mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.11g，两步收率：23％。At room temperature, 3-(3-methyl-2-oxo-5-piperazin-1-yl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperazine-2,6-dione (0.15 g, 0.44 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.26 g, 0.44 mmol) and dichloromethane (5 ml) were added to the reaction bottle in sequence, and TIPT (0.45 ml) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.14 g, 0.66 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.11 g of the product with a two-step yield of 23%.

步骤4：3-(5-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-3-甲基-2-氧代-2，3-二氢-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮的合成
Step 4: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(5-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-3-甲基-2-氧代-2，3-二氢-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮(0.11g，0.12mmol)，10％钯碳(0.10g)和THF(3ml)，置换氢气3-4次，25℃搅拌反应24h。反应完成后，垫硅藻土过滤，滤饼使用THF淋洗，滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.01g，收率：11％。At room temperature, 3-(5-(4-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.11 g, 0.12 mmol), 10% palladium on carbon (0.10 g) and THF (3 ml) were added to the reaction bottle in sequence, the hydrogen was replaced 3-4 times, and the reaction was stirred at 25° C. for 24 h. After the reaction was completed, the mixture was filtered through diatomaceous earth, the filter cake was rinsed with THF, the filtrate was desolvated, and DCM/MeOH system column chromatography was used to obtain 0.01 g of the product, with a yield of 11%.

1H NMR(400MHz，DMSO-d6)δ11.08(s，1H)，9.16(s，1H)，7.11(dd，J＝11.4，6.9Hz，3H)，6.95(d，J＝8.6Hz，1H)，6.82(d，J＝8.6Hz，3H)，6.63-6.48(m，6H)，6.22(d，J＝8.0Hz，2H)，5.76(s，3H)，5.30(dd，J＝12.7，5.5Hz，1H)，4.14(d，J＝5.0Hz，1H)，3.14(s，2H)，3.04(s，2H)，2.94(dd，J＝17.2，9.0Hz，5H)，2.76-2.56(m，10H)，2.30(d，J＝26.0Hz，2H)，2.09(dd，J＝12.9，6.7Hz，2H)，1.98(d，J＝10.8Hz，2H)，1.87-1.40(m，10H)，1.21(s，2H)，0.99(d，J＝13.1Hz，2H).MS(ESI)m/z：837.0[M+H]+.1H NMR (400MHz, DMSO-d6) δ11.08 (s, 1H), 9.16 (s, 1H), 7.11 (dd, J=11.4, 6.9Hz, 3H), 6.95 (d, J=8.6Hz, 1H), 6.82 (d, J=8. 6Hz, 3H), 6.63-6.48 (m, 6H), 6.22 (d, J=8.0Hz, 2H), 5.76 (s, 3H), 5.30 (dd, J=12.7, 5.5Hz, 1H), 4.14 (d, J=5.0Hz, 1H), 3 .14 (s, 2H), 3.04 (s, 2H), 2.94 (dd, J=17.2, 9.0Hz, 5H), 2.76-2.56 (m, 10H), 2.30 (d, J=26.0Hz, 2H), 2.09 (dd, J=12.9, 6.7Hz, 2H), 1.98 (d, J=10.8Hz, 2H), 1.87-1.40 (m, 10H), 1.21 (s, 2H), 0.99 (d, J=13.1Hz, 2H). MS (ESI) m/z: 837.0 [M+H] + .

实施例7：N-(2，6-二氧代哌啶-3-基)-5-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)吡啶甲酰胺的合成(化合物III-1)
Example 7: Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)picolinamide (Compound III-1)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：叔丁基4-(6-(甲氧羰基)吡啶-3-基)哌嗪-1-羧酸甲酯的合成
Step 1: Synthesis of tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylic acid methyl ester

室温下，依次向反应瓶中加入5-溴吡啶-2-羧酸甲酯(2.00g，9.26mmol)，N-Boc-哌嗪(3.45g，18.52mmol)，Pd(OAc)2(0.10g，0.46mmol)，BINAP(0.58g，0.93mmol)，Cs2CO3(9.05g，27.77mmol)和Toluene(20ml)，置换氮气3-4次，升温至100℃反应16h。反应完成后，降温至室温，过滤，滤液浓缩，使用PE/EA体系柱层析，得到产物棕色油状物2.50g，收率83％。At room temperature, 5-bromopyridine-2-carboxylic acid methyl ester (2.00 g, 9.26 mmol), N-Boc-piperazine (3.45 g, 18.52 mmol), Pd(OAc) 2 (0.10 g, 0.46 mmol), BINAP (0.58 g, 0.93 mmol), Cs 2 CO 3 (9.05 g, 27.77 mmol) and Toluene (20 ml) were added to the reaction bottle in sequence, and nitrogen was replaced 3-4 times, and the temperature was raised to 100° C. for reaction for 16 h. After the reaction was completed, the temperature was lowered to room temperature, filtered, and the filtrate was concentrated. The product was subjected to PE/EA system column chromatography to obtain 2.50 g of brown oily product with a yield of 83%.

步骤2：5-(4-(叔丁氧羰基)哌嗪-1-基)吡啶甲酸的合成
Step 2: Synthesis of 5-(4-(tert-butyloxycarbonyl)piperazin-1-yl)picolinic acid

室温下，依次向反应瓶中加入叔丁基4-(6-(甲氧羰基)吡啶-3-基)哌嗪-1-羧酸甲酯(2.50g，7.78mmol)，NaOH(1.24g，31.11mmol)，MeOH(30ml)和H2O(10ml)，升温至50℃反应4h。反应完成后，脱溶，加HCl水溶液调至酸性，DCM萃取三次，得到黄色固体2.20g，收率92％。At room temperature, tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylic acid methyl ester (2.50 g, 7.78 mmol), NaOH (1.24 g, 31.11 mmol), MeOH (30 ml) and H 2 O (10 ml) were added to the reaction bottle in sequence, and the temperature was raised to 50°C for 4 h. After the reaction was completed, the solvent was removed, HCl aqueous solution was added to adjust to acidity, and DCM was extracted three times to obtain 2.20 g of a yellow solid with a yield of 92%.

步骤3：叔丁基4-(6-((2，6-二氧代哌啶-3-基)氨甲酰基)吡啶-3-基)哌嗪-1-羧酸酯的合成
Step 3: Synthesis of tert-butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入5-(4-(叔丁氧羰基)哌嗪-1-基)吡啶甲酸(0.20g，0.65mmol)，3-氨基哌啶-2，6-二酮盐酸盐(0.13g，0.78mmol)，HATU(0.37g，0.98mmol)，DIEA(0.25g，1.95mmol)和DMF(3ml)，室温搅拌反应2h。反应完成后，向反应液加入水(3mL)和饱和食盐水(3mL)，析出大量固体，过滤，滤饼溶于DCM，用无水硫酸镁干燥后直接进行下一步。At room temperature, 5-(4-(tert-butyloxycarbonyl)piperazine-1-yl)picolinic acid (0.20 g, 0.65 mmol), 3-aminopiperidine-2,6-dione hydrochloride (0.13 g, 0.78 mmol), HATU (0.37 g, 0.98 mmol), DIEA (0.25 g, 1.95 mmol) and DMF (3 ml) were added to the reaction bottle in sequence, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, water (3 mL) and saturated brine (3 mL) were added to the reaction solution, and a large amount of solid was precipitated, which was filtered, and the filter cake was dissolved in DCM, dried over anhydrous magnesium sulfate, and then directly proceeded to the next step.

步骤4：N-(2，6-二氧代哌啶-3-基)-5-(哌嗪-1-基)吡啶-3-甲酰胺的合成
Step 4: Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)pyridine-3-carboxamide

室温下，依次向反应瓶中加入叔丁基4-(6-((2，6-二氧代哌啶-3-基)氨甲酰基)吡啶-3-基)哌嗪-1-羧酸酯(0.27mg，0.65mmol)和二氯甲烷(2ml)，溶清后加入盐酸/二氧六环(2ml)，室温搅拌反应3h。反应完成后，脱溶，得到粗品0.26g，直接进行下一步。At room temperature, tert-butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate (0.27 mg, 0.65 mmol) and dichloromethane (2 ml) were added to the reaction bottle in sequence, and hydrochloric acid/dioxane (2 ml) was added after dissolving, and the mixture was stirred at room temperature for 3 h. After the reaction was completed, the solvent was removed to obtain 0.26 g of a crude product, which was directly carried out to the next step.

步骤5：5-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-N-(2，6-二氧代哌啶-3-基)吡啶-3-甲酰胺的合成
Step 5: Synthesis of 5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridine-3-carboxamide

室温下，依次向反应瓶中加入N-(2，6-二氧代哌啶-3-基)-5-(哌嗪-1-基)吡啶-3-甲酰胺(0.15g，0.47mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.28g，0.47mmol)和二氯甲烷(5ml)，再加入TIPT(0.45ml)，室温搅拌16小时，再加入STAB(0.15g，0.71mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.21g，三步收率：62％。At room temperature, N-(2,6-dioxopiperidin-3-yl)-5-(piperazine-1-yl)pyridine-3-carboxamide (0.15 g, 0.47 mmol), (1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-yl)methyl)cyclohexane-1-carboxaldehyde (0.28 g, 0.47 mmol) and dichloromethane (5 ml) were added to the reaction bottle in sequence, and TIPT (0.45 ml) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.15 g, 0.71 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.21 g of the product with a three-step yield of 62%.

步骤6：N-(2，6-二氧代哌啶-3-基)-5-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)吡啶酰胺的合成
Step 6: Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)picolinamide

室温下，依次向反应瓶中加入5-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-N-(2，6-二氧代哌啶-3-基)吡啶-3-甲酰胺(0.21g，0.23mmol)，10％钯碳(0.10g)和THF(3ml)，置换氢气3-4次，室温搅拌反应24h。反应完成后，垫硅藻土过滤，滤饼使用THF淋洗，滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.04g，收率：21％。At room temperature, 5-(4-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridine-3-carboxamide (0.21 g, 0.23 mmol), 10% palladium on carbon (0.10 g) and THF (3 ml) were added to the reaction bottle in sequence, the hydrogen was replaced 3-4 times, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, the mixture was filtered with diatomaceous earth, the filter cake was rinsed with THF, the filtrate was desolvated, and DCM/MeOH system column chromatography was used to obtain 0.04 g of the product, with a yield of 21%.

1H NMR(400MHz，DMSO-d6)δ10.86(s，1H)，9.12(s，1H)，8.73(d，J＝8.3Hz，1H)，8.31(d，J＝2.8Hz，1H)，7.86(d，J＝8.8Hz，1H)，7.41(dd，J＝8.9，2.8Hz，1H)，7.13(dd，J＝10.3，6.8Hz，3H)，6.86-6.82(m，2H)，6.66-6.60(m，2H)，6.54-6.46(m，3H)，6.21(d，J＝8.3Hz，2H)，4.75(ddd，J＝13.0，8.3，5.4Hz，1H)，4.14(d，J＝4.9Hz，1H)，3.26(s，4H)，3.02-2.72(m，8H)，2.60-2.51(m，4H)，2.42(d，J＝32.5Hz，8H)，2.24-1.96(m，6H)，1.86(s，1H)，1.70(dd，J＝13.2，5.8Hz，1H)，1.57(d，J＝8.9Hz，2H)，1.44(s，2H)，1.22(d，J＝12.7Hz，2H)，0.98(s，2H).MS(ESI)m/z：810.4[M+H]+. 1 H NMR (400MHz, DMSO-d 6 )δ10.86 (s, 1H), 9.12 (s, 1H), 8.73 (d, J = 8.3Hz, 1H), 8.31 (d, J = 2.8Hz, 1H), 7.86 (d, J = 8.8Hz, 1H), 7.41 (dd, J = 8.9, 2.8Hz, 1H), 7.13 ( dd, J=10.3, 6.8Hz, 3H), 6.86-6.82 (m, 2H), 6.66-6.60 (m, 2H), 6.54-6.46 (m, 3H), 6.21 (d, J=8.3Hz, 2H), 4.75 (ddd, J=13.0, 8.3, 5.4H z, 1H), 4.14 (d, J = 4.9Hz, 1H), 3.26 (s, 4H), 3.02-2.72 (m, 8H), 2.60-2.51 (m, 4H), 2.42 (d, J = 32.5Hz, 8H), 2.24-1.96 (m, 6H), 1.86 (s, 1H), 1.70 (dd, J=13.2, 5.8Hz, 1H), 1.57 (d, J=8.9Hz, 2H), 1.44 (s, 2H), 1.22 (d, J=12.7Hz, 2H), 0.98 (s, 2H). MS (ESI) m/z: 810.4[M+H] + .

实施例8：3-(4-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-3-甲基-2-氧代-2，3-二氢-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮的合成(化合物VII-3)
Example 8: Synthesis of 3-(4-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound VII-3)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：叔丁基4-(1-(2，6-二氧代哌啶-3-基)-3-甲基-2-氧代-2，3-二氢-1H-苯并[d]咪唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸酯的合成
Step 1: Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate

室温下，依次向反应瓶中加入3-(4-溴-3-甲基-2-氧代-2，3-二氢-1H-苯并[D]咪唑-1-基)哌啶-2，6-二酮(0.25g，0.74mmol)，N-Boc-1，2，5，6-四氢吡啶-4-硼酸频哪醇酯(0.34g，1.11mmol)，Xphos-Pd-G2(0.06g，0.07mmol)，K3PO4(0.31g，1.48mmol)，Do(5mL)和H2O(1ml)，置换氮气3-4次，升温至80℃反应3h。反应完成后，降温至室温，浓缩，使用PE/EA体系柱层析，得到白色固体0.22g，收率67％。At room temperature, 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidine-2,6-dione (0.25 g, 0.74 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (0.34 g, 1.11 mmol), Xphos-Pd-G2 (0.06 g, 0.07 mmol), K 3 PO 4 (0.31 g, 1.48 mmol), Do (5 mL) and H 2 O (1 ml) were added to the reaction bottle in sequence, nitrogen was replaced 3-4 times, and the temperature was raised to 80° C. for reaction for 3 h. After the reaction was completed, the temperature was lowered to room temperature, concentrated, and chromatographed using a PE/EA system column to obtain 0.22 g of a white solid with a yield of 67%.

步骤2：叔丁基4-(1-(2，6-二氧代哌啶-3-基)-3-甲基-2-氧代-2，3-二氢-1H-苯并[d]咪唑-4-基)哌啶-1-羧酸酯的合成
Step 2: Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-1-carboxylate

室温下，依次向反应瓶中加入叔丁基4-(1-(2，6-二氧代哌啶-3-基)-3-甲基-2-氧代-2，3-二氢-1H-苯并[d]咪唑-4-基)-3，6-二氢吡啶-1(2H)-羧酸酯(0.22g，0.50mmol)，10％钯碳(0.10g)和THF(3ml)，置换氢气3-4次，室温搅拌反应8h。反应完成后，垫硅藻土过滤，滤饼使用THF淋洗，滤液脱溶，得到0.20g粗品直接进行下一步。At room temperature, tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.22 g, 0.50 mmol), 10% palladium on carbon (0.10 g) and THF (3 ml) were added to the reaction bottle in sequence, and the hydrogen was replaced 3-4 times. The reaction was stirred at room temperature for 8 hours. After the reaction was completed, diatomaceous earth was used for filtration, the filter cake was rinsed with THF, and the filtrate was desolvated to obtain 0.20 g of crude product, which was directly carried out to the next step.

步骤3：3-(3-甲基-2-氧代-4-(哌啶-4-基)-2，3-二氢-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮的合成
Step 3: Synthesis of 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入叔丁基4-(1-(2，6-二氧代哌啶-3-基)-3-甲基-2-氧代-2，3-二氢-1H-苯并[d]咪唑-4-基)哌啶-1-羧酸酯(0.20mg，0.45mmol)和二氯甲烷(2ml)，溶清后加入盐酸/二氧六环(2ml)，室温搅拌反应3h。反应完成后，脱溶，得到粗品0.11g，直接进行下一步。At room temperature, tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-1-carboxylate (0.20 mg, 0.45 mmol) and dichloromethane (2 ml) were added to the reaction bottle in sequence, and hydrochloric acid/dioxane (2 ml) was added after dissolving, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed to obtain 0.11 g of a crude product, which was directly carried out to the next step.

步骤4：3-(4-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-3-甲基-2-氧代-2，3-二氢-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮的合成
Step 4: Synthesis of 3-(4-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(3-甲基-2-氧代-4-(哌啶-4-基)-2，3-二氢-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮(0.11g，0.32mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.19g，0.32mmol)和二氯甲烷(5ml)，再加入TIPT(0.3ml)，室温搅拌16小时，再加入STAB(0.10g，0.48mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.06g，三步收率：13％。At room temperature, 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.11 g, 0.32 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.19 g, 0.32 mmol) and dichloromethane (5 ml) were added to the reaction bottle in sequence, and TIPT (0.3 ml) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.10 g, 0.48 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring evenly to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.06 g of the product. The three-step yield was 13%.

步骤5：3-(4-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-3-甲基-2-氧代-2，3-二氢-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮的合成
Step 5: Synthesis of 3-(4-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(4-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-3-甲基-2-氧代-2，3-二氢-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮(0.06g，0.06mmol)，10％钯碳(0.05g)和THF(3ml)，置换氢气3-4次，25℃搅拌反应24h。反应完成后，垫硅藻土过滤，滤饼使用THF淋洗，滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.008g，收率：14％。At room temperature, 3-(4-(1-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.06 g, 0.06 mmol), 10% palladium on carbon (0.05 g) and THF (3 ml) were added to the reaction bottle in sequence, the hydrogen was replaced 3-4 times, and the reaction was stirred at 25°C for 24 h. After the reaction was completed, the mixture was filtered through diatomaceous earth, the filter cake was rinsed with THF, the filtrate was desolvated, and DCM/MeOH system column chromatography was used to obtain 0.008 g of the product, with a yield of 14%.

1H NMR(400MHz，DMSO-d6)δ11.11(s，1H)，9.15(s，1H)，7.12(q，J＝5.9，4.5Hz，3H)，7.02-6.95(m，3H)，6.83(d，J＝7.3Hz，2H)，6.59(dd，J＝15.9，6.0Hz，4H)，6.48(d，J＝8.5Hz，1H)，6.23(d，J＝8.1Hz，2H)，5.40-5.33(m，1H)，4.14(d，J＝5.0Hz，1H)，3.59(s，3H)，3.07(s，3H)，2.97-2.86(m，4H)，2.64(dd，J＝17.3，12.2Hz，8H)，2.20-2.08(m，2H)，1.98-1.90(m，4H)，1.68(d，J＝30.7Hz，4H)，1.53-1.44(m，2H)，1.24(s，10H)，1.05-0.97(m，2H)，0.86(t，J＝6.5Hz，1H).MS(ESI)m/z:836.0[M+H]+. 1 H NMR (400MHz, DMSO-d6) δ11.11 (s, 1H), 9.15 (s, 1H), 7.12 (q, J=5.9, 4.5Hz, 3H), 7.02-6.95 (m, 3H), 6.83 (d, J=7.3Hz, 2H ), 6.59 (dd, J=15.9, 6.0Hz, 4H), 6.48 (d, J=8.5Hz, 1H), 6.23 (d, J=8.1Hz, 2H), 5.40-5.33 (m, 1H), 4.14 (d, J=5.0Hz, 1H), 3.59 (s, 3H), 3.07 (s, 3H), 2.97-2.86 (m, 4H), 2.64 (dd, J=17.3, 12.2Hz, 8H), 2.20-2.08 (m, 2H), 1.98-1.90 (m, 4H), 1.68 (d, J=30.7Hz, 4H), 1.53-1.44 (m, 2H), 1.24 (s, 10H), 1.05-0.97 (m, 2H), 0.86 (t, J=6.5Hz, 1H). MS (ESI) m/z: 836.0 [M+H] + .

实施例9：3-(5-(4-(((1R，2R)-2-((4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1H-吲唑-1-基)哌啶-2，6-二酮的合成(化合物VI-6)
Example 9: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione (Compound VI-6)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：4-(3-(2，4-二氧代四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)哌嗪-1-甲酸叔丁酯的合成
Step 1: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入5-溴吲唑(0.50g，2.54mmol)，叔丁醇钾(0.34g，3.05mmol)和四氢呋喃(15ml)，降温至0℃搅拌30分钟，再加入1-(4-甲氧基苄基)-2，6-二氧代哌啶-3-基三氟甲磺酸酯(0.97g，2.54mmol)，加完后恢复室温反应3h。反应完成后，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物0.47g，收率43％。At room temperature, 5-bromoindazole (0.50 g, 2.54 mmol), potassium tert-butoxide (0.34 g, 3.05 mmol) and tetrahydrofuran (15 ml) were added to the reaction bottle in sequence, the temperature was lowered to 0°C and stirred for 30 minutes, and then 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (0.97 g, 2.54 mmol) was added, and the reaction was restored to room temperature for 3 hours after the addition. After the reaction was completed, ethyl acetate and water were added, the liquids were separated, and the organic phase was dried and chromatographed using a PE/EA system column to obtain 0.47 g of the product with a yield of 43%.

步骤2：4-(1-(1-(4-甲氧基苄基)-2，6-二氧代哌啶-3-基)-1H-吲唑-5-基)哌嗪-1-甲酸叔丁酯的合成
Step 2: Synthesis of tert-butyl 4-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1H-indazol-5-yl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入4-(3-(2，4-二氧代四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)哌嗪-1-甲酸叔丁酯(0.47g，1.09mmol)，1-Boc-哌嗪(0.20g，1.09mmol)，PEPPSI IHept-Cl(0.11g，0.11mmol)，碳酸铯(1.07g，3.28mmol)，4A分子筛(0.11g)和1，4-二氧六环(15ml)，置换氮气3-4次，升温至100℃反应15h。反应完成后，降温至室温，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物0.13g，收率21％。At room temperature, tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.47 g, 1.09 mmol), 1-Boc-piperazine (0.20 g, 1.09 mmol), PEPPSI IHept-Cl (0.11 g, 0.11 mmol), cesium carbonate (1.07 g, 3.28 mmol), 4A molecular sieves (0.11 g) and 1,4-dioxane (15 ml) were added to the reaction bottle in sequence, nitrogen was replaced 3-4 times, and the temperature was raised to 100°C for reaction for 15 hours. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, the liquids were separated, and the organic phase was dried and chromatographed using a PE/EA system column to obtain 0.13 g of the product with a yield of 21%.

步骤3：3-(5-(哌嗪-1-基)-1H-吲唑-1-基)哌啶-2，6-二酮的合成
Step 3: Synthesis of 3-(5-(piperazin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入4-(1-(1-(4-甲氧基苄基)-2，6-二氧代哌啶-3-基)-1H-吲唑-5-基)哌嗪-1-甲酸叔丁酯(0.13g，0.23mmol)，三氟乙酸(3ml)和TfOH(0.5ml)，升温65℃搅拌反应2h。反应完成后，脱溶，使用反向柱层析(乙腈/水)体系柱层析，得到粗品0.06g，直接下一步。At room temperature, tert-butyl 4-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1H-indazol-5-yl)piperazine-1-carboxylate (0.13 g, 0.23 mmol), trifluoroacetic acid (3 ml) and TfOH (0.5 ml) were added to the reaction bottle in sequence, and the temperature was raised to 65°C and stirred for 2 hours. After the reaction was completed, the solvent was removed and column chromatography was performed using a reverse column chromatography (acetonitrile/water) system to obtain 0.06 g of a crude product, which was directly used in the next step.

步骤4：3-(5-(4-(((1R，2R)-2-((4-(4-(1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)基)环己基)甲基)哌嗪-1-基)-1H-吲唑-1-基)哌啶-2，6-二酮的合成
Step 4: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-(1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)yl)cyclohexyl)methyl)piperazin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(5-(哌嗪-1-基)-1H-吲唑-1-基)哌啶-2，6-二酮(0.06g，0.18mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.11g，0.18mmol)和二氯甲烷(10ml)，再加入TIPT(0.5ml)，室温搅拌16小时，再加入STAB(0.08g，0.36mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.03g，收率：27％。At room temperature, 3-(5-(piperazine-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione (0.06 g, 0.18 mmol), (1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-yl)methyl)cyclohexane-1-carbaldehyde (0.11 g, 0.18 mmol) and dichloromethane (10 ml) were added to the reaction bottle in sequence, and TIPT (0.5 ml) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.08 g, 0.36 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.03 g of the product with a yield of 27%.

步骤5：3-(5-(4-(((1R，2R)-2-((4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1H-吲唑-1-基)哌啶-2，6-二酮的合成
Step 5: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(5-(4-(((1R，2R)-2-((4-(4-(2R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)基)环己基)甲基)哌嗪1-基)-1H-吲唑-1-基)哌啶-2，6-二酮(0.03g，0.04mmol)，10％钯碳(0.01g)和四氢呋喃(10ml)，再加入置换氢气3-4次，30℃搅拌反应16h。反应完成后，垫硅藻土过滤，滤饼使用四氢呋喃淋洗滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.008g(入库0.004g)，收率：29％。At room temperature, 3-(5-(4-(((1R, 2R)-2-((4-(4-(2R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)yl)cyclohexyl)methyl)piperazin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione (0.03 g, 0.04 mmol), 10% palladium on carbon (0.01 g) and tetrahydrofuran (10 ml) were added to the reaction bottle in sequence, and then hydrogen was replaced 3-4 times, and the reaction was stirred at 30°C for 16 hours. After the reaction was completed, diatomaceous earth was used for filtration, and the filter cake was eluted with tetrahydrofuran and the filtrate was desolvated. The product was chromatographed on a DCM/MeOH system to obtain 0.008 g of the product (0.004 g in storage), with a yield of 29%.

1H NMR(400MHz，DMSO-d6)δ11.08(s，1H)，9.25(s，1H)，7.93(s，1H)，7.53(d，J＝9.0Hz，1H)，7.26(d，J＝9.4Hz，1H)，7.12(d，.J＝10.0Hz，3H)，6.82(d，J＝7.2Hz，2H)，6.63(d，J＝5.9Hz，2H)，6.52(dd，J＝21.0，8.2Hz，3H)，6.22(d，J＝8.1Hz，2H)，5.89-5.77(m，1H)，4.66-4.39(m，1H)，4.13(d，J＝5.0Hz，1H)，3.24-3.02(m，8H)，2.98-2.66(m，9H)，2.40-2.31(m，2H)，2.29-2.16(m，2H)，2.13-2.01(m，2H)，1.87-1.76(m，2H)，1.72-1.63(m，2H)，1.65-1.56(m，2H)，1.46-1.37(m，2H)，1.31-1.13(m，4H)，1.12-0.95(m，2H)，0.87-0.79(m，2H).MS(ESI)m/z:806.6[M+H]+. 1 H NMR (400MHz, DMSO-d 6 ) δ11.08 (s, 1H), 9.25 (s, 1H), 7.93 (s, 1H), 7.53 (d, J = 9.0Hz, 1H), 7.26 (d, J = 9.4Hz, 1H), 7.12 (d, .J = 10.0Hz, 3H), 6.82 (d, J = 7.2Hz, 2H), 6.63 (d, J=5.9Hz, 2H), 6.52 (dd, J=21.0, 8.2Hz, 3H), 6.22 (d, J=8.1Hz, 2H), 5.89-5.77 (m, 1H), 4.66-4.39 (m, 1H), 4.13 (d, J=5. 0Hz, 1H), 3.24-3.02(m, 8H), 2.98-2.66(m, 9H), 2.40-2.31(m, 2H), 2.29-2.16(m, 2H), 2.13-2.01(m, 2H), 1.87-1.76(m, 2H), 1.72-1 .63(m,2H),1.65-1.56(m,2H),1.46-1.37(m,2H),1.31-1.13(m,4H),1.12-0.95(m,2H),0.87-0.79(m,2H).MS(ESI)m/z:806.6[M+H] + .

实施例10：N-(2，6-二氧代哌啶-3-基)-2-氟-4-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)苯甲酰胺的合成(化合物I-67)
Example 10: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)benzamide (Compound I-67)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：4-(3-氟-4-(甲氧羰基)苯基)-3，6-二氢吡啶-1(2H)-甲酸叔丁酯的合成
Step 1: Synthesis of tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

室温下，依次向反应瓶中加入甲基4-溴-2-氟苯甲酸酯(2.00g，8.58mmol)，4-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊二烯-2-基)-3，6-二氢吡啶-1(2H)-甲酸叔丁酯(2.78g，9.01mmol)，dppfPdCl2(0.31g，0.43mmol)，碳酸铯(7.00g，21.46mmol)，水(5mL)和二氧六环(20ml)。90℃下，氮气氛围，反应5h。反应完成后，降温至室温，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物棕色油状物2.50g，收率83％。At room temperature, methyl 4-bromo-2-fluorobenzoate (2.00 g, 8.58 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.78 g, 9.01 mmol), dppfPdCl 2 (0.31 g, 0.43 mmol), cesium carbonate (7.00 g, 21.46 mmol), water (5 mL) and dioxane (20 ml) were added to the reaction bottle in sequence. The reaction was carried out at 90° C. in a nitrogen atmosphere for 5 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, and the liquids were separated. After the organic phase was dried, PE/EA system column chromatography was used to obtain 2.50 g of the product as a brown oil with a yield of 83%.

步骤2：4-(1-(叔丁氧羰基)-1，2，3，6-四氢吡啶-4-基)-2-氟苯甲酸的合成
Step 2: Synthesis of 4-(1-(tert-butyloxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzoic acid

室温下，依次向反应瓶中加入4-(3-氟-4-(甲氧羰基)苯基)-3，6-二氢吡啶-1(2H)-甲酸叔丁酯(2.50g，7.78mmol)，NaOH(1.24g，31.11mmol)，MeOH(30ml)和H2O(10ml)，升温至50℃反应4h。反应完成后，脱溶，加HCl水溶液调至酸性，产物析出，过滤得到白色固体2.20g，收率92％。At room temperature, tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (2.50 g, 7.78 mmol), NaOH (1.24 g, 31.11 mmol), MeOH (30 ml) and H 2 O (10 ml) were added to the reaction bottle in sequence, and the temperature was raised to 50°C for 4 h. After the reaction was completed, the solvent was removed, and HCl aqueous solution was added to adjust the acidity. The product precipitated and filtered to obtain 2.20 g of a white solid with a yield of 92%.

步骤3：4-(4-((2，6-二氧代哌啶-3-基)氨甲酰基)-3-氟苯基)-3，6-二氢吡啶-1(2H)-甲酸叔丁酯的合成
Step 3: Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

室温下，依次向反应瓶中加入4-(1-(叔丁氧羰基)-1，2，3，6-四氢吡啶-4-基)-2-氟苯甲酸(0.20g，0.65mmol)，3-氨基哌啶-2，6-二酮盐酸盐(0.13g，0.78mmol)，HATU(0.37g，0.98mmol)，DIEA(0.25g，1.95mmol)和DMF(3ml)，室温搅拌反应2h。反应完成后，向反应液加入水(3mL)和饱和食盐水(3mL)，析出大量固体，过滤，滤饼溶于DCM，用无水硫酸镁干燥后直接进行下一步。At room temperature, 4-(1-(tert-butyloxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzoic acid (0.20 g, 0.65 mmol), 3-aminopiperidine-2,6-dione hydrochloride (0.13 g, 0.78 mmol), HATU (0.37 g, 0.98 mmol), DIEA (0.25 g, 1.95 mmol) and DMF (3 ml) were added to the reaction bottle in sequence, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, water (3 mL) and saturated brine (3 mL) were added to the reaction solution, and a large amount of solid was precipitated, which was filtered, and the filter cake was dissolved in DCM, dried over anhydrous magnesium sulfate, and then directly proceeded to the next step.

步骤4：N-(2，6-二氧代哌啶-3-基)-2-氟-4-(1，2，3，6-四氢吡啶-4-基)苯甲酰胺的合成
Step 4: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide

室温下，依次向反应瓶中加入4-(4-((2，6-二氧代哌啶-3-基)氨甲酰基)-3-氟苯基)-3，6-二氢吡啶-1(2H)-甲酸叔丁酯(0.27g，0.65mmol)和二氯甲烷(2mL)，溶清后加入盐酸/二氧六环(2mL)，室温搅拌反应3h。反应完成后，脱溶，得到粗品0.26g，直接进行下一步。At room temperature, tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (0.27 g, 0.65 mmol) and dichloromethane (2 mL) were added to the reaction bottle in sequence, and hydrochloric acid/dioxane (2 mL) was added after dissolving, and the reaction was stirred at room temperature for 3 h. After the reaction was completed, the solvent was removed to obtain 0.26 g of a crude product, which was directly carried out to the next step.

步骤5：4-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-1，2，3，6-四氢吡啶-4-基)-N-(2，6-二氧代哌啶-3-基)-2-氟苯甲酰胺的合成
Step 5: Synthesis of 4-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide

室温下，依次向反应瓶中加入N-(2，6-二氧代哌啶-3-基)-2-氟-4-(1，2，3，6-四氢吡啶-4-基)苯甲酰胺(0.15g，0.47mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.28g，0.47mmol)和二氯甲烷(5mL)，再加入TIPT(0.5mL)，室温搅拌16小时，再加入STAB(0.15g，0.71mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.21g，三步收率：62％。At room temperature, N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.15 g, 0.47 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.28 g, 0.47 mmol) and dichloromethane (5 mL) were added to the reaction bottle in sequence, and TIPT (0.5 mL) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.15 g, 0.71 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.21 g of the product with a three-step yield of 62%.

步骤6：N-(2，6-二氧代哌啶-3-基)-2-氟-4-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)苯甲酰胺的合成
Step 6: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)benzamide

室温下，依次向反应瓶中加入4-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-1，2，3，6-四氢吡啶-4-基)-N-(2，6-二氧代哌啶-3-基)-2-氟苯甲酰胺(0.21g，0.23mmol)，10％钯碳(0.10g)和THF(3mL)，置换氢气3-4次，室温搅拌反应24h。反应完成后，垫硅藻土过滤，滤饼使用THF淋洗，滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.01g，收率：5％。At room temperature, 4-(1-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (0.21 g, 0.23 mmol), 10% palladium on carbon (0.10 g) and THF (3 mL) were added to the reaction bottle in sequence, hydrogen was replaced 3-4 times, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, diatomaceous earth was used for filtration, the filter cake was rinsed with THF, the filtrate was desolvated, and DCM/MeOH system column chromatography was used to obtain 0.01 g of the product, with a yield of 5%.

1H NMR(400MHz，DMSO-d6)δ10.88(s，1H)，9.13(s，1H)，8.49(dd，J＝8.3，3.8Hz，1H)，7.64(dd，J＝11.1，4.9Hz，1H)，7.23-7.09(m，5H)，6.83(d，J＝7.1Hz，2H)，6.65-6.46(m，5H)，6.23(d，J＝8.2Hz，2H)，4.85-4.66(m，1H)，4.15(d，J＝4.9Hz，1H)，3.09-2.62(m，15H)，2.28-2.07(m，5H)，1.86-1.43(m，15H)，1.03-0.94(m，3H)，0.87-0.82(m，2H).MS(ESI)m/z:826.6[M+H]+. 1 H NMR (400MHz, DMSO-d 6 ) δ10.88 (s, 1H), 9.13 (s, 1H), 8.49 (dd, J=8.3, 3.8Hz, 1H), 7.64 (dd, J=11.1, 4.9Hz, 1H), 7.23-7.09 (m, 5H), 6.83 (d, J=7.1Hz, 2H), 6.65-6.46 (m, 5H), 6.23 (d, J=8.2Hz, 2 H), 4.85-4.66 (m, 1H), 4.15 (d, J=4.9Hz, 1H), 3.09-2.62 (m, 15H), 2.28-2.07 (m, 5H) ,1.86-1.43(m,15H),1.03-0.94(m,3H),0.87-0.82(m,2H).MS(ESI)m/z:826.6[M+H] + .

实施例11：3-(5-氟-6-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1-甲基-1H-吲唑-3-基)哌嗪-2，6-二酮的合成(化合物IV-1)
Example 11: Synthesis of 3-(5-fluoro-6-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperazine-2,6-dione (Compound IV-1)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：3-(2，6-双(苄氧)吡啶-3-基)-6-溴-5-氟-1-甲基-1H-吲唑的合成
Step 1: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole

室温下，依次向反应瓶中加入6-溴-5-氟-3-碘-1-甲基-1H-吲唑(1.00g，2.97mmol)，2，6-双(苄氧)-3-(4，4，5，5-四甲基-1，3，2-二氧杂环戊烷-2-基)吡啶(1.24g，2.97mmol)，碳酸钠(0.94g，8.90mmol)，四三苯基膦钯(0.34g，0.30mmol)，水(1mL)和二氧六环(10ml)，90℃下，氮气氛围，反应5h。反应完成后，降至室温，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物1.20g，收率81％。At room temperature, 6-bromo-5-fluoro-3-iodo-1-methyl-1H-indazole (1.00 g, 2.97 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridine (1.24 g, 2.97 mmol), sodium carbonate (0.94 g, 8.90 mmol), tetrakistriphenylphosphine palladium (0.34 g, 0.30 mmol), water (1 mL) and dioxane (10 ml) were added to the reaction bottle in sequence, and the mixture was reacted for 5 h at 90° C. in a nitrogen atmosphere. After the reaction was completed, the mixture was cooled to room temperature, ethyl acetate and water were added, and the liquid was separated. After the organic phase was dried, PE/EA system column chromatography was used to obtain 1.20 g of the product with a yield of 81%.

步骤2：4-(3-(2，6-双(苄氧)吡啶-3-基)-5-氟-1-甲基-1H-吲唑-6-基)哌嗪-1-甲酸叔丁酯的合成
Step 2: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入3-(2，6-双(苄氧)吡啶-3-基)-6-溴-5-氟-1-甲基-1H-吲唑(0.25g，0.50mmol)，1-Boc-哌嗪(0.28g，1.50mmol)，Pd2(dba)3(0.05g，0.05mmol)，10％三叔丁基膦甲苯溶液(200mg，0.10mmol)，叔丁醇钠(0.10g，1.00mmol)和甲苯(10ml)。100℃下，氮气氛围，反应5h。反应完成后，降温至室温，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物0.20g，收率66％。At room temperature, 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole (0.25 g, 0.50 mmol), 1-Boc-piperazine (0.28 g, 1.50 mmol), Pd2(dba)3 (0.05 g, 0.05 mmol), 10% tri-tert-butylphosphine toluene solution (200 mg, 0.10 mmol), sodium tert-butoxide (0.10 g, 1.00 mmol) and toluene (10 ml) were added to the reaction bottle in sequence. The reaction was carried out at 100° C. in a nitrogen atmosphere for 5 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, the liquid was separated, and the organic phase was dried and chromatographed on a PE/EA system column to obtain 0.20 g of the product with a yield of 66%.

步骤3：4-(3-(2，6-二氧代哌啶-3-基)-5-氟-1-甲基-1H-吲唑-6-基)哌嗪-1-甲酸叔丁基酯的合成
Step 3: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入4-(3-(2，6-双(苄氧)吡啶-3-基)-5-氟-1-甲基-1H-吲唑-6-基)哌嗪-1-甲酸叔丁酯(0.20g，0.33mmol)，10％Pd/C(0.02g)，四氢呋喃(5mL)和乙醇(5ml)，室温反应24h。反应完成后，过滤旋干，得到粗品0.13g，直接下一步。At room temperature, tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.20 g, 0.33 mmol), 10% Pd/C (0.02 g), tetrahydrofuran (5 mL) and ethanol (5 ml) were added to the reaction bottle in sequence and reacted at room temperature for 24 h. After the reaction was completed, the mixture was filtered and dried to obtain 0.13 g of a crude product, which was directly used in the next step.

步骤4：3-(5-氟-1-甲基-6-(哌嗪-1-基)-1H-吲唑-3-基)哌嗪-2，6-二酮的合成
Step 4: Synthesis of 3-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperazine-2,6-dione

室温下，依次向反应瓶中加入4-(3-(2，6-二氧代哌啶-3-基)-5-氟-1-甲基-1H-吲唑-6-基)哌嗪-1-甲酸叔丁基酯(0.13g，0.30mmol)和HCl二氧六环溶液(5ml)，室温反应2h。反应完成后，旋干，得到粗品0.11g，直接下一步。At room temperature, tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.13 g, 0.30 mmol) and HCl dioxane solution (5 ml) were added to the reaction bottle in sequence and reacted at room temperature for 2 h. After the reaction was completed, the mixture was spin-dried to obtain 0.11 g of a crude product, which was directly used for the next step.

步骤5：3-(6-(4-(((1R，2R)-2-((4-(4-(1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪1-基)-5-氟-1-甲基-1H-吲唑-3-基)哌啶-2，6-二酮的合成
Step 5: Synthesis of 3-(6-(4-(((1R,2R)-2-((4-(4-(1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(5-氟-1-甲基-6-(哌嗪-1-基)-1H-吲唑-3-基)哌嗪-2，6-二酮(0.15g，0.47mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.28g，0.47mmol)和二氯甲烷(5mL)，再加入TIPT(0.5mL)，室温搅拌16小时，再加入STAB(0.15g，0.71mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.21g，三步收率：62％。At room temperature, 3-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperazine-2,6-dione (0.15 g, 0.47 mmol), (1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.28 g, 0.47 mmol) and dichloromethane (5 mL) were added to the reaction bottle in sequence, and TIPT (0.5 mL) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.15 g, 0.71 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.21 g of the product with a three-step yield of 62%.

步骤6：3-(5-氟-6-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1-甲基-1H-吲唑-3-基)哌嗪-2，6-二酮的合成
Step 6: Synthesis of 3-(5-fluoro-6-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperazine-2,6-dione

室温下，依次向反应瓶中加入3-(6-(4-(((1R，2R)-2-((4-(4-(1R、2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪1-基)-5-氟-1-甲基-1H-吲唑-3-基)哌啶-2，6-二酮(0.21g，0.23mmol)，10％钯碳(0.10g)和THF(3mL)，置换氢气3-4次，室温搅拌反应24h。反应完成后，垫硅藻土过滤，滤饼使用THF淋洗，滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.07g，收率：37％。At room temperature, 3-(6-(4-(((1R, 2R)-2-((4-(4-(1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (0.21 g, 0.23 mmol), 10% palladium on carbon (0.10 g) and THF (3 mL) were added to the reaction bottle in sequence, hydrogen was replaced 3-4 times, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, diatomaceous earth was used for filtration, the filter cake was rinsed with THF, the filtrate was desolvated, and DCM/MeOH system column chromatography was used to obtain 0.07 g of the product, with a yield of 37%.

1H NMR(400MHz，DMSO-d6)δ10.88(s，1H)，9.15(d，J＝4.4Hz，1H)，7.48(d，J＝12.6Hz，1H)，7.11(dt，J＝15.7，7.3Hz，4H)，6.83(d，J＝7.2Hz，2H)，6.67-6.54(m，4H)，6.48(dd，J＝8.3，2.5Hz，1H)，6.23(d，J＝8.1Hz，2H)，4.28(dd，J＝9.8，5.1Hz，1H)，4.14(d，J＝5.0Hz，1H)，3.91(d，J＝17.0Hz，3H)，3.24-2.84(m，15H)，2.77-2.53(m，7H)，2.41-2.29(m，2H)，2.26-1.98(m，3H)，1.88-1.40(m，7H)，1.28-1.15(m，3H)，1.07-0.93(m，2H).MS(ESI)m/z:838.6[M+H]+. 1 H NMR (400MHz, DMSO-d 6 ) δ10.88 (s, 1H), 9.15 (d, J = 4.4Hz, 1H), 7.48 (d, J = 12.6Hz, 1H), 7.11 (dt, J = 15.7, 7.3Hz, 4H), 6.83 (d, J = 7 .2Hz, 2H), 6.67-6.54 (m, 4H), 6.48 (dd, J=8.3, 2.5Hz, 1H), 6.23 (d, J=8.1Hz, 2H), 4.28 (dd, J=9.8, 5.1Hz, 1H), 4.14 (d, J=5.0Hz, 1H), 3.91 (d, J=17.0Hz, 3H), 3.24-2.84 (m, 15H), 2.77-2.53 (m, 7H), 2.41-2.29 (m, 2H), 2.26-1.98(m, 3H), 1.88-1.40(m, 7H), 1.28-1.15(m, 3H), 1.07-0.93(m, 2H).MS(ESI)m/z:838.6[M+H] + .

实施例12：3-(6-氟-5-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1-甲基-1H-吲唑-3-基)哌嗪-2，6-二酮的合成(化合物VI-5)
Example 12: Synthesis of 3-(6-fluoro-5-(4-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperazine-2,6-dione (Compound VI-5)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：3-(5-溴-6-氟-1H-吲唑-1-基)-1-(4-甲氧基苯基甲基)哌嗪-2，6-二酮的合成
Step 1: Synthesis of 3-(5-bromo-6-fluoro-1H-indazol-1-yl)-1-(4-methoxyphenylmethyl)piperazine-2,6-dione

室温下，依次向反应瓶中加入5-溴-6-氟-1H-吲唑(0.50g，2.54mmol)，叔丁醇钾(0.34g，3.05mmol)和四氢呋喃(15ml)，降温至0℃搅拌30分钟，再加入1-(4-甲氧基苄基)-2，6-二氧代哌啶-3-基三氟甲磺酸酯(0.97g，2.54mmol)，加完后恢复室温反应3h。反应完成后，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物0.47g，收率43％。步骤2：4-(6-氟-1-(1-(4-甲氧基苯甲基)-2，6-二氧代哌啶-3-基)-1H-吲唑-5-基)哌嗪-1-甲酸叔丁酯的合成
At room temperature, 5-bromo-6-fluoro-1H-indazole (0.50 g, 2.54 mmol), potassium tert-butoxide (0.34 g, 3.05 mmol) and tetrahydrofuran (15 ml) were added to the reaction bottle in sequence, the temperature was lowered to 0°C and stirred for 30 minutes, and then 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (0.97 g, 2.54 mmol) was added. After the addition, the reaction was restored to room temperature for 3 hours. After the reaction was completed, ethyl acetate and water were added, the liquids were separated, and the organic phase was dried and chromatographed using a PE/EA system column to obtain 0.47 g of the product with a yield of 43%. Step 2: Synthesis of tert-butyl 4-(6-fluoro-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1H-indazole-5-yl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入3-(5-溴-6-氟-1H-吲唑-1-基)-1-(4-甲氧基苯基甲基)哌嗪-2，6-二酮(0.47g，1.09mmol)，1-Boc-哌嗪(0.20g，1.09mmol)，PEPPSI IHept-Cl(0.11g，0.11mmol)，碳酸铯(1.07g，3.28mmol)，4A分子筛(0.11g)和1，4-二氧六环(15ml)，置换氮气3-4次，升温至100℃反应16h。反应完成后，降温至室温，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物0.13g，收率21％。At room temperature, 3-(5-bromo-6-fluoro-1H-indazol-1-yl)-1-(4-methoxyphenylmethyl)piperazine-2,6-dione (0.47 g, 1.09 mmol), 1-Boc-piperazine (0.20 g, 1.09 mmol), PEPPSI IHept-Cl (0.11 g, 0.11 mmol), cesium carbonate (1.07 g, 3.28 mmol), 4A molecular sieve (0.11 g) and 1,4-dioxane (15 ml) were added to the reaction bottle in sequence, nitrogen was replaced 3-4 times, and the temperature was raised to 100°C for 16 hours. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, the liquids were separated, and the organic phase was dried and chromatographed using a PE/EA system column to obtain 0.13 g of the product with a yield of 21%.

步骤3：3-(6-氟-5-(哌嗪-1-基)-1H-吲唑-1-基)哌嗪-2，6-二酮的合成
Step 3: Synthesis of 3-(6-fluoro-5-(piperazin-1-yl)-1H-indazol-1-yl)piperazine-2,6-dione

室温下，依次向反应瓶中加入4-(6-氟-1-(1-(4-甲氧基苯甲基)-2，6-二氧代哌啶-3-基)-1H-吲唑-5-基)哌嗪-1-甲酸叔丁酯(0.13g，0.23mmol)，三氟乙酸(3ml)和TfOH(0.5ml)，升温65℃搅拌反应2h。反应完成后，脱溶，使用反向柱层析(乙腈/水)体系柱层析，得到粗品0.07g，直接下一步。At room temperature, tert-butyl 4-(6-fluoro-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1H-indazol-5-yl)piperazine-1-carboxylate (0.13 g, 0.23 mmol), trifluoroacetic acid (3 ml) and TfOH (0.5 ml) were added to the reaction bottle in sequence, and the temperature was raised to 65°C and stirred for 2 hours. After the reaction was completed, the solvent was removed and the product was chromatographed using a reverse column chromatography (acetonitrile/water) system to obtain 0.07 g of a crude product, which was directly used in the next step.

步骤5：3-(5-(4-(((1R，2R)-2-((4-(4-(1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪1-基)-6-氟-1H-吲唑-1-基)哌啶-2，6-二酮的合成
Step 5: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-(1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-6-fluoro-1H-indazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(6-氟-5-(哌嗪-1-基)-1H-吲唑-1-基)哌嗪-2，6-二酮(0.15g，0.47mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.28g，0.47mmol)和二氯甲烷(5mL)，再加入TIPT(0.5mL)，室温搅拌16小时，再加入STAB(0.15g，0.71mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.21g，三步收率：62％。At room temperature, 3-(6-fluoro-5-(piperazine-1-yl)-1H-indazol-1-yl)piperazine-2,6-dione (0.15 g, 0.47 mmol), (1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-yl)methyl)cyclohexane-1-carbaldehyde (0.28 g, 0.47 mmol) and dichloromethane (5 mL) were added to the reaction bottle in sequence, and TIPT (0.5 mL) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.15 g, 0.71 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.21 g of the product with a three-step yield of 62%.

步骤6：3-(6-氟-5-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1-甲基-1H-吲唑-3-基)哌嗪-2，6-二酮的合成
Step 6: Synthesis of 3-(6-fluoro-5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperazine-2,6-dione

室温下，依次向反应瓶中加入3-(5-(4-(((1R，2R)-2-((4-(4-(1R、2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪1-基)-6-氟-1H-吲唑-1-基)哌啶-2，6-二酮(0.21g，0.23mmol)，10％钯碳(0.10g)和THF(3mL)，置换氢气3-4次，室温搅拌反应24h。反应完成后，垫硅藻土过滤，滤饼使用THF淋洗，滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.07g，收率：37％。At room temperature, 3-(5-(4-(((1R, 2R)-2-((4-(4-(1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-6-fluoro-1H-indazol-1-yl)piperidine-2,6-dione (0.21 g, 0.23 mmol), 10% palladium on carbon (0.10 g) and THF (3 mL) were added to the reaction bottle in sequence, hydrogen was replaced 3-4 times, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, diatomaceous earth was used for filtration, the filter cake was rinsed with THF, the filtrate was desolvated, and DCM/MeOH system column chromatography was used to obtain 0.07 g of the product, with a yield of 37%.

1H NMR(400MHz，DMSO-d6)δ11.11(s，1H)，9.14(s，1H)，8.00(s，1H)，7.55(d，J＝12.4Hz，1H)，7.37(d，J＝8.2Hz，1H)，7.10(d，J＝9.5Hz，2H)，6.81(dd，J＝7.5，3.7Hz，2H)，6.65-6.56(m，4H)，6.48(dd，J＝8.3，2.5Hz，1H)，6.26-6.21(m，2H)，5.76(dd，J＝11.5，5.1Hz，1H)，4.15(d，J＝5.0Hz，1H)，3.17-2.89(m，17H)，2.85-2.55(m，8H)，2.26-2.21(m，1H)，2.11-2.05(m，1H)，1.81-1.43(m，8H)，1.26-1.16(m，3H)，1.06-0.95(m，2H).MS(ESI)m/z:824.5[M+H]+. 1 H NMR (400MHz, DMSO-d 6 )δ11.11 (s, 1H), 9.14 (s, 1H), 8.00 (s, 1H), 7.55 (d, J = 12.4Hz, 1H), 7.37 (d, J = 8.2Hz, 1H), 7.10 (d, J = 9.5H z, 2H), 6.81 (dd, J=7.5, 3.7Hz, 2H), 6.65-6.56 (m, 4H), 6.48 (dd, J=8.3, 2.5Hz, 1H), 6.26-6.21 (m, 2H), 5. 76 (dd, J=11.5, 5.1Hz, 1H), 4.15 (d, J=5.0Hz, 1H), 3.17-2.89 (m, 17H), 2.85-2.55 (m, 8H), 2.26-2.21 (m, 1 H), 2.11-2.05(m, 1H), 1.81-1.43(m, 8H), 1.26-1.16(m, 3H), 1.06-0.95(m, 2H).MS(ESI)m/z:824.5[M+H] + .

实施例13：N-(2，6-二氧哌啶-3-基)-5-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)吡啶甲酰胺的合成(化合物III-3)
Example 13: Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)picolinamide (Compound III-3)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：1′-(叔丁基)6-甲基3′，6′-二氢-[3，4′-联吡啶]-1′，6(2′H)-二羧酸酯的合成
Step 1: Synthesis of 1′-(tert-butyl)6-methyl 3′,6′-dihydro-[3,4′-bipyridine]-1′,6(2′H)-dicarboxylate

室温下，依次向反应瓶中加入5-溴吡啶-2-羧酸甲酯(1.00g，4.63mmol)，N-Boc-1，2，5，6-四氢吡啶-4-硼酸频哪醇酯(2.15g，6.94mmol)，Pd(dppf)Cl2(0.34g，0.46mmol)，Cs2CO3(3.00g，9.26mmol)，Do(10ml)和H2O(2ml)，置换氮气3-4次，升温至100℃反应3h。反应完成后，降温至室温，过滤，滤液浓缩，使用PE/EA体系柱层析，得到产物棕色油状物1.25g，收率83％。At room temperature, 5-bromopyridine-2-carboxylic acid methyl ester (1.00 g, 4.63 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (2.15 g, 6.94 mmol), Pd(dppf)Cl 2 (0.34 g, 0.46 mmol), Cs2CO3 (3.00 g, 9.26 mmol), Do (10 ml) and H 2 O (2 ml) were added to the reaction bottle in sequence, nitrogen was replaced 3-4 times, and the temperature was raised to 100° C. for reaction for 3 h. After the reaction was completed, the temperature was lowered to room temperature, filtered, the filtrate was concentrated, and PE/EA system column chromatography was used to obtain 1.25 g of the product as a brown oil with a yield of 83%.

步骤2：1′-(叔丁氧羰基)-1′，2′，3′，6′-四氢-[3，4′-联吡啶]-6-羧酸的合成
Step 2: Synthesis of 1′-(tert-butyloxycarbonyl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carboxylic acid

室温下，依次向反应瓶中加入叔丁基4-(6-(甲氧羰基)吡啶-3-基)哌嗪-1-羧酸甲酯(1.25g，3.93mmol)，NaOH(0.63g，15.72mmol)，MeOH(15ml)和H2O(5ml)，升温至50℃反应4h。反应完成后，脱溶，加HCl水溶液调至酸性，DCM萃取三次，得到黄色固体1.10g，收率92％。At room temperature, tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylic acid methyl ester (1.25 g, 3.93 mmol), NaOH (0.63 g, 15.72 mmol), MeOH (15 ml) and H 2 O (5 ml) were added to the reaction bottle in sequence, and the temperature was raised to 50°C for 4 h. After the reaction was completed, the solvent was removed, HCl aqueous solution was added to adjust to acidity, and DCM was extracted three times to obtain 1.10 g of a yellow solid with a yield of 92%.

步骤3：叔丁基6-((2，6-二氧代哌啶-3-基)氨甲酰基)-3′，6′-二氢-[3，4′-联吡啶]-1′(2′H)-羧酸酯的合成
Step 3: Synthesis of tert-butyl 6-((2,6-dioxopiperidin-3-yl)carbamoyl)-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate

室温下，依次向反应瓶中加入1′-(叔丁氧羰基)-1′，2′，3′，6′-四氢-[3，4′-联吡啶]-6-羧酸(0.20g，0.65mmol)，3-氨基哌啶-2，6-二酮盐酸盐(0.13g，0.78mmol)，HATU(0.37g，0.98mmol)，DIEA(0.25g，1.95mmol)和DMF(3ml)，室温搅拌反应2h。反应完成后，向反应液加入水(3mL)和饱和食盐水(3mL)，析出大量固体，过滤，滤饼溶于DCM，用无水硫酸镁干燥后直接进行下一步。At room temperature, 1'-(tert-butyloxycarbonyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxylic acid (0.20 g, 0.65 mmol), 3-aminopiperidine-2,6-dione hydrochloride (0.13 g, 0.78 mmol), HATU (0.37 g, 0.98 mmol), DIEA (0.25 g, 1.95 mmol) and DMF (3 ml) were added to the reaction bottle in sequence, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, water (3 mL) and saturated brine (3 mL) were added to the reaction solution, and a large amount of solid was precipitated, which was filtered, and the filter cake was dissolved in DCM, dried over anhydrous magnesium sulfate, and then directly proceeded to the next step.

步骤4：N-(2，6-二氧代哌啶-3-基)-1′，2′，3′，6′-四氢-[3，4′-联吡啶]-6-甲酰胺的合成
Step 4: Synthesis of N-(2,6-dioxopiperidin-3-yl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carboxamide

室温下，依次向反应瓶中加入叔丁基6-((2，6-二氧代哌啶-3-基)氨甲酰基)-3′，6′-二氢-[3，4′-联吡啶]-1′(2′H)-羧酸酯(0.27mg，0.65mmol)和二氯甲烷(2ml)，溶清后加入盐酸/二氧六环(2ml)，室温搅拌反应3h。反应完成后，脱溶，得到粗品0.26g，直接进行下一步。At room temperature, tert-butyl 6-((2,6-dioxopiperidin-3-yl)carbamoyl)-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate (0.27 mg, 0.65 mmol) and dichloromethane (2 ml) were added to the reaction bottle in sequence, and hydrochloric acid/dioxane (2 ml) was added after dissolving, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed to obtain 0.26 g of a crude product, which was directly carried out to the next step.

步骤5：1′-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-N-(2，6-二氧代哌啶-3-基)-1′，2′，3′，6′-四氢-[3，4′-联吡啶]-6-甲酰胺的合成
Step 5: Synthesis of 1′-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-N-(2,6-dioxopiperidin-3-yl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carboxamide

室温下，依次向反应瓶中加入N-(2，6-二氧代哌啶-3-基)-1′，2′，3′，6′-四氢-[3，4′-联吡啶]-6-甲酰胺(0.15g，0.47mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.28g，0.47mmol)和二氯甲烷(5ml)，再加入TIPT(0.45ml)，室温搅拌16小时，再加入STAB(0.15g，0.71mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.21g，三步收率：62％。At room temperature, N-(2,6-dioxopiperidin-3-yl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carboxamide (0.15 g, 0.47 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carboxaldehyde (0.28 g, 0.47 mmol) and dichloromethane (5 ml) were added to the reaction bottle in sequence, and TIPT (0.45 ml) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.15 g, 0.71 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.21 g of the product with a three-step yield of 62%.

步骤6：N-(2，6-二氧代哌啶-3-基)-5-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)吡啶-2-甲酰胺的合成
Step 6: Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)pyridine-2-carboxamide

室温下，依次向反应瓶中加入1′-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-N-(2，6-二氧代哌啶-3-基)-1′，2′，3′，6′-四氢-[3，4′-联吡啶]-6-甲酰胺(0.16g，0.18mmol)，10％钯碳(0.05g)和THF(3ml)，置换氢气3-4次，室温搅拌反应24h。反应完成后，垫硅藻土过滤，滤饼使用THF淋洗，滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.033g，入库0.028g，收率：22.9％。At room temperature, 1′-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-N-(2,6-dioxopiperidin-3-yl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carboxamide (0.16 g, 0.18 mmol), 10% palladium on carbon (0.05 g) and THF (3 ml) were added to the reaction bottle in sequence, and the hydrogen was replaced 3-4 times. The reaction was stirred at room temperature for 24 h. After the reaction was completed, diatomaceous earth was used for filtration, the filter cake was eluted with THF, the filtrate was desolvated, and DCM/MeOH system column chromatography was used to obtain 0.033 g of product, 0.028 g was put into storage, and the yield was 22.9%.

1H NMR(400MHz，DMSO-d6)δ10.88(s，1H)，9.15(s，1H)，9.03(d，J＝8.5Hz，1H)，8.58(s，1H)，8.01(d，J＝8.2Hz，1H)，7.88(d，J＝8.4Hz，1H)，7.11(q，J＝10.0，8.6Hz，3H)，6.82(d，J＝7.3Hz，2H)，6.64-6.60(m，2H)，6.55(d，J＝8.5Hz，2H)，6.48(d，J＝8.5Hz，1H)，6.22(d，J＝8.2Hz，2H)，4.79(t，J＝6.8Hz，1H)，4.14(d，J＝5.1Hz，1H)，3.17(s，1H)，3.03-2.96(m，4H)，2.82-2.75(m，2H)，2.54(s，2H)，2.22(dd，J＝12.6，4.2Hz，3H)，2.12-1.96(m，4H)，1.87(d，J＝37.5Hz，8H)，1.72-1.66(m，2H)，1.62(s，2H)，1.50(dd，J＝12.5，7.1Hz，2H)，1.40(s，1H)，1.22(d，J＝11.7Hz，4H)，1.00(p，J＝9.6，8.5Hz，3H)，0.85(q，J＝8.7，7.9Hz，2H).MS(ESI)m/z:809.6[M+H]+. 1 H NMR (400MHz, DMSO-d6) δ10.88 (s, 1H), 9.15 (s, 1H), 9.03 (d, J=8.5Hz, 1H), 8.58 (s, 1H), 8.01 (d, J = 8.2Hz, 1H), 7.88 (d, J = 8.4Hz, 1H), 7.11 (q, J = 10.0, 8.6Hz, 3 H), 6.82 (d, J=7.3Hz, 2H), 6.64-6.60 (m, 2H), 6.55 (d, J=8.5Hz, 2H), 6.48 (d, J= 8.5Hz, 1H), 6.22 (d, J=8.2Hz, 2H), 4.79 (t, J=6.8Hz, 1H), 4.14 (d, J=5.1Hz, 1H), 3.17 (s, 1H), 3.03-2.96 (m, 4H), 2.82-2.75 (m, 2H), 2.54 (s, 2H), 2.22 (dd, J=12 .6, 4.2Hz, 3H), 2.12-1.96 (m, 4H), 1.87 (d, J=37.5Hz, 8H), 1.72-1.66 (m, 2H), 1 .62 (s, 2H), 1.50 (dd, J=12.5, 7.1Hz, 2H), 1.40 (s, 1H), 1.22 (d, J=11.7Hz, 4H), 1.00 (p, J=9.6, 8.5Hz, 3H), 0.85 (q, J=8.7, 7.9Hz, 2H).MS (ESI) m/z: 809.6[M+H] + .

实施例14：3-(5-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-3-甲基-1H-吲唑-1-基)哌啶-2，6-二酮的合成(化合物VI-8)
Example 14: Synthesis of 3-(5-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (Compound VI-8)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：5-(4-(((1S，2S)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-N-(2，6-二氧代哌啶-3-基)吡啶-3-甲酰胺的合成
Step 1: Synthesis of 5-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridine-3-carboxamide

室温下，依次向反应瓶中加入3-(5-溴-3-甲基-1H-吲唑-1-基)-1-(4-甲氧基苯甲基)哌啶-2，6-二酮(0.40g，0.90mmol)，N-Boc-1，2，5，6-四氢吡啶-4-硼酸频哪醇酯(0.28g，0.90mmol)，Xphos-Pd-G2(0.07g，0.09mmol)，K3PO4(0.38g，1.81mmol)，Do(5mL)和H2O(1ml)，置换氮气3-4次，升温至80℃反应2h。反应完成后，降温至室温，浓缩，使用PE/EA体系柱层析，得到白色固体0.30g，收率61％。At room temperature, 3-(5-bromo-3-methyl-1H-indazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (0.40 g, 0.90 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (0.28 g, 0.90 mmol), Xphos-Pd-G2 (0.07 g, 0.09 mmol), K3PO4 (0.38 g, 1.81 mmol), Do (5 mL) and H2O (1 ml) were added to the reaction bottle in sequence, nitrogen was replaced 3-4 times, and the temperature was raised to 80°C for reaction for 2 h. After the reaction was completed, the temperature was lowered to room temperature, concentrated, and chromatographed using a PE/EA system column to obtain 0.30 g of a white solid with a yield of 61%.

步骤2：3-(3-甲基-5-(1，2，3，6-四氢吡啶-4-基)-1H-吲唑-1-基)哌啶-2，6-二酮的合成
Step 2: Synthesis of 3-(3-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione

室温下，将5-(4-(((1S，2S)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-N-(2，6-二氧代哌啶-3-基)吡啶-3-甲酰胺(0.27g，0.50mmol)溶于TFA(6mL)，加入TfOH(1mL)，65℃反应5h。反应完成后，反应液浓缩，使用反相柱层析(H2O/ACN)纯化，得0.12g黄色固体，收率74.6％。At room temperature, 5-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridine-3-carboxamide (0.27 g, 0.50 mmol) was dissolved in TFA (6 mL), TfOH (1 mL) was added, and the mixture was reacted at 65° C. for 5 h. After the reaction was completed, the reaction solution was concentrated and purified by reverse phase column chromatography (H 2 O/ACN) to obtain 0.12 g of a yellow solid with a yield of 74.6%.

步骤3：3-(5-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)-1，2，3，6-四氢吡啶-4-基)-3-甲基-1H-吲唑-1-基)哌啶-2，6-二酮的合成
Step 3: Synthesis of 3-(5-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(3-甲基-5-(1，2，3，6-四氢吡啶-4-基)-1H-吲唑-1-基)哌啶-2，6-二酮(0.12g，0.37mmol)，(1S，2S)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.22g，0.37mmol)和二氯甲烷(5ml)，再加入TIPT(0.4ml)，室温搅拌16小时，再加入STAB(0.12g，0.55mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到白色固体0.06g，收率：16.4％。At room temperature, 3-(3-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione (0.12 g, 0.37 mmol), (1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.22 g, 0.37 mmol) and dichloromethane (5 ml) were added to the reaction bottle in sequence, and TIPT (0.4 ml) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.12 g, 0.55 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.06 g of a white solid with a yield of 16.4%.

步骤4：3-(5-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-3-甲基-1H-吲唑-1-基)哌啶-2，6-二酮的合成
Step 4: Synthesis of 3-(5-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(5-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)-1，2，3，6-四氢吡啶-4-基)-3-甲基-1H-吲唑-1-基)哌啶-2，6-二酮(0.10g，0.11mmol)，10％钯碳(0.05g)和THF(3ml)，置换氢气3-4次，30℃搅拌反应24h。反应完成后，垫硅藻土过滤，滤饼使用THF淋洗，滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.006g，入库0.002g，收率：6.7％。At room temperature, 3-(5-(1-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (0.10 g, 0.11 mmol), 10% palladium on carbon (0.05 g) and THF (3 ml) were added to the reaction bottle in sequence, the hydrogen was replaced 3-4 times, and the reaction was stirred at 30°C for 24 h. After the reaction was completed, the mixture was filtered with diatomaceous earth, the filter cake was washed with THF, the filtrate was desolvated, and DCM/MeOH system column chromatography was used to obtain 0.006 g of the product, 0.002 g was put into storage, and the yield was 6.7%.

1H NMR(400MHz，DMSO-d6)δ11.07(s，1H)，9.15(d，J＝7.1Hz，1H)，7.51-7.43(m，2H)，7.31(d，J＝8.6Hz，1H)，7.08(d，J＝7.3Hz，2H)，6.81(d，J＝7.8Hz，2H)，6.64-6.57(m，4H)，6.48(dd，J＝8.2，2.6Hz，1H)，6.24(d，J＝8.2Hz，2H)，5.73(dd，J＝11.8，5.2Hz，1H)，4.39(t，J＝5.2Hz，1H)，4.15(d，J＝5.1Hz，1H)，2.98-2.85(m，7H)，2.72(qd，J＝13.9，11.0，4.5Hz，5H)，2.37-2.29(m，3H)，2.21(q，J＝8.3，7.4Hz，2H)，2.14-1.88(m，6H)，1.78-1.65(m，6H)，1.43(h，J＝3.1Hz，2H)，1.30(s，8H)，1.10-0.77(m，4H).MS(ESI)m/z:819.7[M+H]+. 1 H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 9.15 (d, J=7.1Hz, 1H), 7.51-7.43 (m, 2H), 7.31 (d, J=8.6Hz, 1H), 7.08 (d, J=7.3Hz, 2H), 6. 81 (d, J=7.8Hz, 2H), 6.64-6.57 (m, 4H), 6.48 (dd, J=8.2, 2.6Hz, 1H), 6.24 (d, J=8.2Hz, 2H), 5.73 (dd, J=11.8, 5.2Hz, 1H), 4.39 (t, J=5.2Hz, 1H), 4.15 (d, J=5.1Hz, 1H), 2.98-2.85 (m, 7H), 2.72 (qd, J=13.9, 11.0, 4.5Hz, 5H), 2.37-2.29 (m, 3H), 2.21 (q, J=8.3, 7 .4Hz, 2H), 2.14-1.88(m, 6H), 1.78-1.65(m, 6H), 1.43(h, J=3.1Hz, 2H), 1.30(s, 8H), 1.10-0.77(m, 4H).MS(ESI)m/z:819.7[M+H] + .

实施例15：3-(6-氟-5-(1-(((1R，2R)-2-((4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-3-甲基-1H-吲唑-1-基)哌啶-2，6-二酮的合成(化合物VI-9)
Example 15: Synthesis of 3-(6-fluoro-5-(1-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (Compound VI-9)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：3-(5-溴-6-氟-3-甲基-1h-吲唑-1-基)-1-(4-甲氧基苄基)哌啶-2，6-二酮的合成
Step 1: Synthesis of 3-(5-bromo-6-fluoro-3-methyl-1h-indazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

室温下，依次向反应瓶中加入5-溴-6-氟-3-甲基吲唑(0.50g，2.18mmol)，叔丁醇钾(0.29g，2.62mmol)和四氢呋喃(15ml)，降温至0℃搅拌30分钟，再加入1-(4-甲氧基苄基)-2，6-二氧代哌啶-3-基三氟甲磺酸酯(0.83g，2.18mmol)，加完后恢复室温反应3h。反应完成后，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物0.88g，收率44％。At room temperature, 5-bromo-6-fluoro-3-methylindazole (0.50 g, 2.18 mmol), potassium tert-butoxide (0.29 g, 2.62 mmol) and tetrahydrofuran (15 ml) were added to the reaction bottle in sequence, the temperature was lowered to 0°C and stirred for 30 minutes, and then 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (0.83 g, 2.18 mmol) was added, and the reaction was restored to room temperature for 3 hours after the addition. After the reaction was completed, ethyl acetate and water were added, the liquids were separated, and the organic phase was dried and chromatographed using a PE/EA system column to obtain 0.88 g of the product with a yield of 44%.

步骤2：4-(6-氟-1-(1-(4-甲氧基苄基)-2，6-二氧代哌啶-3-基)-3-甲基-1H-吲唑-5-基)-3，6-二氢吡啶-1(2H)-甲酸叔丁酯的合成
Step 2: Synthesis of tert-butyl 4-(6-fluoro-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

室温下，依次向反应瓶中加入3-(5-溴-6-氟-3-甲基-1h-吲唑-1-基)-1-(4-甲氧基苄基)哌啶-2，6-二酮(0.88g，1.91mmol)，N-Boc-1，2，5，6-四氢吡啶-4-硼酸频哪醇酯(0.59g，1.91mmol)，Xphos-Pd-G2(0.16g，0.20mmol)，磷酸钾(0.81g，3.82mmol)，水(3ml)和1，4-二氧六环(10ml)，置换氮气3-4次，升温至80℃反应4h。反应完成后，降温至室温，脱溶，加入乙酸乙酯稀释，垫硅藻土过滤，滤液干燥后，脱溶，使用PE/EA体系柱层析，得到产物0.80g，收率80％。At room temperature, 3-(5-bromo-6-fluoro-3-methyl-1h-indazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (0.88 g, 1.91 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (0.59 g, 1.91 mmol), Xphos-Pd-G2 (0.16 g, 0.20 mmol), potassium phosphate (0.81 g, 3.82 mmol), water (3 ml) and 1,4-dioxane (10 ml) were added to the reaction bottle in sequence, nitrogen was replaced 3-4 times, and the temperature was raised to 80° C. for 4 hours. After the reaction was completed, the temperature was lowered to room temperature, desolventized, ethyl acetate was added to dilute, diatomaceous earth was padded and filtered, the filtrate was dried, desolventized, and PE/EA system column chromatography was used to obtain 0.80 g of the product with a yield of 80%.

步骤3：4-(6-氟-1-(1-(4-甲氧基苄基)-2，6-二氧代哌啶-3-基)-3-甲基-1H-吲唑-5-基)哌啶-1-甲酸叔丁酯的合成
Step 3: Synthesis of tert-butyl 4-(6-fluoro-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-5-yl)piperidine-1-carboxylate

室温下，依次向反应瓶中加入4-(6-氟-1-(1-(4-甲氧基苄基)-2，6-二氧代哌啶-3-基)-3-甲基-1H-吲唑-5-基)-3，6-二氢吡啶-1(2H)-甲酸叔丁酯(0.80g，1.42mmol)和四氢呋喃(15ml)，加入10％钯碳(0.08g)，置换氢气3-4次，室温搅拌反应16h。反应完成后，垫硅藻土过滤，脱溶，得到产物0.50g，直接下一步。At room temperature, 4-(6-fluoro-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.80 g, 1.42 mmol) and tetrahydrofuran (15 ml) were added to the reaction bottle in sequence, and 10% palladium carbon (0.08 g) was added, and hydrogen was replaced 3-4 times. The reaction was stirred at room temperature for 16 hours. After the reaction was completed, diatomaceous earth was used for filtration and solvent removal to obtain 0.50 g of the product, which was directly used for the next step.

步骤4：3-(6-氟-3-甲基-5-(哌啶-4-基)-1h-吲唑-1-基)哌啶-2，6-二酮的合成
Step 4: Synthesis of 3-(6-fluoro-3-methyl-5-(piperidin-4-yl)-1h-indazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入4-(6-氟-1-(1-(4-甲氧基苄基)-2，6-二氧代哌啶-3-基)-3-甲基-1H-吲唑-5-基)哌啶-1-甲酸叔丁酯(0.50g，0.89mmol)，三氟乙酸(3ml)和TfOH(0.5ml)，升温65℃搅拌反应2h。反应完成后，脱溶，使用反向柱层析(乙腈/水)体系柱层析，得到粗品0.20g，直接下一步。At room temperature, tert-butyl 4-(6-fluoro-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-5-yl)piperidine-1-carboxylate (0.50 g, 0.89 mmol), trifluoroacetic acid (3 ml) and TfOH (0.5 ml) were added to the reaction bottle in sequence, and the temperature was raised to 65°C and stirred for 2 hours. After the reaction was completed, the solvent was removed and the mixture was chromatographed using a reverse column chromatography (acetonitrile/water) system to obtain 0.20 g of a crude product, which was directly used in the next step.

步骤5：3-(5-(1-(((1R，2R)-2-((4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-6-氟-3-甲基-1H-吲唑-1-基)哌啶-2，6-二酮的合成
Step 5: Synthesis of 3-(5-(1-(((1R,2R)-2-((4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-6-fluoro-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(6-氟-3-甲基-5-(哌啶-4-基)-1h-茚唑-1-基)哌啶-2，6-二酮(0.20g，0.58mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.35g，0.58mmol)和二氯甲烷(10ml)，再加入TIPT(0.5ml)，室温搅拌16小时，再加入STAB(0.25g，0.1.16mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.15g，收率：28％。At room temperature, 3-(6-fluoro-3-methyl-5-(piperidin-4-yl)-1h-indazol-1-yl)piperidine-2,6-dione (0.20 g, 0.58 mmol), (1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.35 g, 0.58 mmol) and dichloromethane (10 ml) were added to the reaction bottle in sequence, and TIPT (0.5 ml) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.25 g, 0.1.16 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.15 g of the product with a yield of 28%.

步骤6：3-(6-氟-5-(1-(((1R，2R)-2-((4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-3-甲基-1H-吲唑-1-基)哌啶-2，6-二酮的合成
Step 6: Synthesis of 3-(6-fluoro-5-(1-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(5-(1-(((1R，2R)-2-((4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-6-氟-3-甲基-1H-吲唑-1-基)哌啶-2，6-二酮(0.15g，0.16mmol)，10％钯碳(0.02g)和四氢呋喃(10ml)，再加入置换氢气3-4次，室温搅拌反应24h。反应完成后，垫硅藻土过滤，滤饼使用四氢呋喃淋洗滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.05g，收率：37％。At room temperature, 3-(5-(1-(((1R, 2R)-2-((4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-6-fluoro-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (0.15 g, 0.16 mmol), 10% palladium on carbon (0.02 g) and tetrahydrofuran (10 ml) were added to the reaction bottle in sequence, and then hydrogen was replaced 3-4 times. The reaction was stirred at room temperature for 24 hours. After the reaction was completed, diatomaceous earth was used for filtration, and the filter cake was eluted with tetrahydrofuran and the filtrate was desolvated. The product was chromatographed on a DCM/MeOH system to obtain 0.05 g of the product with a yield of 37%.

1H NMR(400MHz，DMSO-d6)δ11.09(s，1H)，9.15(s，1H)，7.55-7.38(m，2H)，7.09(q，J＝6.7Hz，2H)，7.01(d，J＝7.2Hz，1H)，6.81(d，J＝7.5Hz，2H)，6.67-6.58(m，4H)，6.48(d，J＝8.2Hz，1H)，6.25(d，J＝8.2Hz，2H)，5.74-5.61(m，1H)，4.16(d，J＝4.9Hz，1H)，3.79-3.47(m，6H)，3.25-3.11(m，5H)，3.04-2.85(m，6H)，2.81-2.65(m，6H)，2.29(s，3H)，2.25-2.19(m，1H)，2.12-1.95(m，4H)，1.76-1.51(m，7H)，1.35-1.13(m，3H)，1.09-0.94(m，2H).MS(ESI)m/z:837.5[M+H]+. 1 H NMR (400MHz, DMSO-d 6 ) δ11.09 (s, 1H), 9.15 (s, 1H), 7.55-7.38 (m, 2H), 7.09 (q, J=6.7Hz, 2H), 7.01 (d, J=7.2Hz, 1H), 6.81 (d, J=7. 5Hz, 2H), 6.67-6.58 (m, 4H), 6.48 (d, J=8.2Hz, 1H), 6.25 (d, J=8.2Hz, 2H), 5.74-5.61 (m, 1H), 4.16 (d, J=4.9H z, 1H), 3.79-3.47 (m, 6H), 3.25-3.11 (m, 5H), 3.04-2.85 (m, 6H), 2.81-2.65 (m, 6H), 2.29 (s, 3H), 2.25-2.19 ( m, 1H), 2.12-1.95 (m, 4H), 1.76-1.51 (m, 7H), 1.35-1.13 (m, 3H), 1.09-0.94 (m, 2H). MS (ESI) m/z: 837.5 [M+H] + .

实施例16：3-(5-氟-6-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)哌啶-2，6-二酮的合成(化合物IV-9)
Example 16: Synthesis of 3-(5-fluoro-6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (Compound IV-9)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：3-(2，6-双(苄氧)吡啶-3-基)-6-溴-5-氟-1-甲基-1H-吲唑的合成
Step 1: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole

室温下，依次向反应瓶中加入6-溴-5-氟-3-碘-1-甲基-1H-吲唑(1.00g，2.97mmol)，2，6-双(苄氧)-3-(4，4，5，5-四甲基-1，3，2-二氧杂环戊烷-2-基)吡啶(1.24g，2.97mmol)，碳酸钠(0.94g，8.90mmol)，四三苯基膦钯(0.34g，0.30mmol)，水(1mL)和二氧六环(10ml)，90℃下，氮气氛围，反应5h。反应完成后，降至室温，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物1.20g，收率81％。At room temperature, 6-bromo-5-fluoro-3-iodo-1-methyl-1H-indazole (1.00 g, 2.97 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridine (1.24 g, 2.97 mmol), sodium carbonate (0.94 g, 8.90 mmol), tetrakistriphenylphosphine palladium (0.34 g, 0.30 mmol), water (1 mL) and dioxane (10 ml) were added to the reaction bottle in sequence, and the mixture was reacted for 5 h at 90° C. in a nitrogen atmosphere. After the reaction was completed, the mixture was cooled to room temperature, ethyl acetate and water were added, and the liquid was separated. After the organic phase was dried, PE/EA system column chromatography was used to obtain 1.20 g of the product with a yield of 81%.

步骤2：4-(3-(2，6-双(苄氧)吡啶-3-基)-5-氟-1-甲基-1H-吲唑-6-基)-3，6-二氢吡啶-1(2H)-甲酸叔丁酯的合成
Step 2: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate

室温下，依次向反应瓶中加入3-(2，6-双(苄氧)吡啶-3-基)-6-溴-5-氟-1-甲基-1H-吲唑(0.60g，1.16mmol)，4-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊二烯-2-基)-3，6-二氢吡啶-1(2H)-甲酸叔丁酯(0.40g，1.27mmol)，dppfPdCl2(0.09g，0.12mmol)，碳酸钾(0.48g，3.47mmol)，水(1mL)和二氧六环(10ml)。90℃下，氮气氛围，反应5h。反应完成后，降温至室温，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物0.47g，收率66％。At room temperature, 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole (0.60 g, 1.16 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.40 g, 1.27 mmol), dppfPdCl 2 (0.09 g, 0.12 mmol), potassium carbonate (0.48 g, 3.47 mmol), water (1 mL) and dioxane (10 ml) were added to the reaction bottle in sequence. The reaction was carried out at 90° C. in a nitrogen atmosphere for 5 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, the liquids were separated, and the organic phase was dried and then chromatographed using a PE/EA system column to obtain 0.47 g of the product with a yield of 66%.

步骤3：4-(3-(2，6-二氧代哌啶-3-基)-5-氟-1-甲基-1H-吲哚-6-基)哌啶-1-甲酸叔丁基酯的合成
Step 3: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indol-6-yl)piperidine-1-carboxylate

室温下，依次向反应瓶中加入4-(3-(2，6-双(苄氧)吡啶-3-基)-5-氟-1-甲基-1H-吲唑-6-基)-3，6-二氢吡啶-1(2H)-甲酸叔丁酯(0.40g，0.66mmol)，10％Pd/C(0.04g)，四氢呋喃(5mL)和乙醇(5ml)，室温反应24h。反应完成后，过滤旋干，得到粗品0.26g，直接下一步。At room temperature, 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.40 g, 0.66 mmol), 10% Pd/C (0.04 g), tetrahydrofuran (5 mL) and ethanol (5 ml) were added to the reaction bottle in sequence and reacted at room temperature for 24 h. After the reaction was completed, the mixture was filtered and dried to obtain 0.26 g of a crude product, which was directly used in the next step.

步骤4：3-(5-氟-1-甲基-6-(哌啶-4-基)-1H-吲哚-3-基)哌啶-2，6-二酮的合成
Step 4: Synthesis of 3-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indol-3-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入4-(3-(2，6-二氧代哌啶-3-基)-5-氟-1-甲基-1H-吲哚-6-基)哌啶-1-甲酸叔丁基酯(0.26g，0.60mmol)和HCl二氧六环溶液(5ml)，室温反应2h。反应完成后，旋干，得到粗品0.22g，直接下一步。At room temperature, tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indol-6-yl)piperidine-1-carboxylate (0.26 g, 0.60 mmol) and HCl dioxane solution (5 ml) were added to the reaction bottle in sequence, and the mixture was reacted at room temperature for 2 h. After the reaction was completed, the mixture was spin-dried to obtain 0.22 g of a crude product, which was directly used for the next step.

步骤5：3-(6-(1-(((1R，2R)-2-((4-(4-(((2R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)哌啶-2，6-二酮的合成
Step 5: Synthesis of 3-(6-(1-(((1R,2R)-2-((4-(4-(((2R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(5-氟-1-甲基-6-(哌啶-4-基)-1H-吲哚-3-基)哌啶-2，6-二酮(0.15g，0.47mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.28g，0.47mmol)和二氯甲烷(5mL)，再加入TIPT(0.5mL)，室温搅拌16小时，再加入STAB(0.15g，0.71mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.21g，三步收率：62％。At room temperature, 3-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indol-3-yl)piperidine-2,6-dione (0.15 g, 0.47 mmol), (1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.28 g, 0.47 mmol) and dichloromethane (5 mL) were added to the reaction bottle in sequence, and TIPT (0.5 mL) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.15 g, 0.71 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.21 g of the product with a three-step yield of 62%.

步骤6：3-(5-氟-6-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)哌啶-2，6-二酮的合成
Step 6: Synthesis of 3-(5-fluoro-6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(6-(1-(((1R，2R)-2-((4-(4-(((2R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)哌啶-2，6-二酮(0.21g，0.23mmol)，10％钯碳(0.10g)和THF(3mL)，置换氢气3-4次，室温搅拌反应24h。反应完成后，垫硅藻土过滤，滤饼使用THF淋洗，滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.11g，收率：58％。At room temperature, 3-(6-(1-(((1R, 2R)-2-((4-(4-(((2R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (0.21 g, 0.23 mmol), 10% palladium on carbon (0.10 g) and THF (3 mL) were added to the reaction bottle in sequence, the hydrogen was replaced 3-4 times, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, the mixture was filtered with diatomaceous earth, the filter cake was rinsed with THF, the filtrate was desolvated, and DCM/MeOH system column chromatography was used to obtain 0.11 g of the product, with a yield of 58%.

1H NMR(400MHz，DMSO-d6)δ10.90(s，1H)，9.15(s，1H)，7.46(d，J＝53.3Hz，2H)，7.04(d，J＝39.6Hz，3H)，6.82(d，J＝7.5Hz，2H)，6.63(t，J＝6.3Hz，4H)，6.49(dd，J＝8.2，2.7Hz，1H)，6.23(d，J＝8.1Hz，2H)，4.34(dd，J＝10.5，5.0Hz，1H)，4.15(d，J＝5.0Hz，1H)，3.90(d，J＝46.4Hz，3H)，3.63(s，1H)，3.22-2.86(m，12H)，2.75-2.57(m，4H)，2.42-2.26(m，3H)，2.17-1.41(m，17H)，1.08-0.78(m，3H).MS(ESI)m/z:837.7[M+H]+. 1 H NMR (400MHz, DMSO-d 6 ) δ10.90 (s, 1H), 9.15 (s, 1H), 7.46 (d, J = 53.3Hz, 2H), 7.04 (d, J = 39.6Hz, 3H), 6.82 (d, J = 7.5Hz, 2 H), 6.63 (t, J=6.3Hz, 4H), 6.49 (dd, J=8.2, 2.7Hz, 1H), 6.23 (d, J=8.1Hz, 2H), 4.34 (dd, J=10.5, 5 .0Hz, 1H), 4.15 (d, J=5.0Hz, 1H), 3.90 (d, J=46.4Hz, 3H), 3.63 (s, 1H), 3.22-2.86 (m, 12H), 2.75- 2.57(m, 4H), 2.42-2.26(m, 3H), 2.17-1.41(m, 17H), 1.08-0.78(m, 3H).MS(ESI)m/z:837.7[M+H] + .

实施例17：N-(2，6-二氧代哌啶-3-基)-5-(4-(((1S，2S)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)吡啶甲酰胺的合成(化合物III-2)
Example 17: Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)picolinamide (Compound III-2)

(1S，2S)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：5-(4-(((1S，2S)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-N-(2，6-二氧代哌啶-3-基)吡啶-3-甲酰胺的合成
Step 1: Synthesis of 5-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridine-3-carboxamide

室温下，依次向反应瓶中加入N-(2，6-二氧代哌啶-3-基)-5-(哌嗪-1-基)吡啶-3-甲酰胺(0.09g，0.28mmol)，(1S，2S)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.17g，0.28mmol)和二氯甲烷(5ml)，再加入TIPT(0.3ml)，室温搅拌16小时，再加入STAB(0.09g，0.42mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.09g，收率：35％。At room temperature, N-(2,6-dioxopiperidin-3-yl)-5-(piperazine-1-yl)pyridine-3-carboxamide (0.09 g, 0.28 mmol), (1S, 2S)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-yl)methyl)cyclohexane-1-carboxaldehyde (0.17 g, 0.28 mmol) and dichloromethane (5 ml) were added to the reaction bottle in sequence, and TIPT (0.3 ml) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.09 g, 0.42 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.09 g of the product with a yield of 35%.

步骤2：N-(2，6-二氧代哌啶-3-基)-5-(4-(((1S，2S)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)吡啶酰胺的合成
Step 2: Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)picolinamide

室温下，依次向反应瓶中加入5-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-N-(2，6-二氧代哌啶-3-基)吡啶-3-甲酰胺(0.09g，0.10mmol)，10％钯碳(0.05g)和THF(3ml)，置换氢气3-4次，室温搅拌反应24h。反应完成后，垫硅藻土过滤，滤饼使用THF淋洗，滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.03g，收率：37％。At room temperature, 5-(4-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridine-3-carboxamide (0.09 g, 0.10 mmol), 10% palladium on carbon (0.05 g) and THF (3 ml) were added to the reaction bottle in sequence, the hydrogen was replaced 3-4 times, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, the mixture was filtered with diatomaceous earth, the filter cake was rinsed with THF, the filtrate was desolvated, and DCM/MeOH system column chromatography was used to obtain 0.03 g of the product, with a yield of 37%.

1H NMR(400MHz，DMSO-d6)δ10.87(s，1H)，9.13(s，1H)，8.74(d，J＝8.3Hz，1H)，8.31(d，J＝2.8Hz，1H)，7.86(d，J＝8.8Hz，1H)，7.41(dd，J＝9.0，2.9Hz，1H)，7.13(dd，J＝9.7，6.7Hz，3H)，6.84(d，J＝7.1Hz，2H)，6.65-6.59(m，2H)，6.53(d，J＝8.3Hz，2H)，6.48(dd，J＝8.3，2.5Hz，1H)，6.21(d，J＝8.3Hz，2H)，4.74(td，J＝8.0，4.1Hz，1H)，4.14(d，J＝5.0Hz，1H)，3.22(d，J＝42.3Hz，4H)，3.08-2.62(m，10H)，2.53(s，5H)，2.31(t，J＝7.4Hz，2H)，2.23-1.95(m，6H)，1.93-1.64(m，4H)，1.57(s，2H)，1.44(d，J＝8.7Hz，2H)，1.22(d，J＝12.2Hz，2H)，0.98(h，J＝7.2Hz，2H).MS(ESI)m/z:810.7[M+H]+.1H NMR (400MHz, DMSO-d6) δ10.87 (s, 1H), 9.13 (s, 1H), 8.74 (d, J = 8.3Hz, 1H), 8.31 (d, J = 2.8Hz, 1H), 7.86 (d, J = 8.8Hz, 1H), 7.41 (dd, J = 9.0, 2.9Hz , 1H), 7.13 (dd, J=9.7, 6.7Hz, 3H), 6.84 (d, J=7.1Hz, 2H), 6.65-6.59 (m, 2H), 6.53 (d, J=8.3Hz, 2H), 6.48 (dd, J=8.3, 2.5Hz, 1H), 6.21 (d, J=8.3 Hz, 2H), 4.74 (td, J=8.0, 4.1Hz, 1H), 4.14 (d, J=5.0Hz, 1H), 3.22 (d, J=42.3Hz, 4H), 3.08-2.62 (m, 10H), 2.53 (s, 5H), 2.31 (t, J=7.4Hz, 2H), 2. 23-1.95 (m, 6H), 1.93-1.64 (m, 4H), 1.57 (s, 2H), 1.44 (d, J=8.7Hz, 2H), 1.22 (d, J=12.2Hz, 2H), 0.98 (h, J=7.2Hz, 2H). MS (ESI) m/z: 810.7[M+H] + .

实施例18：3-(6-(4-(((1S，2S)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1-甲基-1H-吲唑-3-基)哌啶-2，6-二酮的合成(化合物IV-4)
Example 18: Synthesis of 3-(6-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (Compound IV-4)

(1S，2S)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：3-(2，6-双(苄氧)吡啶-3-基)-6-溴-1-甲基-1H-吲唑的合成
Step 1: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole

室温下，依次向反应瓶中加入6-溴-3-碘-1-甲基-1H-吲唑(1.00g，2.97mmol)，2，6-双(苄氧)-3-(4，4，5，5-四甲基-1，3，2-二氧杂环戊烷-2-基)吡啶(1.24g，2.97mmol)，碳酸钠(0.94g，8.90mmol)，四三苯基膦钯(0.34g，0.30mmol)，水(1mL)和二氧六环(10ml)，90℃下，氮气氛围，反应5h。反应完成后，降至室温，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物1.20g，收率81％。At room temperature, 6-bromo-3-iodo-1-methyl-1H-indazole (1.00 g, 2.97 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridine (1.24 g, 2.97 mmol), sodium carbonate (0.94 g, 8.90 mmol), tetrakistriphenylphosphine palladium (0.34 g, 0.30 mmol), water (1 mL) and dioxane (10 ml) were added to the reaction bottle in sequence, and the mixture was reacted for 5 h at 90° C. in a nitrogen atmosphere. After the reaction was completed, the mixture was cooled to room temperature, ethyl acetate and water were added, and the liquid was separated. After the organic phase was dried, PE/EA system column chromatography was used to obtain 1.20 g of the product with a yield of 81%.

步骤2：4-(3-(2，6-双(苄氧)吡啶-3-基)-1-甲基-1H-吲唑-6-基)哌嗪-1-甲酸叔丁酯的合成
Step 2: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入3-(2，6-双(苄氧)吡啶-3-基)-6-溴-1-甲基-1H-吲唑(0.25g，0.50mmol)，1-Boc-哌嗪(0.28g，1.50mmol)，Pd2(dba)3(0.05g，0.05mmol)，10％三叔丁基膦甲苯溶液(200mg，0.10mmol)，叔丁醇钠(0.10g，1.00mmol)和甲苯(10ml)。100℃下，氮气氛围，反应5h。反应完成后，降温至室温，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物0.20g，收率66％。At room temperature, 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (0.25 g, 0.50 mmol), 1-Boc-piperazine (0.28 g, 1.50 mmol), Pd2(dba)3 (0.05 g, 0.05 mmol), 10% tri-tert-butylphosphine toluene solution (200 mg, 0.10 mmol), sodium tert-butoxide (0.10 g, 1.00 mmol) and toluene (10 ml) were added to the reaction bottle in sequence. The reaction was carried out at 100° C. in a nitrogen atmosphere for 5 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, the liquid was separated, and the organic phase was dried and chromatographed on a PE/EA system column to obtain 0.20 g of the product with a yield of 66%.

步骤3：4-(3-(2，6-二氧代哌啶-3-基)-1-甲基-1H-吲唑-6-基)哌嗪-1-甲酸叔丁基酯的合成
Step 3: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入4-(3-(2，6-双(苄氧)吡啶-3-基)-1-甲基-1H-吲唑-6-基)哌嗪-1-甲酸叔丁酯(0.20g，0.33mmol)，10％Pd/C(0.02g)，四氢呋喃(5mL)和乙醇(5ml)，室温反应24h。反应完成后，过滤旋干，得到粗品0.13g，直接下一步。At room temperature, tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.20 g, 0.33 mmol), 10% Pd/C (0.02 g), tetrahydrofuran (5 mL) and ethanol (5 ml) were added to the reaction bottle in sequence and reacted at room temperature for 24 h. After the reaction was completed, the mixture was filtered and dried to obtain 0.13 g of a crude product, which was directly used in the next step.

步骤4：3-(1-甲基-6-(哌嗪-1-基)-1H-吲唑-3-基)哌嗪-2，6-二酮的合成
Step 4: Synthesis of 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperazine-2,6-dione

室温下，依次向反应瓶中加入4-(3-(2，6-二氧代哌啶-3-基)-1-甲基-1H-吲唑-6-基)哌嗪-1-甲酸叔丁基酯(0.13g，0.30mmol)和HCl二氧六环溶液(5ml)，室温反应2h。反应完成后，旋干，得到粗品0.11g，直接下一步。At room temperature, tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.13 g, 0.30 mmol) and HCl dioxane solution (5 ml) were added to the reaction bottle in sequence and reacted at room temperature for 2 h. After the reaction was completed, the mixture was spin-dried to obtain 0.11 g of a crude product, which was directly used for the next step.

步骤5：3-(6-(4-(((1S，2S)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1-甲基-1H-吲唑-3-基)哌嗪-2，6-二酮的合成
Step 5: Synthesis of 3-(6-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperazine-2,6-dione

室温下，依次向反应瓶中加入3-(1-甲基-6-(哌嗪-1-基)-1H-吲唑-3-基)哌嗪-2，6-二酮(0.06g，0.18mmol)，(1S，2S)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.11g，0.18mmol)和二氯甲烷(10ml)，再加入TIPT(0.5ml)，室温搅拌16小时，再加入STAB(0.08g，0.36mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.03g，收率：27％。At room temperature, 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperazine-2,6-dione (0.06 g, 0.18 mmol), (1S, 2S)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.11 g, 0.18 mmol) and dichloromethane (10 ml) were added to the reaction bottle in sequence, and TIPT (0.5 ml) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.08 g, 0.36 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring evenly to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.03 g of the product with a yield of 27%.

步骤6：3-(6-(4-(((1S，2S)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1-甲基-1H-吲唑-3-基)哌啶-2，6-二酮的合成
Step 6: Synthesis of 3-(6-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(6-(4-(((1S，2S)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1-甲基-1H-吲唑-3-基)哌嗪-2，6-二酮(0.03g，0.03mmol)，10％钯碳(0.01g)和四氢呋喃(5ml)，再加入置换氢气3-4次，30℃搅拌反应16h。反应完成后，垫硅藻土过滤，滤饼使用四氢呋喃淋洗滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.01g，收率：37％。At room temperature, 3-(6-(4-(((1S, 2S)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperazine-2,6-dione (0.03 g, 0.03 mmol), 10% palladium on carbon (0.01 g) and tetrahydrofuran (5 ml) were added to the reaction bottle in sequence, and hydrogen was replaced 3-4 times. The reaction was stirred at 30° C. for 16 h. After the reaction was completed, diatomaceous earth was used for filtration, and the filter cake was eluted with tetrahydrofuran and the filtrate was desolvated. The product was chromatographed on a DCM/MeOH system to obtain 0.01 g of the product with a yield of 37%.

1H NMR(400MHz，DMSO-d6)δ10.87(s，1H)，9.12(s，1H)，7.50(d，J＝8.9Hz，1H)，7.17-7.10(m，3H)，6.91(dd，J＝9.0，1.9Hz，1H)，6.86-6.81(m，3H)，6.66-6.60(m，2H)，6.55-6.46(m，3H)，6.21(d，J＝8.3Hz，2H)，4.26(dd，J＝9.2，5.1Hz，1H)，4.14(d，J＝5.0Hz，1H)，3.88(s，3H)，3.30-3.15(m，6H)，3.01-2.88(m，6H)，2.69-2.56(m，3H)，2.47-2.24(m，8H)，2.19-2.04(m，4H)，1.92-1.81(m，2H)，1.73-1.68(m，1H)，1.61-1.53(m，2H)，1.49-1.39(m，2H)，1.23-1.15(m，2H)，1.08-0.68(m，3H).MS(ESI)m/z:821.0[M+H]+. 1 H NMR (400MHz, DMSO-d 6 )δ10.87 (s, 1H), 9.12 (s, 1H), 7.50 (d, J=8.9Hz, 1H), 7.17-7.10 (m, 3H), 6.91 (dd, J=9.0, 1.9Hz, 1H), 6.86-6.81 (m, 3H), 6.66-6.60 (m, 2H), 6.55-6.46 (m, 3H), 6.21 (d, J=8.3Hz, 2H), 4.26 (dd, J=9.2, 5.1Hz, 1H), 4.14 (d, J=5.0Hz, 1H), 3.88 (s, 3H), 3.30-3.15(m, 6H), 3.01-2.88(m, 6H), 2.69-2.56(m, 3H), 2.47-2.24(m, 8H), 2.19-2.04(m, 4H), 1.92-1.81(m, 2H), 1.73-1.68(m, 1H), 1.61-1.53(m, 2H), 1.49-1.39(m, 2H), 1.23-1.15(m, 2H), 1.08-0.68(m, 3H).MS(ESI)m/z:821.0[M+H] + .

实施例19：3-(6-氟-5-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1H-苯并咪唑-1-基)哌啶-2，6-二酮的合成(化合物V-2)
Example 19: Synthesis of 3-(6-fluoro-5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-benzimidazol-1-yl)piperidine-2,6-dione (Compound V-2)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：2，6-双(苄氧基)-3-硝基吡啶的合成
Step 1: Synthesis of 2,6-bis(benzyloxy)-3-nitropyridine

室温下，将BnOH(7.57g，69.95mmol)溶于THF(25mL)，降温至-15℃，加入叔丁醇钾(7.00g，62.18mmol)，室温搅拌30min。-15℃下，将上述反应液滴加到2，6-二氯-3-硝基吡啶(5.00g，25.91mmol)的THF(15mL)中，加毕，室温反应16h。反应完成后，将反应液倒入冰水中，搅拌30min，过滤，滤饼用甲叔醚打浆，得到白色固体6.50g，收率74.6％。At room temperature, BnOH (7.57 g, 69.95 mmol) was dissolved in THF (25 mL), cooled to -15 ° C, potassium tert-butoxide (7.00 g, 62.18 mmol) was added, and stirred at room temperature for 30 min. At -15 ° C, the above reaction solution was added dropwise to 2,6-dichloro-3-nitropyridine (5.00 g, 25.91 mmol) in THF (15 mL), and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was poured into ice water, stirred for 30 min, filtered, and the filter cake was pulped with tertiary methyl ether to obtain 6.50 g of white solid with a yield of 74.6%.

步骤2：2，6-双(苄氧基)吡啶-3-胺的合成
Step 2: Synthesis of 2,6-bis(benzyloxy)pyridin-3-amine

室温下，将2，6-双(苄氧基)-3-硝基吡啶(6.50g，19.32mmol)溶于THF(10mL)和MeOH(10mL)，加入NiCl2·6H2O(0.45g，1.93mmol)，降温至0℃，缓慢加入NaBH4(1.82g，48.31mmol)，冰浴下反应1h。反应完成后，向反应液中加入冰水(1mL)淬灭，浓缩柱层析(EA/PE)，得到4.41g无色油状物，收率74.5％。At room temperature, 2,6-bis(benzyloxy)-3-nitropyridine (6.50 g, 19.32 mmol) was dissolved in THF (10 mL) and MeOH (10 mL), NiCl 2 ·6H 2 O (0.45 g, 1.93 mmol) was added, the temperature was lowered to 0°C, NaBH 4 (1.82 g, 48.31 mmol) was slowly added, and the mixture was reacted under ice bath for 1 h. After the reaction was completed, ice water (1 mL) was added to the reaction solution to quench the reaction, and the solution was concentrated by column chromatography (EA/PE) to obtain 4.41 g of a colorless oil with a yield of 74.5%.

步骤3：2，6-双(苄氧基)N-(4-溴-5-氟-2-硝基苯基)吡啶-3-胺的合成
Step 3: Synthesis of 2,6-bis(benzyloxy)N-(4-bromo-5-fluoro-2-nitrophenyl)pyridin-3-amine

室温下，依次向反应瓶中加入2，4-二氟-5-溴硝基苯(4.41g，13.06mmol)，2，6-双(苄氧基)吡啶-3-胺(4.00g，13.06mmol)，KF(0.90g，15.67mmol)和DMF(20ml)，升温至118℃反应8h。反应完成后，降温至室温，向反应液中加水(20mL)析出固体，过滤，滤饼用甲叔醚打浆，得3.5g黄色固体，收率35.9％。At room temperature, 2,4-difluoro-5-bromonitrobenzene (4.41 g, 13.06 mmol), 2,6-bis(benzyloxy)pyridin-3-amine (4.00 g, 13.06 mmol), KF (0.90 g, 15.67 mmol) and DMF (20 ml) were added to the reaction bottle in sequence, and the temperature was raised to 118°C for reaction for 8 h. After the reaction was completed, the temperature was lowered to room temperature, water (20 mL) was added to the reaction solution to precipitate solids, which were filtered, and the filter cake was slurried with tertiary methyl ether to obtain 3.5 g of yellow solids with a yield of 35.9%.

步骤4：N1-(2，6-双(苄氧基)吡啶-3-基)-4-溴-5-氟苯-1，2-二胺的合成
Step 4: Synthesis of N 1 -(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-5-fluorobenzene-1,2-diamine

室温下，将2，6-双(苄氧基)N-(4-溴-5-氟-2-硝基苯基)吡啶-3-胺(3.50g，6.67mmol)溶于THF(20mL)和MeOH(20mL)，加入NiCl2.6H2O(0.16g，1.67mmol)，降温至0℃，缓慢加入NaBH4(0.63g，16.69mmol)，冰浴下反应1h。反应完成后，向反应液中加入冰水(1mL)淬灭，浓缩柱层析(EA/PE)，得到3.25g棕色油状物，收率98.8％。At room temperature, 2,6-bis(benzyloxy)N-(4-bromo-5-fluoro-2-nitrophenyl)pyridin-3-amine (3.50 g, 6.67 mmol) was dissolved in THF (20 mL) and MeOH (20 mL), NiCl 2 .6H 2 O (0.16 g, 1.67 mmol) was added, the temperature was lowered to 0°C, NaBH 4 (0.63 g, 16.69 mmol) was slowly added, and the mixture was reacted for 1 h in an ice bath. After the reaction was completed, ice water (1 mL) was added to the reaction solution to quench the reaction, and the solution was concentrated by column chromatography (EA/PE) to obtain 3.25 g of a brown oil with a yield of 98.8%.

步骤5：1-(2，6-双苄氧基)吡啶-3-基)-5-溴-6-氟-1H-苯并咪唑的合成
Step 5: Synthesis of 1-(2,6-bisbenzyloxy)pyridin-3-yl)-5-bromo-6-fluoro-1H-benzimidazole

室温下，将N1-(2，6-双(苄氧基)吡啶-3-基)-4-溴-5-氟苯-1，2-二胺(3.25g，6.57mmol)溶于甲苯(30mL)，加入原甲酸三甲酯(1.74g，16.44mmol)和TsOH(0.23g，1.31mmol)，120℃下反应1h。反应完成后，反应液降至室温，浓缩柱层析(EA/PE)，得到3.00g棕色油状物，收率90.5％。At room temperature, N 1 -(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-5-fluorobenzene-1,2-diamine (3.25 g, 6.57 mmol) was dissolved in toluene (30 mL), trimethyl orthoformate (1.74 g, 16.44 mmol) and TsOH (0.23 g, 1.31 mmol) were added, and the mixture was reacted at 120° C. for 1 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated by column chromatography (EA/PE), and 3.00 g of brown oil was obtained, with a yield of 90.5%.

步骤6：叔丁基4-(1-(2，6-双苄氧基)吡啶-3-基)-6-氟-1H-苯并咪唑-5-基)哌嗪-1-羧酸叔丁酯的合成
Step 6: Synthesis of tert-butyl 4-(1-(2,6-bisbenzyloxy)pyridin-3-yl)-6-fluoro-1H-benzimidazol-5-yl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入1-(2，6-双苄氧基)吡啶-3-基)-5-溴-6-氟-1H-苯并咪唑(0.60g，1.19mmol)，N-Boc-哌嗪(0.44g，2.38mmol)，Pd-PEPPSI IHept-Cl(0.12g，0.12mmol)，Cs2CO3(1.16g，3.57mmol)，MS(0.60g)和Do(5ml)，置换氮气3-4次，升温至100℃反应8h。反应完成后，降温至室温，过滤，滤液浓缩，使用DCM/MeOH体系柱层析，再用EA打浆得到白色固体0.60g，收率82.8％。At room temperature, 1-(2,6-bisbenzyloxy)pyridin-3-yl)-5-bromo-6-fluoro-1H-benzimidazole (0.60 g, 1.19 mmol), N-Boc-piperazine (0.44 g, 2.38 mmol), Pd-PEPPSI IHept-Cl (0.12 g, 0.12 mmol), Cs2CO3 (1.16 g, 3.57 mmol) were added to the reaction bottle in sequence. MS (0.60 g) and Do (5 ml) were added, nitrogen was replaced 3-4 times, and the temperature was raised to 100°C for 8 hours. After the reaction was completed, the temperature was lowered to room temperature, filtered, and the filtrate was concentrated and chromatographed using a DCM/MeOH system column, and then slurried with EA to obtain 0.60 g of a white solid with a yield of 82.8%.

步骤7：叔丁基4-(1-(2，6-二氧杂哌啶-3-基)-6-氟-1H-苯并咪唑-5-基)哌嗪-1-羧酸叔丁酯的合成
Step 7: Synthesis of tert-butyl 4-(1-(2,6-dioxapiperidin-3-yl)-6-fluoro-1H-benzimidazol-5-yl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入叔丁基4-(1-(2，6-双苄氧基)吡啶-3-基)-6-氟-1H-苯并咪唑-5-基)哌嗪-1-羧酸叔丁酯(0.60g，0.98mmol)，DMF(15mL)，AcOH(2mL)和Pd/C(200mg)，置换氢气3-4次，升温至35℃反应8h。反应完成后，过滤，滤液加水析出固体，过滤得到产物粗品0.60g，直接进行下一步。At room temperature, tert-butyl 4-(1-(2,6-bisbenzyloxy)pyridin-3-yl)-6-fluoro-1H-benzimidazol-5-yl)piperazine-1-carboxylate (0.60 g, 0.98 mmol), DMF (15 mL), AcOH (2 mL) and Pd/C (200 mg) were added to the reaction bottle in sequence, and the hydrogen was replaced 3-4 times, and the temperature was raised to 35 ° C for 8 hours. After the reaction was completed, the filtrate was filtered, and the solid was precipitated by adding water to the filtrate, and the crude product 0.60 g was obtained by filtration, and the next step was directly carried out.

步骤8：3-(6-氟-5-(哌嗪-1-基)-1H-苯并咪唑-1-基)哌啶-2，6-二酮的合成
Step 8: Synthesis of 3-(6-fluoro-5-(piperazin-1-yl)-1H-benzimidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入叔丁基4-(1-(2，6-二氧杂哌啶-3-基)-6-氟-1H-苯并咪唑-5-基)哌嗪-1-羧酸叔丁酯(0.30g，0.70mmol)，DCM(3mL)和HCl in Do(5mL)，升温至35℃反应30min。反应完成后，浓缩得到产物粗品0.25g，直接进行下一步。At room temperature, tert-butyl 4-(1-(2,6-dioxapiperidin-3-yl)-6-fluoro-1H-benzimidazol-5-yl)piperazine-1-carboxylate (0.30 g, 0.70 mmol), DCM (3 mL) and HCl in Do (5 mL) were added to the reaction bottle in sequence, and the temperature was raised to 35°C for 30 min. After the reaction was completed, the crude product was concentrated to obtain 0.25 g, which was directly carried out to the next step.

步骤9：3-(5-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-6-氟-1H-苯并咪唑-1-基)哌啶-2，6-二酮的合成
Step 9: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-6-fluoro-1H-benzimidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(6-氟-5-(哌嗪-1-基)-1H-苯并咪唑-1-基)哌啶-2，6-二酮(0.10g，0.30mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.15g，0.24mmol)和二氯甲烷(5ml)，再加入TIPT(0.3mL)，室温搅拌8小时，再加入STAB(0.10g，0.45mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到棕色固体0.125g，收率：45.3％。At room temperature, 3-(6-fluoro-5-(piperazine-1-yl)-1H-benzimidazol-1-yl)piperidine-2,6-dione (0.10 g, 0.30 mmol), (1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-yl)methyl)cyclohexane-1-carbaldehyde (0.15 g, 0.24 mmol) and dichloromethane (5 ml) were added to the reaction bottle in sequence, and TIPT (0.3 mL) was added, and the mixture was stirred at room temperature for 8 hours. STAB (0.10 g, 0.45 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring evenly to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.125 g of a brown solid with a yield of 45.3%.

步骤4：3-(6-氟-5-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1H-苯并咪唑-1-基)哌啶-2，6-二酮的合成
Step 4: Synthesis of 3-(6-fluoro-5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-benzimidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(5-(4-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-6-氟-1H-苯并咪唑-1-基)哌啶-2，6-二酮(0.13g，0.14mmol)，10％钯碳(0.05g)和THF(5ml)，置换氢气3-4次，室温搅拌反应8h。反应完成后，垫硅藻土过滤，滤饼使用THF淋洗，滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.017g，入库0.012g。At room temperature, 3-(5-(4-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-6-fluoro-1H-benzimidazol-1-yl)piperidine-2,6-dione (0.13 g, 0.14 mmol), 10% palladium on carbon (0.05 g) and THF (5 ml) were added to the reaction bottle in sequence, the hydrogen was replaced 3-4 times, and the reaction was stirred at room temperature for 8 h. After the reaction was completed, diatomaceous earth was used for filtration, the filter cake was rinsed with THF, the filtrate was desolvated, and DCM/MeOH system column chromatography was used to obtain 0.017 g of the product, and 0.012 g was put into storage.

1H NMR(400MHz，DMSO-d6)δ11.19(s，1H)，9.14(s，1H)，8.20(s，1H)，7.47(d，J＝13.1Hz，1H)，7.32(d，J＝8.1Hz，1H)，7.13-7.08(m，2H)，6.83(d，J＝7.3Hz，2H)，6.62-6.46(m，5H)，6.22(d，J＝8.1Hz，2H)，5.63(dd，J＝13.0，5.1Hz，1H)，4.14(d，J＝5.1Hz，2H)，3.07-2.68(m，19H)，2.23-2.05(m，4H)，1.65(dd，J＝91.4，44.9Hz，10H)，1.27-1.15(m，4H)，0.99(s，2H).MS(ESI)m/z:824.4[M+H]+. 1 H NMR (400MHz, DMSO-d6) δ11.19 (s, 1H), 9.14 (s, 1H), 8.20 (s, 1H), 7.47 (d, J=13.1Hz, 1H), 7.32 (d, J=8.1Hz, 1H), 7.13-7.08 (m, 2H), 6.83 (d, J=7.3Hz, 2H), 6.62-6.46 (m, 5H), 6.22 (d, J=8.1H z, 2H), 5.63 (dd, J=13.0, 5.1Hz, 1H), 4.14 (d, J=5.1Hz, 2H), 3.07-2.68 (m, 19H), 2.23-2.05 (m, 4H), 1.65 (dd, J=91.4, 44.9Hz, 10H), 1.27-1.15 (m, 4H), 0.99 (s, 2H). MS (ESI) m/z: 824.4[M+H] + .

实施例20：3-(6-氟-5-(1-(((1R，2R)-2-((4-(4-(((2R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮的合成(化合物V-5)
Example 20: Synthesis of 3-(6-fluoro-5-(1-(((1R,2R)-2-((4-(4-(((2R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound V-5)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：2，6-双(苄氧基)-3-硝基吡啶的合成
Step 1: Synthesis of 2,6-bis(benzyloxy)-3-nitropyridine

室温下，将BnOH(7.57g，69.95mmol)溶于THF(25mL)，降温至-15℃，加入叔丁醇钾(7.00g，62.18mmol)，室温搅拌30min。-15℃下，将上述反应液滴加到2，6-二氯-3-硝基吡啶(5.00g，25.91mmol)的THF(15mL)中，加毕，室温反应16h。反应完成后，将反应液倒入冰水中，搅拌30min，过滤，滤饼用甲叔醚打浆，得到白色固体6.50g，收率74.6％。At room temperature, BnOH (7.57 g, 69.95 mmol) was dissolved in THF (25 mL), cooled to -15 ° C, potassium tert-butoxide (7.00 g, 62.18 mmol) was added, and stirred at room temperature for 30 min. At -15 ° C, the above reaction solution was added dropwise to 2,6-dichloro-3-nitropyridine (5.00 g, 25.91 mmol) in THF (15 mL), and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was poured into ice water, stirred for 30 min, filtered, and the filter cake was pulped with tertiary methyl ether to obtain 6.50 g of white solid with a yield of 74.6%.

步骤2：2，6-双(苄氧基)吡啶-3-胺的合成
Step 2: Synthesis of 2,6-bis(benzyloxy)pyridin-3-amine

室温下，将2，6-双(苄氧基)-3-硝基吡啶(6.50g，19.32mmol)溶于THF(10mL)和MeOH(10mL)，加入NiCl2·6H2O(0.45g，1.93mmol)，降温至0℃，缓慢加入NaBH4(1.82g，48.31mmol)，冰浴下反应1h。反应完成后，向反应液中加入冰水(1mL)淬灭，浓缩柱层析(EA/PE)，得到4.41g无色油状物，收率74.5％。At room temperature, 2,6-bis(benzyloxy)-3-nitropyridine (6.50 g, 19.32 mmol) was dissolved in THF (10 mL) and MeOH (10 mL), NiCl 2 ·6H 2 O (0.45 g, 1.93 mmol) was added, the temperature was lowered to 0°C, NaBH 4 (1.82 g, 48.31 mmol) was slowly added, and the mixture was reacted under ice bath for 1 h. After the reaction was completed, ice water (1 mL) was added to the reaction solution to quench the reaction, and the solution was concentrated by column chromatography (EA/PE) to obtain 4.41 g of a colorless oil with a yield of 74.5%.

步骤3：2，6-双(苄氧基)N-(4-溴-5-氟-2-硝基苯基)吡啶-3-胺的合成
Step 3: Synthesis of 2,6-bis(benzyloxy)N-(4-bromo-5-fluoro-2-nitrophenyl)pyridin-3-amine

室温下，依次向反应瓶中加入2，4-二氟-5-溴硝基苯(4.41g，13.06mmol)，2，6-双(苄氧基)吡啶-3-胺(4.00g，13.06mmol)，KF(0.90g，15.67mmol)和DMF(20ml)，升温至118℃反应8h。反应完成后，降温至室温，向反应液中加水(20mL)析出固体，过滤，滤饼用甲叔醚打浆，得3.5g黄色固体，收率35.9％。At room temperature, 2,4-difluoro-5-bromonitrobenzene (4.41 g, 13.06 mmol), 2,6-bis(benzyloxy)pyridin-3-amine (4.00 g, 13.06 mmol), KF (0.90 g, 15.67 mmol) and DMF (20 ml) were added to the reaction bottle in sequence, and the temperature was raised to 118°C for reaction for 8 h. After the reaction was completed, the temperature was lowered to room temperature, water (20 mL) was added to the reaction solution to precipitate solids, which were filtered, and the filter cake was slurried with tertiary methyl ether to obtain 3.5 g of yellow solids with a yield of 35.9%.

步骤4：N1-(2，6-双(苄氧基)吡啶-3-基)-4-溴-5-氟苯-1，2-二胺的合成
Step 4: Synthesis of N 1 -(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-5-fluorobenzene-1,2-diamine

室温下，将2，6-双(苄氧基)N-(4-溴-5-氟-2硝基苯基)吡啶-3-胺(3.50g，6.67mmol)溶于THF(20mL)和MeOH(20mL)，加入NiCl2·6H2O(0.16g，1.67mmol)，降温至0℃，缓慢加入NaBH4(0.63g，16.69mmol)，冰浴下反应1h。反应完成后，向反应液中加入冰水(1mL)淬灭，浓缩柱层析(EA/PE)，得到3.25g棕色油状物，收率98.8％。At room temperature, 2,6-bis(benzyloxy)N-(4-bromo-5-fluoro-2-nitrophenyl)pyridin-3-amine (3.50 g, 6.67 mmol) was dissolved in THF (20 mL) and MeOH (20 mL), NiCl 2 ·6H 2 O (0.16 g, 1.67 mmol) was added, the temperature was lowered to 0°C, NaBH 4 (0.63 g, 16.69 mmol) was slowly added, and the mixture was reacted under ice bath for 1 h. After the reaction was completed, ice water (1 mL) was added to the reaction solution to quench the reaction, and the solution was concentrated by column chromatography (EA/PE) to obtain 3.25 g of brown oil with a yield of 98.8%.

步骤5：1-(2，6-双苄氧基)吡啶-3-基)-5-溴-6-氟-1H-苯并咪唑的合成
Step 5: Synthesis of 1-(2,6-bisbenzyloxy)pyridin-3-yl)-5-bromo-6-fluoro-1H-benzimidazole

室温下，将N1-(2，6-双(苄氧基)吡啶-3-基)-4-溴-5-氟苯-1，2-二胺(3.25g，6.57mmol)溶于甲苯(30mL)，加入原甲酸三甲酯(1.74g，16.44mmol)和TsOH(0.23g，1.31mmol)，120℃下反应1h。反应完成后，反应液降至室温，浓缩柱层析(EA/PE)，得到3.00g棕色油状物，收率90.5％。At room temperature, N 1 -(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-5-fluorobenzene-1,2-diamine (3.25 g, 6.57 mmol) was dissolved in toluene (30 mL), trimethyl orthoformate (1.74 g, 16.44 mmol) and TsOH (0.23 g, 1.31 mmol) were added, and the mixture was reacted at 120° C. for 1 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated by column chromatography (EA/PE), and 3.00 g of brown oil was obtained, with a yield of 90.5%.

步骤6：4-(1-(2，6-二(苄氧基)吡啶-3-基)-6-氟-1H-苯并[d]咪唑-5-基)-3，6-二氢吡啶-1(2H)-羧酸叔丁酯的合成
Step 6: Synthesis of tert-butyl 4-(1-(2,6-di(benzyloxy)pyridin-3-yl)-6-fluoro-1H-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

室温下，依次向反应瓶中加入1-(2，6-双苄氧基)吡啶-3-基)-5-溴-6-氟-1H-苯并咪唑(1.20g，2.38mmol)，2，6-双(苄氧)-3-(4，4，5，5-四甲基-1，3，2-二氧杂环戊烷-2-基)吡啶(1.24g，2.97mmol)，碳酸钾(1.23g，8.90mmol)，dppfPdCl2(0.22g，0.30mmol)，水(1mL)和二氧六环(10ml)，90℃下，氮气氛围，反应5h。反应完成后，降至室温，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物1.20g，收率81％。At room temperature, 1-(2,6-bisbenzyloxy)pyridin-3-yl)-5-bromo-6-fluoro-1H-benzimidazole (1.20 g, 2.38 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridine (1.24 g, 2.97 mmol), potassium carbonate (1.23 g, 8.90 mmol), dppfPdCl 2 (0.22 g, 0.30 mmol), water (1 mL) and dioxane (10 ml) were added to the reaction bottle in sequence, and the mixture was reacted for 5 h at 90° C. in a nitrogen atmosphere. After the reaction was completed, the mixture was cooled to room temperature, ethyl acetate and water were added, and the organic phase was dried and then chromatographed on a PE/EA system column to obtain 1.20 g of the product with a yield of 81%.

步骤7：4-(1-(2，6-二氧哌啶-3-基)-6-氟-1H-苯并[d]咪唑-5-基)哌啶-1-羧酸叔丁酯的合成
Step 7: Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate

室温下，依次向反应瓶中加入4-(1-(2，6-二(苄氧基)吡啶-3-基)-6-氟-1H-苯并[d]咪唑-5-基)-3，6-二氢吡啶-1(2H)-羧酸叔丁酯(0.60g，0.98mmol)，DMF(15mL)，AcOH(2mL)和Pd/C(200mg)，置换氢气3-4次，升温至35℃反应8h。反应完成后，过滤，滤液加水析出固体，过滤得到产物粗品0.60g，直接进行下一步。At room temperature, 4-(1-(2,6-di(benzyloxy)pyridin-3-yl)-6-fluoro-1H-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.60 g, 0.98 mmol), DMF (15 mL), AcOH (2 mL) and Pd/C (200 mg) were added to the reaction bottle in sequence, and the hydrogen was replaced 3-4 times. The temperature was raised to 35°C and reacted for 8 hours. After the reaction was completed, the reaction was filtered, and the filtrate was added with water to precipitate the solid, which was filtered to obtain 0.60 g of the crude product, which was directly carried out to the next step.

步骤8：3-(6-氟-5-(哌啶-4-基)-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮的合成
Step 8: Synthesis of 3-(6-fluoro-5-(piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入4-(1-(2，6-二氧哌啶-3-基)-6-氟-1H-苯并[d]咪唑-5-基)哌啶-1-羧酸叔丁酯(0.30g，0.70mmol)，DCM(3mL)和HCl in Do(5mL)，升温至35℃反应30min。反应完成后，浓缩得到产物粗品0.25g，直接进行下一步。At room temperature, tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate (0.30 g, 0.70 mmol), DCM (3 mL) and HCl in Do (5 mL) were added to the reaction bottle in sequence, and the temperature was raised to 35°C for 30 min. After the reaction was completed, the crude product was concentrated to obtain 0.25 g, which was directly carried out to the next step.

步骤9：3-(5-(1-(((1R，2R)-2-((4-(4-(((2R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-6-氟-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮的合成
Step 9: Synthesis of 3-(5-(1-(((1R,2R)-2-((4-(4-(((2R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-6-fluoro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(6-氟-5-(哌啶-4-基)-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮(0.10g，0.30mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.15g，0.24mmol)和二氯甲烷(5ml)，再加入TIPT(0.3mL)，室温搅拌8小时，再加入STAB(0.10g，0.45mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到棕色固体0.13g，收率：46％。At room temperature, 3-(6-fluoro-5-(piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.10 g, 0.30 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.15 g, 0.24 mmol) and dichloromethane (5 ml) were added to the reaction bottle in sequence, and TIPT (0.3 mL) was added, and the mixture was stirred at room temperature for 8 hours. STAB (0.10 g, 0.45 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring evenly to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.13 g of a brown solid with a yield of 46%.

步骤10：3-(6-氟-5-(1-(((1R，2R)-2-((4-(4-(((2R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮
Step 10: 3-(6-fluoro-5-(1-(((1R,2R)-2-((4-(4-(((2R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(5-(1-(((1R，2R)-2-((4-(4-(((2R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-6-氟-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮(0.08g，0.14mmol)，10％钯碳(0.05g)和THF(5ml)，置换氢气3-4次，室温搅拌反应8h。反应完成后，垫硅藻土过滤，滤饼使用THF淋洗，滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.02g，收率27％。At room temperature, 3-(5-(1-(((1R, 2R)-2-((4-(4-(((2R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-6-fluoro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.08 g, 0.14 mmol), 10% palladium on carbon (0.05 g) and THF (5 ml) were added to the reaction bottle in sequence, the hydrogen was replaced 3-4 times, and the reaction was stirred at room temperature for 8 h. After the reaction was completed, the mixture was filtered with diatomaceous earth, the filter cake was rinsed with THF, the filtrate was desolvated, and DCM/MeOH system column chromatography was used to obtain 0.02 g of the product with a yield of 27%.

1H NMR(400MHz，DMSO-d6)δ11.21(s，1H)，9.15(s，1H)，8.26(s，1H)，7.47(d，J＝10.3Hz，1H)，7.11(d，J＝7.5Hz，3H)，6.82(d，J＝7.4Hz，2H)，6.65-6.54(m，4H)，6.48(dd，J＝8.2，2.5Hz，1H)，6.22(d，J＝8.3Hz，2H)，5.73-5.60(m，1H)，4.15-4.11(m，1H)，3.54-3.50(m，1H)，3.15-2.66(m，18H)，2.28-1.94(m，8H)，1.80-1.52(m，9H)，1.09-0.94(m，3H)，0.92-0.77(m，2H).MS(ESI)m/z：821.4[M-H]-. 1 H NMR (400MHz, DMSO-d 6 )δ11.21 (s, 1H), 9.15 (s, 1H), 8.26 (s, 1H), 7.47 (d, J = 10.3Hz, 1H), 7.11 (d, J = 7.5Hz, 3H), 6.82 (d, J=7.4Hz, 2H), 6.65-6.54 (m, 4H), 6.48 (dd, J=8.2, 2.5Hz, 1H), 6.22 (d, J=8.3Hz, 2H ), 5.73-5.60(m, 1H), 4.15-4.11(m, 1H), 3.54-3.50(m, 1H), 3.15-2.66(m, 18H), 2.28-1.9 4(m, 8H), 1.80-1.52(m, 9H), 1.09-0.94(m, 3H), 0.92-0.77(m, 2H).MS(ESI)m/z: 821.4[MH] - .

实施例21：3-(5-(1-(((1R，2R)-2-((4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮的合成(化合物V-7)
Example 21: Synthesis of 3-(5-(1-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound V-7)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：2，6-双(苄氧基)吡啶-3-胺的合成
Step 1: Synthesis of 2,6-bis(benzyloxy)pyridin-3-amine

室温下，依次向反应瓶中加入2，6-二氯-3-氨基吡啶(9.00g，55.21mmol)，叔丁醇钾(18.58g，165.64mmol)，苄醇(17.92g，165.64mmol)和四氢呋喃(200ml)，升温至70℃搅拌反应20h。反应完成后，降温，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物4.08g，收率48％。At room temperature, 2,6-dichloro-3-aminopyridine (9.00 g, 55.21 mmol), potassium tert-butoxide (18.58 g, 165.64 mmol), benzyl alcohol (17.92 g, 165.64 mmol) and tetrahydrofuran (200 ml) were added to the reaction bottle in sequence, and the temperature was raised to 70°C and stirred for reaction for 20 hours. After the reaction was completed, the temperature was lowered, ethyl acetate and water were added, and the liquids were separated. After the organic phase was dried, it was chromatographed using a PE/EA system column to obtain 4.08 g of the product with a yield of 48%.

步骤2：2，6-双(苄氧基)-N-(4-溴-2-硝基苯基)吡啶-3-胺的合成
Step 2: Synthesis of 2,6-bis(benzyloxy)-N-(4-bromo-2-nitrophenyl)pyridin-3-amine

向反应瓶中依次加入2，6-双(苄氧基)吡啶-3-胺(3.58g，11.70mmol)，4-溴-1-氟-2-硝基苯(3.09g，14.03mmol)，氟化钾(0.82g，14.03mmol)和DMF(20ml)，升温130℃搅拌反应18小时。反应完成后，降温，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物5.90g，收率99％。2,6-bis(benzyloxy)pyridin-3-amine (3.58 g, 11.70 mmol), 4-bromo-1-fluoro-2-nitrobenzene (3.09 g, 14.03 mmol), potassium fluoride (0.82 g, 14.03 mmol) and DMF (20 ml) were added to the reaction bottle in sequence, and the temperature was raised to 130°C and stirred for 18 hours. After the reaction was completed, the temperature was lowered, ethyl acetate and water were added, and the liquids were separated. After the organic phase was dried, it was chromatographed using a PE/EA system column to obtain 5.90 g of the product with a yield of 99%.

步骤3：N1-(2，6-双(苄氧基)吡啶-3-基)-4-溴苯-1，2-二胺的合成
Step 3: Synthesis of N1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromobenzene-1,2-diamine

向反应瓶中依次加入甲醇(80ml)，四氢呋喃(80ml)，2，6-双(苄氧基)-N-(4-溴-2-硝基苯基)吡啶-3-胺(5.90g，11.65mmol)和六水合氯化镍(0.28g，1.17mmol)，降温至0℃，分批控温加入硼氢化钠(1.10g，29.01mmol)，加完后冰浴下反应1小时。反应完成后加入水淬灭，搅拌10分钟后脱溶，粗品使用PE/EA体系柱层析，得到产物3.30g，收率：59％。Methanol (80 ml), tetrahydrofuran (80 ml), 2,6-bis(benzyloxy)-N-(4-bromo-2-nitrophenyl)pyridin-3-amine (5.90 g, 11.65 mmol) and nickel chloride hexahydrate (0.28 g, 1.17 mmol) were added to the reaction bottle in sequence, the temperature was lowered to 0°C, sodium borohydride (1.10 g, 29.01 mmol) was added in batches with temperature control, and the mixture was reacted in an ice bath for 1 hour after the addition. After the reaction was completed, water was added to quench the mixture, and the mixture was desolvated after stirring for 10 minutes. The crude product was subjected to PE/EA system column chromatography to obtain 3.30 g of the product with a yield of 59%.

步骤4：1-(2，6-双(苄氧基)吡啶-3-基)-5-溴-1H-苯并[d]咪唑的合成
Step 4: Synthesis of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-1H-benzo[d]imidazole

依次向反应瓶中加入甲苯(15ml)，N1-(2，6-双(苄氧基)吡啶-3-基)-4-溴苯-1，2-二胺(2.00g，4.20mmol)，原甲酸三甲酯(1.11g，10.50mmol)和PTSA(0.14g，0.84mmol)，升温至120℃反应2小时。反应完成后，降温至室温，脱溶甲苯，并使用二氯甲烷带蒸一次。粗品使用PE/EA体系柱层析，得到产物1.21g，收率：59％。Toluene (15 ml), N1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromobenzene-1,2-diamine (2.00 g, 4.20 mmol), trimethyl orthoformate (1.11 g, 10.50 mmol) and PTSA (0.14 g, 0.84 mmol) were added to the reaction bottle in sequence, and the temperature was raised to 120°C for reaction for 2 hours. After the reaction was completed, the temperature was lowered to room temperature, toluene was desolvated, and dichloromethane was used for strip distillation once. The crude product was subjected to PE/EA system column chromatography to obtain 1.21 g of the product, with a yield of 59%.

步骤5：4-(1-(2，6-双(苄氧基)吡啶-3-基)-1H-苯并[d]咪唑-5-基)-3，6-二氢吡啶-1(2H)-甲酸叔丁酯的合成
Step 5: Synthesis of tert-butyl 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-1H-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

室温下，依次向反应瓶中加入1-(2，6-双(苄氧基)吡啶-3-基)-5-溴-1H-苯并[d]咪唑(0.60g，1.23mmol)，N-Boc-1，2，5，6-四氢吡啶-4-硼酸频哪醇酯(0.57g，1.85mmol)，Xphos-Pd-G2(0.10g，0.12mmol)，磷酸钾(0.52g，2.47mmol)，水(3ml)和1，4-二氧六环(10ml)，置换氮气3-4次，升温至80℃反应4h。反应完成后，降温至室温，脱溶，加入乙酸乙酯稀释，垫硅藻土过滤，滤液干燥后，脱溶，使用PE/EA体系柱层析，得到产物0.51g，收率71％。At room temperature, 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-1H-benzo[d]imidazole (0.60 g, 1.23 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (0.57 g, 1.85 mmol), Xphos-Pd-G2 (0.10 g, 0.12 mmol), potassium phosphate (0.52 g, 2.47 mmol), water (3 ml) and 1,4-dioxane (10 ml) were added to the reaction bottle in sequence, nitrogen was replaced 3-4 times, and the temperature was raised to 80° C. for 4 h. After the reaction was completed, the temperature was lowered to room temperature, solvent removed, ethyl acetate was added to dilute, diatomaceous earth was padded and filtered, the filtrate was dried, solvent removed, and PE/EA system column chromatography was used to obtain 0.51 g of the product with a yield of 71%.

步骤6：4-(1-(2，6-二氧代哌啶-3-基)-1H-苯并[d]咪唑-5-基)哌啶-1-甲酸叔丁酯的合成
Step 6: Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate

室温下，依次向反应瓶中加入4-(1-(2，6-双(苄氧基)吡啶-3-基)-1H-苯并[d]咪唑-5-基)-3，6-二氢吡啶-1(2H)-甲酸叔丁酯(0.51g，0.87mmol)和四氢呋喃(15ml)，加入10％钯碳(0.08g)，置换氢气3-4次，室温搅拌反应16h。反应完成后，垫硅藻土过滤，脱溶，得到产物0.15g，收率：41％。At room temperature, 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-1H-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.51 g, 0.87 mmol) and tetrahydrofuran (15 ml) were added to the reaction bottle in sequence, and 10% palladium carbon (0.08 g) was added, and hydrogen was replaced 3-4 times. The reaction was stirred at room temperature for 16 hours. After the reaction was completed, diatomaceous earth was used for filtration and solvent removal to obtain 0.15 g of the product, with a yield of 41%.

步骤7：3-(5-(哌啶-4-基)-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮的合成
Step 7: Synthesis of 3-(5-(piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(5-(哌啶-4-基)-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮(0.15g，0.35mmol)，盐酸/二氧六环溶液(3ml)和二氯甲烷(3ml)，室温搅拌反应2h。反应完成后，脱溶，得到粗品0.16g，直接下一步(下一步按理论收率0.11g投料)。At room temperature, 3-(5-(piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.15 g, 0.35 mmol), hydrochloric acid/dioxane solution (3 ml) and dichloromethane (3 ml) were added to the reaction bottle in sequence, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the solvent was removed to obtain 0.16 g of crude product, which was directly used in the next step (the next step was charged according to the theoretical yield of 0.11 g).

步骤8：3-(5-(1-(((1R，2R)-2-((4-(((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮的合成
Step 8: Synthesis of 3-(5-(1-(((1R,2R)-2-((4-(((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(5-(哌啶-4-基)-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮(0.11g，0.35mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.21g，0.35mmol)和二氯甲烷(10ml)，再加入TIPT(0.5ml)，室温搅拌16小时，再加入STAB(0.15g，0.70mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.26g，收率：83％。At room temperature, 3-(5-(piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.11 g, 0.35 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.21 g, 0.35 mmol) and dichloromethane (10 ml) were added to the reaction bottle in sequence, and TIPT (0.5 ml) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.15 g, 0.70 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.26 g of the product with a yield of 83%.

步骤9：3-(5-(1-(((1R，2R)-2-((4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮的合成
Step 9: Synthesis of 3-(5-(1-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(5-(1-(((1R，2R)-2-((4-(((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮(0.26g，0.29mmol)，10％钯碳(0.02g)和四氢呋喃(10ml)，再加入置换氢气3-4次，室温搅拌反应90h。反应完成后，垫硅藻土过滤，滤饼使用四氢呋喃淋洗滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.006g，收率：5％，入库0.003g。At room temperature, 3-(5-(1-(((1R, 2R)-2-((4-(((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.26 g, 0.29 mmol), 10% palladium on carbon (0.02 g) and tetrahydrofuran (10 ml) were added to the reaction bottle in sequence, and then hydrogen was replaced 3-4 times. The reaction was stirred at room temperature for 90 hours. After the reaction was completed, diatomaceous earth was used for filtration, and the filter cake was eluted with tetrahydrofuran and the filtrate was desolvated. The product was chromatographed on a DCM/MeOH system to obtain 0.006 g of the product with a yield of 5%, and 0.003 g was put into storage.

1H NMR(400MHz，DMSO-d6)δ11.21(s，1H)，9.15(s，1H)，8.25(s，1H)，7.55(s，1H)，7.47(d，J＝8.4Hz，1H)，7.21-7.07(m，4H)，6.82(d，J＝7.7Hz，2H)，6.67-6.54(m，3H)，6.47(dd，J＝8.4，2.5Hz，1H)，6.23(d，J＝7.9Hz，2H)，5.69(dd，J＝12.8，5.0Hz，1H)，4.47(s，1H)，4.14(d，J＝5.0Hz，1H)，3.18-3.05(m，4H)，3.00-2.85(m，6H)，2.82-2.67(m，4H)，2.30-2.14(m，2H)，2.12-1.91(m，4H)，1.77-1.60(m，6H)，1.39-1.18(m，10H)，1.08-0.97(m，2H)，0.90-0.79(m，2H).MS(ESI)m/z：805.2[M+H]+. 1 H NMR (400MHz, DMSO-d 6 )δ11.21 (s, 1H), 9.15 (s, 1H), 8.25 (s, 1H), 7.55 (s, 1H), 7.47 (d, J=8.4Hz, 1H), 7.21-7.07 (m, 4H), 6.82 (d, J=7.7H z, 2H), 6.67-6.54 (m, 3H), 6.47 (dd, J=8.4, 2.5Hz, 1H), 6.23 (d, J=7.9Hz, 2H), 5.69 (dd, J=12.8, 5.0Hz, 1H), 4.47 ( s, 1H), 4.14 (d, J=5.0Hz, 1H), 3.18-3.05 (m, 4H), 3.00-2.85 (m, 6H), 2.82-2.67 (m, 4H), 2.30-2.14 (m, 2H), 2.12-1 .91(m, 4H), 1.77-1.60(m, 6H), 1.39-1.18(m, 10H), 1.08-0.97(m, 2H), 0.90-0.79(m, 2H).MS(ESI)m/z: 805.2[M+H] + .

实施例22：3-(5-(4-(((1R，2R)-2-((4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮的合成(化合物V-3)
Example 22: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound V-3)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：4-(1-(2，6-双(苄氧基)吡啶-3-基)-1H-苯并[d]咪唑-5-基)哌嗪-1-甲酸叔丁酯的合成
Step 1: Synthesis of tert-butyl 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入1-(2，6-双(苄氧基)吡啶-3-基)-5-溴-1H-苯并[d]咪唑(0.42g，0.84mmol)，1-Boc-哌嗪(0.63g，3.37mmol)，Pd2(dba)3(0.08g，0.08mmol)，叔丁醇钠(0.16g，1.69mmol)，10％的三叔丁基膦溶液(0.30g，0.17mmol)和甲苯(10ml)，置换氮气3-4次，升温至100℃反应16h。反应完成后，降温至室温，脱溶，加入乙酸乙酯稀释，垫硅藻土过滤，滤液干燥后，脱溶，使用PE/EA体系柱层析，得到产物0.30g，收率59％。At room temperature, 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-1H-benzo[d]imidazole (0.42 g, 0.84 mmol), 1-Boc-piperazine (0.63 g, 3.37 mmol), Pd 2 (dba) 3 (0.08 g, 0.08 mmol), sodium tert-butoxide (0.16 g, 1.69 mmol), 10% tri-tert-butylphosphine solution (0.30 g, 0.17 mmol) and toluene (10 ml) were added to the reaction bottle in sequence, nitrogen was replaced 3-4 times, and the temperature was raised to 100° C. for 16 h. After the reaction was completed, the temperature was lowered to room temperature, solvent removed, ethyl acetate was added to dilute, diatomaceous earth was padded and filtered, the filtrate was dried, solvent removed, and PE/EA system column chromatography was used to obtain 0.30 g of the product with a yield of 59%.

步骤2：4-(1-(2，6-二氧代哌啶-3-基)-1H-苯并[d]咪唑-5-基)哌嗪-1-甲酸叔丁酯的合成
Step 2: Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入4-(1-(2，6-双(苄氧基)吡啶-3-基)-1H-苯并[d]咪唑-5-基)哌嗪-1-甲酸叔丁酯(0.30g，0.50mmol)和四氢呋喃(15ml)，加入10％钯碳(0.03g)，置换氢气3-4次，室温搅拌反应16h。反应完成后，垫硅藻土过滤，脱溶，得到产物0.08g，收率：35％。步骤3：3-(5-(哌嗪-1-基)-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮的合成
At room temperature, tert-butyl 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate (0.30 g, 0.50 mmol) and tetrahydrofuran (15 ml) were added to the reaction bottle in sequence, and 10% palladium on carbon (0.03 g) was added to replace the hydrogen 3-4 times. The reaction was stirred at room temperature for 16 hours. After the reaction was completed, diatomaceous earth was used for filtration and desolventization to obtain 0.08 g of the product with a yield of 35%. Step 3: Synthesis of 3-(5-(piperazine-1-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入4-(1-(2，6-二氧代哌啶-3-基)-1H-苯并[d]咪唑-5-基)哌嗪-1-甲酸叔丁酯(0.08g，0.18mmol)，盐酸/二氧六环溶液(3ml)和二氯甲烷(3ml)，室温搅拌反应2h。反应完成后，脱溶，得到粗品0.09g，直接下一步。At room temperature, tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate (0.08 g, 0.18 mmol), hydrochloric acid/dioxane solution (3 ml) and dichloromethane (3 ml) were added to the reaction bottle in sequence, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the solvent was removed to obtain 0.09 g of a crude product, which was directly used in the next step.

步骤4：3-(5-(4-(((1R，2R)-2-((4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮的合成
Step 4: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(5-(哌嗪-1-基)-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮(0.07g，0.23mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.11g，0.19mmol)和二氯甲烷(10ml)，再加入TIPT(0.5ml)，室温搅拌16小时，再加入STAB(0.10g，0.47mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.10g，收率：62％。At room temperature, 3-(5-(piperazine-1-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.07 g, 0.23 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-yl)methyl)cyclohexane-1-carbaldehyde (0.11 g, 0.19 mmol) and dichloromethane (10 ml) were added to the reaction bottle in sequence, and TIPT (0.5 ml) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.10 g, 0.47 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.10 g of the product with a yield of 62%.

步骤5：3-(5-(4-(((1R，2R)-2-((4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮
Step 5: 3-(5-(4-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(5-(4-(((1R，2R)-2-((4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮(0.10g，0.12mmol)，10％钯碳(0.01g)和四氢呋喃(10ml)，再加入置换氢气3-4次，室温搅拌反应48h。反应完成后，垫硅藻土过滤，滤饼使用四氢呋喃淋洗滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.006g，收率：5％，入库0.002g。At room temperature, 3-(5-(4-(((1R, 2R)-2-((4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.10 g, 0.12 mmol), 10% palladium on carbon (0.01 g) and tetrahydrofuran (10 ml) were added to the reaction bottle in sequence, and then hydrogen was replaced 3-4 times. The reaction was stirred at room temperature for 48 hours. After the reaction was completed, diatomaceous earth was used for filtration, and the filter cake was eluted with tetrahydrofuran and the filtrate was desolvated. The product was chromatographed on a DCM/MeOH system to obtain 0.006 g of the product with a yield of 5%, and 0.002 g was put into storage.

1H NMR(400MHz，DMSO-d6)δ11.18(s，1H)，8.22(s，1H)，8.14(s，1H)，7.37(d，J＝9.0Hz，1H)，7.14(d，J＝9.1Hz，4H)，7.00(d，J＝8.9Hz，1H)，6.83(d，J＝7.3Hz，2H)，6.69-6.58(m，2H)，6.50(dd，J＝19.9，8.6Hz，3H)，6.21(d，J＝8.0Hz，1H)，5.61(dd，J＝13.0，4.9Hz，1H)，4.13(d，J＝4.8Hz，1H)，3.11-3.02(m，5H)，3.02-2.84(m，6H)，2.81-2.60(m，3H)，2.42-2.31(m，4H)，2.29-2.16(m，2H)，2.14-2.03(m，4H)，1.95-1.78(m，3H)，1.75-1.36(m，7H)，1.25-0.92(m，6H).MS(ESI)m/z：806.4[M+H]+. 1 H NMR (400MHz, DMSO-d 6 ) δ11.18 (s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 7.37 (d, J = 9.0Hz, 1H), 7.14 (d, J = 9.1Hz, 4H), 7.00 (d, J = 8.9Hz, 1H), 6. 83 (d, J=7.3Hz, 2H), 6.69-6.58 (m, 2H), 6.50 (dd, J=19.9, 8.6Hz, 3H), 6.21 (d, J=8.0Hz, 1H), 5.61 (dd, J=13.0, 4.9 Hz, 1H), 4.13 (d, J=4.8Hz, 1H), 3.11-3.02 (m, 5H), 3.02-2.84 (m, 6H), 2.81-2.60 (m, 3H), 2.42-2.31 (m, 4H), 2.29- 2.16(m, 2H), 2.14-2.03(m, 4H), 1.95-1.78(m, 3H), 1.75-1.36(m, 7H), 1.25-0.92(m, 6H).MS(ESI)m/z: 806.4[M+H] + .

实施例23：3-(5-(4-(((1R，2R)-2-((4-(4-(1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪1-基)-2-甲基-1H-苯并咪唑-1-基)哌啶-2，6-二酮的合成(化合物V-1)
Example 23: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-2-methyl-1H-benzimidazol-1-yl)piperidine-2,6-dione (Compound V-1)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：1-(2，6-双(苄氧基)吡啶-3-基)-5-溴-2-甲基-1H-苯并[d]咪唑的合成
Step 1: Synthesis of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-2-methyl-1H-benzo[d]imidazole

依次向反应瓶中加入乙酸(10ml)，N1-(2，6-双(苄氧基)吡啶-3-基)-4-溴苯-1，2-二胺(0.84g，1.77mmol)，原甲酸三乙酯(0.32g，2.65mmol)，升温120℃反应3小时。反应完成后，降温至室温，脱溶至无明显液滴，制砂，使用PE/EA体系柱层析，得到产物0.92g(有少量乙酸残留，不影响下一步)。Acetic acid (10 ml), N1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromobenzene-1,2-diamine (0.84 g, 1.77 mmol), and triethyl orthoformate (0.32 g, 2.65 mmol) were added to the reaction bottle in sequence, and the temperature was raised to 120°C for reaction for 3 hours. After the reaction was completed, the temperature was lowered to room temperature, the solvent was removed until there were no obvious droplets, sand was made, and PE/EA system column chromatography was used to obtain 0.92 g of the product (a small amount of acetic acid remained, which did not affect the next step).

步骤2：4-(1-(2，6-双(苄氧基)吡啶-3-基)-2-甲基-1H-苯并[d]咪唑-5-基)哌嗪-1-甲酸叔丁酯的合成
Step 2: Synthesis of tert-butyl 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-2-methyl-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入1-(2，6-双(苄氧基)吡啶-3-基)-5-溴-2-甲基-1H-苯并[d]咪唑(0.92g，1.84mmol)，1-Boc-哌嗪(1.37g，7.36mmol)，Pd2(dba)3(0.17g，0.18mmol)，叔丁醇钠(0.35g，3.68mmol)，10％的三叔丁基膦溶液(0.74g，0.37mmol)和甲苯(10ml)，置换氮气3-4次，升温至100℃反应16h。反应完成后，降温至室温，脱溶，加入乙酸乙酯稀释，垫硅藻土过滤，滤液干燥后，脱溶，使用PE/EA体系柱层析，得到产物0.46g，收率42％。步骤3：4-(1-(2，6-二氧代哌啶-3-基)-2-甲基-1H-苯并[d]咪唑-5-基)哌嗪-1-甲酸叔丁酯的合成
At room temperature, 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-2-methyl-1H-benzo[d]imidazole (0.92 g, 1.84 mmol), 1-Boc-piperazine (1.37 g, 7.36 mmol), Pd 2 (dba) 3 (0.17 g, 0.18 mmol), sodium tert-butoxide (0.35 g, 3.68 mmol), 10% tri-tert-butylphosphine solution (0.74 g, 0.37 mmol) and toluene (10 ml) were added to the reaction bottle in sequence, nitrogen was replaced 3-4 times, and the temperature was raised to 100° C. for reaction for 16 h. After the reaction was completed, the temperature was lowered to room temperature, solvent removed, ethyl acetate was added to dilute, diatomaceous earth was padded and filtered, the filtrate was dried, solvent removed, and PE/EA system column chromatography was used to obtain 0.46 g of the product with a yield of 42%. Step 3: Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-2-methyl-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate

室温下，依次向反应瓶中加入4-(1-(2，6-双(苄氧基)吡啶-3-基)-2-甲基-1H-苯并[d]咪唑-5-基)哌嗪-1-甲酸叔丁酯(0.46g，0.76mmol)和四氢呋喃(15ml)，加入10％钯碳(0.03g)，置换氢气3-4次，室温搅拌反应16h。反应完成后，垫硅藻土过滤，脱溶，得到产物0.18g，收率：57％。At room temperature, tert-butyl 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-2-methyl-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate (0.46 g, 0.76 mmol) and tetrahydrofuran (15 ml) were added to the reaction bottle in sequence, and 10% palladium carbon (0.03 g) was added, and hydrogen was replaced 3-4 times. The reaction was stirred at room temperature for 16 hours. After the reaction was completed, diatomaceous earth was used for filtration and solvent removal to obtain 0.18 g of the product, with a yield of 57%.

步骤4：3-(2-甲基-5-(哌嗪-1-基)-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮的合成
Step 4: Synthesis of 3-(2-methyl-5-(piperazin-1-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入4-(1-(2，6-二氧代哌啶-3-基)-2-甲基-1H-苯并[d]咪唑-5-基)哌嗪-1-甲酸叔丁酯(0.18g，0.41mmol)，盐酸/二氧六环溶液(3ml)和二氯甲烷(3ml)，室温搅拌反应2h。反应完成后，脱溶，得到粗品，直接下一步，下一步按照理论产率0.13g投料。步骤5：3-(5-(4-(((1R，2R)-2-((4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-2-甲基-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮的合成
At room temperature, tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-2-methyl-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate (0.18 g, 0.41 mmol), hydrochloric acid/dioxane solution (3 ml) and dichloromethane (3 ml) were added to the reaction bottle in sequence, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, the solvent was removed to obtain a crude product, which was directly used for the next step. The next step was charged according to the theoretical yield of 0.13 g. Step 5: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-2-methyl-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(2-甲基-5-(哌嗪-1-基)-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮(0.13g，0.23mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.20g，0.33mmol)和二氯甲烷(10ml)，再加入TIPT(0.5ml)，室温搅拌16小时，再加入STAB(0.13g，0.61mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.04g，两步收率：15％。At room temperature, 3-(2-methyl-5-(piperazine-1-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.13 g, 0.23 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-yl)methyl)cyclohexane-1-carbaldehyde (0.20 g, 0.33 mmol) and dichloromethane (10 ml) were added to the reaction bottle in sequence, and TIPT (0.5 ml) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.13 g, 0.61 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.04 g of the product with a two-step yield of 15%.

步骤6：3-(5-(4-(((1R，2R)-2-((4-(4-(1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪1-基)-2-甲基-1H-苯并咪唑-1-基)哌啶-2，6-二酮的合成
Step 6: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-2-methyl-1H-benzimidazol-1-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(5-(4-(((1R，2R)-2-((4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)-2-甲基-1H-苯并[d]咪唑-1-基)哌啶-2，6-二酮(0.04g，0.04mmol)，10％钯碳(0.01g)和四氢呋喃(10ml)，再加入置换氢气3-4次，室温搅拌反应6h。反应完成后，垫硅藻土过滤，滤饼使用四氢呋喃淋洗滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.002g，收率：6％。MS(ESI)m/z：821.09[M+H]+.At room temperature, 3-(5-(4-(((1R, 2R)-2-((4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-2-methyl-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.04 g, 0.04 mmol), 10% palladium on carbon (0.01 g) and tetrahydrofuran (10 ml) were added to the reaction bottle in sequence, and then hydrogen was replaced 3-4 times. The reaction was stirred at room temperature for 6 h. After the reaction was completed, diatomaceous earth was used for filtration, and the filter cake was eluted with tetrahydrofuran and the filtrate was desolvated. The product was chromatographed on a DCM/MeOH system to obtain 0.002 g of the product, with a yield of 6%. MS (ESI) m/z: 821.09 [M+H] + .

实施例24：3-(5-氟-6-(1-(((1S，2S)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)哌啶-2，6-二酮的合成(化合物IV-10)
Example 24: Synthesis of 3-(5-fluoro-6-(1-(((1S,2S)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (Compound IV-10)

(1S，2S)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：3-(2，6-双(苄氧)吡啶-3-基)-6-溴-5-氟-1-甲基-1H-吲唑的合成
Step 1: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole

室温下，依次向反应瓶中加入6-溴-5-氟-3-碘-1-甲基-1H-吲唑(1.00g，2.97mmol)，2，6-双(苄氧)-3-(4，4，5，5-四甲基-1，3，2-二氧杂环戊烷-2-基)吡啶(1.24g，2.97mmol)，碳酸钠(0.94g，8.90mmol)，四三苯基膦钯(0.34g，0.30mmol)，水(1mL)和二氧六环(10ml)，90℃下，氮气氛围，反应5h。反应完成后，降至室温，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物1.20g，收率81％。At room temperature, 6-bromo-5-fluoro-3-iodo-1-methyl-1H-indazole (1.00 g, 2.97 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridine (1.24 g, 2.97 mmol), sodium carbonate (0.94 g, 8.90 mmol), tetrakistriphenylphosphine palladium (0.34 g, 0.30 mmol), water (1 mL) and dioxane (10 ml) were added to the reaction bottle in sequence, and the mixture was reacted for 5 h at 90° C. in a nitrogen atmosphere. After the reaction was completed, the mixture was cooled to room temperature, ethyl acetate and water were added, and the liquid was separated. After the organic phase was dried, PE/EA system column chromatography was used to obtain 1.20 g of the product with a yield of 81%.

步骤2：4-(3-(2，6-双(苄氧)吡啶-3-基)-5-氟-1-甲基-1H-吲唑-6-基)-3，6-二氢吡啶-1(2H)-甲酸叔丁酯的合成
Step 2: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate

室温下，依次向反应瓶中加入3-(2，6-双(苄氧)吡啶-3-基)-6-溴-5-氟-1-甲基-1H-吲唑(0.60g，1.16mmol)，4-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊二烯-2-基)-3，6-二氢吡啶-1(2H)-甲酸叔丁酯(0.40g，1.27mmol)，dppfPdCl2(0.09g，0.12mmol)，碳酸钾(0.48g，3.47mmol)，水(1mL)和二氧六环(10ml)。90℃下，氮气氛围，反应5h。反应完成后，降温至室温，加入乙酸乙酯和水，分液，有机相干燥后，使用PE/EA体系柱层析，得到产物0.47g，收率66％。At room temperature, 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole (0.60 g, 1.16 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.40 g, 1.27 mmol), dppfPdCl 2 (0.09 g, 0.12 mmol), potassium carbonate (0.48 g, 3.47 mmol), water (1 mL) and dioxane (10 ml) were added to the reaction bottle in sequence. The reaction was carried out at 90° C. in a nitrogen atmosphere for 5 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, the liquids were separated, and the organic phase was dried and then chromatographed using a PE/EA system column to obtain 0.47 g of the product with a yield of 66%.

步骤3：4-(3-(2，6-二氧代哌啶-3-基)-5-氟-1-甲基-1H-吲哚-6-基)哌啶-1-甲酸叔丁基酯的合成
Step 3: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indol-6-yl)piperidine-1-carboxylate

室温下，依次向反应瓶中加入4-(3-(2，6-双(苄氧)吡啶-3-基)-5-氟-1-甲基-1H-吲唑-6-基)-3，6-二氢吡啶-1(2H)-甲酸叔丁酯(0.40g，0.66mmol)，10％Pd/C(0.04g)，四氢呋喃(5mL)和乙醇(5ml)，室温反应24h。反应完成后，过滤旋干，得到粗品0.26g，直接下一步。At room temperature, 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.40 g, 0.66 mmol), 10% Pd/C (0.04 g), tetrahydrofuran (5 mL) and ethanol (5 ml) were added to the reaction bottle in sequence and reacted at room temperature for 24 h. After the reaction was completed, the mixture was filtered and dried to obtain 0.26 g of a crude product, which was directly used in the next step.

步骤4：3-(5-氟-1-甲基-6-(哌啶-4-基)-1H-吲哚-3-基)哌啶-2，6-二酮的合成
Step 4: Synthesis of 3-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indol-3-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入4-(3-(2，6-二氧代哌啶-3-基)-5-氟-1-甲基-1H-吲哚-6-基)哌啶-1-甲酸叔丁基酯(0.26g，0.60mmol)和HCl二氧六环溶液(5ml)，室温反应2h。反应完成后，旋干，得到粗品0.22g，直接下一步。At room temperature, tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indol-6-yl)piperidine-1-carboxylate (0.26 g, 0.60 mmol) and HCl dioxane solution (5 ml) were added to the reaction bottle in sequence, and the mixture was reacted at room temperature for 2 h. After the reaction was completed, the mixture was spin-dried to obtain 0.22 g of a crude product, which was directly used for the next step.

步骤5：3-(6-(1-(((1S，2S)-2-((4-(4-(((2R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)哌啶-2，6-二酮的合成
Step 5: Synthesis of 3-(6-(1-(((1S,2S)-2-((4-(4-(((2R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(5-氟-1-甲基-6-(哌啶-4-基)-1H-吲哚-3-基)哌啶-2，6-二酮(0.15g，0.47mmol)，(1S，2S)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.28g，0.47mmol)和二氯甲烷(5mL)，再加入TIPT(0.5mL)，室温搅拌16小时，再加入STAB(0.15g，0.71mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.21g，三步收率：62％。At room temperature, 3-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indol-3-yl)piperidine-2,6-dione (0.15 g, 0.47 mmol), (1S, 2S)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.28 g, 0.47 mmol) and dichloromethane (5 mL) were added to the reaction bottle in sequence, and TIPT (0.5 mL) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.15 g, 0.71 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.21 g of the product with a three-step yield of 62%.

步骤6：3-(5-氟-6-(1-(((1S，2S)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)哌啶-2，6-二酮的合成
Step 6: Synthesis of 3-(5-fluoro-6-(1-(((1S,2S)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

室温下，依次向反应瓶中加入3-(6-(1-(((1S，2S)-2-((4-(4-(((2R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)哌啶-2，6-二酮(0.21g，0.23mmol)，10％钯碳(0.10g)和THF(3mL)，置换氢气3-4次，室温搅拌反应24h。反应完成后，垫硅藻土过滤，滤饼使用THF淋洗，滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.11g，收率：58％。At room temperature, 3-(6-(1-(((1S, 2S)-2-((4-(4-(((2R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (0.21 g, 0.23 mmol), 10% palladium on carbon (0.10 g) and THF (3 mL) were added to the reaction bottle in sequence, hydrogen was replaced 3-4 times, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, diatomaceous earth was used for filtration, the filter cake was rinsed with THF, the filtrate was desolvated, and DCM/MeOH system column chromatography was used to obtain 0.11 g of the product, with a yield of 58%.

1H NMR(400MHz，DMSO-d6)δ10.91(s，1H)，9.16(s，1H)，7.59-7.40(m，2H)，7.16-7.05(m，3H)，6.78(s，2H)，6.65-6.54(m，4H)，6.47(dd，J＝8.2，2.6Hz，1H)，6.22(d，J＝8.1Hz，2H)，4.32(dd，J＝10.1，5.0Hz，1H)，4.14(d，J＝5.0Hz，1H)，3.95(s，3H)，3.64-3.60(m，1H)，3.20-2.88(m，12H)，2.72-2.59(m，4H)，2.43-2.19(m，3H)，2.17-1.44(m，17H)，1.06-0.83(m，3H).MS(ESI)m/z：837.7[M+H]+. 1 H NMR (400MHz, DMSO-d 6 )δ10.91 (s, 1H), 9.16 (s, 1H), 7.59-7.40 (m, 2H), 7.16-7.05 (m, 3H), 6.78 (s, 2H), 6.65-6. 54 (m, 4H), 6.47 (dd, J=8.2, 2.6Hz, 1H), 6.22 (d, J=8.1Hz, 2H), 4.32 (dd, J=10.1, 5.0Hz, 1H ), 4.14(d, J=5.0Hz, 1H), 3.95(s, 3H), 3.64-3.60(m, 1H), 3.20-2.88(m, 12H), 2.72-2.59( m, 4H), 2.43-2.19 (m, 3H), 2.17-1.44 (m, 17H), 1.06-0.83 (m, 3H). MS (ESI) m/z: 837.7[M+H] + .

实施例25：1-(5-氟-6-(8-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)-8-氮杂双环[3.2.1]辛-3-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成(化合物VI-17)
Example 25: Synthesis of 1-(5-fluoro-6-(8-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-17)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：叔丁基3-(3-(2，4-二氧代四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-8-氮杂双环4辛-2-烯-8-羧酸酯的合成
Step 1: Synthesis of tert-butyl 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-8-azabicyclo-4-oct-2-ene-8-carboxylate

室温下，依次向反应瓶中加入1-(6-溴-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.10g，0.29mmol)，8-叔丁氧羰基-8-氮杂双环[3.2.1]辛-2-烯-3-硼酸频哪醇酯(0.11g，0.32mmol)，Pd(dppf)Cl2(0.02g，0.03mmol)，Cs2CO3(0.29g，0.88mmol)，Do(5ml)和H2O(1ml)，置换氮气3-4次，升温至80℃反应2h。反应完成后，降温至室温，过滤，滤液浓缩，使用DCM/MeOH体系柱层析，再用EA打浆得到白色固体0.10g，收率72.9％。At room temperature, 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.10 g, 0.29 mmol), 8-tert-butyloxycarbonyl-8-azabicyclo[3.2.1]oct-2-ene-3-boronic acid pinacol ester (0.11 g, 0.32 mmol), Pd(dppf)Cl 2 (0.02 g, 0.03 mmol), Cs 2 CO 3 (0.29 g, 0.88 mmol), Do (5 ml) and H 2 O (1 ml) were added to the reaction bottle in sequence, nitrogen was replaced 3-4 times, and the temperature was raised to 80° C. for reaction for 2 h. After the reaction was completed, the temperature was lowered to room temperature, filtered, the filtrate was concentrated, and DCM/MeOH system column chromatography was used, and EA was used for slurrying to obtain 0.10 g of white solid with a yield of 72.9%.

步骤2：1-(6-(8-氮杂双环[3.2.1]辛-2-烯-3-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成
Step 2: Synthesis of 1-(6-(8-azabicyclo[3.2.1]oct-2-en-3-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

室温下，依次向反应瓶中加入叔丁基3-(3-(2，4-二氧代四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲哚-6-基)-8-氮杂双环4辛-2-烯-8-羧酸酯(0.10mg，0.21mmol)和二氯甲烷(2ml)，溶清后加入盐酸/二氧六环(5ml)，室温搅拌反应2h。反应完成后，脱溶，得到白色固体粗品0.10g，直接进行下一步。At room temperature, tert-butyl 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indol-6-yl)-8-azabicyclo-4-oct-2-ene-8-carboxylate (0.10 mg, 0.21 mmol) and dichloromethane (2 ml) were added to the reaction bottle in sequence, and hydrochloric acid/dioxane (5 ml) was added after dissolving, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed to obtain 0.10 g of a white solid crude product, which was directly carried out to the next step.

步骤3：1-(6-(8-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成
Step 3: Synthesis of 1-(6-(8-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)-8-azabicyclo[3.2.1]oct-2-en-3-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

室温下，依次向反应瓶中加入1-(6-(8-氮杂双环[3.2.1]辛-2-烯-3-基)-5-氟-1-甲基-1H-吲哚-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.10g，0.27mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.11g，0.19mmol)和二氯甲烷(5ml)，再加入TIPT(0.30mL)，室温搅拌8小时，再加入STAB(0.086g，0.41mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.15g，三步收率：53.9％。At room temperature, 1-(6-(8-azabicyclo[3.2.1]oct-2-en-3-yl)-5-fluoro-1-methyl-1H-indol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.10 g, 0.27 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.11 g, 0.19 mmol) and dichloromethane (5 ml) were added to the reaction bottle in sequence, and TIPT (0.30 mL) was added. The mixture was stirred at room temperature for 8 hours. STAB (0.086 g, 0.41 mmol) was added and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added to quench the reaction after stirring evenly. After stirring for 20 minutes, the filter cake was slurried twice with dichloromethane, the organic phases were combined, desolventized, and column chromatography using a DCM/MeOH system was used to obtain 0.15 g of the product, with a three-step yield of 53.9%.

步骤4：1-(5-氟-6-(8-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)-8-氮杂双环[3.2.1]辛-3-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成
Step 4: Synthesis of 1-(5-fluoro-6-(8-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

室温下，依次向反应瓶中加入1-(6-(8-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)-5-氟-1-甲基-1H-吲哚-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.15g，0.16mmol)，10％钯碳(0.05g)和THF(3ml)，置换氢气3-4次，室温搅拌反应8h。反应完成后，垫硅藻土过滤，滤饼使用THF淋洗，滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.015g，入库0.010g，收率：11.0％。At room temperature, 1-(6-(8-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)-8-azabicyclo[3.2.1]oct-2-en-3-yl)-5-fluoro-1-methyl-1H-indol-3-yl)dihydropyrimidine Pyridine-2,4(1H,3H)-dione (0.15g, 0.16mmol), 10% palladium carbon (0.05g) and THF (3ml), replace hydrogen 3-4 times, stir at room temperature for 8h. After the reaction is completed, filter with diatomaceous earth, wash the filter cake with THF, desolventize the filtrate, and use DCM/MeOH system column chromatography to obtain 0.015g of product, 0.010g of which is put into storage, with a yield of 11.0%.

1H NMR(400MHz，DMSO-d6)δ10.58(d，J＝2.5Hz，1H)，9.15(s，1H)，7.72(s，1H)，7.41(d，J＝10.7Hz，1H)，7.13(dd，J＝7.4，4.6Hz，3H)，6.83(d，J＝4.2Hz，2H)，6.62-6.60(m，2H)，6.54(d，J＝7.4Hz，2H)，6.49(d，J＝2.9Hz，1H)，6.21(d，J＝8.2Hz，2H)，4.13(d，J＝4.9Hz，1H)，4.01(s，3H)，3.95(s，2H)，3.90(t，J＝6.7Hz，4H)，3.51(s，1H)，3.27(s，2H)，2.98(d，J＝20.0Hz，9H)，2.75(d，J＝2.1Hz，2H)，2.15-1.92(m，8H)，1.72-1.51(m，8H)，1.24(s，4H)，1.13-1.01(m，2H).MS(ESI)m/z：864.7[M+H]+. 1 H NMR (400MHz, DMSO-d6) δ10.58 (d, J=2.5Hz, 1H), 9.15 (s, 1H), 7.72 (s, 1H), 7.41 (d, J=10.7Hz, 1H), 7.13 (dd, J=7.4, 4.6 Hz, 3H), 6.83 (d, J=4.2Hz, 2H), 6.62-6.60 (m, 2H), 6.54 (d, J=7.4Hz, 2H), 6.49 (d, J=2.9Hz, 1H), 6.21 (d, J=8.2Hz, 2H), 4 .13 (d, J=4.9Hz, 1H), 4.01 (s, 3H), 3.95 (s, 2H), 3.90 (t, J=6.7Hz, 4H), 3.51 (s, 1H), 3.27 (s, 2H), 2.98 (d, J=20.0Hz, 9H) , 2.75 (d, J=2.1Hz, 2H), 2.15-1.92 (m, 8H), 1.72-1.51 (m, 8H), 1.24 (s, 4H), 1.13-1.01 (m, 2H).MS (ESI) m/z: 864.7[M+H] + .

实施例26：1-(5-氟-6-(4-((1R，2R)-2-((4-(4-(1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-4-氮杂螺[2.5]辛-7-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成(化合物VI-18)
Example 26: Synthesis of 1-(5-fluoro-6-(4-((1R, 2R)-2-((4-(4-(1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-azaspiro[2.5]octan-7-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-18)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：7-(((三氟甲基)磺酰基)氧基)-4-氮杂螺[2.5]辛-6-烯-4-羧酸叔丁酯的合成
Step 1: Synthesis of tert-butyl 7-(((trifluoromethyl)sulfonyl)oxy)-4-azaspiro[2.5]oct-6-ene-4-carboxylate

室温下，将7-氧代-4-氮杂螺[2.5]辛烷-4-羧酸叔丁酯(1g，4.44mmol)、N-苯基双(三氟甲烷磺酰)亚胺(2.38g，6.66mmol)溶于THF(20mL)，降温至-78℃，加入LiHMDS(7mL，7.00mmol)，加毕，室温反应8h。反应完成后，向反应液中加入水(3mL)，直接浓缩柱层析(EA/PE)，得黄色固体1.2g，收率75％。At room temperature, tert-butyl 7-oxo-4-azaspiro[2.5]octane-4-carboxylate (1 g, 4.44 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (2.38 g, 6.66 mmol) were dissolved in THF (20 mL), cooled to -78 ° C, and LiHMDS (7 mL, 7.00 mmol) was added. After the addition was completed, the reaction was reacted at room temperature for 8 h. After the reaction was completed, water (3 mL) was added to the reaction solution, and the solution was directly concentrated by column chromatography (EA/PE) to obtain 1.2 g of a yellow solid with a yield of 75%.

步骤2：7-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-4-氮杂螺[2.5]辛-6-烯-4-羧酸叔丁酯的合成
Step 2: Synthesis of tert-butyl 7-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-azaspiro[2.5]oct-6-ene-4-carboxylate

室温下，依次向反应瓶中加入7-(((三氟甲基)磺酰基)氧基)-4-氮杂螺[2.5]辛-6-烯-4-羧酸叔丁酯(0.18g，0.77mmol)，1-(5-氟-1-甲基-6-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊二烷-2-基)-1H-吲哚-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.20g，0.52mmol)，Pd(dppf)Cl2(0.04g，0.05mmol)，Na2CO3(0.11g，1.03mmol)，Do(10ml)和H2O(2ml)，置换氮气3-4次，升温至80℃反应2h。反应完成后，降温至室温，过滤，滤液浓缩，使用DCM/MeOH体系柱层析，得到棕色固体0.20g，收率81.3％。At room temperature, tert-butyl 7-(((trifluoromethyl)sulfonyl)oxy)-4-azaspiro[2.5]oct-6-ene-4-carboxylate (0.18 g, 0.77 mmol), 1-(5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.20 g, 0.52 mmol), Pd(dppf)Cl2 (0.04 g, 0.05 mmol), Na2CO3 ( 0.11 g, 1.03 mmol), Do (10 ml) and H2O (2 ml) were added into the reaction bottle in sequence , nitrogen was replaced 3-4 times, and the temperature was raised to 80°C for reaction for 2 h. After the reaction was completed, the temperature was lowered to room temperature, filtered, and the filtrate was concentrated. The filtrate was purified by column chromatography using a DCM/MeOH system to obtain 0.20 g of a brown solid with a yield of 81.3%.

步骤3：1-(5-氟-1-甲基-6-(4-氮杂螺[2.5]辛-6-烯-7-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成
Step 3: Synthesis of 1-(5-fluoro-1-methyl-6-(4-azaspiro[2.5]oct-6-en-7-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

室温下，依次向反应瓶中加入叔丁基4-(3-(2，4-二氧代四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲哚-6-基)-3，3-二氟-3，6-二氢吡啶-1(2H)-羧酸酯(0.20mg，0.42mmol)和二氯甲烷(2ml)，溶清后加入盐酸/二氧六环(3ml)，室温搅拌反应1h。反应完成后，脱溶，得到白色固体粗品0.20g，直接进行下一步。At room temperature, tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indol-6-yl)-3,3-difluoro-3,6-dihydropyridine-1(2H)-carboxylate (0.20 mg, 0.42 mmol) and dichloromethane (2 ml) were added to the reaction bottle in sequence. After dissolving, hydrochloric acid/dioxane (3 ml) was added and stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed to obtain 0.20 g of a white solid crude product, which was directly carried out to the next step.

步骤4：1-(6-(4-(((1R，2R)-2-((4-(4-(2R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-4-氮杂螺[2.5]辛-6-烯-7-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成
Step 4: Synthesis of 1-(6-(4-(((1R,2R)-2-((4-(4-(2R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-azaspiro[2.5]oct-6-en-7-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

室温下，依次向反应瓶中加入1-(5-氟-1-甲基-6-(4-氮杂螺[2.5]辛-6-烯-7-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.10g，0.26mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.11g，0.18mmol)和二氯甲烷(5ml)，再加入TIPT(0.30mL)，室温搅拌8小时，再加入STAB(0.084g，0.40mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.06g，两步收率：30％。At room temperature, 1-(5-fluoro-1-methyl-6-(4-azaspiro[2.5]oct-6-en-7-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.10 g, 0.26 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.11 g, 0.18 mmol) and dichloromethane (5 ml) were added to the reaction bottle in sequence, and TIPT (0.30 mL) was added. The mixture was stirred at room temperature for 8 hours. STAB (0.084 g, 0.40 mmol) was added and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added to quench the reaction after stirring evenly. After stirring for 20 minutes, the filter cake was slurried twice with dichloromethane, the organic phases were combined, desolventized, and column chromatography using a DCM/MeOH system was used to obtain 0.06 g of the product, with a two-step yield of 30%.

步骤5：1-(5-氟-6-(4-((1R，2R)-2-((4-(4-(1R、2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-4-氮杂螺[2.5]辛-7-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成
Step 5: Synthesis of 1-(5-fluoro-6-(4-((1R,2R)-2-((4-(4-(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-azaspiro[2.5]octan-7-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

室温下，依次向反应瓶中加入1-(6-(4-(((1R，2R)-2-((4-(4-(2R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-4-氮杂螺[2.5]辛-6-烯-7-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.060g，0.06mmol)，10％钯碳(0.05g)和THF(5ml)，置换氢气3-4次，室温搅拌反应8h。反应完成后，垫硅藻土过滤，滤饼使用THF淋洗，滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.012g，收率：22.0％。At room temperature, 1-(6-(4-(((1R, 2R)-2-((4-(4-(2R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-azaspiro[2.5]oct-6-en-7-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.060 g, 0.06 mmol), 10% palladium on carbon (0.05 g) and THF (5 ml) were added into the reaction bottle in sequence, hydrogen was replaced 3-4 times, and the reaction was stirred at room temperature for 8 h. After the reaction was completed, the mixture was filtered through a diatomaceous earth pad, the filter cake was rinsed with THF, the filtrate was desolventized, and column chromatography using a DCM/MeOH system was performed to obtain 0.012 g of the product with a yield of 22.0%.

1H NMR(400MHz，DMSO-d6)δ10.59(s，1H)，9.18(s，1H)，7.41(d，J＝11.1Hz，1H)，7.11(q，J＝6.6，6.0Hz，3H)，6.83(d，J＝7.0Hz，2H)，6.69-6.54(m，4H)，6.53-6.41(m，2H)，6.21(t，J＝9.8Hz，2H)，4.16-4.12(m，1H)，4.01-3.93(m，3H)，3.93-3.78(m，4H)，3.06-2.88(m，7H)，2.75(t，J＝6.8Hz，5H)，2.20-1.86(m，10H)，1.75-1.57(m，7H)，1.08-0.87(m，6H).MS(ESI)m/z：866.4[M+H]+. 1 H NMR (400MHz, DMSO-d 6 )δ10.59 (s, 1H), 9.18 (s, 1H), 7.41 (d, J=11.1Hz, 1H), 7.11 (q, J=6.6, 6.0Hz, 3H), 6.83 (d, J=7.0Hz, 2H), 6.69-6.54 (m, 4H), 6.53-6.41 (m, 2H), 6.21 (t, J=9.8Hz, 2H), 4.16-4. 12 (m, 1H), 4.01-3.93 (m, 3H), 3.93-3.78 (m, 4H), 3.06-2.88 (m, 7H), 2.75 (t, J=6.8Hz, 5 H), 2.20-1.86(m, 10H), 1.75-1.57(m, 7H), 1.08-0.87(m, 6H).MS(ESI)m/z: 866.4[M+H] + .

实施例27：1-(6-(3，3-二氟-1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成(化合物IV-12)
Example 27: Synthesis of 1-(6-(3,3-difluoro-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound IV-12)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：叔丁基3，3-二氟-4-(((三氟甲基)磺酰氧基)-3，6-二氢吡啶-1(2H)-羧酸酯的合成
Step 1: Synthesis of tert-butyl 3,3-difluoro-4-(((trifluoromethyl)sulfonyloxy)-3,6-dihydropyridine-1(2H)-carboxylate

室温下，将3，3-二氟-4-氧代哌啶-1-羧酸叔丁酯(5g，21.26mmol)溶于DCM(50mL)，降温至-15℃，加入TEA(6.45g，63.77mmol)，缓慢滴加三氟甲磺酸酐(9.00g，31.88mmol)，加毕，室温反应8h。反应完成后，向反应液中加入饱和碳酸氢钠水溶液(30mL)，DCM萃取，有机相浓缩柱层析(EA/PE)，得黄色固体3.2g，收率41.0％。At room temperature, tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (5 g, 21.26 mmol) was dissolved in DCM (50 mL), cooled to -15 ° C, TEA (6.45 g, 63.77 mmol) was added, trifluoromethanesulfonic anhydride (9.00 g, 31.88 mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 8 h. After the reaction was completed, saturated sodium bicarbonate aqueous solution (30 mL) was added to the reaction solution, extracted with DCM, and the organic phase was concentrated by column chromatography (EA/PE) to obtain 3.2 g of a yellow solid with a yield of 41.0%.

步骤2：叔丁基4-(3-(2，4-二氧代四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-3，3-二氟-3，6-二氢吡啶-1(2H)-羧酸酯的合成
Step 2: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,3-difluoro-3,6-dihydropyridine-1(2H)-carboxylate

室温下，依次向反应瓶中加入叔丁基3，3-二氟-4-(((三氟甲基)磺酰氧基)-3，6-二氢吡啶-1(2H)-羧酸酯(0.18g，0.77mmol)，1-(5-氟-1-甲基-6-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊二烷-2-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.20g，0.52mmol)，Pd(dppf)Cl2(0.04g，0.05mmol)，Na2CO3(0.11g，1.03mmol)，Do(10ml)和H2O(2ml)，置换氮气3-4次，升温至80℃反应2h。反应完成后，降温至室温，过滤，滤液浓缩，使用DCM/MeOH体系柱层析，得到棕色固体0.20g，收率81.3％。At room temperature, tert-butyl 3,3-difluoro-4-(((trifluoromethyl)sulfonyloxy)-3,6-dihydropyridine-1(2H)-carboxylate (0.18 g, 0.77 mmol), 1-(5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.20 g, 0.52 mmol), Pd(dppf)Cl2 (0.04 g, 0.05 mmol), Na2CO3 (0.11 g , 1.03 mmol), Do (10 ml) and H2O were added to the reaction bottle in sequence. O (2 ml), replace nitrogen 3-4 times, heat to 80 ° C for 2 h. After the reaction is completed, cool to room temperature, filter, concentrate the filtrate, and use DCM/MeOH system column chromatography to obtain 0.20 g of brown solid with a yield of 81.3%.

步骤3：1-(6-(3，3-二氟-1，2，3，6-四氢吡啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成
Step 3: Synthesis of 1-(6-(3,3-difluoro-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

室温下，依次向反应瓶中加入叔丁基4-(3-(2，4-二氧代四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲哚-6-基)-3，3-二氟-3，6-二氢吡啶-1(2H)-羧酸酯(0.20mg，0.42mmol)和二氯甲烷(2ml)，溶清后加入盐酸/二氧六环(3ml)，室温搅拌反应1h。反应完成后，脱溶，得到白色固体粗品0.20g，直接进行下一步。At room temperature, tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indol-6-yl)-3,3-difluoro-3,6-dihydropyridine-1(2H)-carboxylate (0.20 mg, 0.42 mmol) and dichloromethane (2 ml) were added to the reaction bottle in sequence. After dissolving, hydrochloric acid/dioxane (3 ml) was added and stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed to obtain 0.20 g of a white solid crude product, which was directly carried out to the next step.

步骤4：1-(6-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)-3，3-二氟-1，2，3，6-四氢吡啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成
Step 4: Synthesis of 1-(6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)-3,3-difluoro-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

室温下，依次向反应瓶中加入1-(6-(3，3-二氟-1，2，3，6-四氢吡啶-4-基)-5-氟-1-甲基-1H-吲哚-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.10g，0.26mmol)，(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.11g，0.18mmol)和二氯甲烷(5ml)，再加入TIPT(0.30mL)，室温搅拌8小时，再加入STAB(0.084g，0.40mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.060g，两步收率：29.9％。At room temperature, 1-(6-(3,3-difluoro-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.10 g, 0.26 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.11 g, 0.18 mmol) and dichloromethane (5 ml) were added into the reaction bottle in sequence, and TIPT (0.30 mL) was added. The mixture was stirred at room temperature for 8 hours. STAB (0.084 g, 0.40 mmol) was added and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added to quench the reaction after stirring evenly. After stirring for 20 minutes, the filter cake was slurried twice with dichloromethane, the organic phases were combined, desolventized, and column chromatography using a DCM/MeOH system was used to obtain 0.060 g of the product, with a two-step yield of 29.9%.

步骤5：1-(6-(3，3-二氟-1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成
Step 5: Synthesis of 1-(6-(3,3-difluoro-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

室温下，依次向反应瓶中加入1-(6-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基哌嗪-1-基)甲基)环己基)甲基)-3，3-二氟-1，2，3，6-四氢吡啶-4-基)-5-氟-1-甲基-1H-吲哚-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.060g，0.06mmol)，10％钯碳(0.05g)和THF(5ml)，置换氢气3-4次，室温搅拌反应8h。反应完成后，垫硅藻土过滤，滤饼使用THF淋洗，滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.012g，入库0.007g，收率：22.0％。At room temperature, 1-(6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)-3,3-difluoro-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indol-3-yl)dihydropyrimidine Pyridine-2,4(1H,3H)-dione (0.060g, 0.06mmol), 10% palladium carbon (0.05g) and THF (5ml), replace hydrogen 3-4 times, stir at room temperature for 8h. After the reaction is completed, filter with diatomaceous earth, wash the filter cake with THF, desolventize the filtrate, and use DCM/MeOH system column chromatography to obtain 0.012g of product, 0.007g of which is put into storage, with a yield of 22.0%.

1H NMR(400MHz，DMSO-d6)δ10.59(s，1H)，9.13(d，J＝1.6Hz，1H)，7.74(d，J＝5.5Hz，1H)，7.43-7.41(m，1H)，7.13(dt，J＝8.8，4.2Hz，3H)，6.85-6.81(m，2H)，6.65-6.59(m，2H)，6.55-6.46(m，3H)，6.21(dd，J＝8.6，3.7Hz，2H)，4.13(t，J＝4.5Hz，1H)，4.02(d，J＝3.6Hz，3H)，3.92(t，J＝6.7Hz，3H)，3.17(s，1H)，3.06-2.91(m，8H)，2.76(t，J＝6.7Hz，4H)，2.36(d，J＝10.4Hz，4H)，2.11(d，J＝6.5Hz，2H)，1.84(s，2H)，1.71-1.38(m，8H)，1.24(s，4H)，0.99(s，2H).MS(ESI)m/z：874.8[M+H]+. 1 H NMR (400MHz, DMSO-d6) δ10.59 (s, 1H), 9.13 (d, J=1.6Hz, 1H), 7.74 (d, J=5.5Hz, 1H), 7.43-7.41 (m, 1H), 7.13 (dt, J=8. 8, 4.2Hz, 3H), 6.85-6.81 (m, 2H), 6.65-6.59 (m, 2H), 6.55-6.46 (m, 3H), 6.21 (dd, J=8.6, 3.7Hz, 2H), 4.13 (t, J=4.5Hz, 1H), 4.02 (d, J=3.6Hz, 3H), 3.92 (t, J=6.7Hz, 3H), 3.17 (s, 1H), 3.06-2.91 (m, 8H), 2.76 (t, J=6.7Hz, 4H), 2.36 (d, J=1 0.4Hz, 4H), 2.11 (d, J=6.5Hz, 2H), 1.84 (s, 2H), 1.71-1.38 (m, 8H), 1.24 (s, 4H), 0.99 (s, 2H). MS (ESI) m/z: 874.8[M+H] + .

实施例28：1-(5-氟-6-(1′-((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-[1，4′-二哌啶]-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成(化合物VI-19)
Example 28: Synthesis of 1-(5-fluoro-6-(1′-((1R, 2R)-2-((4-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-[1,4′-bipiperidinyl]-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-19)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：4-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-[1，4′-二哌啶]-1′-羧酸叔丁酯的合成
Step 1: Synthesis of tert-butyl 4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-[1,4′-bipiperidine]-1′-carboxylate

室温下，依次向反应瓶中加入1-(5-氟-1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮6-溴-3-碘-1-甲基-1H-吲唑(0.50g，1.45mmol)，N-叔丁氧羰基-4-哌啶酮(0.58g，2.90mmol)和二氯甲烷(10mL)，再加入TIPT(0.5mL)，室温搅拌16小时，再加入STAB(0.61g，2.90mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.50g，收率：65％。At room temperature, 1-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 6-bromo-3-iodo-1-methyl-1H-indazole (0.50 g, 1.45 mmol), N-tert-butyloxycarbonyl-4-piperidone (0.58 g, 2.90 mmol) and dichloromethane (10 mL) were added to the reaction bottle in sequence, and TIPT (0.5 mL) was added, and the mixture was stirred at room temperature for 16 hours, and STAB (0.61 g, 2.90 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added to quench the reaction after stirring evenly. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.50 g of the product with a yield of 65%.

步骤2：1-(6-([1，4′-二哌啶]-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成
Step 2: Synthesis of 1-(6-([1,4′-bipiperidinyl]-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

室温下，依次向反应瓶中加入4-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-[1，4′-二哌啶]-1′-羧酸叔丁酯(0.50g，0.95mmol)和HCl二氧六环溶液(10ml)，室温反应2h。反应完成后，旋干，得到粗品0.40g，直接下一步。At room temperature, 4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazole-6-yl)-[1,4′-bipiperidine]-1′-carboxylic acid tert-butyl ester (0.50 g, 0.95 mmol) and HCl dioxane solution (10 ml) were added to the reaction bottle in sequence and reacted at room temperature for 2 h. After the reaction was completed, the mixture was spin-dried to obtain 0.40 g of a crude product, which was directly used in the next step.

步骤3：1-(6-(1′-(((1R，2R)-2-((4-(4-(((3R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-[1，4′-双哌啶]-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成
Step 3: Synthesis of 1-(6-(1′-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-[1,4′-bipiperidinyl]-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

室温下，依次向反应瓶中加入1-(6-([1，4′-二哌啶]-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.08g，0.18mmol)，(1S，2S)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.11g，0.18mmol)和二氯甲烷(10ml)，再加入TIPT(0.5ml)，室温搅拌16小时，再加入STAB(0.08g，0.36mmol)，室温搅拌反应2h。反应完成后，加入二氯甲烷稀释，加入硅藻土，搅拌均匀后加入水淬灭反应。搅拌20分钟后过滤，滤饼使用二氯甲烷打浆2次，合并有机相，脱溶，使用DCM/MeOH体系柱层析，得到产物0.08g，收率：72％。At room temperature, 1-(6-([1,4′-bipiperidinyl]-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.08 g, 0.18 mmol), (1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.11 g, 0.18 mmol) and dichloromethane (10 ml) were added to the reaction bottle in sequence, and TIPT (0.5 ml) was added. The mixture was stirred at room temperature for 16 hours, and STAB (0.08 g, 0.36 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, dichloromethane was added to dilute, diatomaceous earth was added, and water was added after stirring evenly to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM/MeOH system to obtain 0.08 g of the product with a yield of 72%.

步骤4：1-(5-氟-6-(1′-((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-[1，4′-二哌啶]-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮
Step 4: 1-(5-Fluoro-6-(1′-((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-[1,4′-bipiperidinyl]-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

室温下，依次向反应瓶中加入1-(6-(1′-(((1R，2R)-2-((4-(4-(((3R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-[1，4′-双哌啶]-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.08g，0.08mmol)，10％钯碳(0.01g)和四氢呋喃(5ml)，再加入置换氢气3-4次，30℃搅拌反应16h。反应完成后，垫硅藻土过滤，滤饼使用四氢呋喃淋洗滤液脱溶，使用DCM/MeOH体系柱层析，得到产物0.06g，收率：82％。At room temperature, 1-(6-(1′-(((1R, 2R)-2-((4-(4-(((3R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-[1,4′-bipiperidinyl]-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine Pyridine-2,4(1H,3H)-dione (0.08 g, 0.08 mmol), 10% palladium on carbon (0.01 g) and tetrahydrofuran (5 ml), and then added to replace hydrogen 3-4 times, stirred at 30°C for 16 h. After the reaction was completed, diatomaceous earth was used for filtration, and the filter cake was eluted with tetrahydrofuran and the filtrate was desolvated, and a DCM/MeOH system column chromatography was used to obtain 0.06 g of the product, with a yield of 82%.

1H NMR(400MHz，DMSO-d6)δ10.58(s，1H)，9.17(s，1H)，7.40(d，J＝10.8Hz，1H)，7.13(q，J＝6.0，5.6Hz，4H)，6.83(d，J＝7.1Hz，2H)，6.64-6.56(m，5H)，6.50-6.47(m，1H)，6.23(d，J＝8.1Hz，2H)，4.14(d，J＝4.8Hz，1H)，4.00(s，3H)，3.91(t，J＝6.7Hz，2H)，3.14-2.67(m，24H)，2.05-1.58(m，19H)，1.18-0.94(m，4H).MS(ESI)m/z：921.8[M+H]+. 1 H NMR (400MHz, DMSO-d 6 ) δ10.58 (s, 1H), 9.17 (s, 1H), 7.40 (d, J = 10.8Hz, 1H), 7.13 (q, J = 6.0, 5.6Hz, 4H), 6.83 (d, J=7.1Hz, 2H), 6.64-6.56 (m, 5H), 6.50-6.47 (m, 1H), 6.23 (d, J=8 .1Hz, 2H), 4.14 (d, J=4.8Hz, 1H), 4.00 (s, 3H), 3.91 (t, J=6.7Hz, 2H), 3.14-2 .67(m, 24H), 2.05-1.58(m, 19H), 1.18-0.94(m, 4H).MS(ESI)m/z: 921.8[M+H] + .

实施例29：1-(5-氟-6-((2R)-1-(((1R，2R)-2-((4-(4-(((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2-甲基哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成(化合物VI-20)
Example 29: Synthesis of 1-(5-fluoro-6-((2R)-1-(((1R,2R)-2-((4-(4-(((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-20)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：(R)-2-甲基-4-(((三氟甲基)磺酰基)氧基)-3，6-二氢吡啶-1(2H)-羧酸叔丁酯的合成。
Step 1: Synthesis of tert-butyl (R)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate.

-78℃条件下，依次向单口瓶中加入(R)-2-甲基-4-氧代哌啶-1-甲酸叔丁酯(2.00g，9.38mmol)、PhNTf2(3.68g，10.92mmol)、THF(20mL)及LiHMDS(10.50g，10.32mmol)。氮气氛围下升至室温反应16h终止。加饱和氯化铵水溶液稀释，EA萃取，有机相经无水Na2SO4干燥、过滤、浓缩、柱层析纯化(EA/PE体系)得黄色油状物3.00g。At -78°C, (R)-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (2.00 g, 9.38 mmol), PhNTf 2 (3.68 g, 10.92 mmol), THF (20 mL) and LiHMDS (10.50 g, 10.32 mmol) were added to a single-mouth bottle in sequence. The reaction was terminated by warming to room temperature for 16 h under a nitrogen atmosphere. The mixture was diluted with saturated aqueous ammonium chloride solution and extracted with EA. The organic phase was dried over anhydrous Na 2 SO 4 , filtered, concentrated and purified by column chromatography (EA/PE system) to obtain 3.00 g of a yellow oil.

步骤2：(R)-4-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-2-甲基-3，6-二氢吡啶-1(2H)-羧酸叔丁酯的合成。
Step 2: Synthesis of (R)-tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate.

室温下，依次向单口瓶中加入(R)-2-甲基-4-(((三氟甲基)磺酰基)氧基)-3，6-二氢吡啶-1(2H)-羧酸叔丁酯(0.21g，0.62mmol)、1-(5-氟-1-甲基-6-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.20g，0.51mmol)、碳酸钠(0.11g，1.02mmol)、Pd(dppf)Cl2(0.04g，0.05mmol)、1.4-二氧六环(20mL)、H2O(1mL)。氮气保护下升温至85℃反应8h终止。冷却至室温，加水稀释，EA萃取，有机相经无水Na2SO4干燥、过滤、浓缩、柱层析纯化(EA/PE体系)得黄色固体0.20g。At room temperature, (R)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.21 g, 0.62 mmol), 1-(5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.20 g, 0.51 mmol), sodium carbonate (0.11 g, 1.02 mmol), Pd(dppf)Cl 2 (0.04 g, 0.05 mmol), 1.4-dioxane (20 mL), and H 2 O (1 mL) were added into a single-mouth bottle in sequence. The temperature was raised to 85° C. under nitrogen protection for 8 h to terminate the reaction. The mixture was cooled to room temperature, diluted with water, extracted with EA, and the organic phase was dried over anhydrous Na 2 SO 4 , filtered, concentrated, and purified by column chromatography (EA/PE system) to obtain 0.20 g of a yellow solid.

步骤3：(R)-1-(5-氟-1-甲基-6-(2-甲基-1，2，3，6-四氢吡啶-4-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。
Step 3: Synthesis of (R)-1-(5-fluoro-1-methyl-6-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

室温下，依次向单口瓶中加入(R)-4-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-2-甲基-3，6-二氢吡啶-1(2H)-羧酸叔丁酯(0.20g，0.44mmol)、DCM(10mL)、盐酸二氧六环溶液(10mL)，室温反应3h终止。浓缩得黄色固体粗品0.20g。At room temperature, (R)-4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.20 g, 0.44 mmol), DCM (10 mL), and dioxane hydrochloride solution (10 mL) were added to a single-mouth bottle in sequence, and the reaction was terminated at room temperature for 3 h. The reaction was concentrated to obtain 0.20 g of a yellow solid crude product.

步骤4：1-(6-((R)-1-(((1R，2R)-2-((4-(4-(((3R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2-甲基-1，2，3，6-四氢吡啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。
Step 4: Synthesis of 1-(6-((R)-1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

室温下，依次向单口瓶中加入(R)-1-(5-氟-1-甲基-6-(2-甲基-1，2，3，6-四氢吡啶-4-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.16g，0.44mmol)、(1R，2R)-2-((4-(4-((1R、2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.16g，0.44mmol)、DCM(20mL)，室温反应16h，加入三乙酰氧基硼氢化钠(0.18g，0.87mmol)反应1h。加入水(1mL)，搅拌5min，垫上硅藻土过滤，滤液浓缩柱层析(MeOH/DCM体系)得黄色固体0.14g。At room temperature, (R)-1-(5-fluoro-1-methyl-6-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.16 g, 0.44 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.16 g, 0.44 mmol) and DCM (20 mL) were added into a single-necked bottle in sequence. The mixture was reacted at room temperature for 16 h. Sodium triacetoxyborohydride (0.18 g, 0.87 mmol) was added and the reaction was carried out for 1 h. Water (1 mL) was added, stirred for 5 min, and filtered through celite. The filtrate was concentrated and subjected to column chromatography (MeOH/DCM system) to obtain 0.14 g of a yellow solid.

步骤5：1-(5-氟-6-((2R)-1-(((1R，2R)-2-((4-(4-(((3R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2-甲基哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。
Step 5: Synthesis of 1-(5-fluoro-6-((2R)-1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

室温下，依次向单口瓶中加入1-(6-((R)-1-(((1R，2R)-2-((4-(4-(((3R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2-甲基-1，2，3，6-四氢吡啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.14g，0.15mmol)、Pd/C(0.20g，10％)、MeOH(20mL)，氢气球氛围下室温反应16h，垫上硅藻土过滤，滤液浓缩柱层析(MeOH/DCM体系)得白色固体0.50g。MS(ESI)m/z：852.9[M+H]+.At room temperature, 1-(6-((R)-1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indole was added to the single-mouth bottle in sequence. oxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.14 g, 0.15 mmol), Pd/C (0.20 g, 10%), MeOH (20 mL), react at room temperature for 16 h under a hydrogen balloon atmosphere, filter on diatomaceous earth, concentrate the filtrate and perform column chromatography (MeOH/DCM system) to obtain 0.50 g of a white solid. MS (ESI) m/z: 852.9 [M+H] + .

实施例30：1-(5-氟-6-((2S)-1-(((1R，2R)-2-((4-(4-(((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2-甲基哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成(化合物VI-21)
Example 30: Synthesis of 1-(5-fluoro-6-((2S)-1-(((1R, 2R)-2-((4-(4-(((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-21)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：(S)-2-甲基-4-(((三氟甲基)磺酰基)氧基)-3，6-二氢吡啶-1(2H)-羧酸叔丁酯的合成。
Step 1: Synthesis of (S)-tert-butyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate.

-78℃条件下，依次向单口瓶中加入(S)-2-甲基-4-氧代哌啶-1-甲酸叔丁酯(2.00g，9.38mmol)、PhNTf2(3.68g，10.92mmol)、THF(20mL)及LiHMDS(10.50g，10.32mmol)。氮气氛围下升至室温反应16h终止。加饱和氯化铵水溶液稀释，EA萃取，有机相经无水Na2SO4干燥、过滤、浓缩、柱层析纯化(EA/PE体系)得黄色油状物3.00g。At -78°C, (S)-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (2.00 g, 9.38 mmol), PhNTf 2 (3.68 g, 10.92 mmol), THF (20 mL) and LiHMDS (10.50 g, 10.32 mmol) were added to a single-mouth bottle in sequence. The reaction was terminated by warming to room temperature for 16 h under a nitrogen atmosphere. The mixture was diluted with saturated aqueous ammonium chloride solution and extracted with EA. The organic phase was dried over anhydrous Na 2 SO 4 , filtered, concentrated and purified by column chromatography (EA/PE system) to obtain 3.00 g of a yellow oil.

步骤2：(S)-4-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-2-甲基-3，6-二氢吡啶-1(2H)-羧酸叔丁酯的合成。
Step 2: Synthesis of (S)-tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate.

室温下，依次向单口瓶中加入(S)-2-甲基-4-(((三氟甲基)磺酰基)氧基)-3，6-二氢吡啶-1(2H)-羧酸叔丁酯(0.21g，0.62mmol)、1-(5-氟-1-甲基-6-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.20g，0.51mmol)、碳酸钠(0.11g，1.02mmol)、Pd(dppf)Cl2(0.04g，0.05mmol)、1.4-二氧六环(20mL)、H2O(1mL)。氮气保护下升温至85℃反应8h终止。冷却至室温，加水稀释，EA萃取，有机相经无水Na2SO4干燥、过滤、浓缩、柱层析纯化(EA/PE体系)得黄色固体0.20g。At room temperature, (S)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.21 g, 0.62 mmol), 1-(5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.20 g, 0.51 mmol), sodium carbonate (0.11 g, 1.02 mmol), Pd(dppf)Cl 2 (0.04 g, 0.05 mmol), 1.4-dioxane (20 mL), and H 2 O (1 mL) were added to a single-mouth bottle in sequence. The temperature was raised to 85° C. under nitrogen protection for 8 h to terminate the reaction. The mixture was cooled to room temperature, diluted with water, extracted with EA, and the organic phase was dried over anhydrous Na 2 SO 4 , filtered, concentrated, and purified by column chromatography (EA/PE system) to obtain 0.20 g of a yellow solid.

步骤3：(S)-1-(5-氟-1-甲基-6-(2-甲基-1，2，3，6-四氢吡啶-4-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。
Step 3: Synthesis of (S)-1-(5-fluoro-1-methyl-6-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

室温下，依次向单口瓶中加入(S)-4-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-2-甲基-3，6-二氢吡啶-1(2H)-羧酸叔丁酯(0.20g，0.44mmol)、DCM(10mL)、盐酸二氧六环溶液(10mL)，室温反应3h终止。浓缩得黄色固体粗品0.20g。At room temperature, (S)-4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.20 g, 0.44 mmol), DCM (10 mL), and dioxane hydrochloride solution (10 mL) were added to a single-mouth bottle in sequence, and the reaction was terminated at room temperature for 3 h. The reaction was concentrated to obtain 0.20 g of a yellow solid crude product.

步骤4：1-(6-((S)-1-(((1R，2R)-2-((4-(4-(((3R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2-甲基-1，2，3，6-四氢吡啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。
Step 4: Synthesis of 1-(6-((S)-1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

室温下，依次向单口瓶中加入(S)-1-(5-氟-1-甲基-6-(2-甲基-1，2，3，6-四氢吡啶-4-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.16g，0.44mmol)、(1R，2R)-2-((4-(4-((1R、2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.16g，0.44mmol)、DCM(20mL)，室温反应16h，加入三乙酰氧基硼氢化钠(0.18g，0.87mmol)反应1h。加入水(1mL)，搅拌5min，垫上硅藻土过滤，滤液浓缩柱层析(MeOH/DCM体系)得黄色固体0.14g。At room temperature, (S)-1-(5-fluoro-1-methyl-6-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.16 g, 0.44 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.16 g, 0.44 mmol) and DCM (20 mL) were added into a single-necked bottle in sequence. The mixture was reacted at room temperature for 16 h. Sodium triacetoxyborohydride (0.18 g, 0.87 mmol) was added and the reaction was carried out for 1 h. Water (1 mL) was added, stirred for 5 min, and filtered through celite. The filtrate was concentrated and subjected to column chromatography (MeOH/DCM system) to obtain 0.14 g of a yellow solid.

步骤5：1-(5-氟-6-((2S)-1-(((1R，2R)-2-((4-(4-(((3R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2-甲基哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。
Step 5: Synthesis of 1-(5-fluoro-6-((2S)-1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

室温下，依次向单口瓶中加入1-(6-((S)-1-(((1R，2R)-2-((4-(4-(((3R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2-甲基-1，2，3，6-四氢吡啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.14g，0.15mmol)、Pd/C(0.20g，10％)、MeOH(20mL)，氢气球氛围下室温反应16h，垫上硅藻土过滤，滤液浓缩柱层析(MeOH/DCM体系)得白色固体0.50g。MS(ESI)m/z：852.9[M+H]+.At room temperature, 1-(6-((S)-1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indole was added to the single-mouth bottle in sequence. oxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.14 g, 0.15 mmol), Pd/C (0.20 g, 10%), MeOH (20 mL), react at room temperature for 16 h under a hydrogen balloon atmosphere, filter on diatomaceous earth, concentrate the filtrate and perform column chromatography (MeOH/DCM system) to obtain 0.50 g of a white solid. MS (ESI) m/z: 852.9 [M+H] + .

实施例31：1-(5-氟-6-((2S，6R)-1-(((1R，2R)-2-((4-(4-(((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2，6-二甲基哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成(化合物VI-22)
Example 31: Synthesis of 1-(5-fluoro-6-((2S,6R)-1-(((1R,2R)-2-((4-(4-(((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,6-dimethylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-22)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：(2S，6R)-1-(4-甲氧基苄基)-2，6-二甲基哌啶-4-酮的合成。
Step 1: Synthesis of (2S,6R)-1-(4-methoxybenzyl)-2,6-dimethylpiperidin-4-one.

室温下，向丙酮二羧酸(4.00g，27.40mmol)的水(20mL)溶液中加入40％乙醛(6.00g，54.80mmol)。然后在10分钟内以小份加入4-甲氧基苯基甲胺(3.75g，27.40mmol)。室温搅拌24h。用二氯甲烷萃取反应混合物。并将合并的萃取物用盐水洗涤并用无水硫酸钠干燥，过滤，滤液浓缩柱层析(DCM/EA)体系得为浅黄色油状物4.00g。At room temperature, 40% acetaldehyde (6.00 g, 54.80 mmol) was added to a solution of acetone dicarboxylic acid (4.00 g, 27.40 mmol) in water (20 mL). Then 4-methoxyphenyl methylamine (3.75 g, 27.40 mmol) was added in small portions over 10 minutes. The mixture was stirred at room temperature for 24 hours. The reaction mixture was extracted with dichloromethane. The combined extracts were washed with brine and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by column chromatography (DCM/EA) to obtain 4.00 g of a light yellow oil.

步骤2：(2S，6R)-2，6-二甲基哌啶-4-酮的合成。
Step 2: Synthesis of (2S,6R)-2,6-dimethylpiperidin-4-one.

室温下，将顺式-1-(4-甲氧基苄基)-2，6-二甲基哌啶-4-酮(4.00g，16.20mmol)溶解在乙醇(20mL)中，并加入催化剂(0.40g，10％Pd-C)。将混合物在氢气氛下搅拌16h。过滤，滤液浓缩得到黄色油状物粗品1.80g。At room temperature, cis-1-(4-methoxybenzyl)-2,6-dimethylpiperidin-4-one (4.00 g, 16.20 mmol) was dissolved in ethanol (20 mL), and a catalyst (0.40 g, 10% Pd-C) was added. The mixture was stirred under a hydrogen atmosphere for 16 h. The mixture was filtered and the filtrate was concentrated to obtain 1.80 g of a crude yellow oil.

步骤3：(2S，6R)-2，6-二甲基-4-氧代哌啶-1-甲酸叔丁酯的合成。
Step 3: Synthesis of tert-butyl (2S,6R)-2,6-dimethyl-4-oxopiperidine-1-carboxylate.

室温下，将二碳酸二叔丁酯(3.14g，14.40mmol)和DIEA(3.10g，24.0mmol)加入到顺式-1-(4-甲氧基苄基)-2，6-二甲基哌啶-4-酮(1.54g，12.0mmol)的二氯甲烷(30mL)溶液中，并将该混合物在室温下搅拌16h。浓缩反应液柱层析(EA/PE)体系得为白色固体2.0g。At room temperature, di-tert-butyl dicarbonate (3.14 g, 14.40 mmol) and DIEA (3.10 g, 24.0 mmol) were added to a solution of cis-1-(4-methoxybenzyl)-2,6-dimethylpiperidin-4-one (1.54 g, 12.0 mmol) in dichloromethane (30 mL), and the mixture was stirred at room temperature for 16 h. The reaction solution was concentrated and subjected to column chromatography (EA/PE) to obtain 2.0 g of a white solid.

步骤4：(2S，6R)-2，6-二甲基-4-(((三氟甲基)磺酰基)氧基)-3，6-二氢吡啶-1(2H)-羧酸叔丁酯的合成。
Step 4: Synthesis of tert-butyl (2S,6R)-2,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate.

-78℃条件下，依次向单口瓶中加入(2S，6R)-2，6-二甲基-4-氧代哌啶-1-甲酸叔丁酯(2.00g，8.80mmol)、PhNTf2(3.68g，10.92mmol)、THF(20mL)及LiHMDS(10.50mL，10.50mmol)。氮气氛围下升至室温反应16h终止。加饱和氯化铵水溶液稀释，EA萃取，有机相经无水Na2SO4干燥、过滤、浓缩、柱层析纯化(EA/PE体系)得黄色油状物3.00g。Under -78°C, (2S, 6R)-2,6-dimethyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (2.00 g, 8.80 mmol), PhNTf 2 (3.68 g, 10.92 mmol), THF (20 mL) and LiHMDS (10.50 mL, 10.50 mmol) were added to a single-mouth bottle in sequence. The reaction was terminated by warming to room temperature for 16 h under a nitrogen atmosphere. Saturated aqueous ammonium chloride was added for dilution, and EA was extracted. The organic phase was dried over anhydrous Na 2 SO 4 , filtered, concentrated, and purified by column chromatography (EA/PE system) to obtain 3.00 g of a yellow oil.

步骤5：(2S，6R)-4-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-2，6-二甲基-3，6-二氢吡啶-1(2H)-羧酸叔丁酯的合成。
Step 5: Synthesis of tert-butyl (2S,6R)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2,6-dimethyl-3,6-dihydropyridine-1(2H)-carboxylate.

室温下，依次向单口瓶中加入(2S，6R)-2，6-二甲基-4-(((三氟甲基)磺酰基)氧基)-3，6-二氢吡啶-1(2H)-羧酸叔丁酯(0.21g，0.58mmol)、1-(5-氟-1-甲基-6-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.20g，0.51mmol)、碳酸钠(0.11g，1.02mmol)、Pd(dppf)Cl2(0.04g，0.05mmol)、1.4-二氧六环(20mL)、H2O(1mL)。氮气保护下升温至85℃反应8h终止。冷却至室温，加水稀释，EA萃取，有机相经无水Na2SO4干燥、过滤、浓缩、柱层析纯化(EA/PE体系)得黄色固体0.20g。At room temperature, tert-butyl (2S,6R)-2,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (0.21 g, 0.58 mmol), 1-(5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.20 g, 0.51 mmol), sodium carbonate (0.11 g, 1.02 mmol), Pd(dppf)Cl 2 (0.04 g, 0.05 mmol), 1.4-dioxane (20 mL), and H 2 O (1 mL) were added into a single-mouth bottle in sequence. The temperature was raised to 85° C. under nitrogen protection for 8 h to terminate the reaction. The mixture was cooled to room temperature, diluted with water, extracted with EA, and the organic phase was dried over anhydrous Na 2 SO 4 , filtered, concentrated, and purified by column chromatography (EA/PE system) to obtain 0.20 g of a yellow solid.

步骤6：1-(6-((2S，6R)-2，6-二甲基-1，2，3，6-四氢吡啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。
Step 6: Synthesis of 1-(6-((2S,6R)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

室温下，依次向单口瓶中加入(2S，6R)-4-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-2，6-二甲基-3，6-二氢吡啶-1(2H)-羧酸叔丁酯(0.20g，0.42mmol)、DCM(10mL)、盐酸二氧六环溶液(10mL)，室温反应3h终止。浓缩得黄色固体粗品0.20g。At room temperature, (2S,6R)-4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2,6-dimethyl-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.20 g, 0.42 mmol), DCM (10 mL), and dioxane hydrochloride solution (10 mL) were added to a single-mouth bottle in sequence, and the reaction was terminated at room temperature for 3 h. The reaction was concentrated to obtain 0.20 g of a yellow solid crude product.

步骤7：1-(6-((2S，6R)-1-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2，6-二甲基-1，2，3，6-四氢吡啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。
Step 7: Synthesis of 1-(6-((2S,6R)-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

室温下，依次向单口瓶中加入1-(6-((2S，6R)-2，6-二甲基-1，2，3，6-四氢吡啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.16g，0.40mmol)、(1R，2R)-2-((4-(4-((1R、2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.16g，0.44mmol)、DCM(20mL)，室温反应16h，加入三乙酰氧基硼氢化钠(0.18g，0.87mmol)反应1h。加入水(1mL)，搅拌5min，垫上硅藻土过滤，滤液浓缩柱层析(MeOH/DCM体系)得黄色固体0.14g。At room temperature, 1-(6-((2S,6R)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.16 g, 0.40 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.16 g, 0.44 mmol) and DCM (20 mL) were added to a single-necked bottle in sequence. The mixture was reacted at room temperature for 16 h. Sodium triacetoxyborohydride (0.18 g, 0.87 mmol) was added and the reaction was carried out for 1 h. Water (1 mL) was added, stirred for 5 min, and filtered through celite. The filtrate was concentrated and subjected to column chromatography (MeOH/DCM system) to obtain 0.14 g of a yellow solid.

步骤8：1-(5-氟-6-((2S，6R)-1-(((1R，2R)-2-((4-(4-(((3R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2，6-二甲基哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。
Step 8: Synthesis of 1-(5-fluoro-6-((2S,6R)-1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,6-dimethylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

室温下，依次向单口瓶中加入1-(6-((2S，6R)-1-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2，6-二甲基-1，2，3，6-四氢吡啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮0.14g，0.14mmol)、Pd/C(0.20g，10％)、MeOH(20mL)，氢气球氛围下室温反应16h，垫上硅藻土过滤，滤液浓缩柱层析(MeOH/DCM体系)得白色固体0.01g。MS(ESI)m/z：866.9[M+H]+.At room temperature, 1-(6-((2S,6R)-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 0.14 g, 0.14 mmol), Pd/C (0.20 g, 10%) and MeOH (20 mL) were added into a single-necked bottle in sequence. The mixture was reacted at room temperature for 16 h under a hydrogen balloon atmosphere. The mixture was filtered through diatomaceous earth and the filtrate was concentrated and subjected to column chromatography (MeOH/DCM system) to obtain 0.01 g of a white solid. MS (ESI) m/z: 866.9 [M+H] + .

实施例32：1-(5-氟-6-(4-羟基-1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成(化合物VI-23)
Example 32: Synthesis of 1-(5-fluoro-6-(4-hydroxy-1-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-23)

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：4-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-3，6-二氢吡啶-1(2H)-羧酸叔丁酯Step 1: tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate

Figure PCTCN2024137621-ftappb-I100376
Figure PCTCN2024137621-ftappb-I100376

将1-(6-溴-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(10g，29.3mmol)、4-(4，4，5，5-四甲基-1，3，2-二氧杂硼烷-2-基)-3，6-二氢吡啶-1(2H)-羧酸叔丁酯(10.9g，35.2mmol)和Pd(dppf)Cl2(1.1g，1.5mmol)置于200mL 1，4-二氧六环中，加入80mL Na2CO3(6.2g，58.6mmol)水溶液，氮气置换，90℃反应6小时，TLC、LC-MS检测反应结束；反应液浓缩，加水，EA萃取，有机相干燥，浓缩，制砂，柱层析(DCM/MeOH)得到粗产物，用乙酸乙酯打浆得9.5g类白色固体产物。1-(6-Bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (10 g, 29.3 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (10.9 g, 35.2 mmol) and Pd(dppf)Cl 2 (1.1 g, 1.5 mmol) were placed in 200 mL of 1,4-dioxane, and 80 mL of Na 2 CO 3 was added. (6.2 g, 58.6 mmol) aqueous solution, nitrogen replacement, reaction at 90 ° C for 6 hours, TLC, LC-MS detection of the completion of the reaction; the reaction solution was concentrated, water was added, EA was extracted, the organic phase was dried, concentrated, sand made, column chromatography (DCM / MeOH) to obtain a crude product, and ethyl acetate was used to slurry to obtain 9.5 g of an off-white solid product.

步骤2：4-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-4-羟基哌啶-1-甲酸叔丁酯

Figure PCTCN2024137621-ftappb-I100377
Step 2: tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidine-1-carboxylate
Figure PCTCN2024137621-ftappb-I100377

将4-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-3，6-二氢吡啶-1(2H)-羧酸叔丁酯(9.5g，21.4mmol)溶于300mL二氯甲烷和100mL异丙醇中，室温下加入Mn(TMHD)3(1.3g，2.1mmol)，冰水浴条件下加入PhSiH3(3.5g，32.1mmol)，加毕，氧气球氛围下反应2小时，TLC、LC-MS检测反应结束。反应液浓缩，加水，乙酸乙酯萃取，有机相浓缩，制砂，柱层析(PE/EA/DCM/MeOH)得到粗产物，乙酸乙酯打浆得3.6g类白色固体产物。4-(3-(2,4-dioxytetrahydropyrimidine-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (9.5 g, 21.4 mmol) was dissolved in 300 mL of dichloromethane and 100 mL of isopropanol, and Mn(TMHD) 3 (1.3 g, 2.1 mmol) was added at room temperature, and PhSiH 3 (3.5 g, 32.1 mmol) was added under ice-water bath conditions. After the addition was completed, the reaction was carried out under an oxygen ball atmosphere for 2 hours, and the reaction was completed by TLC and LC-MS. The reaction solution was concentrated, water was added, and ethyl acetate was extracted. The organic phase was concentrated, sand was made, and column chromatography (PE/EA/DCM/MeOH) was performed to obtain a crude product, and ethyl acetate was used to beat the product to obtain 3.6 g of an off-white solid product.

步骤3：1-(5-氟-6-(4-羟基哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮盐酸盐

Figure PCTCN2024137621-ftappb-I100378
Step 3: 1-(5-Fluoro-6-(4-hydroxypiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride
Figure PCTCN2024137621-ftappb-I100378

将4-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-4-羟基哌啶-1-甲酸叔丁酯(3.6g，7.8mmol)置于40mL盐酸1，4-二氧六环中，室温反应2小时，LC-MS检测反应结束。反应液过滤，滤饼晾干得3.1g类白色固体产物。4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (3.6 g, 7.8 mmol) was placed in 40 mL of 1,4-dioxane hydrochloride and reacted at room temperature for 2 hours. The reaction was completed by LC-MS detection. The reaction solution was filtered and the filter cake was dried to obtain 3.1 g of an off-white solid product.

步骤4：1-(6-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-4-羟基哌啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮

Figure PCTCN2024137621-ftappb-I100379
Step 4: 1-(6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-hydroxypiperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
Figure PCTCN2024137621-ftappb-I100379

将1-(5-氟-6-(4-羟基哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮盐酸盐(2.6g，7.2mmol)、(1R，2R)-2-((4-(4-((1R、2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-醛(4.3g，7.2mmol)置于150mL二氯甲烷中，加入10mL钛酸四异丙酯，20℃反应16小时，加入三乙酰氧基硼氢化钠(2.3g，10.8mmol)继续反应1小试，TLC、LC-MS检测反应结束。加入3mL水淬灭反应，再加入3mL氨水，搅拌20min，过滤，滤液浓缩制砂，柱层析(DCM/MeOH)得2.6g类白色固体产物。1-(5-Fluoro-6-(4-hydroxypiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (2.6 g, 7.2 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-aldehyde (4.3 g, 7.2 mmol) were placed in 150 mL of dichloromethane, 10 mL of tetraisopropyl titanate was added, the reaction was carried out at 20° C. for 16 hours, sodium triacetoxyborohydride (2.3 g, 10.8 mmol) was added and the reaction was continued for 1 test, and the reaction was completed by TLC and LC-MS detection. 3 mL of water was added to quench the reaction, and then 3 mL of aqueous ammonia was added, stirred for 20 min, filtered, and the filtrate was concentrated to make sand. 2.6 g of off-white solid product was obtained by column chromatography (DCM/MeOH).

步骤5：1-(5-氟-6-(4-羟基-1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮

Figure PCTCN2024137621-ftappb-I100380
Step 5: 1-(5-Fluoro-6-(4-hydroxy-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
Figure PCTCN2024137621-ftappb-I100380

将1-(6-(1-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-4-羟基哌啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(2.6g，2.75mmol)置于50mL四氢呋喃中，加入3.0g质量分数5％的Pd/C，氢气置换，20℃反应16小时，TLC、LC-MS检测反应结束；反应液过滤，滤液浓缩制砂，柱层析(DCM/MeOH)得1.3g类白色固体产物。1H NMR(400MHz，DMSO-d6)δ10.58(s，1H)，9.15(s，1H)，7.77(d，J＝6.3Hz，1H)，7.38(d，J＝12.7Hz，1H)，7.13(dt，J＝11.2，6.7Hz，3H)，6.83(d，J＝7.3Hz，2H)，6.73-6.42(m，5H)，6.22(d，J＝8.2Hz，2H)，5.25(br，1H)，4.14(d，J＝5.1Hz，1H)，4.08-3.78(m，5H)，3.34-3.24(m，6H)，3.07-2.90(m，6H)，2.78-2.73(m，2H)，2.58-2.50(m，6H)，2.37-2.28(m，2H)，2.17-2.05(m，2H)，1.84-1.44(m，8H)，1.28-1.14(m，3H)，0.99(s，2H).MS(ESI)m/z：854.8[M+H]+.1-(6-(1-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-hydroxypiperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (2.6 g, 2.75 mmol) was placed in 50 mL of tetrahydrofuran, 3.0 g of 5% Pd/C was added, hydrogen was replaced, and the reaction was carried out at 20° C. for 16 hours. The reaction was completed by TLC and LC-MS. The reaction solution was filtered, the filtrate was concentrated and sand was made, and column chromatography (DCM/MeOH) was performed to obtain 1.3 g of off-white solid product. 1 H NMR (400 MHz, DMSO-d 6 )δ10.58 (s, 1H), 9.15 (s, 1H), 7.77 (d, J = 6.3Hz, 1H), 7.38 (d, J = 12.7Hz, 1H), 7.13 (dt, J = 11.2, 6.7Hz, 3H ), 6.83 (d, J = 7.3Hz, 2H), 6.73-6.42 (m, 5H), 6.22 (d, J = 8.2Hz, 2H), 5.25 (br, 1H), 4.14 (d, J = 5.1Hz, 1H), 4 .08-3.78(m, 5H), 3.34-3.24(m, 6H), 3.07-2.90(m, 6H), 2.78-2.73(m, 2H), 2.58-2.50(m, 6H), 2.37-2.2 8(m, 2H), 2.17-2.05(m, 2H), 1.84-1.44(m, 8H), 1.28-1.14(m, 3H), 0.99(s, 2H).MS(ESI)m/z: 854.8[M+H] + .

实施例33：1-(5-氟-6-(4-(4-(((1R，2R)-2-((4-(-4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪-1-基)环己基-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成(化合物VI-24)

Figure PCTCN2024137621-ftappb-I100381
Example 33: Synthesis of 1-(5-fluoro-6-(4-(4-(((1R, 2R)-2-((4-(-4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)cyclohexyl-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-24)
Figure PCTCN2024137621-ftappb-I100381

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：1-(5-氟-1-甲基-6-(1，4-二氧阿司匹林[4.5]癸-7-en-8-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。

Figure PCTCN2024137621-ftappb-I100382
Step 1: Synthesis of 1-(5-fluoro-1-methyl-6-(1,4-dioxaspirino[4.5]dec-7-en-8-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure PCTCN2024137621-ftappb-I100382

室温下，依次向单口瓶中加入4，4，5，5-四甲基-2-(1，4-二氧阿司匹林[4.5]癸-7-en-8-基)-1，3，2-二氧杂硼烷(0.96g，1.23mmol)、1-(6-溴-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(1.02g，3.00mmol)、碳酸钠(0.64g，6.00mmol)、Pd(dppf)Cl2(0.22g，0.30mmol)、1.4-二氧六环(20mL)、H2O(1mL)。氮气保护下升温至85℃反应8h终止。冷却至室温，加水稀释，EA萃取，有机相经无水Na2SO4干燥、过滤、浓缩、柱层析纯化(EA/PE体系)得黄色固体1.0g。At room temperature, 4,4,5,5-tetramethyl-2-(1,4-dioxyaspirino[4.5]dec-7-en-8-yl)-1,3,2-dioxaborane (0.96 g, 1.23 mmol), 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.02 g, 3.00 mmol), sodium carbonate (0.64 g, 6.00 mmol), Pd(dppf)Cl 2 (0.22 g, 0.30 mmol), 1.4-dioxane (20 mL), and H 2 O (1 mL) were added to a single-mouth bottle in sequence. The temperature was raised to 85° C. under nitrogen protection for 8 h to terminate the reaction. The mixture was cooled to room temperature, diluted with water, extracted with EA, and the organic phase was dried over anhydrous Na 2 SO 4 , filtered, concentrated, and purified by column chromatography (EA/PE system) to obtain 1.0 g of a yellow solid.

步骤2：1-(5-氟-1-甲基-6-(1，4-二氧阿司匹林[4.5]癸-8-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。

Figure PCTCN2024137621-ftappb-I100383
Step 2: Synthesis of 1-(5-fluoro-1-methyl-6-(1,4-dioxaspirino[4.5]dec-8-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure PCTCN2024137621-ftappb-I100383

室温下，将1-(5-氟-1-甲基-6-(1，4-二氧阿司匹林[4.5]癸-7-en-8-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(1.00g，2.70mmol)溶解在乙醇(20mL)中，并加入催化剂(0.40g，10％Pd-C)。将混合物在氢气氛下搅拌16h。过滤，滤液浓缩得到黄色油状物粗品1.0g。At room temperature, 1-(5-fluoro-1-methyl-6-(1,4-dioxyaspirino[4.5]dec-7-en-8-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.00 g, 2.70 mmol) was dissolved in ethanol (20 mL), and a catalyst (0.40 g, 10% Pd-C) was added. The mixture was stirred under a hydrogen atmosphere for 16 h. The mixture was filtered and the filtrate was concentrated to obtain 1.0 g of a crude yellow oil.

步骤3：1-(5-氟-1-甲基-6-(4-氧代环己基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。

Figure PCTCN2024137621-ftappb-I100384
Step 3: Synthesis of 1-(5-fluoro-1-methyl-6-(4-oxocyclohexyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure PCTCN2024137621-ftappb-I100384

室温下，依次向单口瓶内加入1-(5-氟-1-甲基-6-(1，4-二氧阿司匹林[4.5]癸-8-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(1.0g，2.70mmol)、DCM(10mL)及TFA(2mL)，室温下搅拌6h。浓缩反应液得为黄色固体粗品0.80g。At room temperature, 1-(5-fluoro-1-methyl-6-(1,4-dioxyaspirin[4.5]dec-8-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.0 g, 2.70 mmol), DCM (10 mL) and TFA (2 mL) were added to a single-mouth bottle in sequence and stirred at room temperature for 6 h. The reaction solution was concentrated to obtain 0.80 g of a yellow solid crude product.

步骤4：4-(4-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)环己基)哌嗪-1-羧酸叔丁酯的合成。

Figure PCTCN2024137621-ftappb-I100385
Step 4: Synthesis of tert-butyl 4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)cyclohexyl)piperazine-1-carboxylate.
Figure PCTCN2024137621-ftappb-I100385

室温下，依次向单口瓶中加入1-(5-氟-1-甲基-6-(4-氧代环己基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.80g，2.23mmol)、哌嗪-1-羧酸叔丁酯(0.62g，3.35mmol)、DCM(20mL)及STAB(0.95g，4.46mmol)。室温反应16h终止。加饱和碳酸钠水溶液稀释，DCM萃取，有机相经无水Na2SO4干燥、过滤、浓缩、柱层析纯化(MeOH/DCM体系)得黄色固体1.05g。At room temperature, 1-(5-fluoro-1-methyl-6-(4-oxocyclohexyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.80 g, 2.23 mmol), tert-butyl piperazine-1-carboxylate (0.62 g, 3.35 mmol), DCM (20 mL) and STAB (0.95 g, 4.46 mmol) were added to a single-mouth bottle in sequence. The reaction was terminated at room temperature for 16 h. Saturated aqueous sodium carbonate solution was added for dilution, and DCM was used for extraction. The organic phase was dried over anhydrous Na 2 SO 4 , filtered, concentrated, and purified by column chromatography (MeOH/DCM system) to obtain 1.05 g of a yellow solid.

步骤5：1-(5-氟-1-甲基-6-(4-(哌嗪-1-基)环己基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。

Figure PCTCN2024137621-ftappb-I100386
Step 5: Synthesis of 1-(5-fluoro-1-methyl-6-(4-(piperazin-1-yl)cyclohexyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure PCTCN2024137621-ftappb-I100386

室温下，依次向单口瓶中加入4-(4-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)环己基)哌嗪-1-羧酸叔丁酯(1.05g，2.00mmol)、DCM(10mL)、盐酸二氧六环溶液(10mL)，室温反应3h终止。浓缩得黄色固体粗品1.00g。At room temperature, tert-butyl 4-(4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)cyclohexyl)piperazine-1-carboxylate (1.05 g, 2.00 mmol), DCM (10 mL), and dioxane hydrochloride solution (10 mL) were added to a single-mouth bottle in sequence, and the reaction was terminated at room temperature for 3 h. The reaction was concentrated to obtain 1.00 g of a yellow solid crude product.

步骤6：1-(6-(4-(4-(((1R，2R)-2-)(4-(-4-(((3R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪1-基)环己基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。

Figure PCTCN2024137621-ftappb-I100387
Step 6: Synthesis of 1-(6-(4-(4-(((1R,2R)-2-)(4-(-4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure PCTCN2024137621-ftappb-I100387

室温下，依次向单口瓶中加入1-(5-氟-1-甲基-6-(4-(哌嗪-1-基)环己基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.10g，0.23mmol)、(1R，2R)-2-((4-(4-((1R、2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.14g，0.23mmol)、DCM(20mL)、TIPT(1mL)，室温反应16h，加入三乙酰氧基硼氢化钠(0.07g，0.35mmol)反应1h。加入水(1mL)，搅拌5min，垫上硅藻土过滤，滤液浓缩柱层析(MeOH/DCM体系)得黄色固体0.10g。At room temperature, 1-(5-fluoro-1-methyl-6-(4-(piperazin-1-yl)cyclohexyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.10 g, 0.23 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.14 g, 0.23 mmol), DCM (20 mL), and TIPT (1 mL) were added into a single-necked bottle in sequence. The mixture was reacted at room temperature for 16 h. Sodium triacetoxyborohydride (0.07 g, 0.35 mmol) was added and the reaction was carried out for 1 h. Water (1 mL) was added, stirred for 5 min, and filtered through celite. The filtrate was concentrated and subjected to column chromatography (MeOH/DCM system) to obtain 0.10 g of a yellow solid.

步骤7：1-(5-氟-6-(4-(4-((1R，2R)-2-((4-(-4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪1-基)环己基-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。

Figure PCTCN2024137621-ftappb-I100388
Step 7: Synthesis of 1-(5-fluoro-6-(4-(4-((1R,2R)-2-((4-(-4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)cyclohexyl-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure PCTCN2024137621-ftappb-I100388

室温下，依次向单口瓶中加入1-(6-(4-(4-(((1R，2R)-2-)(4-(-4-(((3R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌嗪1-基)环己基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.10g，0.10mmol)、Pd/C(0.20g，10％)、MeOH(20mL)，氢气球氛围下室温反应16h，垫上硅藻土过滤，滤液浓缩柱层析(MeOH/DCM体系)得白色固体0.02g。1H NMR(400MHz，DMSO-d6)δ10.56(s，1H)，9.14(s，1H)，7.42(d，J＝6.0Hz，1H)，7.35(d，J＝10.9Hz，1H)，7.19-7.08(m，3H)，6.83(d，J＝7.1Hz，2H)，6.67-6.58(m，2H)，6.56-6.44(m，3H)，6.21(d，J＝8.3Hz，2H)，4.13(d，J＝5.0Hz，1H)，3.99(s，3H)，3.90(t，J＝6.7Hz，2H)，3.04-2.89(m，8H)，2.75(t，J＝6.7Hz，2H)，2.48-2.29(m，8H)，2.22-2.17(m，1H)，2.11-2.02(m，4H)，1.88-1.67(m，5H)，1.62-1.37(m，9H)，1.33-1.12(m，8H)，1.03-0.90(m，2H).MS(ESI)m/z：921.9[M+H]+.At room temperature, 1-(6-(4-(4-(((1R, 2R)-2-)(4-(-4-(((3R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.10 g, 0.10 mmol), Pd/C (0.20 g, 10%), and MeOH (20 mL) were added to a single-necked bottle in sequence. The mixture was reacted at room temperature for 16 h under a hydrogen balloon atmosphere, filtered through a pad of diatomaceous earth, and the filtrate was concentrated and subjected to column chromatography (MeOH/DCM system) to obtain 0.02 g of a white solid. NMR (400MHz, DMSO-d6) δ10.56 (s, 1H), 9.14 (s, 1H), 7.42 (d, J=6.0Hz, 1H), 7.35 (d, J=10.9Hz, 1H), 7.19-7.08 (m, 3H ), 6.83 (d, J = 7.1Hz, 2H), 6.67-6.58 (m, 2H), 6.56-6.44 (m, 3H), 6.21 (d, J = 8.3Hz, 2H), 4.13 (d, J = 5.0Hz, 1H), 3.99 ( s, 3H), 3.90 (t, J=6.7Hz, 2H), 3.04-2.89 (m, 8H), 2.75 (t, J=6.7Hz, 2H), 2.48-2.29 (m, 8H), 2.22-2.17 (m, 1H), 2.11 -2.02(m, 4H), 1.88-1.67(m, 5H), 1.62-1.37(m, 9H), 1.33-1.12(m, 8H), 1.03-0.90(m, 2H).MS(ESI)m/z: 921.9[M+H] + .

实施例34：1-(6-(4-(环丙基(((1R，2R)-2-((4-(4-(((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)氨基)环己基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成(化合物VI-25)

Figure PCTCN2024137621-ftappb-I100389
Example 34: Synthesis of 1-(6-(4-(cyclopropyl(((1R,2R)-2-((4-(4-(((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)amino)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-25)
Figure PCTCN2024137621-ftappb-I100389

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：1-(6-(4-(环丙基氨基)环己基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。

Figure PCTCN2024137621-ftappb-I100390
Step 1: Synthesis of 1-(6-(4-(cyclopropylamino)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure PCTCN2024137621-ftappb-I100390

室温下，依次向单口瓶中加入1-(5-氟-1-甲基-6-(4-氧代环己基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.10g，0.28mmol)、环丙胺(0.06g，1.12mmol)、DCM(20mL)及STAB(0.12g，0.56mmol)。室温反应16h终止。加饱和碳酸钠水溶液稀释，DCM萃取，有机相经无水Na2SO4干燥、过滤、浓缩、柱层析纯化(MeOH/DCM体系)得黄色固体0.09g。At room temperature, 1-(5-fluoro-1-methyl-6-(4-oxocyclohexyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.10 g, 0.28 mmol), cyclopropylamine (0.06 g, 1.12 mmol), DCM (20 mL) and STAB (0.12 g, 0.56 mmol) were added to a single-mouth bottle in sequence. The reaction was terminated at room temperature for 16 h. Saturated aqueous sodium carbonate solution was added for dilution, and DCM was used for extraction. The organic phase was dried over anhydrous Na 2 SO 4 , filtered, concentrated, and purified by column chromatography (MeOH/DCM system) to obtain 0.09 g of a yellow solid.

步骤2：1-(6-(4-((((1R，2R)-2-((4-(4-(2R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)(环丙基)氨基)环己基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。

Figure PCTCN2024137621-ftappb-I100391
Step 2: Synthesis of 1-(6-(4-((((1R,2R)-2-((4-(4-(2R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)(cyclopropyl)amino)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure PCTCN2024137621-ftappb-I100391

室温下，依次向单口瓶中加入1-(6-(4-(环丙基氨基)环己基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.09g，0.23mmol)、(1R，2R)-2-((4-(4-((1R、2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.14g，0.23mmol)、DCM(20mL)、TIPT(1mL)，室温反应16h，加入三乙酰氧基硼氢化钠(0.07g，0.35mmol)反应1h。加入水(1mL)，搅拌5min，垫上硅藻土过滤，滤液浓缩柱层析(MeOH/DCM体系)得黄色固体0.08g。At room temperature, 1-(6-(4-(cyclopropylamino)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.09 g, 0.23 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.14 g, 0.23 mmol), DCM (20 mL), and TIPT (1 mL) were added into a single-necked bottle in sequence. The mixture was reacted at room temperature for 16 h. Sodium triacetoxyborohydride (0.07 g, 0.35 mmol) was added and the reaction was carried out for 1 h. Water (1 mL) was added, stirred for 5 min, and filtered through celite. The filtrate was concentrated and subjected to column chromatography (MeOH/DCM system) to obtain 0.08 g of a yellow solid.

步骤3：1-(6-(4-(环丙基(((1R，2R)-2-((4-(4-(((3R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)氨基)环己基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮。

Figure PCTCN2024137621-ftappb-I100392
Step 3: 1-(6-(4-(cyclopropyl(((1R,2R)-2-((4-(4-(((3R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)amino)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure PCTCN2024137621-ftappb-I100392

室温下，依次向单口瓶中加入1-(6-(4-((((1R，2R)-2-((4-(4-(2R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)(环丙基)氨基)环己基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.08g，0.08mmol)、Pd/C(0.20g，10％)、MeOH(20mL)，氢气球氛围下室温反应16h，垫上硅藻土过滤，滤液浓缩柱层析(MeOH/DCM体系)得白色固体0.01g。MS(ESI)m/z：893.1[M+H]+At room temperature, 1-(6-(4-((((1R, 2R)-2-((4-(4-(2R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)(cyclopropyl)amino)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.08 g, 0.08 mmol), Pd/C (0.20 g, 10%), and MeOH (20 mL) were added to a single-necked bottle in sequence. The mixture was reacted at room temperature for 16 h under a hydrogen balloon atmosphere, filtered through diatomaceous earth, and the filtrate was concentrated and subjected to column chromatography (MeOH/DCM system) to obtain 0.01 g of a white solid. MS (ESI) m/z: 893.1 [M+H]+

实施例35：1-(5-氟-6-(6-(((1R，2R)-2-((4-(4-(((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2，6-二氮杂螺[3.3]庚烷-2-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成(化合物VI-26)

Figure PCTCN2024137621-ftappb-I100393
Example 35: Synthesis of 1-(5-fluoro-6-(6-(((1R, 2R)-2-((4-(4-(((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,6-diazaspiro[3.3]heptane-2-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-26)
Figure PCTCN2024137621-ftappb-I100393

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：6-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-2，6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯的合成。

Figure PCTCN2024137621-ftappb-I100394
Step 1: Synthesis of tert-butyl 6-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate.
Figure PCTCN2024137621-ftappb-I100394

室温下，依次向单口瓶中加入1-(6-溴-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(1.00g，2.93mmol)、2，6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(1.16g，5.86mmol)、碳酸铯(1.91g，5.86mmol)、Ruphos(0.27g，0.58mmol)、RuphosPdG2(0.24g，0.29mmol)、DMF(100mL)。氮气氛围下120℃反应16h终止。冷却至室温，加入水稀释，EA萃取三次，合并有机相，，有机相经水洗，食盐水洗、无水Na2SO4干燥、过滤、浓缩、柱层析纯化(MeOH/DCM体系)得黄色固体0.80g。At room temperature, 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.00 g, 2.93 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (1.16 g, 5.86 mmol), cesium carbonate (1.91 g, 5.86 mmol), Ruphos (0.27 g, 0.58 mmol), RuphosPdG 2 (0.24 g, 0.29 mmol), and DMF (100 mL) were added to a single-mouth bottle in sequence. The reaction was terminated at 120° C. for 16 h under a nitrogen atmosphere. The mixture was cooled to room temperature, diluted with water, extracted with EA three times, and the organic phases were combined, washed with water, washed with brine, dried with anhydrous Na 2 SO 4 , filtered, concentrated, and purified by column chromatography (MeOH/DCM system) to obtain 0.80 g of a yellow solid.

步骤2：1-(5-氟-1-甲基-6-(2，6-二氮杂螺[3.3]庚烷-2-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。

Figure PCTCN2024137621-ftappb-I100395
Step 2: Synthesis of 1-(5-fluoro-1-methyl-6-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure PCTCN2024137621-ftappb-I100395

室温下，依次向单口瓶中加入6-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-2，6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(0.80g，1.75mmol)、TFA(2mL)、DCM(10mL)。室温反应3h终止。浓缩得黄色固体粗品0.70g。At room temperature, 6-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (0.80 g, 1.75 mmol), TFA (2 mL), and DCM (10 mL) were added to a single-mouth bottle in sequence. The reaction was terminated at room temperature for 3 h. The solution was concentrated to obtain 0.70 g of a yellow solid crude product.

步骤3：1-(6-(6-(((1R，2R)-2-((4-(4-(((3R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2，6-二氮杂螺[3.3]庚烷-2-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。

Figure PCTCN2024137621-ftappb-I100396
Step 3: Synthesis of 1-(6-(6-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,6-diazaspiro[3.3]heptane-2-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure PCTCN2024137621-ftappb-I100396

室温下，依次向单口瓶中加入1-(5-氟-1-甲基-6-(2，6-二氮杂螺[3.3]庚烷-2-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.20g，0.56mmol)、(1R，2R)-2-((4-(4-((1R、2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.33g，0.56mmol)、DCM(20mL)、TIPT(1mL)，室温反应16h，加入三乙酰氧基硼氢化钠(0.18g，0.84mmol)反应1h。加入水(1mL)，搅拌5min，垫上硅藻土过滤，滤液浓缩柱层析(MeOH/DCM体系)得白色固体0.20g。At room temperature, 1-(5-fluoro-1-methyl-6-(2,6-diazaspiro[3.3]heptane-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.20 g, 0.56 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.33 g, 0.56 mmol), DCM (20 mL) and TIPT (1 mL) were added into a single-necked bottle in sequence. The mixture was reacted at room temperature for 16 h. Sodium triacetoxyborohydride (0.18 g, 0.84 mmol) was added and the reaction was carried out for 1 h. Water (1 mL) was added, stirred for 5 min, and filtered through celite. The filtrate was concentrated and subjected to column chromatography (MeOH/DCM system) to obtain 0.20 g of a white solid.

步骤4：1-(5-氟-6-(6-(((1R，2R)-2-((4-(4-(((3R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2，6-二氮杂螺[3.3]庚烷-2-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。

Figure PCTCN2024137621-ftappb-I100397
Step 4: Synthesis of 1-(5-fluoro-6-(6-(((1R,2R)-2-((4-(4-(((3R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,6-diazaspiro[3.3]heptane-2-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure PCTCN2024137621-ftappb-I100397

室温下，依次向单口瓶中加入1-(6-(6-(((1R，2R)-2-((4-(4-(((3R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2，6-二氮杂螺[3.3]庚烷-2-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.20g，0.21mmol)、Pd/C(0.20g，10％)、MeOH(20mL)，氢气球氛围下室温反应16h，垫上硅藻土过滤，滤液浓缩柱层析(MeOH/DCM体系)得白色固体0.08g。MS(ESI)m/z：851.8[M+H]+.At room temperature, 1-(6-(6-(((1R, 2R)-2-((4-(4-(((3R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,6-diazaspiro[3.3]heptane-2-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.20 g, 0.21 mmol), Pd/C (0.20 g, 10%), and MeOH (20 mL) were added to a single-necked bottle in sequence. The mixture was reacted at room temperature for 16 h under a hydrogen balloon atmosphere, filtered through a diatomaceous earth pad, and the filtrate was concentrated and column chromatography (MeOH/DCM system) was performed to obtain 0.08 g of a white solid. MS (ESI) m/z: 851.8 [M+H] + .

实施例36：1-(5-氟-6-(7-(((1R，2R)-2-((4-(4-(((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2，7-二氮杂螺[3.5]壬-2-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成(化合物VI-27)

Figure PCTCN2024137621-ftappb-I100398
Example 36: Synthesis of 1-(5-fluoro-6-(7-(((1R,2R)-2-((4-(4-(((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-27)
Figure PCTCN2024137621-ftappb-I100398

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：2-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-2，7-二氮杂螺[3.5]壬-7-羧酸叔丁酯的合成。

Figure PCTCN2024137621-ftappb-I100399
Step 1: Synthesis of tert-butyl 2-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate.
Figure PCTCN2024137621-ftappb-I100399

室温下，依次向单口瓶中加入1-(6-溴-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(1.00g，2.93mmol)、2，7-二氮杂螺[3.5]壬烷-7-羧酸叔丁酯(1.20g，5.86mmol)、碳酸铯(1.91g，5.86mmol)、Ruphos(0.27g，0.58mmol)、RuphosPdG2(0.24g，0.29mmol)、DMF(100mL)。氮气氛围下120℃反应16h终止。冷却至室温，加入水稀释，EA萃取三次，合并有机相，，有机相经水洗，食盐水洗、无水Na2SO4干燥、过滤、浓缩、柱层析纯化(MeOH/DCM体系)得黄色固体0.80g。At room temperature, 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.00 g, 2.93 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (1.20 g, 5.86 mmol), cesium carbonate (1.91 g, 5.86 mmol), Ruphos (0.27 g, 0.58 mmol), RuphosPdG 2 (0.24 g, 0.29 mmol), and DMF (100 mL) were added to a single-mouth bottle in sequence. The reaction was terminated at 120° C. for 16 h under a nitrogen atmosphere. The mixture was cooled to room temperature, diluted with water, extracted with EA three times, and the organic phases were combined. The organic phases were washed with water, washed with brine, dried with anhydrous Na 2 SO 4 , filtered, concentrated, and purified by column chromatography (MeOH/DCM system) to obtain 0.80 g of a yellow solid.

步骤2：1-(5-氟-1-甲基-6-(2，7-二氮杂螺[3.5]壬-2-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。

Figure PCTCN2024137621-ftappb-I100400
Step 2: Synthesis of 1-(5-fluoro-1-methyl-6-(2,7-diazaspiro[3.5]nonan-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure PCTCN2024137621-ftappb-I100400

室温下，依次向单口瓶中加入2-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-2，7-二氮杂螺[3.5]壬-7-羧酸叔丁酯(0.80g，1.74mmol)、TFA(2mL)、DCM(10mL)。室温反应3h终止。浓缩得黄色固体粗品0.70g。At room temperature, tert-butyl 2-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazole-6-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (0.80 g, 1.74 mmol), TFA (2 mL), and DCM (10 mL) were added to a single-mouth bottle in sequence. The reaction was terminated at room temperature for 3 h. The solution was concentrated to obtain 0.70 g of a yellow solid crude product.

步骤3：1-(6-(7-(((1R，2R)-2-((4-(4-(((3R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2，7-二氮杂螺[3.5]壬-2-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。

Figure PCTCN2024137621-ftappb-I100401
Step 3: Synthesis of 1-(6-(7-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure PCTCN2024137621-ftappb-I100401

室温下，依次向单口瓶中加入1-(5-氟-1-甲基-6-(2，7-二氮杂螺[3.5]壬-2-基)-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.20g，0.52mmol)、(1R，2R)-2-((4-(4-((1R、2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.31g，0.52mmol)、DCM(20mL)、TIPT(1mL)，室温反应16h，加入三乙酰氧基硼氢化钠(0.16g，0.78mmol)反应1h。加入水(1mL)，搅拌5min，垫上硅藻土过滤，滤液浓缩柱层析(MeOH/DCM体系)得白色固体0.20g。At room temperature, 1-(5-fluoro-1-methyl-6-(2,7-diazaspiro[3.5]nonan-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.20 g, 0.52 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.31 g, 0.52 mmol), DCM (20 mL), and TIPT (1 mL) were added into a single-necked bottle in sequence. The mixture was reacted at room temperature for 16 h. Sodium triacetoxyborohydride (0.16 g, 0.78 mmol) was added and the reaction was carried out for 1 h. Water (1 mL) was added, stirred for 5 min, and filtered through celite. The filtrate was concentrated and subjected to column chromatography (MeOH/DCM system) to obtain 0.20 g of a white solid.

步骤4：1-(5-氟-6-(7-(((1R，2R)-2-((4-(4-(((3R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2，7-二氮杂螺[3.5]壬-2-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。

Figure PCTCN2024137621-ftappb-I100402
Step 4: Synthesis of 1-(5-fluoro-6-(7-(((1R,2R)-2-((4-(4-(((3R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure PCTCN2024137621-ftappb-I100402

室温下，依次向单口瓶中加入1-(6-(7-(((1R，2R)-2-((4-(4-(((3R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2，7-二氮杂螺[3.5]壬-2-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.20g，0.20mmol)、Pd/C(0.20g，10％)、MeOH(20mL)，氢气球氛围下室温反应16h，垫上硅藻土过滤，滤液浓缩柱层析(MeOH/DCM体系)得白色固体0.06g。1H NMR(400MHz，DMSO-d6)δ10.52(s，1H)，9.15(s，1H)，7.28(d，J＝12.8Hz，1H)，7.18-7.08(m，3H)，6.91-6.78(m，2H)，6.67-6.53(m，4H)，6.52-6.46(m，2H)，6.27-6.18(m，2H)，4.18-4.12(m，1H)，3.92-3.84(m，4H)，3.81-3.72(m，4H)，3.14-2.89(m，8H)，2.73(t，J＝6.7Hz，3H)，2.29-2.20(m，1H)，2.15-1.91(m，5H)，1.78-1.59(m，6H)，1.36(s，3H)，1.30-1.16(m，6H)，1.07-0.93(m，1H)，0.89-0.80(m，2H).MS(ESI)m/z：879.8[M+H]+.At room temperature, 1-(6-(7-(((1R, 2R)-2-((4-(4-(((3R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.20 g, 0.20 mmol), Pd/C (0.20 g, 10%), and MeOH (20 mL) were added to a single-necked bottle in sequence. The mixture was reacted at room temperature for 16 h under a hydrogen balloon atmosphere, and filtered through a pad of celite. The filtrate was concentrated and subjected to column chromatography (MeOH/DCM system) to obtain 0.06 g of a white solid. NMR (400MHz, DMSO-d6) δ10.52 (s, 1H), 9.15 (s, 1H), 7.28 (d, J=12.8Hz, 1H), 7.18-7.08 (m, 3H), 6.91-6.78 (m, 2H), 6.67-6.53 (m, 4H), 6.52-6.46 (m, 2H), 6.27-6.18 (m, 2H), 4.18-4.12 (m, 1H), 3.92-3.84 (m, 4H), 3. 81-3.72 (m, 4H), 3.14-2.89 (m, 8H), 2.73 (t, J=6.7Hz, 3H), 2.29-2.20 (m, 1H), 2.15-1.91 (m, 5H), 1.78-1. 59 (m, 6H), 1.36 (s, 3H), 1.30-1.16 (m, 6H), 1.07-0.93 (m, 1H), 0.89-0.80 (m, 2H). MS (ESI) m/z: 879.8 [M+H] + .

实施例37：1-(5-氟-6-(1-(((1R，2R)-2-((4-(4-(((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-4-甲氧基哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成(化合物VI-28)

Figure PCTCN2024137621-ftappb-I100403
Example 37: Synthesis of 1-(5-fluoro-6-(1-(((1R, 2R)-2-((4-(4-(((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-methoxypiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-28)
Figure PCTCN2024137621-ftappb-I100403

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：2-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-2，7-二氮杂螺[3.5]壬-7-羧酸叔丁酯的合成。

Figure PCTCN2024137621-ftappb-I100404
Step 1: Synthesis of tert-butyl 2-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate.
Figure PCTCN2024137621-ftappb-I100404

室温下，依次向单口瓶中加入4-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-4-羟基哌啶-1-甲酸叔丁酯(3.00g，6.50mmol)、碳酸铯(2.12g，6.50mmol)、PMBCl(1.22g，7.80mmol)、DMF(50mL)。氮气氛围下50℃反应3h终止。冷却至室温，加入水稀释，EA萃取三次，合并有机相，有机相经水洗，食盐水洗、无水Na2SO4干燥、过滤、浓缩、柱层析纯化(EA/PE体系)得黄色固体1.90g。At room temperature, tert-butyl 4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidine-1-carboxylate (3.00 g, 6.50 mmol), cesium carbonate (2.12 g, 6.50 mmol), PMBCl (1.22 g, 7.80 mmol), and DMF (50 mL) were added to a single-mouth bottle in sequence. The reaction was terminated at 50°C for 3 h under a nitrogen atmosphere. The mixture was cooled to room temperature, diluted with water, extracted with EA three times, and the organic phases were combined. The organic phases were washed with water, washed with brine, dried with anhydrous Na 2 SO 4 , filtered, concentrated, and purified by column chromatography (EA/PE system) to obtain 1.90 g of a yellow solid.

步骤2：4-(5-氟-3-(3-(4-甲氧基苄基)-2，4-二氧杂四氢嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-4-甲氧基哌啶-1-甲酸叔丁酯的合成。

Figure PCTCN2024137621-ftappb-I100405
Step 2: Synthesis of tert-butyl 4-(5-fluoro-3-(3-(4-methoxybenzyl)-2,4-dioxatetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-4-methoxypiperidine-1-carboxylate.
Figure PCTCN2024137621-ftappb-I100405

室温下，依次向单口瓶中加入2-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-2，7-二氮杂螺[3.5]壬-7-羧酸叔丁酯(1.90g，3.24mmol)、THF(20mL)、NaH(0.26g，6.49mmol)，搅拌10min后，加入碘甲烷(0.92g，6.49mmol)。室温反应16h终止。加入饱和氯化铵水溶液稀释，EA萃取三次，合并有机相，有机相经水洗，食盐水洗、无水Na2SO4干燥、过滤、浓缩、柱层析纯化(EA/PE体系)得黄色固体0.80g。At room temperature, tert-butyl 2-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazole-6-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (1.90 g, 3.24 mmol), THF (20 mL), and NaH (0.26 g, 6.49 mmol) were added to a single-mouth bottle in sequence. After stirring for 10 min, iodomethane (0.92 g, 6.49 mmol) was added. The reaction was terminated at room temperature for 16 h. Saturated aqueous ammonium chloride was added for dilution, and EA was extracted three times. The organic phases were combined, washed with water, washed with brine, dried with anhydrous Na 2 SO 4 , filtered, concentrated, and purified by column chromatography (EA/PE system) to obtain 0.80 g of a yellow solid.

步骤3：1-(5-氟-6-(4-甲氧基哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。

Figure PCTCN2024137621-ftappb-I100406
Step 3: Synthesis of 1-(5-fluoro-6-(4-methoxypiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure PCTCN2024137621-ftappb-I100406

室温下，依次向单口瓶中加入4-(5-氟-3-(3-(4-甲氧基苄基)-2，4-二氧杂四氢嘧啶-1(2H)-基)-1-甲基-1H-吲唑-6-基)-4-甲氧基哌啶-1-甲酸叔丁酯(0.15g，0.25mmol)、TFA(4mL)，TFOH(0.15g，1.00mmol)。65℃反应3h终止。浓缩得黄色固体粗品0.10g。At room temperature, tert-butyl 4-(5-fluoro-3-(3-(4-methoxybenzyl)-2,4-dioxatetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-4-methoxypiperidine-1-carboxylate (0.15 g, 0.25 mmol), TFA (4 mL), and TFOH (0.15 g, 1.00 mmol) were added to a single-mouth bottle in sequence. The reaction was terminated at 65°C for 3 h. The residue was concentrated to obtain 0.10 g of a yellow solid crude product.

步骤4：1-(6-(1-(((1R，2R)-2-((4-(4-(((3R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-4-甲氧基哌啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。

Figure PCTCN2024137621-ftappb-I100407
Step 4: Synthesis of 1-(6-(1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-methoxypiperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure PCTCN2024137621-ftappb-I100407

室温下，依次向单口瓶中加入1-(5-氟-6-(4-甲氧基哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.10g，0.26mmol)、(1R，2R)-2-((4-(4-((1R、2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛(0.16g，0.26mmol)、DCM(20mL)、TIPT(1mL)，室温反应16h，加入三乙酰氧基硼氢化钠(0.08g，0.39mmol)反应1h。加入水(1mL)，搅拌5min，垫上硅藻土过滤，滤液浓缩柱层析(MeOH/DCM体系)得白色固体0.10g。At room temperature, 1-(5-fluoro-6-(4-methoxypiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.10 g, 0.26 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.16 g, 0.26 mmol), DCM (20 mL) and TIPT (1 mL) were added into a single-necked bottle in sequence. The mixture was reacted at room temperature for 16 h. Sodium triacetoxyborohydride (0.08 g, 0.39 mmol) was added and the reaction was carried out for 1 h. Water (1 mL) was added, stirred for 5 min, and filtered through celite. The filtrate was concentrated and subjected to column chromatography (MeOH/DCM system) to obtain 0.10 g of a white solid.

步骤5：1-(5-氟-6-(1-(((1R，2R)-2-((4-(4-(((3R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-4-甲氧基哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。

Figure PCTCN2024137621-ftappb-I100408
Step 5: Synthesis of 1-(5-fluoro-6-(1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-methoxypiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure PCTCN2024137621-ftappb-I100408

室温下，依次向单口瓶中加入1-(6-(1-(((1R，2R)-2-((4-(4-(((3R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-4-甲氧基哌啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.10g，0.10mmol)、Pd/C(0.20g，10％)、MeOH(20mL)，氢气球氛围下室温反应16h，垫上硅藻土过滤，滤液浓缩柱层析(MeOH/DCM体系)得白色固体0.02g。MS(ESI)m/z：868.9[M+H]+.At room temperature, 1-(6-(1-(((1R, 2R)-2-((4-(4-(((3R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-methoxypiperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.10 g, 0.10 mmol), Pd/C (0.20 g, 10%), and MeOH (20 mL) were added to a single-mouth bottle in sequence. The mixture was reacted at room temperature for 16 h under a hydrogen balloon atmosphere, filtered through a diatomaceous earth pad, and the filtrate was concentrated and subjected to column chromatography (MeOH/DCM system) to obtain 0.02 g of a white solid. MS (ESI) m/z: 868.9 [M+H] + .

实施例38：1-(5-氟-6-((2R)-4-羟基-1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2-甲基哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成(化合物VI-29)

Figure PCTCN2024137621-ftappb-I100409
Example 38: Synthesis of 1-(5-fluoro-6-((2R)-4-hydroxy-1-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-29)
Figure PCTCN2024137621-ftappb-I100409

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：(2R)-4-(3-(2，4-二氧代四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-4-羟基-2-甲基哌啶-1-羧酸叔丁酯

Figure PCTCN2024137621-ftappb-I100410
Step 1: (2R)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester
Figure PCTCN2024137621-ftappb-I100410

室温下，将(R)-4-(3-(2，4-二氧代四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-6-甲基-3，6-二氢吡啶-1(2H)-羧酸叔丁酯(0.60g，1.31mmol)溶于30mL二氯甲烷和10mL异丙醇中，室温下加入Mn(TMHD)3(0.08g，0.13mmol)，冰水浴条件下加入PhSiH3(0.21g，1.97mmol)，加毕，氧气置换，室温反应16小时，LC-MS检测反应结束。反应液浓缩制砂，柱层析(DCM/MeOH)得到产物，浓缩得0.22g类白色固体产物。At room temperature, (R)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-6-methyl-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.60 g, 1.31 mmol) was dissolved in 30 mL of dichloromethane and 10 mL of isopropanol, and Mn(TMHD) 3 (0.08 g, 0.13 mmol) was added at room temperature, and PhSiH 3 (0.21 g, 1.97 mmol) was added under ice-water bath conditions. After addition, oxygen was replaced, and the reaction was carried out at room temperature for 16 hours. LC-MS detected that the reaction was complete. The reaction solution was concentrated and sanded, and the product was obtained by column chromatography (DCM/MeOH), and concentrated to obtain 0.22 g of an off-white solid product.

步骤2：1-(5-氟-6-((2R)-4-羟基-2-甲基哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮盐酸盐

Figure PCTCN2024137621-ftappb-I100411
Step 2: 1-(5-Fluoro-6-((2R)-4-hydroxy-2-methylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride
Figure PCTCN2024137621-ftappb-I100411

室温下，将(2R)-4-(3-(2，4-二氧代四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-4-羟基-2-甲基哌啶-1-羧酸叔丁酯(0.22g，0.46mmol)溶于于5mL二氯甲烷，再加入5ml盐酸1，4-二氧六环中，室温反应2小时，LC-MS检测反应结束。反应液旋干，得0.13g类白色固体产物。At room temperature, (2R)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester (0.22 g, 0.46 mmol) was dissolved in 5 mL of dichloromethane, and then 5 ml of hydrochloric acid 1,4-dioxane was added, and the reaction was carried out at room temperature for 2 hours. The reaction was completed by LC-MS detection. The reaction solution was spin-dried to obtain 0.13 g of an off-white solid product.

步骤3：1-(6-((2R)-1-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-4-羟基-2-甲基哌啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮

Figure PCTCN2024137621-ftappb-I100412
Step 3: 1-(6-((2R)-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-hydroxy-2-methylpiperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
Figure PCTCN2024137621-ftappb-I100412

室温下，将1-(5-氟-6-(4-羟基哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮盐酸盐(0.12g，0.32mmol)、(1R，2R)-2-((4-(4-((1R、2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-醛(0.19g，0.32mmol)置于20mL二氯甲烷中，加入1mL钛酸四异丙酯，20℃反应16小时，加入三乙酰氧基硼氢化钠(0.10g，0.48mmol)继续反应1小试，LC-MS检测反应结束。加入1mL水淬灭反应，再加入0.5mL氨水，搅拌20min，过滤，滤液浓缩，爬大板分离(DCM/MeOH)得0.05g黄色油状物。At room temperature, 1-(5-fluoro-6-(4-hydroxypiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (0.12 g, 0.32 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-aldehyde (0.19 g, 0.32 mmol) were placed in 20 mL of dichloromethane, 1 mL of tetraisopropyl titanate was added, the reaction was carried out at 20°C for 16 hours, sodium triacetoxyborohydride (0.10 g, 0.48 mmol) was added and the reaction was continued for 1 test, and the reaction was completed by LC-MS detection. 1 mL of water was added to quench the reaction, and then 0.5 mL of aqueous ammonia was added, stirred for 20 min, filtered, and the filtrate was concentrated and separated on a plate (DCM/MeOH) to obtain 0.05 g of a yellow oil.

步骤4：1-(5-氟-6-((2R)-4-羟基-1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2-甲基哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮

Figure PCTCN2024137621-ftappb-I100413
Step 4: 1-(5-Fluoro-6-((2R)-4-hydroxy-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
Figure PCTCN2024137621-ftappb-I100413

室温下，将1-(6-((2R)-1-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-4-羟基-2-甲基哌啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.05g，0.05mmol)置于10mL甲醇中，加入0.03g质量分数5％的Pd/C，氢气置换，20℃反应16小时，LC-MS检测反应结束；反应液过滤，滤液旋干，硅胶板层析(DCM/MeOH)，过滤，滤液旋干，冻干得0.007g类白色固体产物。MS(ESI)m/z：435.4[M/2+H]+.At room temperature, 1-(6-((2R)-1-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-hydroxy-2-methylpiperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.05 g, 0.05 mmol) was placed in 10 mL of methanol, 0.03 g of 5% Pd/C was added, hydrogen was replaced, the reaction was carried out at 20° C. for 16 hours, and the reaction was completed by LC-MS detection; the reaction solution was filtered, the filtrate was spin-dried, silica gel plate chromatography (DCM/MeOH), filtered, the filtrate was spin-dried, and lyophilized to obtain 0.007 g of an off-white solid product. MS (ESI) m/z: 435.4 [M/2+H] + .

实施例39：1-(5-氟-6-((2S)-4-羟基-1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2-甲基哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成(化合物VI-30)

Figure PCTCN2024137621-ftappb-I100414
Example 39: Synthesis of 1-(5-fluoro-6-((2S)-4-hydroxy-1-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-30)
Figure PCTCN2024137621-ftappb-I100414

(1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己烷-1-甲醛的合成方法参照实施例1。The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde can be referred to Example 1.

步骤1：(2S)-4-(3-(2，4-二氧代四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-4-羟基-2-甲基哌啶-1-羧酸叔丁酯

Figure PCTCN2024137621-ftappb-I100415
Step 1: (2S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester
Figure PCTCN2024137621-ftappb-I100415

室温下，将(S)-4-(3-(2，4-二氧代四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-6-甲基-3，6-二氢吡啶-1(2H)-羧酸叔丁酯(0.60g，1.31mmol)溶于30mL二氯甲烷和10mL异丙醇中，室温下加入Mn(TMHD)3(0.08g，0.13mmol)，冰水浴条件下加入PhSiH3(0.21g，1.97mmol)，加毕，氧气置换，室温反应16小时，LC-MS检测反应结束。反应液浓缩制砂，柱层析(DCM/MeOH)得到产物，浓缩得0.22g类白色固体产物。At room temperature, (S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-6-methyl-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.60 g, 1.31 mmol) was dissolved in 30 mL of dichloromethane and 10 mL of isopropanol, and Mn(TMHD) 3 (0.08 g, 0.13 mmol) was added at room temperature, and PhSiH 3 (0.21 g, 1.97 mmol) was added under ice-water bath conditions. After addition, oxygen was replaced, and the reaction was carried out at room temperature for 16 hours. LC-MS detected that the reaction was complete. The reaction solution was concentrated and sanded, and the product was obtained by column chromatography (DCM/MeOH), and concentrated to obtain 0.22 g of an off-white solid product.

步骤2：1-(5-氟-6-((2S)-4-羟基-2-甲基哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮盐酸盐

Figure PCTCN2024137621-ftappb-I100416
Step 2: 1-(5-Fluoro-6-((2S)-4-hydroxy-2-methylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride
Figure PCTCN2024137621-ftappb-I100416

室温下，将(2S)-4-(3-(2，4-二氧代四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-4-羟基-2-甲基哌啶-1-羧酸叔丁酯(0.22g，0.46mmol)溶于于5mL二氯甲烷，再加入5ml盐酸1，4-二氧六环中，室温反应2小时，LC-MS检测反应结束。反应液旋干，得0.13g类白色固体产物。At room temperature, (2S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester (0.22 g, 0.46 mmol) was dissolved in 5 mL of dichloromethane, and then 5 ml of hydrochloric acid 1,4-dioxane was added, and the reaction was carried out at room temperature for 2 hours. The reaction was completed by LC-MS detection. The reaction solution was spin-dried to obtain 0.13 g of an off-white solid product.

步骤3：1-(6-((2S)-1-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-4-羟基-2-甲基哌啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮

Figure PCTCN2024137621-ftappb-I100417
Step 3: 1-(6-((2S)-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-hydroxy-2-methylpiperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
Figure PCTCN2024137621-ftappb-I100417

室温下，将1-(6-((2S)-1-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-4-羟基-2-甲基哌啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.13g，0.31mmol)置于20mL二氯甲烷中，加入1mL钛酸四异丙酯，20℃反应16小时，加入三乙酰氧基硼氢化钠(0.10g，0.48mmol)继续反应1小试，LC-MS检测反应结束。加入1mL水淬灭反应，再加入0.5mL氨水，搅拌20min，过滤，滤液浓缩，爬大板分离(DCM/MeOH)得0.03g黄色油状物。At room temperature, 1-(6-((2S)-1-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-hydroxy-2-methylpiperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.13 g, 0.31 mmol) was placed in 20 mL of dichloromethane, 1 mL of tetraisopropyl titanate was added, the reaction was carried out at 20° C. for 16 hours, sodium triacetoxyborohydride (0.10 g, 0.48 mmol) was added, the reaction was continued for 1 hour, and the reaction was completed by LC-MS detection. 1 mL of water was added to quench the reaction, and then 0.5 mL of aqueous ammonia was added, stirred for 20 min, filtered, and the filtrate was concentrated and separated on a plate (DCM/MeOH) to obtain 0.03 g of a yellow oil.

步骤4：1-(5-氟-6-((2S)-4-羟基-1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-2-甲基哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮

Figure PCTCN2024137621-ftappb-I100418
Step 4: 1-(5-Fluoro-6-((2S)-4-hydroxy-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
Figure PCTCN2024137621-ftappb-I100418

室温下，将1-(6-((2S)-1-(((1R，2R)-2-((4-(4-((1R，2S)-6-(苄氧基)-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)-4-羟基-2-甲基哌啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.03g，0.03mmol)置于10mL甲醇中，加入0.01g质量分数5％的Pd/C，氢气置换，20℃反应16小时，LC-MS检测反应结束；反应液过滤，滤液旋干，硅胶板层析(DCM/MeOH)，过滤，滤液旋干，冻干得0.002g类白色固体产物。MS(ESI)m/z：435.2[M/2+H]+.At room temperature, 1-(6-((2S)-1-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-hydroxy-2-methylpiperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.03 g, 0.03 mmol) was placed in 10 mL of methanol, 0.01 g of 5% Pd/C was added, hydrogen was replaced, the reaction was carried out at 20° C. for 16 hours, and the reaction was completed by LC-MS detection; the reaction solution was filtered, the filtrate was spin-dried, silica gel plate chromatography (DCM/MeOH), filtered, the filtrate was spin-dried, and lyophilized to obtain 0.002 g of an off-white solid product. MS (ESI) m/z: 435.2 [M/2+H] + .

实施例40：N-(4-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)乙酰胺的合成(化合物VI-31)

Figure PCTCN2024137621-ftappb-I100419
Example 40: Synthesis of N-(4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)acetamide (Compound VI-31)
Figure PCTCN2024137621-ftappb-I100419

1-(5-氟-6-(4-羟基-1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成方法参照实施例32。The synthesis method of 1-(5-fluoro-6-(4-hydroxy-1-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione refers to Example 32.

步骤1：N-(4-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)乙酰胺的合成。

Figure PCTCN2024137621-ftappb-I100420
Step 1: Synthesis of N-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)acetamide.
Figure PCTCN2024137621-ftappb-I100420

室温下，依次向单口瓶中加入1-(5-氟-6-(4-羟基-1-((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮(0.20g，0.23mmol)、乙腈(20mL)及浓硫酸(0.23g，2.34mmol)，80℃反应3h，冷却至室温，用氨水游离，浓缩柱层析纯化(MeOH/DCM体系)得白色固体0.01g。MS(ESI)m/z：895.9[M+H]+.At room temperature, 1-(5-fluoro-6-(4-hydroxy-1-((1R, 2R)-2-((4-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.20 g, 0.23 mmol), acetonitrile (20 mL) and concentrated sulfuric acid (0.23 g, 2.34 mmol) were added to a single-mouth bottle in sequence, reacted at 80°C for 3 h, cooled to room temperature, freed with aqueous ammonia, concentrated and purified by column chromatography (MeOH/DCM system) to obtain 0.01 g of a white solid. MS (ESI) m/z: 895.9 [M+H] + .

实施例41：1-(6-(4-氨基-1-(((1R，2R)-2-((4-(4-(((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成(化合物VI-32)

Figure PCTCN2024137621-ftappb-I100421
Example 41: Synthesis of 1-(6-(4-amino-1-(((1R, 2R)-2-((4-(4-(((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-32)
Figure PCTCN2024137621-ftappb-I100421

N-(4-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)乙酰胺的合成方法参照实施例40。Refer to Example 40 for the synthesis method of N-(4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)acetamide.

步骤1：1-(6-(4-氨基-1-(((1R，2R)-2-((4-(4-(((3R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成。

Figure PCTCN2024137621-ftappb-I100422
Step 1: Synthesis of 1-(6-(4-amino-1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.
Figure PCTCN2024137621-ftappb-I100422

室温下，依次向单口瓶中加入N-(4-(3-(2，4-二氧基四氢嘧啶-1(2H)-基)-5-氟-1-甲基-1H-吲唑-6-基)-1-(((1R，2R)-2-((4-(4-((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)哌啶-4-基)乙酰胺(0.10g，0.11mmol)、MeOH(10mL)及浓盐酸(10mL)，100℃反应8h，冷却至室温，用氨水游离，浓缩柱层析纯化(MeOH/DCM体系)得白色固体0.005g。MS(ESI)m/z：854.0[M+H]+.At room temperature, N-(4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)acetamide (0.10 g, 0.11 mmol), MeOH (10 mL) and concentrated hydrochloric acid (10 mL) were added to a single-necked bottle in sequence, reacted at 100°C for 8 h, cooled to room temperature, freed with aqueous ammonia, concentrated and purified by column chromatography (MeOH/DCM system) to obtain 0.005 g of a white solid. MS (ESI) m/z: 854.0 [M+H] + .

实施例34：1-(6-(4-(环丙基(((1R，2R)-2-((4-(4-(((1R，2S)-6-羟基-2-苯基-1，2，3，4-四氢萘-1-基)苯基)哌嗪-1-基)甲基)环己基)甲基)氨基)环己基)-5-氟-1-甲基-1H-吲唑-3-基)二氢嘧啶-2，4(1H，3H)-二酮的合成(化合物I-34)Example 34: Synthesis of 1-(6-(4-(cyclopropyl(((1R,2R)-2-((4-(4-(((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)amino)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound I-34)

参考上述制备方法得到以下表8化合物：The following compounds in Table 8 were obtained by referring to the above preparation method:

表8

Figure PCTCN2024137621-ftappb-I100423

Figure PCTCN2024137621-ftappb-I100424
Table 8
Figure PCTCN2024137621-ftappb-I100423

Figure PCTCN2024137621-ftappb-I100424

试验例1：MCF7细胞活性测试Test Example 1: MCF7 cell activity test

细胞培养：MCF7细胞(培养条件：MEM培养基+20％FBS+1％必需氨基酸+1mg/100ml胰岛素，37℃，5％的CO2)。铺板：将传代培养至对数生长期的细胞收集转入离心管，800rpm离心5min。用完全培养基重悬，细胞计数。稀释并调整细胞终浓度为30000个/mL。然后将细胞接种到96孔板中，每孔100μL，培养箱中培养过夜。给药：并将各组药液加入96孔板中，每孔100μL，每个药物浓度n＝3，同时设立设阴性孔(n＝6)，空白孔(n＝3)。将96孔板在培养箱中继续培养6天。向96孔板中加入CCK8试剂，每孔20μL，然后置于培养箱中继续培养4h。用酶标仪于450nm波长下测量溶液吸光度值。计算增殖抑制率，利用Graphpad Prism 6.0软件计算半数抑制浓度IC50值。Cell culture: MCF7 cells (culture conditions: MEM medium + 20% FBS + 1% essential amino acids + 1mg/100ml insulin, 37°C, 5% CO 2 ). Plating: Collect cells that have been subcultured to the logarithmic growth phase and transfer them into a centrifuge tube, centrifuge at 800rpm for 5min. Resuspend with complete medium and count the cells. Dilute and adjust the final cell concentration to 30,000 cells/mL. Then inoculate the cells into a 96-well plate, 100μL per well, and culture in an incubator overnight. Dosing: Add each group of drug solutions to a 96-well plate, 100μL per well, n=3 for each drug concentration, and set up negative wells (n=6) and blank wells (n=3). Continue to culture the 96-well plate in the incubator for 6 days. Add CCK8 reagent to the 96-well plate, 20μL per well, and then place it in the incubator for 4h. Measure the absorbance of the solution at a wavelength of 450nm using an enzyme reader. The proliferation inhibition rate was calculated, and the half inhibitory concentration (IC50 ) value was calculated using Graphpad Prism 6.0 software.

T47D细胞活性测试T47D cell activity test

细胞培养：T47D细胞(培养条件：RPMI1640培养基+10％FBS，37℃，5％的CO2)。铺板：将传代培养至对数生长期的细胞收集转入离心管，800rpm离心5min。用完全培养基重悬，细胞计数。稀释并调整细胞终浓度为30000个/mL。然后将细胞接种到96孔板中，每孔100μL，培养箱中培养过夜。给药：并将各组药液加入96孔板中，每孔100μL，每个药物浓度n＝3，同时设立设阴性孔(n＝6)，空白孔(n＝3)。将96孔板在培养箱中继续培养6天。向96孔板中加入CCK8试剂，每孔20μL，然后置于培养箱中继续培养4h。用酶标仪于450nm波长下测量溶液吸光度值。计算增殖抑制率，利用Graphpad Prism 6.0软件计算半数抑制浓度IC50值，结果如表9所述。Cell culture: T47D cells (culture conditions: RPMI1640 medium + 10% FBS, 37°C, 5% CO 2 ). Plating: Collect cells that have been subcultured to the logarithmic growth phase and transfer them into a centrifuge tube, centrifuge at 800rpm for 5min. Resuspend with complete medium and count the cells. Dilute and adjust the final cell concentration to 30,000 cells/mL. Then inoculate the cells into a 96-well plate, 100 μL per well, and culture in an incubator overnight. Dosing: Add each group of drug solutions to a 96-well plate, 100 μL per well, n=3 for each drug concentration, and set up negative wells (n=6) and blank wells (n=3). Continue to culture the 96-well plate in the incubator for 6 days. Add CCK8 reagent to the 96-well plate, 20 μL per well, and then place it in the incubator for 4h. Measure the absorbance of the solution at a wavelength of 450nm using an enzyme reader. The proliferation inhibition rate was calculated, and the half maximal inhibitory concentration IC50 value was calculated using Graphpad Prism 6.0 software. The results are shown in Table 9.

表9

Figure PCTCN2024137621-ftappb-I100425

Figure PCTCN2024137621-ftappb-I100426
Table 9
Figure PCTCN2024137621-ftappb-I100425

Figure PCTCN2024137621-ftappb-I100426

结论：本发明化合物具有显著的MCF7细胞或T47D细胞抑制活性。Conclusion: The compounds of the present invention have significant inhibitory activity against MCF7 cells or T47D cells.

试验例2：ER蛋白降解活性测试Test Example 2: ER protein degradation activity test

细胞培养：MCF7细胞(培养条件：RPMI1640培养基+10％碳吸附FBS，37℃，5％的CO2)，T47D细胞(培养条件：RPMI1640培养基+10％FBS，37℃，5％的CO2)。将传代培养至对数生长期的细胞收集转入离心管，800rpm离心5min。用完全培养基重悬，细胞计数，调整细胞数5×105个/mL。然后将细胞均匀地铺至六孔板中，每孔1ml，过夜培养。药物处理：将稀释好的药液加入六孔板中，每孔1ml，同时设立阴性对照孔两个，加入含等量DMSO的空培养基1ml。将六孔板在培养箱中继续培养48h。提取细胞蛋白：提前配置好含抑制剂的蛋白质裂解液备用，从贴壁细胞培养瓶中吸去培养液，并用预冷的PBS清洗贴壁的细胞2次。六孔板中加入100μl预冷的含抑制剂的蛋白质裂解液，轻轻摇动5分钟。用细胞刮将孔板内的贴壁细胞刮下来，转移细胞悬浮液到离心管中，冰浴下30分钟进行裂解，每5/10分钟摇晃一次。裂解液于预冷4°的离心机中12000rpm离心10分钟。弃去沉淀，上清液立刻转移入新的离心管中保存待用。蛋白浓度检测：按照BCA试剂盒说明书操作规范，用酶标仪检测各孔样本的OD值，根据标准曲线计算样本中蛋白浓度，通过调整裂解液体积使各样本蛋白浓度持平；蛋白变性：按照1：4的比例加入蛋白上样缓冲液(5×)，与样本蛋白上清液混合均匀。混匀后100℃加热10min，结束后于冰箱-80℃保存。上样与电泳：将提前配好的SDS-PAGE胶板固定在电泳盒内，加入电泳液，缓慢轻拔出梳子，开始上样。电泳电压选择150V直至结束。湿法转膜：停止电泳后，并根据Maker确定目的蛋白分子量所在区域，用梳板进行切割，同时剪取大小相似的PVDF膜，使用前甲醇浸泡15s。在托盘中倒入转模液放置海绵垫及滤纸，按照规定的顺序进行摆放。转膜电流选择200mA，时间为1小时。封闭：在PVDF膜右下角剪一个小口记录其与胶接触的正反面，浸没于5％的BSA溶液中，室温状态下水平摇床上低速孵育1个小时。抗体孵育：封闭结束以后，TBST溶液中浸洗3次，每次10min。依次将PVDF膜直接放置于一抗孵育液和二抗孵育液进行孵育。一抗孵育液需4℃水平摇床孵育必须至少超过12小时，而二抗孵育液需在室温条件下水平摇床上孵育，时间1小时。每次孵育结束后，用TBST溶液中浸洗3次，每次10min。显影：显影液的A/B液按照1：1进行混合，现配现用，显影仪按照程序进行显影。Cell culture: MCF7 cells (culture conditions: RPMI1640 medium + 10% carbon adsorbed FBS, 37°C, 5% CO 2 ), T47D cells (culture conditions: RPMI1640 medium + 10% FBS, 37°C, 5% CO 2 ). Collect cells that have been subcultured to the logarithmic growth phase and transfer them into a centrifuge tube, centrifuge at 800rpm for 5min. Resuspend with complete medium, count cells, and adjust the cell number to 5×10 5 /mL. Then spread the cells evenly into a six-well plate, 1ml per well, and culture overnight. Drug treatment: Add the diluted drug solution to the six-well plate, 1ml per well, and set up two negative control wells at the same time, and add 1ml of empty culture medium containing an equal amount of DMSO. Continue to culture the six-well plate in the incubator for 48h. Extract cell protein: Prepare the protein lysis solution containing inhibitors in advance, aspirate the culture solution from the adherent cell culture flask, and wash the adherent cells twice with pre-cooled PBS. Add 100 μl of pre-cooled protein lysis buffer containing inhibitors to the six-well plate and shake gently for 5 minutes. Scrape the adherent cells in the well plate with a cell scraper, transfer the cell suspension to a centrifuge tube, and lyse in an ice bath for 30 minutes, shaking every 5/10 minutes. Centrifuge the lysate at 12000rpm for 10 minutes in a pre-cooled 4° centrifuge. Discard the precipitate and immediately transfer the supernatant to a new centrifuge tube for storage. Protein concentration detection: According to the BCA kit manual, use an enzyme reader to detect the OD value of each well sample, calculate the protein concentration in the sample according to the standard curve, and adjust the lysate volume to make the protein concentration of each sample equal; protein denaturation: Add protein loading buffer (5×) at a ratio of 1:4 and mix evenly with the sample protein supernatant. After mixing, heat at 100℃ for 10min, and store in a refrigerator at -80℃ after the end. Sample loading and electrophoresis: Fix the prepared SDS-PAGE gel plate in the electrophoresis box, add electrophoresis solution, slowly pull out the comb, and start loading. The electrophoresis voltage is selected as 150V until the end. Wet transfer: After stopping the electrophoresis, determine the molecular weight area of the target protein according to the Maker, cut it with a comb, and cut a PVDF membrane of similar size at the same time, and soak it in methanol for 15s before use. Pour the transfer solution into the tray and place the sponge pad and filter paper, and place them in the prescribed order. The transfer current is selected as 200mA, and the time is 1 hour. Blocking: Cut a small hole in the lower right corner of the PVDF membrane to record the front and back sides of the contact with the gel, immerse it in 5% BSA solution, and incubate it at low speed on a horizontal shaker at room temperature for 1 hour. Antibody incubation: After the blocking is completed, wash it in TBST solution 3 times, 10min each time. Place the PVDF membrane directly in the primary antibody incubation solution and the secondary antibody incubation solution for incubation in turn. The primary antibody incubation solution must be incubated on a horizontal shaker at 4°C for at least 12 hours, while the secondary antibody incubation solution must be incubated on a horizontal shaker at room temperature for 1 hour. After each incubation, wash in TBST solution 3 times, 10 minutes each time. Development: The A/B solution of the developer is mixed in a ratio of 1:1, prepared and used immediately, and the developer is developed according to the program.

结论：由图1-6可知，本发明化合物在肿瘤细胞中能显著的降解ER蛋白。Conclusion: As shown in Figures 1-6, the compounds of the present invention can significantly degrade ER protein in tumor cells.

试验例3：体内肿瘤抑制活性测试Experimental Example 3: In vivo tumor suppression activity test

MCF-7细胞培养(培养条件：MEM培养基+20％FBS+1％必需氨基酸+1mg/100ml胰岛素，37℃，5％的CO2)，将传代培养至对数生长期的细胞收集转入离心管，800rpm离心5min。接种当天将细胞密度调整至3*107cells/mL。MCF-7 cells were cultured (culture conditions: MEM medium + 20% FBS + 1% essential amino acids + 1mg/100ml insulin, 37°C, 5% CO 2 ), and cells cultured to the logarithmic growth phase were collected and transferred into centrifuge tubes and centrifuged at 800rpm for 5min. The cell density was adjusted to 3*10 7 cells/mL on the day of inoculation.

雌二醇注射，接种前一天，全部实验动物皮下注射8μg/100μL雌二醇溶液(溶媒：30％丙二醇+70％葡萄糖注射液)，接种当天至实验结束每天皮下注射雌二醇4μg/50μL/只。Estradiol injection: one day before inoculation, all experimental animals were subcutaneously injected with 8μg/100μL estradiol solution (solvent: 30% propylene glycol + 70% glucose injection), and 4μg/50μL/animal was subcutaneously injected with estradiol every day from the day of inoculation to the end of the experiment.

细胞接种：接种位点选择实验动物右侧肩胛骨位置，接种密度3*106cells/100μL/只。Cell inoculation: The inoculation site was the right scapula of the experimental animal, and the inoculation density was 3*106 cells/100 μL/animal.

分组给药：当肿瘤体积平均值达到80-150mm3时，根据肿瘤体积随机分组，肿瘤体积变异系数CV不超过平均体积的1/3。分组当天定义为D0天，并于分组当天开始给药。给药前测量小鼠体重，依据当日体重进行给药。Grouping and dosing: When the average tumor volume reaches 80-150 mm3 , the mice are randomly grouped according to the tumor volume, and the coefficient of variation of the tumor volume CV does not exceed 1/3 of the average volume. The day of grouping is defined as D0, and dosing begins on the day of grouping. The weight of the mice is measured before dosing, and dosing is performed based on the weight of the day.

实验观察和数据采集：细胞接种后，每周常规监测肿瘤对动物正常行为的影响。具体内容有实验动物的活动性，摄食和饮水情况，体重增加或降低情况，眼睛、被毛及其它异常情况。开始给药后，每天进行小鼠体重称量及给药，每周测量瘤体积两次，瘤体积计算方式为：肿瘤体积(mm3)＝0.52×肿瘤长径(mm)×肿瘤短径(mm)2。实验结束时，分析下列指标：肿瘤生长曲线、小鼠体重曲线、肿瘤重量、剥离的肿瘤按照组别进行排列后统一拍照、计算肿瘤体积抑制率TGI。Experimental observation and data collection: After cell inoculation, the effect of tumor on the normal behavior of animals was routinely monitored weekly. The specific contents included the activity of experimental animals, food and water intake, weight gain or loss, eyes, fur and other abnormalities. After the start of drug administration, the mice were weighed and administered every day, and the tumor volume was measured twice a week. The tumor volume was calculated as follows: tumor volume (mm 3 ) = 0.52 × tumor long diameter (mm) × tumor short diameter (mm) 2 . At the end of the experiment, the following indicators were analyzed: tumor growth curve, mouse weight curve, tumor weight, and the peeled tumors were arranged according to groups and photographed uniformly to calculate the tumor volume inhibition rate TGI.

TGITV(相对肿瘤体积抑制率)计算公式：

Figure PCTCN2024137621-ftappb-I100427

Figure PCTCN2024137621-ftappb-I100428
TGI TV (relative tumor volume inhibition rate) calculation formula:
Figure PCTCN2024137621-ftappb-I100427

Figure PCTCN2024137621-ftappb-I100428

Vnt：编号为n的小鼠在第t天的肿瘤体积；V nt : tumor volume of mouse numbered n on day t;

Vn0：编号为n的小鼠在第0天的肿瘤体积；V n0 : tumor volume of mouse numbered n on day 0;

RTVn：编号为n的小鼠在第t天的肿瘤相对体积；RTV n : relative tumor volume of mouse numbered n on day t;

mean RTVtreat：给药组RTV平均值；mean RTV treat : mean RTV of the treatment group;

mean RTVvehicle：Vehicle组RTV平均值；mean RTV vehicle : the mean RTV value of the Vehicle group;

各组动物的肿瘤体积、小鼠体重等实验结果以平均值±标准误差(Mean±SEM)表示。所有的数据均用GraphPad Prism 6.0进行分析，结果如表10所示。P＜0.05为具有显著性差异。The experimental results of tumor volume and mouse weight of each group of animals are expressed as mean ± standard error (Mean ± SEM). All data were analyzed using GraphPad Prism 6.0, and the results are shown in Table 10. P < 0.05 was considered to be significantly different.

表10体内肿瘤抑制活性结果

Figure PCTCN2024137621-ftappb-I100429
Table 10 In vivo tumor inhibitory activity results
Figure PCTCN2024137621-ftappb-I100429

结论：本发明化合物在体内具有显著的肿瘤体内生长抑制作用。Conclusion: The compounds of the present invention have significant tumor growth inhibitory effects in vivo.

以上对本公开技术方案的实施方式进行了示例性的说明。应当理解，本公开的保护范围不拘囿于上述实施方式。凡在本公开的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请权利要求书的保护范围之内。The above is an exemplary description of the implementation of the technical solution of the present disclosure. It should be understood that the protection scope of the present disclosure is not limited to the above-mentioned implementation. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present disclosure shall be included in the protection scope of the claims of this application.

Claims (13)

式(i)所示化合物、其异构体或其药学上可接受的盐：
A-B-C
(i)The compound represented by formula (i), its isomer or its pharmaceutically acceptable salt:
ABC
(i) 其中，in, A为 A is X选自N或CH；X is selected from N or CH; Cy1选自(例如 )和所述(例如 )和未被取代，或各自分别独立地被1-3个Ra1取代；G选自无取代或任选被一个、两个或更多个Ra1取代的下列基团：C6-10芳基或5-10元杂芳基，例如苯基、吡啶基、嘧啶基；Cy1 is selected from (For example )and Said (For example )and unsubstituted or each independently substituted by 1-3 R a1 ; G is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R a1 : C 6-10 aryl or 5-10 membered heteroaryl, such as phenyl, pyridyl, pyrimidinyl; 每个Ra1分别独立地选自氢、氘、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基；Each Ra1 is independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxyl C1-6 alkyl, C1-6 alkylamino, (C1-6 alkyl ) 2amino , C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl) 2aminocarbonyl ; B为-L2-Cy2-L3-Cy3-L4-Cy4-L5-；B is -L2-Cy2-L3-Cy3-L4-Cy4-L5-; L1、L2、L3、L4、L5、L6分别独立地选自键、-(CH2)n-(NH)m-、-O-，-S-，-NR2、-CR31R32-、-C(O)-、-C(O)O-、-C(O)NR4-、-NR5-C(O)-、-S(O)-、-S(O)2-、-P(O)(R6)-、C2-8烯基和C2-8炔基；L1, L2, L3, L4, L5, and L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, -S-, -NR 2 , -CR 31 R 32 -, -C(O)-, -C(O)O-, -C(O)NR 4 -, -NR 5 -C(O)-, -S(O)-, -S(O) 2 -, -P(O)(R 6 )-, C 2-8 alkenyl, and C 2-8 alkynyl; n和m分别独立地为零至六的任意整数；n and m are independently any integer from zero to six; R2、R31、R32、R4和R5和R6分别独立地选自氢、氘、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基，其中所述C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷基羰基氨基、C1-6烷基磺酰氨基、C1-6烷羰氧基、C3-6环烷基、C3-6环烷基羰氧基、C2-8炔基、卤代C1-6烷基、C2-8烯基、卤代C1-6烷氧基的基团取代；R 2 , R 31 , R 32 , R 4 , R 5 and R 6 are each independently selected from hydrogen, deuterium, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, wherein the C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2aminocarbonyl are unsubstituted or optionally substituted by one or more groups independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl ) 2amino , C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonyloxy, C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonyloxy, C 2-8 alkynyl, halo-substituted C 1-6 alkyl, C 2-8 alkenyl, halo-substituted C 1-6 alkoxy; Cy2选自3-13元环烷基、3-13元杂环基、3-13元环烯基、被1-3个Ra2取代的3-13元环烷基、被1-3个Ra2取代的3-13元杂环基、被1-3个Ra2取代的3-13元环烯基、Cy21-Cy22，所述3-13元杂环基的杂原子选自O、N或S；Cy21和Cy22相同或不同，彼此独立地选自3-13元环烷基、3-13元杂环基、3-13元环烯基；Cy2 is selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclyl, 3-13 membered cycloalkenyl, 3-13 membered cycloalkyl substituted by 1-3 R a2 , 3-13 membered heterocyclyl substituted by 1-3 R a2 , 3-13 membered cycloalkenyl substituted by 1-3 R a2 , Cy21-Cy22, wherein the heteroatom of the 3-13 membered heterocyclyl is selected from O, N or S; Cy21 and Cy22 are the same or different and are independently selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclyl, 3-13 membered cycloalkenyl; Cy3选自3-13元环烷基、3-13元杂环基、6-13元双环稠环基或8-21元多环稠环基，所述3-13元环烷基、3-13元杂环基、6-13元双环稠环基或8-21元多环稠环基未被取代或各自分别独立地被1-5个Ra3取代，优选5-6元杂环基，所述5-6元杂环基的杂原子为N、O、S、Si；Cy3 is selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclyl, 6-13 membered bicyclic condensed cyclic group or 8-21 membered polycyclic condensed cyclic group, wherein the 3-13 membered cycloalkyl, 3-13 membered heterocyclyl, 6-13 membered bicyclic condensed cyclic group or 8-21 membered polycyclic condensed cyclic group is unsubstituted or each independently substituted by 1-5 R a3 , preferably a 5-6 membered heterocyclyl, wherein the heteroatom of the 5-6 membered heterocyclyl is N, O, S or Si; Cy4选自3-8元环烷基、3-8元杂环基、3-8元环烯基、6-13元双环稠环环烷基、6-13元双环稠环烯基、6-13元双环稠环杂环基、被1-3个Ra4取代的3-8元环烷基、被1-3个Ra4取代的3-8元杂环基、被1-3个Ra4取代的3-8元环烯基、被1-3个Ra4取代的6-13双环稠环环烷基、被1-3个Ra4取代的6-13元双环稠环烯基、被1-3个Ra4取代的6-13元双环稠环杂环基，所述3-8元杂环基或6-13元双环稠环杂环基的杂原子选自O、N或S；Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclyl, 3-8 membered cycloalkyl substituted by 1-3 R a4 , 3-8 membered heterocyclyl substituted by 1-3 R a4 , 3-8 membered cycloalkenyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring cycloalkyl substituted by 1-3 R a4 , 6-13 membered bicyclic condensed ring alkenyl substituted by 1-3 R a4 , and the heteroatoms of the 3-8 membered heterocyclyl or 6-13 membered bicyclic condensed ring heterocyclyl are selected from O, N or S ; 每个Ra2、Ra3和Ra4在出现时，分别独立地选自氢、氘、卤素、羟基、巯基、硅羟基、硒羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷基-C(O)O-、C1-6烷硫基、C1-6烷硒基、羟基C1-6烷基、C1-6烷基-C(O)NH-、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、3-8元环烷基、3-8元杂环基、3-8元环烯基，其中所述C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、3-8元环烷基、3-8元杂环基、3-8元环烯基未被取代或任选被一至多个选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷基羰基氨基、C1-6烷基磺酰氨基、C1-6烷羰氧基、C3-6环烷基、C3-6环烷基羰氧基、C2-8炔基、卤代C1-6烷基、C2-8烯基、卤代C1-6烷氧基、3-8元环烷基、3-8元杂环基、3-8元环烯基的基团取代；Each of Ra2 , Ra3 and Ra4 , when present, is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, silanol, selenohydroxyl, carboxyl, amino, cyano, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 alkyl -C(O)O-, C1-6 alkylthio, C1-6 alkylseleno, hydroxyC1-6 alkyl, C1-6 alkyl-C(O)NH-, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C2-8alkenyl , C2-8alkynyl , C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl)2aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl, wherein said C1-6 C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted by one or more selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonyloxy, C substituted with a C 3-6 cycloalkyl, a C 3-6 cycloalkylcarbonyloxy, a C 2-8 alkynyl, a halogenated C 1-6 alkyl, a C 2-8 alkenyl, a halogenated C 1-6 alkoxy, a 3-8 membered cycloalkyl, a 3-8 membered heterocyclyl, or a 3-8 membered cycloalkenyl; C为 C is X1为N或CRb1； X1 is N or CR b1 ; X2为N或CRb2； X2 is N or CR b2 ; X3为N或CRb3； X3 is N or CR b3 ; X4为N或CRb4； X4 is N or CR b4 ; X5为N或CRb5； X5 is N or CR b5 ; Rb1、Rb2、Rb3、Rb4和Rb5分别独立地选自氢、氘、卤素、羟基、羧基、氨基、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C2-8烯基、C2-8炔基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基；R b1 , R b2 , R b3 , R b4 and R b5 are each independently selected from hydrogen, deuterium, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl; Cy5选自6-13元双环稠环基和8-21元多环稠环基；所述6-13元双环稠环基或8-21元多环稠环基未被取代或被1-3个Ra5取代；Cy5 is selected from a 6-13 membered bicyclic fused ring group and an 8-21 membered polycyclic fused ring group; the 6-13 membered bicyclic fused ring group or the 8-21 membered polycyclic fused ring group is unsubstituted or substituted with 1-3 R a5 ; 每个Ra5分别独立地选自氢、氘、羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C1-6烷基磺酰基、C1-6烷基硫基、C3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基，其中所述C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C1-6烷基磺酰基、C1-6烷基硫基、C3-6环烷基、4-6元杂环基、5-6元杂芳基、芳基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基、4-6元杂环基羰基和5-6元杂芳基-氧基未被取代或任选被一至多个独立选自羟基、氨基、羧基、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷氧C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷基羰基氨基、C1-6烷基磺酰氨基、C1-6烷羰氧基、C3-6环烷基、C3-6环烷基羰氧基、C2-8炔基、卤代C1-6烷基、C2-8烯基、卤代C1-6烷氧基的基团取代；Each Ra5 is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl)2amino, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, (C1-6 alkyl)2aminocarbonyl, 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy, wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, ( C1-6 alkyl)2amino, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, C2-8 alkenyl, C2-8 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl)2aminocarbonyl, 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2aminocarbonyl , 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy are unsubstituted or optionally substituted by one or more independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2amino , C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkylcarbonyloxy, C substituted with C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 alkyl, C 2-8 alkenyl, or halogenated C 1-6 alkoxy; 条件是当Cy3为时，不为 The condition is that when Cy3 is hour, Not for 根据权利要求1所述的式(i)所示化合物、其异构体或其药学上可接受的盐，其中，Cy1选自 *端与L1连接；The compound represented by formula (i) according to claim 1, its isomer or pharmaceutically acceptable salt thereof, wherein Cy1 is selected from * terminal is connected to L1; 优选地，所述 未被取代，或各自分别独立地被1-3个Ra1取代；更优选地，所述每个Ra1各自分别独立地选自氢、卤素、羟基、羧基、氨基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、羟基C1-6烷基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷羰基、氨基羰基、C1-6烷氨羰基、(C1-6烷基)2氨羰基；更优选地，所述每个Ra1各自分别独立地被1-3个卤素(如F)或C1-6烷基(如甲基)取代；Preferably, the unsubstituted, or each independently substituted by 1-3 Ra1 ; more preferably, each Ra1 is each independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, hydroxy C1-6 alkyl, C1-6 alkylamino, ( C1-6 alkyl) 2amino , C1-6 alkylcarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, ( C1-6 alkyl) 2aminocarbonyl ; more preferably, each Ra1 is each independently substituted by 1-3 halogen (such as F) or C1-6 alkyl (such as methyl); 优选地，Cy1选自 *端与L1连接。Preferably, Cy1 is selected from *Terminal is connected to L1. 根据权利要求1或2所述的式(i)所示化合物、其异构体或其药学上可接受的盐，其中，L1、L2、L3、L4、L5、L6相同或不同，彼此独立地选自键、O、NH、C1-6亚烷基、-NHC(O)-、NH(C1-6亚烷基)、-C(O)-；The compound of formula (i) according to claim 1 or 2, its isomer or pharmaceutically acceptable salt thereof, wherein L1, L2, L3, L4, L5, L6 are the same or different and are independently selected from a bond, O, NH, C 1-6 alkylene, -NHC(O)-, NH(C 1-6 alkylene), -C(O)-; 优选地，L1选自键、-NHC(O)-；优选地，当L1为-NHC(O)-时，C(O)端与Cy1连接；Preferably, L1 is selected from a bond, -NHC(O)-; preferably, when L1 is -NHC(O)-, the C(O) terminus is connected to Cy1; 优选地，L2选自键、NH或NH(C1-3亚烷基)；Preferably, L2 is selected from a bond, NH or NH(C 1-3 alkylene); 优选地，L2选自键、NH或NHCH2；优选为键；Preferably, L2 is selected from a bond, NH or NHCH 2 ; preferably a bond; 优选地，L3选自C1-3亚烷基、-C(O)-、-CH2NR4-、-NR5-CH2-或NH(C1-3亚烷基)；R4、R5彼此独立地选自C3-6环烷基；Preferably, L3 is selected from C 1-3 alkylene, -C(O)-, -CH 2 NR 4 -, -NR 5 -CH 2 - or NH(C 1-3 alkylene); R 4 and R 5 are independently selected from C 3-6 cycloalkyl; 优选地，L3选自亚甲基、-C(O)-或NHCH2；优选为亚甲基；Preferably, L3 is selected from methylene, -C(O)- or NHCH 2 ; preferably methylene; 优选地，L4选自键、C1-3亚烷基或-C(O)-；Preferably, L4 is selected from a bond, C 1-3 alkylene or -C(O)-; 优选地，L4选自键、亚甲基或-C(O)-；优选为亚甲基；Preferably, L4 is selected from a bond, a methylene group or -C(O)-; preferably a methylene group; 优选地，L5选自键或C1-3亚烷基；Preferably, L5 is selected from a bond or a C 1-3 alkylene group; 优选地，L5选自键或亚甲基；优选为键；Preferably, L5 is selected from a bond or a methylene group; preferably a bond; 优选地，L6选自键或-O-；优选为键。Preferably, L6 is selected from a bond or -O-; preferably a bond. 根据权利要求1-3任一项所述的式(i)所示化合物、其异构体或其药学上可接受的盐，其中，Cy2选自4-10元环烷基、4-10元杂环基、4-10元环烯基、被1-3个Ra2取代的4-10元环烷基、被1-3个Ra2取代的4-10元杂环基、被1-3个Ra2取代的4-10元环烯基、Cy21-Cy22，所述4-10元杂环基的杂原子选自O、N或S；Cy21和Cy22相同或不同，彼此独立地选自4-6元环烷基、4-6元杂环基、4-6元环烯基；The compound of formula (i) according to any one of claims 1 to 3, its isomer or pharmaceutically acceptable salt thereof, wherein Cy2 is selected from 4-10 membered cycloalkyl, 4-10 membered heterocyclyl, 4-10 membered cycloalkenyl, 4-10 membered cycloalkyl substituted by 1-3 R a2 , 4-10 membered heterocyclyl substituted by 1-3 R a2 , 4-10 membered cycloalkenyl substituted by 1-3 R a2 , Cy21-Cy22, the heteroatom of the 4-10 membered heterocyclyl is selected from O, N or S; Cy21 and Cy22 are the same or different and are independently selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl; 优选地，Cy2选自4-6元环烷基、4-6元杂环基、4-6元环烯基、被1-3个Ra2取代的4-6元环烷基、被1-3个Ra2取代的4-6元杂环基、被1-3个Ra2取代的4-6元环烯基，所述4-6元杂环基的杂原子选自O、N或S；Preferably, Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl, 4-6 membered cycloalkyl substituted by 1-3 R a2 , 4-6 membered heterocyclyl substituted by 1-3 R a2 , 4-6 membered cycloalkenyl substituted by 1-3 R a2 , wherein the heteroatom of the 4-6 membered heterocyclyl is selected from O, N or S; 优选地，Cy2选自无取代或被1-3个Ra2取代的6-9元杂环基、Cy21-Cy22；Cy21和Cy22相同或不同，彼此独立地选自环己基、哌嗪基、哌啶基；Preferably, Cy2 is selected from a 6-9 membered heterocyclic group which is unsubstituted or substituted by 1-3 R a2 , Cy21-Cy22; Cy21 and Cy22 are the same or different and are independently selected from a cyclohexyl group, a piperazinyl group, a piperidinyl group; 优选地，Cy2选自无取代或被1-3个Ra2取代的哌嗪基、哌啶基、 Preferably, Cy2 is selected from piperazinyl , piperidinyl, 优选地，Cy2选自 (例如 )、(例如)、 (例如)、*端与Cy1连接；Preferably, Cy2 is selected from (For example ), (For example ), (For example ), * end connected to Cy1; 优选地，Cy3选自5-10元环烷基、5-10元杂环基、6-13元双环稠环烷基、6-13双环稠环烯基、6-13元双环稠杂环基、8-13元双环稠杂芳基、8-13元双环稠芳基、8-21元多环稠环烷基、8-21多环稠环烯基、8-21元多环稠杂环基、8-21元多环稠杂芳基、8-21元多环稠芳基；Preferably, Cy3 is selected from 5-10 membered cycloalkyl, 5-10 membered heterocyclyl, 6-13 membered bicyclic condensed cycloalkyl, 6-13 membered bicyclic condensed cycloalkenyl, 6-13 membered bicyclic condensed heterocyclyl, 8-13 membered bicyclic condensed heteroaryl, 8-13 membered bicyclic condensed aryl, 8-21 membered polycyclic condensed cycloalkyl, 8-21 membered polycyclic condensed cycloalkenyl, 8-21 membered polycyclic condensed heterocyclyl, 8-21 membered polycyclic condensed heteroaryl, 8-21 membered polycyclic condensed aryl; 优选地，Cy3选自5-6元环烷基或5-6元杂环基；所述5-6元环烷基或5-6元杂环基未被取代或各自分别独立地被1-3个Ra3取代；Preferably, Cy3 is selected from 5-6 membered cycloalkyl or 5-6 membered heterocyclyl; the 5-6 membered cycloalkyl or 5-6 membered heterocyclyl is unsubstituted or each is independently substituted by 1-3 R a3 ; 优选地，Cy3选自环己基、哌啶基、四氢吡喃基、二氧六环基、四氢吡咯基；所述环己基、哌啶基、四氢吡喃基、二氧六环基、四氢吡咯基未被取代或各自分别独立地被1-3个Ra3取代；优选为环己基；Preferably, Cy3 is selected from cyclohexyl, piperidinyl, tetrahydropyranyl, dioxanyl, tetrahydropyrrolyl; the cyclohexyl, piperidinyl, tetrahydropyranyl, dioxanyl, tetrahydropyrrolyl are unsubstituted or are each independently substituted with 1-3 R a3 ; preferably cyclohexyl; 优选地，Cy3选自所述 未被取代或各自分别独立地被1-3个Ra3取代；Preferably, Cy3 is selected from Said unsubstituted or each independently substituted with 1-3 Ra3 ; 优选地，Cy4选自无取代或任选被一个、两个或更多个C1-6烷基或C1-6烷氧基取代的5-6元杂环基；Preferably, Cy4 is selected from a 5-6 membered heterocyclic group which is unsubstituted or optionally substituted by one, two or more C 1-6 alkyl or C 1-6 alkoxy groups; 优选地，Cy4选自哌嗪基，例如*端与L5连接；Preferably, Cy4 is selected from piperazinyl, such as * end is connected to L5; 优选地，Cy5选自未被取代或被1-3个Ra5取代的下列基团：6-13元双环并环烯基、6-13元双环并杂芳基、8-21元多环并杂环基；Preferably, Cy5 is selected from the following groups which are unsubstituted or substituted by 1-3 R a5 : 6-13-membered bicyclic cycloalkenyl, 6-13-membered bicyclic heteroaryl, 8-21-membered polycyclic heterocyclyl; 优选地，Cy5选自未被取代或被1-3个OH或苯基取代的例如 Preferably, Cy5 is selected from unsubstituted or substituted with 1-3 OH or phenyl groups. For example 优选地，Cy5为例如 Preferably, Cy5 is For example 根据权利要求1-4任一项所述的式(i)所示化合物、其异构体或其药学上可接受的盐，其中，Ra1选自卤素、C1-6烷基、C1-6烷氧基；The compound represented by formula (i) according to any one of claims 1 to 4, its isomer or a pharmaceutically acceptable salt thereof, wherein R a1 is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy; 优选地，Ra1选自F、甲基、乙基、甲氧基；Preferably, R a1 is selected from F, methyl, ethyl, methoxy; 优选地，Ra2、Ra3和Ra4相同或不同，彼此独立地选自H、OH、氨基、巯基、硅羟基、硒羟基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷基-NH-、C3-6环烷基、C1-6烷基-C(O)NH-、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基；Preferably, Ra2 , Ra3 and Ra4 are the same or different and are independently selected from H, OH, amino, mercapto, silanol, selenohydroxy, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl-NH-, C3-6 cycloalkyl, C1-6 alkyl-C(O)NH-, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, hydroxyl C1-6 alkyl; 优选地，Ra2选自H、OH、氨基、卤素、C1-6烷基、C1-6烷氧基、C1-6烷基-NH-、C3-6环烷基、C1-6烷基-C(O)NH-；Preferably, Ra2 is selected from H, OH, amino, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl-NH-, C3-6 cycloalkyl, C1-6 alkyl-C(O)NH-; 优选地，Ra2选自H、F、OH、氨基、甲氨基、乙酰胺基、甲基、甲氧基、环丙基；Preferably, R a2 is selected from H, F, OH, amino, methylamino, acetamido, methyl, methoxy, cyclopropyl; 优选地，Ra3和Ra4相同或不同，彼此独立地选自H、卤素；Preferably, Ra3 and Ra4 are the same or different and are independently selected from H, halogen; 优选地，Ra3和Ra4相同或不同，彼此独立地选自H、F；Preferably, Ra3 and Ra4 are the same or different and are independently selected from H and F; 优选地，Ra5选自羟基或C6-10芳基；Preferably, R a5 is selected from hydroxyl or C 6-10 aryl; 优选地，Ra5选自羟基或苯基；Preferably, R a5 is selected from hydroxyl or phenyl; 优选地，Ra5选自羟基或C6-10芳基、卤素取代的C6-10芳基；Preferably, R a5 is selected from hydroxyl or C 6-10 aryl, halogen-substituted C 6-10 aryl; 优选地，选自无取代或任选被Rb1、Rb2、Rb3、Rb4、Rb5中的1至4个取代基所取代的下列基团：苯基、含1个或2个杂原子的6元杂芳基，例如 Preferably, Selected from the following groups which are unsubstituted or optionally substituted by 1 to 4 substituents selected from R b1 , R b2 , R b3 , R b4 , and R b5 : phenyl, 6-membered heteroaryl containing 1 or 2 heteroatoms, for example 根据权利要求1-5任一项所述的式(i)所示化合物、其异构体或其药学上可接受的盐，其中，具有如下所示的结构：
The compound of formula (i) according to any one of claims 1 to 5, its isomer or a pharmaceutically acceptable salt thereof, wherein it has the structure shown below:
其中，Y选自N或CRa2；X、L1、Cy1、Ra2具有权利要求1-5任一项所述的定义。Wherein, Y is selected from N or CR a2 ; X, L 1 , Cy1 and Ra2 have the definitions as described in any one of claims 1-5. 根据权利要求6所述的式(i-1)所示化合物、其异构体或其药学上可接受的盐，其中，具有如下所示的结构：
The compound represented by formula (i-1) according to claim 6, its isomer or pharmaceutically acceptable salt thereof, wherein it has the following structure:
其中，Y选自N或CRa2；X、L1、Cy1、Ra2具有权利要求1-5任一项所述的定义。Wherein, Y is selected from N or CR a2 ; X, L 1 , Cy1 and Ra2 have the definitions as described in any one of claims 1-5. 根据权利要求1-5任一项所述的式(i)所示化合物、其异构体或其药学上可接受的盐，其中，具有如下所示的结构：
The compound of formula (i) according to any one of claims 1 to 5, its isomer or a pharmaceutically acceptable salt thereof, wherein it has the structure shown below:
其中，Z1和Z2相同或不同，彼此独立地选自C(Ra3)(Ra3)、O、N(Ra3)、S、Si(Ra3)(Ra3)；X、G、L2、L3、L4、L5、L6、Cy2、Cy4、Cy5、Ra1、Ra3、X1、X2、X4、X5具有权利要求1-5任一项所述的定义。wherein Z1 and Z2 are the same or different and are independently selected from C(R a3 )(R a3 ), O, N(R a3 ), S, Si(R a3 )(R a3 ); X, G, L 2 , L 3 , L 4 , L 5 , L 6 , Cy2, Cy4, Cy5, R a1 , R a3 , X 1 , X 2 , X 4 , X 5 have the meanings as defined in any one of claims 1 to 5. 根据权利要求8所述的式(i-2)所示化合物、其异构体或其药学上可接受的盐，其中，具有如下所示的结构：
The compound represented by formula (i-2) according to claim 8, its isomer or pharmaceutically acceptable salt thereof, wherein it has the structure shown below:
其中，Z3选自N、C或CRa4；表示单键或双键；G、Y、Z1、Z2、Rb1、Rb2、Rb4、Rb5、Ra1、Ra5具有权利要求1-5任一项所述的定义。Wherein, Z 3 is selected from N, C or CR a4 ; represents a single bond or a double bond; G, Y, Z 1 , Z 2 , R b1 , R b2 , R b4 , R b5 , Ra1 and Ra5 have the meanings as defined in any one of claims 1 to 5. 如权利要求1-9任一项所述的化合物、其异构体或其药学上可接受的盐，其选自如下所示的化合物：









The compound according to any one of claims 1 to 9, its isomer or a pharmaceutically acceptable salt thereof, which is selected from the compounds shown below:









一种药物组合物，所述药物组合物包含权利要求1-10任一项所述的化合物、其异构体或其药学上可接受的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, its isomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. 权利要求1-10任一项所述的化合物、其异构体或其药学上可接受的盐，或权利要求11所述药物组合物在制备通过降解靶蛋白治疗和/或预防疾病或病症的药物中的用途；Use of the compound according to any one of claims 1 to 10, its isomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11 in the preparation of a medicament for treating and/or preventing a disease or condition by degrading a target protein; 优选地，所述疾病或病症选自异常细胞增殖、肿瘤、免疫疾病、糖尿病、心血管疾病、传染性疾病和炎性疾病；优选为肿瘤和传染性疾病；Preferably, the disease or disorder is selected from abnormal cell proliferation, tumors, immune diseases, diabetes, cardiovascular diseases, infectious diseases and inflammatory diseases; preferably tumors and infectious diseases; 优选地，所述的肿瘤为癌症；优选选自乳腺癌、子宫内膜癌、睾丸癌、宫颈癌、前列腺癌、卵巢癌、输卵管肿瘤、白血病、皮肤癌、鳞状细胞癌、基底细胞癌、膀胱癌、结直肠癌、食管癌、头颈癌、肾癌、肝癌、肺癌、胰腺癌、胃癌、淋巴瘤、黑色素瘤、肉瘤、外周神经上皮瘤、神经胶质瘤、星形细胞瘤、室管膜瘤、成胶质细胞瘤、成神经细胞瘤、神经节细胞瘤、成神经管细胞瘤、松果体细胞肿瘤、脑膜瘤、神经纤维瘤、神经鞘瘤、甲状腺癌、维尔姆斯瘤和畸胎癌；更优选选自乳腺癌、子宫内膜癌、睾丸癌、宫颈癌、前列腺癌、卵巢癌和输卵管肿瘤；Preferably, the tumor is cancer; preferably selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube tumor, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, colorectal cancer, esophageal cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, pancreatic cancer, gastric cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelioma, glioma, astrocytoma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, medulloblastoma, pineal cell tumor, meningioma, neurofibroma, neurilemoma, thyroid cancer, Wilms' tumor and teratoma; more preferably selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer and fallopian tube tumor; 优选地，所述的传染性疾病选自病毒性肺炎、流感、禽流感、脑膜炎、淋病或是感染HIV、HBV、HCV、HSV、HPV、RSV、CMV、埃博拉病毒、黄病毒、痕病毒、轮状病毒、冠状病毒、EBV、耐药病毒、RNA病毒、DNA病毒、腺病毒、痘病毒、小核糖核酸病毒、披膜病毒、正粘病毒、逆转录病毒、嗜肝DNA病毒、革兰氏阴性菌、革兰氏阳性菌、非典型菌、葡萄球菌、链球菌、大肠杆菌、沙门氏菌、幽门螺旋杆菌、衣原体科、支原体科、真菌、原生动物、肠虫、蠕虫、朊病毒或寄生虫的疾病。Preferably, the infectious disease is selected from viral pneumonia, influenza, avian influenza, meningitis, gonorrhea or infection with HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, flavivirus, rotavirus, coronavirus, EBV, drug-resistant virus, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, togavirus, orthomyxovirus, retrovirus, hepadnavirus, Gram-negative bacteria, Gram-positive bacteria, atypical bacteria, Staphylococcus, Streptococcus, Escherichia coli, Salmonella, Helicobacter pylori, Chlamydiaceae, Mycoplasmaceae, fungi, protozoa, intestinal worms, worms, prions or parasites. 权利要求1-10任一项所述的化合物、其异构体或其药学上可接受的盐，或权利要求11所述药物组合物在制备用于治疗和/或预防雌激素受体介导的或依赖性的疾病或病症的药物中的用途，所述的雌激素受体介导的或依赖性的疾病或病症为肿瘤，优选为癌症，更优选为乳腺癌、子宫内膜癌、睾丸癌、宫颈癌、前列腺癌、卵巢癌和输卵管肿瘤，最优选为乳腺癌。Use of the compound according to any one of claims 1 to 10, its isomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11 in the preparation of a medicament for treating and/or preventing estrogen receptor-mediated or dependent diseases or conditions, wherein the estrogen receptor-mediated or dependent diseases or conditions are tumors, preferably cancer, more preferably breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer and fallopian tube tumors, and most preferably breast cancer.
PCT/CN2024/137621 2023-12-08 2024-12-06 Estrogen receptor modulator and use thereof Pending WO2025119380A1 (en)

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