Estrogen receptor modulators and uses thereof

Abstract

The invention belongs to the technical field of medicines, and relates to an estrogen receptor modulator and application thereof, in particular to a compound shown as a general formula (i), an isomer or pharmaceutically acceptable salt thereof and application thereof. The invention also relates to the use thereof as an estrogen receptor degradation agent, in particular as an estrogen receptor degradation agent, in the preparation of medicaments for treating and / or preventing estrogen receptor mediated or dependent diseases or disorders, and in the preparation of medicaments for treating and / or preventing diseases or disorders by degrading target proteins.

Description

[0001] This invention claims the benefit of:

[0002] Priority of a prior application filed with the China National Intellectual Property Administration on December 8, 2023, with patent application number 202311681737.X and title "Estrogen Receptor Modulators and Their Uses";

[0003] Priority of a prior application filed with the China National Intellectual Property Administration on December 12, 2023, with patent application number 202311700571.1 and title "Estrogen Receptor Modulators and Their Uses";

[0004] Priority of a prior application filed with the China National Intellectual Property Administration on December 13, 2023, with patent application number 202311711928.6 and title "Estrogen Receptor Modulators and Their Uses";

[0005] Priority of a prior application filed with the China National Intellectual Property Administration on December 26, 2023, with patent application number 202311808960.6 and title "Estrogen Receptor Modulators and Their Uses";

[0006] Priority of a prior application filed with the China National Intellectual Property Administration on January 25, 2024, with patent application number 202410106933.2 and title "Estrogen Receptor Modulators and Their Uses";

[0007] Priority of a prior application filed with the China National Intellectual Property Administration on February 27, 2024, with patent application number 202410214069.8 and title "Estrogen Receptor Modulators and Their Uses";

[0008] Priority of a prior application filed with the China National Intellectual Property Administration on June 29, 2024, with patent application number 202410863924.8 and title "Estrogen Receptor Modulators and Their Uses";

[0009] The entire text of the said prior application is incorporated into this invention by reference. Technical Field

[0010] This invention belongs to the field of pharmaceutical technology and relates to estrogen receptor modulators represented by formula (I), their isomers, or their pharmaceutically acceptable salts and their uses. Background Art

[0011] Antiestrogen (hormone) therapy is the preferred therapy for estrogen-positive breast cancer. Antiestrogen 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 categories of antiestrogen therapies act through different mechanisms of action to block estrogen and inhibit tumor growth.

[0012] Targeted protein degradation chimeras (PROTACs) are a completely new therapeutic technology that exerts therapeutic effects by degrading target proteins to block signal pathways. PROTAC molecules generally consist of three parts: a target protein-binding ligand, an E3 ubiquitin ligase ligand, and a linker. One end of the PROTAC molecule tightly binds to the target protein through the chimera, and the other end binds to the E3 ubiquitin ligase, forming a ternary complex of target protein-PROTAC-E3 ubiquitin ligase. Through E3 ubiquitin ligase-mediated ubiquitination, the target protein is "tagged" with ubiquitin; subsequently, the ubiquitinated "tagged" target protein is transported to the proteasome and then degraded by the proteasome.

[0013] Compared with traditional small molecule inhibitors, the PROTAC technology has the following advantages: 1. It may require a smaller dosage. The target protein degradation process is similar to a catalytic reaction, and PROTAC molecules can be reused, and only a catalytic amount of the drug is required to inhibit the target protein. 2. It can avoid the feedback upregulation of the target protein expression level caused by inhibiting the target protein. 3. It expands the drug targeting range. The PROTAC technology enables proteins that cannot be directly targeted by traditional small molecule inhibitors, such as transcription factors, regulatory proteins, and other non-enzymatic proteins, to become regulatable proteins, turning the target from "undruggable" to "druggable".

[0014] ER-PROTAC drugs that target the degradation of estrogen receptors have initially demonstrated efficacy and excellent safety in clinical studies and are expected to become a new type of hormone therapy, which is an important supplement for patients who are resistant to, intolerant of, or have poor efficacy with traditional therapies. Summary of the Invention

[0015] An object of the invention is to provide a class of compounds of ER-PROTACs that target the degradation of estrogen receptors, their isomers, or their pharmaceutically acceptable salts.

[0016] The technical solution of the present invention is as follows:

[0017] The compound shown in formula (i), its isomer, or its pharmaceutically acceptable salt:

[0018] A - B - C

[0019] (i)

[0020] Among them,

[0021] A is

[0022] X is selected from N or CH;

[0023] Cy1 is selected from (for example )、 the said (for example )、 unsubstituted, or each is independently substituted by 1 - 3 R a1 substituted; G is selected from unsubstituted or optionally substituted by one, two or more R a1 substituted with the following groups: C 6-10 aryl or 5 - 10 - membered heteroaryl, such as phenyl, pyridyl, pyrimidinyl;

[0024] Each R a1 is independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halo - C 1-6 alkyl, C 1-6 alkoxy, halo - 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 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl;

[0025] B is -L2 - Cy2 - L3 - Cy3 - L4 - Cy4 - L5 -; A is connected to L2; C is connected to L5;

[0026] L1, L2, L3, L4, L5, L6 are 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)(R6 )-, C 2-8 alkenyl and C 2-8 alkynyl;

[0027] n and m are each independently any integer from zero to six; for example, 0, 1, 2, 3, 4, 5, or 6;

[0028] R 2 , R 31 , R 32 , R 4 and R 5 and R 6 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo 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 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, wherein the C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo 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 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl is unsubstituted or optionally substituted with one or more groups independently selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkanoyloxy, C 3-6Naphthenyl, C 3-6 Naphthenylcarbonyloxy, C 2-8 Alkynyl, halo C 1-6 Alkyl, C 2-8 Alkenyl, halo C 1-6 substituted by an alkoxy group;

[0029] Cy2 is selected from 3- to 13-membered naphthenyl, 3- to 13-membered heterocyclic, 3- to 13-membered cycloalkenyl, 3- to 13-membered naphthenyl substituted by 1-3 Rs a2 3- to 13-membered heterocyclic substituted by 1-3 Rs a2 3- to 13-membered cycloalkenyl substituted by 1-3 Rs, the heteroatom of the 3- to 13-membered heterocyclic being selected from O, N or S; Cy21 and Cy22 are the same or different and are each independently selected from 3- to 13-membered naphthenyl, 3- to 13-membered heterocyclic, 3- to 13-membered cycloalkenyl; a2 Cy3 is selected from 3- to 13-membered naphthenyl, 3- to 13-membered heterocyclic, 6- to 13-membered bicyclic fused ring group or 8- to 21-membered polycyclic fused ring group, the 3- to 13-membered naphthenyl, 3- to 13-membered heterocyclic, 6- to 13-membered bicyclic fused ring group or 8- to 21-membered polycyclic fused ring group being unsubstituted or each independently substituted by 1-5 Rs

[0030] a3 , the heteroatom of the 5- to 6-membered heterocyclic being N, O, S, Si;

[0031] Cy4 is selected from 3- to 8-membered naphthenyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkenyl, 6- to 13-membered bicyclic fused naphthenyl, 6- to 13-membered bicyclic fused cycloalkenyl, 6- to 13-membered bicyclic fused heterocyclic, 3- to 8-membered naphthenyl substituted by 1-3 Rs a4 3- to 8-membered heterocyclic substituted by 1-3 Rs a4 3- to 8-membered cycloalkenyl substituted by 1-3 Rs a4 6- to 13-membered bicyclic fused naphthenyl substituted by 1-3 Rs a4 6- to 13-membered bicyclic fused cycloalkenyl substituted by 1-3 Rs a4 6- to 13-membered bicyclic fused heterocyclic substituted by 1-3 Rs, the heteroatom of the 3- to 8-membered heterocyclic or 6- to 13-membered bicyclic fused heterocyclic being selected from O, N or S; a4

[0032] a2 , R a3 and R a4 when present, are each independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, silanol, selenol, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, C 1-6 alkoxy, halo C​1-6 alkoxy, C 1-6 alkyl-C(O)O-, C 1-6 alkylthio, C 1-6 alkylseleno, hydroxy C 1-6 alkyl, C 1-6 alkyl-C(O)NH-, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, 3- to 8-membered cycloalkenyl, wherein the C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo 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 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, 3- to 8-membered cycloalkenyl, unsubstituted or optionally substituted with one or more groups selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkanoyloxy, C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonyloxy, C 2-8 alkynyl, halo C 1-6 alkyl, C 2-8 alkenyl, halo C 1-6 alkoxy, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, 3- to 8-membered cycloalkenyl groups;

[0033] C is

[0034] X 1 is N or CR b1 ;

[0035] X 2 is N or CR b2 ;

[0036] X 3 is N or CR b3 ;

[0037] X 4 is N or CR b4 ;

[0038] X 5 is N or CR b5 ;

[0039] R b1 、R b2 、R b3 、R b4 and R b5 are each independently selected from hydrogen, deuterium, halogen, hydroxy, carboxy, amino, cyano, nitro, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo 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 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl;

[0040] Cy5 is selected from 6- to 13-membered bicyclic fused ring groups and 8- to 21-membered polycyclic fused ring groups; the 6- to 13-membered bicyclic fused ring group or 8- to 21-membered polycyclic fused ring group is unsubstituted or substituted with 1 to 3 R a5 substituents;

[0041] Each R a5 is independently selected from hydrogen, deuterium, hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl, C 2-8Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl, aryl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl) 2 Aminocarbonyl, 4- to 6-membered heterocyclic group carbonyl and 5- to 6-membered heteroaryloxy, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halo C 1-6 alkyl, halo 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- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl, aryl, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 4- to 6-membered heterocyclic group carbonyl and 5- to 6-membered heteroaryloxy 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 alkoxy C 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, halo C 1-6 alkyl, C 2-8 alkenyl, halo C 1-6 alkoxy;

[0042] Provided that when Cy3 is , is not

[0043] In one embodiment, the compound of formula (i), its isomers or its pharmaceutically acceptable salts:

[0044] Among them,

[0045] A is

[0046] X is selected from N or CH;

[0047] Cy1 is selected from and phenyl, and the and phenyl are unsubstituted, or each is independently substituted by 1 - 3 R a1 substituents;

[0048] Each R a1 is independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halo - C 1-6 alkyl, C 1-6 alkoxy, halo - 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 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl;

[0049] B is -L2 - Cy2 - L3 - Cy3 - L4 - Cy4 - L5-;

[0050] L1, L2, L3, L4, L5, L6 are 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;

[0051] n and m are each independently any integer from zero to six;

[0052] R 2 、R 31, R 32 , R 4 and R 5 are each independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo 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 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, where the C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo 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 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl is unsubstituted or optionally substituted by one or more groups independently selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkanoyloxy, C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonyloxy, C 2-8 alkynyl, halo C 1-6 alkyl, C 2-8 alkenyl, halo C 1-6 alkoxy;

[0053] Cy2 is selected from 4-6-membered cycloalkyl, 4-6-membered heterocyclic group, 4-6-membered cycloalkenyl, and is substituted by 1-3 R a2Substituted 4- to 6-membered cycloalkyl, substituted by 1 to 3 Rs a2 Substituted 4- to 6-membered heterocyclic group, substituted by 1 to 3 Rs a2 Substituted 4- to 6-membered cycloalkenyl, wherein the heteroatom of the 4- to 6-membered heterocyclic group is selected from O, N or S;

[0054] Cy3 is selected from 5- to 6-membered cycloalkyl or 5- to 6-membered heterocyclic group, wherein the 5- to 6-membered cycloalkyl or 5- to 6-membered heterocyclic group is unsubstituted or each is independently substituted by 1 to 3 Rs a3 Substituted, and the heteroatom of the 5- to 6-membered heterocyclic group is N;

[0055] Cy4 is selected from 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, 3- to 8-membered cycloalkenyl, 6- to 13-membered bicyclic fused cycloalkyl, 6- to 13-membered bicyclic fused cycloalkenyl, 6- to 13-membered bicyclic fused heterocyclic group, substituted 3- to 8-membered cycloalkyl, substituted 3- to 8-membered heterocyclic group, substituted 3- to 8-membered cycloalkenyl, substituted 6- to 13-membered bicyclic fused cycloalkyl, substituted 6- to 13-membered bicyclic fused cycloalkenyl, substituted 6- to 13-membered bicyclic fused heterocyclic group, wherein the heteroatom of the 3- to 8-membered heterocyclic group or 6- to 13-membered bicyclic fused heterocyclic group is selected from O, N or S; a4 Substituted 3- to 8-membered cycloalkyl, substituted by 1 to 3 Rs a4 Substituted 3- to 8-membered heterocyclic group, substituted by 1 to 3 Rs a4 Substituted 3- to 8-membered cycloalkenyl, substituted by 1 to 3 Rs a4 Substituted 6- to 13-membered bicyclic fused cycloalkyl, substituted by 1 to 3 Rs a4 Substituted 6- to 13-membered bicyclic fused cycloalkenyl, substituted by 1 to 3 Rs a4 Substituted 6- to 13-membered bicyclic fused heterocyclic group, wherein the heteroatom of the 3- to 8-membered heterocyclic group or 6- to 13-membered bicyclic fused heterocyclic group is selected from O, N or S;

[0056] Each R a2 、R a3 and R a4 When present, are each independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo 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 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, 3- to 8-membered cycloalkenyl, wherein the C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, 3- to 8-membered cycloalkenyl, unsubstituted or optionally substituted with one or more groups selected from hydroxy, amino, carboxy, 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 alkanoyloxy, C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonyloxy, C 2-8 alkynyl, haloC 1-6 alkyl, C 2-8 alkenyl, haloC 1-6 alkoxy, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, 3- to 8-membered cycloalkenyl, substituted with a group;

[0057] C is

[0058] X 1 is N or CR b1 ;

[0059] X 2 is N or CR b2 ;

[0060] X 3 is N or CR b3 ;

[0061] X 4 is N or CR b4 ;

[0062] X 5 is N or CR b5 ;

[0063] R b1 、R b2 、R b3 、R b4 and R b5Independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo 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 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl;

[0064] Cy5 is selected from 6- to 13-membered bicyclic fused ring groups and 8- to 21-membered polycyclic fused ring groups; the 6- to 13-membered bicyclic fused ring group or 8- to 21-membered polycyclic fused ring group is unsubstituted or substituted with 1 to 3 R a5 substituents;

[0065] Each R a5 is independently selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halo C 1-6 alkyl, halo 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- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl, aryl, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 4- to 6-membered heterocyclic carbonyl and 5- to 6-membered heteroaryl-oxy, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C3-6 Cycloalkyl, 4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl group, aryl group, C 1-6 alkylcarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 4- to 6-membered heterocyclic group carbonyl and 5- to 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) 2 amino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkoxycarbonyl, C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonoxy, C 2-8 alkynyl, haloC 1-6 alkyl, C 2-8 alkenyl, haloC 1-6 alkoxy groups;

[0066] Provided that when Cy3 is , is not

[0067] Another embodiment of the present invention relates to a compound represented by formula (i), its isomer or its pharmaceutically acceptable salt,

[0068] wherein,

[0069] A is

[0070] X is selected from N or CH;

[0071] Cy1 is selected from and phenyl, and the and phenyl are unsubstituted, or each is independently substituted by 1-3 R a1 substituents;

[0072] Each R a1 is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, hydroxyC 1-6 alkyl, C 1-6alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl;

[0073] B is -L2-Cy2-L3-Cy3-L4-Cy4-L5-;

[0074] 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;

[0075] n and m are each independently any integer from zero to six;

[0076] R 2 、R 31 、R 32 、R 4 and R 5 are each independently selected from hydrogen, halogen, hydroxy, carboxy, amino, cyano, nitro, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo 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 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, wherein the C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl is unsubstituted or optionally substituted by one or more groups independently selected from hydroxy, amino, carboxy, 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 alkanoyloxy, C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonyloxy, C 2-8 alkynyl, haloC 1-6 alkyl, C 2-8 alkenyl, haloC 1-6 alkoxy;

[0077] Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclic, 4-6 membered cycloalkenyl, 4-6 membered cycloalkyl substituted with 1-3 R a2 substituents, 4-6 membered heterocyclic substituted with 1-3 R a2 substituents, 4-6 membered cycloalkenyl substituted with 1-3 R a2 substituents, wherein the heteroatoms of the 4-6 membered heterocyclic are selected from O, N or S;

[0078] Cy3 is selected from 5-6 membered cycloalkyl or 5-6 membered heterocyclic, wherein the 5-6 membered cycloalkyl or 5-6 membered heterocyclic is unsubstituted or each is independently substituted with 1-3 R a3 substituents, and the heteroatom of the 5-6 membered heterocyclic is N;

[0079] Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, 6-13 bicyclic fused cycloalkyl, 6-13 membered bicyclic fused cycloalkenyl, 6-13 membered bicyclic fused heterocyclic, 3-8 membered cycloalkyl substituted with 1-3 R a4 substituents, 3-8 membered heterocyclic substituted with 1-3 R a4 substituents, 3-8 membered cycloalkenyl substituted with 1-3 R a4 substituents, 6-13 bicyclic fused cycloalkyl substituted with 1-3 R a4 substituents, 6-13 membered bicyclic fused cycloalkenyl substituted with 1-3 R a4Substituted 6- to 13-membered bicyclic fused alkenyl, substituted by 1 to 3 Rs a4 Substituted 6- to 13-membered bicyclic fused heterocyclic group, wherein the heteroatoms of the 3- to 8-membered heterocyclic group or 6- to 13-membered bicyclic fused heterocyclic group are selected from O, N, or S;

[0080] Each R a2 、R a3 and R a4 When present, are each independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo 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 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, 3- to 8-membered cycloalkenyl, wherein the C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo 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 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, 3- to 8-membered cycloalkenyl, unsubstituted or optionally substituted by one or more selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkanoyloxy, C 3-6 cycloalkyl, C 3-6Cycloalkylcarbonyloxy, C 2-8 Alkynyl, halo C 1-6 Alkyl, C 2-8 Alkenyl, halo C 1-6 Alkoxy, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, 3- to 8-membered cycloalkenyl group substituted;

[0081] C is

[0082] X 1 is N or CR b1 ;

[0083] X 2 is N or CR b2 ;

[0084] X 3 is N or CR b3 ;

[0085] X 4 is N or CR b4 ;

[0086] X 5 is N or CR b5 ;

[0087] R b1 、R b2 、R b3 、R b4 and R b5 are each independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halo C 1-6 Alkyl, C 1-6 Alkoxy, halo 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;

[0088] Cy5 is selected from 6- to 13-membered bicyclic fused ring groups and 8- to 21-membered polycyclic fused ring groups; the 6- to 13-membered bicyclic fused ring group or 8- to 21-membered polycyclic fused ring group is unsubstituted or substituted by 1 to 3 R a5 substituted;

[0089] Each R a5 is independently selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halo C 1-6 alkyl, halo 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 heterocyclic group, 5-6 membered heteroaryl, aryl, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 4-6 membered heterocyclic group carbonyl and 5-6 membered heteroaryl-oxy, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halo C 1-6 alkyl, halo 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 heterocyclic group, 5-6 membered heteroaryl, aryl, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 4-6 membered heterocyclic group carbonyl and 5-6 membered heteroaryl-oxy are unsubstituted or optionally substituted with one or more independently selected from hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkanoyloxy, C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonyloxy, C 2-8 alkynyl, halo C 1-6 alkyl, C 2-8 alkenyl, halo C 1-6Substitution with alkoxy groups;

[0090] Provided that when Cy3 is at the time, is not

[0091] Another embodiment of the present invention relates to a compound of formula (i), its isomers or its pharmaceutically acceptable salts,

[0092] wherein,

[0093] A is

[0094] X is selected from N or CH;

[0095] Cy1 is selected from and phenyl, and the said and phenyl are unsubstituted, or each is independently substituted by 1 - 3 R a1 substituents;

[0096] Each R a1 is independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo 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 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl;

[0097] B is -L2-Cy2-L3-Cy3-L4-Cy4-L5-;

[0098] L1, L2, L3, L4, L5, L6 are 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;

[0099] n and m are each independently any integer from zero to six;

[0100] R 2 、R 31 、R 32 、R 4 and R 5 are each independently selected from hydrogen, halogen, hydroxy, carboxy, amino, cyano, nitro, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo 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, where the C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo 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 is unsubstituted or optionally substituted by one or more groups independently selected from hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 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, halo C 1-6 alkyl, C 2-8 alkenyl, halo C1-6 substituted by an alkoxy group;

[0101] Cy2 is selected from a 4-6 membered cycloalkyl group, a 4-6 membered heterocyclic group, a 4-6 membered cycloalkenyl group, a 4-6 membered cycloalkyl group substituted by 1-3 Rs a2 a 4-6 membered heterocyclic group substituted by 1-3 Rs a2 a 4-6 membered cycloalkenyl group substituted by 1-3 Rs a2 wherein the heteroatom of the 4-6 membered heterocyclic group is selected from O, N or S;

[0102] Cy3 is selected from said unsubstituted or each independently substituted by 1-3 Rs a3 substituted;

[0103] Cy4 is selected from a 3-8 membered cycloalkyl group, a 3-8 membered heterocyclic group, a 3-8 membered cycloalkenyl group, a 6-13 bicyclic fused cycloalkyl group, a 6-13 membered bicyclic fused cycloalkenyl group, a 6-13 membered bicyclic fused heterocyclic group, a 3-8 membered cycloalkyl group substituted by 1-3 Rs a4 a 3-8 membered heterocyclic group substituted by 1-3 Rs a4 a 3-8 membered cycloalkenyl group substituted by 1-3 Rs a4 a 6-13 bicyclic fused cycloalkyl group substituted by 1-3 Rs a4 a 6-13 membered bicyclic fused cycloalkenyl group substituted by 1-3 Rs a4 a 6-13 membered bicyclic fused heterocyclic group substituted by 1-3 Rs, wherein the heteroatom of the 3-8 membered heterocyclic group or the 6-13 membered bicyclic fused heterocyclic group is selected from O, N or S; a4

[0104] Each R a2 、R a3 and R a4 , when present, are each independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo 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 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, a 3-8 membered cycloalkyl group, a 3-8 membered heterocyclic group, a 3-8 membered cycloalkenyl group, wherein the C 1-6 ​Alkyl, halo C 1-6 Alkyl, C 1-6 Alkoxy, halo 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- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, 3- to 8-membered cycloalkenyl unsubstituted or optionally substituted with one or more groups selected from hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 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, halo C 1-6 Alkyl, C 2-8 Alkenyl, halo C 1-6 Alkoxy, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, 3- to 8-membered cycloalkenyl groups substituted;

[0105] C is

[0106] X 1 is N or CR b1 ;

[0107] X 2 is N or CR b2 ;

[0108] X 3 is N or CR b3 ;

[0109] X 4 is N or CR b4 ;

[0110] X 5 is N or CR b5 ;

[0111] R b1 、Rb2 , R b3 , R b4 and R b5 are each independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo 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 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl;

[0112] Cy5 is selected from 6- to 13-membered bicyclic fused ring groups and 8- to 21-membered polycyclic fused ring groups; the 6- to 13-membered bicyclic fused ring groups and 8- to 21-membered polycyclic fused ring groups are unsubstituted or optionally substituted by 1 to 3 R a5 substituents;

[0113] Each R a5 is independently selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halo C 1-6 alkyl, halo 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- to 6-membered heterocyclic groups, 5- to 6-membered heteroaryl groups, aryl, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 4- to 6-membered heterocyclic carbonyl groups and 5- to 6-membered heteroaryl-oxy, where the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl, C2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 4 - 6 - membered heterocyclic group, 5 - 6 - membered heteroaryl, aryl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl) 2 Aminocarbonyl, 4 - 6 - membered heterocyclic group carbonyl and 5 - 6 - membered heteroaryl - oxy are unsubstituted or optionally substituted by one or more independently selected from hydroxyl, 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 alkyloxycarbonyl, C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonyloxy, C 2-8 alkynyl, haloC 1-6 alkyl, C 2-8 alkenyl, haloC 1-6 alkoxy groups;

[0114] Provided that when Cy3 is , is not

[0115] Another embodiment of the present invention relates to a compound of formula (i), its isomers or its pharmaceutically acceptable salts,

[0116] A is

[0117] X is selected from N or CH;

[0118] Cy1 is selected from and phenyl, said and phenyl are unsubstituted, or each is independently substituted by 1 - 3 R a1 substituents;

[0119] Each R a1 is independently selected from hydrogen, halogen, hydroxyl, amino, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, hydroxyC 1-6Alkyl;

[0120] B is -L2-Cy2-L3-Cy3-L4-Cy4-L5-;

[0121] L1, L2, L3, L4, L5, and L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, -C(O)-;

[0122] n and m are each independently 0, 1, or 2;

[0123] Cy2 is selected from a 4- to 6-membered cycloalkyl, a 4- to 6-membered heterocyclic group, a 4- to 6-membered cycloalkenyl, a 4- to 6-membered cycloalkyl substituted with 1 to 3 Rs a2 , a 4- to 6-membered heterocyclic group substituted with 1 to 3 Rs a2 , a 4- to 6-membered cycloalkenyl substituted with 1 to 3 Rs a2 , wherein the heteroatom of the 4- to 6-membered heterocyclic group is selected from O, N, or S;

[0124] Cy3 is selected from the unsubstituted or each independently substituted with 1 to 3 Rs a3 ;

[0125] Cy4 is selected from a 3- to 8-membered cycloalkyl, a 3- to 8-membered heterocyclic group, a 3- to 8-membered cycloalkenyl, a 6- to 13-membered bicyclic fused cycloalkyl, a 6- to 13-membered bicyclic fused cycloalkenyl, a 6- to 13-membered bicyclic fused heterocyclic group, a 3- to 8-membered cycloalkyl substituted with 1 to 3 Rs a4 , a 3- to 8-membered heterocyclic group substituted with 1 to 3 Rs a4 , a 3- to 8-membered cycloalkenyl substituted with 1 to 3 Rs a4 , a 6- to 13-membered bicyclic fused cycloalkyl substituted with 1 to 3 Rs a4 , a 6- to 13-membered bicyclic fused cycloalkenyl substituted with 1 to 3 Rs a4 , a 6- to 13-membered bicyclic fused heterocyclic group substituted with 1 to 3 Rs a4 , wherein the heteroatom of the 3- to 8-membered heterocyclic group or the 6- to 13-membered bicyclic fused heterocyclic group is selected from O, N, or S;

[0126] Each R a2 , R a3 and R a4 , when present, are each independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6Alkylamino, (C 1-6 alkyl) 2 amino, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, 3- to 8-membered cycloalkenyl, wherein the C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, 3- to 8-membered cycloalkenyl are unsubstituted or optionally substituted by one or more groups selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, 3- to 8-membered cycloalkenyl;

[0127] C is

[0128] X 1 is N or CR b1 ;

[0129] X 2 is N or CR b2 ;

[0130] X 4 is N or CR b4 ;

[0131] X 5 is N or CR b5 ;

[0132] R b1 , R b2 , R b3 , R b4 and R b5 are each independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino;

[0133] Cy5 is selected from 6- to 13-membered bicycloannulenyl, 6- to 13-membered bicycloheterocyclic, 6- to 13-membered bicycloheteroaryl, 8- to 21-membered polycycloheterocyclic, 8- to 21-membered polycycloheteroaryl; the 6- to 13-membered bicycloannulenyl, 6- to 13-membered bicycloheterocyclic, 6- to 13-membered bicycloheteroaryl, 8- to 21-membered polycycloheterocyclic, 8- to 21-membered polycycloheteroaryl are unsubstituted or optionally substituted with 1-3 R a5 substituents;

[0134] Each R a5 is independently selected from hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic, 5- to 6-membered heteroaryl, aryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclic, 5- to 6-membered heteroaryl, aryl are unsubstituted or optionally substituted with one or more groups independently selected from hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 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, halo C 1-6 alkyl, C 2-8 alkenyl, halo C 1-6 alkoxy.

[0135] Another embodiment of the present invention relates to a compound of formula (i), its isomers or its pharmaceutically acceptable salts, having the structure shown in formula (ii),

[0136]

[0137] X is selected from N or CH;

[0138] Ring Cy1 is selected from and phenyl, wherein the and phenyl are unsubstituted, or each is independently substituted by 1-3 R a1 substituents;

[0139] Each R a1 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy;

[0140] L1, L2, L3, L4, L5, L6 are independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, -C(O)-;

[0141] n and m are independently 0, 1 or 2;

[0142] 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 substituents;

[0143] Cy4 is selected from a 3-8 membered heterocyclic group, a 3-8 membered heterocyclic group substituted by 1-3 R a4 substituents, a 6-13 membered bicyclic spiro heterocyclic group or a 6-13 membered bicyclic spiro heterocyclic group substituted by 1-3 R a4 substituents, wherein the heteroatom of the 3-8 membered heterocyclic group or 6-13 membered bicyclic spiro heterocyclic group is selected from O, N or S;

[0144] Each R a2 and R a4 , when present, are independently selected from hydrogen, C 1-6 alkyl, a 3-8 membered heterocyclic group, wherein the C 1-6 alkyl or 3-8 membered heterocyclic group is unsubstituted or substituted by one or more C 1-6 alkyl or 3-8 membered heterocyclic group;

[0145] X 1 is N or CR b1 ;

[0146] X 2 is N or CR b2 ;

[0147] X 4 is N or CR b4 ;

[0148] X 5 is N or CR b5 ;

[0149] R b1 、R b2 、R b3 、R b4 and R b5 are each independently selected from hydrogen, halogen;

[0150] Cy5 is selected from 6- to 13-membered bicyclic annulenyl, 6- to 13-membered bicyclic heteroaryl, 8- to 21-membered polycyclic heterocyclic group, and the 6- to 13-membered bicyclic annulenyl, 6- to 13-membered bicyclic heteroaryl, 8- to 21-membered polycyclic heterocyclic group are unsubstituted or optionally substituted with 1 to 3 R a5 substituents;

[0151] Each R a5 is independently selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, phenyl, and the phenyl is unsubstituted or substituted with one or more halogens, halo C 1-6 alkyl, C 1-6 alkoxy.

[0152] Another embodiment of the present invention relates to a compound of formula (ii), its isomer or its pharmaceutically acceptable salt,

[0153] X is selected from N or CH;

[0154] Cy1 is selected from and phenyl, and the and phenyl are unsubstituted, or each is independently substituted with 1 to 3 R a1 substituents;

[0155] Each R a1 is independently selected from hydrogen, methoxy, methyl, ethyl;

[0156] L1 is selected from a bond, -NH-;

[0157] L2 is selected from a bond, -NH-;

[0158] Cy2 is selected from

[0159] L3 is selected from -CH 2 -, -C(O)-, -NH-CH 2 -;

[0160] Cy3 is selected from

[0161] L4 is selected from -CH2 -, -NH-CH 2 -, -C(O)-;

[0162] Cy4 is selected from

[0163] L5 is selected from a bond;

[0164] selected from L6 is selected from a bond, -O-;

[0165] Cy5 is selected from the is unsubstituted or optionally substituted by 1 - 3 R a5 substituted;

[0166] each R a5 is independently selected from hydroxy, methyl, methoxy, phenyl, the phenyl is unsubstituted or substituted by one or more fluorine, methoxy, trifluoromethyl, substituted.

[0167] In another embodiment of the present invention, Cy1 is selected from The * end is connected to L1.

[0168] In another embodiment of the present invention, the is unsubstituted, or each is independently substituted by 1 - 3 R a1 substituted; more preferably, each of the R a1 is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl; even more preferably, each of the R a1 is independently substituted by 1 - 3 halogens (such as F) or C 1-6 alkyl (such as methyl).

[0169] In another embodiment of the present invention, Cy1 is selected from The * end is connected to L1.

[0170] In another embodiment of the present invention, L1, L2, L3, L4, L5, and 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)-.

[0171] In another embodiment of the present invention, L1 is selected from a bond, -NHC(O)-; preferably, when L1 is -NHC(O)-, the C(O) end is connected to Cy1.

[0172] In another embodiment of the present invention, L2 is selected from a bond, NH, or NH(C 1-3 alkylene).

[0173] In another embodiment of the present invention, L2 is selected from a bond, -NH-, or -NHCH 2- ; preferably a bond.

[0174] 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, R 4 、R 5 are independently selected from C3-6 cycloalkyl.

[0175] In another embodiment of the present invention, L3 is selected from methylene, -C(O)-, or NHCH 2- ; preferably methylene.

[0176] In another embodiment of the present invention, L4 is selected from a bond, C 1-3 alkylene or -C(O)-.

[0177] In another embodiment of the present invention, L4 is selected from a bond, methylene, or -C(O)-; preferably methylene.

[0178] In another embodiment of the present invention, L5 is selected from a bond or C 1-3 alkylene.

[0179] In another embodiment of the present invention, L5 is selected from a bond or methylene; preferably a bond.

[0180] In another embodiment of the present invention, L6 is selected from a bond or -O-; preferably a bond.

[0181] In another embodiment of the present invention, Cy2 is selected from a 4- to 10-membered cycloalkyl group, a 4- to 10-membered heterocyclic group, a 4- to 10-membered cycloalkenyl group, a 4- to 10-membered cycloalkyl group substituted with 1 to 3 Ra2 groups, a 4- to 10-membered heterocyclic group substituted with 1 to 3 Ra2 groups, a 4- to 10-membered cycloalkenyl group substituted with 1 to 3 Ra2 groups, Cy21-Cy22, wherein the heteroatom of the 4- to 10-membered heterocyclic group is selected from O, N, or S; Cy21 and Cy22 are the same or different and are independently selected from a 4- to 6-membered cycloalkyl group, a 4- to 6-membered heterocyclic group, and a 4- to 6-membered cycloalkenyl group.

[0182] In another embodiment of the present invention, Cy2 is selected from a 4- to 6-membered cycloalkyl group, a 4- to 6-membered heterocyclic group, a 4- to 6-membered cycloalkenyl group, a 4- to 6-membered cycloalkyl group substituted with 1 to 3 R a2 substituted with 1 to 3 R a2 substituted with 1 to 3 R a2 substituted 4- to 6-membered heterocyclic group, and a 4- to 6-membered cycloalkenyl group substituted with 1 to 3 R, wherein the heteroatom of the 4- to 6-membered heterocyclic group is selected from O, N, or S.

[0183] In another embodiment of the present invention, Cy2 is selected from an unsubstituted or 1- to 3-R a2 substituted 6- to 9-membered heterocyclic group, Cy21-Cy22; Cy21 and Cy22 are the same or different and are independently selected from a cyclohexyl group, a piperazinyl group, and a piperidinyl group.

[0184] In another embodiment of the present invention, Cy2 is selected from an unsubstituted or 1- to 3-H- or F-substituted piperazinyl group and a piperidinyl group.

[0185] In another embodiment of the present invention, Cy2 is selected from an unsubstituted or 1- to 3-R a2 substituted piperazinyl group, piperidinyl group,

[0186] In another embodiment of the present invention, Cy2 is selected from (for example ), (for example ), (for example ), The * end is connected to Cy1.

[0187] In another embodiment of the present invention, Cy3 is selected from a 5- to 10-membered cycloalkyl group, a 5- to 10-membered heterocyclic group, a 6- to 13-membered bicyclic fused cycloalkyl group, a 6- to 13-membered bicyclic fused cycloalkenyl group, a 6- to 13-membered bicyclic fused heterocyclic group, an 8- to 13-membered bicyclic fused heteroaryl group, an 8- to 13-membered bicyclic fused aryl group, an 8- to 21-membered polycyclic fused cycloalkyl group, an 8- to 21-membered polycyclic fused cycloalkenyl group, an 8- to 21-membered polycyclic fused heterocyclic group, an 8- to 21-membered polycyclic fused heteroaryl group, and an 8- to 21-membered polycyclic fused aryl group.

[0188] In another embodiment of the present invention, Cy3 is selected from a 5- to 6-membered cycloalkyl group or a 5- to 6-membered heterocyclic group, and the 5- to 6-membered cycloalkyl group or 5- to 6-membered heterocyclic group is unsubstituted or is independently substituted by 1 to 3 Ra3 groups respectively, and the heteroatoms of the 5- to 6-membered heterocyclic group are N, O, S, or Si.

[0189] In another embodiment of the present invention, Cy3 is selected from a 5- to 6-membered cycloalkyl group or a 5- to 6-membered heterocyclic group; the 5- to 6-membered cycloalkyl group or 5- to 6-membered heterocyclic group is unsubstituted or is independently substituted by 1 to 3 R a3 substituents.

[0190] In another embodiment of the present invention, Cy3 is selected from cyclohexyl, piperidinyl, tetrahydropyranyl, dioxanyl, and pyrrolidinyl; the cyclohexyl, piperidinyl, tetrahydropyranyl, dioxanyl, and pyrrolidinyl are unsubstituted or are independently substituted by 1 to 3 R a3 substituents; preferably cyclohexyl.

[0191] In another embodiment of the present invention, Cy3 is selected from the is unsubstituted or is independently substituted by 1 to 3 R a3 substituents.

[0192] In another embodiment of the present invention, Cy4 is selected from a 5- to 6-membered heterocyclic group that is unsubstituted or optionally substituted by one, two, or more C 1-6 alkyl groups or C 1-6 alkoxy groups.

[0193] In another embodiment of the present invention, Cy4 is selected from piperazinyl, for example The * end is connected to L5.

[0194] In another embodiment of the present invention, Cy5 is selected from the following groups that are unsubstituted or substituted by 1 to 3 R a5 substituents: a 6- to 13-membered bicyclic fused cycloalkenyl group, a 6- to 13-membered bicyclic fused heteroaryl group, and an 8- to 21-membered polycyclic fused heterocyclic group.

[0195] In another embodiment of the present invention, Cy5 is selected from those that are unsubstituted or substituted by 1 to 3 OH groups or phenyl groups For example

[0196] In another embodiment of the present invention, Cy5 is For example

[0197] In another embodiment of the present invention, R a1 is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy.

[0198] In another embodiment of the present invention, R a1 is selected from F, methyl, ethyl, methoxy.

[0199] In another embodiment of the present invention, each R a2 、R a3 and R a4 is the same or different and is independently selected from H, OH, amino, mercapto, silanol, selenol, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-NH-, C 3-6 cycloalkyl, C 1-6 alkyl-C(O)NH-, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, hydroxy-C 1-6 alkyl.

[0200] In another embodiment of the present invention, R a2 is selected from H, OH, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-NH-, C 3-6 cycloalkyl, C 1-6 alkyl-C(O)NH-.

[0201] In another embodiment of the present invention, R a2 is selected from H, F, OH, amino, methylamino, acetamido, methyl, methoxy, cyclopropyl.

[0202] In another embodiment of the present invention, R a3 and R a4 are the same or different and are independently selected from H, halogen.

[0203] In another embodiment of the present invention, R a3 and R a4 are the same or different and are independently selected from H, F.

[0204] In another embodiment of the present invention, Ra5 Selected from hydroxy or C 6-10 aryl.

[0205] In another embodiment of the present invention, R a5 is selected from hydroxy or phenyl.

[0206] In another embodiment of the present invention, Ra5 is selected from hydroxy or C6-10 aryl, halogen-substituted C6-10 aryl.

[0207] In another embodiment of the present invention, is selected from the following groups unsubstituted or optionally substituted by 1 to 4 substituents of R b1 , R b2 , R b3 , R b4 , R b5 : phenyl, 6-membered heteroaryl containing 1 or 2 heteroatoms, such as

[0208] Another embodiment of the present invention relates to a compound of formula (i), its isomers or its pharmaceutically acceptable salts, having the structure shown in formula (iii):

[0209]

[0210] X is selected from N or CH;

[0211] R a1 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy;

[0212] L2, L3, L4, L5, L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, -C(O)-;

[0213] n and m are each independently 0, 1 or 2;

[0214] 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 ;

[0215] Cy4 is selected from a 3-8 membered heterocyclic group, a 3-8 membered heterocyclic group substituted by 1-3 R a4 , a 6-13 membered bicyclic spiro heterocyclic group or a 6-13 membered bicyclic spiro heterocyclic group substituted by 1-3 R a4 , and the heteroatoms of the 3-8 membered heterocyclic group or 6-13 membered bicyclic spiro heterocyclic group are selected from O, N or S;

[0216] Each R a2 and Ra4 When present, are each independently selected from hydrogen, C 1-6 alkyl, 3- to 8-membered heterocyclic group, and the C 1-6 alkyl or 3- to 8-membered heterocyclic group is unsubstituted or substituted with one or more C 1-6 alkyl or 3- to 8-membered heterocyclic group;

[0217] X 1 is N or CR b1 ;

[0218] X 2 is N or CR b2 ;

[0219] X 4 is N or CR b4 ;

[0220] X 5 is N or CR b5 ;

[0221] R b1 、R b2 、R b3 、R b4 and R b5 are each independently selected from hydrogen, halogen;

[0222] Cy5 is selected from 6- to 13-membered bicyclic annulenyl, 6- to 13-membered bicyclic heteroaryl, 8- to 21-membered polycyclic heterocyclic group, and the 6- to 13-membered bicyclic annulenyl, 6- to 13-membered bicyclic heteroaryl, 8- to 21-membered polycyclic heterocyclic group is unsubstituted or optionally substituted with 1-3 R a5 ;

[0223] Each R a5 is each independently selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, phenyl, and the phenyl is unsubstituted or substituted with one or more halogen, halo C 1-6 alkyl, C 1-6 alkoxy.

[0224] Another embodiment of the present invention relates to a compound of formula (i), its isomer or its pharmaceutically acceptable salt, having the structure shown in formula (iv):

[0225]

[0226] X is selected from N or CH;

[0227] Each R a1 is each independently selected from hydrogen, halogen, hydroxy, carboxy, amino, cyano, nitro, C 1-6 alkyl, halo C1-6 alkyl, C 1-6 alkoxy, halo-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 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl;

[0228] L2, L3, L4, L5, L6 are each independently selected from a bond, -(CH 2 ) n -(NH) m -, -O-, -C(O)-;

[0229] n and m are each independently 0, 1 or 2;

[0230] Cy2 is selected from a 4- to 6-membered nitrogen-containing heterocyclic group or a 4- to 6-membered nitrogen-containing heterocyclic group substituted with 1 to 3 R a2 substituents;

[0231] Cy4 is selected from a 3- to 8-membered heterocyclic group, a 3- to 8-membered heterocyclic group substituted with 1 to 3 R a4 substituents, a 6- to 13-membered bicyclic spiroheterocyclic group or a 6- to 13-membered bicyclic spiroheterocyclic group substituted with 1 to 3 R a4 substituents, and the heteroatoms of the 3- to 8-membered heterocyclic group or 6- to 13-membered bicyclic spiroheterocyclic group are selected from O, N or S;

[0232] Each R a2 and R a4 , when present, are each independently selected from hydrogen, C 1-6 alkyl, a 3- to 8-membered heterocyclic group, and the C 1-6 alkyl or 3- to 8-membered heterocyclic group is unsubstituted or substituted with one or more C 1-6 alkyl or 3- to 8-membered heterocyclic groups;

[0233] X 1 is N or CR b1 ;

[0234] X 2 is N or CR b2 ;

[0235] X 4 is N or CR b4 ;

[0236] X 5 is N or CR b5;

[0237] R b1 , R b2 , R b3 , R b4 and R b5 are independently selected from hydrogen and halogen;

[0238] 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 replace;

[0239] Each R a5 are independently selected from hydrogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, phenyl, the phenyl is unsubstituted or substituted with one or more halogen, halogenated C 1-6 Alkyl, C 1-6 Alkoxy substitution.

[0240] 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):

[0241]

[0242] A is

[0243] X is selected from N or CH;

[0244] Cy1 is selected from and phenyl, the and phenyl are unsubstituted, or each is independently substituted with 1 to 3 R a1 replace;

[0245] Each R a1 are independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl 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, (C1-6 alkyl) 2 aminocarbonyl;

[0246] 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)-, C 2-8 alkenyl, and C 2-8 alkynyl;

[0247] n and m are each independently any integer from zero to six;

[0248] R 2 , R 31 , R 32 , R 4 and R 5 are each independently selected from hydrogen, halogen, hydroxy, carboxy, amino, cyano, nitro, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo 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 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, where the C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo 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 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2The carbamoyl group is unsubstituted or optionally substituted by one or more groups independently selected from hydroxy, amino, carboxy, 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, haloC 1-6 alkyl, C 2-8 alkenyl, haloC 1-6 alkoxy;

[0249] Cy2 is selected from 4- to 6-membered cycloalkyl, 4- to 6-membered heterocyclic, 4- to 6-membered cycloalkenyl, 4- to 6-membered cycloalkyl substituted with 1-3 R a2 substituents, 4- to 6-membered heterocyclic substituted with 1-3 R a2 substituents, 4- to 6-membered cycloalkenyl substituted with 1-3 R a2 substituents, the heteroatoms of the 4- to 6-membered heterocyclic being selected from O, N or S;

[0250] Cy4 is selected from 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic, 3- to 8-membered cycloalkenyl, 6- to 13-membered bicyclo-fused cycloalkyl, 6- to 13-membered bicyclo-fused cycloalkenyl, 6- to 13-membered bicyclo-fused heterocyclic, 3- to 8-membered cycloalkyl substituted with 1-3 R a4 substituents, 3- to 8-membered heterocyclic substituted with 1-3 R a4 substituents, 3- to 8-membered cycloalkenyl substituted with 1-3 R a4 substituents, 6- to 13-membered bicyclo-fused cycloalkyl substituted with 1-3 R a4 substituents, 6- to 13-membered bicyclo-fused cycloalkenyl substituted with 1-3 R a4 substituents, 6- to 13-membered bicyclo-fused heterocyclic substituted with 1-3 R a4 substituents, the heteroatoms of the 3- to 8-membered heterocyclic or 6- to 13-membered bicyclo-fused heterocyclic being selected from O, N or S;

[0251] Each R a2 and R a4 when present, are each independently selected from hydrogen, halogen, hydroxy, carboxy, amino, cyano, nitro, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, hydroxyC 1-6alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered cycloalkenyl, wherein the C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo 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 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered cycloalkenyl unsubstituted or optionally substituted by one or more groups selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkanoyloxy, C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonyloxy, C 2-8 alkynyl, halo C 1-6 alkyl, C 2-8 alkenyl, halo C 1-6 alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered cycloalkenyl;

[0252] X 1 is N or CR b1 ;

[0253] X 2 is N or CR b2 ;

[0254] X 4 is N or CRb4 ;

[0255] X 5 is N or CR b5 ;

[0256] R b1 、R b2 、R b3 、R b4 and R b5 are each independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo 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 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl;

[0257] Cy5 is selected from 6- to 13-membered bicyclic fused ring groups and 8- to 21-membered polycyclic fused ring groups; the 6- to 13-membered bicyclic fused ring group or 8- to 21-membered polycyclic fused ring group is unsubstituted or substituted with 1-3 R a5 substituents;

[0258] Each R a5 is independently selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halo C 1-6 alkyl, halo 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- to 6-membered heterocyclic groups, 5- to 6-membered heteroaryl groups, aryl, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 4- to 6-membered heterocyclic group carbonyl and 5- to 6-membered heteroaryl-oxy, wherein the C 1-6 alkyl, C 1-6 alkoxy, C1-6 alkylamino, (C 1-6 alkyl) 2 amino, halo-C 1-6 alkyl, halo-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 heterocyclic group, 5-6 membered heteroaryl, aryl, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, 4-6 membered heterocyclic group carbonyl and 5-6 membered heteroaryl-oxy unsubstituted or optionally substituted by one or more independently selected from hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkanoyloxy, C 3-6 cycloalkyl, C 3-6 cycloalkylcarbonyloxy, C 2-8 alkynyl, halo-C 1-6 alkyl, C 2-8 alkenyl, halo-C 1-6 alkoxy groups.

[0259] The compound, its isomer or its pharmaceutically acceptable salt according to any one of the embodiments,

[0260] Cy1 is selected from and phenyl, and the and phenyl are unsubstituted, or each is independently substituted by 1-3 R a1 substituents.

[0261] The compound, its isomer or its pharmaceutically acceptable salt according to any one of the embodiments,

[0262] Cy1 is unsubstituted, or substituted by 1-3 R a1 substituents

[0263] The compound, its isomer or its pharmaceutically acceptable salt according to any one of the embodiments,

[0264] Cy1 is unsubstituted or substituted by 1 - 3 R a1 substituted

[0265] the compound, its isomer or its pharmaceutically acceptable salt according to any one of the embodiments,

[0266] Cy1 is unsubstituted or substituted by 1 - 3 R a1 substituted

[0267] the compound, its isomer or its pharmaceutically acceptable salt according to any one of the embodiments,

[0268] Cy1 is unsubstituted or substituted by 1 - 3 R a1 substituted

[0269] the compound, its isomer or its pharmaceutically acceptable salt according to any one of the embodiments,

[0270] Cy1 is unsubstituted or substituted by 1 - 3 R a1 substituted

[0271] In another embodiment of the present invention, the compound represented by formula (i) has the structure shown below:

[0272]

[0273] wherein, Y is selected from N or CR a2 ; X, L 1 , Cy1, R a2 have the definitions described above.

[0274] In another embodiment of the present invention, the compound represented by formula (i - 1) has the structure shown below:

[0275]

[0276] wherein, Y is selected from N or CR a2 ; X, L 1 , Cy1, R a2 have the definitions described above.

[0277] In another embodiment of the present invention, the compound represented by formula (i) has the structure shown below:

[0278]

[0279] wherein, Z 1 and Z 2 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 as described above.

[0280] In another embodiment of the present invention, the compound represented by formula (i-2) has the structure shown below:

[0281]

[0282] 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 、R a1 、R a5 have the definitions as described above.

[0283] In some embodiments of the present invention, the compounds, their isomers or their pharmaceutically acceptable salts as described in formula (i) above are shown in the following table:

[0284] Table 1

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293] Table 2

[0294]

[0295]

[0296]

[0297] Table 3

[0298]

[0299] Table 4

[0300]

[0301]

[0302]

[0303] Table 5

[0304]

[0305]

[0306] Table 6

[0307]

[0308]

[0309]

[0310]

[0311] Table 7

[0312]

[0313] The present invention also provides a pharmaceutical composition, which comprises the compound of formula (i), its isomers or its pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0314] The present invention also provides the use of the compound of formula (i), its isomers or its pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of a medicament for treating and / or preventing a disease or disorder by degrading a target protein.

[0315] 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.

[0316] 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 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, schwannoma, thyroid cancer, Wilms tumor, and teratocarcinoma; more preferably selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, and fallopian tube tumor.

[0317] According to an embodiment of the present invention, the infectious disease is selected from viral pneumonia, influenza, avian influenza, meningitis, gonorrhea, or diseases infected with HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, flavivirus, prion virus, 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, Mycoplasmataceae, fungi, protozoa, intestinal worms, helminths, prions, or parasites.

[0318] The present invention also provides the use of the compound of formula (i), its isomer, or its pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of a drug for treating and / or preventing estrogen receptor-mediated or -dependent diseases or disorders, wherein the estrogen receptor-mediated or -dependent diseases or disorders are tumors, preferably cancer, more preferably selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, and fallopian tube tumor, and most preferably breast cancer.

[0319] The present invention also provides a method for treating and / or preventing a disease or disorder by degrading a target protein, comprising administering to a patient a therapeutically effective amount of the compound of formula (i), its isomer, or its pharmaceutically acceptable salt.

[0320] The present invention also provides a method for treating and / or preventing estrogen receptor-mediated or -dependent diseases or disorders, comprising administering to a patient a therapeutically effective amount of the compound of formula (i), its isomer, or its pharmaceutically acceptable salt.

[0321] Beneficial effects

[0322] The present invention provides a compound represented by formula (i), its isomers or pharmaceutically acceptable salts thereof, which can be used as estrogen receptor degradants for preparing drugs for treating and / or preventing estrogen receptor-mediated or -dependent diseases or disorders. Description of the Drawings

[0323] Figure 1 Shows the ER protein degradation effect of compound IV-9 on MCF-7 cells;

[0324] Figure 2 Shows the ER protein degradation effect of compound VI-20 on MCF-7 cells;

[0325] Figure 3 Shows the ER protein degradation effect of compound VI-23 on MCF-7 cells;

[0326] Figure 4 Shows the ER protein degradation effect of compound VI-24 on MCF-7 cells;

[0327] Figure 5 Shows the ER protein degradation effect of compound VI-29 on MCF-7 cells;

[0328] Figure 6 Shows the ER protein degradation effect of compound VI-28 on MCF-7 cells.

[0329] Term Definitions and Explanations

[0330] Unless otherwise specified, the group and term definitions described in the specification and claims of this application, including their definitions by way of example, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be combined and combined with each other arbitrarily. The group definitions and compound structures after such combination and combination should be understood to be within the scope described in the specification and / or claims of this application.

[0331] The "halogen" as used in the present invention refers to fluorine, chlorine, bromine, iodine, etc., preferably fluorine and chlorine.

[0332] The "halogenated" as used in the present invention means that any hydrogen atom in the substituent can be substituted by one or more identical or different halogen atoms. "Halogen" is defined as above.

[0333] The "C" as used in the present invention 1-6"Alkyl" refers to a straight-chain or branched alkyl group derived by removing one hydrogen atom from a hydrocarbon moiety containing 1 to 6 carbon atoms, 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 C 1-4 alkyl, C 1-3 alkyl.

[0334] The "C 2-8 alkenyl" as used in the present invention refers to a straight-chain, branched-chain or cyclic alkenyl group derived by removing one hydrogen atom from an olefin moiety containing 2 to 8 carbon atoms and having a carbon-carbon double bond, such as vinyl, 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, 1,4-hexadienyl.

[0335] The "C 2-8 alkynyl" as used in the present invention refers to a straight-chain or branched-chain alkynyl group derived by removing one hydrogen atom from an alkyne moiety containing 2 to 8 carbon atoms and having a carbon-carbon triple bond, 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, C 2-3 alkynyl.

[0336] The "C 1-6 alkoxy" as used in 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., the "C 1-6 alkyl-O-" group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, neopentyloxy, and n-hexyloxy, etc. The "C 1-6 alkoxy" is preferably C 1-4 alkoxy, C 1-3 alkoxy.

[0337] 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", "hydroxyC 1-6 alkyl" respectively 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)N-C(O)-, C 1-6 alkyl-O-C(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".

[0338] The "fused ring" as used in the present invention refers to a polycyclic system structure formed by connecting two or more cyclic structures in a fused, spiro or bridged manner. Each cyclic structure refers to any monocyclic alkyl group, monocyclic heterocyclic group, monocyclic alkenyl group, phenyl group, monocyclic heteroaryl group. The fused ring refers to a fused ring structure formed by two or more cyclic structures sharing two adjacent ring atoms (i.e., sharing one bond). The bridged ring refers to a fused ring structure formed by two or more ring structures sharing two non-adjacent ring atoms. The spiro ring refers to a fused ring structure formed by two or more cyclic structures sharing one ring atom. The multiple cyclic structures are optionally connected by fused, spiro and bridged methods.

[0339] Two cyclic structures connected in a fused, spiro or bridged manner form a bicyclic fused ring group, such as a 6-13 membered bicyclic fused ring group. The 6-13 membered bicyclic fused ring group further includes a 6-13 membered bicyclic fused ring alkyl group, a 6-13 bicyclic fused ring alkenyl group, a 6-13 membered bicyclic fused heterocyclic group, an 8-13 membered bicyclic fused heteroaryl group, an 8-13 membered bicyclic fused aryl group.

[0340] Two or more cyclic structures connected by fusion, spiro or bridge linkages form a polycyclic fused ring group. For example, a monocyclic structure is connected to a 6- to 13-membered bicyclic fused ring group by fusion, spiro or bridge linkages, such as an 8- to 21-membered polycyclic fused ring group. The 8- to 21-membered polycyclic fused ring group further includes an 8- to 21-membered polycyclic fused cycloalkyl group, an 8- to 21-membered polycyclic fused cycloalkenyl group, an 8- to 21-membered polycyclic fused heterocyclic group, an 8- to 21-membered polycyclic fused heteroaryl group, and an 8- to 21-membered polycyclic fused aryl group.

[0341] The 8- to 21-membered polycyclic fused heterocyclic group includes an 8- to 21-membered polycyclic bridged heterocyclic group, an 8- to 21-membered polycyclic fused heterocyclic group, and an 8- to 21-membered polycyclic spiro heterocyclic group.

[0342] Examples of the 8- to 21-membered polycyclic fused heterocyclic group include, but are not limited to

[0343] The 3- to 8-membered monocyclic group described in the present invention includes a monocyclic alkyl group, a monocyclic heterocyclic group, a monocyclic alkenyl group, a monocyclic heteroaryl group, and a phenyl group.

[0344] The monocyclic alkyl group is a cycloalkyl group containing 3 to 13 carbon atoms, including a 3- to 13-membered cycloalkyl group, a 3- to 8-membered cycloalkyl group, a 4- to 7-membered cycloalkyl group, a 4- to 6-membered cycloalkyl group, and a 5- to 6-membered cycloalkyl group. Examples of the 3- to 8-membered cycloalkyl group include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

[0345] A monocyclic hetero 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 1-3 heteroatoms. The monocyclic hetero group can be saturated or partially saturated, including 3- to 13-membered hetero cyclic groups, 3- to 8-membered hetero cyclic groups, 3- to 6-membered hetero cyclic groups, 4- to 6-membered hetero cyclic groups, 4- to 7-membered hetero cyclic groups, 5- to 7-membered hetero cyclic groups, 5- to 6-membered hetero cyclic groups, 4- to 6-membered nitrogen-containing hetero cyclic groups, 5- to 6-membered oxygen-containing hetero cyclic groups, 3- to 8-membered nitrogen-containing hetero cyclic groups, 5- to 6-membered nitrogen-containing hetero cyclic groups, 5- to 6-membered saturated hetero cyclic groups, etc. Examples of the "3- to 8-membered saturated hetero cyclic group" include, but are not limited to, aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, 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-oxathianyl; Examples of the "3- to 8-membered partially saturated hetero cyclic group" include, but are not limited to, 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2,5-dihydrooxazolyl, 2,3-dihydrooxazolyl, 3,4-dihydro-2H-pyrrolyl, 2,3-dihydro-1H-pyrrolyl, 2,5-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-tetrahydropyridyl, 1,2-isoxazinyl, 1,4-isoxazinyl, or 6H-1,3-oxazinyl, etc.

[0346] A monocyclic alkenyl group refers to a partially saturated carbocyclic group, including 3- to 13-membered cycloalkenyl groups, 3- to 8-membered cycloalkenyl groups, 4- to 7-membered cycloalkenyl groups, and 5- to 6-membered cycloalkenyl groups.

[0347] The heteroaryl group described in 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 monocyclic heteroaryl group can be a 5- to 7-membered heteroaryl group or a 5- to 6-membered heteroaryl group. Examples include, but are not limited to, furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thienyl, triazolyl, and triazinyl.

[0348] The 6-13 bicyclic fused cycloalkyl groups include fused cycloalkyl groups, bridged cycloalkyl groups, and spirocycloalkyl groups. They can be saturated, partially saturated, or unsaturated, but not aromatic. The fused cycloalkyl groups can be 6-11 membered fused cycloalkyl groups, 7-10 membered fused cycloalkyl groups, and representative examples thereof 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 spiro groups can be 7-12 membered spiro groups, 7-11 membered spiro groups, 10-11 membered spiro groups, and examples thereof include, but are not limited to: The bridged cycloalkyl groups can be 6-11 membered bridged cycloalkyl groups, 7-10 membered bridged cycloalkyl groups, and examples thereof include, but are not limited to:

[0349] The 6-13 bicyclic fused cycloalkenyl groups include fused cycloalkenyl groups, bridged cycloalkenyl groups, and spirocycloalkenyl groups. Representative examples of the 6-13 membered bicyclic fused cycloalkenyl groups include, but are not limited to

[0350] The 6-13 membered bicyclic fused heterocyclic groups include fused heterocyclic groups, spiro heterocyclic groups, and bridged heterocyclic groups, and can be saturated, partially saturated, or unsaturated, but not aromatic. The fused heterocyclic groups are 5-6 membered monocyclic heterocyclic groups fused to a benzene ring, 5-6 membered monocyclic cycloalkyl group, 5-6 membered monocyclic cycloalkenyl group, 5-6 membered monocyclic heterocyclic group, or 5-6 membered monocyclic heteroaryl group. The fused heterocyclic groups can be 6-12 membered fused ring groups, 7-10 membered fused ring groups, 6-10 membered fused ring groups, 8-10 membered bicyclic fused heterocyclic groups, 6-12 membered saturated fused ring groups, and representative examples thereof include, but are not limited to: 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.2.0]heptyl, 3,8-diazabicyclo[4.2.0]octyl, 3,7-diazabicyclo[4.2.0]octyl, 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, dihydroindol-1-yl, dihydroindol-2-yl, dihydroindol-3-yl, 2,3-dihydrobenzothiophen-2-yl, octahydro-1H-indolyl, octahydrobenzofuranyl. The spiro heterocyclic groups can be 6-12 membered spiro heterocyclic groups, 7-11 membered spiro heterocyclic groups, 6-12 membered saturated spiro ring groups, 10-11 membered bicyclic spiro heterocyclic groups, and examples thereof include, but are not limited to:

[0351] The bridged heterocyclic group described above can 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 include, but are not limited to:

[0352] An 8-13 membered bicyclic fused heteroaryl group refers to a group formed by fusing a monocyclic heteroaryl ring to a phenyl group or a monoheteroaryl group. The fused heteroaryl group can be an 8-13 membered fused heteroaryl group, a 9-10 membered fused heteroaryl group, or an 8-10 membered bicyclic fused heteroaryl group. Examples include, but are not limited to

[0353]

[0354] An 8-13 membered bicyclic fused aryl group refers to a group formed by fusing a monoaryl ring to a monoaryl group, including naphthalene, phenanthrene, etc.

[0355] The "pharmaceutically acceptable salts" described in the present invention refer to addition salts of pharmaceutically acceptable acids and bases or their solvates. 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 acids (such as acetic acid, HOOC-(CH 2 )n-COOH (where n is 0 to 4)), etc. Salts of bases: sodium salts, potassium salts, calcium salts, ammonium salts, etc. Those skilled in the art are aware of a variety of non-toxic pharmaceutically acceptable addition salts.

[0356] The "isomers" described in the present invention refer to stereoisomers and tautomers.

[0357] Stereoisomers refer to enantiomers that are generated when a compound has an asymmetric atom; cis-trans isomers are generated when a compound has a double bond or a cyclic structure; all enantiomers, diastereomers, racemates, cis-trans isomers, geometric isomers, epimers, and mixtures thereof of the compounds of formula (I) are included within the scope of the present invention.

[0358] "Tautomers" refer to functional group isomers generated due to the rapid movement of a certain 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 For other proton transfer tautomers, specifically such as phenol-ketone tautomerism, nitroso-oxime tautomerism, imine-enamine tautomerism.

[0359] T, T1, and T2 are each independently any group that conforms to the bonding rules of the compound.

[0360] R described in the present invention a2 and R a4, when conforming to the bonding rules, it can be optionally connected to L2, L3, L4 or L5. Detailed implementation manners

[0361] The technical solutions of the present disclosure will be further described in detail below in combination with specific embodiments. It should be understood that the following embodiments are only used to illustrate and explain the present disclosure exemplarily, and should not be construed as limiting the protection scope of the present disclosure. All technologies implemented based on the above content of the present disclosure are covered within the scope of protection intended by the present disclosure.

[0362] Unless otherwise specified, the raw materials and reagents used in the following embodiments are all commercially available products, or can be prepared by known methods.

[0363] Abbreviations of some reagents

[0364] BnBr, benzyl bromide

[0365] TIPT, titanium tetraisopropoxide

[0366] STAB, sodium triacetoxyborohydride

[0367] TBAF, tetrabutylammonium fluoride

[0368] NMO, N-methylmorpholine N-oxide

[0369] TPAP, tetrapropylammonium perruthenate

[0370] 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

[0371] Xphos-Pd-G2, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0372] Pd(dppf)Cl2, 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II)

[0373] Mn(TMHD)3, tris(2,2,6,6-tetramethyl-3,5-heptanedionate)manganese

[0374] PhSiH3, phenylsilane

[0375] PMBCl, methoxybenzyl chloride

[0376] The individual specific compound structures 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:

[0377]

[0378] Step 1: Using the aldehyde compound int-1 and the amino compound int-2 as starting materials, through reductive amination, the intermediate int-3 is obtained.

[0379] Step 2: The intermediate int-3 is further reduced by hydrogenation to obtain the final product compound.

[0380] In the above general formula, X is selected from N or CH;

[0381] Y 1 、Y 2 and Y 3 are each independently selected from N, NR a1 , CR a1 , C(R a1 ) 2 or C(O);

[0382] M is selected from N or CR a2 ;

[0383] refers to a single bond or a double bond that conforms to the bonding rules.

[0384] The above general formulas int-1, int-2, int-3 and compound may be further substituted by substituents, and the range of substituents is the same as that described in any embodiment of the specification.

[0385] 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)

[0386]

[0387] Step 1: Synthesis of 6-methoxy-2-phenyl-3,4-dihydronaphthalen-1(2H)-one

[0388]

[0389] At room temperature, toluene (750 mL), potassium tert-butoxide (75.60 g, 673.73 mmol), palladium acetate (7.8 g, 34.74 mmol), and 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (25.8 g, 41.43 mmol) were successively added to a single-necked flask and stirred evenly. 6-Methoxy-1-tetralone (60 g, 340.5 mmol) and bromobenzene (53.4 g, 340.5 mmol) were added again, and the mixture was heated to 100 °C and reacted for 3 h. After cooling to room temperature, the reaction was quenched with saturated ammonium chloride solution (500 mL), and extracted with methyl tert-butyl ether (500 mL × 3). The organic phases were combined and washed successively with saturated brine and water. Dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: ethyl acetate / petroleum ether = 0 - 15%), obtaining 51 g of 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(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] + .

[0390] Step 2: Synthesis of 4-bromo-7-methoxy-3-phenyl-1,2-dihydronaphthalene

[0391]

[0392] 6-Methoxy-2-phenyl-3,4-dihydronaphthalen-1(2H)-one (51 g, 202.2 mmol) and toluene (800 mL) were added to a 500 mL flask and stirred until completely dissolved. A solution of phosphorus tribromide (108 g, 398.9 mmol) in toluene (400 mL) was slowly added, and the mixture was heated to reflux. After reacting for 24 h, most of the toluene was distilled off. After cooling, 1000 mL of dichloromethane was added, and it was washed once with 500 mL of saturated sodium bisulfite and once with water. Dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: dichloromethane / petroleum ether = 0 - 30%), obtaining 42 g of white solid with a yield of 66%.

[0393] Step 3: Synthesis of 4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenol

[0394]

[0395] The compound 4-bromo-7-methoxy-3-phenyl-1,2-dihydronaphthalene (42 g, 133.2 mmol), 4-hydroxybenzeneboronic acid (23.85 g, 172.9 mmol), tetrakis(triphenylphosphine)palladium(0) (5.13 g, 4.4 mmol) and tetrahydrofuran (600 ml) were added to a 2 L three-necked flask, and an aqueous solution (200 mL) of sodium carbonate (42.34 g, 399.4 mmol) was added. The mixture was stirred and heated to reflux for 18 h. After cooling, it was adjusted to obvious stratification with dilute hydrochloric acid, and the layers were separated. The aqueous layer was extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed successively with saturated sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: dichloromethane / petroleum ether = 0 - 30%), obtaining 30.4 g of a 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).

[0396] Step 4: Synthesis of 4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenol

[0397]

[0398] At room temperature, methanol (250 ml), tetrahydrofuran (250 ml), 20% palladium hydroxide on carbon (13 g), and 4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenol (26.94 g, 82.03 mmol) were successively added to a 1 L autoclave, and the autoclave was sealed. The nitrogen was replaced once and hydrogen three times, and finally the pressure under hydrogen was controlled to be 3 MPa, and it 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 an off-white solid with a yield of 100%. 1 H NMR(400MHz,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),3.12–2.91(m,2H),2.12(qd,J=12.6,6.1Hz,1H),1.73(dd,J=13.0,6.1Hz,1H).

[0399] Step 5: Preparation of 4-((1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenol

[0400]

[0401] 4-((1R,2S)-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 of absolute configuration B peak, 0.05 g of white solid, with a yield of 35%.

[0402] Separation and preparation method:

[0403] Instrument: WATERS SFC-350

[0404] Chromatographic column: CHIRALPAK IA 5 cm × 25 cm, 5 μm

[0405] Mobile phase: A is CO2, B is IPA

[0406] Wavelength: 220 nm

[0407] Flow rate: 200 ml / min

[0408] Solvent: MeOH, DCM

[0409] Gradient condition: B: 50%

[0410] Cycle time: 11 min

[0411] Column temperature: 35 °C

[0412] Separation and detection method:

[0413] Instrument: WATERS ACQUITY UPC 2

[0414] Chromatographic column: Lux 3u-Cellulose-3 4.6×50mm, 3um

[0415] Mobile phase: A is CO2, B is MeOH(0.1%DEA)

[0416] Wavelength: 220nm

[0417] Column temperature: 35℃

[0418] Flow rate: 4ml / min

[0419] Injection volume: 1uL

[0420] Injection concentration: 1mg / ml

[0421] Solvent: MeOH

[0422] Gradient condition: B: 10% to 50% in 2min, hold 1min at 50%

[0423] Running time: 3min

[0424] Retention time: 0.972min, 1.095min

[0425] 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-nonafluorobutane-1-sulfonate

[0426]

[0427] At room temperature, 4-((1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenol (22.00 g, 66.58 mmol), perfluorobutanesulfonyl 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 successively added to a single-necked flask. The reaction was terminated after 20 h at room temperature 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%. 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

[0428]

[0429] 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-dicyclohexylphosphino-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 the reaction was carried out at 95 °C for 4 hours under nitrogen protection. The reaction was monitored by TLC until completion. After cooling to room temperature, the reaction mixture was poured into ice water, extracted with EA, the organic phase was concentrated, triturated, and column chromatography was performed using PE / EA (0 - 8%) to obtain 4.7 g of a brown oil, with a yield of 78%. Step 8: Synthesis of (5R,6S)-6-phenyl-5-(4-(piperazin-1-yl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol

[0430]

[0431] 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 the addition was complete, the mixture was allowed to warm to room temperature overnight. The reaction was quenched by dropwise addition of methanol, concentrated, and purified by silica gel column chromatography to obtain 1.7 g of a yellow solid, with a yield of 73%. MS(ESI) m / z: 385.2 [M+H] + .

[0432] 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

[0433]

[0434] 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 mixture was stirred for 2 hours, the reaction solution was evaporated to dryness, EA / NaHCO 3 aqueous solution was added, the pH was adjusted to 8, the layers were separated, and the organic phase was concentrated to obtain 0.36 g of a white solid, with a yield of 75%. MS(ESI) m / z: 485.2 [M+H] + .

[0435] 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

[0436]

[0437] 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), and acetonitrile (2 L) were successively added to a reaction flask. BnBr (89.28 g, 0.52 mol) was added dropwise. The reaction was carried out at 60 °C for 18 h. After cooling to room temperature, the reaction solution was added to water for crystallization and filtration. The filter cake was slurried with methanol and filtered to obtain 247.90 g of the product with a yield of 95%.

[0438] Step 11: Synthesis of 1-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine hydrochloride

[0439]

[0440] 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 successively added to a reaction flask. The reaction was carried out at room temperature for 2 h. After completion of the reaction, filtration was carried out to obtain 235.65 g of the product with a yield of 100%.

[0441] 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

[0442]

[0443] 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 successively added to a reaction flask. TIPT (50 mL) was added, and the mixture was stirred at room temperature for 16 hours. Then STAB (31.00 g, 146.74 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, it was filtered, the filter cake was slurried with dichloromethane twice, the organic phases were combined, concentrated by evaporation, and slurried with methanol to obtain 74.00 g of the product, yield: 90%.

[0444] 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

[0445]

[0446] 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 successively added to a reaction flask, and the reaction was stirred at 50 °C for 4 h. After the reaction was completed, it was concentrated by evaporation, dichloromethane and water were added for liquid separation, the organic phase was dried and concentrated by evaporation, and slurried with methanol to obtain 45.00 g of the product, yield: 85%.

[0447] 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

[0448]

[0449] 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) was successively added to a reaction flask. Molecular sieve (45 g, 100% w / w), NMO (13.16 g, 112.34 mmol) and DCM (450 mL), then TPAP (2.63 g, 7.49 mmol) was added and the reaction was carried out at room temperature for 12 h. After the reaction was completed, it was filtered, water was added for liquid separation, the organic phase was dried and concentrated by rotary evaporation, and column chromatography (MeOH / DCM system) was carried out to obtain 40.00 g of the product, yield: 89%.

[0450] 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

[0451]

[0452] 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 successively added to the reaction flask. Nitrogen was displaced 3 - 4 times, and the temperature was raised to 100 °C for reaction for 15 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, liquid separation was carried out, and after the organic phase was dried, column chromatography was carried out using the PE / EA system to obtain 0.14 g of the product, yield 44%.

[0453] Step 16: Synthesis of 1-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0454]

[0455] 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 successively added to the reaction flask. After dissolution, hydrochloric acid / dioxane (4 ml) was added, and the reaction was stirred at room temperature for 3 h. After the reaction was completed, the solvent was removed to obtain 0.11 g of the crude product, which was directly used in the next step.

[0456] 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

[0457]

[0458] At room temperature, 1-(5-fluoro-1-methyl-6-(piperazin-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)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.19 g, 0.31 mmol) and dichloromethane (10 ml) were successively added to a reaction flask, then TIPT (0.5 ml) was added, and the mixture was stirred at room temperature for 16 hours. Then STAB (0.13 g, 0.62 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, it was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, the solvent was removed, and column chromatography was carried out using the DCM / MeOH system to obtain 0.20 g of the product, yield: 63%.

[0459] 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

[0460]

[0461] 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-indazole-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 successively added to a reaction flask. After replacing hydrogen 3 - 4 times, the mixture was stirred at room temperature for 24 h. After the reaction was completed, it was filtered through diatomaceous earth. The filter cake was rinsed with tetrahydrofuran, and the filtrate was concentrated by evaporation. Column chromatography using a DCM / MeOH system was carried out to obtain 0.07 g of the product, with a yield of 39%.

[0462] 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),3.31–3.21(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] + .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)

[0463]

[0464] The synthetic 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 refers to Example 1.

[0465] Step 1: Synthesis of 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate

[0466]

[0467] At room temperature, 3-hydroxy-1-(4-methoxybenzyl)piperidine-2,6-dione (4.00 g, 16.05 mmol) and dichloromethane (50 ml) were successively added to the reaction flask. After dissolution and clarification, the temperature was lowered to -10 °C, and trifluoromethanesulfonic anhydride (6.80 g, 24.07 mmol) was slowly added while controlling the temperature. After addition, the reaction was carried out at 0 °C for 2 hours. After the reaction was completed, the solvent was directly removed by evaporation, and column chromatography was carried out using a PE / EA system to obtain 4.41 g of the product, with a yield of 72%.

[0468] Step 2: Synthesis of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

[0469]

[0470] At room temperature, 7-bromo-1-methyl-1,3-dihydro-2H-benzoimidazol-2-one (1.00 g, 3.61 mmol), potassium tert-butoxide (0.49 g, 4.33 mmol) and tetrahydrofuran (20 ml) were successively added to the reaction flask. 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. After addition, the reaction was carried out at room temperature for 3 h. After the reaction was completed, ethyl acetate and water were added, and the layers were separated. The organic layer was dried and then column chromatography was carried out using a PE / EA system to obtain 1.48 g of the product, with a yield of 90%.

[0471] 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

[0472]

[0473] At room temperature, 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (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 successively added to a reaction flask. Nitrogen was displaced 3 - 4 times, and the temperature was raised to 100 °C for reaction for 15 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, and liquid separation was carried out. After the organic phase was dried, column chromatography using a PE / EA system was performed to obtain 0.41 g of the product with a yield of 45%. Step 4: Synthesis of 3-(3-methyl-2-oxo-4-(piperazin-1-yl)-2,3-dihydro-1H-benzoimidazol-1-yl)piperidine-2,6-dione

[0474]

[0475] 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 successively added to a reaction flask. The temperature was raised to 65 °C and stirred for reaction for 2 h. After the reaction was completed, the solvent was removed, and column chromatography using a reverse column chromatography (acetonitrile / water) system was performed to obtain 0.10 g of the crude product, which was directly used for the next step.

[0476] 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

[0477]

[0478] At room temperature, 3-(3-methyl-2-oxo-4-(piperazin-1-yl)-2,3-dihydro-1H-benzoimidazol-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)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.13 g, 0.21 mmol) and dichloromethane (10 ml) were successively added to a reaction flask, then TIPT (0.5 ml) was added, and the mixture was stirred at room temperature for 16 hours. Then STAB (0.09 g, 0.42 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, it was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, the solvent was removed, and column chromatography was carried out using the DCM / MeOH system to obtain 0.11 g of the product with a yield of 58%.

[0479] 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

[0480]

[0481] 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 successively added to a reaction flask, and then hydrogen was displaced 3 - 4 times, and the reaction was stirred at 30 °C for 16 h. After the reaction was completed, it was filtered through diatomaceous earth, the filter cake was washed with tetrahydrofuran, the filtrate was concentrated, and column chromatography was carried out using the DCM / MeOH system to obtain 0.030 g of the product (0.026 g was put into storage), with a yield of 29%. 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] + .

[0482] 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)

[0483]

[0484] (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 was synthesized according to the method of Example 1.

[0485] 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

[0486]

[0487] 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 successively added to a reaction flask. Nitrogen was displaced 3 - 4 times, and the temperature was raised to 80 °C for reaction for 4 h. After the reaction was completed, the temperature was lowered to room temperature, the solvent was removed, diluted with ethyl acetate, filtered through diatomaceous earth, and after the filtrate was dried, the solvent was removed. Column chromatography using a PE / EA system gave 0.25 g of the product with a yield of 78%.

[0488] 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

[0489]

[0490] At room temperature, tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.25 g, 0.57 mmol) and tetrahydrofuran (15 ml) were successively added to a reaction flask. 10% palladium on carbon (0.03 g) was added, hydrogen was displaced 3 - 4 times, and the reaction was stirred at room temperature for 16 h. After the reaction was completed, it was filtered through diatomaceous earth and the solvent was removed to obtain 0.25 g of the product, which was directly used in the next step.

[0491] Step 3: Synthesis of 1-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0492]

[0493] 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 successively added to a reaction flask. After it was dissolved clearly, hydrochloric acid / dioxane (9 ml) was added, and the reaction was stirred at room temperature for 3 h. After the reaction was completed, the solvent was removed to obtain 0.19 g of the crude product, which was directly used in the next step.

[0494] 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)pyrimidine-2,4(1H,3H)-dione

[0495]

[0496] At room temperature, 1-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)pyrimidine-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 successively added to a reaction flask. Then TIPT (0.5 ml) was added, and the mixture was stirred at room temperature for 16 hours. Then STAB (0.19 g, 0.91 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, it was filtered. The filter cake was slurried twice with dichloromethane, the organic phases were combined, the solvent was removed, and column chromatography was carried out using the DCM / MeOH system to obtain 0.27 g of the product, yield: 58%.

[0497] 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)pyrimidine-2,4(1H,3H)-dione

[0498]

[0499] 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 successively added to a reaction flask. After replacing hydrogen 3 - 4 times, the mixture was stirred at room temperature for 24 h. After the reaction was completed, it was filtered through diatomaceous earth. The filter cake was washed with tetrahydrofuran, and the filtrate was concentrated by evaporation. Column chromatography was performed using a DCM / MeOH system to obtain 0.135 g of the product (0.130 g was stored in the warehouse), and the yield was 54%.

[0500] 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),1.73–1.64(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] + .

[0501] 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)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)benzamide (Compound I-69)

[0502]

[0503] (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 was synthesized according to Example 1.

[0504] Step 1: Synthesis of tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[0505]

[0506] 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 successively added to the reaction flask. Nitrogen was displaced 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, the filtrate was concentrated, and column chromatography was carried out using the PE / EA system to obtain 2.50 g of the product as a brown oil, with a yield of 83%.

[0507] Step 2: Synthesis of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid

[0508]

[0509] 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 successively added to the reaction flask. The temperature was raised to 50 °C for reaction for 4 h. After the reaction was completed, the solvent was removed, and the solution was adjusted to acidic with HCl aqueous solution. The product precipitated out, and 2.20 g of white solid was obtained by filtration, with a yield of 92%.

[0510] Step 3: Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazine-1-carboxylate

[0511]

[0512] At room temperature, 4-(4-(tert-butoxycarbonyl)piperazin-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 successively added to a reaction flask, 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, a large amount of solid was precipitated, filtered, and the filter cake was dissolved in DCM, dried over anhydrous magnesium sulfate and directly subjected to the next step.

[0513] Step 4: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide

[0514]

[0515] 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 successively added to a reaction flask. After dissolution and clarification, hydrochloric acid / dioxane (2 mL) was added, 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 crude product, which was directly subjected to the next step.

[0516] 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

[0517]

[0518] At room temperature, N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-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)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.28 g, 0.47 mmol) and dichloromethane (5 mL) were successively added to a reaction flask, then TIPT (0.5 mL) was added, and the mixture was stirred at room temperature for 16 hours. Then STAB (0.15 g, 0.71 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, it was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.21 g of the product, and the three-step yield was 62%.

[0519] 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)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)benzamide

[0520]

[0521] 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 successively added to a reaction flask, the hydrogen was displaced 3 - 4 times, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, it was filtered through diatomaceous earth, the filter cake was washed with THF, the filtrate was concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.07 g of the product, and the yield was 37%.

[0522] 1 H NMR(400MHz,DMSO-d 6)δ 10.86 (s, 1H), 9.12 (s, 1H), 8.05 (t, J = 7.2 Hz, 1H), 7.62 (t, J = 9.0 Hz, 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 = 8.3 Hz, 2H), 4.73 (dt, J = 12.9, 6.8 Hz, 1H), 4.14 (d, J = 4.9 Hz, 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] + .

[0523] 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)

[0524]

[0525] (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 was synthesized according to the method of Example 1.

[0526] Step 1: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole

[0527]

[0528] 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-dioxolane-2-yl)pyridine (1.24 g, 2.97 mmol), sodium carbonate (0.94 g, 8.90 mmol), tetrakis(triphenylphosphine)palladium(0) (0.34 g, 0.30 mmol), water (1 mL) and dioxane (10 mL) were successively added to a reaction flask. Under a nitrogen atmosphere at 90 °C, the reaction was carried out for 5 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, and the layers were separated. After the organic phase was dried, column chromatography using a PE / EA system was carried out to obtain 1.20 g of the product with a yield of 81%.

[0529] Step 2: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

[0530]

[0531] 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 in toluene solution (200 mg, 0.10 mmol), sodium tert-butoxide (0.10 g, 1.00 mmol) and toluene (10 mL) were successively added to a reaction flask. Under a nitrogen atmosphere at 100 °C, the reaction was carried out for 5 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, and the layers were separated. After the organic phase was dried, column chromatography using a PE / EA system was carried out to obtain 0.20 g of the product with a yield of 66%.

[0532] Step 3: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

[0533]

[0534] 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 successively added to a reaction flask. The reaction was carried out at room temperature for 24 h. After the reaction was completed, the mixture was filtered and concentrated by rotary evaporation to obtain 0.13 g of the crude product, which was directly used in the next step.

[0535] Step 4: Synthesis of 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperazine-2,6-dione

[0536]

[0537] 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 successively added to a reaction flask, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the solvent was evaporated to dryness to obtain 0.11 g of crude product, which was directly used in the next step.

[0538] 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

[0539]

[0540] 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 successively added to a reaction flask, then TIPT (0.5 ml) was added, and the mixture was stirred at room temperature for 16 h. Then STAB (0.08 g, 0.36 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the mixture was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, the solvent was removed, and column chromatography was carried out using the DCM / MeOH system to obtain 0.03 g of the product, with a yield of 27%.

[0541] 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

[0542]

[0543] 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 successively added to a reaction flask. After replacing hydrogen 3 - 4 times, the mixture was stirred at 30 °C for 16 h. After completion of the reaction, it was filtered through diatomaceous earth. The filter cake was washed with tetrahydrofuran, and the filtrate was concentrated by evaporation. Column chromatography was carried out using a DCM / MeOH system to obtain 0.01 g of the product, with a yield of 37%.

[0544] 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=8.2Hz,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

[0545] [M+H] + .

[0546] 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)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-2)

[0547]

[0548] (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 was synthesized according to Example 1.

[0549] 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

[0550]

[0551] 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 successively added to the reaction flask. Nitrogen was displaced 3 - 4 times, and the temperature was raised to 100 °C for reaction for 5 h. After the reaction was completed, the temperature was lowered to room temperature, concentrated, and column chromatography was carried out using the PE / EA system to obtain 0.45 g of a brown oil, with a yield of 68%.

[0552] 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

[0553]

[0554] 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 successively added to the reaction flask. After dissolution, hydrochloric acid / dioxane (2 ml) was added, and the reaction was stirred at room temperature for 3 h. After the reaction was completed, the solvent was removed to obtain 0.30 g of a crude product, which was directly used for the next step.

[0555] 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)phenyl)piperazin-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

[0556]

[0557] 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 successively added to a reaction flask, then TIPT (0.45 ml) was added, and the mixture was stirred at room temperature for 16 hours. Then STAB (0.14 g, 0.66 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, it was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, the solvent was removed, and column chromatography was carried out using a DCM / MeOH system to obtain 0.11 g of the product, and the two-step yield was 23%.

[0558] 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)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

[0559]

[0560] At room temperature, 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)-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 successively added to a reaction flask, the hydrogen was replaced 3 - 4 times, and the reaction was stirred at 25 °C for 24 h. After the reaction was completed, it was filtered through diatomaceous earth, the filter cake was washed with THF, the filtrate was concentrated, and column chromatography was carried out using a DCM / MeOH system to obtain 0.01 g of the product, and the yield was 11%.

[0561] 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.16 (s, 1H), 7.11 (dd, J = 11.4, 6.9 Hz, 3H), 6.95 (d, J = 8.6 Hz, 1H), 6.82 (d, J = 8.6 Hz, 3H), 6.63–6.48 (m, 6H), 6.22 (d, J = 8.0 Hz, 2H), 5.76 (s, 3H), 5.30 (dd, J = 12.7, 5.5 Hz, 1H), 4.14 (d, J = 5.0 Hz, 1H), 3.14 (s, 2H), 3.04 (s, 2H), 2.94 (dd, J = 17.2, 9.0 Hz, 5H), 2.76–2.56 (m, 10H), 2.30 (d, J = 26.0 Hz, 2H), 2.09 (dd, J = 12.9, 6.7 Hz, 2H), 1.98 (d, J = 10.8 Hz, 2H), 1.87–1.40 (m, 10H), 1.21 (s, 2H), 0.99 (d, J = 13.1 Hz, 2H). MS (ESI) m / z: 837.0 [M+H] + .

[0562] 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)

[0563]

[0564] (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 was synthesized according to the method of Example 1.

[0565] Step 1: Synthesis of methyl tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate

[0566]

[0567] At room temperature, methyl 5-bromopyridine-2-carboxylate (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), the 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, the filtrate was concentrated, and column chromatography was carried out using the PE / EA system to obtain 2.50 g of the product as a brown oil, with a yield of 83%.

[0568] Step 2: Synthesis of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinate

[0569]

[0570] At room temperature, methyl tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)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 successively added to the reaction flask, and the temperature was raised to 50 °C for reaction for 4 h. After the reaction was completed, the solvent was removed, the solution was adjusted to acidic with aqueous HCl solution, and extracted three times with DCM to obtain 2.20 g of a yellow solid, with a yield of 92%.

[0571] Step 3: Synthesis of tert-butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0572]

[0573] At room temperature, 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinate (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 successively added to the reaction flask, 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, a large amount of solid was precipitated, filtered, and the filter cake was dissolved in DCM, dried over anhydrous magnesium sulfate and directly used for the next step.

[0574] Step 4: Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)pyridine-3-carboxamide

[0575]

[0576] 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 successively added to a reaction flask. After dissolution, hydrochloric acid / dioxane (2 ml) was added, and the reaction was stirred at room temperature for 3 h. After completion of the reaction, the solvent was removed to obtain 0.26 g of the crude product, which was directly used for the next step.

[0577] Step 5: Synthesis of 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)-N-(2,6-dioxopiperidin-3-yl)pyridine-3-carboxamide

[0578]

[0579] At room temperature, N-(2,6-dioxopiperidin-3-yl)-5-(piperazin-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)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.28 g, 0.47 mmol) and dichloromethane (5 ml) were successively added to a reaction flask. Then TIPT (0.45 ml) was added, and the mixture was stirred at room temperature for 16 h. Then STAB (0.15 g, 0.71 mmol) was added, and the reaction was stirred at room temperature for 2 h. After completion of the reaction, the mixture was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, the solvent was removed, and column chromatography was carried out using the DCM / MeOH system to obtain 0.21 g of the product. The overall yield in three steps was 62%.

[0580] 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)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)pyridinecarboxamide

[0581]

[0582] 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 successively added to a reaction flask. The hydrogen was replaced 3 - 4 times, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, it was filtered through diatomaceous earth. The filter cake was washed with THF, and the filtrate was concentrated under reduced pressure. Column chromatography was carried out using a DCM / MeOH system to obtain 0.04 g of the product, and the yield was 21%.

[0583] 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=13.0,8.3,5.4Hz,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] + . 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)

[0584]

[0585] 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 was referred to Example 1.

[0586] 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

[0587]

[0588] 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 successively added to the reaction flask. After displacing nitrogen 3 - 4 times, the temperature was raised to 80 °C and the reaction was carried out for 3 h. After the reaction was completed, the temperature was lowered to room temperature, concentrated, and column chromatography was carried out using the PE / EA system to obtain 0.22 g of white solid with a yield of 67%.

[0589] 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

[0590]

[0591] 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 successively added to the reaction flask. After displacing hydrogen 3 - 4 times, the reaction was stirred at room temperature for 8 h. After the reaction was completed, it was filtered through diatomaceous earth, the filter cake was washed with THF, and the filtrate was concentrated to obtain 0.20 g of crude product which was directly used for the next step.

[0592] 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

[0593]

[0594] 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 successively added to a reaction flask. After dissolution, hydrochloric acid / dioxane (2 ml) was added, and the reaction was stirred at room temperature for 3 h. After completion of the reaction, the solvent was removed to obtain 0.11 g of the crude product, which was directly used for the next step.

[0595] 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)phenyl)piperazin-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

[0596]

[0597] 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 successively added to a reaction flask. Then TIPT (0.3 ml) was added, and the mixture was stirred at room temperature for 16 h. Then STAB (0.10 g, 0.48 mmol) was added, and the reaction was stirred at room temperature for 2 h. After completion of the reaction, it was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, it was filtered. The filter cake was slurried twice with dichloromethane, the organic phases were combined, the solvent was removed, and column chromatography was carried out using the DCM / MeOH system to obtain 0.06 g of the product. The yield over three steps was 13%.

[0598] 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)phenyl)piperazin-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

[0599]

[0600] At room temperature, 3-(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)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 successively added to a reaction flask. Hydrogen was displaced 3 - 4 times, and the reaction was stirred at 25 °C for 24 h. After completion of the reaction, it was filtered through diatomaceous earth. The filter cake was washed with THF, the filtrate was concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.008 g of the product, yield: 14%.

[0601] 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.15 (s, 1H), 7.12 (q, J = 5.9, 4.5 Hz, 3H), 7.02–6.95 (m, 3H), 6.83 (d, J = 7.3 Hz, 2H), 6.59 (dd, J = 15.9, 6.0 Hz, 4H), 6.48 (d, J = 8.5 Hz, 1H), 6.23 (d, J = 8.1 Hz, 2H), 5.40–5.33 (m, 1H), 4.14 (d, J = 5.0 Hz, 1H), 3.59 (s, 3H), 3.07 (s, 3H), 2.97–2.86 (m, 4H), 2.64 (dd, J = 17.3, 12.2 Hz, 8H), 2.20–2.08 (m, 2H), 1.98–1.90 (m, 4H), 1.68 (d, J = 30.7 Hz, 4H), 1.53–1.44 (m, 2H), 1.24 (s, 10H), 1.05–0.97 (m, 2H), 0.86 (t, J = 6.5 Hz, 1H). MS (ESI) m / z: 836.0 [M+H] + .

[0602] 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)

[0603]

[0604] (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 was synthesized according to Example 1.

[0605] 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

[0606]

[0607] 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 successively added to the reaction flask. The temperature was lowered to 0 °C and stirred for 30 minutes, then 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (0.97 g, 2.54 mmol) was added. After addition, the reaction was allowed to proceed at room temperature for 3 h. After completion of the reaction, ethyl acetate and water were added, and the layers were separated. The organic layer was dried and then purified by column chromatography using a PE / EA system to obtain 0.47 g of the product with a yield of 43%. Step 2: Synthesis of tert-butyl 4-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1H-indazol-5-yl)piperazine-1-carboxylate

[0608]

[0609] 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 sieve (0.11 g) and 1,4-dioxane (15 ml) were successively added to a reaction flask. Nitrogen was displaced 3 - 4 times, and the temperature was raised to 100 °C for reaction for 15 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, and liquid separation was carried out. After the organic phase was dried, column chromatography using a PE / EA system was performed to obtain 0.13 g of the product with a yield of 21%.

[0610] Step 3: Synthesis of 3-(5-(piperazin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione

[0611]

[0612] 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 successively added to a reaction flask. The temperature was raised to 65 °C and stirred for reaction for 2 h. After the reaction was completed, the solvent was removed, and column chromatography using a reverse column chromatography (acetonitrile / water) system was performed to obtain 0.06 g of the crude product, which was directly used for the next step.

[0613] 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)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione

[0614]

[0615] At room temperature, 3-(5-(piperazin-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)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.11 g, 0.18 mmol) and dichloromethane (10 ml) were successively added to a reaction flask, then TIPT (0.5 ml) was added, and the mixture was stirred at room temperature for 16 hours. Then STAB (0.08 g, 0.36 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, it was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.03 g of the product, yield: 27%. 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

[0616]

[0617] 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)methyl)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 successively added to a reaction flask, and then the hydrogen was replaced 3 - 4 times, and the reaction was stirred at 30 °C for 16 h. After the reaction was completed, it was filtered through diatomaceous earth, the filter cake was washed with tetrahydrofuran, the filtrate was concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.008 g of the product (0.004 g was put into storage), yield: 29%.

[0618] 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] + .

[0619] 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)

[0620]

[0621] (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 was synthesized according to the method of Example 1.

[0622] Step 1: Synthesis of tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0623]

[0624] 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-dioxaborolan-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 successively added to the reaction flask. The reaction was carried out at 90 °C under 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 layers were separated. After the organic phase was dried, column chromatography using the PE / EA system was carried out to obtain 2.50 g of the product as a brown oil, with a yield of 83%.

[0625] Step 2: Synthesis of 4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzoic acid

[0626]

[0627] 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 successively added to the reaction flask, and the temperature was raised to 50 °C for reaction for 4 h. After the reaction was completed, the solvent was removed, and the solution was adjusted to acidic with aqueous HCl solution. The product precipitated out, and 2.20 g of white solid was obtained by filtration, with a yield of 92%.

[0628] Step 3: Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0629]

[0630] At room temperature, 4-(1-(tert-butoxycarbonyl)-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 successively added to the reaction flask, 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 precipitated out. The solid was filtered, and the filter cake was dissolved in DCM and dried over anhydrous magnesium sulfate and directly used for the next step.

[0631] Step 4: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide

[0632]

[0633] 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 successively added to a reaction flask. After dissolution, hydrochloric acid / dioxane (2 mL) was added, and the reaction was stirred at room temperature for 3 h. After completion of the reaction, the solvent was removed to obtain 0.26 g of crude product, which was directly used for the next step.

[0634] 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

[0635]

[0636] 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 successively added to a reaction flask. Then TIPT (0.5 mL) was added, and the mixture was stirred at room temperature for 16 h. Then STAB (0.15 g, 0.71 mmol) was added, and the reaction was stirred at room temperature for 2 h. After completion of the reaction, the mixture was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, the solvent was removed, and column chromatography was carried out using a DCM / MeOH system to obtain 0.21 g of the product. The overall yield of the three steps was 62%.

[0637] 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

[0638]

[0639] 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 successively added to a reaction flask. The hydrogen was displaced 3 - 4 times, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, it was filtered through diatomaceous earth. The filter cake was washed with THF, the filtrate was concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.01 g of the product, yield: 5%.

[0640] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.88 (s, 1H), 9.13 (s, 1H), 8.49 (dd, J = 8.3, 3.8 Hz, 1H), 7.64 (dd, J = 11.1, 4.9 Hz, 1H), 7.23–7.09 (m, 5H), 6.83 (d, J = 7.1 Hz, 2H), 6.65–6.46 (m, 5H), 6.23 (d, J = 8.2 Hz, 2H), 4.85–4.66 (m, 1H), 4.15 (d, J = 4.9 Hz, 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

[0641] [M + H] + .

[0642] 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)

[0643]

[0644] (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 was synthesized according to Example 1.

[0645] Step 1: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole

[0646]

[0647] 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-dioxaborolan-2-yl)pyridine (1.24 g, 2.97 mmol), sodium carbonate (0.94 g, 8.90 mmol), tetrakis(triphenylphosphine)palladium(0) (0.34 g, 0.30 mmol), water (1 mL) and dioxane (10 mL) were successively added to a reaction flask. Under a nitrogen atmosphere, the reaction was carried out at 90 °C for 5 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, and the layers were separated. The organic layer was dried and then purified by column chromatography using a PE / EA system to obtain 1.20 g of the product with a yield of 81%.

[0648] 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

[0649]

[0650] 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), Pd 2 (dba) 3 (0.05 g, 0.05 mmol), 10% tris(tert-butyl)phosphine in toluene solution (200 mg, 0.10 mmol), sodium tert-butoxide (0.10 g, 1.00 mmol) and toluene (10 mL) were successively added to a reaction flask. Under a nitrogen atmosphere, the reaction was carried out at 100 °C for 5 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, and the layers were separated. The organic layer was dried and then purified by column chromatography using a PE / EA system to obtain 0.20 g of the product with a yield of 66%.

[0651] Step 3: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

[0652]

[0653] 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 successively added to a reaction flask, and the reaction was carried out at room temperature for 24 h. After the reaction was completed, the mixture was filtered and concentrated by rotary evaporation to obtain 0.13 g of a crude product, which was directly used in the next step.

[0654] Step 4: Synthesis of 3-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperazine-2,6-dione

[0655]

[0656] 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 successively added to a reaction flask, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the mixture was concentrated by rotary evaporation to obtain 0.11 g of a crude product, which was directly used in the next step.

[0657] 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

[0658]

[0659] 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 successively added to a reaction flask, then TIPT (0.5 mL) was added, and the mixture was stirred at room temperature for 16 hours. Then STAB (0.15 g, 0.71 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, it was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, the solvent was removed, and column chromatography was carried out using the DCM / MeOH system to obtain 0.21 g of the product, and the overall yield in three steps was 62%.

[0660] 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

[0661]

[0662] 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 successively added to a reaction flask, the hydrogen was replaced 3 - 4 times, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, it was filtered through diatomaceous earth, the filter cake was washed with THF, the filtrate was concentrated, and column chromatography was carried out using the DCM / MeOH system to obtain 0.07 g of the product, and the yield was 37%.

[0663] 1 H NMR(400MHz,DMSO-d 6)δ 10.88 (s, 1H), 9.15 (d, J = 4.4 Hz, 1H), 7.48 (d, J = 12.6 Hz, 1H), 7.11 (dt, J = 15.7, 7.3 Hz, 4H), 6.83 (d, J = 7.2 Hz, 2H), 6.67–6.54 (m, 4H), 6.48 (dd, J = 8.3, 2.5 Hz, 1H), 6.23 (d, J = 8.1 Hz, 2H), 4.28 (dd, J = 9.8, 5.1 Hz, 1H), 4.14 (d, J = 5.0 Hz, 1H), 3.91 (d, J = 17.0 Hz, 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] + . 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)

[0664]

[0665] (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 was synthesized according to the method of Example 1.

[0666] Step 1: Synthesis of 3-(5-bromo-6-fluoro-1H-indazol-1-yl)-1-(4-methoxyphenylmethyl)piperazine-2,6-dione

[0667]

[0668] 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 successively added to a reaction flask. The temperature was lowered to 0 °C and stirred for 30 minutes, then 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (0.97 g, 2.54 mmol) was added. After the addition, the reaction was allowed to resume at room temperature for 3 h. After the reaction was completed, ethyl acetate and water were added, and the layers were separated. The organic phase was dried and then subjected to column chromatography using a PE / EA system to obtain 0.47 g of the product with a yield of 43%.

[0669] Step 2: Synthesis of tert-butyl 4-(6-fluoro-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1H-indazol-5-yl)piperazine-1-carboxylate

[0670]

[0671] 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 successively added to a reaction flask. Nitrogen was displaced 3 - 4 times, and the temperature was raised to 100 °C and the reaction was carried out for 16 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, and the layers were separated. The organic phase was dried and then subjected to column chromatography using a PE / EA system to obtain 0.13 g of the product with a yield of 21%.

[0672] Step 3: Synthesis of 3-(6-fluoro-5-(piperazin-1-yl)-1H-indazol-1-yl)piperazine-2,6-dione

[0673]

[0674] 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 successively added to a reaction flask. The temperature was raised to 65 °C and stirred for 2 h. After the reaction was completed, the solvent was removed, and the crude product (0.07 g) was obtained by column chromatography using a reverse phase (acetonitrile / water) system and directly used in the next step.

[0675] 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

[0676]

[0677] At room temperature, 3-(6-fluoro-5-(piperazin-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)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.28 g, 0.47 mmol) and dichloromethane (5 mL) were successively added to a reaction flask, then TIPT (0.5 mL) was added, and the mixture was stirred at room temperature for 16 hours. Then STAB (0.15 g, 0.71 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, it was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.21 g of the product, and the overall yield in three steps was 62%.

[0678] 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

[0679]

[0680] 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 successively added to a reaction flask, the hydrogen was replaced 3 - 4 times, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, it was filtered through diatomaceous earth, the filter cake was washed with THF, the filtrate was concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.07 g of the product, and the yield was 37%.

[0681] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 11.11 (s, 1H), 9.14 (s, 1H), 8.00 (s, 1H), 7.55 (d, J = 12.4 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.10 (d, J = 9.5 Hz, 2H), 6.81 (dd, J = 7.5, 3.7 Hz, 2H), 6.65–6.56 (m, 4H), 6.48 (dd, J = 8.3, 2.5 Hz, 1H), 6.26–6.21 (m, 2H), 5.76 (dd, J = 11.5, 5.1 Hz, 1H), 4.15 (d, J = 5.0 Hz, 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] + .

[0682] 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)

[0683]

[0684] (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 was synthesized according to Example 1.

[0685] Step 1: Synthesis of 1'-(tert-butyl) 6-methyl 3',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylate

[0686]

[0687] At room temperature, methyl 5-bromopyridine-2-carboxylate (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), Cs 2CO 3 (3.00 g, 9.26 mmol), Do (10 ml) and H 2 O (2 ml), displace nitrogen 3 - 4 times, heat up to 100 °C and react for 3 h. After the reaction is completed, cool down to room temperature, filter, concentrate the filtrate, and use the PE / EA system for column chromatography to obtain 1.25 g of the product as a brown oil, with a yield of 83%.

[0688] Step 2: Synthesis of 1'-(tert-butoxycarbonyl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxylic acid

[0689]

[0690] At room temperature, successively add methyl tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (1.25 g, 3.93 mmol), NaOH (0.63 g, 15.72 mmol), MeOH (15 ml) and H 2 O (5 ml) to the reaction flask, heat up to 50 °C and react for 4 h. After the reaction is completed, remove the solvent, adjust to acidic with aqueous HCl solution, extract three times with DCM to obtain 1.10 g of a yellow solid, with a yield of 92%.

[0691] Step 3: Synthesis of tert-butyl 6-((2,6-dioxopiperidin-3-yl)carbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate

[0692]

[0693] At room temperature, successively add 1'-(tert-butoxycarbonyl)-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) to the reaction flask, stir at room temperature for 2 h. After the reaction is completed, add water (3 mL) and saturated brine (3 mL) to the reaction solution, a large amount of solid precipitates, filter, dissolve the filter cake in DCM, dry with anhydrous magnesium sulfate and directly proceed to the next step.

[0694] Step 4: Synthesis of N-(2,6-dioxopiperidin-3-yl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide

[0695]

[0696] 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 successively added to a reaction flask. After dissolution, hydrochloric acid / dioxane (2 ml) was added, and the reaction was stirred at room temperature for 3 h. After completion of the reaction, the solvent was removed to obtain 0.26 g of the crude product, which was directly used for the next step.

[0697] 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

[0698]

[0699] 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-carbaldehyde (0.28 g, 0.47 mmol) and dichloromethane (5 ml) were successively added to a reaction flask. Then TIPT (0.45 ml) was added, and the mixture was stirred at room temperature for 16 h. Then STAB (0.15 g, 0.71 mmol) was added, and the reaction was stirred at room temperature for 2 h. After completion of the reaction, the mixture was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, the solvent was removed, and column chromatography was performed using the DCM / MeOH system to obtain 0.21 g of the product. The overall yield of the three steps was 62%.

[0700] 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

[0701]

[0702] 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 successively added to a reaction flask. The hydrogen was displaced 3 - 4 times, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, it was filtered through diatomaceous earth. The filter cake was washed with THF, the filtrate was concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.033 g of the product, 0.028 g was stored in the warehouse, and the yield was 22.9%.

[0703] 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.15 (s, 1H), 9.03 (d, J = 8.5 Hz, 1H), 8.58 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.11 (q, J = 10.0, 8.6 Hz, 3H), 6.82 (d, J = 7.3 Hz, 2H), 6.64–6.60 (m, 2H), 6.55 (d, J = 8.5 Hz, 2H), 6.48 (d, J = 8.5 Hz, 1H), 6.22 (d, J = 8.2 Hz, 2H), 4.79 (t, J = 6.8 Hz, 1H), 4.14 (d, J = 5.1 Hz, 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, 4.2 Hz, 3H), 2.12–1.96 (m, 4H), 1.87 (d, J = 37.5 Hz, 8H), 1.72–1.66 (m, 2H), 1.62 (s, 2H), 1.50 (dd, J = 12.5, 7.1 Hz, 2H), 1.40 (s, 1H), 1.22 (d, J = 11.7 Hz, 4H), 1.00 (p, J = 9.6, 8.5 Hz, 3H), 0.85 (q, J = 8.7, 7.9 Hz, 2H). MS (ESI) m / z: 809.6 [M+H] + .

[0704] 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)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (Compound VI-8)

[0705]

[0706] (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 was synthesized according to Example 1.

[0707] Step 1: Synthesis of 5-(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)-N-(2,6-dioxopiperidin-3-yl)pyridine-3-carboxamide

[0708]

[0709] 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), K 3 PO 4 (0.38 g, 1.81 mmol), Do (5 mL) and H 2 O (1 ml) were successively added to the reaction flask. The nitrogen was displaced 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 column chromatography was carried out using the PE / EA system to obtain 0.30 g of a white solid with a yield of 61%.

[0710] Step 2: Synthesis of 3-(3-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione

[0711]

[0712] At room temperature, 5-(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)-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 reaction was carried out 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%.

[0713] 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)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione

[0714]

[0715] 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 successively added to the reaction flask, then TIPT (0.4 ml) was added, and the mixture was stirred at room temperature for 16 h. Then STAB (0.12 g, 0.55 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, the solvent was removed, and column chromatography was carried out using the DCM / MeOH system to obtain 0.06 g of a white solid with a yield of 16.4%.

[0716] 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)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione

[0717]

[0718] At room temperature, 3-(5-(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)-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 successively added to a reaction flask. Hydrogen was displaced 3 - 4 times, and the reaction was stirred at 30 °C for 24 h. After the reaction was completed, it was filtered through diatomaceous earth. The filter cake was washed with THF, the filtrate was concentrated by evaporation, and column chromatography was performed using a DCM / MeOH system to obtain 0.006 g of the product, 0.002 g was stored in the warehouse, and the yield was 6.7%.

[0719] 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.15 (d, J = 7.1 Hz, 1H), 7.51–7.43 (m, 2H), 7.31 (d, J = 8.6 Hz, 1H), 7.08 (d, J = 7.3 Hz, 2H), 6.81 (d, J = 7.8 Hz, 2H), 6.64–6.57 (m, 4H), 6.48 (dd, J = 8.2, 2.6 Hz, 1H), 6.24 (d, J = 8.2 Hz, 2H), 5.73 (dd, J = 11.8, 5.2 Hz, 1H), 4.39 (t, J = 5.2 Hz, 1H), 4.15 (d, J = 5.1 Hz, 1H), 2.98–2.85 (m, 7H), 2.72 (qd, J = 13.9, 11.0, 4.5 Hz, 5H), 2.37–2.29 (m, 3H), 2.21 (q, J = 8.3, 7.4 Hz, 2H), 2.14–1.88 (m, 6H), 1.78–1.65 (m, 6H), 1.43 (h, J = 3.1 Hz, 2H), 1.30 (s, 8H), 1.10–0.77 (m, 4H). MS (ESI) m / z: 819.7 [M + H] + .

[0720] 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)

[0721]

[0722] (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 was synthesized according to Example 1.

[0723] Step 1: Synthesis of 3-(5-bromo-6-fluoro-3-methyl-1H-indazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

[0724]

[0725] 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 successively added to the reaction flask. 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. After the addition, the reaction was carried out at room temperature for 3 h. After the reaction was completed, ethyl acetate and water were added, and the layers were separated. The organic phase was dried and then column chromatographed using a PE / EA system to obtain 0.88 g of the product with a yield of 44%.

[0726] 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

[0727]

[0728] 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 successively added to the reaction flask. Nitrogen was displaced 3-4 times, and the temperature was raised to 80 °C and the reaction was carried out for 4 h. After the reaction was completed, the temperature was lowered to room temperature, the solvent was removed, and the residue was diluted with ethyl acetate and filtered through a pad of diatomaceous earth. The filtrate was dried and the solvent was removed, and then column chromatographed using a PE / EA system to obtain 0.80 g of the product with a yield of 80%.

[0729] 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

[0730]

[0731] 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 successively added to a reaction flask. 10% palladium on carbon (0.08 g) was added, and the hydrogen was displaced 3 - 4 times. The reaction was stirred at room temperature for 16 h. After the reaction was completed, it was filtered through diatomaceous earth, and the solvent was removed to obtain 0.50 g of the product, which was directly used for the next step.

[0732] Step 4: Synthesis of 3-(6-fluoro-3-methyl-5-(piperidin-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione

[0733]

[0734] At room temperature, 4-(6-fluoro-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-5-yl)piperidine-1-carboxylic acid tert-butyl ester (0.50 g, 0.89 mmol), trifluoroacetic acid (3 ml) and TfOH (0.5 ml) were successively added to a reaction flask. The temperature was raised to 65 °C and the reaction was stirred for 2 h. After the reaction was completed, the solvent was removed, and column chromatography was carried out using a reverse column chromatography (acetonitrile / water) system to obtain 0.20 g of the crude product, which was directly used for the next step.

[0735] 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

[0736]

[0737] 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 successively added to a reaction flask, then TIPT (0.5 ml) was added, and the mixture was stirred at room temperature for 16 hours. Then STAB (0.25 g, 0.116 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, it was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, concentrated by evaporation, and column chromatography was carried out using the DCM / MeOH system to obtain 0.15 g of the product, yield: 28%.

[0738] 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

[0739]

[0740] 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 successively added to a reaction flask, and then hydrogen was displaced 3 - 4 times, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, it was filtered through diatomaceous earth, the filter cake was washed with tetrahydrofuran, the filtrate was concentrated by evaporation, and column chromatography was carried out using the DCM / MeOH system to obtain 0.05 g of the product, yield: 37%.

[0741] 1 H NMR(400MHz,DMSO-d 6)δ 11.09 (s, 1H), 9.15 (s, 1H), 7.55–7.38 (m, 2H), 7.09 (q, J = 6.7 Hz, 2H), 7.01 (d, J = 7.2 Hz, 1H), 6.81 (d, J = 7.5 Hz, 2H), 6.67–6.58 (m, 4H), 6.48 (d, J = 8.2 Hz, 1H), 6.25 (d, J = 8.2 Hz, 2H), 5.74–5.61 (m, 1H), 4.16 (d, J = 4.9 Hz, 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] + .

[0742] 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)

[0743]

[0744] (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 was synthesized according to the method of Example 1.

[0745] Step 1: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole

[0746]

[0747] 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-dioxolane-2-yl)pyridine (1.24 g, 2.97 mmol), sodium carbonate (0.94 g, 8.90 mmol), tetrakis(triphenylphosphine)palladium(0), water (1 mL) and dioxane (10 mL) were successively added to a reaction flask. Under a nitrogen atmosphere at 90 °C, the reaction was carried out for 5 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, and the layers were separated. After the organic phase was dried, column chromatography using a PE / EA system was performed to obtain 1.20 g of the product, with a yield of 81%.

[0748] 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

[0749]

[0750] 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-dioxaborolane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (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 a reaction flask. Under a nitrogen atmosphere at 90 °C, the reaction was carried out for 5 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, and the layers were separated. After the organic phase was dried, column chromatography using a PE / EA system was performed to obtain 0.47 g of the product, with a yield of 66%.

[0751] Step 3: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indol-6-yl)piperidine-1-carboxylate

[0752]

[0753] At room temperature, 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 (0.40 g, 0.66 mmol), 10% Pd / C (0.04 g), tetrahydrofuran (5 mL) and ethanol (5 mL) were successively added to a reaction flask, and the reaction was carried out at room temperature for 24 h. After the reaction was completed, it was filtered and concentrated by rotary evaporation to obtain 0.26 g of crude product, which was directly used for the next step.

[0754] Step 4: Synthesis of 3-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indol-3-yl)piperidine-2,6-dione

[0755]

[0756] 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 successively added to a reaction flask, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, it was concentrated by rotary evaporation to obtain 0.22 g of crude product, which was directly used for the next step.

[0757] 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

[0758]

[0759] 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 successively added to a reaction flask, then TIPT (0.5 mL) was added, and the mixture was stirred at room temperature for 16 h. Then STAB (0.15 g, 0.71 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, it was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, concentrated, and column chromatography was carried out using a DCM / MeOH system to obtain 0.21 g of the product, and the three-step yield was 62%.

[0760] 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

[0761]

[0762] 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 successively added to a reaction flask. The hydrogen was displaced 3 - 4 times, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, it was filtered through diatomaceous earth. The filter cake was washed with THF, the filtrate was concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.11 g of the product, with a yield of 58%.

[0763] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.90 (s, 1H), 9.15 (s, 1H), 7.46 (d, J = 53.3 Hz, 2H), 7.04 (d, J = 39.6 Hz, 3H), 6.82 (d, J = 7.5 Hz, 2H), 6.63 (t, J = 6.3 Hz, 4H), 6.49 (dd, J = 8.2, 2.7 Hz, 1H), 6.23 (d, J = 8.1 Hz, 2H), 4.34 (dd, J = 10.5, 5.0 Hz, 1H), 4.15 (d, J = 5.0 Hz, 1H), 3.90 (d, J = 46.4 Hz, 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] + .

[0764] Synthesis of Example 17: 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)picolylamide (Compound III-2)

[0765]

[0766] (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 was synthesized according to Example 1.

[0767] Step 1: Synthesis of 5-(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)-N-(2,6-dioxopiperidin-3-yl)pyridine-3-carboxamide

[0768]

[0769] At room temperature, N-(2,6-dioxopiperidin-3-yl)-5-(piperazin-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)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.17 g, 0.28 mmol) and dichloromethane (5 ml) were successively added to a reaction flask, followed by TIPT (0.3 ml). The mixture was stirred at room temperature for 16 hours, then STAB (0.09 g, 0.42 mmol) was added, and the reaction was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was diluted with dichloromethane, diatomaceous earth was added, and the mixture was stirred evenly and then quenched with water. After stirring for 20 minutes, the mixture was filtered, and the filter cake was slurried twice with dichloromethane. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography using a DCM / MeOH system to obtain 0.09 g of the product, with a yield of 35%.

[0770] 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)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)picolylamide

[0771]

[0772] At room temperature, 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)-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 successively added to a reaction flask. The hydrogen was displaced 3 - 4 times, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, it was filtered through diatomaceous earth. The filter cake was washed with THF, the filtrate was concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.03 g of the product, yield: 37%.

[0773] 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.13 (s, 1H), 8.74 (d, J = 8.3 Hz, 1H), 8.31 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.41 (dd, J = 9.0, 2.9 Hz, 1H), 7.13 (dd, J = 9.7, 6.7 Hz, 3H), 6.84 (d, J = 7.1 Hz, 2H), 6.65–6.59 (m, 2H), 6.53 (d, J = 8.3 Hz, 2H), 6.48 (dd, J = 8.3, 2.5 Hz, 1H), 6.21 (d, J = 8.3 Hz, 2H), 4.74 (td, J = 8.0, 4.1 Hz, 1H), 4.14 (d, J = 5.0 Hz, 1H), 3.22 (d, J = 42.3 Hz, 4H), 3.08–2.62 (m, 10H), 2.53 (s, 5H), 2.31 (t, J = 7.4 Hz, 2H), 2.23–1.95 (m, 6H), 1.93–1.64 (m, 4H), 1.57 (s, 2H), 1.44 (d, J = 8.7 Hz, 2H), 1.22 (d, J = 12.2 Hz, 2H), 0.98 (h, J = 7.2 Hz, 2H). MS (ESI) m / z: 810.7 [M + H] + .

[0774] 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)

[0775]

[0776] (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 was synthesized according to Example 1.

[0777] Step 1: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole

[0778]

[0779] 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-dioxaborolan-2-yl)pyridine (1.24 g, 2.97 mmol), sodium carbonate (0.94 g, 8.90 mmol), tetrakis(triphenylphosphine)palladium(0) (0.34 g, 0.30 mmol), water (1 mL) and dioxane (10 mL) were successively added to a reaction flask. Under a nitrogen atmosphere, the reaction was carried out at 90 °C for 5 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, and the layers were separated. After the organic phase was dried, column chromatography using a PE / EA system was performed to obtain 1.20 g of the product, with a yield of 81%.

[0780] Step 2: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

[0781]

[0782] 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 in toluene solution (200 mg, 0.10 mmol), sodium tert-butoxide (0.10 g, 1.00 mmol) and toluene (10 mL) were successively added to a reaction flask. Under a nitrogen atmosphere, the reaction was carried out at 100 °C for 5 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, and the layers were separated. After the organic phase was dried, column chromatography using a PE / EA system was performed to obtain 0.20 g of the product, with a yield of 66%.

[0783] Step 3: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

[0784]

[0785] 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 successively added to a reaction flask, and the reaction was carried out at room temperature for 24 h. After the reaction was completed, it was filtered and concentrated by rotary evaporation to obtain 0.13 g of crude product, which was directly used for the next step.

[0786] Step 4: Synthesis of 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperazine-2,6-dione

[0787]

[0788] 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 successively added to a reaction flask, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, it was concentrated by rotary evaporation to obtain 0.11 g of crude product, which was directly used for the next step.

[0789] 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

[0790]

[0791] 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 successively added to a reaction flask, then TIPT (0.5 mL) was added, and the mixture was stirred at room temperature for 16 h. Then STAB (0.08 g, 0.36 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, it was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, the solvent was removed, and column chromatography was carried out using the DCM / MeOH system to obtain 0.03 g of the product, and the yield was 27%.

[0792] 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

[0793]

[0794] 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 successively added to a reaction flask, and then hydrogen was replaced 3 - 4 times, and the reaction was stirred at 30 °C for 16 h. After the reaction was completed, it was filtered through diatomaceous earth, the filter cake was washed with tetrahydrofuran, the filtrate was concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.01 g of the product, yield: 37%.

[0795] 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–

[0796] 1.15(m,2H),1.08–0.68(m,3H).MS(ESI)m / z:821.0[M+H] + .

[0797] 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)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-benzimidazol-1-yl)piperidine-2,6-dione (Compound V-2)

[0798]

[0799] (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 was synthesized according to Example 1.

[0800] Step 1: Synthesis of 2,6-bis(benzyloxy)-3-nitropyridine

[0801]

[0802] At room temperature, dissolve BnOH (7.57 g, 69.95 mmol) in THF (25 mL), cool to -15 °C, add potassium tert-butoxide (7.00 g, 62.18 mmol), and stir at room temperature for 30 min. At -15 °C, drop the above reaction solution into 2,6-dichloro-3-nitropyridine (5.00 g, 25.91 mmol) in THF (15 mL). After addition, react at room temperature for 16 h. After the reaction is completed, pour the reaction solution into ice water, stir for 30 min, filter, and slurry the filter cake with methyl tert-butyl ether to obtain 6.50 g of white solid, with a yield of 74.6%.

[0803] Step 2: Synthesis of 2,6-bis(benzyloxy)pyridin-3-amine

[0804]

[0805] At room temperature, dissolve 2,6-bis(benzyloxy)-3-nitropyridine (6.50 g, 19.32 mmol) in THF (10 mL) and MeOH (10 mL), add NiCl 2 ·6H 2 O (0.45 g, 1.93 mmol), cool to 0 °C, and slowly add NaBH 4 (1.82 g, 48.31 mmol), and react under ice bath for 1 h. After the reaction is completed, quench the reaction solution by adding ice water (1 mL), concentrate and perform column chromatography (EA / PE) to obtain 4.41 g of colorless oil, with a yield of 74.5%.

[0806] Step 3: Synthesis of 2,6-bis(benzyloxy)-N-(4-bromo-5-fluoro-2-nitrophenyl)pyridin-3-amine

[0807]

[0808] 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 successively added to a reaction flask, 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 a solid, which was filtered, and the filter cake was slurried with methyl tert-butyl ether to obtain 3.5 g of a yellow solid with a yield of 35.9%.

[0809] Step 4:N 1 -Synthesis of (2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-5-fluorobenzene-1,2-diamine

[0810]

[0811] 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, and NaBH 4 (0.63 g, 16.69 mmol) was slowly added, and the reaction was carried out under an ice bath for 1 h. After the reaction was completed, ice water (1 mL) was added to the reaction solution to quench it, and it was concentrated and subjected to column chromatography (EA / PE) to obtain 3.25 g of a brown oil with a yield of 98.8%.

[0812] Step 5: Synthesis of 1-(2,6-dibenzyloxy)pyridin-3-yl)-5-bromo-6-fluoro-1H-benzimidazole

[0813]

[0814] 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 reaction was carried out at 120 °C for 1 h. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated and subjected to column chromatography (EA / PE) to obtain 3.00 g of a brown oil with a yield of 90.5%.

[0815] Step 6: Synthesis of tert-butyl 4-(1-(2,6-dibenzyloxypyridin-3-yl)-6-fluoro-1H-benzoimidazol-5-yl)piperazine-1-carboxylate

[0816]

[0817] At room temperature, 1-(2,6-dibenzyloxypyridin-3-yl)-5-bromo-6-fluoro-1H-benzoimidazole (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), MS (0.60 g) and Do (5 ml) were added successively to a reaction flask. Nitrogen was displaced 3 - 4 times, and the temperature was raised to 100 °C for reaction for 8 h. After the reaction was completed, the temperature was lowered to room temperature, filtered, the filtrate was concentrated, column chromatography was carried out using a DCM / MeOH system, and then triturated with EA to obtain 0.60 g of a white solid with a yield of 82.8%.

[0818] Step 7: Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1H-benzoimidazol-5-yl)piperazine-1-carboxylate

[0819]

[0820] At room temperature, tert-butyl 4-(1-(2,6-dibenzyloxypyridin-3-yl)-6-fluoro-1H-benzoimidazol-5-yl)piperazine-1-carboxylate (0.60 g, 0.98 mmol), DMF (15 mL), AcOH (2 mL) and Pd / C (200 mg) were added successively to a reaction flask. Hydrogen was displaced 3 - 4 times, and the temperature was raised to 35 °C for reaction for 8 h. After the reaction was completed, filtered, water was added to the filtrate to precipitate a solid, and 0.60 g of the crude product was obtained by filtration and directly used for the next step.

[0821] Step 8: Synthesis of 3-(6-fluoro-5-(piperazin-1-yl)-1H-benzoimidazol-1-yl)piperidine-2,6-dione

[0822]

[0823] At room temperature, tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1H-benzoimidazol-5-yl)piperazine-1-carboxylate (0.30 g, 0.70 mmol), DCM (3 mL) and HCl in Do (5 mL) were successively added to the reaction flask, and the temperature was raised to 35 °C and reacted for 30 min. After the reaction was completed, the crude product of the product was concentrated to obtain 0.25 g, which was directly used for the next step.

[0824] 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)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-6-fluoro-1H-benzoimidazol-1-yl)piperidine-2,6-dione

[0825]

[0826] At room temperature, 3-(6-fluoro-5-(piperazin-1-yl)-1H-benzoimidazol-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 successively added to the reaction flask, and then TIPT (0.3 mL) was added. The mixture was stirred at room temperature for 8 h, and then STAB (0.10 g, 0.45 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, it was filtered, the filter cake was slurried with dichloromethane twice, the organic phases were combined, concentrated, and column chromatography was carried out using the DCM / MeOH system to obtain 0.125 g of a brown solid, yield: 45.3%.

[0827] 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)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-benzoimidazol-1-yl)piperidine-2,6-dione

[0828]

[0829] 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-benzoimidazol-1-yl)piperidine-2,6-dione (0.13 g, 0.14 mmol), 10% palladium on carbon (0.05 g) and THF (5 ml) were successively added to a reaction flask. The hydrogen was replaced 3 - 4 times, and the reaction was stirred at room temperature for 8 h. After the reaction was completed, it was filtered through diatomaceous earth. The filter cake was washed with THF, the filtrate was concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.017 g of the product, and 0.012 g was stored in the warehouse.

[0830] 1 H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 9.14 (s, 1H), 8.20 (s, 1H), 7.47 (d, J = 13.1 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.13–7.08 (m, 2H), 6.83 (d, J = 7.3 Hz, 2H), 6.62–6.46 (m, 5H), 6.22 (d, J = 8.1 Hz, 2H), 5.63 (dd, J = 13.0, 5.1 Hz, 1H), 4.14 (d, J = 5.1 Hz, 2H), 3.07–2.68 (m, 19H), 2.23–2.05 (m, 4H), 1.65 (dd, J = 91.4, 44.9 Hz, 10H), 1.27–1.15 (m, 4H), 0.99 (s, 2H). MS (ESI) m / z: 824.4 [M + H] + .

[0831] 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)

[0832]

[0833] (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 was synthesized according to Example 1.

[0834] Step 1: Synthesis of 2,6-bis(benzyloxy)-3-nitropyridine

[0835]

[0836] At room temperature, dissolve BnOH (7.57 g, 69.95 mmol) in THF (25 mL), cool down to -15 °C, add potassium tert-butoxide (7.00 g, 62.18 mmol), and stir at room temperature for 30 min. At -15 °C, dropwise add the above reaction solution to 2,6-dichloro-3-nitropyridine (5.00 g, 25.91 mmol) in THF (15 mL). After addition, react at room temperature for 16 h. After the reaction is completed, pour the reaction solution into ice water, stir for 30 min, filter, and slurry the filter cake with methyl tert-butyl ether to obtain 6.50 g of white solid with a yield of 74.6%.

[0837] Step 2: Synthesis of 2,6-bis(benzyloxy)pyridin-3-amine

[0838]

[0839] At room temperature, dissolve 2,6-bis(benzyloxy)-3-nitropyridine (6.50 g, 19.32 mmol) in THF (10 mL) and MeOH (10 mL), add NiCl 2 ·6H 2 O (0.45 g, 1.93 mmol), cool down to 0 °C, and slowly add NaBH 4 (1.82 g, 48.31 mmol), and react under ice bath for 1 h. After the reaction is completed, add ice water (1 mL) to quench the reaction solution, concentrate and perform column chromatography (EA / PE) to obtain 4.41 g of colorless oil with a yield of 74.5%.

[0840] Step 3: Synthesis of 2,6-bis(benzyloxy)-N-(4-bromo-5-fluoro-2-nitrophenyl)pyridin-3-amine

[0841]

[0842] At room temperature, sequentially add 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) to the reaction flask, heat up to 118 °C and react for 8 h. After the reaction is completed, cool down to room temperature, add water (20 mL) to the reaction solution to precipitate a solid, filter, and slurry the filter cake with methyl tert-butyl ether to obtain 3.5 g of yellow solid with a yield of 35.9%.

[0843] Step 4: Synthesis of N 1 -(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-5-fluorobenzene-1,2-diamine

[0844]

[0845] At room temperature, dissolve 2,6-bis(benzyloxy)-N-(4-bromo-5-fluoro-2-nitrophenyl)pyridin-3-amine (3.50 g, 6.67 mmol) in THF (20 mL) and MeOH (20 mL), add NiCl 2 ·6H 2 O (0.16 g, 1.67 mmol), cool down to 0 °C, and slowly add NaBH 4 (0.63 g, 16.69 mmol), and react under an ice bath for 1 h. After the reaction is completed, add ice water (1 mL) to the reaction solution to quench it, concentrate it, and perform column chromatography (EA / PE) to obtain 3.25 g of a brown oil, with a yield of 98.8%.

[0846] Step 5: Synthesis of 1-(2,6-dibenzyloxypyridin-3-yl)-5-bromo-6-fluoro-1H-benzoimidazole

[0847]

[0848] At room temperature, dissolve N 1 -(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-5-fluorobenzene-1,2-diamine (3.25 g, 6.57 mmol) in toluene (30 mL), add trimethyl orthoformate (1.74 g, 16.44 mmol) and TsOH (0.23 g, 1.31 mmol), and react at 120 °C for 1 h. After the reaction is completed, cool the reaction solution to room temperature, concentrate it, and perform column chromatography (EA / PE) to obtain 3.00 g of a brown oil, with a yield of 90.5%.

[0849] 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

[0850]

[0851] At room temperature, sequentially add 1-(2,6-dibenzyloxypyridin-3-yl)-5-bromo-6-fluoro-1H-benzoimidazole (1.20 g, 2.38 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxolane-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). Under a nitrogen atmosphere at 90 °C, the reaction was carried out for 5 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, and the layers were separated. After drying the organic layer, column chromatography using the PE / EA system was performed to obtain 1.20 g of the product with a yield of 81%.

[0852] Step 7: Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate

[0853]

[0854] At room temperature, tert-butyl 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-fluoro-1H-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.60 g, 0.98 mmol), DMF (15 mL), AcOH (2 mL) and Pd / C (200 mg) were successively added to the reaction flask. The hydrogen was displaced 3 - 4 times, and the temperature was raised to 35 °C for reaction for 8 h. After the reaction was completed, filtration was carried out. The filtrate was added with water to precipitate a solid, and 0.60 g of the crude product was obtained by filtration and directly subjected to the next step.

[0855] Step 8: Synthesis of 3-(6-fluoro-5-(piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0856]

[0857] 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 successively added to the reaction flask. The temperature was raised to 35 °C for reaction for 30 min. After the reaction was completed, concentration was carried out to obtain 0.25 g of the crude product, which was directly subjected to the next step.

[0858] 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

[0859]

[0860] 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 successively added to a reaction flask, then TIPT (0.3 mL) was added, and the mixture was stirred at room temperature for 8 hours. Then STAB (0.10 g, 0.45 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, it was filtered, the filter cake was slurried with dichloromethane twice, the organic phases were combined, the solvent was removed, and column chromatography was carried out using the DCM / MeOH system to obtain 0.13 g of a brown solid, yield: 46%.

[0861] 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

[0862]

[0863] 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 successively added to a reaction flask, the hydrogen was replaced 3 - 4 times, and the reaction was stirred at room temperature for 8 h. After the reaction was completed, it was filtered through diatomaceous earth, the filter cake was washed with THF, the filtrate was concentrated, and column chromatography was carried out using the DCM / MeOH system to obtain 0.02 g of the product, yield 27%.

[0864] 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),2.28–1.94(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] - .

[0865] 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)

[0866]

[0867] (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 was synthesized according to the method of Example 1.

[0868] Step 1: Synthesis of 2,6-bis(benzyloxy)pyridin-3-amine

[0869]

[0870] 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 successively added to the reaction flask, and the temperature was raised to 70 °C and stirred for 20 h. After the reaction was completed, the temperature was lowered, ethyl acetate and water were added, and the layers were separated. The organic layer was dried and then purified by column chromatography using a PE / EA system to obtain 4.08 g of the product with a yield of 48%.

[0871] Step 2: Synthesis of 2,6-bis(benzyloxy)-N-(4-bromo-2-nitrophenyl)pyridin-3-amine

[0872]

[0873] To the reaction flask, 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 successively. The temperature was raised to 130 °C and stirred for reaction for 18 hours. After the reaction was completed, the temperature was lowered, ethyl acetate and water were added, and liquid separation was carried out. After the organic phase was dried, column chromatography was carried out using the PE / EA system to obtain 5.90 g of the product with a yield of 99%.

[0874] Step 3: Synthesis of N1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromobenzene-1,2-diamine

[0875]

[0876] To the reaction flask, 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(II) chloride hexahydrate (0.28 g, 1.17 mmol) were added successively. The temperature was lowered to 0 °C, and sodium borohydride (1.10 g, 29.01 mmol) was added in batches while controlling the temperature. After addition, the reaction was carried out for 1 hour in an ice bath. After the reaction was completed, water was added to quench the reaction. After stirring for 10 minutes, the solvent was removed. The crude product was subjected to column chromatography using the PE / EA system to obtain 3.30 g of the product with a yield of 59%.

[0877] Step 4: Synthesis of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-1H-benzo[d]imidazole

[0878]

[0879] To the reaction flask, 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 successively. The temperature was raised to 120 °C and reacted for 2 hours. After the reaction was completed, the temperature was lowered to room temperature, toluene was removed by solvent evaporation, and the residue was co-evaporated with dichloromethane once. The crude product was subjected to column chromatography using the PE / EA system to obtain 1.21 g of the product with a yield of 59%.

[0880] 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

[0881]

[0882] 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 successively added to a reaction flask. Nitrogen was displaced 3 - 4 times, and the temperature was raised to 80 °C for reaction for 4 h. After the reaction was completed, the temperature was lowered to room temperature, the solvent was removed, diluted with ethyl acetate, filtered through diatomaceous earth, and after the filtrate was dried, the solvent was removed. Column chromatography using the PE / EA system was used to obtain 0.51 g of the product with a yield of 71%.

[0883] Step 6: Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate

[0884]

[0885] At room temperature, tert-butyl 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-1H-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.51 g, 0.87 mmol) and tetrahydrofuran (15 ml) were successively added to a reaction flask. 10% palladium on carbon (0.08 g) was added, hydrogen was displaced 3 - 4 times, and the reaction was stirred at room temperature for 16 h. After the reaction was completed, it was filtered through diatomaceous earth and the solvent was removed to obtain 0.15 g of the product with a yield of 41%.

[0886] Step 7: Synthesis of 3-(5-(piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0887]

[0888] 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 successively added to a reaction flask. The reaction was stirred at room temperature for 2 h. After the reaction was completed, the solvent was removed to obtain 0.16 g of the crude product, which was directly used in the next step (in the next step, the theoretical yield of 0.11 g was used as the feed).

[0889] 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

[0890]

[0891] 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 successively added to a reaction flask. Then TIPT (0.5 ml) was added, and the mixture was stirred at room temperature for 16 hours. Then STAB (0.15 g, 0.70 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, it was filtered. The filter cake was slurried twice with dichloromethane, the organic phases were combined, concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.26 g of the product, yield: 83%.

[0892] 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

[0893]

[0894] 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 successively added to a reaction flask. Then hydrogen was replaced 3 - 4 times, and the reaction was stirred at room temperature for 90 h. After the reaction was completed, it was filtered through diatomaceous earth. The filter cake was washed with tetrahydrofuran, the filtrate was concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.006 g of the product, yield: 5%, and 0.003 g was put into storage.

[0895] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.21 (s, 1H), 9.15 (s, 1H), 8.25 (s, 1H), 7.55 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.21–7.07 (m, 4H), 6.82 (d, J = 7.7 Hz, 2H), 6.67–6.54 (m, 3H), 6.47 (dd, J = 8.4, 2.5 Hz, 1H), 6.23 (d, J = 7.9 Hz, 2H), 5.69 (dd, J = 12.8, 5.0 Hz, 1H), 4.47 (s, 1H), 4.14 (d, J = 5.0 Hz, 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] + .

[0896] 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)

[0897]

[0898] (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 was synthesized according to the method of Example 1.

[0899] Step 1: Synthesis of tert-butyl 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate

[0900]

[0901] 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), and Pd2 (dba) 3 (0.08 g, 0.08 mmol), sodium tert-butoxide (0.16 g, 1.69 mmol), 10% tris(tert-butyl)phosphine solution (0.30 g, 0.17 mmol) and toluene (10 ml). The nitrogen was displaced 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, the solvent was removed, diluted with ethyl acetate, filtered through diatomaceous earth, and after the filtrate was dried, the solvent was removed. Column chromatography using the PE / EA system was used to obtain 0.30 g of the product, with a yield of 59%.

[0902] Step 2: Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate

[0903]

[0904] 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 successively added to the reaction flask. 10% palladium on carbon (0.03 g) was added, and the hydrogen was displaced 3 - 4 times. The reaction was stirred at room temperature for 16 h. After the reaction was completed, it was filtered through diatomaceous earth, and the solvent was removed to obtain 0.08 g of the product, with a yield of 35%.

[0905] Step 3: Synthesis of 3-(5-(piperazin-1-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0906]

[0907] 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 successively added to the reaction flask. The reaction was stirred at room temperature for 2 h. After the reaction was completed, the solvent was removed to obtain 0.09 g of the crude product, which was directly used in the next step.

[0908] 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

[0909]

[0910] At room temperature, 3-(5-(piperazin-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)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.11 g, 0.19 mmol) and dichloromethane (10 ml) were successively added to a reaction flask. Then TIPT (0.5 ml) was added, and the mixture was stirred at room temperature for 16 hours. Then STAB (0.10 g, 0.47 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, it was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.10 g of the product, yield: 62%.

[0911] 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

[0912]

[0913] 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 successively added to a reaction flask. Then hydrogen was replaced 3 - 4 times, and the reaction was stirred at room temperature for 48 h. After the reaction was completed, it was filtered through diatomaceous earth, the filter cake was washed with tetrahydrofuran, the filtrate was concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.006 g of the product, yield: 5%, and 0.002 g was put into storage.

[0914] 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=13.0,4.9Hz,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] + .

[0915] 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-benzoimidazol-1-yl)piperidine-2,6-dione (Compound V-1)

[0916]

[0917] (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 was synthesized according to the method of Example 1.

[0918] Step 1: Synthesis of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-2-methyl-1H-benzo[d]imidazole

[0919]

[0920] Add 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) to the reaction flask in sequence, and heat to 120 °C for reaction for 3 hours. After the reaction is completed, cool to room temperature, remove the solvent until there are no obvious droplets, make it into sand, and use column chromatography with the PE / EA system to obtain 0.92 g of the product (there is a small amount of acetic acid residue, which does not affect the next step).

[0921] 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

[0922]

[0923] At room temperature, add 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% tris(tert-butyl)phosphine solution (0.74 g, 0.37 mmol) and toluene (10 ml) to the reaction flask in sequence, displace nitrogen 3 - 4 times, and heat to 100 °C for reaction for 16 h. After the reaction is completed, cool to room temperature, remove the solvent, add ethyl acetate for dilution, filter through diatomaceous earth, dry the filtrate, remove the solvent, and use column chromatography with the PE / EA system 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

[0924]

[0925] At room temperature, add 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) to the reaction flask in sequence, add 10% palladium on carbon (0.03 g), displace hydrogen 3 - 4 times, and stir at room temperature for reaction for 16 h. After the reaction is completed, filter through diatomaceous earth, remove the solvent, and obtain 0.18 g of the product, with a yield of 57%.

[0926] Step 4: Synthesis of 3-(2-methyl-5-(piperazin-1-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0927]

[0928] 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 successively added to the reaction flask, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the solvent was removed to obtain the crude product, which was directly used for the next step. For the next step, the feed was based on the theoretical yield of 0.13 g.

[0929] 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

[0930]

[0931] At room temperature, 3-(2-methyl-5-(piperazin-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)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.20 g, 0.33 mmol) and dichloromethane (10 ml) were successively added to the reaction flask, then TIPT (0.5 ml) was added, and the mixture was stirred at room temperature for 16 h. Then STAB (0.13 g, 0.61 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, the solvent was removed, and column chromatography was carried out using the DCM / MeOH system to obtain 0.04 g of the product. The two-step yield was 15%.

[0932] 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-benzoimidazol-1-yl)piperidine-2,6-dione

[0933]

[0934] 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 successively added to a reaction flask. After replacing the hydrogen 3 - 4 times, the mixture was stirred at room temperature for 6 h. After the reaction was completed, it was filtered through diatomaceous earth. The filter cake was washed with tetrahydrofuran, and the filtrate was concentrated by evaporation. Column chromatography was carried out using 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] + . 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)

[0935]

[0936] (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 was synthesized according to the method of Example 1.

[0937] Step 1: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole

[0938]

[0939] 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-dioxolane-2-yl)pyridine (1.24 g, 2.97 mmol), sodium carbonate (0.94 g, 8.90 mmol), tetrakis(triphenylphosphine)palladium (0.34 g, 0.30 mmol), water (1 mL), and dioxane (10 mL) were successively added to a reaction flask. Under a nitrogen atmosphere, the reaction was carried out at 90 °C for 5 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, and the layers were separated. The organic layer was dried and then column chromatography was carried out using a PE / EA system to obtain 1.20 g of the product, with a yield of 81%.

[0940] 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

[0941]

[0942] 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), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (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 successively added to the reaction flask. Under a nitrogen atmosphere, the reaction was carried out at 90 °C for 5 h. After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate and water were added, and the layers were separated. After drying the organic phase, column chromatography using a PE / EA system was performed to obtain 0.47 g of the product with a yield of 66%.

[0943] Step 3: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indol-6-yl)piperidine-1-carboxylate

[0944]

[0945] At room temperature, 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 (0.40 g, 0.66 mmol), 10% Pd / C (0.04 g), tetrahydrofuran (5 mL) and ethanol (5 mL) were successively added to the reaction flask, and the reaction was carried out at room temperature for 24 h. After the reaction was completed, it was filtered and concentrated by rotary evaporation to obtain 0.26 g of the crude product, which was directly used in the next step.

[0946] Step 4: Synthesis of 3-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indol-3-yl)piperidine-2,6-dione

[0947]

[0948] 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 successively added to a reaction flask, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the solvent was evaporated to dryness to obtain 0.22 g of the crude product, which was directly used in the next step.

[0949] 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

[0950]

[0951] 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 successively added to a reaction flask, then TIPT (0.5 mL) was added, and the mixture was stirred at room temperature for 16 h. Then STAB (0.15 g, 0.71 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, the solvent was evaporated, and column chromatography was carried out using the DCM / MeOH system to obtain 0.21 g of the product, and the overall yield in three steps was 62%.

[0952] 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

[0953]

[0954] 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 successively added to a reaction flask. Hydrogen was displaced 3 - 4 times, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, it was filtered through diatomaceous earth. The filter cake was washed with THF, the filtrate was concentrated by evaporation, and column chromatography was performed using a DCM / MeOH system to obtain 0.11 g of the product, with a yield of 58%.

[0955] 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] + .

[0956] 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)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-8-azabicyclo[3.2.1]oct-3-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-17)

[0957]

[0958] (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 was synthesized according to the method of Example 1.

[0959] Step 1: Synthesis of tert-butyl 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-8-azabicyclo[4.2.1]oct-2-ene-8-carboxylate

[0960]

[0961] 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-butoxycarbonyl-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 successively added to the reaction flask. The nitrogen was displaced 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, column chromatography was carried out using the DCM / MeOH system, and then slurried with EA to obtain 0.10 g of white solid, with a yield of 72.9%. 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

[0962]

[0963] At room temperature, tert-butyl 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indol-6-yl)-8-azabicyclo[4.2.1]oct-2-ene-8-carboxylate (0.10 mg, 0.21 mmol) and dichloromethane (2 ml) were successively added to the reaction flask. After dissolution and clarification, hydrochloric acid / dioxane (5 ml) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the solvent was removed to obtain 0.10 g of crude white solid, which was directly used for the next step.

[0964] 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)phenyl)piperazin-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

[0965]

[0966] 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 successively added to a reaction flask. Then TIPT (0.30 mL) was added, and the mixture was stirred at room temperature for 8 hours. Then STAB (0.086 g, 0.41 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, it was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.15 g of the product, and the overall yield of the three steps was 53.9%.

[0967] 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)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-8-azabicyclo[3.2.1]oct-3-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0968]

[0969] At room temperature, 1-(6-(8-(((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)-8-azabicyclo[3.2.1]oct-2-en-3-yl)-5-fluoro-1-methyl-1H-indol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.15 g, 0.16 mmol), 10% palladium on carbon (0.05 g) and THF (3 ml) were successively added to a reaction flask. The hydrogen was replaced 3 - 4 times, and the reaction was stirred at room temperature for 8 h. After the reaction was completed, it was filtered through diatomaceous earth, the filter cake was washed with THF, the filtrate was concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.015 g of the product, 0.010 g was stored in the warehouse, and the yield was 11.0%.

[0970] 11H NMR (400 MHz, DMSO-d6) δ 10.58 (d, J = 2.5 Hz, 1H), 9.15 (s, 1H), 7.72 (s, 1H), 7.41 (d, J = 10.7 Hz, 1H), 7.13 (dd, J = 7.4, 4.6 Hz, 3H), 6.83 (d, J = 4.2 Hz, 2H), 6.62–6.60 (m, 2H), 6.54 (d, J = 7.4 Hz, 2H), 6.49 (d, J = 2.9 Hz, 1H), 6.21 (d, J = 8.2 Hz, 2H), 4.13 (d, J = 4.9 Hz, 1H), 4.01 (s, 3H), 3.95 (s, 2H), 3.90 (t, J = 6.7 Hz, 4H), 3.51 (s, 1H), 3.27 (s, 2H), 2.98 (d, J = 20.0 Hz, 9H), 2.75 (d, J = 2.1 Hz, 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] + .

[0971] 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)

[0972]

[0973] (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 was synthesized according to the method of Example 1.

[0974] Step 1: Synthesis of tert-butyl 7-(((trifluoromethyl)sulfonyl)oxy)-4-azaspiro[2.5]oct-6-ene-4-carboxylate

[0975]

[0976] 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). The temperature was lowered to -78 °C, and LiHMDS (7 mL, 7.00 mmol) was added. After the addition was complete, the reaction was carried out at room temperature for 8 h. After the reaction was completed, water (3 mL) was added to the reaction solution, and it was directly concentrated and subjected to column chromatography (EA / PE) to obtain 1.2 g of a yellow solid with a yield of 75%.

[0977] Step 2: Synthesis of tert-butyl 7-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-azaspiro[2.5]oct-6-ene-4-carboxylate

[0978]

[0979] 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)Cl 2 (0.04 g, 0.05 mmol), Na 2 CO 3 (0.11 g, 1.03 mmol), Do (10 ml) and H 2 O (2 ml) were added to the reaction flask in sequence. Nitrogen was displaced 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 column chromatography was carried out using the DCM / MeOH system to obtain 0.20 g of a brown solid with a yield of 81.3%.

[0980] 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

[0981]

[0982] 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 successively added to a reaction flask. After dissolution, hydrochloric acid / dioxane (3 ml) was added, and the reaction was stirred at room temperature for 1 h. After completion of the reaction, the solvent was removed to obtain 0.20 g of a crude white solid, which was directly used for the next step.

[0983] 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

[0984]

[0985] 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 successively added to a reaction flask. Then TIPT (0.30 mL) was added, and the mixture was stirred at room temperature for 8 h. Then STAB (0.084 g, 0.40 mmol) was added, and the reaction was stirred at room temperature for 2 h. After completion of the reaction, the mixture was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, the solvent was removed, and column chromatography was carried out using a DCM / MeOH system to obtain 0.06 g of the product. The two-step yield was 30%.

[0986] 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]oct-7-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0987]

[0988] 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 successively added to a reaction flask. The hydrogen was replaced 3 - 4 times, and the reaction was stirred at room temperature for 8 h. After the reaction was completed, it was filtered through diatomaceous earth. The filter cake was washed with THF, the filtrate was concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.012 g of the product, with a yield of 22.0%.

[0989] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.59 (s, 1H), 9.18 (s, 1H), 7.41 (d, J = 11.1 Hz, 1H), 7.11 (q, J = 6.6, 6.0 Hz, 3H), 6.83 (d, J = 7.0 Hz, 2H), 6.69–6.54 (m, 4H), 6.53–6.41 (m, 2H), 6.21 (t, J = 9.8 Hz, 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 = 6.8 Hz, 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] + .

[0990] 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)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 IV-12)

[0991]

[0992] (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 was synthesized according to the method of Example 1.

[0993] Step 1: Synthesis of tert-butyl 3,3-difluoro-4-(((trifluoromethyl)sulfonyloxy)-3,6-dihydropyridine-1(2H)-carboxylate

[0994]

[0995] At room temperature, dissolve tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (5 g, 21.26 mmol) in DCM (50 mL). Cool the solution to -15 °C, add TEA (6.45 g, 63.77 mmol), and slowly dropwise add trifluoromethanesulfonic anhydride (9.00 g, 31.88 mmol). After addition, stir the reaction mixture at room temperature for 8 h. After completion of the reaction, add saturated aqueous sodium bicarbonate solution (30 mL) to the reaction mixture, extract with DCM, concentrate the organic phase, and perform column chromatography (EA / PE) to obtain 3.2 g of a yellow solid with a yield of 41.0%.

[0996] 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

[0997]

[0998] At room temperature, sequentially add 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)Cl 2 (0.04 g, 0.05 mmol), Na 2 CO 3 (0.11 g, 1.03 mmol), Do (10 ml), and H 2 O (2 ml) to the reaction flask. Replace the nitrogen 3 - 4 times, heat the reaction mixture to 80 °C, and react for 2 h. After completion of the reaction, cool the reaction mixture to room temperature, filter, concentrate the filtrate, and perform column chromatography using a DCM / MeOH system to obtain 0.20 g of a brown solid with a yield of 81.3%.

[0999] 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

[1000]

[1001] 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 successively added to a reaction flask. After dissolution, hydrochloric acid / dioxane (3 ml) was added, and the reaction was stirred at room temperature for 1 h. After the reaction was completed, the solvent was removed to obtain 0.20 g of a crude white solid, which was directly used for the next step.

[1002] 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)-3,3-difluoro-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[1003]

[1004] 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 successively added to a reaction flask. Then TIPT (0.30 mL) was added, and the mixture was stirred at room temperature for 8 h. Then STAB (0.084 g, 0.40 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the mixture was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, the solvent was removed, and column chromatography was carried out using a DCM / MeOH system to obtain 0.060 g of the product. The two-step yield was 29.9%.

[1005] 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)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[1006]

[1007] At room temperature, 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)-3,3-difluoro-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.060 g, 0.06 mmol), 10% palladium on carbon (0.05 g) and THF (5 ml) were successively added to a reaction flask. The hydrogen was displaced 3 - 4 times, and the reaction was stirred at room temperature for 8 h. After the reaction was completed, it was filtered through diatomaceous earth. The filter cake was washed with THF, the filtrate was concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.012 g of the product, 0.007 g was put into storage, and the yield was 22.0%.

[1008] 1 H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 9.13 (d, J = 1.6 Hz, 1H), 7.74 (d, J = 5.5 Hz, 1H), 7.43–7.41 (m, 1H), 7.13 (dt, J = 8.8, 4.2 Hz, 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, 3.7 Hz, 2H), 4.13 (t, J = 4.5 Hz, 1H), 4.02 (d, J = 3.6 Hz, 3H), 3.92 (t, J = 6.7 Hz, 3H), 3.17 (s, 1H), 3.06–2.91 (m, 8H), 2.76 (t, J = 6.7 Hz, 4H), 2.36 (d, J = 10.4 Hz, 4H), 2.11 (d, J = 6.5 Hz, 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] + . 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'-dipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-19)

[1009]

[1010] (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 was synthesized according to Example 1.

[1011] Step 1: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-[1,4'-bipiperidine]-1'-carboxylate

[1012]

[1013] At room temperature, 1-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, 6-bromo-3-iodo-1-methyl-1H-indazole (0.50 g, 1.45 mmol), N-Boc-4-piperidone (0.58 g, 2.90 mmol) and dichloromethane (10 mL) were successively added to a reaction flask. Then TIPT (0.5 mL) was added, and the mixture was stirred at room temperature for 16 hours. Then STAB (0.61 g, 2.90 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, it was filtered, the filter cake was slurried twice with dichloromethane, the organic phases were combined, concentrated under reduced pressure, and column chromatography was carried out using the DCM / MeOH system to obtain 0.50 g of the product, yield: 65%.

[1014] Step 2: Synthesis of 1-(6-([1,4'-bipiperidine]-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[1015]

[1016] At room temperature, tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-[1,4'-bipiperidine]-1'-carboxylate (0.50 g, 0.95 mmol) and HCl dioxane solution (10 ml) were successively added to a reaction flask, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, it was evaporated to dryness to obtain 0.40 g of the crude product, which was directly used for the next step.

[1017] 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'-bipiperidin]-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[1018]

[1019] At room temperature, 1-(6-([1,4'-bipiperidin]-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 successively added to a reaction flask. Then TIPT (0.5 ml) was added, and the mixture was stirred at room temperature for 16 hours. Then STAB (0.08 g, 0.36 mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, it was diluted with dichloromethane, diatomaceous earth was added, and after stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, it was filtered. The filter cake was slurried twice with dichloromethane, the organic phases were combined, the solvent was removed, and column chromatography was carried out using the DCM / MeOH system to obtain 0.08 g of the product, yield: 72%.

[1020] 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'-bipiperidin]-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[1021]

[1022] 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'-bipiperidin]-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.08 g, 0.08 mmol), 10% palladium on carbon (0.01 g) and tetrahydrofuran (5 ml) were successively added to a reaction flask, and then the hydrogen was replaced 3 - 4 times, and the reaction was stirred at 30 °C for 16 h. After the reaction was completed, it was filtered through diatomaceous earth, the filter cake was washed with tetrahydrofuran, the filtrate was concentrated by evaporation, and column chromatography was carried out using a DCM / MeOH system to obtain 0.06 g of the product, yield: 82%.

[1023] 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] + .

[1024] 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)

[1025]

[1026] (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 was synthesized according to Example 1.

[1027] Step 1: Synthesis of tert-butyl (R)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate.

[1028]

[1029] - At -78 °C, successively add tert-butyl (R)-2-methyl-4-oxopiperidine-1-carboxylate (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) to a single-necked flask. Raise the temperature to room temperature under a nitrogen atmosphere and terminate the reaction after 16 h. Dilute with saturated ammonium chloride aqueous solution, extract with EA, and the organic phase is dried over anhydrous Na 2 SO 4 dry, filter, concentrate, and purify by column chromatography (EA / PE system) to obtain 3.00 g of a yellow oil.

[1030] Step 2: Synthesis of tert-butyl (R)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate.

[1031]

[1032] - At room temperature, successively add tert-butyl (R)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (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) to a single-necked flask. Raise the temperature to 85 °C under nitrogen protection and terminate the reaction after 8 h. Cool to room temperature, dilute with water, extract with EA, and the organic phase is dried over anhydrous Na 2 SO 4 dry, filter, concentrate, and purify by column chromatography (EA / PE system) to obtain 0.20 g of a yellow solid.

[1033] 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.

[1034]

[1035] At room temperature, (R)-tert-butyl 2-methyl-3,6-dihydropyridine-1(2H)-carboxylate (0.20 g, 0.44 mmol), DCM (10 mL), and dioxane hydrochloride solution (10 mL) were successively added to a single-necked flask, and the reaction was terminated after 3 h at room temperature. The mixture was concentrated to obtain 0.20 g of a crude yellow solid.

[1036] 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)pyrimidine-2,4(1H,3H)-dione.

[1037]

[1038] At room temperature, (R)-1-(5-fluoro-1-methyl-6-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-3-yl)pyrimidine-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 successively added to a single-necked flask. The reaction was carried out at room temperature for 16 h, and then sodium triacetoxyborohydride (0.18 g, 0.87 mmol) was added and the reaction was continued for 1 h. Water (1 mL) was added, and the mixture was stirred for 5 min. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated and purified by column chromatography (MeOH / DCM system) to obtain 0.14 g of a yellow solid.

[1039] 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)pyrimidine-2,4(1H,3H)-dione.

[1040]

[1041] 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-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.14 g, 0.15 mmol), Pd / C (0.20 g, 10%), and MeOH (20 mL) were successively added to a single-necked flask. The reaction was carried out at room temperature for 16 h under a hydrogen balloon atmosphere, filtered through diatomaceous earth, and the filtrate was concentrated and purified by column chromatography (MeOH / DCM system) to obtain 0.50 g of a white solid. MS (ESI) m / z: 852.9 [M+H] + .

[1042] 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)

[1043]

[1044] (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 was synthesized according to Example 1.

[1045] Step 1: Synthesis of (S)-tert-butyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate.

[1046]

[1047] At -78 °C, (S)-tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (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 successively added to a single-necked flask. The reaction was terminated after being warmed to room temperature under a nitrogen atmosphere for 16 h. Dilute with saturated ammonium chloride aqueous solution, extract with EA, and the organic phase was dried over anhydrous Na 2 SO 4It was dried, filtered, concentrated, and purified by column chromatography (EA / PE system) to obtain 3.00 g of a yellow oil.

[1048] Step 2: Synthesis of tert-butyl (S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate.

[1049]

[1050] At room temperature, (S)-tert-butyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (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 successively added to a single-necked flask. The reaction was terminated after heating to 85 °C for 8 h under nitrogen protection. After cooling to room temperature, it was diluted with water and extracted with EA. The organic phase was dried over anhydrous Na 2 SO 4 It was dried, filtered, concentrated, and purified by column chromatography (EA / PE system) to obtain 0.20 g of a yellow solid.

[1051] 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.

[1052]

[1053] At room temperature, tert-butyl (S)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate (0.20 g, 0.44 mmol), DCM (10 mL), and hydrochloric acid dioxane solution (10 mL) were successively added to a single-necked flask. The reaction was terminated after reacting at room temperature for 3 h. It was concentrated to obtain 0.20 g of a crude yellow solid.

[1054] 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)pyrimidine-2,4(1H,3H)-dione.

[1055]

[1056] At room temperature, (S)-1-(5-fluoro-1-methyl-6-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-3-yl)pyrimidine-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 successively added to a single-necked flask. The reaction was carried out at room temperature for 16 h, and then sodium triacetoxyborohydride (0.18 g, 0.87 mmol) was added and the reaction was continued for 1 h. Water (1 mL) was added, and the mixture was stirred for 5 min. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated and purified by column chromatography (MeOH / DCM system) to obtain 0.14 g of a yellow solid.

[1057] 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)pyrimidine-2,4(1H,3H)-dione.

[1058]

[1059] 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-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.14 g, 0.15 mmol), Pd / C (0.20 g, 10%), and MeOH (20 mL) were successively added to a single-necked flask. The reaction was carried out at room temperature for 16 h under a hydrogen balloon atmosphere. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated and purified by column chromatography (MeOH / DCM system) to obtain 0.50 g of a white solid. MS(ESI) m / z: 852.9 [M+H] + .

[1060] 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)

[1061]

[1062] (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 was synthesized according to the method of Example 1.

[1063] Step 1: Synthesis of (2S,6R)-1-(4-methoxybenzyl)-2,6-dimethylpiperidin-4-one.

[1064]

[1065] At room temperature, 40% acetaldehyde (6.00 g, 54.80 mmol) was added to an aqueous solution (20 mL) of acetonedicarboxylic acid (4.00 g, 27.40 mmol). Then, 4-methoxyphenylmethylamine (3.75 g, 27.40 mmol) was added in small portions within 10 minutes. The mixture was stirred at room temperature for 24 h. 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 and purified by column chromatography (DCM / EA system) to obtain 4.00 g of a light yellow oil.

[1066] Step 2: Synthesis of (2S,6R)-2,6-dimethylpiperidin-4-one.

[1067]

[1068] 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. After filtration, the filtrate was concentrated to obtain 1.80 g of a crude yellow oil.

[1069] Step 3: Synthesis of tert-butyl (2S,6R)-2,6-dimethyl-4-oxopiperidine-1-carboxylate.

[1070]

[1071] 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 purified by column chromatography (EA / PE system) to obtain 2.0 g of a white solid.

[1072] Step 4: Synthesis of tert-butyl (2S,6R)-2,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate.

[1073]

[1074] Under the condition of -78 °C, (2S,6R)-2,6-dimethyl-4-oxopiperidine-1-carboxylate 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 successively added to a single-necked flask. The reaction was terminated after rising to room temperature under a nitrogen atmosphere for 16 h. Dilute with saturated ammonium chloride aqueous solution, extract 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 3.00 g of a yellow oil.

[1075] 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.

[1076]

[1077] At room temperature, successively add 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), H 2 O (1 mL) into a single-necked flask. Heat to 85 °C under nitrogen protection and react for 8 h to terminate. Cool to room temperature, dilute with water, extract with EA, and the organic phase is 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.

[1078] 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.

[1079]

[1080] At room temperature, successively add 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 (0.20 g, 0.42 mmol), DCM (10 mL), and dioxane hydrochloride solution (10 mL) into a single-necked flask. React at room temperature for 3 h to terminate. Concentrate to obtain 0.20 g of a crude yellow solid.

[1081] 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)pyrimidine-2,4(1H,3H)-dione.

[1082]

[1083] 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)pyrimidine-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 successively added to a single-necked flask. The reaction was carried out at room temperature for 16 h, and then sodium triacetoxyborohydride (0.18 g, 0.87 mmol) was added and the reaction was continued for 1 h. Water (1 mL) was added, and the mixture was stirred for 5 min. It was filtered through diatomaceous earth, and the filtrate was concentrated and purified by column chromatography (MeOH / DCM system) to obtain 0.14 g of a yellow solid.

[1084] 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)pyrimidine-2,4(1H,3H)-dione.

[1085]

[1086] At room temperature, 0.14 g (0.14 mmol) 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, Pd / C (0.20 g, 10%), and MeOH (20 mL) were successively added to a single-necked flask. The reaction was carried out at room temperature for 16 h under a hydrogen balloon atmosphere, filtered through diatomaceous earth, and the filtrate was concentrated and purified by column chromatography (MeOH / DCM system) to obtain 0.01 g of a white solid. MS (ESI) m / z: 866.9 [M+H] + .

[1087] 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)

[1088]

[1089] (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 was synthesized according to Example 1.

[1090] 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

[1091]

[1092] 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 CO3 (6.2 g, 58.6 mmol) aqueous solution, purged with nitrogen, reacted at 90 °C for 6 hours, and the reaction was monitored by TLC and LC-MS until completion; the reaction solution was concentrated, water was added, extracted with EA, the organic phase was dried, concentrated, triturated, and purified by column chromatography (DCM / MeOH) to obtain the crude product, which was slurried with ethyl acetate to give 9.5 g of a white solid product.

[1093] Step 2: tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidine-1-carboxylate

[1094]

[1095] Dissolve tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (9.5 g, 21.4 mmol) in 300 mL of dichloromethane and 100 mL of isopropanol, add Mn(TMHD) 3 (1.3 g, 2.1 mmol) at room temperature, and add PhSiH 3 (3.5 g, 32.1 mmol) under an ice-water bath. After addition, react under an oxygen balloon atmosphere for 2 hours, and monitor the reaction by TLC and LC-MS until completion. The reaction solution was concentrated, water was added, extracted with ethyl acetate, the organic phase was concentrated, triturated, and purified by column chromatography (PE / EA / DCM / MeOH) to obtain the crude product, which was slurried with ethyl acetate to give 3.6 g of a white solid product.

[1096] Step 3: 1-(5-Fluoro-6-(4-hydroxypiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride

[1097]

[1098] Place tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidine-1-carboxylate (3.6 g, 7.8 mmol) in 40 mL of 1,4-dioxane hydrochloride, react at room temperature for 2 hours, and monitor the reaction by LC-MS until completion. The reaction solution was filtered, and the filter cake was air-dried to give 3.1 g of a white solid product.

[1099] 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

[1100]

[1101] 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) and (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 (4.3 g, 7.2 mmol) were placed in 150 mL of dichloromethane. 10 mL of titanium tetraisopropoxide was added, and 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 hour. The reaction was monitored by TLC and LC-MS until completion. 3 mL of water was added to quench the reaction, then 3 mL of ammonia water was added, and the mixture was stirred for 20 min. After filtration, the filtrate was concentrated to obtain a solid, and column chromatography (DCM / MeOH) gave 2.6 g of a white solid product.

[1102] 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

[1103]

[1104] 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, and the system was purged with hydrogen. The reaction was carried out at 20 °C for 16 hours. The reaction was monitored by TLC and LC-MS until completion. The reaction solution was filtered, and the filtrate was concentrated to obtain a solid. Column chromatography (DCM / MeOH) gave 1.3 g of a white solid product.1 H NMR (400 MHz, DMSO-d 6 ) δ 10.58 (s, 1H), 9.15 (s, 1H), 7.77 (d, J = 6.3 Hz, 1H), 7.38 (d, J = 12.7 Hz, 1H), 7.13 (dt, J = 11.2, 6.7 Hz, 3H), 6.83 (d, J = 7.3 Hz, 2H), 6.73–6.42 (m, 5H), 6.22 (d, J = 8.2 Hz, 2H), 5.25 (br, 1H), 4.14 (d, J = 5.1 Hz, 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] + .

[1105] 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)

[1106]

[1107] (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 was synthesized according to the method of Example 1.

[1108] Step 1: Synthesis of 1-(5-Fluoro-1-methyl-6-(1,4-dioxaspiro[4.5]deca-7-en-8-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[1109]

[1110] At room temperature, 4,4,5,5-tetramethyl-2-(1,4-dioxoaspirin[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (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), H 2 O (1 mL) were successively added into a single-necked flask. The temperature was raised to 85 °C under nitrogen protection and the reaction was terminated after 8 h. After cooling to room temperature, it was 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.

[1111] Step 2: Synthesis of 1-(5-fluoro-1-methyl-6-(1,4-dioxoaspirin[4.5]dec-8-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[1112]

[1113] At room temperature, 1-(5-fluoro-1-methyl-6-(1,4-dioxoaspirin[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. It was filtered, and the filtrate was concentrated to obtain 1.0 g of a crude yellow oil.

[1114] Step 3: Synthesis of 1-(5-fluoro-1-methyl-6-(4-oxocyclohexyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[1115]

[1116] At room temperature, 1-(5-fluoro-1-methyl-6-(1,4-dioxoaspirin[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 successively added into a single-necked flask and stirred at room temperature for 6 h. The reaction solution was concentrated to obtain 0.80 g of a crude yellow solid.

[1117] 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.

[1118]

[1119] 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 successively added to a single-necked flask. The reaction was terminated after 16 h at room temperature. It was diluted with saturated aqueous sodium carbonate solution and extracted with DCM. The organic phase was dried over anhydrous Na 2 SO 4 dried, filtered, concentrated and purified by column chromatography (MeOH / DCM system) to obtain 1.05 g of a yellow solid. 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.

[1120]

[1121] At room temperature, tert-butyl 4-(4-(3-(2,4-dioxotetrahydropyrimidin-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 successively added to a single-necked flask. The reaction was terminated after 3 h at room temperature. The concentrate was obtained as 1.00 g of a crude yellow solid.

[1122] 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.

[1123]

[1124] 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 successively added to a single-necked flask. The reaction was carried out at room temperature for 16 h, and then sodium triacetoxyborohydride (0.07 g, 0.35 mmol) was added and the reaction was continued for 1 h. Water (1 mL) was added, and the mixture was stirred for 5 min. It was filtered through diatomaceous earth, and the filtrate was concentrated and purified by column chromatography (MeOH / DCM system) to obtain 0.10 g of a yellow solid. 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.

[1125]

[1126] 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 successively added to a single-necked flask. The reaction was carried out at room temperature for 16 h under a hydrogen balloon atmosphere, filtered through diatomaceous earth, and the filtrate was concentrated and purified by column chromatography (MeOH / DCM system) to obtain 0.02 g of a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 9.14 (s, 1H), 7.42 (d, J = 6.0 Hz, 1H), 7.35 (d, J = 10.9 Hz, 1H), 7.19–7.08 (m, 3H), 6.83 (d, J = 7.1 Hz, 2H), 6.67–6.58 (m, 2H), 6.56–6.44 (m, 3H), 6.21 (d, J = 8.3 Hz, 2H), 4.13 (d, J = 5.0 Hz, 1H), 3.99 (s, 3H), 3.90 (t, J = 6.7 Hz, 2H), 3.04–2.89 (m, 8H), 2.75 (t, J = 6.7 Hz, 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] + .

[1127] 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)

[1128]

[1129] (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 was synthesized according to the method of Example 1.

[1130] Step 1: Synthesis of 1-(6-(4-(cyclopropylamino)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[1131]

[1132] 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 successively added to a single-necked flask. The reaction was terminated after 16 h at room temperature. Dilute with saturated aqueous sodium carbonate solution, extract with DCM, and the organic phase was dried over anhydrous Na 2 SO 4 dried, filtered, concentrated, and purified by column chromatography (MeOH / DCM system) to obtain 0.09 g of a yellow solid.

[1133] 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.

[1134]

[1135] 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 successively added to a single-necked flask. The reaction was carried out at room temperature for 16 h, and sodium triacetoxyborohydride (0.07 g, 0.35 mmol) was added and the reaction was continued for 1 h. Water (1 mL) was added, and the mixture was stirred for 5 min. It was filtered through diatomaceous earth, and the filtrate was concentrated and purified by column chromatography (MeOH / DCM system) to obtain 0.08 g of a yellow solid. 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.

[1136]

[1137] 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 successively added to a single-necked flask. The reaction was carried out at room temperature for 16 h under a hydrogen balloon atmosphere. It was filtered through diatomaceous earth, and the filtrate was concentrated and purified by column chromatography (MeOH / DCM system) to obtain 0.01 g of a white solid. MS(ESI) m / z: 893.1 [M+H]+

[1138] 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]heptan-2-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-26)

[1139]

[1140] 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 was referred to Example 1.

[1141] 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.

[1142]

[1143] 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 successively added to a single-necked flask. The reaction was terminated after reacting at 120 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, water was added for dilution, and extraction was performed three times with EA. The organic phases were combined, washed with water, brine, and anhydrous Na 2 SO 4 dried, filtered, concentrated, and purified by column chromatography (MeOH / DCM system) to obtain 0.80 g of a yellow solid.

[1144] 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.

[1145]

[1146] At room temperature, 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 (0.80 g, 1.75 mmol), TFA (2 mL), and DCM (10 mL) were successively added to a single-necked flask. The reaction was terminated after reacting at room temperature for 3 h. The crude product of the yellow solid, 0.70 g, was obtained by concentration.

[1147] 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]heptan-2-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)pyrimidine-2,4(1H,3H)-dione.

[1148]

[1149] At room temperature, 1-(5-fluoro-1-methyl-6-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-indazol-3-yl)pyrimidine-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 successively added to a single-necked flask. The reaction was carried out at room temperature for 16 h, and then sodium triacetoxyborohydride (0.18 g, 0.84 mmol) was added and the reaction was continued for 1 h. Water (1 mL) was added, and the mixture was stirred for 5 min. It was filtered through diatomaceous earth, and the filtrate was concentrated and purified by column chromatography (MeOH / DCM system) to obtain 0.20 g of a white solid.

[1150] 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]heptan-2-yl)-1-methyl-1H-indazol-3-yl)pyrimidine-2,4(1H,3H)-dione.

[1151]

[1152] 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-diazas...

Claims

1. A compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof: ABC (i) in, A is X is selected from N or CH; Cy1 is selected from (For example )and Said (For example )and are unsubstituted, or are each independently substituted with 1 to 3 R a1 substituted; G is selected from unsubstituted or optionally substituted with one, two or more R a1 Substituted with the following groups: C 6-10 Aryl or 5-10 membered heteroaryl, such as phenyl, pyridyl, pyrimidinyl; Each R a1 are independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 Alkyl)2-aminocarbonyl; B is -L2-Cy2-L3-Cy3-L4-Cy4-L5-; L1, L2, L3, L4, L5, L6 are independently selected from a bond, -(CH2) n -(NH) m -, -O-, -S-, -NR2, -CR 31 R 32 -, -C(O)-, -C(O)O-, -C(O)NR4-, -NR5-C(O)-, -S(O)-, -S(O)2-, -P(O)(R6)-, C 2-8 Alkenyl and C 2-8 Alkynyl; n and m are each independently any integer from zero to six; R2, R 31 , R 32 R4, R5 and R6 are independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2aminocarbonyl, wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 The aminocarbonyl group is 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 Alkoxy C 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 C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy group substitution; Cy2 is selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic group, 3-13 membered cycloalkenyl, 1-3 R a2 Substituted 3-13-membered cycloalkyl, 1-3 R a2 substituted 3-13 membered heterocyclic group, 1-3 R a2 Substituted 3-13 membered cycloalkenyl, Cy21-Cy22, wherein the heteroatom of the 3-13 membered heterocyclic group 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 heterocyclic group, 3-13 membered cycloalkenyl; Cy3 is selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic group, 6-13 membered bicyclic condensed ring group or 8-21 membered polycyclic condensed ring group, wherein the 3-13 membered cycloalkyl, 3-13 membered heterocyclic group, 6-13 membered bicyclic condensed ring group or 8-21 membered polycyclic condensed ring group is unsubstituted or each of them is independently substituted with 1-5 R a3 Substitution, preferably 5-6 membered heterocyclic group, wherein the heteroatom of the 5-6 membered heterocyclic group is N, O, S, Si; Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclic group, 1-3 R a4 Substituted 3-8 membered cycloalkyl, 1-3 R a4 substituted 3-8 membered heterocyclic group, 1-3 R a4 Substituted 3-8 membered cycloalkenyl, 1-3 R a4 Substituted 6-13 bicyclic condensed ring cycloalkyl, 1-3 R a4 Substituted 6-13 membered bicyclic condensed cycloalkenyl, 1-3 R a4 A substituted 6-13 membered bicyclic fused ring heterocyclic group, wherein the heteroatom of the 3-8 membered heterocyclic group or the 6-13 membered bicyclic fused ring heterocyclic group is selected from O, N or S; Each R a2 , R a3 and R a4 When present, each is independently selected from hydrogen, deuterium, halogen, hydroxyl, thiol, silanol, selenohydroxyl, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-C(O)O-, C 1-6 Alkylthio, C 1-6 Alkyl selenyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkyl-C(O)NH-, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, 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 heterocyclic group, 3-8-membered cycloalkenyl, wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, 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, unsubstituted or optionally substituted with one or more selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 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 C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl; C is 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 independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, 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 replaced by 1-3 R a5 replace; Each R a5 are independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, halogenated 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, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, halogenated 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)2-aminocarbonyl, 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 Alkoxy C 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 C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy group substitution; The condition is that when Cy3 is hour, Not for 2. The compound of formula (i) according to claim 1, its isomer or a pharmaceutically acceptable salt thereof, wherein: Cy1 is selected from * terminal is connected to L1; Preferably, the are unsubstituted, or are each independently substituted with 1 to 3 R a1 More preferably, each R a1 Each is independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 More preferably, each R a1 Each is independently substituted by 1-3 halogens (such as F) or C 1-6 Alkyl (such as methyl) substitution; Preferably, Cy1 is selected from *Terminal is connected to L1.

3. The compound of formula (i) according to claim 1 or 2, its isomer or a 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)-; Preferably, L1 is selected from a bond, -NHC(O)-; preferably, when L1 is -NHC(O)-, the C(O) terminus is connected to Cy1; Preferably, L2 is selected from a bond, NH or NH(C 1-3 Alkylene); Preferably, L2 is selected from a bond, NH or NHCH2; preferably a bond; Preferably, L3 is selected from C 1-3 Alkylene, -C(O)-, -CH2NR4-, -NR5-CH2- or NH(C 1-3 R4, R5 are independently selected from C 3-6 Cycloalkyl; Preferably, L3 is selected from methylene, -C(O)- or NHCH2; preferably methylene; Preferably, L4 is selected from a bond, C 1-3 Alkylene or -C(O)-; Preferably, L4 is selected from a bond, a methylene group or -C(O)-; preferably a methylene group; Preferably, L5 is selected from a bond or C 1-3 Alkylene; Preferably, L5 is selected from a bond or a methylene group; preferably a bond; Preferably, L6 is selected from a bond or -O-; preferably a bond.

4. The compound of formula (i) according to any one of claims 1 to 3, its isomer or a pharmaceutically acceptable salt thereof, wherein Cy2 is selected from a 4-10 membered cycloalkyl, a 4-10 membered heterocyclic group, a 4-10 membered cycloalkenyl group, a a2 Substituted 4-10 membered cycloalkyl, 1-3 R a2 substituted 4-10 membered heterocyclic group, 1-3 R a2 Substituted 4-10 membered cycloalkenyl, Cy21-Cy22, wherein the heteroatom of the 4-10 membered heterocyclic group 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 heterocyclic group, 4-6 membered cycloalkenyl; Preferably, Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl, a2 Substituted 4-6 membered cycloalkyl, 1-3 R a2 substituted 4-6 membered heterocyclic group, 1-3 R a2 A substituted 4-6 membered cycloalkenyl group, wherein the heteroatom of the 4-6 membered heterocyclic group is selected from O, N or S; Preferably, Cy2 is selected from unsubstituted or substituted with 1-3 R a2 Substituted 6-9 membered heterocyclic group, Cy21-Cy22; Cy21 and Cy22 are the same or different and are independently selected from cyclohexyl, piperazinyl, piperidinyl; Preferably, Cy2 is selected from unsubstituted or substituted with 1-3 R a2 Substituted piperazinyl, piperidinyl, Preferably, Cy2 is selected from (For example ), (For example ), (For example ), * end connected to Cy1; 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; Preferably, Cy3 is selected from 5-6 membered cycloalkyl or 5-6 membered heterocyclic group; the 5-6 membered cycloalkyl or 5-6 membered heterocyclic group is unsubstituted or each is independently substituted with 1-3 R a3 replace; 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 Substituted; preferably cyclohexyl; Preferably, Cy3 is selected from Said are unsubstituted or are each independently substituted with 1 to 3 R a3 replace; Preferably, Cy4 is selected from unsubstituted or optionally substituted with one, two or more C 1-6 Alkyl or C 1-6 Alkoxy-substituted 5-6-membered heterocyclic group; Preferably, Cy4 is selected from piperazinyl, such as * end is connected to L5; Preferably, Cy5 is selected from unsubstituted or substituted with 1-3 R a5 Substituted groups: 6-13 membered bicyclic cycloalkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclic group; Preferably, Cy5 is selected from unsubstituted or substituted with 1-3 OH or phenyl groups. For example Preferably, Cy5 is For example 5. The compound of formula (i) according to any one of claims 1 to 4, its isomer or a pharmaceutically acceptable salt thereof, wherein: R a1 Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy; Preferably, R a1 Selected from F, methyl, ethyl, methoxy; Preferably, R a2 , R a3 and R a4 are the same or different and are independently selected from H, OH, amino, thiol, silanol, selenohydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-NH-, C 3-6 Cycloalkyl, C 1-6 Alkyl-C(O)NH-, halo-C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 alkyl; Preferably, R a2 Selected from H, OH, amino, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-NH-, C 3-6 Cycloalkyl, C 1-6 Alkyl-C(O)NH-; Preferably, R a2 is selected from H, F, OH, amino, methylamino, acetamido, methyl, methoxy, and cyclopropyl; Preferably, R a3 and R a4 are the same or different and are independently selected from H, halogen; Preferably, R a3 and R a4 The same or different, independently selected from H, F; Preferably, R a5 Selected from hydroxyl or C 6-10 Aryl; Preferably, R a5 Selected from hydroxyl or phenyl; Preferably, R a5 Selected from hydroxyl or C 6-10 Aryl, halogen substituted C 6-10 Aryl; Preferably, Selected from unsubstituted or optionally substituted by R b1 , R b2 , R b3 , R b4 , R b5 The following groups substituted by 1 to 4 substituents in: phenyl, 6-membered heteroaryl containing 1 or 2 heteroatoms, for example 6. The compound of formula (i) according to any one of claims 1 to 5, its isomer or a pharmaceutically acceptable salt thereof, wherein: Has the following structure: Wherein, Y is selected from N or CR a2 ; X, L1, Cy1, R a2 It has the definition as described in any one of claims 1 to 5.

7. The compound represented by formula (i-1) according to claim 6, its isomer or a pharmaceutically acceptable salt thereof, wherein: Has the following structure: Wherein, Y is selected from N or CR a2 ; X, L1, Cy1, R a2 It has the definition as described in any one of claims 1 to 5.

8. The compound of formula (i) according to any one of claims 1 to 5, its isomer or a pharmaceutically acceptable salt thereof, wherein: Has the following structure: 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, L2, L3, L4, L5, L6, Cy2, Cy4, Cy5, R a1 , R a3 , X1, X2, X4, X5 have the definitions as described in any one of claims 1-5.

9. The compound represented by formula (i-2) according to claim 8, its isomer or a pharmaceutically acceptable salt thereof, wherein: Has the following structure: Wherein, Z3 is selected from N, C or CR a4 ; Indicates a single bond or a double bond; G, Y, Z1, Z2, R b1 , R b2 , R b4 , R b5 , R a1 , R a5 It has the definition as described in any one of claims 1 to 5.

10. 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:

11. 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.

12. 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 drug for treating and / or preventing a disease or condition by degrading a target protein; 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; 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; 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.

13. 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 an estrogen receptor-mediated or dependent disease or condition, wherein the estrogen receptor-mediated or dependent disease or condition is a tumor, preferably cancer, more preferably breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer and fallopian tube tumor, and most preferably breast cancer.

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