EGFR degradant, and preparation method and use therefor

Abstract

As shown in formula (I), a bifunctional chimeric heterocyclic compound targeting the epidermal growth factor receptor (EGFR), and a pharmaceutical composition thereof, a preparation method therefor and a use thereof. The bifunctional chimeric heterocyclic compound is prepared by recruiting E3 ubiquitin ligase to the EGFR, thereby promoting the ubiquitination of the EGFR and degradation of same by a proteasome. Research results show that the compound shows good EGFR degradation activity and can be used for treating EGFR-mediated diseases.

Description

An EGFR degradation agent and its preparation method and use Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a novel bifunctional compound capable of degrading EGFR or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, deuterated compounds, and pharmaceutical compositions, preparation methods, and uses thereof. Background Art

[0002] Cancer is currently one of the most serious diseases threatening human health. With the development of targeted drugs, progress has been made in the treatment of cancer. For example, small molecule inhibitors targeting the epidermal growth factor receptor (EGFR) can selectively block the binding of EGFR to ATP, thereby inhibiting EGFR activation and downstream signaling pathways, leading to stagnation of cell growth, proliferation, and metastasis, and subsequently apoptosis, thereby achieving effective control of EGFR-mediated tumors. Unfortunately, acquired drug resistance is common after the clinical use of EGFR inhibitors. The main cause is point mutations in EGFR that prevent small molecules from effectively binding to it, resulting in a decrease or even disappearance of inhibitory effects, such as the most common T790M mutation. To address this situation, researchers have gradually developed a new generation of inhibitors that can effectively overcome the resistance problem of the previous generation. Currently, third-generation EGFR inhibitors (such as osimertinib and ametinib) can effectively overcome the T790M mutation and have weaker activity against wild-type EGFR, reducing the toxic side effects of second-generation drugs. However, resistance to osimertinib has emerged (Nature Medicine, 2015, 21, 560-562). The primary mechanism is the mutation of the cysteine ​​residue at position 797 of the EGFR to a serine residue (C797S), which results in the loss of the covalent bond between the cysteine ​​residue and the inhibitor, leading to resistance. Therefore, developing fourth-generation EGFR therapeutics that can overcome the C797S mutation is of great significance and clinical value.

[0003] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. These compounds can be recognized by the cell's proteasome, causing degradation of the target protein and effectively reducing the target protein's content in the cell. By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology can be applied to the treatment of various diseases. In recent years, some patents (WO2019149922A1, WO2021127561A1, WO2022194269A1, WO2022012622A1, WO2022228547A, etc.) have reported that a series of PROTAC-type compounds can overcome the drug resistance problem of C797S by degrading EGFR protein, which has become a new research direction. Among them, the EGFR-PROTAC bifunctional molecules of HSK40118 of Sichuan Hiseco, HJ-002-03 of Hejing Pharmaceutical Technology (Shanghai) Co., Ltd. and CFT8919 of C4 Company have been approved for clinical use.

[0004] Although some progress has been made in EGFR allosteric inhibitors and EGFR degraders, the clinical demand for treating EGFR protein-related diseases has not yet been met. Therefore, the development of new PROTAC drugs that bind to EGFR protein and E3 ubiquitin ligase for the treatment of EGFR protein-related diseases will be full of application prospects.

[0005] Summary of the Invention

[0006] The present invention aims to provide a novel bifunctional compound capable of inhibiting and degrading EGFR, or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, deuterated compounds, and pharmaceutical compositions, preparation methods, and uses thereof for treating EGFR-related diseases.

[0007] The present invention also aims to provide a novel bifunctional compound that can degrade mutant EGFR protein, significantly inhibit the proliferation of cells with mutant EGFR protein, but has no proliferation inhibitory effect on cells with wild-type EGFR, and has high selectivity and / or oral bioavailability, or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, deuterated compounds, and pharmaceutical compositions, preparation methods and uses for treating EGFR-related diseases.

[0008] The first aspect of the present invention provides a compound represented by the following formula (I) or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, and deuterated compounds:

[0009] in,

[0010] Z1, Z2, Z3, and Z4 are independently selected from: N or CR 6 , the R 6 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogen, 4-6 membered heterocyclic group or 5-6 membered heteroaryl, wherein the cycloalkyl or heteroaryl group may be substituted by one or more C 1-6 Alkyl, C 1-6 Alkoxy or halogen atom substitution;

[0011] R 1 、R 2 are independently selected from: hydrogen, deuterium, C 1-6 Alkyl or C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 3-6 The cycloalkyl group may be substituted with 1-5 (e.g., 1, 2, 3, 4, 5) substituents selected from deuterium and halogen;

[0012] R 3 Selected from: hydrogen, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl, the C 1-6 Alkyl or C 1-6 The alkoxy group may be substituted by one or more halogen atoms;

[0013] R 4 Selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 2-6 Alkynyl, the C 1-6 Alkyl or C 1-6 The alkoxy group may be substituted by one or more halogen atoms;

[0014] R 5 Selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, phenyl, heteroaryl may be substituted by 1-4 (e.g., 1, 2, 3, 4) selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6The cycloalkyl group is substituted by a substituent, and the heterocyclic group or heteroaryl group contains 1 to 3 heteroatoms independently selected from O, S or N;

[0015] L represents a connecting chain selected from -L1-L2-L3-L4-L5-, wherein,

[0016] L1 is selected from 3-12 membered heterocyclic diyl or C 3-10 Cycloalkanediyl, the heterocyclic diyl or cycloalkanediyl is optionally substituted by 1 to 4 (e.g., 1, 2, 3, 4) selected from deuterium, halogen, hydroxyl, amino, -OR L1 、-N(R L1 )(R L1’ ) substituted, wherein R L1 、R L1’ are independently selected from hydrogen, deuterium or C 1-6 alkyl;

[0017] L2, L3, L4 and L5 are independently selected from a bond, C 1-6 Alkylene, 3-12 membered heterocyclic diyl, C 3-12 Cycloalkanediyl, C 2-6 Alkenylene, C 2-6 Alkynylidene, -C(O)-, -C(O)-C 1-6 Alkylene-, -C(O)-N(R L2 )-、-O-、-N(R L2 )-, -S-, -C(S)-, -C(O)-O-, -C(S)-O-, -S(O)2-, -S(O)(R L2 )=N-, -S(O)2NH- or -C=N-; wherein the C 3-12 The cycloalkanediyl and 3-12 membered heterocyclic diyl may be optionally each independently replaced by one or more R L3 Substitution; said C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 The alkynylene groups may be optionally each independently replaced by one or more R L4 replace;

[0018] In this article, L5 (if L5 exists) is connected to LBM, or L4 (if L5 does not exist) is connected to LBM;

[0019] R L2 Selected from hydrogen or C 1-6 Alkyl, which may be optionally substituted with one or more deuterium groups;

[0020] Each R L3 Each independently selected from oxo, hydroxy, -OC 1-6 Alkyl, halogen, nitro, cyano, amino, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 1-6 a haloalkyl group or a 3-12 membered heterocyclic group;

[0021] Each R L4 Each independently selected from halogen, oxo, cyano, hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl or -OC 1-6 Alkyl; wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl or -OC 1-6 The alkyl group may be substituted by 1-3 F atoms;

[0022] LBM is a group that binds to ubiquitin ligase.

[0023] In some embodiments of the present invention,

[0024] Z1, Z2, Z3, and Z4 are independently selected from: N or CR 6 , the R 6 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or halogen;

[0025] R 1 、R 2 are independently selected from: hydrogen, deuterium, C 1-6 Alkyl or C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl can be substituted by 1-5 deuterium or halogen;

[0026] R 3 Selected from: hydrogen, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl, the C 1-6 Alkyl or C 1-6 The alkoxy group may be substituted by one or more halogen atoms;

[0027] R 4 Selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 2-6 Alkynyl, the C 1-6 Alkyl or C 1-6 The alkoxy group may be substituted by one or more halogen atoms;

[0028] R 5 Selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-8 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, phenyl or heteroaryl may be substituted by 1-4 deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl substituted, the heterocyclic group or heteroaryl group contains 1-3 heteroatoms independently selected from O, S or N;

[0029] L represents a connecting chain selected from -L1-L2-L3-L4-, wherein,

[0030] L1 is selected from 3-12 membered heterocyclic diyl or C 3-10 Cycloalkanediyl, the heterocyclic diyl or cycloalkanediyl is optionally substituted by 1 to 4 deuterium, halogen, hydroxyl, amino, -OR L1 、-N(R L1 )(R L1’ ) substituted, wherein R L1 、R L1’ are independently selected from hydrogen, deuterium or C 1-6 alkyl;

[0031] L2, L3 and L4 are independently selected from a bond, C 1-6 Alkylene, 3-12 membered heterocyclic diyl, C 3-12 Cycloalkanediyl, C 2-6 Alkenylene, C 2-6 Alkynylidene, -C(O)-, -C(O)-C 1-6 Alkylene-, -C(O)-N(R L2 )-、-O-、-N(R L2 )-, -S-, -C(S)-, -C(O)-O-, -C(S)-O-, -S(O)2-, -S(O)(R L2 )=N-, -S(O)2NH- or -C=N-; wherein the C 3-12 The cycloalkanediyl and 3-12 membered heterocyclic diyl may be optionally each independently replaced by one or more R L3 Substitution; said C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkyne groups may be optionally each independently replaced by one or more R L4 replace;

[0032] R L2 Selected from hydrogen or C1-6 Alkyl, which may be optionally substituted with one or more deuterium groups;

[0033] Each R L3 Each independently selected from oxo, hydroxy, -OC 1-6 Alkyl, halogen, nitro, cyano, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 1-6 a haloalkyl group or a 3-12 membered heterocyclic group;

[0034] Each R L4 Each independently selected from halogen, oxo, cyano, hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl or -OC 1-6 Alkyl; wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl or -OC 1-6 The alkyl group may be substituted by 1-3 F atoms;

[0035] LBM is a group that binds to ubiquitin ligase.

[0036] In some embodiments of the present invention,

[0037] Z1, Z2, Z3, Z4 are selected from: N or CR 6 , the R 6 Selected from hydrogen, C 1-6 Alkyl or C 1-6 alkoxy;

[0038] R 1 、R 2 are independently selected from: hydrogen, deuterium, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the alkyl and cycloalkyl groups may be substituted with 1 to 5 deuterium or halogen;

[0039] R 3 Selected from: hydrogen, halogen, cyano, nitro, C 1-6 Alkyl or C 1-6 Alkoxy,;

[0040] R 4 Selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 Alkynyl;

[0041] R 5 Selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-8 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, phenyl or heteroaryl may be substituted by 1-4 deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl substituted, the heterocyclic group or heteroaryl group contains 1-3 heteroatoms independently selected from O, S or N;

[0042] L represents a connecting chain selected from -L1-L2-L3-L4-, wherein,

[0043] L1 is selected from 3-12 membered heterocyclic diyl or C 3-10 Cycloalkanediyl, the heterocyclic diyl or cycloalkanediyl is optionally substituted by 1 to 4 deuterium, halogen, hydroxyl, amino, -OR L1 、-N(R L1 )(R L1’ ) substituted, wherein R L1 、R L1’ are independently selected from hydrogen, deuterium or C 1-6 alkyl;

[0044] L2, L3 and L4 are independently selected from a bond, C 1-6 Alkylene, 3-12 membered heterocyclic diyl, C 3-12 Cycloalkanediyl, C 2-6 Alkenylene, C 2-6 Alkynylidene, -C(O)-, -C(O)-N(R L2 )-、-O-、-N(R L2 )-, -S-, -C(S)-, -C(O)-O-, -C(S)-O-, -S(O)2-, -S(O)(R L2 )=N-, -S(O)2NH- or -C=N-; wherein the C 3-12 The cycloalkanediyl and 3-12 membered heterocyclic diyl may be optionally each independently replaced by one or more R L3 Substitution; said C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 The alkynylene groups may be optionally each independently replaced by one or more R L4 replace;

[0045] R L2 Selected from hydrogen or C 1-6 Alkyl, which may be optionally substituted with one or more deuterium groups;

[0046] Each R L3Each independently selected from oxo, hydroxy, -OC 1-6 Alkyl, halogen, nitro, cyano, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 1-6 a haloalkyl group or a 3-12 membered heterocyclic group;

[0047] Each R L4 Each independently selected from halogen, oxo, cyano, hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl or -OC 1-6 Alkyl; wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl or -OC 1-6 The alkyl group may be substituted by 1-3 F atoms;

[0048] LBM is a group that binds to ubiquitin ligase.

[0049] In some embodiments of the present invention,

[0050] R 1 、R 2 are independently selected from: hydrogen, deuterium, C 1-3 Alkyl or C 3-4 Cycloalkyl, the alkyl and cycloalkyl groups may be substituted by 1 to 5 deuterium or halogen.

[0051] In some embodiments of the present invention,

[0052] R 4 Selected from: hydrogen, deuterium, halogen, C 1-3 Alkyl or C 1-3 alkoxy;

[0053] In some embodiments of the present invention,

[0054] R 5 Selected from: hydrogen, C 1-3 Alkyl, C 2-4 Alkenyl, C 3-4 Cycloalkyl or 5 to 6 membered heteroaryl, wherein the alkyl, alkenyl, cycloalkyl or heteroaryl may be substituted by 1 to 4 deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl or C 1-3 The heteroaryl group is substituted with an alkoxy group, and the heteroaryl group contains 1-2 nitrogen atoms.

[0055] In some embodiments of the present invention,

[0056] Z1, Z2, Z3, and Z4 are independently selected from N or CR 6 , the R 6 Selected from hydrogen, C1-3 Alkyl, C 1-3 Alkoxy, C 3- 6 cycloalkyl or halogen;

[0057] R 1 、R 2 Each is independently selected from: hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

[0058] R 3 Selected from: hydrogen, F, Cl, Br, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group may be substituted by one or more F, Cl or Br atoms;

[0059] R 4 is selected from: hydrogen, methoxy, ethoxy or isopropoxy, wherein the methoxy, ethoxy or isopropoxy may be substituted by one or more halogen atoms;

[0060] R 5 Selected from: hydrogen, C 1-3 Alkyl, C 2-4 Alkenyl, C 3-4 Cycloalkyl or 5 to 6 membered heteroaryl, wherein the alkyl, alkenyl, cycloalkyl or heteroaryl may be substituted by 1 to 4 deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl or C 1-3 The heteroaryl group is substituted with an alkoxy group, and the heteroaryl group contains 1-2 nitrogen atoms.

[0061] In some embodiments of the present invention,

[0062] Z1, Z2, Z3, and Z4 are independently selected from N or CR 6 , the R 6 Selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 3- 6-membered cycloalkyl, halogen or 5-6-membered heteroaryl, wherein the cycloalkyl or heteroaryl may be C 1-3 Alkyl, C 1-3 Alkoxy or F atom substitution;

[0063] R 1 、R 2 Each is independently selected from: hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

[0064] R 3 Selected from: hydrogen, F, Cl, Br, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C1-3 The alkoxy group may be substituted by one or more F, Cl or Br atoms;

[0065] R 4 is selected from: hydrogen, methoxy, ethoxy or isopropoxy, wherein the methoxy, ethoxy or isopropoxy may be substituted by one or more halogen atoms;

[0066] R 5 Selected from: hydrogen, C 1-3 Alkyl, C 2-4 Alkenyl, C 3-4 Cycloalkyl or 5 to 6 membered heteroaryl, wherein the alkyl, alkenyl, cycloalkyl or heteroaryl may be substituted by 1 to 4 deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl or C 1-3 The heteroaryl group is substituted with an alkoxy group, and the heteroaryl group contains 1-2 nitrogen atoms.

[0067] In some embodiments of the present invention,

[0068] Z1, Z2, Z3, and Z4 are independently selected from N or CR 6 , the R 6 is selected from hydrogen, methyl, ethyl, cyclopropyl, F, Br or pyrazolyl, which may be substituted with methyl or ethyl;

[0069] R 1 、R 2 are independently selected from: hydrogen, methyl, ethyl, isopropyl or cyclopropyl;

[0070] R 3 is selected from the group consisting of hydrogen, F, Cl, Br, methyl, ethyl, isopropyl, methoxy or ethoxy, wherein the methyl, ethyl, isopropyl, methoxy or ethoxy may be substituted by one or more F, Cl or Br atoms;

[0071] R 4 is selected from: hydrogen, methoxy, ethoxy or isopropoxy, wherein the methoxy, ethoxy or isopropoxy may be substituted by one or more F, Cl or Br atoms;

[0072] R 5 Selected from: hydrogen, C 1-3 Alkyl, C 2-4 Alkenyl, C 3-4 Cycloalkyl or 5 to 6 membered heteroaryl, wherein the alkyl, alkenyl, cycloalkyl or heteroaryl may be substituted by 1 to 4 deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl or C 1-3 The heteroaryl group is substituted with an alkoxy group, and the heteroaryl group contains 1-2 nitrogen atoms.

[0073] In some embodiments of the present invention,

[0074] Z1, Z2, Z3, and Z4 are independently selected from N or CR 6 , the R 6 Selected from hydrogen, methyl, ethyl, cyclopropyl, F, Br or

[0075] R 1 、R 2 are independently selected from: hydrogen, methyl, ethyl, isopropyl or cyclopropyl;

[0076] R 3 Selected from: hydrogen, F, Cl or Br;

[0077] R 4 is selected from: hydrogen, methoxy, ethoxy or isopropoxy, wherein the methoxy, ethoxy or isopropoxy may be substituted by 1 or 3 F, Cl or Br atoms;

[0078] R 5 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, vinyl, propenyl or pyrazolyl, wherein the pyrazolyl may be substituted with methyl or ethyl; further preferably methyl, ethyl, vinyl, isopropyl, cyclopropyl or

[0079] In some embodiments of the present invention,

[0080] Z1, Z2, Z3, and Z4 are independently selected from N or CR 6 , the R 6 is selected from hydrogen, methyl, ethyl, cyclopropyl, F or Br;

[0081] R 1 、R 2 are independently selected from: hydrogen, methyl, ethyl, isopropyl or cyclopropyl;

[0082] R 3 is selected from the group consisting of hydrogen, F, Cl, Br, methyl, ethyl, isopropyl, methoxy or ethoxy, wherein the methyl, ethyl, isopropyl, methoxy or ethoxy may be substituted by one or more F, Cl or Br atoms;

[0083] R 4 is selected from: hydrogen, methoxy, ethoxy or isopropoxy, wherein the methoxy, ethoxy or isopropoxy may be substituted by one or more F or Br atoms;

[0084] R 5 Selected from: hydrogen, C 1-3 Alkyl, C 2-4 Alkenyl, C 3-4 Cycloalkyl or 5 to 6 membered heteroaryl, wherein the alkyl, alkenyl, cycloalkyl or heteroaryl may be substituted by 1 to 4 deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl or C1-3 The heteroaryl group is substituted with an alkoxy group, and the heteroaryl group contains 1-2 nitrogen atoms.

[0085] In some embodiments of the present invention,

[0086] Z1, Z2, Z3, and Z4 are independently selected from N or CR 6 , the R 6 is selected from hydrogen, methyl, ethyl, cyclopropyl, F or Br;

[0087] R 1 、R 2 are independently selected from: hydrogen, methyl, ethyl, isopropyl or cyclopropyl;

[0088] R 3 Selected from: hydrogen, F, Cl or Br;

[0089] R 4 is selected from: hydrogen, methoxy, ethoxy or isopropoxy, wherein the methoxy, ethoxy or isopropoxy may be substituted by one or more F or Br atoms;

[0090] R 5 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, vinyl, propenyl or pyrazolyl, wherein the pyrazolyl may be substituted with methyl or ethyl; further preferably methyl, ethyl, vinyl, cyclopropyl or

[0091] In some embodiments of the present invention,

[0092] Z1 and Z4 are selected from N; Z2 and Z3 are selected from CR 6 , the R 6 Selected from hydrogen, C 1-6 Alkyl or C 1-6 alkoxy;

[0093] R 1 、R 2 are independently selected from: hydrogen, methyl, ethyl, isopropyl or cyclopropyl;

[0094] R 3 Selected from: hydrogen, F, Cl or Br;

[0095] R 4 is selected from: hydrogen, methoxy, ethoxy or isopropoxy, wherein the methoxy, ethoxy or isopropoxy may be substituted by one or more halogen atoms;

[0096] R 5 Selected from: hydrogen, C 1-3 Alkyl, C 2-4 Alkenyl, C 3-4Cycloalkyl or 5 to 6 membered heteroaryl, wherein the alkyl, alkenyl, cycloalkyl or heteroaryl may be substituted by 1 to 4 deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl or C 1-3 The heteroaryl group is substituted with an alkoxy group, and the heteroaryl group contains 1-2 nitrogen atoms.

[0097] In some embodiments of the present invention,

[0098] Z1 and Z4 are selected from N; Z2 and Z3 are selected from CR 6 , the R 6 Selected from hydrogen, C 1-6 Alkyl or C 1-6 alkoxy;

[0099] R 1 、R 2 are independently selected from: hydrogen, methyl, ethyl, isopropyl or cyclopropyl;

[0100] R 3 Selected from: hydrogen, F, Cl or Br;

[0101] R 4 Selected from: hydrogen, methoxy, ethoxy or isopropoxy;

[0102] R 5 Selected from: hydrogen, C 1-3 Alkyl, C 2-4 Alkenyl, C 3-4 Cycloalkyl or 5 to 6 membered heteroaryl, wherein the alkyl, alkenyl, cycloalkyl or heteroaryl may be substituted by 1 to 4 deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl or C 1-3 The heteroaryl group is substituted with an alkoxy group, and the heteroaryl group contains 1-2 nitrogen atoms.

[0103] In some embodiments of the present invention,

[0104] Z1 and Z4 are selected from N; Z2 and Z3 are selected from -CR 6 -, the R 6 is selected from hydrogen, methyl or methoxy;

[0105] R 1 、R 2 Each independently selected from: hydrogen, methyl or ethyl;

[0106] R 3 Selected from: hydrogen, Cl or Br;

[0107] R 4 Selected from: hydrogen, methoxy or ethoxy;

[0108] R 5is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, vinyl, propenyl or pyrazolyl, which may be substituted by methyl or ethyl.

[0109] In some embodiments of the present invention,

[0110] Z1 and Z4 are selected from N; Z2 and Z3 are selected from -CR 6 -, the R 6 is selected from hydrogen, methyl or methoxy;

[0111] R 1 、R 2 Each independently selected from: hydrogen, methyl or ethyl;

[0112] R 3 Selected from: hydrogen, Cl or Br;

[0113] R 4 Selected from: hydrogen, methoxy or ethoxy, wherein the methoxy or ethoxy may be substituted by one or more F or Br atoms;

[0114] R 5 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, vinyl, propenyl or pyrazolyl, wherein the pyrazolyl may be substituted with methyl or ethyl; further preferably methyl, ethyl, vinyl, cyclopropyl or

[0115] In some embodiments of the present invention, the LBM is selected from the following compound of formula (B-1) or a stereoisomer thereof:

[0116] Wherein, W is selected from C(R b ) or N, said R b Selected from hydrogen or C 1-6 alkyl;

[0117] X1 is selected from CH2 or C=O;

[0118] Each R a Each independently selected from halogen, nitro, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl or -OC 1-4 alkyl;

[0119] q is selected from 0, 1, 2 or 3.

[0120] In some embodiments of the present invention, the compound of formula (B-1) or its stereoisomers:

[0121] W is selected from CH or N;

[0122] X1 is selected from CH2 or C=O;

[0123] R a Selected from halogen, nitro, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl or -OC 1-4 alkyl;

[0124] q is selected from 0 or 1.

[0125] In some embodiments of the present invention, the compound of formula (B-1) or its stereoisomers:

[0126] W is selected from CH;

[0127] X1 is selected from CH2 or C=O;

[0128] R a Selected from halogen, nitro, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl or -OC 1-4 alkyl;

[0129] q is selected from 0 or 1.

[0130] In some embodiments of the present invention, the LBM is selected from:

[0131] In some embodiments of the present invention, the LBM is selected from a compound of formula (B-2) or a stereoisomer thereof:

[0132] wherein M1 is selected from NH, O or S;

[0133] W and M2 are independently selected from CH or N;

[0134] M3 selected from CR c or N, the R c Selected from hydrogen, hydroxyl, -OC 1-4 Alkyl, -OC 1-4 Alkylene-4-6 membered heterocyclic group, wherein the heterocyclic group may be optionally substituted by hydroxyl, halogen, C 1-4 Alkyl or C 1-4 Alkoxy substituted, the heterocyclic group contains 1-3 heteroatoms selected from O, S or N;

[0135] R d is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, F, Cl, nitro, cyano, hydroxy or methoxy;

[0136] Y is selected from absent or -NR e -;

[0137] R e Selected from H or C1-4 alkyl.

[0138] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-2-1):

[0139] wherein M1 is selected from O or S;

[0140] W and M2 are independently selected from CH or N;

[0141] M3 selected from CR c or N, the R c Selected from H, hydroxyl, -O-CH3, -O-CH2CH3, -OC 1-4 Alkyl-4-6 membered heterocyclyl, wherein the heterocyclyl may be optionally substituted with methyl or ethyl;

[0142] R d Can be selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, F, Cl or Br;

[0143] Y is selected from absent or -NH-.

[0144] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-2-1') or formula (B-2-1"):

[0145] wherein M1 is selected from O or S;

[0146] W and M2 are independently selected from CH or N;

[0147] M3 is selected from CRc or N, wherein Rc is selected from H, hydroxyl, -O-CH3, -O-CH2CH3, -OC 1-4 Alkyl-4-6 membered heterocyclyl, wherein the heterocyclyl may be optionally substituted with methyl or ethyl;

[0148] Rd may be selected from methyl, ethyl, n-propyl, isopropyl, F, Cl or Br.

[0149] In some embodiments of the present invention, the LBM is selected from:

[0150] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-3):

[0151] wherein W, M4 and M5 are each independently selected from CH or N;

[0152] In some embodiments of the present invention, the LBM is selected from:

[0153] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-4):

[0154] wherein W and M6 are independently selected from CH or N;

[0155] R f is selected from hydrogen, methyl, ethyl, n-propyl or isopropyl.

[0156] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-4-1):

[0157] Among them, R f is selected from hydrogen, methyl, ethyl, n-propyl or isopropyl.

[0158] In some embodiments of the present invention, the LBM is selected from:

[0159] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-5):

[0160] wherein W and M7 are independently selected from CH or N.

[0161] In some embodiments of the present invention, the LBM is selected from:

[0162] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-6):

[0163] in,

[0164] W is selected from CH or N;

[0165] Ring F is selected from a 5-6 membered heterocyclic group; wherein the heterocyclic group contains 1-3 heteroatoms independently selected from N, O, and S;

[0166] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-6-1):

[0167] Wherein, X2 and X3 are each independently selected from O or S; n is selected from 1 or 2.

[0168] In some embodiments of the present invention, the LBM is selected from:

[0169] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-7):

[0170] Among them, R gSelected from hydrogen, halogen, nitro, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl or -OC 1-4 alkyl;

[0171] R g1 is selected from hydrogen or halogen;

[0172] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-7-1):

[0173] wherein W is selected from CH or N; preferably CH;

[0174] R g Selected from hydrogen, halogen, nitro, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl or -OC 1-4 alkyl;

[0175] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-7-1):

[0176] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-7-1'):

[0177] Among them, R g is selected from hydrogen, methyl or ethyl;

[0178] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-7-1"):

[0179] Among them, R g is selected from hydrogen, methyl or ethyl;

[0180] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-7-2'):

[0181] Among them, R g is selected from hydrogen, methyl or ethyl;

[0182] R g1 is selected from hydrogen, F or Br;

[0183] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-7-2"):

[0184] Among them, R g is selected from hydrogen, methyl or ethyl;

[0185] R g1is selected from hydrogen, F or Br;

[0186] In some embodiments of the present invention, the LBM is selected from:

[0187] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-8):

[0188] in,

[0189] W is selected from CH or N;

[0190] Indicates a single bond or a double bond; when When it represents a single bond, W1 is selected from CH2 or NH; when When representing a double bond, W1 is selected from CH or N;

[0191] Cy2 is selected from 6-8 membered aryl or 5-6 membered heteroaryl; wherein the aryl or heteroaryl may be substituted by 1-2 R h replace;

[0192] Each R h are each independently selected from halogen, nitro, cyano, hydroxy, methyl, ethyl, n-propyl or isopropyl;

[0193] Y1 is selected from: absent, NR i or -C(O)NH-, the R i Selected from H or C 1-4 Alkyl; preferably absent or NR i , the R i Selected from H or C 1-4 alkyl.

[0194] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-8):

[0195] wherein W is selected from CH or N;

[0196] Indicates a single bond or a double bond; when When it represents a single bond, W1 is selected from CH2; when When it represents a double bond, W1 is selected from N;

[0197] Cy2 is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl or pyrrolyl; wherein the phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl or pyrrolyl may be substituted by 1-2 R h replace;

[0198] Each R h Each is independently selected from F, Cl, Br, nitro, cyano, hydroxyl or methyl.

[0199] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-8):

[0200] Wherein, Cy2 is selected from phenyl, pyrimidinyl or pyridinyl; wherein said phenyl, pyrimidinyl or pyridinyl may be R h replace;

[0201] R h Selected from F, Cl, Br, hydroxyl or methyl;

[0202] Y1 is selected from: absent, NH or -C(O)NH-; preferably absent or NH.

[0203] In some embodiments of the present invention, the LBM is selected from:

[0204] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-9):

[0205] wherein X is selected from CH or N; Y is selected from CH or N;

[0206] R h1 Selected from hydrogen, halogen, amino, cyano, nitro, C 1-6 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl;

[0207] R h2 Selected from hydrogen, C 1-6 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl may be substituted by one or more halogen, amino, hydroxyl, carboxyl, cyano groups;

[0208] In one embodiment, R h1 and R h2 At least one of R h1 and R h2 Neither is hydrogen;

[0209] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-9-1):

[0210] wherein Y is selected from CH or N;

[0211] R h1 is selected from hydrogen or halogen; preferably hydrogen, F or Br;

[0212] R h2 Selected from hydrogen or C 1-6Alkyl; preferably hydrogen, methyl, ethyl or isopropyl;

[0213] In one embodiment, R h1 and R h2 At least one of R h1 and R h2 Neither is hydrogen;

[0214] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-9-2):

[0215] wherein Y is selected from CH or N, preferably N;

[0216] R h1 is selected from hydrogen or halogen; preferably hydrogen, F or Br;

[0217] R h2 Selected from hydrogen or C 1-6 Alkyl; preferably hydrogen, methyl, ethyl or isopropyl;

[0218] In one embodiment, R h1 and R h2 At least one of R h1 and R h2 Neither is hydrogen;

[0219] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-9-3):

[0220] wherein Y is selected from CH or N; preferably N;

[0221] R h1 is selected from hydrogen or halogen; preferably hydrogen, F or Br;

[0222] R h2 Selected from hydrogen or C 1-6 Alkyl; preferably hydrogen, methyl, ethyl or isopropyl;

[0223] In one embodiment, R h1 and R h2 At least one of R h1 and R h2 Neither is hydrogen;

[0224] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-9-4):

[0225] wherein Y is selected from CH or N, preferably N;

[0226] R h1is selected from hydrogen or halogen, preferably hydrogen, F or Br;

[0227] R h2 Selected from hydrogen or C 1-6 Alkyl, preferably hydrogen, methyl, ethyl or isopropyl;

[0228] In one embodiment, R h1 and R h2 At least one of R h1 and R h2 Neither is hydrogen;

[0229] In some embodiments of the present invention, the LBM is selected from:

[0230] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-10):

[0231] Among them, R k1 Selected from hydrogen, halogen, amino, cyano, nitro, C1-6 alkyl, 3-6 membered cycloalkyl, 4-6 heterocycloalkyl;

[0232] R k2 Selected from hydrogen, C 1-6 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, wherein the C 1-6 The alkyl group, the 3-6 membered cycloalkyl group, and the 4-6 membered heterocycloalkyl group may be substituted by one or more halogen groups, amino groups, hydroxyl groups, carboxyl groups, and cyano groups.

[0233] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-10-1):

[0234] Among them, R k1 is selected from hydrogen or halogen; preferably hydrogen, F or Br;

[0235] R k2 Selected from hydrogen or C 1-6 Alkyl; preferably hydrogen, methyl, ethyl or isopropyl.

[0236] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-10-2):

[0237] Among them, R k1 is selected from hydrogen or halogen; preferably hydrogen, F or Br;

[0238] R k2 Selected from hydrogen or C 1-6 Alkyl; preferably hydrogen, methyl, ethyl or isopropyl.

[0239] In some embodiments of the present invention, the LBM is selected from:

[0240] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-11):

[0241] wherein X is selected from CH or N;

[0242] R m Selected from hydrogen, halogen, amino, cyano, nitro, C 1-6 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl.

[0243] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-11-1):

[0244] Among them, R m is selected from hydrogen or halogen; preferably hydrogen, F or Br.

[0245] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-11-2):

[0246] Among them, R m is selected from hydrogen or halogen; preferably hydrogen, F or Br.

[0247] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-11-3):

[0248] Among them, R m is selected from hydrogen or halogen; preferably hydrogen, F or Br.

[0249] In some embodiments of the present invention, the LBM is selected from the compound of formula (B-11-4):

[0250] Among them, R m is selected from hydrogen or halogen; preferably hydrogen, F or Br.

[0251] In some embodiments of the present invention, the LBM is selected from:

[0252] In some embodiments of the present invention, the L is selected from -L1-L2-L3-L4-L5, wherein,

[0253] L1 is selected from 4-7 membered monoheterocyclic diyl (e.g. 4, 5, 6, 7 membered monoheterocyclic diyl) or 7-11 membered heterospirocyclic diyl, wherein the monoheterocyclic diyl or heterospirocyclic diyl may be optionally substituted with one to four deuterium, halogen, hydroxyl, amino, -OR L1、-N(R L1 )(R L1’ ) substituted, wherein R L1 、R L1’ are independently selected from hydrogen, deuterium or C 1-3 alkyl;

[0254] L2, L3, L4 and L5 are independently selected from: a bond, C 1-6 Alkylene, 4-7 membered monoheterocyclic diyl, 7-11 membered heterospirocyclic diyl, C 4-7 Cycloalkanediyl, C 2-6 Alkenylene, C 2-4 Alkynylidene, -C(O)-, -C(O)-C 1-3 Alkylene-, -C(O)-N(R L2 )-or-N(R L2 )-; wherein the monoheterocyclic diyl or heterospirocyclic diyl may be optionally substituted by hydroxyl, C 1-3 Alkyl or C 1-3 Alkoxy substituted; R L2 Selected from hydrogen or C 1-3 Alkyl, which may be optionally substituted with 1 to 7 deuterium groups.

[0255] In some embodiments of the present invention, the L is selected from -L1-L2-L3-L4-L5, wherein,

[0256] L1 is selected from a 6-membered monoheterocyclic diyl or a 7-11-membered heterospirocyclic diyl, wherein the monoheterocyclic diyl or heterospirocyclic diyl may be optionally substituted with one to four deuterium, halogen, hydroxyl, amino, -OR L1 、-N(R L1 )(R L1’ ) substituted, wherein R L1 、R L1’ are independently selected from hydrogen, deuterium or C 1-3 alkyl;

[0257] L2, L3, L4 and L5 are independently selected from: a bond, C 1-6 Alkylene, 4-6 membered monoheterocyclic diyl, 7-11 membered heterospirocyclic diyl, C 4-6 Cycloalkanediyl, C 2-4 Alkynylidene, -C(O)-, -C(O)-C 1-3 Alkylene-, -C(O)-N(R L2 )-or-N(R L2 )-; wherein the monoheterocyclic diyl or heterospirocyclic diyl may be optionally substituted by hydroxyl, C 1-3 Alkyl or C 1-3 Alkoxy substituted; R L2 Selected from hydrogen, methyl or ethyl, the alkyl group may be optionally substituted with 1 to 4 deuterium groups.

[0258] In some embodiments of the present invention, the L is selected from -L1-L2-L3-L4-, wherein,

[0259] L1 is selected from 4-7 membered monoheterocyclic diyl or 7-11 membered heterospirocyclic diyl, wherein the monoheterocyclic diyl or heterospirocyclic diyl may be optionally substituted with one to four deuterium, halogen, hydroxyl, amino, -OR L1 、-N(R L1 )(R L1’ ) substituted, wherein R L1 、R L1’ are independently selected from hydrogen, deuterium or C 1-3 alkyl;

[0260] L2, L3 and L4 are independently selected from: a bond, C 1-3 Alkylene, 4-7 membered monoheterocyclic diyl, 7-11 membered heterospirocyclic diyl, C 2-6 Alkenylene, C 2-4 Alkynylidene, -C(O)-, -C(O)-C 1-3 Alkylene-, -C(O)-N(R L2 )-or-N(R L2 )-; wherein the monoheterocyclic diyl or heterospirocyclic diyl may be optionally substituted by hydroxyl, C 1-3 Alkyl or C 1-3 Alkoxy substituted; R L2 Selected from hydrogen or C 1-3 alkyl, which may be optionally substituted with 1 to 7 deuterium groups;

[0261] In some embodiments of the present invention, the L is selected from -L1-L2-L3-L4-, wherein,

[0262] L1 is selected from 4-7 membered monoheterocyclic diyl or 7-11 membered heterospirocyclic diyl, wherein the monoheterocyclic diyl or heterospirocyclic diyl may be optionally substituted with one to four deuterium, halogen, hydroxyl, amino, -OR L1 、-N(R L1 )(R L1’ ) substituted, wherein R L1 、R L1’ are independently selected from hydrogen, deuterium or C 1-3 alkyl;

[0263] L2, L3 and L4 are independently selected from: a bond, C 1-3 Alkylene, 4-7 membered heterocyclic diyl, 7-11 membered heterospirocyclic diyl, C 2-6 Alkenylene, C 2-4 Alkynylidene, -C(O)-, -C(O)-N(R L2 )-or-N(R L2)-; wherein the monoheterocyclic diyl or heterospirocyclic diyl may be optionally substituted by hydroxyl, C 1-3 Alkyl or C 1-3 Alkoxy substituted; R L2 Selected from hydrogen or C 1-3 alkyl, which may be optionally substituted with 1 to 7 deuterium groups;

[0264] In some embodiments of the present invention, the L is selected from -L1-L2-L3-L4-, wherein,

[0265] L1 is selected from a 4-7 membered monoheterocyclic diyl or a 7-11 membered heterospirocyclic diyl, wherein the monoheterocyclic diyl or heterospirocyclic diyl is optionally substituted with hydroxy, methoxy, ethoxy, isopropoxy, -NHCH3, -N(CH3)2, -NHCH2CH3 or -N(CH2CH3)2;

[0266] L2, L3 and L4 are independently selected from: a bond, C 1-3 Alkylene, 4-7 membered monoheterocyclic diyl, 7-11 membered heterospirocyclic diyl, C 2-4 Alkynylidene, -C(O)-, C(O)-CH2-, -NCH3- or -NCD3-; wherein the monoheterocyclic diyl or heterospirocyclic diyl may be optionally substituted by hydroxyl or methoxy;

[0267] In some embodiments of the present invention, the L is selected from -L1-L2-L3-L4-, wherein,

[0268] L1 is selected from a 4-7 membered monoheterocyclic diyl or a 7-11 membered heterospirocyclic diyl, wherein the monoheterocyclic diyl or heterospirocyclic diyl is optionally substituted with hydroxy, methoxy, ethoxy, isopropoxy, -NHCH3, -N(CH3)2, -NHCH2CH3 or -N(CH2CH3)2;

[0269] L2, L3 and L4 are independently selected from: a bond, C 1-3 Alkylene, 4-7 membered heterocyclic diyl, 7-11 membered heterospirocyclic diyl, C 2-4 Alkyne, -C(O)-, -N(CH3)- or -N(CD3)-; wherein the monoheterocyclic diyl or heterospirocyclic diyl may be optionally substituted by hydroxy or methoxy;

[0270] In some embodiments of the present invention, the L is selected from -L1-L2-L3-L4-L5-, wherein,

[0271] L1-L2 are selected from:

[0272] L2, L3, L4 and L5 are independently selected from: a bond, a methylene group, an ethylene group, a propylene group, a butylene group, a piperidine diyl group (preferably ), piperazinediyl (preferably ), Cyclobutanediyl, ethynylene, 1-propynylene, 1-butynylene, -C(O)-, C(O)-CH2-, -C(O)-NH-, -C(O)-N(CH3)-, -NH-, -N(CH3)- or -N(CD3)-; wherein the piperidinediyl or piperazinediyl may be substituted by hydroxyl, methoxy or ethoxy.

[0273] In some embodiments of the present invention, the L is selected from -L1-L2-L3-L4-, wherein,

[0274] L1-L2 are selected from:

[0275] L2, L3 and L4 are independently selected from the group consisting of: a bond, a methylene group, an ethylene group, a piperidinediyl group, a piperazinediyl group, an ethynyl group, a 1-propynyl group, a 1-butynyl group, -C(O)-, -C(O)-NH-, -C(O)-N(CH3)-, -NH-, -N(CH3)- or -N(CD3)-; wherein the piperidinediyl group or piperazinediyl group may be substituted with a hydroxyl group, a methoxy group or an ethoxy group;

[0276] In some embodiments of the present invention, the L-LBM is selected from:

[0277] In some embodiments of the present invention, the compound of formula (I) is a compound of formula (I-1):

[0278] Among them, R 1 、R 2 、R 3 、R 4 、R 5 , L and LBM are as described above for the compound of formula (I).

[0279] In some embodiments of the present invention, the compound of formula (I) is a compound of formula (I-2):

[0280] Among them, Z1, Z2, Z3, Z4, R 1 、R 2 、R 3 、R 4 、R 5 , L and LBM are as described above for the compound of formula (I);

[0281] The L is preferably:

[0282] The LBM is preferably the above-mentioned compound of formula (B-1), compound of formula (B-7-2"), compound of formula (B-9-1), compound of formula (B-9-3), compound of formula (B-10-1) or compound of formula (B-8), and further preferably the compound of formula (B-1) or compound of formula (B-9-1).

[0283] In some embodiments of the present invention, the compound of formula (I) is a compound of formula (I-3):

[0284] in

[0285] Z 1 is CH or N;

[0286] Two R's 6 The groups are independently selected from hydrogen, C 1-6 Alkyl (preferably C 1-3 Alkyl), C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogen (preferably F, Br), 4-6 membered heterocyclic group or 5-6 membered heteroaryl, wherein the cycloalkyl or heteroaryl may be substituted by one or more C 1- 6 alkyl, C 1-6 Alkoxy or halogen atom substitution;

[0287] R 5 Selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, phenyl, heteroaryl may be substituted by 1-4 (e.g., 1, 2, 3, 4) selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 The cycloalkyl group is substituted by a substituent, and the heterocyclic group or heteroaryl group contains 1 to 3 heteroatoms independently selected from O, S or N;

[0288] Said L is as described in the compound of formula (I) above;

[0289] LBM is selected from the compound of formula (B-1), the compound of formula (B-9) or a stereoisomer thereof:

[0290] in,

[0291] W is selected from C(Rb ) or N, said R b Selected from hydrogen or C 1-6 Alkyl (preferably C 1-3 alkyl); preferably, W is selected from CH or N; more preferably, W is selected from CH;

[0292] X1 is selected from CH2 or C=O;

[0293] Each R a Each independently selected from halogen (preferably F, Cl, Br), nitro, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl or -OC 1-4 alkyl;

[0294] q is selected from 0, 1, 2 or 3; preferably, q is selected from 0 or 1;

[0295] wherein X is selected from CH or N; Y is selected from CH or N;

[0296] R h1 Selected from hydrogen, halogen (preferably F, Cl, Br), amino, cyano, nitro, C 1-6 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl;

[0297] R h2 Selected from hydrogen, C 1-6 Alkyl (preferably C 1-3 alkyl), 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl may be substituted by one or more halogen (preferably F, Cl, Br), amino, hydroxyl, carboxyl, cyano;

[0298] Preferably, R h1 and R h2 At least one of R h1 and R h2 Neither is hydrogen.

[0299] In some embodiments of the present invention, the compound of formula (I) is a compound of formula (I-4):

[0300] in

[0301] Z 1 is CH or N;

[0302] Two R's 6 The groups are independently selected from hydrogen, C 1-6 Alkyl (preferably C 1-3 Alkyl), C 1-6 Alkoxy, C3-6 Cycloalkyl, halogen, 4-6 membered heterocyclic group or 5-6 membered heteroaryl, wherein the cycloalkyl or heteroaryl group may be substituted by one or more C 1-6 Alkyl, C 1-6 Alkoxy or halogen atom substitution;

[0303] Selected from: C 3-7 Cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, phenyl or heteroaryl may be substituted by 1-4 (e.g., 1, 2, 3, 4) selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl (preferably C 1-3 Alkyl), C 1-6 Alkoxy or C 3-6 The cycloalkyl group is substituted by a substituent, and the heterocyclic group or heteroaryl group contains 1 to 3 heteroatoms independently selected from O, S or N;

[0304] Said L is as described in the compound of formula (I) above;

[0305] LBM is selected from the compound of formula (B-1), the compound of formula (B-9) or a stereoisomer thereof:

[0306] in,

[0307] W is selected from C(R b ) or N, said R b Selected from hydrogen or C 1-6 Alkyl (preferably C 1-3 alkyl); preferably, W is selected from CH or N; more preferably, W is selected from CH;

[0308] X1 is selected from CH2 or C=O;

[0309] Each R a Each independently selected from halogen (preferably F, Cl, Br), nitro, cyano, hydroxyl, C 1-6 Alkyl (preferably C 1-3 Alkyl), C 1-6 Haloalkyl or -OC 1-4 alkyl;

[0310] q is selected from 0, 1, 2 or 3; preferably, q is selected from 0 or 1;

[0311] wherein X is selected from CH or N; Y is selected from CH or N;

[0312] R h1 Selected from hydrogen, halogen (preferably F, Cl, Br), amino, cyano, nitro, C 1-6 Alkyl (preferably C 1-3alkyl), 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl;

[0313] R h2 Selected from hydrogen, C 1-6 Alkyl (preferably C 1-3 alkyl), 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl may be substituted by one or more halogen (preferably F, Cl, Br), amino, hydroxyl, carboxyl, cyano;

[0314] Preferably, R h1 and R h2 At least one of R h1 and R h2 Neither is hydrogen.

[0315] In one embodiment of the compound of formula (I-3), Z 1 It is CH.

[0316] In one embodiment of the compound of formula (I-3), Z 1 It's N.

[0317] In one embodiment of the compound of formula (I-4), Z 1 It is CH.

[0318] In one embodiment of the compound of formula (I-4), Z 1 It's N.

[0319] Herein, in the case of groups containing heteroatoms, the heterocyclyl, heterocyclyldiyl, heterocyclylalkyl, heteroaryl and heterospirocyclyldiyl described in the present invention may contain one or more heteroatoms selected from N, O or S, wherein the maximum value of "more than one" corresponds to the maximum number of heteroatoms that the heteroatom-containing group can accommodate without violating the valence principle, for example, "one or more" refers to 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1, 2, 3, 4 or 5, and more preferably 1, 2 or 3.

[0320] In a second aspect, the present invention provides a compound having the following structure, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, and deuterated compounds thereof:

[0321] Table 1

[0322] The present invention also provides a pharmaceutical composition comprising the compound of the present invention, or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, or deuterated compounds.

[0323] The present invention also provides a pharmaceutical composition comprising the compound of the present invention, or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, deuterated compounds, and a pharmaceutically acceptable carrier.

[0324] The present invention also aims to provide the use of the compound of the present invention, or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, and deuterated products as medicines.

[0325] The present invention also aims to provide the use of the compound of the present invention, or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, deuterated substances or pharmaceutical compositions of the present invention in the preparation of drugs for treating diseases mediated by EGFR.

[0326] The present invention also aims to provide the use of the compound of the present invention, or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, deuterated substances or pharmaceutical compositions of the present invention in the preparation of drugs for treating cancers mediated by EGFR.

[0327] The present invention also aims to provide the use of the compound of the present invention, or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, deuterated compounds or pharmaceutical compositions of the present invention in the preparation of drugs for treating EGFR-mediated lung cancer; the lung cancer is preferably non-small cell lung cancer.

[0328] The present invention also aims to provide a method for degrading and / or inhibiting EGFR protein kinase in a patient or biological sample, comprising administering to the patient, or contacting the biological sample with the compound of the present invention or its pharmaceutical composition.

[0329] The present invention also aims to provide the use of the compound of the present invention, or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, deuterated products in the preparation of drugs for treating diseases mediated by EGFR, which can be administered in combination with other drugs.

[0330] The present invention also aims to provide a method for preventing and / or treating diseases mediated by EGFR, which comprises administering to a patient a therapeutically effective dose of the compound of the present invention, or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, deuterated compounds or pharmaceutical compositions of the present invention.

[0331] In the above-mentioned pharmaceutical composition, the weight of the compound of the present invention, or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, or deuterated compounds is 0.1-99.9% by weight of the weight of the pharmaceutical composition, for example, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or a range formed by a combination of any two of the above-mentioned points, and the balance is a pharmaceutically acceptable carrier.

[0332] As used herein, the term "therapeutically effective dose" or "therapeutically effective amount" refers to the amount of a compound or combination of compounds that provides the desired clinical or therapeutic benefit in the subject being treated. The therapeutically effective amount will depend on factors such as the general condition of the subject being treated (e.g., weight, age, and sex), the severity of the disease, the specific compound being administered, the dosing regimen, the use of concomitant medications, and can be determined by the prescribing physician according to routine practice.

[0333] The present invention also provides the following two general preparation methods for the compounds of the present invention:

[0334] Synthesis Scheme 1

[0335] i) Compound I-a1 undergoes chemical conversion to obtain Compound I-a2;

[0336] For example, compound I-a1 and hydroxylamine hydrochloride are used as basic raw materials to obtain compound I-a2;

[0337] ii) Compound I-a2 undergoes chemical conversion to obtain Compound I-a3;

[0338] For example, compound I-a2 and R 1 Substituted sulfonyl chloride, R 2 Substituted iodine reagents and the like are used as basic raw materials to obtain compound I-a3;

[0339] iii) Compound I-a3 undergoes chemical conversion to obtain Compound I-a4;

[0340] For example, compound I-a3 and reduced iron powder are used as basic raw materials to obtain compound I-a4 through reduction reaction;

[0341] iv) Compounds I-a4 and I-a5 undergo chemical conversion to obtain compound I-a6;

[0342] For example, using compounds I-a4 and I-a5 as basic raw materials, compound I-a6 can be obtained through substitution reaction;

[0343] v) Compound I-b1 undergoes chemical conversion to obtain Compound I-b2;

[0344] For example, compound I-b1 and a linker moiety are used as basic raw materials to obtain compound I-b2 through a substitution reaction;

[0345] vi) Compound I-b2 undergoes chemical conversion to obtain Compound I-b3;

[0346] For example, compound I-b2 and a ligase binding moiety are used as basic raw materials to obtain compound I-b3 through condensation, reductive amination, and other reactions;

[0347] vii) Compound I-b3 undergoes chemical conversion to obtain Compound I-b4;

[0348] For example, compound I-b3 and reduced iron powder are used as basic raw materials to obtain compound I-b4 through reduction reaction;

[0349] viii) chemical conversion of compounds I-b4 and I-a6 to obtain compound I-1;

[0350] For example, using compounds I-b4 and I-a6 as basic raw materials, a compound of the general formula I-1 can be obtained through a substitution reaction.

[0351] Synthesis Scheme 2

[0352] Step i) to step v) are the same as in Synthesis Scheme 1;

[0353] vi) Compound I-b2 undergoes chemical conversion to obtain Compound I-b5;

[0354] For example, compound I-b3 and reduced iron powder are used as basic raw materials to obtain compound I-b5 through reduction reaction;

[0355] vii) Compounds I-b5 and I-a6 undergo chemical conversion to produce compound I-b6;

[0356] For example, using compounds I-b5 and I-a6 as basic raw materials, compound I-b6 can be obtained through substitution reaction;

[0357] viii) chemical conversion of compound I-b6 to obtain compound I-1;

[0358] For example, compound I-b6 and a ligase binding moiety are used as basic raw materials, and the general formula compound I-1 is obtained through condensation, reductive amination and other reactions.

[0359] Synthesis Scheme 3-4

[0360] According to the above-mentioned synthesis scheme 1 or 2, only I-a1 is replaced by I-c1 to prepare the general formula (I).

[0361] In the building-up process of compound, for the convenience of operation (such as purification step), free base compound can be prepared into the form of its acid salt such as hydrochloride and trifluoroformate.In synthetic scheme and subsequent embodiment, free base compound and its hydrochloride and trifluoroformate can be used interchangeably.Those skilled in the art can judge the form of specific compound or its hydrochloride and trifluoroformate in conjunction with context.

[0362] Explanation of terms

[0363] The terms “may,” “optionally,” “optionally,” or “optionally” mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0364] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1 to 20 carbon atoms, for example, "C 1-12 Alkyl", "C 1-10 Alkyl", "C 1-8 Alkyl", "C 1-6 Alkyl", "C 1-3 "Alkyl" means that the group is an alkyl group, and the number of carbon atoms in the carbon chain is between 1-10, 1-6, and 1-3 respectively. It includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0365] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic, bicyclic or polycyclic saturated or partially saturated aliphatic hydrocarbon group having a specific number of carbon atoms. Unless otherwise specified, this application includes all possible monocyclic and fused rings (including those fused in the form of bis-, spiro- or bridged rings), including C 3-15 Cycloalkyl (3-15 membered cycloalkyl), preferably C 3-12Cycloalkyl (3-12 membered cycloalkyl), preferably C 3-11 Cycloalkyl (3-11 membered cycloalkyl), more preferably C 3-9 Cycloalkyl (3-9 membered cycloalkyl), more preferably C 3-8 Cycloalkyl (3-8 membered cycloalkyl), more preferably C 3-7 Cycloalkyl (3-7 membered cycloalkyl), further preferably C 3-6 Cycloalkyl (3-6 membered cycloalkyl), further preferably C 3-4 Cycloalkyl (3-4 membered cycloalkyl); preferably C 4-12 Cycloalkyl (4-12 membered cycloalkyl), preferably C 4-8 Cycloalkyl (4-8 membered cycloalkyl), more preferably C 5-7 Cycloalkyl (5-7 membered cycloalkyl), or C 4-6 Cycloalkyl (4-6 membered cycloalkyl). Monocyclic cycloalkyl usually refers to preferably C 3-12 Monocyclic alkyl (3-12 membered monocyclic alkyl), more preferably C 3-10 Monocycloalkyl (3-10 membered monocycloalkyl), more preferably C 3-8 Monocycloalkyl (3-8 membered monocycloalkyl), C 3-7 Monocycloalkyl (3-7 membered monocycloalkyl), C 4-7 Monocycloalkyl (4-7 membered monocycloalkyl), C 3-6 Monocyclic alkyl (3-6 membered monocyclic alkyl), examples of which include but are not limited to: cyclopropyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, etc. Condensed ring cycloalkyl includes spirocyclic alkyl, paracycloalkyl, and bridged cycloalkyl. Spirocyclic alkyl can be 7-12 membered spirocyclic alkyl, preferably 7-11 membered spirocyclic alkyl, further preferably 7-9 membered spirocyclic alkyl, examples of which include but are not limited to: The cycloalkyl group may be a 6-11-membered cycloalkyl group, preferably a 7-10-membered cycloalkyl group, more preferably an 8-10-membered cycloalkyl group, and further preferably a 9-10-membered cycloalkyl group, and its representative examples include but are not limited to Preferred examples of partially saturated cycloalkyl groups include but are not limited to The bridged cycloalkyl group may be a 6-10 membered bridged cycloalkyl group, preferably a 7-10 membered bridged cycloalkyl group, examples of which include but are not limited to:

[0366] Unless otherwise specified, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially saturated monocyclic or polycyclic non-aromatic substituent having ring carbon atoms and 1 to more ring heteroatoms, containing 3 to 20 ring atoms ("3-20 membered heterocyclyl"), wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C, and the number of heteroatoms is preferably 1 to 5 (i.e., 1, 2, 3, 4 or 5), more preferably 1 to 4, further preferably 1 to 3, and even more preferably 1 to 2. It preferably contains 3-14 ring atoms (“3-14-membered heterocyclyl”), further preferably contains 3-12 ring atoms (“3-12-membered heterocyclyl”), further preferably contains 4-11 ring atoms (“4-11-membered heterocyclyl”), or further preferably contains 3-8 ring atoms (“3-8-membered heterocyclyl”), further preferably contains 4-7 ring atoms (“4-7-membered heterocyclyl”), further preferably contains 5-10 ring atoms (“5-10-membered heterocyclyl”), further preferably contains 5-6 ring atoms (“5-6-membered heterocyclyl”); the number of heteroatoms is preferably 1, 2 or 3. "Heterocyclyl" may be a monocyclic ("monocyclic heterocyclyl" or "monoheterocyclyl") or a fused ("fused heterocyclyl" or "heterofused heterocyclyl"), bridged ("heterobridged heterocyclyl" or "bridged heterocyclyl") or spiro-fused ("heterospirocyclyl" or "spiroheterocyclyl") ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. The monoheterocyclyl includes saturated or partially saturated monoheterocyclyls, including 3-9 membered monoheterocyclyls, preferably 3-7 membered monoheterocyclyls, more preferably 4-7 membered monoheterocyclyls, further preferably 4-6 membered monoheterocyclyls, even more preferably 5-6 membered monoheterocyclyls, and even more preferably 6 membered monoheterocyclyls. The heterospirocyclyl comprises a saturated or partially saturated heterospirocyclyl, a 7-11 member heterospirocyclyl, preferably a 7-9 member heterospirocyclyl, more preferably a 7-8 member heterospirocyclyl, and further preferably a 7 member heterospirocyclyl. The heterobridged cyclic group comprises a saturated or partially saturated heterobridged cyclic group, preferably a 7-9 member heterobridged cyclic group, more preferably a 7-8 member heterobridged cyclic group, and further preferably a 7 member heterobridged cyclic group. The heterocyclyl bicyclic system may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which the heterocyclyl ring as defined above is fused to one or more carbocyclyl or heteroaryl groups, or a ring system in which the heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, and in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system. In certain embodiments, each instance of heterocyclyl is independently optionally substituted, eg, unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents.

[0367] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, aziridine, oxirane, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to azetidinyl, oxetane, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, imidazolidinyl, dioxolane, oxathiolanyl, dithiolanyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazacyclohexane, oxadiazinyl, thiadiazinyl, oxathiazinyl, and dioxazacyclohexane. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepanyl, and thianyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azocanyl, oxocanyl, and thianyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocycle) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary heterobridged ring groups include, but are not limited to, the following structures: Exemplary structures of heterospirocyclic groups include, but are not limited to, the following structures:

[0368] Unless otherwise specified, the term "aryl" or "aromatic ring group" refers to a group containing 6 to 16 carbon atoms (C 6-16 aryl or 6-16 membered aryl), or 6-14 carbon atoms (C 6-14 aryl or 6-14 membered aryl), or 6-12 carbon atoms (C 6-12 aryl or 6-12 membered aryl), or 6-10 carbon atoms (C 6-10 aryl or 6-10 membered aryl) or 6-8 carbon atoms (C 6-8The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups include phenyl, naphthyl, anthracenyl, phenanthrenyl, or pyrenyl.

[0369] Unless otherwise specified, the term "heteroaryl" or "heteroaromatic ring group" means an aromatic monocyclic or polycyclic ring system containing a 5-14 membered structure (5-14 membered heteroaryl), or a 5-12 membered structure (5-12 membered heteroaryl), or a 5-10 membered structure (or 5-10 membered heteroaryl), preferably a 5-8 membered structure (5-8 membered heteroaryl), more preferably a 5-6 membered structure (5-6 membered heteroaryl), wherein at least one ring atom is a heteroatom and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3. Examples of heteroaryl groups include furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, 1,2-b]pyridinyl, imidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, etc.

[0370] Unless otherwise specified, the term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. The alkenyl group may contain 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms (i.e., C 2-12 alkenyl), preferably containing 2 to 10 carbon atoms (ie, C 2-10 alkenyl), further preferably containing 2-8 carbon atoms (ie C 2-8 alkenyl), more preferably containing 2 to 6 carbon atoms (ie, C 2-6 alkenyl), 2-5 carbon atoms (ie C 2-5 alkenyl), 2-4 carbon atoms (ie C 2-4 alkenyl), 2-3 carbon atoms (ie C 2-3 alkenyl), 2 carbon atoms (i.e., C2 alkenyl), for example, "C 2-6The term "alkenyl" refers to an alkenyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl and 1,3-butadienyl.

[0371] Unless otherwise specified, the term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. The alkynyl group may contain 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms (i.e., C 2-12 Alkynyl), preferably containing 2 to 10 carbon atoms (ie, C 2-10 Alkynyl), further preferably containing 2-8 carbon atoms (ie C 2-8 Alkynyl), more preferably containing 2-6 carbon atoms (ie, C 2-6 Alkynyl), 2-5 carbon atoms (ie C 2-5 Alkynyl), 2-4 carbon atoms (ie C 2-4 Alkynyl), 2-3 carbon atoms (ie C 2-3 alkynyl), 2 carbon atoms (i.e., C2 alkynyl), for example, "C 2-6 "Alkynyl" means that the group is an alkynyl group, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl and 1-butynyl.

[0372] Unless otherwise specified, the term "alkylene" (which is used interchangeably with "alkylene chain"), used alone or in combination, refers to a straight or branched divalent saturated hydrocarbon group consisting of carbon and hydrogen atoms. The term "Cx-y alkylene" (x and y are each an integer) refers to a straight or branched alkylene group containing x to y carbon atoms, including C 1-30 Alkylene, preferably C 1-15 Alkylene, C 1-12 Alkylene, C 1-8 Alkylene, C 1-7 Alkylene, C 1-6 Alkylene, C 1-5 Alkylene, C 1-4 Alkylene, C 1-3Representative examples include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene, neopentylene, tert-pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecylene, octadecylene, nonadecylene, eicosylene, heneicosylene, docosylene, tricosylene, tetracosylene, pentacosylene, hexacosylene, heptacosylene, octacosylene, nonacosylene, and triacontylene.

[0373] Unless otherwise specified, the "alkylene" is optionally substituted, and the substituents are preferably one or more selected from hydroxy, amino, mercapto, halogen, cyano, C 1-3 Alkyl, C 1-3 The substituent may be an alkoxy group, a trifluoromethyl group, a heterocyclic group or a combination thereof.

[0374] Unless otherwise specified, the term "alkynylene", used alone or in combination, refers to a group consisting of 2 to 12 carbon atoms having one or more carbon-carbon triple bonds. 2-12 alkynylene), preferably 2 to 8 (C 2-8 Alkynylidene), preferably 2 to 6 (C 2-6 Alkyne), more preferably 2 to 4 (C 2-4 Examples of preferred alkynylene groups include, but are not limited to, ethynylene, 1-propynylene, 1-butynylene, and 1,3-butadiynylene.

[0375] Unless otherwise specified, the term "alkenylene", used alone or in combination, refers to an alkylene group containing 2 to 12 carbon atoms and one or more carbon-carbon double bonds. 2-12 alkenylene), preferably 2 to 8 (C 2-8 alkenylene), preferably 2 to 6 (C 2-6 Alkenylene), further preferably 2 to 4 (C 2-4 Examples of preferred alkenylene groups include, but are not limited to, vinylene (e.g., -CH=CH-), 1-propenylene, and 1-butenylene.

[0376] Unless otherwise specified, the term "halogen" or "halo" refers to F (fluorine), Cl (chlorine), Br (bromine), I (iodine). The term "haloalkyl" refers to an alkyl group as defined above in which one, two or more hydrogen atoms, or all of the hydrogen atoms, are replaced by halogen. Representative examples of haloalkyl groups include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, CF2CF3, and the like.

[0377] Unless otherwise specified, the term "alkoxy" refers to an -O-alkyl group, where the alkyl group is as defined above. Preferably, it has 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. Representative examples include methoxy, ethoxy, propoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, and the like.

[0378] Unless otherwise specified, "cycloalkenyl" refers to a group consisting of monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings, however, the system is unsaturated, i.e., there is at least one C—C double bond but no aromatic system. Preferably, it contains 3 to 12 carbon atoms (i.e., C 3-12 cycloalkenyl), more preferably containing 3 to 10 carbon atoms (C 3-10 cycloalkenyl), further preferably 3-6 carbon atoms (C 3-6 Cycloalkenyl), 4-6 carbon atoms (C 4-6 Cycloalkenyl), 5-6 carbon atoms (C 5-6 cycloalkenyl).

[0379] As used herein, "diyl" is also used to describe a divalent group of a cyclic group, such as a heterocyclic diyl, a cycloalkane diyl, a heterospirocyclic diyl, a cyclobutane diyl, a piperidine diyl, and a piperazine diyl. "Diyl" refers to a group formed by losing two hydrogen atoms from the corresponding ring, and the two hydrogen atoms can be on the same ring atom or on two different reducing atoms.

[0380] Unless otherwise specified, the terms "pharmaceutically acceptable salt" and "pharmaceutically acceptable salt" refer to salts that are suitable for contact with mammalian tissues, especially human tissues, without excessive toxicity, irritation, allergic reaction, etc., and are commensurate with a reasonable benefit / risk ratio within the scope of reasonable medical judgment. For example, medically acceptable salts of amines, carboxylic acids and other types of compounds are well known in the art.

[0381] Unless otherwise specified, the term "salt" encompasses salts derived from inorganic acids as well as salts prepared from organic acids. If the compound of the present invention is acidic, pharmaceutically acceptable non-toxic bases include salts prepared from inorganic bases and organic bases.

[0382] Unless otherwise specified, the term "solvate" means a physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be capable of isolation. The solvent molecules in the solvate may exist in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution-phase and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0383] Unless otherwise specified, the term "optical isomers" refers to substances with identical molecular structures, similar physical and chemical properties, but different optical rotations.

[0384] Unless otherwise specified, the term "stereoisomer" refers to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, etc. Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on the differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0385] Unless otherwise indicated, the structural formulas described herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers)): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are within the scope of the present invention.

[0386] Unless otherwise specified, the term "prodrug" refers to a drug that is converted into the parent drug in vivo. Prodrugs are often useful because, in certain circumstances, they may be easier to administer than the parent drug. For example, they may be bioavailable by oral administration, whereas the parent drug is not. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. An example of a prodrug, but not limited to, would be any compound of Formula (I) or Formula (III) administered as an ester ("prodrug") to facilitate transport across cell membranes, where water solubility is detrimental to mobility, but once inside the cell water solubility is beneficial, which is then metabolically hydrolyzed to the carboxylic acid, the active entity. Another example of a prodrug would be a short peptide (polyamino acid) conjugated to an acid group, where the peptide is metabolized to reveal the active moiety.

[0387] Unless otherwise specified, the terms "isotopically labeled analogues" and "isotopic derivatives" refer to molecules in a compound that are isotopically labeled to provide an isotopically labeled analogue that may have improved pharmacological activity. The isotopes commonly used as isotopic labels are: hydrogen isotopes: deuterium ( 2 H) and tritium ( 3 H); Carbon isotope: 11 C, 13 C and 14 C; Chlorine isotope: 35 Cl and 37 Cl; Fluorine isotope: 18 F; Iodine isotope: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. 13 C, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2 H), substitution can enhance metabolic stability, prolong half-life, thereby achieving the purpose of reducing dosage and providing therapeutic advantages. The compounds of the present invention include their isotopic derivatives, such as deuterated compounds and deuterated compounds.

[0388] Unless otherwise specified, the term "optionally substituted" means that the hydrogen at the substitutable site of the group is not replaced or is replaced by one or more substituents, the substituents being preferably selected from the group consisting of halogen, hydroxy, thiol, cyano, nitro, amino, azido, oxo, carboxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, 6-14 membered aryl or 5-10 membered heteroaromatic ring group, wherein the C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered cycloalkyl, 3-10 membered cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, 6-14 membered aryl or 5-10 membered heteroaromatic ring group can be optionally selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl or C 1- 6 alkoxy groups.

[0389] Unless otherwise specified, the term "plurality" refers to 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1, 2, 3, 4 or 5, more preferably 1, 2 or 3.

[0390] The pharmaceutical composition of the present invention may comprise an effective amount of a compound of the present invention, or a stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, or deuterated form thereof. The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier. In the pharmaceutical composition, the compound of the present invention, or a stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, or deuterated form thereof may comprise 0.1-99.9% by weight of the pharmaceutical composition, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% by weight, with the remainder being a pharmaceutically acceptable carrier.

[0391] When administered to a subject, it is necessary to provide a therapeutically effective amount of the compound of the present invention, or a stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, or deuterated compound thereof; the term "therapeutically effective amount" refers to the amount of the compound or combination of compounds that provides the expected clinical or therapeutic benefit in the subject being treated. The therapeutically effective amount will depend on factors such as the general condition of the subject being treated (e.g., weight, age, and sex), the severity of the disease, the specific compound being administered, the dosing regimen, the use of concomitant medications, and can be determined by the prescribing physician according to conventional practice. For example, the pharmaceutical composition can be administered at a dose appropriate for the disease to be treated (or prevented), for example, administering about 0.5 μg to about 50 mg of at least one compound / kg of subject body weight, preferably about 10 μg to about 100 mg / kg of body weight / day.

[0392] As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. Any conventional pharmaceutically acceptable carrier may be used, the selection of which depends on factors such as the particular mode of administration, the effect of the carrier on solubility and stability, and the nature of the dosage form and is within the ordinary skill of those skilled in the art.

[0393] Examples of the pharmaceutically acceptable carrier include, but are not limited to, conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, lubricants, colorants, flavors, absorption enhancers, surfactants, adsorption carriers, and the like in the pharmaceutical field.

[0394] The beneficial effects of the present invention are one or more combinations of the following:

[0395] The present invention provides a novel class of PROTAC bifunctional compounds that bind to EGFR protein and E3 ubiquitin ligase, as well as stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, and deuterated compounds thereof. Test results indicate that the compounds of the present invention:

[0396] (1) It has a good degradation effect on EGFR protein in BaF3-EGFR-L858R / T790M / C797S cells;

[0397] (2) It has a good degradation effect on EGFR protein in H1975-EGFR-L858R / T790M / C797S cells;

[0398] (3) It has a good degradation effect on EGFR protein in H1975 cells;

[0399] (4) It can significantly downregulate the expression level of pEGFR protein in H1975 cells;

[0400] (5) Good selectivity;

[0401] (6) It is well absorbed in mice and can be used to treat diseases mediated by EGFR. DETAILED DESCRIPTION

[0402] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. Experimental methods in the following examples where specific conditions are not specified are generally performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to professionals in the field. In addition, any methods and materials similar or equivalent to those described herein can be applied to the present invention. The preferred embodiments and materials shown herein are for demonstration purposes only.

[0403] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or liquid chromatography (HPLC). NMR measurements were performed using a Bruker AVANCE III 600 MHz instrument, LC-MS using a Waters arc / QDa instrument, and HPLC using a Waters e2695-2998 instrument.

[0404] The starting materials in the examples of the present invention are known and commercially available, or can be synthesized according to methods known in the art.

[0405] The abbreviations used in the Preparation Examples, Examples, Test Examples and elsewhere herein are:

[0406] Intermediate Preparation Example 1: Synthesis of N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide

[0407] Step 1: Synthesis of 6-nitroquinoxaline-5-amine

[0408] To a 100 mL reaction flask, add hydroxylamine hydrochloride (1.5 g, 21.58 mmol) and methanol (20 mL). Cool the mixture and add 5 M sodium methoxide methanol solution (9 mL) at 0°C. After the addition is complete, filter the mixture and save the filtrate. In another 250 mL reaction flask, add 6-nitroquinoxaline (2.5 g, 14.27 mmol) and methanol (20 mL). Heat the reaction system to 80°C, add the above filtrate, and maintain the reaction temperature for 1.5 hours. LCMS indicates completion of the reaction. Cool the reaction system to 0°C, filter the mixture, rinse the filter cake with methanol, and dry the filter cake to obtain the crude product (1.6 g).

[0409] Step 2: Synthesis of N-(6-nitroquinoxalin-5-yl)methanesulfonamide

[0410] To a 100 mL reaction flask, crude 6-nitroquinoxaline-5-amine (1.6 g) and DMF (30 mL) were added sequentially. 60% NaH (2 g, 50 mmol) was then added at room temperature, and the reaction system was heated to 60°C and stirred for 30 minutes. Methanesulfonyl chloride (4.8 g, 41.88 mmol) was added dropwise, maintaining the reaction system at 60°C. After completion of the addition, the reaction was continued for 1 hour. The reaction system was then cooled to room temperature, 3M NaOH solution (14 mL) was added, and stirred for 5 minutes. Water and ethyl acetate were then added to the reaction solution, stirred, and separated. The aqueous phase was adjusted to pH 5 with 3N hydrochloric acid. Solid precipitated, which was filtered, and the filter cake was dried to yield the product (1.2 g).

[0411] Step 3: Synthesis of N-methyl-N-(6-nitroquinoxalin-5-yl)methanesulfonamide

[0412] To a 100 mL reaction flask, N-(6-nitroquinoxalin-5-yl)methanesulfonamide (1.2 g), anhydrous DMF (15 mL), and potassium carbonate (2.5 g, 18.08 mmol) were added sequentially. Methyl iodide (1.3 g, 9.15 mmol) was added dropwise at room temperature. After addition, the reaction was continued for 1.5 hours. LCMS indicated completion of the reaction. Water and ethyl acetate were added, and the mixture was extracted. The resulting organic phase was washed with water and saturated sodium chloride solution and concentrated to dryness under reduced pressure to yield the product (1.2 g).

[0413] Step 4: Synthesis of N-(6-aminoquinoxalin-5-yl)-N-methylmethanesulfonamide

[0414] To a 100 mL reaction flask, crude N-methyl-N-(6-nitroquinoxalin-5-yl)methanesulfonamide (1.2 g), ethanol (40 mL), water (8 mL), reduced iron powder (1.2 g, 21.42 mmol), and ammonium chloride (1.2 g, 22.22 mmol) were added sequentially. The reaction system was reacted at 80°C for 2 hours. LCMS indicated completion of the reaction. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product (1.2 g).

[0415] Step 5: Synthesis of N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide

[0416] To a 100 mL reaction flask, N-(6-aminoquinoxalin-5-yl)-N-methylmethanesulfonamide (0.8 g, crude) and anhydrous DMF (5 mL) were added sequentially. 60% NaH (0.2 g, 5.00 mmol) was added at room temperature. After stirring for 10 minutes, 5-bromo-2,4-dichloropyrimidine (0.8 g, 3.52 mmol) was added. The reaction system was allowed to react for 1 hour at room temperature. LCMS indicated completion of the reaction. Saturated aqueous ammonium chloride was added to the reaction mixture, resulting in the precipitation of a solid. The solid was filtered and the filter cake dried to afford the product (1.2 g). ESI-MS (m / z): 442.96 / 444.96 [M+H] + .

[0417] Intermediate Preparation Example 2: Synthesis of 4-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole

[0418] To a 100 mL reaction flask, 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (1.0 g, 4.00 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (0.85 g, 6.75 mmol), Pd(dppf)Cl2 (0.3 g, 0.41 mmol), potassium carbonate (1.1 g, 7.96 mmol), 1,4-dioxane (20 mL), and water (4 mL) were added sequentially. The reaction system was allowed to react at 100°C under nitrogen protection for 2 hours. LCMS indicated the reaction was complete. Ethyl acetate and water were added to the reaction solution, stirred, and the resulting organic phase was concentrated to dryness under reduced pressure. The concentrate was then slurried with methyl tert-butyl ether to obtain the product (1.1 g). ESI-MS (m / z): 252.07 [M+H] + .

[0419] Intermediate Preparation Example 3: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxaldehyde

[0420] Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione

[0421] To a 250 mL reaction flask, 4,5-difluorophthalic anhydride (9.00 g, 48.89 mmol), acetic acid (100 mL), 3-aminopiperidine-2,6-dione hydrochloride (8.05 g, 48.89 mmol), and potassium acetate (9.59 g, 97.77 mmol) were added. The reaction system was heated to 85°C and allowed to react for 4 hours. After completion of the reaction, the reaction system was cooled to room temperature and the reaction solution was poured into water (300 mL). Solid precipitated and was filtered. The filter cake was dried at 50°C to obtain a crude product (10 g). ESI-MS (m / z): 295.05 [M+H] + .

[0422] Step 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione

[0423] To a 50 mL reaction flask, 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (1.00 g, crude), diisopropylethylamine (0.88 g, 6.8 mmol), 4-hydroxymethylpiperidine (0.43 g, 3.7 mmol), and dimethyl sulfoxide (10 mL) were added. The reaction system was heated to 90°C and allowed to react for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature and poured into water (50 mL). Extraction was performed with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product (1 g). ESI-MS (m / z): 390.14 [M+H] + .

[0424] Step 3: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxaldehyde

[0425] In a 100 mL reaction flask, crude 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione (1 g) and dichloromethane (15 mL) were added, followed by Dess-Martin periodinane (1.63 g, 3.85 mmol). The reaction system was allowed to react at room temperature for 16 hours. After completion of the reaction, LCMS analysis confirmed the addition of water (50 mL) and extraction with dichloromethane (20 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM:MeOH = 50:1) to yield the product (600 mg). ESI-MS (m / z): 388.12 [M+H] + .

[0426] Intermediate Preparation Example 4: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxaldehyde

[0427] Referring to the preparation method of Compound Intermediate Preparation Example 3, only 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione in step 2 was replaced with 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione to obtain the product (0.5 g). ESI-MS (m / z): 370.13 [M+H] + .

[0428] Intermediate Preparation Example 5: Synthesis of tert-butyl 9-(4-amino-5-methoxy-2-methylphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0429] Step 1: Synthesis of tert-butyl 9-(5-methoxy-2-methyl-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0430] The synthesis method was as described in Example 1, step 1, except that tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate was replaced with tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate to obtain the product. ESI-MS (m / z): 420.24 [M+H] + .

[0431] Step 2: Synthesis of tert-butyl 9-(4-amino-5-methoxy-2-methylphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0432] To a 100 mL reaction flask, tert-butyl 9-(5-methoxy-2-methyl-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (0.60 g, 1.43 mmol), ethanol (10 mL), water (2 mL), reduced iron powder (0.56 g, 10.01 mmol), and ammonium chloride (0.54 g, 10.01 mmol) were added sequentially. The reaction system was incubated at 80°C for 3 hours. LCMS indicated the reaction was complete. The filtrate was filtered and concentrated to dryness under reduced pressure. The concentrate was dissolved in dichloromethane, washed with saturated NaHCO₃ solution, washed with saturated NaCl aqueous solution, and dried over anhydrous Na₂SO₄ to obtain the crude product (0.56 g). ESI-MS (m / z): 390.29 [M+H] + .

[0433] Intermediate Preparation Example 6: Synthesis of N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(3,9-diazaspiro[5.5]undec-3-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide

[0434] To a 100 mL reaction flask, tert-butyl 9-(4-amino-5-methoxy-2-methylphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (0.11 g, 0.29 mmol), DMF (5 mL), N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (0.13 g, 0.29 mmol), and p-toluenesulfonic acid monohydrate (0.35 g, 1.84 mmol) were added sequentially. The reaction system was heated to 100°C for 16 hours. LCMS indicated the reaction was complete. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated aqueous NaCl and dried over anhydrous NaSO. The crude product was then purified by preparative HPLC to yield the product (0.06 g). ESI-MS (m / z): 696.25 / 698.24 [M+H]. + .

[0435] Intermediate Preparation Example 7: Synthesis of (S)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-10-methyl-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetic acid

[0436] Step 1: Synthesis of tert-butyl (S)-10-bromo-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate

[0437] To a 100 mL reaction flask, 1-bromo-2,3-difluoro-5-nitrobenzene (2.2 g, 9.24 mmol), (S)-tert-butyl 3-hydroxymethylpiperazine-1-carboxylate (2.2 g, 10.2 mmol), DMSO (30 mL), and potassium hydroxide (1.5 g, 26.8 mmol) were added sequentially. The reaction was allowed to react at room temperature for 3 hours, after which the reaction system was heated to 40°C and continued for another 3 hours. LCMS indicated completion of the reaction. The reaction solution was quenched by addition of water (100 mL) and subsequently extracted with ethyl acetate (200 mL). The organic phase was separated and collected. The resulting organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The concentrate was purified by flash liquid chromatography (Biotage Selekt) using a medium-pressure preparative (PE:EA = 10:1) to afford the product (2.1 g, 5.08 mmol). ESI-MS (m / z): 414.06 [M+H]. + .

[0438] Step 2: Synthesis of tert-butyl (S)-10-methyl-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate

[0439] In a 250 mL reaction flask, (S)-tert-butyl 10-bromo-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (2.1 g, 5.08 mmol), potassium carbonate (1.4 g, 10.13 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (370 mg, 0.45 mmol), trimethylcyclotriboroxane (3.8 g, 30.27 mmol), dioxane (40 mL) and water (10 mL) were added in sequence; the reaction system was reacted at 80 ° C for 3 hours under nitrogen environment. LCMS showed the reaction was complete. The reaction system was cooled to room temperature, and then water (30 mL) was slowly added. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was separated and washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The concentrate was subjected to medium pressure preparation (PE:EA = 8:1) to obtain the product (0.9 g, 2.58 mmol). ESI-MS (m / z): 350.16 [M+H] + .

[0440] Step 3: Synthesis of tert-butyl (S)-8-amino-10-methyl-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate

[0441] To a 100 mL hydrogenation bottle was added tert-butyl (S)-10-methyl-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (0.9 g, 2.58 mmol), tetrahydrofuran (10 mL), methanol (10 mL), and Pd / C (450 mg). The reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. LCMS indicated the reaction was complete. The reaction mixture was filtered through celite, the filter cake was rinsed with ethyl acetate (100 mL), the filtrate was collected, and the mixture was concentrated to dryness under reduced pressure to give the crude product (0.8 g). ESI-MS (m / z): 320.19 [M+H] + .

[0442] Step 4: Synthesis of (S)-3-((3-(tert-Butyloxycarbonyl)-10-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)propanoic acid

[0443] To a 50 mL reaction flask, add tert-butyl (S)-8-amino-10-methyl-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (0.8 g) and toluene (20 mL), followed by acrylic acid (180 mg, 2.5 mmol). The reaction mixture was heated to 110°C and stirred for 6 hours. LCMS indicated the reaction was complete. The reaction mixture was cooled to room temperature and the solvent was concentrated under reduced pressure to dryness to obtain the crude product (1.05 g). ESI-MS (m / z): 378.20 [M+H] + .

[0444] Step 5: Synthesis of (S)-1-(3-acetyl-10-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0445] To a 50 mL reaction flask was added crude (S)-3-((3-(tert-butyloxycarbonyl)-10-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)propanoic acid (1.05 g), urea (450 mg, 7.5 mmol), and acetic acid (10 mL). The reaction system was stirred at 120°C for 8 hours. LCMS indicated the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure and the concentrate was purified by medium pressure preparative purification (DCM:MeOH = 20:1) to afford the product (160 mg, 0.45 mmol). ESI-MS (m / z): 359.16 [M+H] + .

[0446] Step 6: Synthesis of (S)-1-(10-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0447] To a 50 mL reaction flask, (S)-1-(3-acetyl-10-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione (160 mg, 0.45 mmol) and HCl (5 mL, 3N) were added. The reaction system was stirred at 50°C for 6 hours. LCMS indicated the reaction was complete, and the reaction solution was concentrated to dryness under reduced pressure to obtain the crude product. ESI-MS (m / z): 317.15 [M+H] + .

[0448] Step 7: Synthesis of tert-butyl (S)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-10-methyl-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetate

[0449] To a 25 mL reaction vial was added crude (S)-1-(10-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride, tert-butyl 2-bromoacetate (109 mg, 0.56 mmol), acetonitrile (4 mL), and N,N-diisopropylethylamine (231 mg, 1.79 mmol). The reaction mixture was incubated at 80°C for 3 hours. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure and purified by medium pressure preparative purification (DCM:MeOH = 25:1) to afford the product (100 mg, 0.23 mmol). ESI-MS (m / z): 431.22 [M+H]. + .

[0450] Step 8: Synthesis of (S)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-10-methyl-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetic acid

[0451] To a 25 mL reaction flask, add tert-butyl (S)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-10-methyl-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetate (100 mg, 0.23 mmol), trifluoroacetic acid (1 mL), and dichloromethane (1 mL). The reaction mixture was reacted at 25°C for 2 hours. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure to obtain the crude product (120 mg). ESI-MS (m / z): 375.16 [M+H] + .

[0452] Intermediate Preparation Example 8: Synthesis of (S)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetic acid

[0453] Step 1: Synthesis of tert-butyl (S)-4-(2-fluoro-4-nitrophenyl)-3-(hydroxymethyl)piperazine-1-carboxylate

[0454] To a 250 mL reaction flask, 1,2-difluoro-4-nitrobenzene (5.00 g, 31.43 mmol), (S)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (7.50 g, 34.68 mmol), DMSO (50 mL), and DIPEA (8.20 g, 63.44 mmol) were added sequentially. The reaction mixture was heated to 120°C and reacted for 8 hours. LCMS indicated the reaction was complete. Water (100 mL) was added to the reaction mixture, and a solid precipitated. The filter cake was filtered to obtain the product. The filter cake was purified by column chromatography (PE:EA = 3:1) to obtain the product (9.9 g). ESI-MS (m / z): 356.15 [M+H] + .

[0455] Step 2: Synthesis of tert-butyl (S)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate

[0456] To a 250 mL reaction flask, tert-butyl (S)-4-(2-fluoro-4-nitrophenyl)-3-(hydroxymethyl)piperazine-1-carboxylate (9.5 g, 26.76 mmol) and DMF (55 mL) were added sequentially. The reaction solution was cooled to below 0°C and 60% NaH (1.3 g, 54.17 mmol) was slowly added. After the addition was complete, the mixture was allowed to react at room temperature for 0.5 hours. After LCMS showed the reaction was complete, water (100 mL) was slowly added to the reaction solution to quench the reaction. The mixture was then extracted with ethyl acetate (200 mL). The organic phase was collected and washed once with water and then with saturated sodium chloride solution. The organic phase was then concentrated to dryness under reduced pressure to obtain the product (9.20 g). ESI-MS (m / z): 336.15 [M+H] + .

[0457] Step 3: Synthesis of tert-butyl (S)-8-amino-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate

[0458] To a 250 mL hydrogenation bottle, tert-butyl (S)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (5.0 g), methanol (50 mL), and Pd / C (2 g) were added sequentially. The reaction mixture was stirred at 25°C under a hydrogen atmosphere (pressure 20 psi) for 8 hours. After LCMS showed the reaction was complete, the reaction mixture was filtered through celite, the filter cake was rinsed with ethyl acetate (100 mL), and the filtrate was concentrated to dryness under reduced pressure to obtain the product (4.7 g). ESI-MS (m / z): 306.17 [M+H] + .

[0459] Step 4: Synthesis of (S)-3-((3-(tert-Butoxycarbonyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)propanoic acid

[0460] To a 250 mL reaction flask, add (S)-8-amino-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester (4.7 g) and toluene (50 mL), followed by acrylic acid (1.25 g, 17.36 mmol). The reaction mixture was heated to 110°C and stirred for 8 hours. After LCMS showed the reaction was complete, the reaction mixture was directly concentrated to dryness under reduced pressure to obtain the crude product (6.9 g). ESI-MS (m / z): 378.20 [M+H] + .

[0461] Step 5: Synthesis of (S)-1-(3-acetyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0462] To a 250 mL reaction flask was added (S)-3-((3-(tert-butoxycarbonyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)propanoic acid (6.50 g), urea (3.2 g), and acetic acid (60 mL). The reaction mixture was stirred at 120°C for 12 hours. LCMS indicated the reaction was complete. The reaction mixture was concentrated to dryness under reduced pressure and the concentrate was purified by column chromatography (DCM:MeOH = 20:1) to obtain the product (3.4 g). ESI-MS (m / z): 345.15 [M+H] + .

[0463] Step 6: Synthesis of (S)-1-(1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0464] To a 250 mL reaction flask, (S)-1-(3-acetyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione (3.4 g, 9.88 mmol) and HCl (20 mL, 3N) were added. The reaction mixture was stirred at 50°C for 8 hours. LCMS indicated the reaction was complete, and the reaction mixture was concentrated to dryness under reduced pressure to obtain the crude product (2.9 g). ESI-MS (m / z): 303.14 [M+H] + .

[0465] Step 7: Synthesis of tert-butyl (S)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetate

[0466] To a 100 mL reaction flask, (S)-1-(1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione (2.0 g), tert-butyl 2-bromoacetate (1.55 g, 7.95 mmol), acetonitrile (50 mL), and N,N-diisopropylethylamine (4.28 g, 33.1 mmol) were added. The reaction mixture was reacted at 80°C for 3 hours. After completion of the reaction, the solvent was concentrated to dryness under reduced pressure, and the concentrate was purified by silica gel column chromatography (DCM:MeOH = 30:1) to obtain the product (1.44 g). ESI-MS (m / z): 417.21 [M+H] + .

[0467] Step 8: Synthesis of (S)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetic acid

[0468] To a 250 mL reaction flask, add tert-butyl (S)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetate (1.44 g, 3.46 mmol), trifluoroacetic acid (10 mL), and dichloromethane (10 mL). The reaction mixture was incubated at 25°C for 2 hours. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure to obtain the crude product (1.52 g). ESI-MS (m / z): 361.14 [M+H] + .

[0469] Intermediate Preparation Example 9: Synthesis of (S)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-10-fluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetic acid.

[0470] The product was obtained by referring to the preparation method of Compound Intermediate Preparation Example 8, except that 1,2-difluoro-4-nitrobenzene in step 1 was replaced with 1,2,3-trifluoro-5-nitrobenzene. ESI-MS (m / z): 379.13 [M+H] + .

[0471] Intermediate Preparation Example 10: Synthesis of (R)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetic acid

[0472] Referring to the synthesis method of Intermediate Preparation Example 8, the (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester in step 1 was replaced with (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester to obtain the product. ESI-MS (m / z): 361.14 [M+H] + .

[0473] Intermediate Preparation Example 11: Synthesis of (R)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-10-methyl-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetic acid.

[0474] Referring to the synthesis method of Intermediate Preparation Example 7, the (S)-3-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester in step 1 was replaced with (R)-3-hydroxymethylpiperazine-1-carboxylic acid tert-butyl ester to obtain the product. ESI-MS (m / z): 375.16 [M+H] + .

[0475] Intermediate Preparation Example 12: Synthesis of 2-((4aS)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetic acid.

[0476] Step 1: Synthesis of tert-butyl (4aS)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate

[0477] To a 100 mL reaction flask, tert-butyl (S)-8-amino-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (2.72 g, 8.91 mmol), 3-bromopiperidine-2,6-dione (1.71 g, 8.91 mmol), DIPEA (6.93 g, 53.62 mmol), and DMF (20 mL) were added sequentially. The mixture was reacted at 80°C for 16 hours. LCMS indicated the reaction was complete. The product was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 1:1) to give the product (1.12 g, 2.69 mmol). ESI-MS (m / z): 417.21 [M+H] + .

[0478] Step 2: Synthesis of 3-(((S)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)piperidine-2,6-dione hydrochloride

[0479] To a 50 mL reaction flask, add tert-butyl (4aS)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (0.54 g, 1.30 mmol) and 1,4-dioxane hydrochloride (6 mL). The reaction mixture was incubated at 25°C for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product (0.41 g). ESI-MS (m / z): 317.29 [M+H] + .

[0480] Step 3: Synthesis of tert-butyl 2-((4aS)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetate

[0481] To a 100 mL reaction flask was added 3-(((S)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)piperidine-2,6-dione hydrochloride (0.41 g), tert-butyl 2-bromoacetate (0.34 g, 1.74 mmol), N,N-diisopropylethylamine (0.68 g, 5.3 mmol), and acetonitrile (20 mL). The reaction mixture was stirred at 70°C for 8 hours. After completion of the reaction, the product was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH = 92:8) to obtain the product (0.47 g, 1.1 mmol). ESI-MS (m / z): 431.46 [M+H]. + .

[0482] Step 4: Synthesis of 2-((4aS)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetic acid

[0483] To a 50 mL reaction flask, tert-butyl 2-((4aS)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetate (0.10 g, 0.23 mmol), trifluoroacetic acid (2 mL), and dichloromethane (2 mL) were added. The reaction mixture was incubated at 25°C for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product (0.09 g). ESI-MS (m / z): 375.40 [M+H] + .

[0484] Intermediate Preparation Example 13: Synthesis of 2-((4aR)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetic acid

[0485] Referring to the preparation method of Compound Intermediate Preparation Example 12, the product was obtained by replacing (S)-8-amino-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester with (R)-8-amino-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester in step 1. ESI-MS (m / z): 375.16 [M+H] + .

[0486] Intermediate Preparation Example 14: Synthesis of 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde

[0487] Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-hydroxyethyl)piperidin-1-yl)isoindoline-1,3-dione

[0488] Piperidineethanol (1 g, 7.73 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (2.56 g, 9.28 mmol) were dissolved in dimethyl sulfoxide (10 mL), DIEA (6.7 mL) was added, and the mixture was reacted at 110°C for 6 hours. LCMS indicated the reaction was complete. Water was added and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with water and saturated sodium chloride solution, concentrated under reduced pressure, and slurried with tert-butyl methyl ether to obtain the crude product (2.1 g). ESI-MS (m / z): 386.16 [M+H] + .

[0489] Step 2: Synthesis of 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde

[0490] 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-hydroxyethyl)piperidin-1-yl)isoindoline-1,3-dione (100 mg) was dissolved in dichloromethane (5 mL). Dess-Martin reagent (165 mg, 0.39 mmol) was added with stirring and allowed to react at room temperature for 1 hour. LCMS indicated the reaction was complete. Sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phase was concentrated under reduced pressure and purified by thin-layer chromatography to obtain the product (48 mg). ESI-MS (m / z): 384.40 [M+H] + .

[0491] Intermediate Preparation Example 15: Synthesis of N-(6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(3,9-diazaspiro[5.5]undec-3-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide

[0492] Step 1: Synthesis of tert-butyl 9-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0493] 4-(2-Fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (0.80 g, 3.18 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (0.97 g, 3.82 mmol) were dissolved in DMSO (10 mL), potassium carbonate (1.32 g, 9.54 mmol) was added, and the mixture was reacted at 120°C for 12 hours. LCMS indicated the reaction was complete. The reaction solution was poured into stirred water and extracted with EA. The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (DCM:MeOH = 50:1 (v / v)) to obtain the product (0.80 g). ESI-MS (m / z): 486.21 [M+H]. + .

[0494] Step 2: Synthesis of 3-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane

[0495] Dissolve tert-butyl 9-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (0.80 g, 1.64 mmol) in DCM (1 mL) and add trifluoroacetic acid (1 mL). The reaction was allowed to react at room temperature for 2 hours. LCMS showed that the reaction was complete, and the reaction solution was dried to give a crude product (0.63 g). ESI-MS (m / z): 386.25 [M+H] + .

[0496] Step 3: Synthesis of 2,2,2-trifluoro-1-(9-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-3,9-diazaspiro[5.5]undec-3-yl)ethan-1-one

[0497] 3-(5-Methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane (0.32 g) and DMAP (0.10 g, 0.82 mmol) were added to dichloromethane (5 mL) at room temperature and stirred for 5 minutes. Trifluoroacetic anhydride (0.34 g, 1.64 mmol) was then added and the mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and the resulting concentrate was purified by column chromatography (EA:PE = 3:2 (v / v)) to obtain the product (0.29 g). ESI-MS (m / z): 482.20 [M+H] + .

[0498] Step 4: Synthesis of 1-(9-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3,9-diazaspiro[5.5]undec-3-yl)-2,2,2-trifluoroethane-1-one

[0499] To a 50 mL reaction flask, 2,2,2-trifluoro-1-(9-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)-3,9-diazaspiro[5.5]undec-3-yl)ethan-1-one (0.29 g, 0.60 mmol), ethanol (5.0 mL), water (1.0 mL), reduced iron powder (0.17 g, 2.98 mmol), and ammonium chloride (0.16 g, 2.98 mmol) were added sequentially. The reaction system was reacted at 80°C for 3 hours. LCMS indicated the reaction was complete. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The concentrate was dissolved in dichloromethane, washed with saturated NaHCO₃ solution, washed with saturated aqueous NaCl solution, and dried over anhydrous Na₂SO₄ to give the crude product (0.21 g). ESI-MS (m / z): 452.25 [M+H] + .

[0500] Step 5: Synthesis of N-(6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(9-(2,2,2-trifluoroacetyl)-3,9-diazaspiro[5.5]undec-3-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide

[0501] To a 50 mL reaction flask, 1-(9-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)-3,9-diazaspiro[5.5]undec-3-yl)-2,2,2-trifluoroethane-1-one (0.21 g), DMF (5 mL), N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (0.16 g, 0.36 mmol), and trifluoroacetic acid (0.53 g, 4.68 mmol) were added sequentially. The reaction system was heated to 95°C for 16 hours. LCMS indicated completion of the reaction, and the reaction solution was concentrated to dryness under reduced pressure. The concentrate was purified by column chromatography (MeOH:DCM = 1:20 (v / v)) to afford the product (0.14 g). ESI-MS(m / z):858.27 / 860.27[M+H] + .

[0502] Step 6: Synthesis of N-(6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(3,9-diazaspiro[5.5]undec-3-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide

[0503] N-(6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(9-(2,2,2-trifluoroacetyl)-3,9-diazaspiro[5.5]undec-3-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (0.14 g, 0.16 mmol) was dissolved in methanol (5 mL) and water (0.5 mL), potassium hydroxide (0.09 g, 1.57 mmol) was added, and the mixture was reacted at 60°C for 5 hours. LCMS showed that the reaction was complete. The reaction solution was poured into stirred water and extracted with DCM. The organic phase was washed with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product (0.13 g). ESI-MS (m / z): 762.24 / 764.21 [M+H] + .

[0504] Intermediate Preparation Example 16: Synthesis of 1-(4-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazin-1-yl)-2-(piperidin-4-yl)ethan-1-one trifluoroacetate

[0505] Step 1: Synthesis of tert-butyl 4-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate

[0506] The synthesis method refers to Intermediate Preparation Example 15, except that the starting material 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester is replaced with 4-(piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester to obtain the product (0.21 g). ESI-MS (m / z): 501.27 [M+H] + .

[0507] Step 2: Synthesis of 1-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazine

[0508] Dissolve tert-butyl 4-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (0.21 g, 0.42 mmol) in DCM (1 mL) and add trifluoroacetic acid (1 mL). The reaction was allowed to react at room temperature for 2 hours. LCMS showed that the reaction was complete. The reaction solution was spin-dried, and NaHCO3 solution was added to adjust the base. The solution was extracted with DCM, and the organic phase was concentrated under reduced pressure to give the crude product (0.16 g). ESI-MS (m / z): 401.24 [M+H] + .

[0509] Step 3: Synthesis of tert-butyl 4-(2-(4-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)piperidine-1-carboxylate

[0510] To a 50 mL reaction flask, 2-(1-(tert-Butoxycarbonyl)piperidin-4-yl)acetic acid (0.09 g, 0.38 mmol) and N,N-dimethylformamide (2 mL) were added. 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.17 g, 0.46 mmol) and N,N-diisopropylethylamine (0.15 g, 1.14 mmol) were added at 0°C. After a half-hour reaction, 1-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazine (0.17 g) was added. The reaction mixture was allowed to react at 25°C for 2 hours. Water was added for extraction and separation. The organic phase was collected, concentrated, and separated on a silica gel column (DCM:MeOH = 12:1 (v / v)) to obtain the product (0.23 g). ESI-MS (m / z): 626.41 [M+H] + .

[0511] Step 4: Synthesis of 1-(4-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazin-1-yl)-2-(piperidin-4-yl)ethan-1-one trifluoroacetate

[0512] Tert-butyl 4-(2-(4-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)piperidine-1-carboxylate (0.23 g, 0.37 mmol) was dissolved in DCM (1 mL) and trifluoroacetic acid (1 mL) was added. The reaction was allowed to react at room temperature for 2 hours. LCMS showed that the reaction was complete, and the reaction solution was dried, and NaHCO3 solution was added to adjust the base. The mixture was extracted with DCM, and the organic phase was concentrated under reduced pressure to give the crude product (0.19 g). ESI-MS (m / z): 526.31 [M+H] + .

[0513] Intermediate Preparation Example 17: Synthesis of 1-(4-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazin-1-yl)-2-(pyrrolidin-3-yl)ethan-1-one trifluoroacetate

[0514] The synthesis method refers to Intermediate Preparation Example 16, except that the starting material in Step 3, 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid, was replaced with 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)acetic acid to obtain the product (0.17 g). ESI-MS (m / z): 512.28 [M+H] + .

[0515] Intermediate Preparation Example 18: Synthesis of 1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidine-4-carboxaldehyde

[0516] Step 1: Synthesis of (1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methanol

[0517] To a 100 mL reaction flask, 4-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (0.50 g, 1.99 mmol), DMSO (5 mL), piperidin-4-ylmethanol (0.27 g, 2.39 mmol), and DIPEA (1.28 g, 9.90 mmol) were added sequentially. The reaction system was heated to 130°C and reacted for 12 hours. LCMS indicated completion of the reaction. Water and DCM were added to the reaction solution, stirred, and separated. The organic phase was washed with water and saturated sodium chloride solution, concentrated under reduced pressure, and separated by column chromatography (DCM:MeOH = 45:1 (v / v)) to afford the product (0.40 g). ESI-MS (m / z): 347.17 [M+H] + .

[0518] Step 2: Synthesis of 1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidine-4-carbaldehyde

[0519] To a 100 mL reaction flask, (1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methanol (0.38 g, 1.08 mmol) and DMF (5 mL) were added sequentially. Dess-Martin periodinane (1.38 g, 3.25 mmol) was added at 0°C. The reaction system was warmed to 25°C and reacted for 12 hours. LCMS showed that the reaction was complete. The reaction solution was diluted with DCM and washed with sodium thiosulfate, then with aqueous sodium bicarbonate, and finally with saturated sodium chloride water. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (DCM:MeOH = 15:1 (v / v)) to obtain the product (0.21 g). ESI-MS (m / z): 345.13 [M+H] + .

[0520] Intermediate Preparation Example 19: Synthesis of N-(6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidin-4-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide

[0521] The synthesis method refers to Intermediate Preparation Example 15, except that the starting material in Step 1, tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate, was replaced with tert-butyl 4-(piperazin-1-yl)piperidine-1-carboxylate to obtain the product. ESI-MS (m / z): 779.23 / 777.23 [M+H] + .

[0522] Intermediate Preparation Example 20: Synthesis of 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0523] Step 1: Synthesis of 6-bromo-5-fluoro-1-methyl-1H-indazol-3-amine

[0524] 4-Bromo-2,5-difluorobenzonitrile (25 g, 114.68 mmol) was added to EtOH (250 mL), followed by the addition of methylhydrazine sulfate (66.12 g, 458.71 mmol) and triethylamine (104.44 g, 1.03 mol). The mixture was heated to 80°C and allowed to react for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was concentrated under reduced pressure and poured into ice water (300 mL). Extraction was performed with EA (300 mL). The organic phase was washed with saturated sodium chloride solution (200 mL), dried over sodium sulfate, and concentrated to yield the product (17 g). ESI-MS (m / z): 243.98 / 245.98.

[0525] Step 2: Synthesis of 3-((6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)amino)propanoic acid

[0526] 6-Bromo-5-fluoro-1-methyl-1H-indazol-3-amine (17 g) was added to 2N HCl (170 mL), followed by TBAB (1.69 g, 5.24 mmol) and acrylic acid (7.53 g, 104.48 mmol). The reaction system was heated to 100°C for 16 hours. LCMS showed that the reaction was complete. The reaction solution was poured into ice water (400 mL), and the pH was adjusted to 8 with sodium bicarbonate, and then to about 5 with acetic acid. The reaction solution was extracted with EA, washed with saturated sodium chloride water, dried over sodium sulfate, and the organic phase was concentrated to dryness under reduced pressure to obtain the product (15.5 g). ESI-MS (m / z): 316.0 / 318.0 [M+H] + .

[0527] Step 3: Synthesis of 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0528] 3-((6-Bromo-5-fluoro-1-methyl-1H-indazol-3-yl)amino)propionic acid (15.0 g) was added to AcOH (150 mL) and NaCN (6.17 g, 125.90 mmol). The reaction system was heated to 60°C and reacted for 16 hours. 2N HCl (150 mL) was then added and stirred at 60°C for 3 hours. LCMS showed that the reaction was complete. The reaction system was cooled to room temperature and the reaction solution was filtered. The filter cake was washed three times with water and then dried to obtain the product (6.0 g). ESI-MS (m / z): 341.00 / 343.00 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ 10.61 (s, 1H), 8.17 (d, J = 5.6 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 4.01 (s, 3H), 3.93 (t, J = 6.8 Hz, 2H), 2.76 (t, J = 6.8 Hz, 2H).

[0529] Intermediate Preparation Example 21: Synthesis of 1-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate

[0530] 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

[0531] To a 100 mL reaction flask, 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.3 g, 0.88 mmol), tert-butyl piperazine-1-carboxylate (0.25 g, 1.32 mmol), RuPhosPdG2 (0.14 g, 0.17 mmol), cesium carbonate (0.86 g, 2.65 mmol), and 1,4-dioxane (5 mL) were added sequentially. The reaction system was allowed to react at 120°C under nitrogen for 8 hours. LCMS indicated completion of the reaction. Ethyl acetate and water were added to the reaction mixture, stirred, and the organic phase was separated. The organic phase was concentrated under reduced pressure and separated by column chromatography (DCM:MeOH = 40:1 (v / v)) to afford the product (0.18 g). ESI-MS (m / z): 447.21 [M+H] + .

[0532] Step 2: Synthesis of 1-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate

[0533] Dissolve tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.11 g, 0.25 mmol) in DCM (1 mL) and add trifluoroacetic acid (1 mL). The reaction was allowed to react at room temperature for 2 hours. LCMS indicated the reaction was complete, and the reaction solution was concentrated to dryness under reduced pressure to give the crude product (0.09 g). ESI-MS (m / z): 347.15 [M+H].

[0534] Intermediate Preparation Example 22: Synthesis of N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinolin-5-yl)-N-methylmethanesulfonamide

[0535] Step 1: Synthesis of 2-methyl-6-nitroquinoline

[0536] 2-Chloro-6-nitroquinoline (1.30 g, 6.23 mmol), trimethylboroxane (50% in THF, 6.24 g, 25 mmol), triphenylphosphine (0.32 g, 1.22 mmol), cesium carbonate (6.08 g, 18.66 mmol), palladium acetate (0.13 g, 0.57 mmol), dioxane (40 mL), and water (10 mL) were added to the reaction flask in sequence. The reaction system was reacted at 80°C under a nitrogen atmosphere for 3 hours. LCMS showed the reaction was complete. The reaction system was cooled to room temperature, and then water (30 mL) was slowly added. The mixture was extracted with ethyl acetate (30 mL × 3) and separated. The resulting organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The concentrate was purified by medium pressure (PE:EA = 8:1) to obtain the product (0.8 g). ESI-MS (m / z): 189.19 [M+H] + .

[0537] Step 2: Synthesis of 2-methyl-6-nitroquinolin-5-amine

[0538] 2-Methyl-6-nitroquinoline (0.8 g, 4.25 mmol), 4-amino-1,2,4-triazole (1.78 g, 21.17 mmol), sodium methoxide (2.29 g, 42.39 mmol), and dimethyl sulfoxide (10 mL) were added to the reaction flask and stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. Dilute hydrochloric acid was slowly added dropwise to the reaction solution to adjust the pH to 6-7. Solid precipitated and was filtered to obtain a filter cake. The filter cake was purified by column chromatography (DCM:MeOH=40:1) to obtain the product (0.45 g). ESI-MS (m / z): 204.07 [M+H] + .

[0539] Step 3: Synthesis of N-(2-methyl-6-nitroquinolin-5-yl)methanesulfonamide

[0540] 2-Methyl-6-nitroquinolin-5-amine (0.45 g, 2.21 mmol) and anhydrous DMF (10 mL) were added to the reaction flask, followed by 60% NaH (0.5 g, 12.5 mmol) at room temperature. The reaction system was then heated to 60°C and stirred for 30 minutes. Methanesulfonyl chloride (1.26 g, 11 mmol) was added dropwise at 60°C. After the addition was complete, the reaction was continued for 1 hour. The reaction system was then cooled to room temperature and 3M NaOH solution (4 mL) was added. The mixture was stirred for 5 minutes, and LCMS indicated that the reaction was complete. Water and ethyl acetate were then added to the reaction solution, stirred, and separated. The aqueous phase was adjusted to pH 5 with 3N hydrochloric acid. Solids precipitated and were filtered. The filter cake was purified by column chromatography (PE:EA = 1:1) to obtain the product (0.3 g). ESI-MS (m / z): 204.20 [M+H] + .

[0541] Step 4: Synthesis of N-methyl-N-(2-methyl-6-nitroquinolin-5-yl)methanesulfonamide

[0542] N-(2-methyl-6-nitroquinolin-5-yl)methanesulfonamide (0.3 g, 1.07 mmol), anhydrous DMF (10 mL), and potassium carbonate (0.55 g, 4 mmol) were added sequentially to the reaction flask. Methyl iodide (0.28 g, 2 mmol) was added dropwise at room temperature until complete, and the reaction was continued for 1.5 hours. LCMS showed that the reaction was complete. Water and ethyl acetate were added, and the resulting organic phase was extracted with water and saturated sodium chloride solution and concentrated to dryness under reduced pressure to obtain the crude product (0.3 g). ESI-MS (m / z): 296.31 [M+H] + .

[0543] Step 5: Synthesis of N-(6-amino-2-methylquinolin-5-yl)-N-methylmethanesulfonamide

[0544] Crude N-methyl-N-(2-methyl-6-nitroquinolin-5-yl)methanesulfonamide (0.3 g), ethanol (10 mL), water (2 mL), reduced iron powder (0.3 g, 5.37 mmol), and ammonium chloride (0.3 g, 5.61 mmol) were added to a reaction flask in this order. The reaction system was incubated at 80°C for 2 hours. LCMS indicated the reaction was complete. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product (0.25 g). ESI-MS (m / z): 266.33 [M+H] + .

[0545] Step 6: Synthesis of N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinolin-5-yl)-N-methylmethanesulfonamide

[0546] Crude N-(6-amino-2-methylquinolin-5-yl)-N-methylmethanesulfonamide (0.25 g) and anhydrous DMF (5 mL) were added to a reaction flask. 60% NaH (0.05 g, 1.4 mmol) was added at room temperature. After stirring for 10 minutes, 5-bromo-2,4-dichloropyrimidine (0.23 g, 1.0 mmol) was added. The reaction system was allowed to react for 1 hour at room temperature. LCMS indicated completion of the reaction. Saturated aqueous ammonium chloride was added to the reaction mixture, resulting in the precipitation of a solid. The solid was filtered and the filter cake dried to obtain the product (0.2 g). ESI-MS (m / z): 455.98 / 457.96 [M+H] + .

[0547] Intermediate Preparation Example 23: Synthesis of 1-(2-cyclopropyl-5-methoxy-4-nitrophenyl)piperidine-4-carboxaldehyde

[0548] Step 1: Synthesis of 1-cyclopropyl-2-fluoro-4-methoxy-5-nitrobenzene

[0549] To a reaction flask, 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (1.0 g, 4.00 mmol), cyclopropylboronic acid (0.5 g, 5.82 mmol), Pd(dppf)Cl2 (0.3 g, 0.41 mmol), potassium carbonate (1.1 g, 7.96 mmol), 1,4-dioxane (20 mL), and water (4 mL) were added sequentially. The reaction system was allowed to react at 100°C under nitrogen protection for 2 hours. TLC indicated the reaction was complete. Ethyl acetate and water were added to the reaction mixture, stirred, and the resulting organic phase was concentrated to dryness under reduced pressure. The product (0.8 g) was then separated by column chromatography (DCM:MeOH = 40:1 (v / v)).

[0550] Step 2: Synthesis of (1-(2-cyclopropyl-5-methoxy-4-nitrophenyl)piperidin-4-yl)methanol

[0551] 1-Cyclopropyl-2-fluoro-4-methoxy-5-nitrobenzene (0.8 g, 3.79 mmol), DMSO (10 mL), 4-piperidinemethanol (0.65 g, 5.64 mmol), and DIPEA (1.47 g, 11.37 mmol) were added to the reaction flask in sequence. The reaction system was heated to 120°C and reacted for 5 hours. LCMS indicated the reaction was complete. Water and DCM were added to the reaction solution, stirred, and separated. The organic phase was washed with water and saturated sodium chloride solution, concentrated under reduced pressure, and separated by column chromatography (DCM:MeOH = 30:1 (v / v)) to obtain the product (0.60 g). ESI-MS (m / z): 307.36 [M+H] + .

[0552] Step 3: Synthesis of 1-(2-cyclopropyl-5-methoxy-4-nitrophenyl)piperidine-4-carboxaldehyde

[0553] To the reaction flask, (1-(2-cyclopropyl-5-methoxy-4-nitrophenyl)piperidin-4-yl)methanol (0.6 g, 1.96 mmol) and DMF (10 mL) were added sequentially. Dess-Martin periodinane (1.25 g, 2.95 mmol) was added at 0°C. The reaction system was heated to 25°C and reacted for 3 hours. LCMS showed that the reaction was complete. The reaction solution was diluted with DCM and washed with sodium thiosulfate, then with aqueous sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (DCM:MeOH = 30:1 (v / v)) to obtain the product (0.32 g). ESI-MS (m / z): 305.35 [M+H] + .

[0554] Intermediate Preparation Example 24: N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(2-oxoethyl)piperidin-1-yl)benzamide

[0555] Step 1: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-iodobenzamide

[0556] 2-Fluoro-4-iodobenzoic acid (10.0 g, 37.593 mmol), 3-aminopiperidine-2,6-dione hydrochloride (6.19 g, 37.593 mmol), DMF (80 mL), HOBt (7.62 g, 56.389 mmol), EDCI (10.81 g, 56.389 mmol), and DIEA (14.58 g, 112.779 mmol) were added to the reaction flask. The mixture was stirred at 25°C for 12.0 hours. LCMS showed that the starting materials were completely reacted. The reaction solution was poured into 200 mL of water, filtered, and the solid was dried to obtain the product (12.4 g). ESI-MS (m / z): 376.97 [M+H] + .

[0557] Step 2: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(2-hydroxyethyl)piperidin-1-yl)benzamide

[0558] To a reaction flask, N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-iodobenzamide (10.0 g, 26.59 mmol), 4-piperidineethanol (4.89 g, 37.85 mmol), DMSO (80 mL), KCO (6.98 g, 50.50 mmol), CuI (4.81 g, 25.26 mmol), and L-proline (1.45 g, 12.59 mmol) were added and stirred at 90°C under N2 for 3 hours. LCMS showed complete reaction. The reaction mixture was poured into 1M HCl (100 mL) and saturated NH4Cl (100 mL), and extracted twice with NH3·H2O (15 mL) and EA (200 mL). The organic phase was washed three times with saturated sodium chloride solution, dried, and concentrated to obtain the crude product, which was then slurried with MeOH (40 mL) to yield the product (3.28 g). ESI-MS (m / z): 378.18 [M+H] + .

[0559] Step 3: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(2-oxoethyl)piperidin-1-yl)benzamide

[0560] N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(2-hydroxyethyl)piperidin-1-yl)benzamide (3.0 g), DMF (20 mL), and Dess-Martin periodinane (4.80 g, 11.327 mmol) were added to a reaction flask and stirred at 25°C for 3.0 hours. LCMS indicated that the starting material had reacted completely. The reaction solution was filtered, and the filtrate was adjusted to pH 8 by adding saturated NaHCO₃(aq). H₂O (30 mL) was added and extracted twice with EA (100 mL). The organic phase was washed three times with saturated aqueous sodium chloride solution, dried, and concentrated to obtain the crude product. The crude product was slurried in DCM (40 mL) to obtain the product (1.67 g). ESI-MS (m / z): 376.15 [M+H] + .

[0561] Intermediate Preparation Example 25: Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)pyridine-2-carboxamide trifluoroacetate

[0562] Step 1: Synthesis of 5-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)picolinic acid

[0563] 5-Fluoropyridine-2-carboxylic acid (5 g, 35.44 mmol) was dissolved in DMSO (50 mL), and tert-butyl piperazine-1-carboxylate (6.6 g, 35.44 mmol) and DIPEA (13.74 g, 106.31 mmol) were added. The temperature was raised to 110°C and the reaction was allowed to react for 2 hours. The reaction solution was poured into ice water (100 mL) and extracted twice with EA (100 mL). The organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the product (5 g). ESI-MS (m / z): 308.17 [M+H] + .

[0564] Step 2: Synthesis of tert-butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0565] 5-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)picolinic acid (5.0 g) was dissolved in DMF (50 mL), and 3-aminopiperidine-2,6-dione (2.08 g, 16.27 mmol) and DIPEA (6.31 g, 48.80 mmol) were added, followed by HATU (7.45 g, 19.59 mmol). The reaction was allowed to react at room temperature for 1 hour. LCMS confirmed the completion of the reaction. The reaction solution was slowly poured into ice water (200 mL), stirred for 10 minutes, and filtered. The filter cake was washed twice with water and dried in an oven at 50°C to obtain tert-butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate (2.0 g). ESI-MS (m / z): 418.21 [M+H] + .

[0566] Step 3: Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)pyridine-2-carboxamide trifluoroacetate

[0567] Dissolve tert-butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate (2.0 g, 4.79 mmol) in DCM (20 mL) and add TFA (6 mL). The mixture is allowed to react at room temperature for 1 hour. LCMS indicates that the reaction is complete. The reaction solution is concentrated to dryness under reduced pressure, and the residue is dissolved in distilled water and lyophilized to obtain the product (0.8 g). ESI-MS (m / z): 318.16 [M+H] + .

[0568] Intermediate Preparation Example 26: Synthesis of 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione trifluoroacetate

[0569] Step 1: Synthesis of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate

[0570] Dissolve 1,2-difluoro-4-nitrobenzene (0.40 g, 2.51 mmol) in DMF (50 mL), add tert-butyl piperazine-1-carboxylate (0.56 g, 3.02 mmol) and potassium carbonate (1.04 g, 7.53 mmol), and heat to 100°C for 8 hours. Add water for extraction and separation, collect the organic phase, and concentrate under reduced pressure to obtain the crude product. ESI-MS (m / z): 326.17 [M+H] + .

[0571] Step 2: Synthesis of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate

[0572] To a reaction flask, tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate (0.35 g, 1.08 mmol), ethanol (5.0 mL), water (1.0 mL), reduced iron powder (0.60 g, 10.80 mmol), and ammonium chloride (0.58 g, 10.80 mmol) were added sequentially. The reaction system was allowed to react at 80°C for 3 hours. LCMS indicated the reaction was complete. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The concentrate was dissolved in dichloromethane, and the organic phase was washed with saturated NaHCO3 solution and saturated NaCl aqueous solution, then dried over anhydrous Na2SO4 to obtain the crude product (0.31 g). ESI-MS (m / z): 296.10 [M+H] + .

[0573] Step 3: Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate

[0574] Crude tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate (0.31 g), 3-bromopiperidine-2,6-dione (0.25 g, 1.28 mmol), and DMF (5 mL) were added to the reaction flask in sequence, followed by DIPEA (0.42 g, 3.21 mmol). The reaction system was heated to 100°C and reacted for 5 hours. LCMS showed that the reaction was complete, and water was added for extraction and separation. The organic phase was collected and concentrated under reduced pressure. The concentrate was separated on a silica gel column (MeOH:DCM = 1:20 (v / v)) to obtain the product (0.17 g). ESI-MS (m / z): 407.24 [M+H] + .

[0575] Step 4: Synthesis of 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione trifluoroacetate

[0576] Dissolve tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (0.17 g, 0.41 mmol) in DCM (1 mL) and add trifluoroacetic acid (1 mL). Allow to react at room temperature for 2 hours. LCMS indicated the reaction was complete, and the reaction solution was dried to give a crude product (0.13 g). ESI-MS (m / z): 307.24 [M+H] + .

[0577] Intermediate Preparation Example 27: Synthesis of 3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione trifluoroacetate

[0578] Referring to the synthetic method of Intermediate Preparation Example 21, the starting material of Step 1, 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, was replaced with 3-(6-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione, and the 1,4-dioxane solvent was replaced with DMF to obtain the product. ESI-MS (m / z): 329.17 [M+H] + .

[0579] Intermediate Preparation Example 28: Synthesis of N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylcyclopropanesulfonamide

[0580] Referring to the synthesis method of Intermediate Preparation Example 1, the starting material of step 2, methylsulfonyl chloride, was replaced with cyclopropylsulfonyl chloride to obtain the product. ESI-MS (m / z): 470.91 [M+H] + .

[0581] Intermediate Preparation Example 29: Synthesis of N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinolin-5-yl)-N-methylmethanesulfonamide

[0582] Referring to the synthesis method of Intermediate Preparation Example 1, the starting material 6-nitroquinoxaline in step 1 was replaced with 6-nitroquinoline to obtain the product. ESI-MS (m / z): 443.94 [M+H] + .

[0583] Intermediate Preparation Example 30: Synthesis of 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0584] Referring to the synthesis method of Intermediate Preparation Example 20, the starting material of step 1, 4-bromo-2,5-difluorobenzonitrile, was replaced with 4-bromo-2-fluorobenzonitrile to obtain the product. ESI-MS (m / z): 322.01 / 324.00 [M+H] + .

[0585] Intermediate Preparation Example 31: Synthesis of 1-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione trifluoroacetate

[0586] Referring to the synthetic method of Intermediate Preparation Example 21, the starting material of Step 1, 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, was replaced with 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione to obtain the product. ESI-MS (m / z): 329.17 [M+H] + .

[0587] Intermediate Preparation Example 32: Synthesis of tert-butyl 4-(4-(2-oxoethyl)piperidin-1-yl)benzoate

[0588] Step 1: Synthesis of tert-butyl 4-(4-(2-hydroxyethyl)piperidin-1-yl)benzoate

[0589] Dissolve tert-butyl 4-fluorobenzoate (0.30 g, 1.53 mmol) in DMF (5 mL), add 2-(piperidin-4-yl)ethan-1-ol (0.20 g, 1.53 mmol) and potassium carbonate (0.63 g, 4.59 mmol), and heat to 100°C for 16 hours. The reaction solution was poured into water and extracted twice with EA. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was separated on a silica gel column (MeOH:DCM = 1:50 (v / v)) to obtain the product (0.15 g). ESI-MS (m / z): 306.12 [M+H] + .

[0590] Step 2: Synthesis of tert-butyl 4-(4-(2-oxoethyl)piperidin-1-yl)benzoate

[0591] Tert-butyl 4-(4-(2-hydroxyethyl)piperidin-1-yl)benzoate (0.15 g, 0.49 mmol) was dissolved in DMSO (2 mL), and IBX (0.17 g, 0.59 mmol) was added. The mixture was heated to 50°C and reacted for 16 hours. The reaction solution was poured into water and extracted twice with EA. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was separated on a silica gel column (MeOH:DCM = 1:100 (v / v)) to obtain the product (0.04 g). ESI-MS (m / z): 304.11 [M+H] + .

[0592] Intermediate Preparation Example 33: Synthesis of N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)-N-methylmethanesulfonamide

[0593] Step 1: Synthesis of 3-fluoro-2-methyl-6-nitroquinoline

[0594] 2-Methyl-5-nitro-1H-indole (7 g, 39.73 mmol) was added to xylene (70 mL), followed by dibromomonofluoromethane (20.45 g, 106.60 mmol) and t-BuOLi (9.55 g, 119.24 mmol). The temperature was raised to 140°C and the reaction was allowed to react for 1 hour. TLC indicated the formation of the product. The reaction mixture was poured into ice water and extracted with EA. The mixture was washed with saturated sodium chloride solution and purified by column chromatography (PE:EA = 20:1) to obtain the product (1.7 g). ESI-MS (m / z): 207.11 [M+H]. + .

[0595] Step 2: Synthesis of 3-fluoro-2-methyl-6-nitroquinolin-5-amine

[0596] Dissolve 3-fluoro-2-methyl-6-nitroquinoline (0.45 g, 2.18 mmol) and 4H-1,2,4-triazol-4-amine (0.92 g, 10.95 mmol) in dimethyl sulfoxide (10 mL). Add sodium methoxide (1.18 g, 21.84 mmol) with stirring and allow to react at room temperature for 2 hours. LCMS confirmed the reaction was complete. Water was added, followed by extraction with EA, washing with saturated sodium chloride solution, and purification by column chromatography (DCM:MeOH = 20:1) to obtain the product (376 mg). ESI-MS (m / z): 222.06 [M+H] + .

[0597] Step 3: Synthesis of N-(3-fluoro-2-methyl-6-nitroquinolin-5-yl)-N-(methylsulfonyl)methanesulfonamide

[0598] Dissolve 3-fluoro-2-methyl-6-nitroquinolin-5-amine (300 mg) in DMF (10 mL). Add 60% NaH (326 mg, 8.15 mmol) with stirring. Add MsCl (933 mg, 8.14 mmol) at 60°C with stirring. React at 60°C for 0.5 h. Cool to room temperature for use in the next step.

[0599] Step 4: Synthesis of N-(3-fluoro-2-methyl-6-nitroquinolin-5-yl)methanesulfonamide

[0600] To the reaction solution cooled to room temperature in step 3, NaOH (5 M, 5 mL) was added and stirred at room temperature for 0.5 h. LCMS confirmed the reaction was complete, and water was added. Extraction was performed with EA, followed by washing with saturated sodium chloride solution. Purification was performed by column chromatography (DCM:MeOH = 20:1) to obtain the product (86 mg). ESI-MS (m / z): 300.02 [M+H] + .

[0601] Step 5: Synthesis of N-(3-fluoro-2-methyl-6-nitroquinolin-5-yl)-N-methylmethanesulfonamide

[0602] Dissolve N-(3-fluoro-2-methyl-6-nitroquinolin-5-yl)methanesulfonamide (86 mg, 0.29 mmol) and K2CO3 (160 mg, 1.16 mmol) in DMF. Add iodomethane (81 mg, 0.57 mmol) with stirring and allow to react at room temperature for 1 hour. LCMS confirmed the reaction was complete, and the mixture was filtered with water. The residue was purified by column chromatography (DCM:MeOH = 50:1) to obtain the product (87 mg). ESI-MS (m / z): 314.29 [M+H] + .

[0603] Step 6: Synthesis of N-(6-amino-3-fluoro-2-methylquinolin-5-yl)-N-methylmethanesulfonamide

[0604] N-(3-Fluoro-2-methyl-6-nitroquinolin-5-yl)-N-methylmethanesulfonamide (87 mg, 0.28 mmol), iron powder (78 mg, 1.39 mmol), and ammonium chloride (75 mg, 1.39 mmol) were dissolved in EtOH:H2O (5:1) and reacted at 80°C for 1 hour. LCMS confirmed the reaction was complete, and the mixture was filtered and concentrated under reduced pressure to obtain the crude product (65 mg). ESI-MS (m / z): 284.01 [M+H] + .

[0605] Step 7: Synthesis of N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)-N-methylmethanesulfonamide

[0606] N-(6-Amino-3-fluoro-2-methylquinolin-5-yl)-N-methylmethanesulfonamide (65 mg) was dissolved in DMF (5 mL). 60% NaH (18.4 mg, 0.77 mmol) was added with stirring, followed by 5-bromo-2,4-dichloropyrimidine (57 mg, 0.25 mmol). The reaction was allowed to react at room temperature for 1 hour. LCMS confirmed the completion of the reaction. The product was quenched with saturated ammonium chloride solution, filtered, extracted with EA, washed with saturated sodium chloride solution, and purified by column chromatography (DCM:MeOH = 30:1) to obtain the product (93 mg). ESI-MS (m / z): 474.11 [M+H]. + .

[0607] Intermediate Preparation Example 34: Synthesis of 2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetic acid

[0608] Step 1: Synthesis of piperidin-4-one

[0609] Dissolve tert-butyl 4-oxopiperidine-1-carboxylate (5 g, 25.09 mmol) in dichloromethane (30 mL), add TFA with stirring, and react at room temperature for 1 hour. After TLC monitoring, the reaction was completed and concentrated under reduced pressure to obtain the crude product (2.49 g). ESI-MS (m / z): 100.01 [M+H] + .

[0610] Step 2: Synthesis of 1-(2-fluoro-4-nitrophenyl)piperidin-4-one

[0611] Crude piperidin-4-one (2.49 g) and 1,2-difluoro-4-nitrobenzene (3.99 g, 25.08 mmol) were dissolved in DMF (20 mL). DIPEA (6.45 g, 49.91 mmol) was added with stirring and the mixture was allowed to react at 110°C for 7 hours. TLC monitored the reaction completion. Water was added, followed by extraction with EA, and the mixture was washed with saturated sodium chloride solution. The product was purified by column chromatography (PE:EA = 30:1) to obtain the product (2.37 g). ESI-MS (m / z): 239.02 [M+H] + .

[0612] Step 3: Synthesis of tert-butyl 2-(1-(2-fluoro-4-nitrophenyl)-4-hydroxypiperidin-4-yl)acetate

[0613] Dissolve tert-butyl acetate (0.98 mL, 7.3 mmol) in THF (20 mL) under Ar. Add LDA (2 M in THF) (6.1 mL, 12.2 mmol) dropwise with stirring at -78°C. After stirring for 10 minutes, add 1-(2-fluoro-4-nitrophenyl)piperidin-4-one (2 g, 8.4 mmol) and react at -78°C for 2 hours. TLC monitored the reaction completion, quenched with aqueous ammonium chloride, extracted with EA, washed with saturated aqueous sodium chloride, and purified by column chromatography (DCM:MeOH = 20:1) to obtain the product (2.48 g). ESI-MS (m / z): 355.08 [M+H]. + .

[0614] Step 4: Synthesis of tert-butyl 2-(1-(4-amino-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetate

[0615] Dissolve tert-butyl 2-(1-(2-fluoro-4-nitrophenyl)-4-hydroxypiperidin-4-yl)acetate (2.4 g, 6.78 mmol), iron powder (1.9 g, 33.9 mmol), and ammonium chloride (1.9 g, 35.5 mmol) in EtOH:H2O (5:1) and react at 80°C for 1 hour. LCMS confirmed the reaction was complete, and the mixture was filtered and concentrated under reduced pressure to obtain a crude product (1.71 g). ESI-MS (m / z): 325.33 [M+H] + .

[0616] Step 5: Synthesis of tert-butyl 2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetate

[0617] Tert-butyl 2-(1-(4-amino-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetate (1.68 g), bromopiperidine-2,6-dione (1.98 g, 10.32 mmol), and DIPEA (2 g, 15.48 mmol) were dissolved in DMF (10 mL) and reacted at 80°C for 10 hours. LCMS confirmed the completion of the reaction, followed by filtration with water. The residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain the product (1.43 g). ESI-MS (m / z): 436.22 [M+H] + .

[0618] Step 6: Synthesis of 2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetic acid

[0619] Tert-butyl 2-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-4-hydroxypiperidin-4-yl)acetate (100 mg, 0.23 mmol) was dissolved in dichloromethane (3 mL). TFA was added with stirring and the mixture was allowed to react at room temperature for 1 hour. The reaction was monitored for completion by TLC and concentrated under reduced pressure to obtain the crude product (87 mg). ESI-MS (m / z): 380.01 [M+H] + .

[0620] Intermediate Preparation Example 35: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide trifluoroacetate

[0621] Referring to Intermediate Preparation Example 25, the starting material 5-fluoropyridine-2-carboxylic acid in step 1 was replaced with 2,4-difluorobenzoic acid to obtain the product. ESI-MS (m / z): 335.21 [M+H] + .

[0622] Intermediate Preparation Example 36: Synthesis of 2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)acetaldehyde

[0623] Step 1: Synthesis of 2-(1-(4-nitrophenyl)piperidin-4-yl)ethan-1-ol

[0624] 2-(Piperidin-4-yl)ethan-1-ol (2 g, 15.48 mmol) was dissolved in DMSO (20 mL), 1-fluoro-4-nitrobenzene (2.4 g, 17.01 mmol) and potassium carbonate (6.45 g, 46.67 mmol) were added, and the mixture was heated to 120°C for 2 hours. LCMS confirmed the completion of the reaction. The reaction solution was poured into water and extracted twice with EA. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure. The concentrate was separated by column chromatography (DCM:MeOH = 50:1) to obtain the product (3.87 g). ESI-MS (m / z): 251.13 [M+H] + .

[0625] Step 2: Synthesis of 2-(1-(4-aminophenyl)piperidin-4-yl)ethan-1-ol

[0626] 2-(1-(4-nitrophenyl)piperidin-4-yl)ethan-1-ol (3.87 g, 15.46 mmol), iron powder (2.6 g, 46.38 mmol), and ammonium chloride (2.5 g, 46.74 mmol) were dissolved in EtOH:H2O (5:1) and reacted at 80°C for 1 hour. LCMS confirmed the reaction was complete, and the mixture was filtered and concentrated under reduced pressure to obtain the crude product (840 mg). ESI-MS (m / z): 221.01 [M+H] + .

[0627] Step 3: Synthesis of 3-((4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)amino)propionic acid

[0628] The crude product of 2-(1-(4-aminophenyl)piperidin-4-yl)ethan-1-ol (400 mg) was dissolved in toluene (10 mL), and acrylic acid (393 mg, 5.45 mmol) was added with stirring. The reaction system was then heated to 100°C and reacted for 16 hours. LCMS confirmed the completion of the reaction. Water was added, and the reaction solution was extracted with EA, washed with saturated sodium chloride solution, and dried over sodium sulfate. The organic phase was concentrated to dryness under reduced pressure to obtain the crude product (531 mg). ESI-MS (m / z): 293.33 [M+H] + .

[0629] Step 4: Synthesis of ethyl 2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)acetate

[0630] The crude product of 3-((4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)amino)propionic acid (531 mg) and urea (547 mg, 9.10 mmol) were dissolved in acetic acid (10 mL) and reacted at 120° C. for 12 hours. The reaction was complete as determined by LCMS. Water was added, and the reaction solution was extracted with EA, washed with saturated sodium chloride water, and dried over sodium sulfate. The organic phase was concentrated to dryness under reduced pressure and separated by column chromatography (DCM:MeOH=30:1) to obtain the product (62 mg). ESI-MS (m / z): 293.33 [M+H] + .

[0631] Step 5: Synthesis of 1-(4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0632] Ethyl 2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)acetate (62 mg, 0.17 mmol) was dissolved in HCl solution (4 M, 3 mL) and reacted at 100°C for 2 hours. LCMS confirmed the completion of the reaction, and the mixture was adjusted to neutrality with saturated sodium bicarbonate aqueous solution. The reaction solution was extracted with EA, washed with saturated sodium chloride water, and dried over sodium sulfate. The organic phase was concentrated to dryness under reduced pressure and separated by thin-layer chromatography (DCM:MeOH=15:1) to obtain the product (36 mg). ESI-MS (m / z): 318.35 [M+H] + .

[0633] Step 6: Synthesis of 2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)acetaldehyde

[0634] 1-(4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (36 mg, 0.11 mmol) was dissolved in DMSO (3 mL) and IBX (48 mg, 0.17 mmol) was added with stirring. The mixture was allowed to react at room temperature for 1 hour. LCMS confirmed the completion of the reaction. The mixture was diluted with water and extracted with EA, washed with saturated sodium chloride water, and dried over sodium sulfate. The organic phase was concentrated to dryness under reduced pressure and separated by thin-layer chromatography (DCM:MeOH=20:1) to obtain the product (34 mg). ESI-MS (m / z): 316.05 [M+H] + .

[0635] Intermediate Preparation Example 37: Synthesis of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine

[0636] 5-Bromo-1,3-difluoro-2-iodobenzene (1 g, 3.14 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.31 g, 3.14 mmol), K2CO3 (1.3 g, 9.42 mmol), and Pd(dppf)Cl2 (256 mg, 0.35 mmol) were dissolved in a mixture of 1,4-dioxane and H2O (5:1) under nitrogen protection and reacted at 100°C for 10 hours. LCMS confirmed the completion of the reaction, which was then diluted with water. The reaction solution was extracted with EA, washed with saturated sodium chloride water, and dried over sodium sulfate. The organic phase was concentrated to dryness under reduced pressure and separated by column chromatography (PE:EA = 30:1) to give the product (1.33 g). ESI-MS (m / z): 482.26 / 484.01 [M+H] + .

[0637] Intermediate Preparation Example 38: Synthesis of 3-(2,6-difluoro-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione trifluoroacetate

[0638] Step 1: Synthesis of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)piperidine-1-carboxylate

[0639] 2,6-Bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)piperidine (154 mg, 0.32 mmol), N-Boc piperazine (400 mg, 2.15 mmol), Pd2(dba)3 (76 mg, 0.08 mmol), Xantphos (96 mg, 0.17 mmol), and cesium carbonate (814 mg, 2.51 mmol) were dissolved in DMA and reacted at 100°C under N2 protection for 5 hours. LCMS indicated that the reaction was complete, and the product was diluted with water and extracted with ethyl acetate. The organic phases were combined, the solvent evaporated, and the product was purified by column chromatography (DCM:MeOH = 50:1) to afford the product (109 mg). ESI-MS (m / z): 588.26 [M+H] + .

[0640] Step 2: Synthesis of tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidine-1-carboxylate

[0641] Tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)piperidine-1-carboxylate (109 mg, 0.19 mmol) was dissolved in a mixed solvent (EtOH:EA:DCM = 5:5:1). Pd / C (20 mg) was added with stirring, and the mixture was stirred at room temperature for 10 hours under a H2 atmosphere. LCMS indicated that the reaction was complete. The mixture was filtered, and the residue was washed with ethyl acetate. The organic phases were combined, the solvent evaporated, and the product was purified by column chromatography (DCM:MeOH = 30:1) to give the product (68 mg). ESI-MS (m / z): 410.18 [M+H] + .

[0642] Step 3: Synthesis of 3-(2,6-difluoro-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione trifluoroacetate

[0643] Dissolve tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidine-1-carboxylate (68 mg, 0.17 mmol) in DCM, add TFA (5 M) with stirring, and stir at room temperature for 1 hour. LCMS indicates the reaction is complete, and the organic phase is removed to obtain the crude product (51 mg). ESI-MS (m / z): 310.13 [M+H] + .

[0644] Intermediate Preparation Example 39: Synthesis of 1-(5-methoxy-2-methyl-4-nitrophenyl)piperidine-4-carboxaldehyde

[0645] Refer to the synthesis method of Intermediate 18, only replace the starting material 4-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole in step 1 with 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene to obtain the product. ESI-MS (m / z): 279.13 [M+H] + .

[0646] Intermediate Preparation Example 40: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((3-(4-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazin-1-yl)azetidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione

[0647] Step 1: Synthesis of tert-butyl 3-(4-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazin-1-yl)azetidine-1-carboxylate

[0648] 4-(2-Fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (1 g, 3.98 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (1.15 g, 4.78 mmol), and potassium carbonate (1.1 g, 7.96 mmol) were dissolved in DMSO and reacted at 120°C for 5 hours. LCMS indicated that the reaction was complete. The mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined, the solvent evaporated, and the product was purified by column chromatography (DCM:MeOH = 50:1) to obtain the product (1.32 g). ESI-MS (m / z): 473.24 [M+H] + .

[0649] Step 2: Synthesis of 1-(azetidin-3-yl)-4-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazine trifluoroacetate

[0650] tert-Butyl 3-(4-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazin-1-yl)azetidine-1-carboxylate (410 mg, 1.48 mmol) was dissolved in DCM (6.0 mL), TFA (2.0 mL) was added, and the mixture was stirred at room temperature for 2.0 hours. LCMS analysis showed that the reaction was complete, and the reaction solution was concentrated to obtain the crude product (323 mg). ESI-MS (m / z): 373.19 [M+H] + .

[0651] Step 3: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((3-(4-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazin-1-yl)azetidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione

[0652] 1-(Azetidin-3-yl)-4-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazine trifluoroacetate (290 mg) was dissolved in DMF (5.0 mL), and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (Intermediate Preparation Example 4) (316 mg, 0.86 mmol) and TEA (158 mg, 1.56 mmol) were added. The mixture was stirred at room temperature (25°C) for 1.0 hour, and then NaBH3CN (147 mg, 2.34 mmol) was added and stirred at room temperature for 1.0 hour. LCMS showed the reaction was complete, and the reaction was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic phases were combined, the solvent was evaporated, and the product (129 mg) was isolated by column chromatography (DCM:MeOH=30:1). ESI-MS (m / z): 726.33 [M+H] + .

[0653] Intermediate Preparation Example 41: Synthesis of 1-(3-methoxy-4-nitrophenyl)piperidine-4-carboxaldehyde

[0654] The synthesis method refers to Intermediate Preparation Example 18, replacing the starting material in step 1 with 4-fluoro-2-methoxy-1-nitrobenzene to obtain the product. ESI-MS (m / z): 265.17 [M+H] + .

[0655] Example 1: Synthesis of N-(6-((5-bromo-2-((4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 1)

[0656] Step 1: Synthesis of tert-butyl 4-((1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[0657] 1-Fluoro-5-methoxy-2-methyl-4-nitrobenzene (1.0 g, 5.40 mmol), DMSO (10 mL), tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (1.6 g, 5.64 mmol), and potassium carbonate (1.12 g, 8.10 mmol) were added to the reaction flask in sequence. The reaction system was heated to 100°C and reacted for 8 hours. LCMS showed that the reaction was complete. Water and ethyl acetate were added to the reaction solution, stirred, and separated. The organic phase was washed with water and saturated sodium chloride aqueous solution, and concentrated to dryness under reduced pressure to obtain the product (2.3 g). ESI-MS (m / z): 449.27 [M+H] + .

[0658] Step 2: Synthesis of 1-((1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)methyl)piperazine trifluoroacetate

[0659] 4-((1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (0.5 g), DCM (6 mL), and TFA (2 mL) were added to the reaction flask, and the reaction system was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete, and the reaction solution was concentrated to dryness under reduced pressure to obtain a crude product (0.5 g). It was used directly in the next reaction without further purification. ESI-MS (m / z): 349.22 [M+H] + .

[0660] Step 3: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione

[0661] The product obtained in step 2 (0.5 g) and DMSO (10 mL) were added to the reaction flask in sequence. DIPEA was then added to adjust the pH of the solution to 10. 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (0.37 g, 1.34 mmol) was then added. The reaction system was heated to 100°C and reacted for 8 hours. LCMS indicated the reaction was complete. Water was added to the reaction solution, and solids precipitated. The solids were filtered and the filter cake was dried to obtain the product (0.4 g). ESI-MS (m / z): 605.26 [M+H] + .

[0662] Step 4: Synthesis of 5-(4-((1-(4-amino-5-methoxy-2-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0663] 2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione (0.4 g), ethanol (10 mL), water (2 mL), reduced iron powder (0.19 g, 3.39 mmol), and ammonium chloride (0.19 g, 3.52 mmol) were added to a reaction flask in sequence. The reaction system was reacted at 80°C for 2 hours. LCMS indicated the reaction was complete. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The concentrate was purified by column chromatography (DCM:MeOH = 40:1) to obtain the product (0.27 g). ESI-MS (m / z): 575.29 [M+H] + .

[0664] Step 5: Synthesis of compound 1

[0665] The product obtained in step 4 (80 mg, 0.14 mmol), DMF (5 mL), N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (65 mg, 0.14 mmol) and p-toluenesulfonic acid monohydrate (133 mg, 0.70 mmol) were added to the reaction flask in sequence. The reaction system was heated to 100°C and reacted for 16 hours. LCMS showed that the reaction was complete. Saturated sodium bicarbonate aqueous solution was added to the reaction solution, and solid precipitated. The solid was filtered and the filter cake was purified by TLC to obtain a crude product. The crude product was then purified by preparative HPLC to obtain the product (50 mg). ESI-MS (m / z): 981.28 / 983.27 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ11.08(s,1H),9.12-8.69(m,3H),8.58(s,1H),8.36(d,J=56 .7Hz,2H),7.91(s,1H),7.70(s,1H),7.47-7.18(m,2H),6.77(s,1H),5.08(s,1H),3 .77(s,3H),3.52-3.36(m,6H),3.27-3.02(m,4H),2.89(s,1H),2.69(s,6H),2.29(s ,3H),2.18-1.98(m,3H),1.87(s,2H),1.72(s,1H),1.41-1.12(m,4H),0.85(s,2H).

[0666] Example 2: Synthesis of N-(6-((5-bromo-2-((4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 2)

[0667] The product was obtained by referring to the synthesis method of Example 1, except that the starting material 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene was replaced with 4-(2-fluoro-4-methoxy-5-nitrophenyl)-1-methyl-1H-pyrazole (Intermediate Preparation Example 2). ESI-MS (m / z): 1047.30 / 1049.29 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ11.09(s,1H),9.01-8.72(m, 3H),8.54(d,J=18.2Hz,2H),8.32(s,1H),8.04(s,1H),7.79(s,1H),7.69(d,J=8.2Hz,1H),7.60(s ,1H),7.36(s,1H),7.27(d,J=8.2Hz,1H),6.85(s,1H),5.08(d,J=7.5Hz,1H),3.80(d,J=5.4Hz,6H ),3.47(s,3H),3.38(s,3H),3.23(s,3H),3.11(s,2H),2.89(t,J=13.9Hz,1H),2.73-2.52(m,7H), 2.31(d,J=5.8Hz,2H),2.10-1.92(m,2H),1.82(d,J=10.6Hz,2H),1.69(s,1H),1.42-1.27(m,3H).

[0668] Example 3: Synthesis of N-(6-((5-bromo-2-((4-(9-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undec-3-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 3)

[0669] Step 1: Synthesis of tert-butyl 9-(5-methoxy-2-methyl-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0670] The synthesis method was as described in Example 1, step 1, except that tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate was replaced with tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate to obtain the product. ESI-MS (m / z): 420.24 [M+H] + .

[0671] Step 2: Synthesis of 3-(5-methoxy-2-methyl-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane trifluoroacetate

[0672] Synthesis Method: Refer to Step 2 of Example 1, replacing tert-butyl 4-((1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate with tert-butyl 9-(5-methoxy-2-methyl-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate to obtain a crude product. The product was used directly in the next reaction without further purification. ESI-MS (m / z): 320.19 [M+H] + .

[0673] Step 3: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-((9-(5-methoxy-2-methyl-4-nitrophenyl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione

[0674] A reaction flask was charged with crude 3-(5-methoxy-2-methyl-4-nitrophenyl)-3,9-diazaspiro[5.5]undecane trifluoroacetate (0.4 g), THF (3 mL), and DMF (3 mL). DIPEA was then added to adjust the solution to pH 10 and stirred for 5 minutes. Glacial acetic acid was then added to adjust the solution to pH 5. 1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (0.4 g, 1.03 mmol) was then added. The reaction system was allowed to react at room temperature for 1 hour. Sodium triacetoxyborohydride (0.6 g, 2.83 mmol) was then added and the reaction was allowed to proceed overnight at room temperature. LCMS indicated the reaction was complete. Water and ethyl acetate were added to the reaction solution, stirred, and the layers separated. The organic phase was washed with water and saturated sodium chloride solution and concentrated to dryness under reduced pressure to obtain the product (0.38 g). ESI-MS (m / z): 691.32 [M+H] + .

[0675] Step 4: Synthesis of 5-(4-((9-(4-amino-5-methoxy-2-methylphenyl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

[0676] Synthesis Method: Refer to Step 4 of Example 1, replacing 2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione with 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-((9-(5-methoxy-2-methyl-4-nitrophenyl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione to obtain the product. ESI-MS (m / z): 661.34 [M+H] + .

[0677] Step 5: Synthesis of compound 3

[0678] Synthesis Method: Referring to Step 5 of Example 1, 5-(4-((1-(4-amino-5-methoxy-2-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione was replaced with 5-(4-((9-(4-amino-5-methoxy-2-methylphenyl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione to obtain the product. ESI-MS (m / z): 1067.33 / 1069.33 [M+H] + . 1H NMR(600MHz, DMSO-d6)δ:11.11(s,1H),9.02-8.78(m,3H),8.58(s,1H),8.38(s,1H),8.30(s,1H),7.92(d,J=7.8Hz, 1H),7.71(d,J=11.4Hz,1H),7.44(d,J=7.4Hz,1H),7.32(s,1H),6.81(s,1H),5.11(dd,J=12.9,5.4Hz,1H),3.78(s,3 H),3.61(d,J=11.6Hz,2H),3.38(s,3H),3.31(s,1H),3.24(s,3H),2.99-2.75(m,6H),2.62-2.53(m,2H),2.47(s,2H) ,2.37(s,4H),2.20(d,J=6.8Hz,2H),2.13-1.97(m,4H),1.83(d,J=11.6Hz,2H),1.74(s,1H),1.57(d,J=27.1Hz,8H).

[0679] Example 4: Synthesis of N-(6-((5-bromo-2-((4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 6)

[0680] Step 1: Synthesis of tert-butyl 4-((1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[0681] The synthesis method was similar to that of Example 1, step 1, except that 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene was replaced with 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene to obtain the product. ESI-MS (m / z): 513.16 / 515.16 [M+H] + .

[0682] Step 2: Synthesis of tert-butyl 4-((1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[0683] To a reaction flask, tert-butyl 4-((1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (500 mg, 0.97 mmol), potassium ethylene trifluoroborate (200 mg, 1.49 mmol), Pd(dppf)Cl2 (285 mg, 0.39 mmol), sodium carbonate (310 mg, 2.92 mmol), 1,4-dioxane (10 mL), and water (2 mL) were added sequentially. The reaction system was allowed to react at 100°C under N2 protection for 6 hours. LCMS indicated the reaction was complete. Ethyl acetate and water were added, stirred, and the mixture separated. The resulting organic phase was concentrated to dryness under reduced pressure. The concentrate was purified by column chromatography (DCM:MeOH = 80:1) to afford the product (210 mg). ESI-MS (m / z): 461.27 [M+H] + .

[0684] Step 3: Synthesis of tert-butyl 4-((1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[0685] In a reaction flask, tert-butyl 4-((1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (210 mg, 0.46 mmol) was dissolved in methanol (10 mL). 5% Pd / C (40 mg) was added and the reaction system was allowed to react at room temperature under hydrogen protection for 3 hours. LCMS indicated the reaction was complete. The filtrate was collected by filtration and concentrated to dryness under reduced pressure to obtain the crude product (170 mg). ESI-MS (m / z): 433.31 [M+H] + .

[0686] Step 4: Synthesis of 5-ethyl-2-methoxy-4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)aniline trifluoroacetate

[0687] Synthesis method: Refer to step 2 of Example 1, replacing tert-butyl 4-((1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate with tert-butyl 4-((1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate to obtain a crude product. ESI-MS (m / z): 333.26 [M+H] + .

[0688] Step 5: Synthesis of 5-(4-((1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0689] The synthesis method was as described in Step 3 of Example 1. 1-((1-(5-methoxy-2-methyl-4-nitrophenyl)piperidin-4-yl)methyl)piperazine trifluoroacetate was replaced with 5-ethyl-2-methoxy-4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)aniline trifluoroacetate to obtain a crude product. ESI-MS (m / z): 589.31 [M+H] + .

[0690] Step 6: Synthesis of compound 6

[0691] Synthesis Method: Referring to Step 5 of Example 1, 5-(4-((1-(4-amino-5-methoxy-2-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione was replaced with 5-(4-((1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione to give the product. ESI-MS (m / z): 995.29 / 997.29 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ11.09(s,1H),9.04-8.70(m,3H),8.58(s,1H),8.41(s,1H),8.31(s,1H),7.90(s ,1H),7.69(d,J=7.9Hz,1H),7.36(s,2H),7.27(d,J=7.1Hz,1H),6.82(s,1H),5.08(d,J=7.9Hz,1H),3.7 7(s,3H),3.52-3.27(m,8H),3.24(s,4H),3.00(s,2H),2.89(t,J=12.7Hz,1H),2.72(t,J=10.0Hz,2H),2 .59(d,J=19.0Hz,2H),2.28(s,2H),2.03(s,2H),1.86(d,J=9.8Hz,2H),1.71(s,1H),1.33-1.18(m,8H).

[0692] Example 5: Synthesis of N-(6-((5-bromo-2-((4-(9-(2-((4aR)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetyl)-3,9-diazaspiro[5.5]undec-3-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino]quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 24)

[0693] Crude 2-((4R)-8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetic acid (0.02 g) and N,N-dimethylformamide (2 mL) were added to a reaction flask. 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.02 g, 0.06 mmol) and N,N-diisopropylethylamine (0.02 g, 0.15 mmol) were then added at 0°C. After half an hour of reaction, N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(3,9-diazaspiro[5.5]undec-3-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (0.04 g) was added. The reaction solution was reacted at 25°C for 2 hours. Water and ethyl acetate were added for extraction and separation. The organic phase was collected, concentrated, and separated on a silica gel column (DCM:MeOH=15:1) to obtain the product (0.02 g). ESI-MS (m / z): 1052.39 / 1054.40 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ: 10.73 (s, 1H), 8.95 (d, J = 1.8Hz, 1H), 8.87 (s, 1H), 8.89 (s, 1H), 8.56 (s, 1 H),8.38(s,1H),8.29(s,1H),7.90(d,J=8.9Hz,1H),7.30(s,1H),6.82(s,1H),6.64(d,J=8.8Hz,1H ),6.20(d,J=8.9Hz,1H),6.15(s,1H),5.32(d,J=5.7Hz,1H),4.22-4.07(m,2H),3.85(t,J=10.0Hz ,1H),3.76(s,3H),3.57(s,1H),3.52(d,J=27.4Hz,4H),3.23(s,3H),3.13(dt,J=43.4,5.9Hz,2H), 2.84(s,3H),2.71(ddd,J=17.3,11.8,5.3Hz,2H),2.63-2.53(m,2H),2.27(s,2H),2.06(s,3H) ,1.99(dt,J=19.4,7.0Hz,2H),1.92-1.77(m,4H),1.64(s,4H),1.57(s,2H),1.51-1.41(m,4H).

[0694] Example 6: Synthesis of (R)-N-(6-((5-bromo-2-((4-(9-(2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)acetyl)-3,9-diazaspiro[5.5]undec-3-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 22)

[0695] To a reaction flask, add crude (R)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)yl)-acetic acid (0.04 g) and N,N-dimethylformamide (2 mL). At 0°C, add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.04 g, 0.11 mmol) and N,N-diisopropylethylamine (0.03 g, 0.26 mmol). After half an hour of reaction, N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(3,9-diazaspiro[5.5]undec-3-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (0.06 g) was added. The reaction solution was reacted at 25°C for 2 hours. Water and ethyl acetate were added for extraction and separation. The organic phase was collected, concentrated, and separated on a silica gel column (DCM:MeOH=15:1) to obtain the product (0.05 g). ESI-MS (m / z): 1038.40 / 1040.38 [M+H] + ; 1H NMR (600MHz, DMSO-d6) δ10.24(s,1H),8.95(d,J=1.9Hz,1H),8.89(s,1H),8.86(s,1H),8.57(s,1H),8.38(s,1H),8.29(s,1H),7.91(d,J=9.4H z,1H),7.31(s,1H),6.86(d,J=8.8Hz,1H),6.82(s,1H),6.74(dd,J=8.6,2.5Hz,1H),6.69(d,J=2.4Hz,1H),4.30-4.25(m,1H),3.91(t,J=9.8H z,1H),3.76(s,3H),3.67(t,J=6.7Hz,2H),3.52(d,J=25.8Hz,4H),3.36(s,3H),3.23(s,3H),3.04(s,1H),2.92(dd,J=37.8,10.4Hz,2H),2.84 (t,J=5.6Hz,4H),2.66(t,J=6.7Hz,2H),2.62(s,2H),2.28(s,2H),2.06 (s,3H),1.90(d,J=10.6Hz,2H),1.64(s,4H),1.56(s,2H),1.48(s,2H).

[0696] Example 7: Synthesis of N-(6-((5-bromo-2-((4-(4-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperidin-4-yl)piperazin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 108)

[0697] N-(6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidin-4-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (88 mg, 0.11 mmol) was dissolved in a 1:1 mixed solution of DMF:THF (5 mL), and acetic acid was added to adjust the pH to 4-5. The mixture was stirred at room temperature for 15 minutes, and then 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)piperidin-4-yl)acetaldehyde (48 mg, 0.13 mmol) was added. The mixture was stirred at room temperature for 40 minutes. Finally, NaBH(OAc)3 (73 mg, 0.34 mmol) was added, and the reaction was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete. The reaction solution was poured into stirred water and saturated sodium bicarbonate was added. The precipitated solid was filtered and the residue was purified by thin layer chromatography to obtain the product (70 mg). ESI-MS (m / z): 1144.39 / 1146.38 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ11.09(s,1H),10.21(s,1H),9.85(s,1H),8.96(s,1H),8.89(s,1H),8.65(d,J=10.6Hz,2H),8.35(s,1H),8.10(s,1 H),7.83(s,1H),7.68(d,J=8.7Hz,2H),7.34(s,1H),7.26(d,J=7.0Hz,1H),6.78(s,1H),5.08(dd,J=12.8,5.4Hz,1H),3.83(s,3H),3.81(s ,3H),3.73(d,J=11.0Hz,2H),3.63(s,2H),3.53(s,1H),3.39(s,3H),3.28(s,3H),3.23(s,3H),3.17(d,J=6.0Hz,2H),2.98(t,J=11.7Hz,5 H),2.63-2.54(m,2H),2.43(d,J=11.6Hz,2H),1.99(ddd,J=41.2,22.5,8.4Hz,4H),1.78(d,J=11.8Hz,2H),1.64(s,3H),1.28-1.20(m,6H).

[0698] Example 8: Synthesis of N-(6-((5-bromo-2-((4-(4-((9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 109)

[0699] Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(9-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undec-3-yl)isoindoline-1,3-dione

[0700] To the reaction flask, crude hydrochloride of 3-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecane (0.21 g), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (0.15 g, 0.53 mmol), and DMSO (5 mL) were added sequentially, followed by solid sodium bicarbonate (0.15 g, 1.77 mmol). The reaction system was heated to 100°C and reacted for 5 hours. LCMS showed that the reaction was complete. Water was added to the reaction solution, filtered, and the filter cake was rinsed with water. The crude product was then purified by preparative HPLC to obtain the product (0.23 g). ESI-MS (m / z): 739.36 [M+H] + .

[0701] Step 2: Synthesis of 5-(9-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undec-3-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0702] To a reaction flask were added 2-(2,6-dioxopiperidin-3-yl)-5-(9-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undec-3-yl)isoindoline-1,3-dione (0.23 g, 0.30 mmol), ethanol (5.0 mL), water (1.0 mL), reduced iron powder (0.12 g, 2.13 mmol), and ammonium chloride (0.11 g, 2.13 mmol). The reaction system was reacted at 80°C for 3 hours. LCMS showed the reaction was complete, and the filtrate was filtered and concentrated to dryness under reduced pressure. The concentrate was dissolved in dichloromethane, washed with saturated NaHCO3 solution, washed with saturated NaCl aqueous solution, and dried over anhydrous Na2SO4 to give a crude product (0.21 g). ESI-MS (m / z): 709.40 [M+H] + .

[0703] Step 3: Synthesis of compound 109

[0704] Crude 5-(9-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undec-3-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.12 g), DMF (5 mL), N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (0.08 g, 0.17 mmol), and p-toluenesulfonic acid monohydrate (0.20 g, 1.08 mmol) were added to a reaction flask in sequence. The reaction system was heated to 100°C and reacted for 16 hours. LCMS showed the reaction was complete. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The crude product was then purified by preparative HPLC to obtain the product (0.05 g). ESI-MS (m / z): 1115.43 / 1117.41 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ: 11.07(s,1H),8.94(d,J=1.9Hz,1H),8.87(d,J=1.9Hz,1H),8.81(sl,1H),8.53(d,J=17.5Hz,2H),8.31(s,1H),8.02(s,1H) ,7.78(s,1H),7.65(d,J=8.5Hz,1H),7.59(s,1H),7.51(sl,1H),7.32-7.2 9(m,1H),7.22(dd,J=8.8,2.3Hz,1H),6.83(s,1H),5.06(dd,J=12.8,5.5Hz ,1H),3.79(d,J=5.2Hz,6H),3.48-3.45(m,4H),3.41(s,1H),3.38(s,3H), 3.30(s,2H),3.23(s,3H),3.09(s,2H),2.88(ddd,J=17.0,13.9,5.5Hz,1H ),2.65-2.58(m,2H),2.57-2.51(m,3H),2.02(dd,J=11.2,6.1Hz,2H),1.7 7(d,J=12.1Hz,2H),1.54(s,6H),1.37-1.28(m,2H),1.24(d,J=5.8Hz,4H).

[0705] Example 9: Synthesis of N-(6-((5-bromo-2-((4-(4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonyl)azetidin-3-yl)piperazin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 110)

[0706] Step 1: Synthesis of tert-butyl 3-(4-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazin-1-yl)azetidine-1-carboxylate

[0707] 1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazine (0.5 g, 1.58 mmol), N,N-dimethylacetamide (3 mL), and tert-butyl 3-oxoazetidine-1-carboxylate (0.32 g, 1.87 mmol) were added to the reaction flask and stirred at room temperature for 0.5 hours. Sodium triacetoxyborohydride (1 g, 4.72 mmol) was added and the mixture was allowed to react overnight at room temperature. LCMS showed that the reaction was complete. After post-treatment, saturated sodium bicarbonate aqueous solution was added to precipitate a solid, which was filtered and the filter cake was dried to obtain the product (0.65 g). ESI-MS (m / z): 473.24 [M+H] + .

[0708] Step 2: Synthesis of 1-(azetidin-3-yl)-4-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazine trifluoroacetate

[0709] The crude product was obtained by referring to step 2 of Example 1. It was used directly in the next step without further purification. ESI-MS (m / z): 373.19 [M+H] + .

[0710] Step 3: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(4-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazin-1-yl)azetidine-1-carbonyl)azetidine-1-yl)isoindoline-1,3-dione

[0711] The crude product obtained in step 2 (120 mg), 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carboxylic acid (100 mg, 0.28 mmol), DMF (3 mL) and HATU (126 mg, 0.33 mmol) were added to the reaction flask, and the reaction solution was reacted at room temperature for 2 hours. LCMS showed that the reaction was complete. After post-treatment, water was added to precipitate a solid, which was filtered and the filter cake was dried to obtain the product (90 mg). ESI-MS (m / z): 712.28 [M+H] + .

[0712] Step 4: Synthesis of 5-(3-(3-(4-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)azetidine-1-carbonyl)azetidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0713] The synthesis method was similar to that of step 4 in Example 1 to obtain the product. ESI-MS (m / z): 682.30 [M+H] + .

[0714] Step 5: Synthesis of compound 110

[0715] 5-(3-(3-(4-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)azetidine-1-carbonyl)azetidine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (77 mg, 0.11 mmol), DMF (2 mL), N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (55 mg, 0.12 mmol), p-toluenesulfonic acid monohydrate (110 mg, 0.58 mmol), and TEA (11 mg, 0.11 mmol) were added to the reaction flask in sequence, and the reaction was heated to 100° C. for 12 hours. LCMS showed that the reaction was complete. After post-treatment, saturated sodium bicarbonate aqueous solution was added to precipitate solids. The solids were filtered and the filter cake was purified by TLC to obtain a crude product. The crude product was further purified by preparative HPLC to obtain the product (13 mg). ESI-MS (m / z): 1088.29 / 1090.29 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ11.08(s,1H),8.95-8.85(m,3H),8.56(d,J=5.2Hz,2H),8.32(s,1H),8.04(s,1H),7.79(s,1 H),7.67(d,J=8.2Hz,1H),7.61(s,1H),6.90-6.79(m,2H),6.69(dd,J=8.4,2.0Hz,1H),5.07(dd,J=12.8,5.4Hz,1H), 4.20(dd,J=18.1,9.7Hz,3H),4.10-3.92(m,5H),3.85-3.74(m,6H),3.67(td,J=8.2,4.2Hz,1H),3.39(s,3H),3.28( dd,J=11.1,5.5Hz,1H),3.24(s,3H),3.00-2.82(m,5H),2.62-2.52(m,4H),2.07-1.97(m,2H),1.18(t,J=7.1Hz,1H).

[0716] Example 10: Synthesis of N-(6-((5-bromo-2-((4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)piperazin-1-yl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 111)

[0717] Step 1: Synthesis of tert-butyl 3-(4-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazin-1-yl)pyrrolidine-1-carboxylate

[0718] The synthesis method was similar to that of step 1 in Example 9 to obtain the product. ESI-MS (m / z): 570.33 [M+H] + .

[0719] Step 2: Synthesis of 1-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)-4(pyrrolidin-3-yl)piperazine trifluoroacetate

[0720] The crude product was obtained by referring to step 2 of Example 1. It was used directly in the next step without further purification. ESI-MS (m / z): 470.28 [M+H] + .

[0721] Step 3: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazin-1-yl)pyrrolidin-1-yl)isoindoline-1,3-dione

[0722] The synthesis method was similar to that of step 3 in Example 1 to obtain the product. ESI-MS (m / z): 726.33 [M+H] + .

[0723] Step 4: Synthesis of 5-(3-(4-(1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)piperazin-1-yl)pyrrolidin-1-yl)-2-(2,6-dioxopyrimidin-3-yl)isoindoline-1,3-dione

[0724] The synthesis method was similar to that of step 4 in Example 1 to obtain the product (180 mg). ESI-MS (m / z): 696.35 [M+H] + .

[0725] Step 5: Synthesis of compound 111

[0726] The synthesis method was similar to that of step 5 in Example 1 to obtain the product. ESI-MS (m / z): 1102.34 / 1104.34 [M+H] + . 1 HNMR (600MHz, DMSO-d6) δ: 11.08 (s, 1H), 8.98-8.74 (m, 3H), 8.54 (d, J = 24.2Hz, 2H), 8.32 (s, 1H), 8.04 (s, 1H), 7.78(s,1H),7.65(d,J=8.3Hz,1H),7.60(s,1H),6.97(s,1H),6.85(d,J=11.7Hz,2H),5.06(dd,J=12.7,5.4Hz ,1H),3.80(s,5H),3.74-3.63(m,2H),3.58(t,J=8.4Hz,2H),3.46-3.37(m,6H),3.23(s,4H),3.19-3.09(m,2H ),3.00-2.83(m,2H),2.71-2.54(m,8H),2.26(s,2H),2.11-1.96(m,2H),1.95-1.80(m,3H),1.67-1.52(m,2H).

[0727] Example 11: Synthesis of N-(6-((5-bromo-2-((4-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 112)

[0728] Step 1: Synthesis of 1-(5-fluoro-6-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0729] Crude 1-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.09 g) was dissolved in DMF (5 mL) and triethylamine was added to adjust the pH to 8. 1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidine-4-carbaldehyde (0.09 g, 0.25 mmol) and acetic acid (0.15 g, 2.53 mmol) were then added and the mixture was allowed to react at room temperature for 1 hour. Finally, sodium triacetylborohydride (0.16 g, 0.76 mmol) was added and the mixture was allowed to react at room temperature for 3 hours. LCMS indicated the reaction was complete. The reaction mixture was poured into aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The concentrate was separated by column chromatography (DCM:MeOH=12:1 (v / v)) to give the product (0.17 g). ESI-MS (m / z): 675.23 [M+1] + .

[0730] Step 2: Synthesis of 1-(6-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0731] To a reaction flask were added 1-(5-fluoro-6-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.17 g, 0.25 mmol), ethanol (5.0 mL), water (1.0 mL), reduced iron powder (0.14 g, 2.53 mmol), and ammonium chloride (0.14 g, 2.53 mmol). The reaction system was reacted at 80°C for 3 hours. LCMS showed that the reaction was complete, and the filtrate was filtered and concentrated to dryness under reduced pressure. The concentrate was dissolved in dichloromethane, washed with saturated NaHCO3 solution, washed with saturated NaCl aqueous solution, and dried over anhydrous Na2SO4 to give a crude product (0.16 g). ESI-MS (m / z): 645.16 [M+H] + .

[0732] Step 3: Synthesis of compound 112

[0733] To a reaction flask, 1-(6-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.16 g, 0.26 mmol), DMF (3 mL), N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (0.10 g, 0.23 mmol), and p-toluenesulfonic acid monohydrate (0.22 g, 1.15 mmol) were added sequentially. The reaction system was heated to 100°C and reacted for 16 hours. LCMS showed that the reaction was complete. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The crude product was purified by preparative HPLC to obtain the product (0.02 g). ESI-MS (m / z): 1051.27 / 1053.27 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ: 10.53(s,1H),8.94(s,1H),8.88(s,1H),8.81(sl,1H),8.55(s,1H),8.52(s,1H),8.31(s,1H),8.04( s,1H),7.79(s,1H),7.60(s,1H),7.51(sl,1H),7.36(d,J=12.8Hz,1H),7.11(d,J=7.1Hz,1H),6.85(s,1H),3.94(s,3H),3.89 (t,J=6.7Hz,2H),3.80(d,J=4.1Hz,6H),3.38(s,3H),3.23(s,3H),3.11(s,4H),2.89(s,1H),2.76-2.71(m,2H),2.66-2.55(m ,4H),2.34(d,J=6.8Hz,2H),1.98(q,J=6.9Hz,1H),1.81(d,J=12.3Hz,2H),1.69(s,1H),1.36(d,J=11.3Hz,2H),1.27(s,2H).

[0734] Example 12: Synthesis of N-(6-((5-bromo-2-((4-(9-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetyl)-3,9-diazaspiro[5.5]undec-3-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino]quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 113)

[0735] 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetic acid (0.05 g, 0.15 mmol) and N,N-dimethylformamide (3 mL) were added to a reaction flask. 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.05 g, 0.12 mmol) and N,N-diisopropylethylamine (0.04 g, 0.33 mmol) were added at 0°C. After a half-hour reaction, N-(6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(3,9-diazaspiro[5.5]undec-3-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (0.08 g, 0.11 mmol) was added. The reaction mixture was reacted at 25°C for 2 hours. Water was added for extraction and separation. The organic phase was collected, concentrated, and separated on a silica gel column (DCM:MeOH = 12:1 (v / v)) to obtain the product (0.03 g). ESI-MS (m / z): 1089.41 / 1091.41 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ: 10.77(s,1H),9.42(sl,1H),8.94(s,1H),8.87(s,1H),8.82(sl,1H),8.53(d,J=17.9Hz,2H),8.31(s,1H), 8.04(s,1H),7.81(s,1H),7.59(s,1H),7.48(sl,1H),6.97(s,2H),6.89(s,1H),6.63(d,J=6.3Hz,2H),5.75(s,2H),4.29-4.24(m,2H ),3.80(d,J=13.4Hz,6H),3.61-3.52(m,4H),3.37(s,3H),3.23(s,3H),2.86(d,J=6.1Hz,4H),2.73(ddd,J=17.4,12.1,5.4Hz,1H), 2.61-2.52(m,4H),2.09(dq,J=13.8,4.9Hz,1H),2.03-1.94(m,2H),1.87(qd,J=12.1,4.6Hz,4H),1.65(s,4H),1.60(s,2H),1.52(s, 2H).

[0736] Example 13: Synthesis of N-(6-((5-bromo-2-((4-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 114)

[0737] Step 1: Synthesis of 6-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0738] 4-Bromo-2-methylaminoaniline (2 g, 9.95 mmol), acetonitrile (20 mL), and CDI (1.95 g, 12.02 mmol) were added to the reaction flask and the reaction mixture was heated under reflux for 8 hours. LCMS indicated the reaction was complete. After cooling to room temperature, a solid precipitated. The solid was filtered and the filter cake was dried to obtain the product (1.17 g). ESI-MS (m / z): 226.97 [M+H] + .

[0739] Step 2: Synthesis of 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

[0740] 6-Bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (1 g), DCM (20 mL), and pyridine (0.7 g, 8.86 mmol) were added to the reaction flask. The temperature was lowered and a DCM solution of 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (1.7 g, 6.03 mmol) was added dropwise below 0°C. After the addition was complete, the mixture was allowed to react at room temperature for 1 hour. LCMS indicated the reaction was complete. After post-treatment, the reaction solution was washed with 1N hydrochloric acid and purified water, respectively. The resulting organic phase was concentrated to dryness under reduced pressure to obtain the product (1.57 g). ESI-MS (m / z): 458.06 [M+H]. + .

[0741] Step 3: Synthesis of 3-(5-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

[0742] To a reaction flask, 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (310 mg, 0.68 mmol), 1-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazine (250 mg, 0.60 mmol), Ruphos-Pd-G2 (100 mg, 0.13 mmol), cesium carbonate (400 mg, 1.23 mmol), and 1,4-dioxane (20 mL) were added sequentially. The system was reacted at 100°C under nitrogen protection for 8 hours. LCMS showed the reaction was complete. After post-treatment, ethyl acetate and water were added, stirred, and the resulting organic phase was concentrated to dryness under reduced pressure. The concentrate was purified by column chromatography (DCM:MeOH = 40:1 (v / v)) to obtain the product (0.31 g). ESI-MS (m / z): 792.38 [M+H] + .

[0743] Step 4: Synthesis of 3-(5-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0744] 3-(5-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (250 mg, 0.32 mmol), toluene (6 mL), and methanesulfonic acid (3 mL) were added to the reaction flask, and the reaction solution was heated to 100°C for 6 hours. LCMS showed that the reaction was complete, and aqueous sodium bicarbonate solution and DCM were added for extraction. The resulting organic phase was concentrated to dryness under reduced pressure to obtain the product (200 mg). ESI-MS (m / z): 672.32 [M+H] + .

[0745] Step 5: Synthesis of 3-(5-(4-(1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0746] The synthesis method was similar to that of step 4 in Example 1 to obtain the product. ESI-MS (m / z): 642.34 [M+H]+ .

[0747] Step 6: Synthesis of compound 114

[0748] The synthesis method was similar to that of step 5 in Example 1 to obtain the product. ESI-MS (m / z): 1048.33 / 1050.33 [M+H] + . 1 HNMR (600MHz, DMSO-d6) δ: 11.07 (s, 1H), 8.99-8.74 (m, 3H), 8.54 (d, J = 19.4Hz, 2H), 8.32 (s, 1H), 8.04 (s, 1H), 7.79 (s, 1H), 7.60(s,1H),6.95(d,J=8.6Hz,1H),6.85(s,2H),6.64(d,J=8.6Hz,1H),5.30(dd,J=12.9,5.4Hz,1H),3.80(d,J=5.4Hz,5H), 3.59(t,J=3.9Hz,1H),3.39(s,3H),3.32(s,3H),3.23(s,3H),3.12(s,4H),2.94-2.84(m,1H),2.61(dd,J=29.6,18.6Hz,7H) ,2.33(dd,J=15.2,7.2Hz,2H),2.05-1.93(m,2H),1.81(d,J=11.4Hz,2H),1.73-1.61(m,2H),1.33(dt,J=29.5,14.2Hz,3H).

[0749] Example 14: Synthesis of N-(6-((5-bromo-2-((4-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)acetyl)piperazin-1-yl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 115)

[0750] The synthesis method was similar to Example 8, except that the starting material in step 1, 3-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecane hydrochloride, was replaced with 1-(4-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazin-1-yl)-2-(pyrrolidin-3-yl)ethan-1-one to give the product. ESI-MS (m / z): 1144.33 / 1146.32 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ: 11.07(s,1H),8.93(s,1H),8.87(s,1H),8.81(sl,1H), 8.55(s,1H),8.50(s,1H),8.31(s,1H),8.01(s,1H),7.77(s,1H),7.65-7.59(m,2 H),7.50(sl,1H),6.86(s,1H),6.82(s,1H),6.78(d,J=8.6Hz,1H),5.05(dd,J=1 2.7,5.5Hz,1H),3.79(d,J=4.8Hz,6H),3.63(dd,J=10.3,7.3Hz,1H),3.55-3.43( m,6H),3.41-3.38(m,1H),3.37(s,3H),3.22(s,3H),3.16-3.11(m,2H),3.06(dd ,J=10.3,7.5Hz,1H),2.88(ddd,J=16.7,13.6,5.4Hz,1H),2.70-2.51(m,10H),2. 32-2.28(m,1H),2.20(tt,J=11.6,5.0Hz,1H),2.00(ddd,J=10.3,5.7,3.3Hz,1H ),1.85-1.80(m,2H),1.72(dq,J=11.9,8.3Hz,1H),1.59(qd,J=12.1,3.8Hz,2H).

[0751] Example 15: Synthesis of N-(6-((5-bromo-2-((4-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetyl)piperazin-1-yl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 116)

[0752] The synthesis method was similar to Example 8, except that the starting material in step 1, 3-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecane hydrochloride, was replaced with 1-(4-(1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)piperazin-1-yl)-2-(piperidin-4-yl)ethan-1-one to give the product. ESI-MS (m / z): 1158.44 / 1160.46 [M+H] + . 1 H NMR(600MHz, DMSO-d6))δ:11.07(s,1H),8.94(d,J=1.9Hz,1H),8.87(d,J=1.8H z,1H),8.82(s,1H),8.55(s,1H),8.51(s,1H),8.31(d,J=2.0Hz,1H),8.02(s,1H ),7.77(s,1H),7.65(d,J=8.6Hz,1H),7.59(s,1H),7.52(s,1H),7.31(d,J=2.2H z,1H),7.23(dd,J=8.6,2.3Hz,1H),6.82(s,1H),5.06(dd,J=12.8,5.5Hz,1H),4 .04(d,J=13.0Hz,2H),3.79(d,J=4.1Hz,6H),3.48(s,5H),3.37(s,3H),3.30(s, 4H),3.22(s,3H),3.14(d,J=10.5Hz,2H),2.98(t,J=12.5Hz,2H),2.93-2.84(m, 1H),2.67-2.53(m,4H),2.28(d,J=6.9Hz,2H),2.01(d,J=7.8Hz,2H),1.84(d,J= 11.7Hz, 2H), 1.77 (d, J = 12.5Hz, 2H), 1.60 (d, J = 12.0Hz, 2H), 1.36-1.27 (m, 2H).

[0753] Example 16: Synthesis of N-(6-((5-bromo-2-(4-(4-((4-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 16)

[0754] The synthesis method was similar to that of Example 2, except that the raw material 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione in Step 3 was replaced with 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione to obtain the product. ESI-MS (m / z): 1065.29 / 1067.30 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ11.12(s,1H),8.96-8.77(m,3H),8.54 (d,J=20.0Hz,2H),8.32(s,1H),8.04(s,1H),7.96(s,1H),7.79(s,1H),7.74(d,J=11.4Hz,1H),7.61 (s,1H),7.47(d,J=7.3Hz,1H),6.85(s,1H),5.11(dd,J=12.9,5.4Hz,1H),3.80(d,J=4.6Hz,6H),3.3 8(s,3H),3.28(s,3H),3.23(s,3H),3.12(d,J=8.3Hz,2H),2.90(s,3H),2.74(s,2H),2.64-2.55(m,6 H), 2.32 (d, J = 6.8Hz, 2H), 2.03 (ddd, J = 23.9, 12.0, 5.3Hz, 2H), 1.81 (d, J = 11.1Hz, 2H), 1.69 (s, 1H).

[0755] Example 17: Synthesis of (S)-N-(6-((5-bromo-2-((4-(4-((8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 33)

[0756] Step 1: Synthesis of (S)-1-(3-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0757] (S)-1-(1,2,3,4,4a,5-Hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.24 g, 0.79 mmol) was dissolved in DMF (3 mL) and triethylamine was added to adjust the pH to approximately 8. The reaction mixture was stirred at room temperature for 10 minutes. Acetic acid (0.35 g, 5.83 mmol) was added, followed by 1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidine-4-carbaldehyde (0.20 g, 0.58 mmol), and the mixture was allowed to react at room temperature for 0.5 hour. Finally, sodium triacetylborohydride (0.37 g, 1.75 mmol) was added, and the reaction was allowed to react at room temperature for 3 hours. LCMS showed the reaction was complete. The reaction solution was poured into aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The concentrate was separated by column chromatography (DCM:MeOH = 20:1 (v / v)) to obtain the product (0.04 g, 0.06 mmol). ESI-MS (m / z): 631.32 [M+1] + .

[0758] Step 2: Synthesis of (S)-1-(3-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0759] Into the reaction flask, (S)-1-(3-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.04 g, 0.06 mmol), ethanol (2.5 mL), water (0.5 mL), iron powder (0.022 g, 0.39 mmol) and ammonium chloride (0.021 g, 0.39 mmol) were added in sequence, and the reaction system was reacted at 80°C for 3 hours. LCMS showed that the reaction was complete, and the mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The concentrate was dissolved in dichloromethane, washed with saturated NaHCO3 solution, washed with saturated NaCl aqueous solution, and dried over anhydrous Na2SO4 to obtain a crude product (0.04 g). ESI-MS (m / z): 601.34 [M+H] + .

[0760] Step 3: Synthesis of compound 33

[0761] To a reaction flask, crude (S)-1-(3-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.04 g), DMF (2 mL), N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (0.03 g, 0.06 mmol), and p-toluenesulfonic acid monohydrate (0.78 g, 0.45 mmol) were added sequentially. The reaction system was heated to 100°C and reacted for 16 hours. LCMS showed the reaction was complete. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The crude product was then purified by preparative HPLC to obtain the product (0.02 g). ESI-MS (m / z): 1007.27 / 1009.33 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ10.25(s,1H),8.94(d,J=1.9Hz,1H),8.88(d,J=1.9H z,1H),8.82(d,J=21.6Hz,1H),8.54(d,J=18.0Hz,2H),8.32(s,1H),8.03(s, 1H),7.79(s,1H),7.60(s,1H),7.53(d,J=22.5Hz,1H),6.88-6.83(m,2H),6. 74(d,J=8.7Hz,1H),6.71-6.68(m,1H),4.28(d,J=10.5Hz,1H),3.92(t,J=9. 8Hz,1H),3.80(d,J=6.8Hz,6H),3.73(d,J=11.3Hz,1H),3.68(t,J=6.7Hz,2H ),3.38(s,3H),3.23(s,3H),3.11(s,2H),3.04(s,1H),2.96(dd,J=28.7,10. 8Hz,2H),2.71-2.62(m,4H),2.33-2.28(m,2H),2.21-2.13(m,2H),1.80(d,J =13.2Hz,1H),1.72(q,J=15.5,13.1Hz,1H),1.41-1.33(m,2H),1.24(s,2H).

[0762] Example 18: Synthesis of (R)-N-(6-((5-bromo-2-((4-(4-((8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)aminopyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 35)

[0763] The synthesis method was similar to Example 17, except that the starting material (S)-1-(1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione was replaced with (R)-1-(1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione to obtain the product. ESI-MS (m / z): 1007.23 / 1009.25 [M+H] + ;ESI-MS(m / z):1007.27 / 1009.33[M+H] + .

[0764] 1H NMR (600MHz, DMSO-d6) δ10.23(s,1H),8.91(d,J=1.9Hz,1H),8.85(d,J=1.9H z,1H),8.81(d,J=21.6Hz,1H),8.53(d,J=18.0Hz,2H),8.30(s,1H),8.00(s, 1H),7.77(s,1H),7.58(s,1H),7.52(d,J=22.5Hz,1H),6.86-6.81(m,2H),6. 73(d,J=8.7Hz,1H),6.70-6.67(m,1H),4.27(d,J=10.5Hz,1H),3.90(t,J=9. 8Hz,1H),3.77(d,J=6.8Hz,6H),3.71(d,J=11.3Hz,1H),3.67(t,J=6.7Hz,2H ),3.37(s,3H),3.21(s,3H),3.10(s,2H),3.02(s,1H),2.93(dd,J=28.7,10. 8Hz,2H),2.70-2.61(m,4H),2.32-2.27(m,2H),2.20-2.12(m,2H),1.77(d,J =13.2Hz,1H),1.69(q,J=15.5,13.1Hz,1H),1.40-1.32(m,2H),1.22(s,2H).

[0765] Example 19: Synthesis of N-(6-((5-bromo-2-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindol-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 118)

[0766] The synthesis method was similar to Example 11, except that the starting material in Step 1, 1-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, was replaced with 3-(1-oxo-6-(piperazin-1-yl)isoindol-2-yl)piperidine-2,6-dione to obtain the product. ESI-MS (m / z): 1033.23 / 1035.20 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ10.97(s,1H),8.94(d,J=1.9Hz,1H),8.88(d,J=1.9H z,1H),8.82(sl,1H),8.55(s,1H),8.52(s,1H),8.31(s,1H),8.03(s,1H),7. 78(s,1H),7.59(s,1H),7.51(sl,1H),7.43(d,J=8.4Hz,1H),7.27(dd,J=8.6 ,2.3Hz,1H),7.17(d,J=2.3Hz,1H),6.85(s,1H),5.09(dd,J=13.3,5.1Hz,1H) ,4.34(d,J=16.6Hz,1H),4.21(d,J=16.6Hz,1H),3.79(d,J=5.1Hz,6H),3.38 (s,3H),3.22(s,5H),3.11(d,J=10.2Hz,2H),2.91(ddd,J=18.0,13.5,5.5Hz, 1H),2.67-2.60(m,1H),2.56(t,J=4.9Hz,5H),2.41-2.19(m,2H),2.03-1.97 (m,1H),1.83-1.73(m,2H),1.69(s,1H),1.35(d,J=11.3Hz,1H),1.23(s,5H).

[0767] Example 20: Synthesis of N-(6-((5-bromo-2-((4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 119)

[0768] The synthesis method was similar to Example 11, except that the starting material in Step 1, 1-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, was replaced with 1-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione to obtain the product. ESI-MS (m / z): 1033.36 / 1035.36 [M+H] + . 1H NMR(600MHz,DMSO-d6)δ10.50(s,1H),8.94(s,1H),8.87(s,1H),8.82(s,1H),8.55(s,1H),8.52(s,1H),8.31(s,1H),8.0 3(s,1H),7.79(s,1H),7.60(s,1H),7.46(d,J=8.9Hz,1H),6.93(d,J=9.1Hz,1H),6.84(d,J=9.2Hz,2H),3.89(q,J=5.2,3 .5Hz,6H),3.80(d,J=5.9Hz,6H),3.38(s,4H),3.24(d,J=15.7Hz,7H),3.11(d,J=10.1Hz,2H),2.74(t,J=6.7Hz,2H),2.6 4(q,J=9.5,7.8Hz,1H),2.57(s,3H),2.32(d,J=7.0Hz,2H),1.81(d,J=12.3Hz,2H),1.70(s,1H),1.35(d,J=11.1Hz,2H).

[0769] Example 21: Synthesis of N-(6-((5-bromo-2-((4-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 120)

[0770] Step 1: Synthesis of 6-bromo-5-fluoro-3-iodo-1H-indazole

[0771] 6-Bromo-5-fluoro-1H-indazole (4.5 g, 20.9 mmol), DMF (50 mL), and NIS (5.7 g, 25.3 mmol) were added to the reaction flask in sequence and the reaction system was allowed to react at room temperature for 2 hours. LCMS showed the reaction was complete. After post-treatment, sodium thiosulfate aqueous solution was added, the mixture was filtered, and the filter cake was dried to obtain the product (7.1 g). ESI-MS (m / z): 340.85 / 342.85 [M+H] + .

[0772] Step 2: Synthesis of 6-bromo-5-fluoro-3-iodo-1-methyl-1H-indazole

[0773] 6-Bromo-5-fluoro-3-iodo-1H-indazole (2 g, 5.9 mmol), DMF (20 mL), cesium carbonate (5.8 g, 17.8 mmol), and iodomethane (1 g, 7.0 mmol) were added to the reaction flask in sequence. The reaction system was allowed to react at room temperature for 2 hours. LCMS showed that the reaction was complete. After post-treatment, water was added, the mixture was filtered, and the filter cake was dried to obtain the product (2.0 g). ESI-MS (m / z): 354.87 / 356.86 [M+H] + .

[0774] Step 3: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole

[0775] To a reaction flask, 6-bromo-5-fluoro-3-iodo-1-methyl-1H-indazole (2.0 g, 5.6 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.5 g, 6.0 mmol), Pd(dppf)Cl2 (0.45 g, 0.6 mmol), potassium carbonate (1.6 g, 11.6 mmol), 1,4-dioxane (30 mL), and water (6 mL) were added sequentially. The system was reacted at 100°C under nitrogen protection for 6 hours. LCMS indicated the reaction was complete. Ethyl acetate and water were added, stirred, and the mixture separated. The organic phase was concentrated to dryness under reduced pressure and purified by column chromatography (PE:EA = 10:1 (v / v)) to afford the product (1.7 g). ESI-MS (m / z): 518.08 / 520.08 [M+H] + .

[0776] Step 4: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

[0777] To a reaction flask, 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole (1.6 g, 3.1 mmol), N-tert-butyloxycarbonyl-piperazine (0.7 g, 3.8 mmol), RuPhos-Pd-G2 (0.5 g, 0.64 mmol), cesium carbonate (2.0 g, 6.1 mmol), 1,4-dioxane (30 mL), and water (6 mL) were added sequentially. The system was reacted at 100°C under nitrogen protection for 8 hours. LCMS indicated the reaction was complete. Ethyl acetate and water were added for post-processing, and the mixture was separated by stirring. The resulting organic phase was concentrated to dryness under reduced pressure and purified by column chromatography (PE:EA = 2:1 (v / v)) to yield the product (1.0 g). ESI-MS (m / z): 624.29 [M+H] + .

[0778] Step 5: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

[0779] To the reaction flask, tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (400 mg, 0.64 mmol), trifluoroethanol (10 mL), and 5% Pd (50 mg) were added sequentially. The reaction was allowed to proceed under a hydrogen atmosphere for 8 hours. LCMS indicated the reaction was complete, and the mixture was filtered and the filtrate was concentrated to dryness under reduced pressure to give the product (270 mg). ESI-MS (m / z): 446.21 [M+H] + .

[0780] Step 6: Synthesis of 3-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate

[0781] Dissolve tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.25 g, 0.56 mmol) in DCM (1 mL) and add trifluoroacetic acid (1 mL). The reaction was allowed to react at room temperature for 2 hours. LCMS showed the reaction was complete, and the reaction solution was concentrated to dryness under reduced pressure to obtain a crude product (0.23 g). ESI-MS (m / z): 346.16 [M+H] + .

[0782] Step 7: Synthesis of 3-(5-fluoro-6-(4-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0783] The synthesis method was similar to that of Example 11, step 1, to obtain the product. ESI-MS (m / z): 674.31 [M+H] + .

[0784] Step 8: Synthesis of 3-(6-(4-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0785] The synthesis method was similar to that of step 2 in Example 11 to obtain the product. ESI-MS (m / z): 644.34 [M+H] + .

[0786] Step 9: Synthesis of compound 120

[0787] The synthesis method was similar to that of step 3 in Example 11 to obtain the product. ESI-MS (m / z): 1050.32 / 1052.33 [M+H] + .

[0788] Example 22: Synthesis of N-(6-((5-bromo-2-((5-cyclopropyl-4-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 129)

[0789] The synthesis method was similar to Example 11, except that 1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidine-4-carboxaldehyde in Step 1 was replaced with 1-(2-cyclopropyl-5-methoxy-4-nitrophenyl)piperidine-4-carboxaldehyde to obtain the product. ESI-MS (m / z): 1011.34 / 1013.34 [M+H] +

[0790] Example 23: Synthesis of N-(6-((5-bromo-2-((4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)-N-methylmethanesulfonamide (Compound 134)

[0791] The synthesis method was similar to Example 11, except that the starting material in step 3, N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide, was replaced with N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinolin-5-yl)-N-methylmethanesulfonamide to obtain the product. ESI-MS (m / z): 1050.33 / 1052.27 [M+H] + 1H NMR (600MHz, DMSO-d 6)δ:10.53(s,1H),8.85(dd,J=4.2,1.6Hz,1H),8.51(d,J=9.4Hz,1H),8.36(d,J=8.5Hz,1H),8.32(s,1H),8.27(d ,J=9.6Hz,2H),7.95(s,1H),7.80(s,1H),7.63-7.53(m,3H),7.36(d,J=12.8Hz,1H),7.11(d,J=7.0Hz,1H),6.79 (s,1H),3.94(s,3H),3.89(t,J=6.7Hz,2H),3.78(d,J=11.2Hz,6H),3.29(d,J=2.4Hz,6H),3.12-3.05(m,7H),2. 74(t,J=6.7Hz,2H),2.60(s,6H),2.33(d,J=7.1Hz,2H),2.03-1.95(m,1H),1.80(d,J=12.3Hz,2H),1.68(s,1H).

[0792] Example 24: Synthesis of N-(6-((5-bromo-2-((4-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino-2-methylquinolin-5-yl)-N-methylmethanesulfonamide (Compound 136)

[0793] The synthesis method was similar to that in Example 11, except that N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide in Step 3 was replaced with N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-methylquinolin-5-yl)-N-methylmethanesulfonamide to obtain the product. ESI-MS (m / z): 1064.34 / 1066.34 [M+H] + . 1H NMR(600MHz,DMSO-d6)δ:10.53(s,1H),8.40(s,1H),8.25(d,J=7.3Hz,3H),7.94(s,1H),7.79(s,1H),7.57(s,1H),7.49( d,J=7.7Hz,1H),7.37(d,J=12.8Hz,1H),7.11(d,J=7.0Hz,1H),6.77(s,1H),3.95(s,2H),3.90(t,J=6.7Hz,2H),3.77(s,4 H),3.27(s,3H),3.09(d,J=26.7Hz,4H),2.75(t,J=6.7Hz,2H),2.64(d,J=20.5Hz,3H),2.62(s,4H),2.33(d,J=6.1Hz,1H ),2.03-1.97(m,1H),1.80(d,J=10.9Hz,2H),1.68(s,1H),1.31(dd,J=21.5,11.7Hz,3H),1.24(s,3H),0.90-0.82(m,2H).

[0794] Example 25: Synthesis of N-(6-((5-bromo-2-(4-(4-((9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 137)

[0795] The synthesis method was similar to that of step 3 in Example 11 to obtain the product. ESI-MS (m / z): 1082.33 / 1084.31 [M+H] + . 1HNMR(600MHz,DMSO-d6)δ10.53(s,1H),8.39(s,1H),8.29(s,2H),8.25(s,1H),8.02(d,J=10.8Hz,1H),7.95( s,1H),7.72(s,1H),7.55(s,2H),7.36(d,J=12.8Hz,1H),7.10(d,J=7.1Hz,1H),6.77(s,1H),3.94(s,3H),3.8 9(t,J=6.7Hz,2H),3.81(s,3H),3.76(s,3H),3.30(s,3H),3.26(s,3H),3.10(s,3H),3.05(m,2H),2.74(t,J= 6.7Hz,2H),2.66-2.54(m,8H),2.33(d,J=6.9Hz,2H),1.79(d,J=11.2Hz,2H),1.67(s,1H),1.39-1.20(m,4H).

[0796] Example 26: Synthesis of N-(6-((5-bromo-2-((4-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-cyclopropylquinolin-5-yl)-N-methylmethanesulfonamide (Compound 138)

[0797] Step 1: Synthesis of 2-cyclopropyl-6-nitroquinoline

[0798] To a reaction flask were added 2-chloro-6-nitroquinoline (3.0 g, 14.4 mmol), cyclopropylboronic acid (5 g, 58.2 mmol), Pd(OAc)2 (0.35 g, 1.56 mmol), cesium carbonate (14 g, 43.0 mmol), triphenylphosphine (0.76 g, 2.90 mmol), 1,4-dioxane (60 mL), and water (12 mL). The system was reacted at 100°C under nitrogen protection for 8 hours. LCMS indicated the reaction was complete. Ethyl acetate and water were added, stirred, and the phases separated. The organic phase was concentrated to dryness under reduced pressure and purified by column chromatography (DCM:MeOH = 40:1 (v / v)) to yield the product (2.0 g). ESI-MS (m / z): 215.07 [M+H] + .

[0799] Step 2: Synthesis of 2-cyclopropyl-6-nitroquinolin-5-amine

[0800] The synthesis method refers to Step 1 of Intermediate Preparation Example 1 to obtain 2-cyclopropyl-6-nitroquinolin-5-amine. ESI-MS (m / z): 230.09 [M+H] + .

[0801] Step 3: Synthesis of N-(2-cyclopropyl-6-nitroquinolin-5-yl)methanesulfonamide

[0802] The synthetic method refers to step 2 of intermediate preparation example 1 to obtain the product. ESI-MS (m / z): 308.06 [M+H] + .

[0803] Step 4: Synthesis of N-(2-cyclopropyl-6-nitroquinolin-5-yl)-N-methylmethanesulfonamide

[0804] The synthesis method refers to step 3 of intermediate preparation example 1 to obtain the product. ESI-MS (m / z): 322.08 [M+H] + .

[0805] Step 5: Synthesis of N-(6-amino-2-cyclopropylquinolin-5-yl)-N-methylmethanesulfonamide

[0806] The synthesis method refers to step 4 of intermediate preparation example 1 to obtain the product. ESI-MS (m / z): 292.10 [M+H] + .

[0807] Step 6: Synthesis of N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-cyclopropylquinolin-5-yl)-N-methylmethanesulfonamide

[0808] The synthesis method refers to step 5 of intermediate preparation example 1 to obtain the product. ESI-MS (m / z): 482.00 [M+H] + .

[0809] Step 7: Synthesis of compound 138

[0810] The synthesis method was similar to that of step 5 in Example 1 to obtain the product. ESI-MS (m / z): 1090.36 / 1092.36 [M+H] + . 1HNMR(600MHz,DMSO-d6)δ10.53(s,1H),8.34-8.18(m,4H),7.92(s,1H),7.80(s,1H),7.56-7.45(m,2H) ,7.37(d,J=12.8Hz,1H),7.11(d,J=7.1Hz,1H),6.78(s,1H),3.95(s,3H),3.90(t,J=6.7Hz,2H),3.78(d ,J=21.7Hz,5H),3.26(d,J=5.7Hz,5H),3.17-3.03(m,5H),2.75(t,J=6.7Hz,2H),2.61(s,5H),2.32(ddd ,J=22.7,18.9,16.1Hz,3H),2.05-1.92(m,1H),1.82(d,J=11.6Hz,2H),1.69(s,2H),1.43-1.11(m,8H).

[0811] Example 27: Synthesis of N-(6-((5-bromo-2-((4-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)-N-methylmethanesulfonamide (Compound 139)

[0812] The synthesis method was similar to Example 26, except that the starting material cyclopropylboronic acid in step 1 was replaced with ethylboronic acid to obtain the product. ESI-MS (m / z): 1078.36 / 1080.38 [M+H] + .

[0813] Example 28: Synthesis of 5-(4-((1-(4-((5-bromo-4-((5-(N-methylmethylsulfonamido)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide (Compound 169)

[0814] The synthesis method was similar to Example 11, except that the starting material in Step 1, 1-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, was replaced with N-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)pyridine-2-carboxamide to obtain the product. ESI-MS (m / z): 1022.31 / 1024.26 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ10.84(s,1H),8.94(d,J=1.9Hz,1H),8.88(d,J=1.9Hz,1H) ,8.84(sl,1H),8.73(d,J=8.3Hz,1H),8.55(s,1H),8.52(s,1H),8.32(d,J=11.4Hz, 2H),8.03(s,1H),7.87(d,J=8.7Hz,1H),7.78(s,1H),7.60(s,1H),7.55(sl,1H),7 .43(dd,J=9.0,2.8Hz,1H),6.84(s,1H),5.76(s,2H),5.32(t,J=4.9Hz,1H),4.74(d dd,J=13.2,8.2,5.3Hz,1H),3.79(d,J=6.1Hz,6H),3.38(s,3H),3.23(s,3H),3.11 (d,J=10.2Hz,2H),2.79(ddd,J=17.1,13.7,5.5Hz,1H),2.69-2.60(m,3H),2.55(s, 4H), 2.31 (d, J=7.0Hz, 2H), 2.18 (qd, J=13.0, 4.3Hz, 1H), 1.99 (tt, J=12.7, 5.8Hz, 2H),1.81(d,J=12.3Hz,2H),1.69(s,1H),1.46(d,J=8.1Hz,1H),1.40-1.33(m,1H).

[0815] Example 29: Synthesis of N-(6-((5-bromo-2-(4-(4-((4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 172)

[0816] The synthesis method was similar to Example 11, except that the starting material in Step 1, 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, was replaced with 3-(2,6-difluoro-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione to obtain the product. ESI-MS (m / z): 1014.26 / 1016.29 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ: 10.88(s,1H),8.94(s,1H),8.88(s,1H),8.84(s,1H),8.54(d,J=20.5Hz,2H),8.32(s,1H),8.03(s,1 H),7.79(s,1H),7.60(s,1H),7.55-7.44(m,1H),6.85(s,1H),6.65(d,J=12.7Hz,2H),4.07(dd,J=12.5,4.9Hz,1H),3.80(d,J =5.8Hz,6H),3.39(d,J=9.6Hz,4H),3.23(s,3H),3.21(s,4H),3.11(d,J=8.2Hz,2H),2.85-2.75(m,2H),2.67-2.60(m,2H),2. 30(d,J=5.0Hz,2H),2.10(dt,J=13.0,9.6Hz,2H),2.03-1.93(m,2H),1.80(d,J=11.3Hz,2H),1.68(s,1H),1.39-1.30(m,3H).

[0817] Example 30: Synthesis of 4-(4-(2-(4-(4-((5-bromo-4-((5-N-methylmethanesulfonamido)quinoxalin-6-yl)amino)pyrimidin-2-amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)ethyl)piperidin-1-yl-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (Compound 178)

[0818] The synthesis method was the same as in Example 7, except that the starting material 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperidin-4-yl)acetaldehyde was replaced with N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(2-oxoethyl)piperidin-1-yl)benzamide to obtain the product. ESI-MS (m / z): 1136.39 / 1138.40 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ10.85(s,1H),8.94(s,1H),8.88(s,1H),8.55(d,J=10.8Hz,2H),8.32(s,1H),8.01(dd,J=1 4.1,6.7Hz,2H),7.80(s,1H),7.62(dd,J=17.2,7.9Hz,2H),6.85(s,1H),6.81(d,J=8.7Hz,1H),6.75(d,J=15.7Hz, 1H),4.76-4.69(m,1H),3.88(d,J=12.5Hz,3H),3.80(d,J=15.2Hz,6H),3.38(s ,3H),3.23(s,3H),2.90(s,4H),2.78(dd,J=24.3,12.0Hz,4H),2.66(s,4H),2.1 2(dt,J=12.8,8.8Hz,2H),2.05-1.98(m,2H),1.90(d,J=19.3Hz,2H),1.74(d,J= 11.5Hz, 2H), 1.54 (s, 4H), 1.22 (dd, J = 35.8, 13.1Hz, 6H), 0.86 (t, J = 6.6Hz, 1H).

[0819] Example 31: Synthesis of N-(6-((5-bromo-2-((4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-vinylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 179)

[0820] Step 1: Synthesis of 1-(6-(4-((1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0821] The synthesis method was similar to that of Example 11, step 1, to obtain the product. ESI-MS (m / z): 673.18 [M+H] + .

[0822] Step 2: Synthesis of 1-(5-fluoro-6-(4-((1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0823] To a reaction flask were added 1-(6-(4-((1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.7 g, 1.04 mmol), potassium vinylborofluoride (0.3 g, 2.2 mmol), Pd(dppf)Cl2 (0.3 g, 0.41 mmol), sodium carbonate (0.33 g, 3.1 mmol), 1,4-dioxane (20 mL), and water (4 mL). The reaction system was reacted under nitrogen at 100°C for 8 hours. LCMS indicated the reaction was complete. Ethyl acetate and water were added to the reaction solution, stirred, and the resulting organic phase was concentrated to dryness under reduced pressure. The concentrate was then slurried with methyl tert-butyl ether to obtain the product (0.3 g). ESI-MS (m / z): 621.29 [M+H] + .

[0824] Step 3: Synthesis of 1-(6-(4-((1-(4-amino-5-methoxy-2-vinylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0825] The synthesis method was similar to that of step 2 in Example 11 to obtain the product. ESI-MS (m / z): 591.31 [M+H] + .

[0826] Step 4: Synthesis of compound 179

[0827] The synthesis method was similar to that of step 3 in Example 11 to obtain the product. ESI-MS (m / z): 997.30 / 999.31 [M+H] + . 1HNMR(600MHz,DMSO-d6)δ10.53(s,1H),8.98-8.77(m,3H),8.59(s,1H),8.31-8.19(m,4H),7.85(s,1H ),7.72(s,1H),7.34(d,J=12.8Hz,1H),7.04(s,1H),6.91(dd,J=17.8,11.1Hz,1H),6.73(s,1H),5.45 -5.23(m,2H),4.93(d,J=9.8Hz,1H),3.97-3.90(m,4H),3.82(s,3H),3.39(s,3H),3.24-3.03(m,8H), 2.80-2.68(m,4H),2.62(s,2H),2.34(s,2H),1.89(d,J=12.0Hz,2H),1.73(s,2H),1.45-1.34(m,2H).

[0828] Example 32: Synthesis of N-(6-((5-bromo-2-((4-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 180)

[0829] Step 1: Synthesis of 1-(6-(4-((1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0830] 1-(5-fluoro-6-(4-((1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (110 mg, 0.18 mmol), trifluoroethanol (10 mL), and 5% Pd (20 mg) were added to the reaction flask in sequence. The reaction was allowed to proceed under a hydrogen atmosphere for 8 hours. LCMS showed that the reaction was complete, and the product was filtered and the filtrate was concentrated to dryness under reduced pressure to obtain the product (60 mg). ESI-MS (m / z): 593.33 [M+H] + .

[0831] Step 2: Synthesis of compound 180

[0832] The synthesis method was similar to that of step 3 in Example 11 to obtain the product. ESI-MS (m / z): 999.31 / 1001.30 [M+H] + .

[0833] Example 33: Synthesis of N-(6-((5-bromo-2-((4-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 182)

[0834] The synthesis method was similar to Example 11, except that the starting material in step 1 was replaced with 1-(5-methoxy-2-methyl-4-nitrophenyl)piperidine-4-carboxaldehyde to obtain the product. ESI-MS (m / z): 985.30 / 987.29 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ10.56(s,1H),9.50(s,1H),8.98(d,J=1.3Hz,1H),8.92(s,1H),8.90-8.85(m,1H),8.59(s,1H),8.45( d,J=13.3Hz,1H),8.30(d,J=20.2Hz,1H),7.92(s,1H),7.45(d,J=12.8Hz,1H),7.35(s,1H),6.77(s,1H),3.99(d,J=8.9Hz,2H ),3.91(t,J=6.6Hz,2H),3.78(s,2H),3.67(dd,J=41.0,11.1Hz,3H),3.52(s,1H),3.39(d,J=11.3Hz,7H),3.25(s,5H),3.22( s,2H),3.13(s,2H),2.75(dd,J=18.3,11.7Hz,3H),2.10(s,2H),1.96-1.89(m,2H),1.48(d,J=9.3Hz,3H),1.32-1.26(m,2H).

[0835] Example 34: Synthesis of N-(6-((5-bromo-2-((4-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-(1-methyl-1H-pyrazol-4-yl)quinolin-5-yl)-N-methylmethanesulfonamide (Compound 183)

[0836] The synthesis method was similar to Example 26, except that the starting material in step 1, cyclopropylboronic acid, was replaced with (1-methyl-1H-pyrazol-4-yl)boronic acid to obtain the product. ESI-MS (m / z): 1130.29 / 1132.31 [M+H] + .

[0837] 1 H NMR (600MHz, DMSO-d6) δ11.95(s,1H),7.96(d,J=15.4Hz,1H),7.90(d,J=7.7Hz,1H ),7.81(s,1H),7.73(d,J=6.3Hz,1H),7.68(s,1H),7.64(d,J=13.0Hz,1H),7.56(d, J=8.6Hz,1H),7.42(dd,J=13.3,8.2Hz,2H),7.37(s,1H),7.34(d,J=7.3Hz,1H),7.2 6(dd,J=8.6,2.4Hz,1H),7.20(s,1H),6.66(s,1H),6.51(d,J=8.6Hz,1H),5.34(dd, J=12.6,8.0Hz,2H),4.28-4.18(m,2H),4.04(s,2H),4.01-3.96(m,2H),3.95-3.92 (m,1H),3.91-3.86(m,2H),3.63(s,1H),3.58(d,J=3.2Hz,1H),2.64-2.60(m,1H),2 .44(dd,J=20.9,10.1Hz,2H),2.39(s,2H),2.19(t,J=7.4Hz,2H),2.00(dt,J=12.7, 7.1Hz,5H),1.48-1.45(m,3H),1.39(s,3H),1.37(s,2H),1.30(s,4H),1.26(s,5H).

[0838] Example 35: Synthesis of N-(6-((5-bromo-2-((4-(4-(((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino]quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 184)

[0839] The synthesis method was similar to Example 11, except that the starting material in Step 1, 1-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione, was replaced with 3-(3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione to obtain the product. ESI-MS (m / z): 1011.32 / 1013.30 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ10.77(s,1H),8.94(d,J=1.8Hz,1H),8.88(d,J=1.9Hz,1H),8.83(sl,1H),8.55(s,1H),8.51(s,1H),8.31(s,1H),8.03 (s,1H),7.79-7.72(m,1H),7.59(s,1H),7.56(sl,1H),6.83(d,J=10.2Hz,2H),6.51(d,J=14 .8Hz,1H),6.42(d,J=8.6Hz,1H),5.80(d,J=7.7Hz,1H),3.83-3.78(m,7H),3.38(s,3H),3.23 (s,3H),3.10(s,2H),2.87(s,4H),2.72(td,J=12.2,6.1Hz,1H),2.65-2.55(m,3H),2.38(p,J =1.9Hz,1H),2.29(d,J=7.4Hz,3H),2.11-1.95(m,5H),1.86-1.74(m,3H),1.69-1.39(m,1H).

[0840] Example 36: Synthesis of N-(6-((5-bromo-2-((4-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylcyclopropanesulfonamide (Compound 185)

[0841] The synthesis method was similar to Example 11, except that the starting material in Step 3, N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide, was replaced with N-(6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylcyclopropanemethanesulfonamide to obtain the product. ESI-MS (m / z): 1077.25 / 1079.28 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ10.53(s,1H),8.94(d,J=1.9Hz,1H),8.87(d,J=1.9Hz,1H),8.83-8.71(m,1H),8.56(s,1H),8.51(s,1H),8.31 (s,1H),8.03(s,1H),7.80(s,1H),7.60(s,1H),7.52(d,J=9.6Hz,1H),7.36(d,J=12.8Hz,1H),7.11(d,J=7.0Hz,1H),6.85(s,1H),3.94 (s,3H),3.89(t,J=6.7Hz,2H),3.80(d,J=4.0Hz,6H),3.41(s,3H),3.11(s,4H),2.94-2.87(m,2H),2.76-2.71(m,2H),2.68-2.59(m,6H ),2.36-2.33(m,2H),2.03-1.94(m,1H),1.81(d,J=12.2Hz,2H),1.70(s,1H),1.40-1.32(m,2H),1.20-1.05(m,2H),0.88-0.73(m,2H).

[0842] Example 37: Synthesis of 4-(4-(2-(4-(4-(4-((5-bromo-4-((5-(N-methylmethylsulfonamido)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)ethyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)benzamide (Compound 187)

[0843] Step 1: Synthesis of tert-butyl 4-(4-(2-(4-(5-bromo-4-((5-(N-methylmethanesulfonamido)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)ethyl)piperidin-1-yl)benzoate

[0844] N-(6-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperidin-4-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Intermediate Preparation Example 19) (0.10 g, 0.13 mmol) was dissolved in DMF (3 mL), and acetic acid (0.08 g, 1.29 mmol) and tert-butyl 4-(4-(2-oxoethyl)piperidin-1-yl)benzoate (0.04 g, 0.13 mmol) were added in sequence, and the mixture was reacted at room temperature for 1 hour. Finally, sodium triacetylborohydride (0.08 g, 0.39 mmol) was added, and the mixture was reacted at room temperature for 3 hours. LCMS showed that the reaction was complete, and the reaction solution was poured into an aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The concentrate was separated by column chromatography (MeOH:DCM=1:12 (v / v)) to give the product (0.10 g). ESI-MS (m / z): 1064.36 / 1066.38 [M+1] + .

[0845] Step 2: Synthesis of 4-(4-(2-(4-(4-(5-bromo-4-((5-(N-methylmethylsulfonamido)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)ethyl)piperidin-1-yl)benzoic acid

[0846] Tert-butyl 4-(4-(2-(4-(5-bromo-4-((5-(N-methylmethanesulfonamido)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)ethyl)piperidin-1-yl)benzoate (0.10 g, 0.09 mmol) was dissolved in DCM (1 mL) and trifluoroacetic acid (1 mL) was added. The reaction was allowed to react at room temperature for 2 hours. LCMS showed that the reaction was complete, and the reaction solution was spin-dried to give a crude product (0.10 g). ESI-MS (m / z): 1008.38 / 1010.38 [M+H] + .

[0847] Step 3: Synthesis of compound 187

[0848] Crude 4-(4-(2-(4-(4-(5-bromo-4-((5-(N-methylmethanesulfonamido)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)piperidin-1-yl)ethyl)piperidin-1-yl)benzoic acid (0.10 g) and N,N-dimethylformamide (2 mL) were added to a reaction flask. 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.04 g, 0.10 mmol) and N,N-diisopropylethylamine (0.04 g, 0.28 mmol) were added at 0°C. After half an hour of reaction, 3-aminopiperidine-2,6-dione (0.02 g, 0.09 mmol) was added. The reaction solution was reacted at 25°C for 2 hours. Water was added for extraction and separation, the organic phase was collected and concentrated under reduced pressure, and the concentrate was separated on a silica gel column (MeOH:DCM=1:10 (v / v)) to obtain the product (0.04 g). ESI-MS (m / z): 1118.44 / 1120.42 [M+H] + .

[0849] 1 H NMR(600MHz,DMSO-d6)δ10.81(s,1H),8.94(d,J=1.8Hz,1H),8.87(d,J=1.9 Hz,1H),8.82(sl,1H),8.54(d,J=12.4Hz,2H),8.44(d,J=8.4Hz,1H),8.31(s ,1H),8.02(s,1H),7.79(s,1H),7.73(d,J=8.5Hz,2H),7.58(s,1H),7.45(sl ,1H),6.95(d,J=8.6Hz,2H),6.85(s,1H),4.73(ddd,J=13.0,8.3,5.3Hz,1H) ,3.85(d,J=12.5Hz,2H),3.79(d,J=14.8Hz,6H),3.37(s,3H),3.22(s,3H),3 .01-2.83(m,6H),2.82-2.71(m,3H),2.64(s,3H),2.54(t,J=3.3Hz,2H),2.3 2(s,1H),2.21(s,1H),2.11(qd,J=12.9,4.4Hz,1H),1.96-1.89(m,1H),1.83 -1.78(m,2H),1.77-1.72(m,2H),1.42(d,J=23.8Hz,4H),1.29-1.13(m,6H).

[0850] Example 38: Synthesis of N-6-((5-bromo-2-((4-(4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperidin-4-yl)methyl)azetidin-3-yl)piperazin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 188)

[0851] Synthesis Method: Refer to Example 10, except that the starting material in step 1 was replaced with 2-(2,6-dioxopiperidin-3-yl)-5-(4-((3-(4-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperazin-1-yl)azetidin-1-yl)methyl)piperidin-1-yl)isoindole-1,3-dione to give the product. ESI-MS (m / z): 1102.22 / 1104.37 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ11.08(s,1H),8.95(s,1H),8.88(s,1H),8.85-8.76(m,1H),8.55(d,J=4.2Hz,2H),8.32(s,1H),8.02( s,1H),7.80(s,1H),7.66(d,J=8.5Hz,1H),7.59(s,1H),7.56-7.46(m,1H),7.31(s,1H),7.23(d,J=7.9Hz,1H),6.86(s,1H),5. 07(dd,J=12.8,5.4Hz,1H),4.03(dd,J=14.2,7.1Hz,5H),3.81(s,3H),3.78(s,3H),3.39(s,3H),3.23(s,3H),2.91(dd,J=34.0 ,14.8Hz,8H),2.63-2.56(m,3H),2.56-2.53(m,2H),2.44(s,4H),2.02(d,J=13.3Hz,2H),1.76(d,J=11.5Hz,2H),1.24(s,2H).

[0852] Example 39: Synthesis of N-(6-((5-bromo-2-((4-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 189)

[0853] The synthesis method was similar to Example 13, except that the starting material in step 1, 4-bromo-2-methylaminoaniline, was replaced with 3-bromo-2-methylaminoaniline to obtain the product. ESI-MS (m / z): 1048.33 / 1050.34 [M+H] + .

[0854] Example 41: Synthesis of N-(6-((5-bromo-2-((4-(4-((8-((2,6-dioxopiperidin-3-yl)amino)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-3(4H)-yl)methyl)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 247)

[0855] Step 1: Synthesis of 3-((3-((1-(5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)piperidine-2,6-dione

[0856] The synthesis method was similar to that of Example 11, step 1, to obtain the product. ESI-MS (m / z): 645.31 [M+H] + .

[0857] Step 2: Synthesis of 3-((3-((1-(4-amino-5-methoxy-2-(1-methyl-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)piperidine-2,6-dione

[0858] The synthesis method was similar to that of step 2 in Example 11 to obtain the product. ESI-MS (m / z): 615.33 [M+H] + .

[0859] Step 3: Synthesis of compound 247

[0860] The synthesis method was similar to that of step 3 in Example 11 to obtain the product. ESI-MS (m / z): 1021.32 / 1023.32 [M+H] + . 1 HNMR(600MHz,DMSO-d6)δ10.75(s,1H),8.99-8.74(m,3H),8.54(d,J=21.9Hz,2H),8.32(s,1H),8.03(s,1H),7.78(s,1H ),7.66-7.38(m,2H),6.84(s,1H),6.64(d,J=8.3Hz,1H),6.24-6.08(m,2H),5.30(d,J=6.2Hz,1H),4.25-4.08(m,2H),3. 92-3.83(m,1H),3.84-3.71(m,6H),3.64-3.51(m,2H),3.38(s,3H),3.23(s,3H),3.11(s,3H),3.01-2.91(m,1H),2.91-2 .80(m,2H),2.79-2.67(m,1H),2.67-2.53(m,3H),2.29(s,2H),2.15-2.05(m,2H),1.85-1.63(m,4H),1.35-1.28(m,2H).

[0861] Example 42: Synthesis of N-(6-((5-bromo-2-((4-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)-N-methylmethanesulfonamide (Compound 248)

[0862] The synthesis method was the same as Example 11 (Compound 112), except that the starting material in step 1 was replaced with 1-(3-methoxy-4-nitrophenyl)piperidine-4-carboxaldehyde to obtain the product. ESI-MS (m / z): 971.31 / 973.25 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ10.53(s,1H),8.97-9.00(m,1H),8.95(d,J=1.6Hz,1H),8.90(d,J=1.7Hz,1H),8.54(s,1H),8.42(s,1 H),8.27(s,1H),7.91(s,1H),7.36(d,J=12.8Hz,1H),7.29(s,1H),7.12(d,J=7.0Hz,1H),6.68(s,1H),6.51(d,J=9.4Hz,1H), 3.95(s,2H),3.89(t,J=6.7Hz,2H),3.76(s,2H),3.75-3.73(m,1H),3.41(s,1H),3.37(s,3H),3.24(s,2H),3.11(s,3H),2.71 -2.75(m,4H),2.63-2.56(m,4H),2.30(d,J=6.6Hz,2H),1.86(d,J=11.9Hz,2H),1.76(s,2H),1.32-1.28(m,2H),1.23(s,3H).

[0863] Biological activity

[0864] Experimental Example 1: Western Blot-based EGFR protein degradation and pEGFR protein inhibition assay in cells

[0865] 1. Cell Lines

[0866] Cell line source: Nanjing Kebai Biotechnology Co., Ltd.

[0867] Cell types: BaF3-EGFR-L858R / T790M / C797S (BaF3-LTC) cells, H1975-EGFR-L858R / T790M / C797S (H1975-LTC) cells, H1975 cells.

[0868] 2. Reagents, consumables, and instruments

[0869] 3. Test methods

[0870] Protein sample preparation: Cells were harvested and the cell suspension was adjusted to an appropriate concentration with complete culture medium (RPMI1640 + 10% FBS) before plating on a 6-well plate. The cells were cultured overnight in a 37°C, 5% CO2 incubator. The next day, different concentrations of the test compound (see Table 2) were added, and DMSO control wells were set up. The DMSO concentration in all wells was 0.1%. The 6-well plate was incubated in a 37°C, 5% CO2 incubator for 48 hours. The cells were harvested and lysed on ice with 50 μL of RIPA lysis buffer containing protease and phosphatase inhibitors. The cells were centrifuged at 4°C, 12,000 rpm, and the protein supernatant was collected. Protein was quantified using the BCA assay, and samples were prepared for Western Blot analysis.

[0871] Western Assay: Add an appropriate amount of protein sample to each well, run electrophoresis on a polyacrylamide gel, and transfer to the membrane. After transfer, transfer the membrane to blocking buffer. After blocking for 2 hours, transfer the membrane to a hybridization bag and add diluted anti-EGFR, pEGFR, or β-actin antibodies, respectively, and incubate overnight at 4°C. Transfer the membrane to elution buffer and elute four times. After washing, add diluted goat anti-rabbit or goat anti-mouse antibodies. Incubate at room temperature for 2 hours, transfer the membrane to elution buffer and elute four times. Place the membrane in the exposure cassette of a gel imaging system, add substrate working solution, expose, and save the exposure image.

[0872] The degradation rates corresponding to different concentrations of compounds were calculated according to formula (1), where EGFR 化合物 is the gray value of EGFR protein after compound incubation, vehicle is the grayscale value of EGFR protein in the DMSO control group.

[0873] The inhibition rate of pEGFR protein by compounds at different concentrations was calculated according to formula (2), where pEGFR 化合物 is the gray value of pEGFR protein after compound incubation, pEGFR vehicle is the gray value of pEGFR protein in the DMSO control group. Degradation rate (%) = [1-(EGFR 化合物 / β-actin 化合物 ) / (EGFR vehicle / β-actin vehicle )]×100% (Formula 1) Inhibition rate (%)=[1-(pEGFR 化合物 / β-actin 化合物 ) / (pEGFR vehicle / β-actin vehicle )]×100% (Formula 2)

[0874] 4. Test results: The results are shown in Table 2:

[0875] Table 2 Effects on EGFR protein degradation activity and pEGFR protein inhibitory activity in different cells

[0876] The results showed that the compounds of the present invention had a good degradation effect on the EGFR protein of BaF3-EGFR-L858R / T790M / C797S cells, H1975-EGFR-L858R / T790M / C797S cells and H1975 cells, and significantly downregulated the expression level of pEGFR protein in H1975 cells.

[0877] Experimental Example 2: Degradation of EGFR protein in H1975-EGFR-L858R / T790M / C797S cells based on the HiBiT method

[0878] 1. Cell Lines

[0879] Cell line source: Shanghai Runnuo Biotechnology Co., Ltd.

[0880] Cell type: H1975-EGFR-L858R / T790M / C797S-HiBiT

[0881] 2. Test methods

[0882] Cells were harvested, resuspended in complete culture medium, counted, and plated in 384-well plates, with approximately 10,000 cells per well. Compounds were added to each well at varying concentrations (starting at 10 μM or 3 μM, with 10 concentrations, 1:3 dilutions, and duplicate wells). A control group containing cells supplemented with DMSO and a blank control group containing cell culture medium were also established. The cell culture plates were incubated at 37°C, 5% CO2 for 16 hours.

[0883] Prepare Nano-Glo HiBiT Detection Solution by mixing Nano-Glo HiBiT Lytic Buffer: Substate: Protein at a ratio of 100:2:1. Add 20 μL of Nano-Glo HiBiT Detection Solution to each well, shake on a shaker at 300 rpm, and incubate at room temperature in the dark for 10 minutes.

[0884] The assay was performed on an Envision microplate reader, the data were read, and the protein degradation rate was calculated.

[0885] Degradation rate=(1-(positive control-compound wells) / (positive control-negative control))*100.

[0886] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0887] DC50 was calculated using Prism software after fitting the curve using the four-parameter method.

[0888] Table 3 EGFR protein degradation activity of the compounds of the present invention in H1975-EGFR-L858R / T790M / C797S cells

[0889] Note:

[0890] 1.A stands for DC 50 ≤5nΜ; B represents 5nΜ <DC 50 ≤10nM; C represents 10nM <DC 50 ≤50nΜ.

[0891] 2. The control compound is compound 106 of WO2022228547A.

[0892] The test results show that the compound of the present invention has a good EGFR protein degradation effect on H1975-EGFR-L858R / T790M / C797S cells.

[0893] Experimental Example 3: Experimental study on the inhibition of cell proliferation based on MTT method

[0894] 1. Cell Lines

[0895] Cell line source: Nanjing Kebai Biotechnology Co., Ltd.

[0896] Cell types: BaF3-EGFR-L858R / T790M / C797S (BaF3-LTC) cells, H1975-EGFR-L858R / T790M / C797S (H1975-LTC) cells, H1975 cells, BaF3-EGFR-19del / T790M / C797S (BaF3-DTC) cells, A431 cells (EGFR-WT).

[0897] 2. Reagents, consumables, and instruments

[0898] 3. Test methods

[0899] Cells were harvested and resuspended in complete culture medium (RPMI1640 + 10% FBS or DMEM + 15% FBS), counted, and plated in 96-well plates. Test compounds were added at 10,000 nM, 2,500 nM, 625 nM, 156.25 nM, 39.06 nM, 9.77 nM, 2.44 nM, and 0.61 nM, respectively. A control group containing cells supplemented with DMSO and a blank control group containing cell culture medium were set up. The DMSO concentration was 0.1%. The cell culture plates were incubated at 37°C, 5% CO2 for 72 hours. After incubation, the plates were removed and 20 μL / well of MTT was added. The cells were incubated at 37°C, 5% CO2 for 4 hours. The supernatant was discarded, and 150 μL / well of DMSO was added. The cells were mixed by vortexing, and the OD values ​​were measured on a microplate reader at 550 nM. The cell proliferation inhibition rate data were processed using formula (3) to calculate the inhibition rate corresponding to different concentrations of compounds, where OD 化合物 is the OD value detected after compound incubation, OD 空白孔 is the OD value of the cell culture medium well detection, OD DMSO对照孔 The OD value of the control wells with DMSO added was measured. The inhibition rate curve was plotted using GraphPad Prism software and the IC was calculated using SPSS software. 50 value.

[0900] Inhibition rate (Inh%) = (OD 化合物 -OD 空白孔 ) / (OD DMSO对照孔 -OD 空白孔 )×100%(Formula 3)

[0901] The compounds of the present invention have significant inhibitory effects on different cells. The data of exemplary compounds are shown in Table 4.

[0902] Table 4 Proliferation inhibition activity of the compounds of the present invention on cells with different EGFR mutations

[0903] The experimental results show that the compound of the present invention has obvious proliferation inhibitory activity on BaF3-EGFR-L858R / T790M / C797S cells, H1975-EGFR-L858R / T790M / C797S cells, H1975 cells and BaF3-EGFR-19del / T790M / C797S cells, but has weaker proliferation inhibitory activity on A431 (EGFR-WT) cells, and has good selectivity.

[0904] Test Example 4: Pharmacokinetics in mice

[0905] 1. Experimental Animals

[0906] ICR mice, SPF grade, female, 20-30 g, were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0907] 2. Test methods

[0908] The animals were fasted but not watered for 12 hours one day before administration. On the day of the experiment, ICR mice were randomly divided into groups according to body weight, with 3 mice in each group, and the compound was administered orally at 10 mpk or intravenously at 1 mpk.

[0909] Sample collection: 100 μL of blood was collected from the orbital venous plexus of mice in the intravenous injection group (G2 and G4) before (0) and 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after the administration, respectively, and placed in sodium heparin anticoagulant tubes; 100 μL of blood was collected from the orbital venous plexus of mice in the oral gavage administration group (G1 and G3) before (0) and 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after the administration, respectively, and placed in sodium heparin anticoagulant tubes. The plasma was separated by centrifugation and transferred to 1.5 mL centrifuge tubes and stored in a -80°C refrigerator. The drug concentration in plasma was determined by LC-MS / MS method.

[0910] The compounds of the present invention have good oral absorption properties in mice. The data of exemplary compounds are shown in Table 5.

[0911] Table 5 Pharmacokinetics of the compounds of the present invention in mice

[0912] Note:

[0913] Oral administration group: vehicle: 5% DMSO + 5% solutol + 30% PEG400 + 60% (20% HP-β-CD);

[0914] Intravenous group solvent: 5% DMSO + 30% PEG400 + 65% (20% HP-β-CD)

[0915] The test results show that the compound of the present invention has good oral absorption in mice.

Claims

1. A compound represented by formula (I) or its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates, deuterated products: in, Z1, Z2, Z3, and Z4 are independently selected from: N or CR 6 , the R 6 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3- 6-membered cycloalkyl, halogen, 4-6-membered heterocyclic group or 5-6-membered heteroaryl, wherein the cycloalkyl or heteroaryl group may be substituted by one or more C 1-6 Alkyl, C 1-6 Alkoxy or halogen atom substitution; Preferably, Z1, Z2, Z3, and Z4 are independently selected from N or CR 6 , the R 6 Selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, halogen or 5-6 membered heteroaryl, the cycloalkyl or heteroaryl may be C 1-3 Alkyl, C 1-3 Alkoxy or F atom substitution; More preferably, Z1, Z2, Z3, and Z4 are independently selected from N or CR 6 , the R 6 is selected from hydrogen, methyl, ethyl, cyclopropyl, F, Br or R 1 , R 2 are independently selected from: hydrogen, deuterium, C 1-6 Alkyl or C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 3-6 The cycloalkyl group may be substituted with 1-5 (e.g., 1, 2, 3, 4, 5) substituents selected from deuterium and halogen; Preferably, R 1 , R 2 Each is independently selected from: hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; More preferably, R 1 , R 2 are independently selected from: hydrogen, methyl, ethyl, isopropyl or cyclopropyl; R 3 Selected from: hydrogen, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl, the C 1-6 Alkyl or C 1-6 The alkoxy group may be substituted by one or more halogen atoms; Preferably, R 3 Selected from: Hydrogen, F, Cl, Br, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy group may be substituted by one or more F, Cl or Br atoms; More preferably, R 3 Selected from: hydrogen, F, Cl or Br; R 4 Selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 2-6 Alkynyl, the C 1-6 Alkyl or C 1-6 The alkoxy group may be substituted by one or more halogen atoms; Preferably, R 4 is selected from: hydrogen, methoxy, ethoxy or isopropoxy, wherein the methoxy, ethoxy or isopropoxy may be substituted by one or more halogen atoms; More preferably, R 4 is selected from: hydrogen, methoxy, ethoxy or isopropoxy, wherein the methoxy, ethoxy or isopropoxy may be substituted by 1 or 3 F, Cl or Br atoms; R 5 Selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-8 The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, phenyl, heteroaryl may be substituted by 1 to 4 (e.g., 1, 2, 3, 4) selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 The cycloalkyl group is substituted by a substituent, and the heterocyclic group or heteroaryl group contains 1 to 3 heteroatoms independently selected from O, S or N; Preferably, R 5 Selected from: hydrogen, C 1-3 Alkyl, C 2-4 Alkenyl, C 3-4 Cycloalkyl or 5- to 6-membered heteroaryl, wherein the alkyl, alkenyl, cycloalkyl or heteroaryl may be substituted by 1-4 deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl or C 1-3 Alkoxy substituted, the heteroaryl contains 1-2 N atoms, More preferably, R 5 is selected from: hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, vinyl, propenyl or pyrazolyl, wherein the pyrazolyl may be substituted by methyl or ethyl; More preferably, R 5 Selected from: methyl, ethyl, vinyl, isopropyl, cyclopropyl or L represents a connecting chain selected from -L1-L2-L3-L4-L5-, wherein, L1 is selected from 3-12 membered heterocyclic diyl or C 3-10 Cycloalkanediyl, the heterocyclic diyl or cycloalkanediyl is optionally substituted by 1 to 4 (e.g., 1, 2, 3, 4) selected from deuterium, halogen, hydroxyl, amino, -OR L1 、-N(R L1 )(R L1’ ) substituted, wherein R L1 , R L1’ are independently selected from hydrogen, deuterium or C 1-6 alkyl; L2, L3, L4 and L5 are independently selected from a bond, C 1-6 Alkylene, 3-12 membered heterocyclic diyl, C 3-12 Cycloalkanediyl, C 2- 6-Alkenylene, C 2-6 Alkyne, -C(O)-, -C(O)-C 1-6 Alkylene-, -C(O)-N(R L2 )-、-O-、-N(R L2 )-, -S-, -C(S)-, -C(O)-O-, -C(S)-O-, -S(O)2-, -S(O)(R L2 )=N-, -S(O)2NH- or -C=N-; wherein the C 3-12 The cycloalkanediyl and 3-12 membered heterocyclic diyl may be optionally each independently substituted with one or more R L3 Replacement; said C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 The alkynylene group may be optionally each independently substituted with one or more R L4 replace; R L2 Selected from hydrogen or C 1-6 Alkyl, which may be optionally substituted with one or more deuteriums; Each R L3 Each independently selected from oxo, hydroxyl, -OC 1-6 Alkyl, halogen, nitro, cyano, amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 1-6 A haloalkyl group or a 3-12 membered heterocyclic group; Each R L4 Each independently selected from halogen, oxo, cyano, hydroxyl, C 1-6 Alkyl, C 3-8 Cycloalkyl or -OC 1-6 Alkyl; wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl or -OC 1-6 The alkyl group may be substituted by 1-3 F atoms; LBM is a group that binds to ubiquitin ligase.

2. The compound according to claim 1 or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, deuterated product, wherein: LBM is selected from the compound of formula (B-1) or its stereoisomers: in, W is selected from C(R b ) or N, said R b Selected from hydrogen or C 1-6 alkyl; X1 is selected from CH2 or C=O; Each R a Each is independently selected from halogen, nitro, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl or -OC 1-4 alkyl base; q is selected from 0, 1, 2 or 3; Preferably, wherein W is selected from CH or N; X1 is selected from CH2 or C=O; Each R a Each is independently selected from halogen, nitro, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl or -OC 1-4 alkyl; q is selected from 0 or 1; Alternatively, LBM is selected from a compound of formula (B-2) or a stereoisomer thereof: wherein M1 is selected from NH, O or S; W and M2 are independently selected from CH or N; M3 selected from CR c or N, the R c Selected from hydrogen, hydroxyl, -OC 1-4 Alkyl, -OC 1-4 Alkylene-4-6 membered heterocyclic group, wherein the heterocyclic group may be optionally substituted by hydroxyl, halogen, C 1-4 Alkyl or C 1-4 Alkoxy substituted, the heterocyclic group contains 1-3 heteroatoms independently selected from O, S or N; R d is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, F, Cl, nitro, cyano, hydroxyl or methoxy; Y is selected from absent or -NR e -; R e Select from H or C 1-4 alkyl; Preferably, LBM is selected from the compound of formula (B-2-1) or its stereoisomers: wherein W is selected from CH or N; M3 selected from CR c or N, the R c Selected from H, hydroxyl, -O-CH3, -O-CH2CH3, -OC 1-4 Alkyl-4-6 membered heterocyclyl, wherein the heterocyclyl may be optionally substituted with methyl or ethyl; R d can be selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, F, Cl or Br; Y is selected from absent or -NH-; More preferably, LBM is selected from the compound of formula (B-2-1') or formula (B-2-1") or a stereoisomer thereof: wherein W is selected from CH or N; M3 is selected from CRc or N, wherein Rc is selected from H, hydroxyl, -O-CH3, -O-CH2CH3, -OC 1-4 Alkyl-4-6 membered hetero Cycyl, wherein the heterocyclic group may be optionally substituted with methyl or ethyl; Rd can be selected from methyl, ethyl, n-propyl, isopropyl, F, Cl or Br; Y is selected from absent or -NH-; Alternatively, LBM is selected from compounds of formula (B-3): Wherein, W, M4 and M5 are each independently selected from CH or N; Or LBM is selected from the compound of formula (B-4): Wherein, W and M6 are independently selected from CH or N; R f is selected from hydrogen, methyl, ethyl, n-propyl or isopropyl; Preferably, the LBM is selected from the compound of formula (B-4-1): Among them, R f is selected from hydrogen, methyl, ethyl, n-propyl or isopropyl; Or LBM is selected from the compound of formula (B-5): Wherein, W and M7 are independently selected from CH or N; Or LBM is selected from the compound of formula (B-6): in, W is selected from CH or N; Ring F is selected from a 5-6 membered heterocyclic group; wherein the heterocyclic group contains 1-3 heteroatoms independently selected from N, O, and S; Preferably, the LBM is selected from the compound of formula (B-6-1): Wherein, X2 and X3 are each independently selected from O or S; n is selected from 1 or 2; Or the LBM is selected from the compound of formula (B-7): Among them, R g Selected from hydrogen, halogen, nitro, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl or -OC 1-4 alkyl; R g1 is selected from hydrogen or halogen; Preferably, the LBM is selected from the compound of formula (B-7-2') and the compound of formula (B-7-2"): Among them, R g is selected from hydrogen, methyl or ethyl; R g1 is selected from hydrogen, F or Br, Among them, R g is selected from hydrogen, methyl or ethyl; R g1 is selected from hydrogen, F or Br; Or LBM is selected from the compound of formula (B-8): in, W is selected from CH or N; represents a single bond or a double bond; when When it represents a single bond, W1 is selected from CH2 or NH; when When representing a double bond, W1 is selected from CH or N; Cy2 is selected from a 6-8 membered aryl group or a 5-6 membered heteroaryl group; wherein the aryl or heteroaryl group may be substituted by 1-2 R h replace; Each R h Each is independently selected from halogen, nitro, cyano, hydroxy, methyl, ethyl, n-propyl or isopropyl; Y1 is selected from: absent, NR i or -C(O)NH-, the R i Select from H or C 1-4 Alkyl; preferably, Y1 is selected from: absent or NR i , the R i Select from H or C 1-4 alkyl; Preferably, W is selected from CH or N; represents a single bond or a double bond; when When it represents a single bond, W1 is selected from CH2; when When it represents a double bond, W1 is selected from N; Cy2 is selected from phenyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, thiazolyl or pyrrolyl; wherein the phenyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, thiazolyl or pyrrolyl may be substituted by 1-2 R h replace; Each R h Each is independently selected from F, Cl, Br, nitro, cyano, hydroxyl or methyl; More preferably, Wherein Cy2 is selected from phenyl, pyrimidinyl or pyridinyl; wherein the phenyl, pyrimidinyl or pyridinyl can be R h replace; R h is selected from F, Cl, Br, hydroxyl or methyl; Y1 is selected from: absent, NH or -C(O)NH-; preferably absent or NH; Or LBM is selected from the compound of formula (B-9): wherein X is selected from CH or N; Y is selected from CH or N; R h1 is selected from hydrogen, halogen, amino, cyano, nitro, C 1-6 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl; R h2 Selected from hydrogen, C 1-6 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl may be substituted by one or more halogen, amino, hydroxyl, carboxyl, cyano; Preferably, R h1 and R h2 At least one of R is not hydrogen, more preferably, h1 and R h2 Neither is hydrogen; Preferably, LBM is selected from the group consisting of a compound of formula (B-9-1), a compound of formula (B-9-2), a compound of formula (B-9-3), and a compound of formula (B-9-4): wherein Y is selected from CH or N; R h1 is selected from hydrogen or halogen; preferably hydrogen, F or Br; R h2 Selected from hydrogen or C 1-6 Alkyl; preferably hydrogen, methyl, ethyl or isopropyl; Preferably, R h1 and R h2 At least one of R is not hydrogen, more preferably, h1 and R h2 Neither is hydrogen; Wherein, Y is selected from CH or N, preferably N; R h1 is selected from hydrogen or halogen; preferably hydrogen, F or Br; R h2 Selected from hydrogen or C 1-6 Alkyl; preferably hydrogen, methyl, ethyl or isopropyl; Preferably, R h1 and R h2 At least one of R is not hydrogen, more preferably, h1 and R h2 Neither is hydrogen; Wherein, Y is selected from CH or N; preferably N; R h1 is selected from hydrogen or halogen; preferably hydrogen, F or Br; R h2 Selected from hydrogen or C 1-6 Alkyl; preferably hydrogen, methyl, ethyl or isopropyl; Preferably, R h1 and R h2 At least one of R is not hydrogen, more preferably, h1 and R h2 Neither is hydrogen; Wherein, Y is selected from CH or N, preferably N; R h1 is selected from hydrogen or halogen, preferably hydrogen, F or Br; R h2 Selected from hydrogen or C 1-6 Alkyl, preferably hydrogen, methyl, ethyl or isopropyl; Preferably, R h1 and R h2 At least one of R is not hydrogen, more preferably, h1 and R h2 Neither is hydrogen; Or LBM is selected from the compound of formula (B-10): Among them, R k1 Selected from hydrogen, halogen, amino, cyano, nitro, C1-6 alkyl, 3-6 membered cycloalkyl, 4-6 heterocycloalkyl; R k2 Selected from hydrogen, C 1-6 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, wherein the C 1-6 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl may be substituted by one or more halogen, amino, hydroxyl, carboxyl, cyano; Preferably, LBM is selected from the compound of formula (B-10-1), and the compound of formula (B-10-2): Among them, R k1 is selected from hydrogen or halogen; preferably hydrogen, F or Br; R k2 Selected from hydrogen or C 1-6 Alkyl; preferably hydrogen, methyl, ethyl or isopropyl; Among them, R k1 is selected from hydrogen or halogen; preferably hydrogen, F or Br; R k2 Selected from hydrogen or C 1-6 Alkyl; preferably hydrogen, methyl, ethyl or isopropyl; Or LBM is selected from the compound of formula (B-11): wherein X is selected from CH or N; R m is selected from hydrogen, halogen, amino, cyano, nitro, C 1-6 Alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl; Preferably, LBM is selected from the group consisting of a compound of formula (B-11-1), a compound of formula (B-11-2), a compound of formula (B-11-3), and a compound of formula (B-11-4): Among them, R m is selected from hydrogen or halogen; preferably hydrogen, F or Br; Among them, R m is selected from hydrogen or halogen; preferably hydrogen, F or Br; Among them, R m is selected from hydrogen or halogen; preferably hydrogen, F or Br; Among them, R m is selected from hydrogen or halogen; preferably hydrogen, F or Br.

3. The compound according to claim 1 or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, deuterated product, wherein: LBM is selected from: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) 4. The compound according to any one of claims 1 to 3 or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, deuterated product, wherein: The L is selected from -L1-L2-L3-L4-L5, wherein L1 is selected from a 4-7 membered monoheterocyclic diyl (e.g., a 4, 5, 6, 7 membered monoheterocyclic diyl) or a 7-11 membered heterospirocyclic diyl, wherein the monoheterocyclic diyl or heterospirocyclic diyl may be optionally substituted with one to four deuterium, halogen, hydroxyl, amino, -OR L1 、-N(R L1 )(R L1’ ) substituted, wherein R L1 , R L1’ are independently selected from hydrogen, deuterium or C 1-3 alkyl; L2, L3, L4 and L5 are independently selected from: a bond, C 1-6 Alkylene, 4-7 membered monoheterocyclic diyl, 7-11 membered heterospirocyclic diyl, C 4-7 Cycloalkanediyl, C 2-6 Alkenylene, C 2-4 Alkyne, -C(O)-, -C(O)-C 1-3 Alkylene-, -C(O)-N(R L2 )-or-N(R L2 )-; wherein the monoheterocyclic diyl or heterospirocyclic diyl may be optionally substituted by hydroxyl, C 1-3 Alkyl or C 1-3 Alkoxy substituted; R L2 Selected from hydrogen or C 1-3 Alkyl, which may be optionally substituted with 1 to 7 deuteriums; Preferably, L is selected from -L1-L2-L3-L4-L5, wherein: L1 is selected from a 6-membered monoheterocyclic diyl or a 7-11-membered heterospirocyclic diyl, wherein the monoheterocyclic diyl or heterospirocyclic diyl may be optionally substituted with one to four deuterium, halogen, hydroxyl, amino, -OR L1 、-N(R L1 )(R L1’ ) substituted, wherein R L1 , R L1’ are independently selected from hydrogen, deuterium or C 1-3 alkyl; L2, L3, L4 and L5 are independently selected from: a bond, C 1-6 Alkylene, 4-6 membered monoheterocyclic diyl, 7-11 membered heterospirocyclic diyl, C 4-6 Cycloalkanediyl, C 2-4 Alkyne, -C(O)-, -C(O)-C 1-3 Alkylene-, -C(O)-N(R L2 )-or-N(R L2 )-; wherein the monoheterocyclic diyl or heterospirocyclic diyl may be optionally substituted by hydroxyl, C 1-3 Alkyl or C 1-3 Alkoxy substituted; R L2 is selected from hydrogen, methyl or ethyl, the alkyl group being optionally substituted with 1 to 4 deuteriums; More preferably, said L is selected from -L1-L2-L3-L4-L5, wherein: L1-L2 is selected from: L2, L3, L4 and L5 are independently selected from: a bond, a methylene group, an ethylene group, a propylene group, a butylene group, a piperidine diyl group (preferably ), piperazinediyl (preferably )、 Cyclobutanediyl, ethynyl, 1-propynyl, 1-butynyl, -C(O)-, C(O)-CH2-, -C(O)-NH-, -C(O)-N(CH3)-, -NH-, -N(CH3)- or -N(CD3)-; wherein the piperidinediyl or piperazinediyl may be substituted by hydroxyl, methoxy or ethoxy.

5. The compound according to any one of claims 1 to 4 or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, deuterated product, wherein: The L-LBM is selected from:

6. The compound according to any one of claims 1 to 5, or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, deuterated product, wherein: The compound of formula (I) is the compound of formula (I-2): Among them, Z1, Z2, Z3, Z4, R 1 , R 2 , R 3 , R 4 , R 5 , L and LBM are as described in the compound of formula (I) of claim 1; Preferably, L-LBM is selected from More preferably, LBM is a compound of formula (B-1), a compound of formula (B-7-2"), a compound of formula (B-9-1), a compound of formula (B-9-3), a compound of formula (B-10-1) or a compound of formula (B-8).

7. The compound according to any one of claims 1 to 6 or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, deuterated product, wherein the compound is selected from:

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, deuterated product.

9. The pharmaceutical composition according to claim 8, comprising the compound according to any one of claims 1 to 7 or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, deuterated product and a pharmaceutically acceptable carrier.

10. Use of a compound according to any one of claims 1 to 7, or a stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, deuterated compound thereof, or a composition according to claim 8 or 9 in the preparation of a medicament for treating a disease mediated by EGFR, such as a cancer mediated by EGFR, such as lung cancer, preferably non-small cell lung cancer.

11. Use of a compound as described in any one of claims 1 to 7, or a stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, deuterated product thereof, or a composition as described in claim 8 or 9, in the preparation of a medicament for treating a disease mediated by EGFR, for example a cancer mediated by EGFR, such as lung cancer, preferably non-small cell lung cancer, wherein the compound, or a stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, deuterated product thereof, or a composition as described in claim 8 or 9 is administered in combination with other drugs.

12. A method for treating a disease mediated by EGFR, such as a cancer mediated by EGFR, such as lung cancer, preferably non-small cell lung cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 7, or a stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, deuterated compound thereof, or a composition according to claim 8 or 9.

13. A method for treating a disease mediated by EGFR, such as a cancer mediated by EGFR, such as lung cancer, preferably non-small cell lung cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described in any one of claims 1 to 7, or a stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, deuterated compound thereof, or a composition as described in claim 8 or 9 in combination with other drugs.

14. A compound according to any one of claims 1 to 7, or a stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, deuterated compound or a composition according to claim 8 or 9, for use in treating a disease mediated by EGFR, such as a cancer mediated by EGFR, such as lung cancer, preferably non-small cell lung cancer.

15. A compound as described in any one of claims 1 to 7, or a stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, deuterated product thereof, or a composition as described in claim 8 or 9, for use in treating a disease mediated by EGFR, such as a cancer mediated by EGFR, such as lung cancer, preferably non-small cell lung cancer, wherein the compound, or a stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate, deuterated product thereof, or the composition is administered in combination with other drugs.

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