Fused ring compounds, pharmaceutical compositions thereof, and uses thereof

Abstract

A fused ring compound, a pharmaceutical composition thereof, and an application thereof are disclosed. Specifically, a compound as shown in formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof is disclosed. The fused ring compound has good inhibitory activity or protein degradation activity on AURKA.

Description

Condensed ring compound, pharmaceutical composition and application thereof

[0001] This application claims priority from the following Chinese applications:

[0002] Chinese patent application 2023116376216 with a filing date of December 1, 2023;

[0003] Chinese patent application 2024102542376, filed on March 6, 2024;

[0004] Chinese patent application 2024111068336 with an application date of August 13, 2024.

[0005] This application cites the full text of the above-mentioned Chinese patent application. Technical Field

[0006] The present invention relates to fused ring compounds, pharmaceutical compositions and applications thereof. Background Art

[0007] Aurora-A (also known as AURKA, Aurora kinase A) is a serine / threonine kinase that plays an important role in cell mitosis. It is a member of the Aurora Kinases family. It participates in the centrosome maturation process, promotes the transition of cells from G2 to mitosis, and is a key mitotic regulator required to maintain chromosome stability.

[0008] Aurora-A regulates numerous molecular and signaling pathways by phosphorylating various substrates, including p53 / p73, p27, PP1, BRCA, Ras, the MEK / ERK pathway, PLK1, TPX2, the NF-κB pathway, the Hippo pathway, the PI3K / Akt / mTOR pathway, RIPK1 / 3, MLKL, the Wnt / β-catenin pathway, and the p38 mitogen-activated protein kinase (MAPK) pathway. This involvement in tumor progression, including tumorigenesis, proliferation, migration, invasion, and metastasis, has led to its recognition as an oncogene. Aurora-A is overexpressed in various tumors, including neuroblastoma, lymphoma, breast cancer, colorectal cancer, ovarian cancer, and prostate cancer. High levels of Aurora-A have been associated with tumor proliferation, epithelial-mesenchymal transition, drug resistance, and metastasis. Therefore, inhibiting the catalytic activity of Aurora-A may be beneficial in inhibiting tumor progression.

[0009] The MYC oncogene family consists of three members: MYCC, MYCN, and MYCL, encoding c-Myc, N-Myc, and L-Myc proteins, respectively. These proteins primarily function as transcriptional regulators, and their expression is tightly controlled in normal tissues. MYC abnormalities are drivers of tumorigenesis. MYC gene mutations are found in approximately 70% of human malignancies, with gene amplification being the most common. Inhibiting Myc expression or function can reverse oncogenic processes, including restoring arrested cell cycle activity, triggering apoptosis, inducing cellular senescence, promoting cell differentiation, inhibiting angiogenesis, and upregulating anti-tumor immune responses, thereby reversing tumorigenesis. Aurora-A stabilizes c-Myc. Studies have shown that in liver cancer cells that are dependent on PKA (protein kinase A) or harbor p53 mutations, Aurora-A, relying on its structure, directly binds to c-Myc, mediating its stability. Some inhibitors can induce conformational changes in Aurora-A, thereby interfering with the protein-protein interaction between Aurora-A and C-Myc and affecting the formation of the complex, leading to proteasomal degradation of C-Myc and causing cell death. However, cells are insensitive to inhibitors that only inhibit the kinase activity of Aurora-A. Aurora-A also promotes c-Myc expression as a transactivator in a non-kinase-dependent manner. The human MYCC gene is mainly transcribed by two tandem promoters P1 and P2. The 283-333 domain of Aurora-A can interact with the KI domain of hnRNP K (MYCC promoter regulatory protein) to form a complex, thereby activating the P1 promoter and promoting c-Myc expression. In addition, Aurora-A can also stabilize N-Myc. The proteasomal degradation pathway of N-Myc depends on the E3 ubiquitin ligase complex SCF. FBXW7 trigger, and the Aurora-A catalytic domain interacts with SCF FBXW7 Competitive binding to the MBI region of N-Myc can interfere with the interaction between N-Myc and SCF FBXW7 Therefore, eliminating the structure-dependent oncogenic effects of Aurora-A is beneficial for inhibiting tumor progression.

[0010] Currently, small molecule inhibitors of Aurora-A for targeted cancer treatment are in clinical trials, including VE465, tozasertib (VX-680), MK-0457, MK-5108, alisertib (MLN-8237), and LY3295668. However, the therapeutic effects have been unsatisfactory, and no such drugs have yet been approved for marketing. Simultaneously inhibiting both the kinase activity and cytoskeletal function of Aurora-A may improve the therapeutic efficacy of related cancers.

[0011] PROTAC (Proteolysis Targeting Chimera) is a bifunctional compound whose molecular structure includes a target protein binding ligand and an E3 ubiquitin ligase ligand, and the two ligands are connected by a linker. PROTAC molecules can simultaneously bind to target proteins and E3 ubiquitin ligases to form a ternary complex, and use the E3 ubiquitin ligase system to ubiquitinate the target protein, thereby inducing the degradation of the target protein under the action of proteolytic enzymes, thereby achieving the purpose of clearing pathogenic proteins. Unlike small molecule kinase inhibitors that can only inhibit the kinase activity of the target protein, PROTAC molecules can not only inhibit the kinase activity of the target protein by inducing the degradation of the target protein, but also eliminate the skeletal protein function of the target protein.

[0012] The development of PROTAC molecules that induce Aurora-A degradation and simultaneously eliminate the tumor-promoting effects of Aurora-A's enzymatic activity and scaffold protein function is likely to have superior tumor inhibition performance than small molecule inhibitors, and has the potential to become a more effective new treatment option in tumor indications related to Aurora-A activity (head and neck cancer, lung cancer, breast cancer, gastroesophageal adenocarcinoma, uterine leiomyosarcoma, urothelial carcinoma, ovarian cancer, prostate cancer, advanced or metastatic sarcoma, lymphoma, acute myeloid leukemia) and Myc amplification-related tumor indications (colorectal cancer, non-small cell lung cancer, triple-negative breast cancer). Summary of the Invention

[0013] The technical problem to be solved by the present invention is to address the deficiency of the existing technology in the types of AURKA inhibitors or degraders, and to provide a fused ring compound, a pharmaceutical composition thereof, and its application. The fused ring compound of the present invention has good inhibitory activity or protein degradation activity against AURKA.

[0014] The present invention solves the above technical problems through the following technical solutions.

[0015] The present invention provides a compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof:

[0016] in,

[0017] Indicates a single bond or a double bond;

[0018] X 1 is CH, CD or N;

[0019] R 3 is H, D, C1-C6 alkyl or optionally substituted C1-C6 alkyl;

[0020] R 4 is H or C1-C6 alkyl;

[0021] X 2 N, CH or CD;

[0022] X 3 CR 2 or N;

[0023] R 2 H, D, cyano, halogen, -OR 2-7 、-P(=O)(R 2-1 )2、-S(=O)2R 2-2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

[0024] R 2-1 and R 2-2 Each is independently an optionally substituted C1-C6 alkyl group;

[0025] R 2-7 is optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

[0026] R 1 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

[0027] R 1-1 and R 1-2 Each is independently halogen, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy;

[0028] A is -R A1 C(=O)-、-R A2 CH2-、-R A2 CD2-, -R A2 CHD-, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene, or optionally substituted heterocycloalkylene;

[0029] R A1 and R A2 each independently is optionally substituted aryl, optionally substituted heteroarylene, optionally substituted cycloalkylene, or optionally substituted heterocycloalkylene;

[0030] L is the connecting chain;

[0031] B is optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene or optionally substituted heterocycloalkylene;

[0032] And the compound represented by formula (I) is not any of the following compounds:

[0033] In certain preferred embodiments of any of the above inventions, certain groups of the compound as shown in formula (I), its pharmaceutically acceptable salts, its solvates and solvates of its pharmaceutically acceptable salts are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in a certain embodiment of the present invention").

[0034] In one embodiment of the present invention,

[0035] Indicates a single bond or a double bond;

[0036] X 1 is CH, CD or N;

[0037] R 3 is H, D, C1-C6 alkyl or optionally substituted C1-C6 alkyl;

[0038] R 4 is H;

[0039] X 2 N, CH or CD;

[0040] X 3 CR 2 or N;

[0041] R 2 H, D, cyano, halogen, -OR 2-7 、-P(=O)(R 2-1 )2、-S(=O)2R 2-2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

[0042] R 2-1 and R 2-2 Each is independently an optionally substituted C1-C6 alkyl group;

[0043] R 2-7 is optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

[0044] R 1 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

[0045] R 1-1 and R 1-2 Each is independently halogen, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy;

[0046] A is -R A1 C(=O)-、-R A2 CH2-、-R A2 CD2-, -R A2 CHD-, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene, or optionally substituted heterocycloalkylene;

[0047] R A1 and R A2 each independently is optionally substituted aryl, optionally substituted heteroarylene, optionally substituted cycloalkylene, or optionally substituted heterocycloalkylene;

[0048] L is the connecting chain;

[0049] B is optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene or optionally substituted heterocycloalkylene;

[0050] And the compound represented by formula (I) is not any of the following compounds:

[0051] In one embodiment of the present invention,

[0052] Indicates a single bond or a double bond;

[0053] X 1 is CH, CD or N;

[0054] R 3 is H, D, C1-C6 alkyl or optionally substituted C1-C6 alkyl;

[0055] R 4 is H;

[0056] X 2 N, CH or CD;

[0057] X 3 CR 2 or N;

[0058] R 2 H, D, halogen, -OR 2-7 、-P(=O)(R 2-1 )2、-S(=O)2R 2-2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

[0059] R 2-1 and R 2-2 Each is independently an optionally substituted C1-C6 alkyl group;

[0060] R 2-7 is optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

[0061] R 1 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;

[0062] R 1-1 and R 1-2 Each is independently halogen, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy;

[0063] A is -R A1 C(=O)-、-R A2 CH2-、-R A2 CD2-, -R A2 CHD-, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene, or optionally substituted heterocycloalkylene;

[0064] R A1 and R A2 each independently is optionally substituted aryl, optionally substituted heteroarylene, optionally substituted cycloalkylene, or optionally substituted heterocycloalkylene;

[0065] L is the connecting chain;

[0066] B is optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene or optionally substituted heterocycloalkylene;

[0067] And the compound represented by formula (I) is not any of the following compounds:

[0068] In one embodiment of the present invention,

[0069] Indicates a single bond or a double bond;

[0070] X 1 is CH or N;

[0071] R 3 is H or C1-C6 alkyl;

[0072] R 4 is H or C1-C6 alkyl;

[0073] X 2 N or CH;

[0074] X 3 CR 2 or N;

[0075] R2 is H, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, saturated C3-C 11 Cycloalkyl, saturated 3-11 membered heterocycloalkyl, -P(=O)(R 2-1 )2、-S(=O)2R 2-2 、-OR 2-7 , by one or more R 2-3 Substituted C1-C6 alkyl, one or more R 2-4 Substituted C1-C6 alkoxy, one or more R 2-5 Substituted saturated C3-C 11 Cycloalkyl or one or more R 2-6 Substituted saturated 3-11 membered heterocycloalkyl, wherein the saturated 3-11 membered heterocycloalkyl and one or more R 2-6 In the 3-11-membered heterocycloalkyl group of the substituted saturated 3-11-membered heterocycloalkyl group, the type of heteroatoms is independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3;

[0076] R 2-1 and R 2-2 Each is independently a C1-C6 alkyl group;

[0077] R 2-7 is saturated C3-C 11 Cycloalkyl;

[0078] R 2-3 and R 2-4 Each is independently -N(R 2-3-1 )2. Saturated C3-C 11 Cycloalkyl, saturated 3-11 membered heterocycloalkyl, 2-3-2 Substituted saturated C3-C 11 Cycloalkyl or one or more R 2-3-3 Substituted saturated 3-11 membered heterocycloalkyl, wherein the saturated 3-11 membered heterocycloalkyl and one or more R 2-3-3 In the 3-11-membered heterocycloalkyl group of the substituted saturated 3-11-membered heterocycloalkyl group, the type of heteroatoms is independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3;

[0079] R 2-3-1 are independently H or C1-C6 alkyl;

[0080] R 2-3-2 and R 2-3-3 Each is independently a C1-C6 alkyl group;

[0081] R 2-5 and R 2-6 Each independently C1-C6 alkyl;

[0082] R 1 C6-C 10 Aryl, 5-10 membered heteroaryl, saturated C3-C 11 Cycloalkyl, saturated 3-11 membered heterocycloalkyl, 1-1 Substituted C6-C 10 Aryl, one or more R 1-2 substituted 5-10 membered heteroaryl, substituted by one or more R 1-3 Substituted saturated C3-C 11 Cycloalkyl or one or more R 1-4 A substituted saturated 3-11 membered heterocycloalkyl, wherein the type of heteroatom in the saturated 3-11 membered heterocycloalkyl is selected from one or more of N, O, S and C(=O), and the number of heteroatoms is 1, 2 or 3, and the 5-10 membered heteroaryl and the substituted 5-10 membered heteroaryl are replaced by one or more R 1-2 In the 5-10 membered heteroaryl group of the substituted 5-10 membered heteroaryl group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0083] R 1-1 、R 1-2 、R 1-3 and R 1-4 Each is independently halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0084] A is -R A1 C(=O)-、-R A2 CH2-、C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 11 Cycloalkylene, saturated 3-11 membered heterocycloalkylene, By one or more R A3 Substituted C6-C 10 Arylene or one or more R A4 The substituted 5-10 membered heteroaryl group, the saturated 3-11 membered heterocycloalkylene group, the type of heteroatom is selected from one or more of N, O, S and C (= O), the number of heteroatoms is 1, 2 or 3, the 5-10 membered heteroaryl group and the substituted 5-10 membered heteroaryl group are replaced by one or more R A4 In the 5-10 membered heteroarylene group of the substituted 5-10 membered heteroarylene group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0085] R A1 and R A2 Each independently is C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 11 Cycloalkylene, saturated 3-11 membered heterocycloalkylene, substituted by one or more R A1-1 Substituted C6-C 10 Arylene or one or more R A1-2 substituted 5-10 membered heteroarylene, wherein the 5-10 membered heteroarylene is replaced by one or more R A1-2 In the 5-10 membered heteroarylene group of the substituted 5-10 membered heteroarylene group, the type of heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; in the 3-11 membered heterocycloalkylene group, the type of heteroatom is selected from one or more of N, O, S and C(═O), and the number of heteroatoms is 1, 2 or 3;

[0086] R A1-1 and R A1-2 are independently CN, -P(=O)(R A3-1 )2, C1-C6 alkyl or C1-C6 alkoxy;

[0087] Ring C1 is a partially unsaturated 3-8 membered heterocyclic ring or is replaced by one or more R C1 A partially unsaturated 3-8 membered heterocyclic ring substituted with one or more R C1 In the 3- to 8-membered heterocyclic ring of the substituted partially unsaturated 3- to 8-membered heterocyclic ring, the type of heteroatoms is independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3;

[0088] R C1 are independently C1-C6 alkyl;

[0089] R A3 and R A4 are independently CN, -P(=O)(R A3-1 )2, C1-C6 alkyl or C1-C6 alkoxy;

[0090] R A3-1 are independently C1-C6 alkyl;

[0091] L is -(CH2)n-, n is any integer from 1 to 18, and one or more -(CH2)- in -(CH2)n- are replaced by one or more of the following groups: -NR L1 -、-O-、-S-、-CR L6 R L7-、-C(=O)-、 Saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, C6-C 10 Arylene, 5-10 membered heteroarylene, By one or more R L2 Substituted saturated C3-C 12 Cycloalkylene, one or more R L3 Substituted saturated 3-12 membered heterocycloalkylene, one or more R L4 Substituted C6-C 10 Arylene or one or more R L5 substituted 5-10 membered heteroaryl, the saturated 3-12 membered heterocycloalkyl and one or more R L3 In the 3-12 membered heterocycloalkyl in the substituted saturated 3-12 membered heterocycloalkylene, the types of heteroatoms are independently selected from one or more of N, O, S and C(=O), and the number of heteroatoms is independently 1, 2 or 3, and the 5-10 membered heteroaryl and the one or more R L5 In the substituted 5-10 membered heteroarylene group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0092] R L1 is H or C1-C6 alkyl;

[0093] Ring C2 is a benzene ring or a 5-6 membered heteroaromatic ring, wherein the type of heteroatom in the 5-6 membered heteroaromatic ring is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0094] Ring C3 is a partially unsaturated C3-C7 carbocycle or a partially unsaturated 3-7 membered heterocycle, wherein the type of heteroatom in the partially unsaturated 3-7 membered heterocycle is selected from one or more of N, O, S and C(=O), and the number of heteroatoms is 1, 2 or 3;

[0095] Ring C4 is a saturated C3-C7 carbocycle or a saturated 3-7 membered heterocycle, wherein the type of heteroatom in the saturated 3-7 membered heterocycle is selected from one or more of N, O, S and C(=O), and the number of heteroatoms is 1, 2 or 3;

[0096] R L2 and R L3 Each is independently CN, OH, halogen, C1-C6 alkyl, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl;

[0097] R L4 and RL5 Each is independently a C1-C6 alkyl group;

[0098] R L6 is H or C1-C6 alkyl;

[0099] R L7 is a C1-C6 alkyl group;

[0100] B is C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, B1 Substituted C6-C 10 Arylene or one or more R B2 substituted 5-10 membered heteroarylene, wherein the 5-10 membered heteroarylene is replaced by one or more R B2 In the 5-10 membered heteroarylene group of the substituted 5-10 membered heteroarylene group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; in the saturated 3-12 membered heterocycloalkylene group, the type of heteroatoms is independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3;

[0101] Y1, Y2, Y3 and Y4 are each independently CH2 or C(=O);

[0102] Y5 stands for NY 5-1 , O or S, Y 5-1 is H or C1-C6 alkyl;

[0103] Ring C5, Ring C6, Ring C7, Ring C8 and Ring C9 are each independently a benzene ring or a 5-6 membered heteroaromatic ring, wherein the type of heteroatom in the 5-6 membered heteroaromatic ring is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0104] Ring C 10 is a partially unsaturated C3-C7 carbocycle or a partially unsaturated 3-7 membered heterocycle, wherein the type of heteroatom in the partially unsaturated 3-7 membered heterocycle is selected from one or more of N, O, S and C(=O), and the number of heteroatoms is 1, 2 or 3;

[0105] R B1 and R B2 Each is independently halogen, cyano, -P=O(C1-C6 alkyl)2, -C(=O)NH2, C1-C6 alkyl, C1-C6 alkoxy, B1-1Substituted C1-C6 alkyl or one or more R B1-2 Substituted C1-C6 alkoxy;

[0106] R B1-1 and R B1-2 are each independently halogen;

[0107] Furthermore, the compound represented by formula (I) satisfies one or both of the following conditions:

[0108] i: B is L is -(CH2)n-, n is any integer from 1 to 18,

[0109] At least one -(CH2)- in -(CH2)n- is replaced by the following groups: saturated C3-C 12 Cycloalkylene, saturated 3-5 membered heterocycloalkylene, saturated 7-12 membered heterocycloalkylene, C6-C 10 Arylene, 6-10 membered heteroarylene, By one or more R L2 Substituted saturated C3-C 12 Cycloalkylene, one or more R L3 Substituted saturated 3-12 membered heterocycloalkylene, one or more R L4 Substituted C6-C 10 Arylene or one or more R L5 substituted 5-10 membered heteroarylene;

[0110] Alternatively, at least two -(CH2)- in -(CH2)n- are replaced by the following groups: saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, C6-C 10 Arylene, 5-10 membered heteroarylene, By one or more R L2 Substituted saturated C3-C 12 Cycloalkylene, one or more R L3 Substituted saturated 3-12 membered heterocycloalkylene, one or more R L4 Substituted C6-C 10 Arylene or one or more R L5 substituted 5-10 membered heteroarylene;

[0111] ii: B is C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, B1Substituted C6-C 10 Arylene or one or more R B2 Substituted 5-10 membered heteroarylene, ring C 5-1 5-6 membered heteroaromatic ring in the same ring C5, ring C 5-2 A 5-6 membered heteroaromatic ring in the same ring C5.

[0112] In one embodiment of the present invention,

[0113] Indicates a single bond or a double bond;

[0114] X 1 is CH or N;

[0115] R 3 is H or C1-C6 alkyl;

[0116] R 4 is H;

[0117] X 2 N or CH;

[0118] X 3 CR 2 or N;

[0119] R 2 is H, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, saturated C3-C 11 Cycloalkyl, saturated 3-11 membered heterocycloalkyl, -P(=O)(R 2-1 )2、-S(=O)2R 2-2 、-OR 2-7 , by one or more R 2-3 Substituted C1-C6 alkyl, one or more R 2-4 Substituted C1-C6 alkoxy, one or more R 2-5 Substituted saturated C3-C 11 Cycloalkyl or one or more R 2-6 Substituted saturated 3-11 membered heterocycloalkyl, wherein the saturated 3-11 membered heterocycloalkyl and one or more R 2-6 In the 3-11-membered heterocycloalkyl group of the substituted saturated 3-11-membered heterocycloalkyl group, the type of heteroatoms is independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3;

[0120] R 2-1 and R 2-2 Each is independently a C1-C6 alkyl group;

[0121] R 2-7 is saturated C3-C 11Cycloalkyl;

[0122] R 2-3 and R 2-4 Each is independently -N(R 2-3-1 )2. Saturated C3-C 11 Cycloalkyl, saturated 3-11 membered heterocycloalkyl, 2-3-2 Substituted saturated C3-C 11 Cycloalkyl or one or more R 2-3-3 Substituted saturated 3-11 membered heterocycloalkyl, wherein the saturated 3-11 membered heterocycloalkyl and one or more R 2-3-3 In the 3-11-membered heterocycloalkyl group of the substituted saturated 3-11-membered heterocycloalkyl group, the type of heteroatoms is independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3;

[0123] R 2-3-1 are independently H or C1-C6 alkyl;

[0124] R 2-3-2 and R 2-3-3 Each is independently a C1-C6 alkyl group;

[0125] R 2-5 and R 2-6 Each independently C1-C6 alkyl;

[0126] R 1 C6-C 10 Aryl, 5-10 membered heteroaryl, saturated C3-C 11 Cycloalkyl, saturated 3-11 membered heterocycloalkyl, 1-1 Substituted C6-C 10 Aryl or one or more R 1-2 The 5-10 membered heteroaryl group is substituted, wherein the type of heteroatom in the saturated 3-11 membered heterocycloalkyl group is selected from one or more of N, O, S and C(=O), and the number of heteroatoms is 1, 2 or 3. The 5-10 membered heteroaryl group and the saturated 3-11 membered heterocycloalkyl group are substituted. 1-2 In the 5-10 membered heteroaryl group of the substituted 5-10 membered heteroaryl group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0127] R 1-1 and R 1-2 Each is independently halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0128] A is -R A1 C(=O)-、-R A2CH2-、C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 11 Cycloalkylene, saturated 3-11 membered heterocycloalkylene, By one or more R A3 Substituted C6-C 10 Arylene or one or more R A4 The substituted 5-10 membered heteroaryl group, the saturated 3-11 membered heterocycloalkylene group, the type of heteroatom is selected from one or more of N, O, S and C (= O), the number of heteroatoms is 1, 2 or 3, the 5-10 membered heteroaryl group and the substituted 5-10 membered heteroaryl group are replaced by one or more R A4 In the 5-10 membered heteroarylene group of the substituted 5-10 membered heteroarylene group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0129] R A1 and R A2 Each independently is C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 11 Cycloalkylene, saturated 3-11 membered heterocycloalkylene, substituted by one or more R A1-1 Substituted C6-C 10 Arylene or one or more R A1-2 substituted 5-10 membered heteroarylene, wherein the 5-10 membered heteroarylene is replaced by one or more R A1-2 In the 5-10 membered heteroarylene group of the substituted 5-10 membered heteroarylene group, the type of heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; in the 3-11 membered heterocycloalkylene group, the type of heteroatom is selected from one or more of N, O, S and C(═O), and the number of heteroatoms is 1, 2 or 3;

[0130] R A1-1 and R A1-2 are independently CN, -P(=O)(R A3-1 )2, C1-C6 alkyl or C1-C6 alkoxy;

[0131] Ring C1 is a partially unsaturated 3-8 membered heterocyclic ring or is replaced by one or more R C1 A partially unsaturated 3-8 membered heterocyclic ring substituted with one or more R C1 In the 3- to 8-membered heterocyclic ring of the substituted partially unsaturated 3- to 8-membered heterocyclic ring, the type of heteroatoms is independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3;

[0132] R C1 are independently C1-C6 alkyl;

[0133] R A3 and R A4 are independently CN, -P(=O)(R A3-1 )2, C1-C6 alkyl or C1-C6 alkoxy;

[0134] R A3-1 are independently C1-C6 alkyl;

[0135] L is -(CH2)n-, n is any integer from 1 to 18, and one or more -(CH2)- in -(CH2)n- are replaced by one or more of the following groups: -NR L1 -, -O-, -S-, -C(=O)-, Saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, C6-C 10 Arylene, 5-10 membered heteroarylene, By one or more R L2 Substituted saturated C3-C 12 Cycloalkylene, one or more R L3 Substituted saturated 3-12 membered heterocycloalkylene, one or more R L4 Substituted C6-C 10 Arylene or one or more R L5 substituted 5-10 membered heteroaryl, the saturated 3-12 membered heterocycloalkyl and one or more R L3 In the 3-12 membered heterocycloalkyl in the substituted saturated 3-12 membered heterocycloalkylene, the types of heteroatoms are independently selected from one or more of N, O, S and C(=O), and the number of heteroatoms is independently 1, 2 or 3, and the 5-10 membered heteroaryl and the one or more R L5 In the substituted 5-10 membered heteroarylene group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0136] R L1 is H or C1-C6 alkyl;

[0137] Ring C2 is a benzene ring or a 5-6 membered heteroaromatic ring, wherein the type of heteroatom in the 5-6 membered heteroaromatic ring is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0138] Ring C3 is a partially unsaturated C3-C7 carbocycle or a partially unsaturated 3-7 membered heterocycle, wherein the type of heteroatom in the partially unsaturated 3-7 membered heterocycle is selected from one or more of N, O, S and C(=O), and the number of heteroatoms is 1, 2 or 3;

[0139] Ring C4 is a saturated C3-C7 carbocycle or a saturated 3-7 membered heterocycle, wherein the type of heteroatom in the saturated 3-7 membered heterocycle is selected from one or more of N, O, S and C(=O), and the number of heteroatoms is 1, 2 or 3;

[0140] R L2 and R L3 Each is independently CN, OH, halogen, C1-C6 alkyl, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl;

[0141] R L4 and R L5 Each is independently a C1-C6 alkyl group;

[0142] B is C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, B1 Substituted C6-C 10 Arylene or one or more R B2 substituted 5-10 membered heteroarylene, wherein the 5-10 membered heteroarylene is replaced by one or more R B2 In the 5-10 membered heteroarylene group of the substituted 5-10 membered heteroarylene group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; in the saturated 3-12 membered heterocycloalkylene group, the type of heteroatoms is independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3;

[0143] Y1, Y2, Y3 and Y4 are each independently CH2 or C(=O);

[0144] Y5 stands for NY 5-1 , O or S, Y 5-1 is H or C1-C6 alkyl;

[0145] Ring C5, Ring C6, Ring C7, Ring C8 and Ring C9 are each independently a benzene ring or a 5-6 membered heteroaromatic ring, wherein the type of heteroatom in the 5-6 membered heteroaromatic ring is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0146] Ring C 10 is a partially unsaturated C3-C7 carbocycle or a partially unsaturated 3-7 membered heterocycle, wherein the type of heteroatom in the partially unsaturated 3-7 membered heterocycle is selected from one or more of N, O, S and C(=O), and the number of heteroatoms is 1, 2 or 3;

[0147] R B1 and R B2 Each is independently halogen, cyano, -P=O(CH3)2, C1-C6 alkyl, C1-C6 alkoxy, B1- 1 Substituted C1-C6 alkyl or one or more R B1-2 Substituted C1-C6 alkoxy;

[0148] R B1-1 and R B1-2 are each independently halogen;

[0149] Furthermore, the compound represented by formula (I) satisfies one or both of the following conditions:

[0150] i: B is L is -(CH2)n-, n is any integer from 1 to 18, and at least one -(CH2)- in -(CH2)n- is replaced by the following groups: saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, C6-C 10 Arylene, 5-10 membered heteroarylene, By one or more R L2 Substituted saturated C3-C 12 Cycloalkylene, one or more R L3 Substituted saturated 3-12 membered heterocycloalkylene, one or more R L4 Substituted C6-C 10 Arylene or one or more R L5 substituted 5-10 membered heteroarylene;

[0151] ii: B is C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, substituted by one or more R B1 Substituted C6-C 10 Arylene or one or more R B2 Substituted 5-10 membered heteroarylene, ring C 5-1 5-6 membered heteroaromatic ring in the same ring C5, ring C 5-2 Same ring as C5.

[0152] In one embodiment of the present invention,

[0153] Indicates a single bond or a double bond;

[0154] X 1 is CH or N;

[0155] R 3 is H or C1-C6 alkyl;

[0156] R 4 is H;

[0157] X 2 N or CH;

[0158] X 3 CR 2 or N;

[0159] R 2 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, saturated C3-C 11 Cycloalkyl, saturated 3-11 membered heterocycloalkyl, -P(=O)(R 2-1 )2、-S(=O)2R 2-2 、-OR 2-7 , by one or more R 2-3 Substituted C1-C6 alkyl, one or more R 2-4 Substituted C1-C6 alkoxy, one or more R 2-5 Substituted saturated C3-C 11 Cycloalkyl or one or more R 2-6 Substituted saturated 3-11 membered heterocycloalkyl, wherein the saturated 3-11 membered heterocycloalkyl and one or more R 2-6 In the 3-11-membered heterocycloalkyl group of the substituted saturated 3-11-membered heterocycloalkyl group, the type of heteroatoms is independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3;

[0160] R 2-1 and R 2-2 Each is independently a C1-C6 alkyl group;

[0161] R 2-7 is saturated C3-C 11 Cycloalkyl;

[0162] R 2-3 and R 2-4 Each is independently -N(R 2-3-1 )2. Saturated C3-C 11Cycloalkyl, saturated 3-11 membered heterocycloalkyl, 2-3-2 Substituted saturated C3-C 11 Cycloalkyl or one or more R 2-3-3 Substituted saturated 3-11 membered heterocycloalkyl, wherein the saturated 3-11 membered heterocycloalkyl and one or more R 2-3-3 In the 3-11-membered heterocycloalkyl group of the substituted saturated 3-11-membered heterocycloalkyl group, the type of heteroatoms is independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3;

[0163] R 2-3-1 are independently H or C1-C6 alkyl;

[0164] R 2-3-2 and R 2-3-3 Each is independently a C1-C6 alkyl group;

[0165] R 2-5 and R 2-6 Each independently C1-C6 alkyl;

[0166] R 1 C6-C 10 Aryl, 5-10 membered heteroaryl, saturated C3-C 11 Cycloalkyl, saturated 3-11 membered heterocycloalkyl, 1-1 Substituted C6-C 10 Aryl or one or more R 1-2 The 5-10 membered heteroaryl group is substituted, wherein the type of heteroatom in the saturated 3-11 membered heterocycloalkyl group is selected from one or more of N, O, S and C(=O), and the number of heteroatoms is 1, 2 or 3. The 5-10 membered heteroaryl group and the saturated 3-11 membered heterocycloalkyl group are substituted. 1-2 In the 5-10 membered heteroaryl group of the substituted 5-10 membered heteroaryl group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0167] R 1-1 and R 1-2 Each is independently halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0168] A is -R A1 C(=O)-、-R A2 CH2-、C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 11 Cycloalkylene, saturated 3-11 membered heterocycloalkylene, By one or more RA3 Substituted C6-C 10 Arylene or one or more R A4 The substituted 5-10 membered heteroaryl group, the saturated 3-11 membered heterocycloalkylene group, the type of heteroatom is selected from one or more of N, O, S and C (= O), the number of heteroatoms is 1, 2 or 3, the 5-10 membered heteroaryl group and the substituted 5-10 membered heteroaryl group are replaced by one or more R A4 In the 5-10 membered heteroarylene group of the substituted 5-10 membered heteroarylene group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0169] R A1 and R A2 Each independently is C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 11 Cycloalkylene, saturated 3-11 membered heterocycloalkylene, substituted by one or more R A1-1 Substituted C6-C 10 Arylene or one or more R A1-2 substituted 5-10 membered heteroarylene, wherein the 5-10 membered heteroarylene is replaced by one or more R A1-2 In the 5-10 membered heteroarylene group of the substituted 5-10 membered heteroarylene group, the type of heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; in the 3-11 membered heterocycloalkylene group, the type of heteroatom is selected from one or more of N, O, S and C(═O), and the number of heteroatoms is 1, 2 or 3;

[0170] R A1-1 and R A1-2 are independently CN, -P(=O)(R A3-1 )2, C1-C6 alkyl or C1-C6 alkoxy;

[0171] Ring C1 is a partially unsaturated 3-8 membered heterocyclic ring or is replaced by one or more R C1 A partially unsaturated 3-8 membered heterocyclic ring substituted with one or more R C1 In the 3- to 8-membered heterocyclic ring of the substituted partially unsaturated 3- to 8-membered heterocyclic ring, the type of heteroatoms is independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3;

[0172] R C1 are independently C1-C6 alkyl;

[0173] R A3 and RA4 are independently CN, -P(=O)(R A3-1 )2, C1-C6 alkyl or C1-C6 alkoxy;

[0174] R A3-1 are independently C1-C6 alkyl;

[0175] L is -(CH2)n-, n is any integer from 1 to 18, and one or more -(CH2)- in -(CH2)n- are replaced by one or more of the following groups: -NR L1 -, -O-, -S-, -C(=O)-, Saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, C6-C 10 Arylene, 5-10 membered heteroarylene, By one or more R L2 Substituted saturated C3-C 12 Cycloalkylene, one or more R L3 Substituted saturated 3-12 membered heterocycloalkylene, one or more R L4 Substituted C6-C 10 Arylene or one or more R L5 substituted 5-10 membered heteroaryl, the saturated 3-12 membered heterocycloalkyl and one or more R L3 In the 3-12 membered heterocycloalkyl in the substituted saturated 3-12 membered heterocycloalkylene, the types of heteroatoms are independently selected from one or more of N, O, S and C(=O), and the number of heteroatoms is independently 1, 2 or 3, and the 5-10 membered heteroaryl and the one or more R L5 In the substituted 5-10 membered heteroarylene group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0176] R L1 is H or C1-C6 alkyl;

[0177] Ring C2 is a benzene ring or a 5-6 membered heteroaromatic ring, wherein the type of heteroatom in the 5-6 membered heteroaromatic ring is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0178] Ring C3 is a partially unsaturated C3-C7 carbocycle or a partially unsaturated 3-7 membered heterocycle, wherein the type of heteroatom in the partially unsaturated 3-7 membered heterocycle is selected from one or more of N, O, S and C(=O), and the number of heteroatoms is 1, 2 or 3;

[0179] Ring C4 is a saturated C3-C7 carbocycle or a saturated 3-7 membered heterocycle, wherein the type of heteroatom in the saturated 3-7 membered heterocycle is selected from one or more of N, O, S and C(=O), and the number of heteroatoms is 1, 2 or 3;

[0180] R L2 and R L3 Each is independently CN, OH, halogen, C1-C6 alkyl, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl;

[0181] R L4 and R L5 Each is independently a C1-C6 alkyl group;

[0182] B is C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, B1 Substituted C6-C 10 Arylene or one or more R B2 substituted 5-10 membered heteroarylene, wherein the 5-10 membered heteroarylene is replaced by one or more R B2 In the 5-10 membered heteroarylene group of the substituted 5-10 membered heteroarylene group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; in the saturated 3-12 membered heterocycloalkylene group, the type of heteroatoms is independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3;

[0183] Y1, Y2, Y3 and Y4 are each independently CH2 or C(=O);

[0184] Y5 stands for NY 5-1 , O or S, Y 5-1 is H or C1-C6 alkyl;

[0185] Ring C5, Ring C6, Ring C7, Ring C8 and Ring C9 are each independently a benzene ring or a 5-6 membered heteroaromatic ring, wherein the type of heteroatom in the 5-6 membered heteroaromatic ring is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0186] Ring C 10 is a partially unsaturated C3-C7 carbocycle or a partially unsaturated 3-7 membered heterocycle, wherein the type of heteroatom in the partially unsaturated 3-7 membered heterocycle is selected from one or more of N, O, S and C(=O), and the number of heteroatoms is 1, 2 or 3;

[0187] R B1 and R B2 Each independently represents halogen, C1-C6 alkyl, C1-C6 alkoxy, one or more R B1-1 Substituted C1-C6 alkyl or one or more R B1-2 Substituted C1-C6 alkoxy;

[0188] R B1-1 and R B1-2 are each independently halogen;

[0189] Furthermore, the compound represented by formula (I) satisfies one or both of the following conditions:

[0190] i: B is L is -(CH2)n-, n is any integer from 1 to 18, and at least one -(CH2)- in -(CH2)n- is replaced by the following groups: saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, C6-C 10 Arylene, 5-10 membered heteroarylene, By one or more R L2 Substituted saturated C3-C 12 Cycloalkylene, one or more R L3 Substituted saturated 3-12 membered heterocycloalkylene, one or more R L4 Substituted C6-C 10 Arylene or one or more R L5 substituted 5-10 membered heteroarylene;

[0191] ii: B is C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, substituted by one or more R B1 Substituted C6-C 10 Arylene or one or more R B2 Substituted 5-10 membered heteroarylene, ring C 5-1 5-6 membered heteroaromatic ring in the same ring C5, ring C 5-2 Same ring as C5.

[0192] In one embodiment of the present invention, R 3 is H or methyl.

[0193] In one embodiment of the present invention, R 2 -H, -CN, -F, -Cl, -CH3, cyclopropyl, -OCH3,

[0194] In one embodiment of the present invention, R 2 -H, -F, -Cl, -CH3, cyclopropyl, -OCH3,

[0195] In a certain embodiment of the present invention, A is The a side is connected to L.

[0196] In one embodiment of the present invention, in the condition ii, L is:

[0197] Among them, side b is connected to B;

[0198] Xa1 is O or -NR L1 -, R L1 is H or C1-C6 alkyl;

[0199] Xa2 is R M is a C1-C6 alkyl group, and ring C4 is a saturated C3-C6 carbocycle or a saturated 3-6-membered heterocycle, wherein the type of heteroatom in the saturated 3-6-membered heterocycle is selected from one or more of N, O, S and C(═O), and the number of heteroatoms is 1, 2 or 3;

[0200] Ring A1 and Ring A2 are saturated 3-12 membered nitrogen-containing heterocyclic rings or are replaced by one or more R L3 Substituted saturated 3-12 membered nitrogen-containing heterocyclic ring, R L3 independently CN, OH, halogen, C1-C6 alkyl, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl, the saturated 3-12 membered nitrogen-containing heterocycle or the 3-12 membered nitrogen-containing heterocycle in the substituted saturated 3-12 membered nitrogen-containing heterocycle is independently a 3-6 membered monocyclic nitrogen-containing heterocycle, a 7-12 membered spirocycle or a 7-12 membered bridged nitrogen-containing heterocycle, wherein the heteroatom, in addition to N, may be selected from one or more of O, S and C(=O), and the number of heteroatoms is 1, 2 or 3;

[0201] Ring A3 is independently a saturated C3-C 12 Carbocyclic or one or more R L2 Substituted saturated C3-C 12 Carbon ring, R L2are independently CN, OH, halogen, C1-C6 alkyl, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl, the saturated C3-C 12 Carbocyclic or substituted saturated C3-C 12 C3-C in carbon ring 12 The carbocycle is independently a C3-C6 monocyclic carbocycle or a C5-C 12 spirocyclic carbocycle;

[0202] Ring A4 is independently a 5-10 membered heteroaromatic ring or is substituted by one or more R L5 Substituted 5-10 membered heteroaromatic ring, R L5 are independently C1-C6 alkyl; the 5-10 membered heteroaromatic ring and one or more R L5 In the 5-10 membered heteroaromatic ring of the substituted 5-10 membered heteroaromatic ring, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0203] Ring A5 is independently Ring C2 is a benzene ring or a 5-6 membered heteroaromatic ring, wherein the type of heteroatom in the 5-6 membered heteroaromatic ring is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Ring C3 is a partially unsaturated 3-7 membered nitrogen-containing heterocyclic ring, wherein the heteroatom in the partially unsaturated 3-7 membered nitrogen-containing heterocyclic ring, in addition to N, may also be selected from one or more of O, S and C(=O), and the number of heteroatoms is 1, 2 or 3;

[0204] n1a is independently any integer from 0 to 8;

[0205] n2a is independently any integer from 0 to 3;

[0206] n3a is independently any integer from 0 to 5;

[0207] Preferably:

[0208] Among them, side b is connected to B.

[0209] In a certain embodiment of the present invention, in the condition ii, L is Wherein, n1 is any integer from 1 to 8, n2 is any integer from 1 to 3, n3 is any integer from 1 to 5, and side b is connected to B;

[0210] Preferably

[0211] The b side is connected to B.

[0212] In one embodiment of the present invention, in the condition i, L is G1 or G2:

[0213] G1:

[0214] Among them, side b is connected to B;

[0215] Xa1 is O or -NR L1 -, R L1 is H or C1-C6 alkyl;

[0216] Ring A1 and Ring A2 are saturated 3-12 membered nitrogen-containing heterocyclic rings or are replaced by one or more R L3 Substituted saturated 3-12 membered nitrogen-containing heterocyclic ring, R L3 independently CN, OH, halogen, C1-C6 alkyl, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl, the saturated 3-12 membered nitrogen-containing heterocycle or the 3-12 membered nitrogen-containing heterocycle in the substituted saturated 3-12 membered nitrogen-containing heterocycle is independently a 4-membered monocyclic nitrogen-containing heterocycle, a 7-12 membered spirocyclic nitrogen-containing heterocycle or a 7-12 membered bridged nitrogen-containing heterocycle, wherein the heteroatom, in addition to N, may be selected from one or more of O, S and C(=O), and the number of heteroatoms is 1, 2 or 3;

[0217] Ring A3 is independently a saturated C3-C 12 Carbocyclic or one or more R L2 Substituted saturated C3-C 12 Carbon ring, R L2 are independently CN, OH, halogen, C1-C6 alkyl, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl, the saturated C3-C 12 Carbocyclic or substituted saturated C3-C 12 C3-C in carbon ring 12 The carbocycles are independently C3-C6 monocyclic carbocycles, C7-C 12 Spirocyclic carbocyclic ring or C7-C 12 bridged carbon ring;

[0218] Ring A5 is independently Ring C2 is a benzene ring or a 5-6 membered heteroaromatic ring, wherein the type of heteroatom in the 5-6 membered heteroaromatic ring is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Ring C3 is a partially unsaturated 3-7 membered nitrogen-containing heterocyclic ring, wherein the heteroatom in the partially unsaturated 3-7 membered nitrogen-containing heterocyclic ring, in addition to N, may also be selected from one or more of O, S and C(=O), and the number of heteroatoms is 1, 2 or 3;

[0219] n2a is independently any integer from 0 to 3;

[0220] n3a is independently any integer from 0 to 5;

[0221] G2:

[0222] Among them, side b is connected to B;

[0223] Xa1 is O or -NR L1 -, R L1 is H or C1-C6 alkyl;

[0224] Xa2 is R M is a C1-C6 alkyl group, and ring C4 is a saturated C3-C6 carbocycle or a saturated 3-6-membered heterocycle, wherein the type of heteroatom in the saturated 3-6-membered heterocycle is selected from one or more of N, O, S and C(═O), and the number of heteroatoms is 1, 2 or 3;

[0225] Ring A1 and Ring A2 are saturated 3-12 membered nitrogen-containing heterocyclic rings or are replaced by one or more R L3 Substituted saturated 3-12 membered nitrogen-containing heterocyclic ring, R L3 independently CN, OH, halogen, C1-C6 alkyl, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl, the saturated 3-12 membered nitrogen-containing heterocycle or the 3-12 membered nitrogen-containing heterocycle in the substituted saturated 3-12 membered nitrogen-containing heterocycle is independently a 3-6 membered monocyclic nitrogen-containing heterocycle or a 5-12 membered spirocyclic nitrogen-containing heterocycle, wherein the heteroatom, in addition to N, may be selected from one or more of O, S and C(=O), and the number of heteroatoms is 1, 2 or 3;

[0226] Ring A4 is independently a 5-10 membered heteroaromatic ring or is substituted by one or more R L5 Substituted 5-10 membered heteroaromatic ring, R L5 are independently C1-C6 alkyl; the 5-10 membered heteroaromatic ring and one or more R L5In the 5-10 membered heteroaromatic ring of the substituted 5-10 membered heteroaromatic ring, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0227] n2a is independently any integer from 0 to 3.

[0228] In one embodiment of the present invention, in the condition i, L is G1 or G2:

[0229] G1: Wherein, n1 is any integer from 1 to 8, n2 is any integer from 1 to 3, n3 is any integer from 1 to 5, and side b is connected to B;

[0230] G2:

[0231] The b side is connected to B.

[0232] In a certain embodiment of the present invention, L is wherein n1 is any integer from 1 to 8, n2 is any integer from 1 to 3, n3 is any integer from 1 to 5, and the side b is connected to B; preferably, in scheme i, L is any of the aforementioned groups except Any other group other than .

[0233] In one embodiment of the present invention, L is: Wherein the b side is connected to B; preferably, in scheme i, L is the aforementioned group except Any other group other than .

[0234] In one embodiment of the present invention, L is: wherein n1 is any integer from 1 to 8, n2 is any integer from 1 to 3, n3 is any integer from 1 to 5, and the side b is connected to B; preferably, in scheme i, L is any of the aforementioned groups except Any other group other than .

[0235] In one embodiment of the present invention, L is: Wherein the b side is connected to B; preferably, in scheme i, L is the aforementioned group except Any other group other than .

[0236] In one embodiment of the present invention, B is: Wherein the c side is connected to L; in scheme ii, B is the aforementioned group except Any group other than .

[0237] In one embodiment of the present invention, B is: Wherein the c side is connected to L; in scheme ii, B is the aforementioned group except Any group other than .

[0238] In one embodiment of the present invention, in the condition ii, -ALB- is G11 or G12:

[0239] G11:

[0240] G12:

[0241] The d side and connected.

[0242] In a certain embodiment of the present invention, in embodiment i, -ALB- is:

[0243] The d side and connected.

[0244] In one embodiment of the present invention, -ALB- is:

[0245] The d side and Preferably, in Scheme ii, -ALB- is the aforementioned group except Any other group except

[0246] In one embodiment of the present invention, -ALB- is:

[0247] The d side and Preferably, in Scheme ii, -ALB- is the aforementioned group except Any other group except

[0248] In one embodiment of the present invention, for:

[0249] In one embodiment of the present invention, for

[0250] In one embodiment of the present invention, the compound represented by formula (I) is any one of the following compounds:

[0251] The present invention also provides a compound as shown below:

[0252] The compound that elutes first under the following conditions: chromatographic column: CHIRALPAK IE-3, mobile phase: 0.1% diethylamine in acetonitrile: 0.1% diethylamine in isopropanol (40:60), flow rate: 1.0 ml / min; preferably, under the above conditions, the retention time of the compound that elutes first is 9.78 min;

[0253] The compound eluting later under the following conditions: chromatographic column: CHIRALPAK IE-3, mobile phase: 0.1% diethylamine in acetonitrile solution: 0.1% diethylamine in isopropanol solution (40:60), flow rate: 1.0 ml / min; preferably, under the said conditions, the retention time of the said compound eluting later is 11.36 min.

[0254] The above retention time test conditions do not limit the compounds. As long as the retention time obtained by the above test conditions is the same as that recorded above or is within the error range, and the compound is a stereoisomer of the compound defined by the retention time, it falls within the scope of protection of the present invention.

[0255] The present invention also provides a pharmaceutical composition comprising the compound of formula (I) as described in any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0256] The present invention also provides a use of a compound as shown in formula (I) according to any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of an AURKA inhibitor or degrader.

[0257] The present invention also provides a use of a compound as shown in formula (I) according to any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a medicament for treating and / or preventing a disease associated with AURKA. Preferably, the disease associated with AURKA is neuroblastoma, retinoblastoma, colorectal cancer, breast cancer, lung cancer, kidney cancer, or leukemia.

[0258] The present invention also provides a use of a compound as shown in formula (I) according to any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a medicament for treating and / or preventing a disease mediated by an AURKA inhibitor or degrader. Preferably, the disease mediated by the AURKA inhibitor or degrader is neuroblastoma, retinoblastoma, colorectal cancer, breast cancer, lung cancer, kidney cancer, or leukemia.

[0259] The present invention also provides a use of a compound as shown in formula (I) according to any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a drug for treating and / or preventing neuroblastoma, retinoblastoma, colorectal cancer, breast cancer, lung cancer, kidney cancer, or leukemia.

[0260] The present invention also provides a substance X for use as a drug, wherein the substance X is a compound as represented by formula (I) according to any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition.

[0261] The present invention also provides a substance X for use in treatment, wherein the substance X is a compound as represented by formula (I) as described in any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition.

[0262] The present invention also provides a substance X for preventing and / or treating a disease associated with AURKA, wherein the substance X is a compound as represented by formula (I) according to any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition. Preferably, the disease associated with AURKA is neuroblastoma, retinoblastoma, colorectal cancer, breast cancer, lung cancer, kidney cancer, or leukemia.

[0263] The present invention also provides a substance X for preventing and / or treating a disease mediated by an AURKA inhibitor or degrader, wherein the substance X is a compound as shown in formula (I) according to any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition. Preferably, the disease mediated by the AURKA inhibitor or degrader is neuroblastoma, retinoblastoma, colorectal cancer, breast cancer, lung cancer, kidney cancer, or leukemia.

[0264] The present invention also provides a substance X for preventing and / or treating neuroblastoma, retinoblastoma, colorectal cancer, breast cancer, lung cancer, kidney cancer or blood cancer, wherein the substance X is a compound as represented by formula (I) according to any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof or the above pharmaceutical composition.

[0265] The present invention also provides a method for treating an AURKA-related disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a substance X, wherein the substance X is a compound of formula (I) as described in any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition. Preferably, the AURKA-related disease is neuroblastoma, retinoblastoma, colorectal cancer, breast cancer, lung cancer, kidney cancer, or leukemia.

[0266] The present invention also provides a method for treating a disease mediated by an AURKA inhibitor or degrader in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a substance X, wherein the substance X is a compound as shown in formula (I) according to any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition. Preferably, the disease mediated by the AURKA inhibitor or degrader is neuroblastoma, retinoblastoma, colorectal cancer, breast cancer, lung cancer, kidney cancer, or leukemia.

[0267] The present invention also provides a method for treating neuroblastoma, retinoblastoma, colorectal cancer, breast cancer, lung cancer, kidney cancer or blood cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a substance X, wherein the substance X is a compound as represented by formula (I) according to any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof or the above pharmaceutical composition.

[0268] The present invention also provides a method for treating an AURKA-related disease in a non-human subject, comprising administering to the subject a therapeutically effective amount of a substance X, wherein the substance X is a compound of formula (I) as described in any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition. Preferably, the AURKA-related disease is neuroblastoma, retinoblastoma, colorectal cancer, breast cancer, lung cancer, kidney cancer, or leukemia.

[0269] The present invention also provides a method for treating a disease mediated by an AURKA inhibitor or degrader in a non-human subject, comprising administering to the subject a therapeutically effective amount of a substance X, wherein the substance X is a compound as shown in formula (I) according to any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition. Preferably, the disease mediated by the AURKA inhibitor or degrader is neuroblastoma, retinoblastoma, colorectal cancer, breast cancer, lung cancer, kidney cancer, or leukemia.

[0270] The present invention also provides a method for treating neuroblastoma, retinoblastoma, colorectal cancer, breast cancer, lung cancer, kidney cancer or blood cancer in a non-human subject, comprising administering to the subject a therapeutically effective amount of a substance X, wherein the substance X is a compound as represented by formula (I) according to any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof or the above pharmaceutical composition.

[0271] In the above applications, the AURKA inhibitors or degraders can be used in mammalian organisms; they can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide detection of AURKA inhibition or degradation effects.

[0272] It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. It means that the corresponding group is connected to other fragments and groups in the compound through this site.

[0273] As used herein, a substituent may be preceded by a single dash "-" to indicate that the named substituent is attached to the parent moiety by a single bond. When a linking group is listed herein without specifying the direction of attachment, the direction of attachment is assumed to be the same as when reading from left to right.

[0274] The term "pharmaceutically acceptable salt" refers to salts prepared from compounds of the present invention with relatively nontoxic, pharmaceutically acceptable acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.

[0275] The term "solvate" refers to a compound of the present invention combined with a stoichiometric or non-stoichiometric solvent. The solvent molecules in the solvate may be present in an ordered or non-ordered arrangement. Such solvents include, but are not limited to, water, methanol, and ethanol.

[0276] The term "pharmaceutically acceptable salt" and "solvate" as used herein refer to compounds of the present invention prepared with (1) a relatively non-toxic, pharmaceutically acceptable acid or base and (2) a stoichiometric or non-stoichiometric amount of a solvent.

[0277] When any variable (such as R 2-3 ) appears multiple times in the definition of a compound, the definition of each position of the variable is independent of the definition of the other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is replaced by 1, 2 or 3 R 2-3 group substituted, that is, the group may be replaced by up to 3 R 2-3 Replace, the position R 2-3 Definition and other positions R 2-3 In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0278] The term "AB member," where A and B are integers, describes a range where the number of ring-forming atoms is from A to B.

[0279] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group having a specified number of carbon atoms. 1-6 Alkyl groups, such as C 1-5 Alkyl, C 1-4 Alkyl, C1-3 Alkyl, C 1-2 Alkyl, etc. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0280] The term "alkoxy" refers to the group -OR X , where R X is an alkyl group as defined above.

[0281] The term "cycloalkyl" refers to a non-aromatic, saturated, partially unsaturated, monocyclic, fused, bridged or spirocyclic group whose ring atoms consist only of carbon atoms.

[0282] The term "cycloalkylene" refers to a non-aromatic, saturated, partially unsaturated, monocyclic, fused, bridged or spirocyclic alkane whose ring atoms consist solely of carbon atoms, resulting from the elimination of two hydrogen atoms, wherein the two hydrogen atoms eliminated may be on the same atom or on different atoms.

[0283] The term "carbocycle" satisfies any of the following conditions, and the rest of the definition is the same as the term "cycloalkyl": 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

[0284] The term "heterocycloalkyl" refers to a non-aromatic, saturated, partially unsaturated, monocyclic, fused, bridged or spirocyclic group containing at least one heteroatom independently selected from N, O, S and C(=O) as the ring atoms.

[0285] The term "heterocycloalkylene" refers to a non-aromatic, saturated, partially unsaturated, monocyclic, fused, bridged or spirocyclic cyclic alkane containing at least one heteroatom independently selected from N, O, S and C(=O) in the ring, formed by eliminating two hydrogen atoms, wherein the two eliminated hydrogen atoms may be on the same atom or on different atoms.

[0286] The term "heterocycle" satisfies any of the following conditions, and the rest of the definition is the same as the term "heterocycloalkyl": 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

[0287] The term "halogen" refers to F, Cl, Br, I.

[0288] In the present invention, the term "optionally" means that the event or situation described subsequently may but need not occur, and the description includes instances where the event or situation occurs as well as instances where the event or situation does not occur. For example, the term "optionally substituted" means that a compound may or may not be substituted, and unless otherwise specified, the type and number of substituents may be any on the basis of chemical feasibility.

[0289] The term "aryl" refers to a cyclic aromatic group having the specified number of carbon atoms, which may be a single ring or a fused ring. In the case of a fused ring, each ring has aromatic properties.

[0290] The term "arylene" refers to a divalent aromatic group, and "aryl" is as defined above.

[0291] The term "heteroaryl" refers to a cyclic aromatic group having a specified number of ring atoms, a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (1, 2, or 3 of N, O, and S), which is a single ring or a fused ring. When it is a fused ring, each ring has aromatic properties.

[0292] The term "heteroarylene" refers to a divalent heteroaryl group, and "heteroaryl" is as defined above.

[0293] The term "heteroaromatic ring" satisfies any of the following conditions, and the rest of the definition is the same as the term "heteroaryl": 1. It is connected to the rest of the molecule through two or more single bonds; 2. It shares two atoms and one bond with the rest of the molecule.

[0294] The term "pharmaceutically acceptable excipients" refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions. These excipients are all substances contained in pharmaceutical preparations, other than the active ingredient. For more information, see Part IV of the Pharmacopoeia of the People's Republic of China (2020 Edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009, Sixth Edition).

[0295] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0296] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0297] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a subject, is sufficient to effectively treat a disease or condition described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the subject to be treated, but can be adjusted as needed by those skilled in the art.

[0298] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0299] The reagents and raw materials used in the present invention are commercially available.

[0300] The positive effect of the present invention is that the compounds of the present invention have good inhibitory activity against AURKA (IC of the example compounds in HCC1806 cells or H82 cells) 50 Preferably, the concentration is below 1000 nM) and / or degradation (the Example compounds can degrade AURKA by more than 70% at a concentration of 1 μM or 100 nM in Jurkat cells). DETAILED DESCRIPTION

[0301] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0302] Example 1 Synthesis of Compound A1:

[0303] Step 1:

[0304] To a solution of compound A1-1 (20 mg, 0.055 mmol) in N,N-dimethylformamide (2 mL) were added SM1 (15 mg, 0.03 mmol, synthesis method reference ACS Medicinal Chemistry Letters (2015), 6(6), 630-634), HATU (14 mg, 0.04 mmol), and DIPEA (12.2 mg, 0.09 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was separated and purified by reverse phase (acetonitrile / 0.1% formic acid aqueous solution) to obtain a light yellow solid A1 (10.6 mg, yield 43%). LCMS (ESI) m / z = 819.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.07(s,1H),10.14(s,1H),8.72(s,1H),8.34–8.28(m,2H),7.90–7. 86(m,3H),7.81(d,J=8.8Hz,2H),7.59–7.51(m,2H),7.33(d,J=4.0Hz,1H),7.21–7.10(m,3H) ,7.03(d,J=4.0Hz,1H),6.63(t,J=6.0Hz,1H),5.07–5.01(m,1H),3.65(t,J=5.6Hz,2H),3.59 (t,J=6.0Hz,2H),3.52–3.40(m,4H),2.92–2.80(m,1H),2.69–2.54(m,2H),2.04–1.96(m,1H).

[0305] Example 2 Synthesis of Compound A2:

[0306] Step 1:

[0307] To a solution of 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (100 mg, 0.36 mmol) in N-methylpyrrolidone (5 mL) at room temperature were added tert-butyl (5-aminopentyl)(methyl)carbamate (86 mg, 0.4 mmol) and DIPEA (93 mg, 0.72 mmol). The reaction mixture was heated to 90°C and stirred under argon for 4 h. Water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (methanol / dichloromethane = 1:30) to afford A2-1 (120 mg, 70% yield) as a yellow solid. LCMS (ESI) m / z = 473.1 [M+H] + .

[0308] Step 2:

[0309] To a dichloromethane solution (2 mL) of compound A2-1 (30 mg, 0.06 mmol) was added trifluoroacetic acid (0.5 mL) at room temperature. The reaction was stirred at 30°C for 1 h. The reaction solution was concentrated under reduced pressure to obtain a light yellow solid A2-2 (23 mg, 99% yield). LCMS (ESI) m / z = 373.1 [M+H] + .

[0310] Step 3:

[0311] To a solution of compound A2-2 (23 mg, 0.06 mmol) in N,N-dimethylformamide (2 mL) were added SM2 (15 mg, 0.03 mmol, synthesis method reference WO2008063525A1), HATU (15.5 mg, 0.04 mmol), and DIPEA (12.2 mg, 0.09 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous formic acid) to afford A2 (11.4 mg, 43.5% yield) as a pale yellow solid. LCMS (ESI) m / z = 873.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.10(s,1H),10.02(d,J=12.0Hz,1H),8.70(d,J=4.0Hz,1H),8.31(t,J=8 .4Hz,1H),7.88(s,1H),7.84–7.79(m,1H),7.67–7.34(m,3H),7.25–6.96(m,3H),6.64–6.44(m,1H ),5.14–5.01(m,1H),3.81(d,J=4.0Hz,3H),3.52–3.39(m,1H),3.26–3.04(m,2H),2.98–2.76(m,4 H),2.65–2.54(m,2H),2.10–1.96(m,1H),1.71–1.60(m,2H),1.55–1.39(m,3H),1.21–1.13(m,1H).

[0312] Example 3 Synthesis of Compound A3:

[0313] Compound A3 (6.0 mg, yield 27%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 859.1 [M+H] + .

[0314] Example 4 Synthesis of Compound A4:

[0315] To a solution of lenalidomide (100.0 mg, 0.43 mmol) in N-methylpyrrolidone and DIPEA (3 mL / 0.2 mL) was added N-Boc-2-(2-bromoethoxy)ethanamine (113.8 mg, 0.40 mmol) at room temperature. The reaction mixture was heated to 110°C and stirred for 5 h. The reaction mixture was washed with water and extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to afford A4-1 (100.0 mg, 90% yield) as a white solid. LCMS (ESI) m / z = 447.21 [M+H] + .

[0316] Step 2:

[0317] To a solution of compound A4-1 (100.0 mg, 0.20 mmol) in dichloromethane (3 mL) was added HCl (4.0 M in 1,4-dioxane), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was directly dried to afford a yellow solid A4-2 (60.0 mg, 77% yield). LCMS (ESI) m / z = 347.13 [M+H] + .

[0318] Step 3:

[0319] To a solution of compound A4-2 (20.0 mg, 0.052 mmol) in N,N-dimethylformamide (2 mL) were added SM2 (15.0 mg, 0.026 mmol), HATU (15.0 mg, 0.039 mmol), and DIPEA (10.1 mg, 0.078 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous formic acid = 2 / 1) to afford A4 (5.0 mg, 20% yield) as a yellow solid. LCMS (ESI) m / z = 847.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.22(s,1H),10.40(s,1H),8.73(s,1H),8.33(d,J=8.4Hz,1H),8.15(d,J=5.6Hz,1H),7.96(s,1H),7.8 8(d,J=8.4Hz,1H),7.85(dd,J1=8.4Hz,J1=2.0Hz,1H),7.45-7.41(m,3H),7.31(d,J=7.6Hz,1H),6.96(d,J=7.2Hz,1H),6.88(d,J =8.0Hz,1H),5.64(t,J=5.6Hz,1H),5.12(dd,J1=13.2Hz,J2=5.2Hz,1H),4.43-4.30(m,2H),3.91(s,3H),3.69-3.66(m,2H),3.62 -3.60(m,2H),3.53-3.48(m,2H),3.40-3.37(m,2H),2.97-2.89(m,1H),2.69-2.60(m,2H),2.35-2.27(m,2H),2.06-2.03(m,1H).

[0320] Example 5 Synthesis of Compound A5:

[0321] Step 1:

[0322] To a solution of 2-(2,6-dioxo-piperidin-3-yl)-4-hydroxy-isoindole-1,3-dione (2 g, 7.3 mmol) in N,N-dimethylformamide (10 mL) at room temperature were added 2-bromoethanol (912 mg, 7.3 mmol) and DIPEA (2.8 g, 21.9 mmol). The reaction mixture was heated to 80°C and stirred under argon for 16 h. Water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1:30) to afford A5-1 as a yellow oil (620 mg, 27% yield). LCMS (ESI) m / z = 319.1 [M+H] + .

[0323] Step 2:

[0324] To a solution of compound A5-1 (620 mg, 1.95 mmol) in tetrahydrofuran (10 mL) was added methylsulfonyl chloride (290 mg, 2.54 mmol) and DIPEA (756 mg, 5.85 mmol) under ice. The reaction mixture was stirred at 25°C for 3 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:30) to obtain a yellow oil, A5-2 (465 mg, 60% yield). LCMS (ESI) m / z = 397.1 [M+H] + .

[0325] Step 3:

[0326] To a solution of compound A5-2 (310 mg, 0.78 mmol) in N,N-dimethylformamide (5 mL) was added 3-N-tert-butyloxycarbonylaminocyclobutylamine (135 mg, 0.78 mmol) and DIPEA (302 mg, 2.34 mmol) at room temperature. The reaction mixture was stirred at 80°C for 16 h. Water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:20) to afford A5-3 (96 mg, 26% yield) as a yellow oil. LCMS (ESI) m / z = 473.2 [M+H] + .

[0327] Step 4:

[0328] To a dichloromethane solution (2 mL) of compound A5-3 (35 mg, 0.07 mmol) was added trifluoroacetic acid (0.5 mL) at room temperature. The reaction was stirred at 30°C for 1 h. The reaction solution was concentrated under reduced pressure to obtain a light yellow solid A5-4 (28 mg, 99% yield). LCMS (ESI) m / z = 373.1 [M+H] + .

[0329] Step 5:

[0330] To a solution of compound A5-4 (28 mg, 0.07 mmol) in N,N-dimethylformamide (2 mL) were added SM2 (15 mg, 0.03 mmol), HATU (14 mg, 0.04 mmol), and DIPEA (12.2 mg, 0.09 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous formic acid) to afford A5 (11.3 mg, 43% yield) as a pale yellow solid. LCMS (ESI) m / z = 872.9 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.18(s,1H),8.72(s,1H),8.33(d,J=8.0Hz,1H),8.27(d,J=8 .0Hz,1H),7.94(s,1H),7.85–7.78(m,2H),7.74(d,J=8.0Hz,1H),7.51(d,J=8.0Hz,1H),7.47–7.39( m,3H),7.22(bs,1H),5.12–5.06(m,1H),4.49(q,J=6.8Hz,1H),4.21(t,J=8.0Hz,2H),3.93(s,3H),3 .70(t,J=8.0Hz,2H),3.14(t,J=7.2Hz,2H),2.93–2.78(m,3H),2.68–2.53(m,2H),2.07–1.98(m,1H).

[0331] Example 6 Synthesis of Compound A6:

[0332] Step 1:

[0333] To a solution of tert-butyl cis-3-hydroxymethylcyclobutylcarbamate (2.22 g, 9.94 mmol) in dichloromethane (20 mL) was added pyridinium chlorochromate (2.60 g, 11.60 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was washed with water and extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to afford A6-1 (1.20 g, 54% yield) as a white solid. LCMS (ESI) m / z = 200.1 [M+H] + .

[0334] Step 2:

[0335] To a methanol solution (10 mL) of compound A6-1 (842 mg, 3.80 mmol), dimethyl (1-diazo-2-oxopropyl)phosphonate (1.22 g, 5.71 mmol) and potassium carbonate (1.06 g, 7.61 mmol) were added, and the mixture was stirred at room temperature for 3 h. The reaction mixture was washed with water and extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain A6-2 (500.0 mg, 57% yield) as a white solid. LCMS (ESI) m / z = 196.2 [M+H] + .

[0336] Step 3:

[0337] Compound A6-2 (55.5 mg, 0.26 mmol), TEA (55.0 mg, 0.52 mmol), CuI (10.0 mg, 0.052 mmol), and Pd(PPh3)2Cl2 (19.6 mg, 0.026 mmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature. The reaction mixture was stirred at 80°C for 4 h. The reaction mixture was washed with water and extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain A6-3 (50.0 mg, 57% yield) as a white solid. LCMS (ESI) m / z = 438.1 [M+H] + .

[0338] Step 4:

[0339] To a solution of compound A6-3 (50.0 mg, 0.10 mmol) in dichloromethane (2 mL) was added HCl (4.0 M in 1,4-dioxane, 2 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was directly dried to afford A6-4 as a white solid (30.5 mg, 86% yield). LCMS (ESI) m / z = 338.2 [M+H] + .

[0340] Step 5:

[0341] To a solution of compound A6-4 (29.0 mg, 0.077 mmol) in N,N-dimethylformamide (1 mL) were added SM2 (22.0 mg, 0.039 mmol), HATU (22.6 mg, 0.11 mmol), and DIPEA (15.3 mg, 0.11 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous formic acid = 2.3 / 1) to afford A6 (8.0 mg, 23% yield) as a yellow solid. LCMS (ESI) m / z = 838.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ11.04(s,1H),10.42(s,1H),8.77(s,1H),8.33–8.24(m,2H), 7.96(s,1H),7.74(dd,J1=8.4Hz,J2=2.4Hz,1H),7.80–7.60(m,3H),7.56(d,J=7.6Hz ,1H),7.49–7.44(m,2H),7.24(s,1H),5.20–5.15(m,1H),4.75(d,J=7.6Hz,1H),4.56 –4.36(m,2H),3.96(s,3H),3.10–2.95(m,2H),2.70–2.63(m,4H),2.35–2.29(m,3H).

[0342] Example 7 Synthesis of Compound A7:

[0343] Compound A7 (6.0 mg, yield 13%) was synthesized according to the synthesis method of Compound A6 described in Example 6. LCMS (ESI) m / z = 838.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.04(s,1H),10.42(s,1H),8.77(s,1H),8.32(d,J=8.0Hz,1H),8. 27(d,J=8.0Hz,1H),7.96(s,1H),7.74(dd,J1=8.4Hz,J2=2.4Hz,1H),7.80–7.60(m,3H),7.5 6(d,J=7.6Hz,1H),7.49–7.44(m,2H),7.24(s,1H),5.20–5.15(m,2H),4.75(d,J=7.6Hz,1H ),4.56–4.36(m,2H),3.96(s,3H),3.04–2.92(m,2H),2.72–2.60(m,4H),2.35–2.29(m,3H).

[0344] Example 8 Synthesis of Compound A8:

[0345] Step 1:

[0346] To a solution of 1-(N-Boc-aminoethyl)piperazine (10 g, 43.6 mmol) in N,N-dimethylformamide (50 mL) at room temperature were added 4-nitrofluorobenzene (5 g, 35.4 mmol) and potassium carbonate (9.8 g, 70.8 mmol). The reaction mixture was heated to 80°C and stirred under argon for 16 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:2) to afford A8-1 (10.2 g, 82% yield) as a yellow solid. LCMS (ESI) m / z = 350.8 [M+H] + .

[0347] Step 2:

[0348] To a methanol solution (30 mL) of compound A8-1 (3 g, 8.56 mmol) was added 10% palladium on carbon (910 mg, 1.71 mmol) at room temperature. The atmosphere was replaced with hydrogen three times, and the reaction was stirred at 30°C for 16 h. The reaction solution was filtered and concentrated under reduced pressure to afford a brown solid A8-2 (2.7 g, 98% yield). LCMS (ESI) m / z = 321.1 [M+H] + .

[0349] Step 3:

[0350] To a room temperature solution of compound A8-2 (2.7 g, 8.43 mmol) in toluene (30 mL) was added acrylic acid (910 mg, 12.6 mmol). The reaction mixture was heated to 110°C and stirred for 18 hours under argon. The reaction mixture was cooled to room temperature, and urea (2.53 g, 42.2 mmol) and acetic acid (30 mL) were added. The reaction mixture was heated to 110°C and stirred for 18 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The mixture was extracted with ethyl acetate and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (methanol / dichloromethane = 1:20) to afford A8-3 (617 mg, 18% yield) as a white solid. LCMS (ESI) m / z = 418.1 [M+H] + .

[0351] Step 4:

[0352] To a solution of compound A8-3 (30 mg, 0.07 mmol) in dichloromethane (2 mL) was added HCl (4 M in dioxane, 0.5 mL) at room temperature. The reaction was stirred at 30°C for 1 h. The reaction solution was concentrated under reduced pressure to afford a light yellow solid A8-4 (23 mg, 99% yield). LCMS (ESI) m / z = 318.1 [M+H] + .

[0353] Step 5:

[0354] To a solution of compound A8-4 (23 mg, 0.08 mmol) in N,N-dimethylformamide (2 mL) were added SM2 (15 mg, 0.03 mmol), HATU (14 mg, 0.04 mmol), and DIPEA (12.2 mg, 0.09 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous formic acid) to afford A8 (12.1 mg, 46% yield) as a pale yellow solid. LCMS (ESI) m / z = 818.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),10.17(s,1H),8.71(s,1H),8.33–8.27(m,2H),7.97( s,1H),7.89(d,J=8.0Hz,1H),7.82(dd,J1=8.0Hz,J2=2.0Hz,1H),7.45–7.38(m,2H),7.21(s ,1H),7.18–7.14(m,2H),6.99–6.93(m,2H),3.94(s,3H),3.70(t,J=4.0Hz,2H),3.50-3.46 (m,2H),3.21-3.19(m,4H),2.68(t,J=4.0Hz,2H),2.64–2.58(m,4H),2.56(t,J=4.0Hz,2H).

[0355] Example 9 Synthesis of Compound A9:

[0356] Compound A9 (9.8 mg, yield 39.9%) was synthesized according to the synthesis method of Compound A8 described in Example 8. LCMS (ESI) m / z = 818.5 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),10.18(s,1H),8.71(s,1H),8.32–8.27(m,2H),7.99–7.95(m,1 H),7.88(d,J=8.0Hz,1H),7.82(dd,J1=8.0Hz,J2=2.0Hz,1H),7.46–7.38(m,2H),7.21(t,J=8.0Hz,2H ),6.91(d,J=4.0Hz,1H),6.86–6.82(m,1H),6.75–6.70(m,1H),3.94(s,3H),3.75(t,J=8.0Hz,2H),3 .50–3.43(m,2H),3.23–3.16(m,4H),2.68(t,J=6.4Hz,2H),2.63–2.58(m,4H),2.56(d,J=8.0Hz,2H).

[0357] Example 10 Synthesis of Compound A10:

[0358] Compound A10 (16.7 mg, yield 72%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 776.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.25(s,1H),10.15(s,1H),8.72(s,1H),8.31–8.25(m ,2H),7.92–7.81(m,5H),7.58–7.51(m,1H),7.33(d,J=4.0Hz,1H),7.22–7.12( m,4H),6.93(d,J=8.0Hz,2H),3.69(t,J=8.0Hz,2H),3.42(q,J=6.4Hz,2H),3.1 4(t,J=4.0Hz,4H),2.68(t,J=6.4Hz,2H),2.62–2.56(m,4H),2.55–2.52(m,2H).

[0359] Example 11 Synthesis of Compound A11:

[0360] Step 1:

[0361] To a solution of compound A8-3 (1.11 g, 2.85 mmol) in N,N-dimethylformamide (10 mL) at room temperature and at 0°C, sodium hydride (137.0 mg, 3.42 mmol) was added. The mixture was stirred for 0.5 h, followed by the addition of iodomethane (388.7 mg, 2.71 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was washed with water and extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to afford A11-1 (600.0 mg, 51% yield) as a white solid. LCMS (ESI) m / z = 365.2 [M+H] + .

[0362] Step 2:

[0363] Compound A11 (5.6 mg, yield 26%) was synthesized according to the synthesis method of compound A8 described in Example 8. LCMS (ESI) m / z = 790.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.27(s,1H),10.11(s,1H),8.73(s,1H),8.32(d,J=8.4Hz,1H ),7.91(d,J=8.4Hz,2H),7.87(d,J=8.4Hz,1H),7.60–7.53(m,1H),7.42(d,J=8.0Hz,2H ),7.35(d,J=2.4Hz,1H),7.17–7.10(m,4H),6.94(bs,2H),3.71(t,J=7.2Hz,2H),3.62– 3.51(m,2H),3.12–3.01(m,4H),2.98(s,3H),2.70(d,J=5.9Hz,2H),2.69–2.59(m,6H).

[0364] Example 12 Synthesis of Compound A12:

[0365] Compound A12 (16.38 mg, yield 67.31%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 761.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.24(s,1H),10.15(s,1H),8.73(s,1H),8.41–8.26(m,2H),7.93–7.80(m,5H),7.61–7.49(m,1H),7.34(d,J=2.1Hz,1H ),7.24–7.07(m,4H),6.93(d,J=8.8Hz,2H),3.77–3.62(m,4H),3.19(m, 2H),2.75–2.51(m,4H),1.87–1.74(d,J=13.2Hz,3H),1.38–1.25(m,2H).

[0366] Example 13 Synthesis of Compound A13:

[0367] Compound A13 (15.33 mg, yield 63.45%) was synthesized according to the synthesis method of compound A8 described in Example 8. LCMS (ESI) m / z = 803.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),10.16(s,1H),8.72(s,1H),8.30(d,J=8.4Hz,1H),8.08( t,J=6.0Hz,1H),7.96(s,1H),7.86–7.75(m,2H),7.48–7.35(m,2H),7.22(s,1H),7.17–7.07(m, 2H),7.00–6.87(m,2H),3.92(s,3H),3.77–3.63(m,4H),3.31–3.29(m,3H),3.25(m,2H),2.67( dd, J1=8.8Hz, J2=4.8Hz, 4H), 2.52 (d, J=3.2Hz, 2H), 1.76 (d, J=12.8Hz, 3H), 1.39–1.21 (m, 2H).

[0368] Example 14 Synthesis of Compound A14:

[0369] Compound A14 (8.27 mg, yield 33.09%) was synthesized according to the synthesis method of compound A8 described in Example 8. LCMS (ESI) m / z = 803.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.31(s,1H),10.19(s,1H),8.74(s,1H),8.33(d,J=7.2 Hz,1H),8.12–8.09(m,1H),7.90(s,1H),7.86–7.81(m,2H),7.47–7.41(m,2H),7. 24–7.91(m,1H),6.91–6.83(m,2H),6.71–6.69(m,1H),3.95(s,3H),3.78–3.73(m ,4H),3.29–3.25(,2H),2.72-2.61(m,4H),1.79–1.71(m,3H),1.34–1.31(m,2H).

[0370] Example 15 Synthesis of Compound A15:

[0371] Step 1:

[0372] Acrylic acid (573 mg, 8.0 mmol) was added to a toluene solution (20 mL) of 1-BOC-4-(4-aminophenyl)piperidine (2 g, 7.23 mmol) at room temperature. The reaction mixture was heated to 110°C and stirred for 18 hours under argon. The reaction mixture was cooled to room temperature, and urea (2.16 g, 36 mmol) and acetic acid (20 mL) were added. The reaction mixture was heated to 110°C and stirred for 18 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The mixture was extracted with ethyl acetate and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (methanol / dichloromethane = 1:20) to afford A15-1 (300 mg, 12% yield) as a white solid. LCMS (ESI) m / z = 374.2 [M+H] + .

[0373] Step 2:

[0374] To a solution of compound A15-1 (300 mg, 0.8 mmol) in dichloromethane (5 mL) was added HCl (4 M in dioxane, 1 mL) at room temperature. The reaction was stirred at 30°C for 1 h. The reaction solution was concentrated under reduced pressure to afford a light yellow solid A15-2 (220 mg, 99% yield). LCMS (ESI) m / z = 274.1 [M+H] + .

[0375] Step 3:

[0376] To a solution of compound A15-2 (220 mg, 0.8 mmol) in N-methylpyrrolidone (5 mL) at room temperature were added N-Boc-bromoethylamine (270 mg, 1.2 mmol) and DIPEA (312 mg, 2.4 mmol). The reaction mixture was heated to 80°C and stirred under argon for 16 h. Water was added to the reaction mixture, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:20) to afford A15-3 (80 mg, 24% yield) as a yellow solid. LCMS (ESI) m / z = 417.1 [M+H] + .

[0377] Step 4:

[0378] To a solution of compound A15-3 (80 mg, 0.19 mmol) in dichloromethane (2 mL) was added HCl (4 M in dioxane, 1 mL) at room temperature. The reaction was stirred at 30°C for 1 h. The reaction solution was concentrated under reduced pressure to afford a light yellow solid A15-4 (60 mg, 99% yield). LCMS (ESI) m / z = 317.0 [M+H] + .

[0379] Step 5:

[0380] To a solution of compound A15-4 (20 mg, 0.06 mmol) in N,N-dimethylformamide (2 mL) were added SM2 (15 mg, 0.03 mmol), HATU (15.5 mg, 0.04 mmol), and DIPEA (12.2 mg, 0.09 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 10 M aqueous ammonium bicarbonate) to afford A15 (11.6 mg, 47.3% yield) as a pale yellow solid. LCMS (ESI) m / z = 817.5 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),10.20(s,1H),8.72(s,1H),8.34–8.28(m,2H),8.00(s,1 H),7.89(d,J=12.0Hz,1H),7.83(dd,J1=8.4Hz,J2=2.4Hz,1H),7.46–7.39(m,2H),7.32–7.21( m,5H),3.98(s,3H),3.76(t,J=6.8Hz,2H),3.46–3.40(m,2H),3.04(d,J=12.0Hz,2H),2.68(t, J=6.8Hz,2H),2.61–2.56(m,3H),2.11(t,J=8.0Hz,2H),1.86–1.77(m,2H),1.74–1.63(m,2H).

[0381] Example 16 Synthesis of Compound A16:

[0382] Step 1:

[0383] At room temperature, 5-bromo-2-iodopyridine (11.11 g, 35.22 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (14.52 g, 42.27 mmol), Pd(dppf)Cl2 (2.71 g, 3.52 mmol), and sodium carbonate (7.86 g, 70.45 mmol) were dissolved in 1,4-dioxane / H2O (100 mL / 20 mL). The reaction mixture was stirred at 80°C for 16 h. The reaction mixture was washed with water and extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain A16-1 (10.00 g, 75% yield) as a white solid. LCMS (ESI) m / z = 339.2 [M+H] + .

[0384] Step 2:

[0385] Compound A16-1 (923.8 mg, 2.72 mmol), cesium carbonate (1.77 g, 5.45 mmol), trans-(1S,2S)-N,N-dimethylcyclohexanediamine (77.5 mg, 0.55 mmol), cuprous iodide (103.7 mg, 3.45 mmol), and 3-(4-methoxybenzyl)-dihydropyrimidine-2,4(1H,3H)-dione (4.49 g, 0.55 mmol, synthesis reference WO2022125790) were dissolved in dioxane (5 mL) at room temperature. The reaction mixture was stirred at 80°C for 16 h. The solvent was removed by concentration, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to afford A16-2 (1.00 g, 74%) as a white solid. LCMS (ESI) m / z = 493.2 [M+H] + .

[0386] Step 3:

[0387] To a solution of compound A16-2 (900.0 mg, 1.83 mmol) in dichloromethane (2 mL) was added HCl (4.0 M in 1,4-dioxane, 2 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was directly dried to afford A16-3 as a white solid (600.0 mg, 83% yield). LCMS (ESI) m / z = 393.1 [M+H] + .

[0388] Step 4:

[0389] To a solution of compound A16-3 (100.0 mg, 0.25 mmol) in N,N-dimethylformamide (3 mL) were added DIPEA (65.8 mg, 0.50 mmol) and N-BOC-bromoethylamine (57.1 mg, 0.25 mmol) at room temperature. The reaction mixture was heated to 100°C and stirred for 4 h. The reaction mixture was washed with water and extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to afford A16-4 (100.0 mg, 73% yield) as a white solid. LCMS (ESI) m / z = 536.2 [M+H] + .

[0390] Step 5:

[0391] To a solution of compound A16-4 (80.0 mg, 0.15 mmol) in methanol (3 mL) was added Pd / C (20.0 mg, 10%) at room temperature, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was directly filtered and dried to give A16-5 (75.0 mg, 93% yield) as a white solid. LCMS (ESI) m / z = 538.2 [M+H]+ .

[0392] Step 6:

[0393] To a dichloromethane solution (2 mL) of compound A16-5 (75.0 mg, 0.14 mmol) was added trifluoroacetic acid (0.5 mL), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was directly dried to afford A16-6 (65.0 mg, 90% yield) as a white solid. LCMS (ESI) m / z = 318.2 [M+H] + .

[0394] Step 7:

[0395] To a solution of compound A16-6 (15.3 mg, 0.048 mmol) in N,N-dimethylformamide (2 mL) were added SM2 (15.0 mg, 0.029 mmol), HATU (16.5 mg, 0.043 mmol), and DIPEA (11.2 mg, 0.086 mmol). The reaction was stirred at room temperature for 2 h. The reaction solution was separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous formic acid = 2.3 / 1) to afford A16 (7.0 mg, 30% yield) as a yellow solid. LCMS (ESI) m / z = 818.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),10.23(s,1H),8.75(s,1H),8.51(d,J=2.4Hz,1H),8.39–8.32(m,2H ),8.03(s,1H),7.92(d,J=8.4Hz,1H),7.85(dd,J1=8.4Hz,J2=2.0Hz,1H),7.71(d,J=2.4Hz,1H),7.50–7. 42(m,2H),7.38(d,J=8.4Hz,1H),7.25(s,1H),4.02(s,3H),3.85(t,J=6.4Hz,2H),3.50–3.44(m,2H),3.0 6(d,J=10.8Hz,2H),2.75(t,J=6.4Hz,2H),2.65–2.54(m,3H),2.15(t,J=11.2Hz,2H),1.93–1.81(m,4H).

[0396] Example 17 Synthesis of Compound A17:

[0397] Step 1:

[0398] To a dichloromethane solution (10 mL) of compound A17-1 (200 mg, 0.67 mmol, synthesis method reference patent WO2021041664) was added N-tert-butoxycarbonyl-2-aminoacetaldehyde (117 mg, 0.74 mmol) and acetic acid (120 mg, 2 mmol) at room temperature. The reaction was stirred at 30°C for 1 hour. Sodium triacetoxyborohydride (425 mg, 2 mmol) was then added, and the reaction was stirred at 30°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:20) to obtain A17-2 (90 mg, 30% yield) as a white solid. LCMS (ESI) m / z = 443.2 [M+H] + .

[0399] Step 2:

[0400] Trifluoroacetic acid (0.5 mL) was added to a dichloromethane solution (2 mL) of compound A17-2 (30 mg, 0.07 mmol) at room temperature. The reaction was stirred at 30°C for 1 h. The reaction solution was concentrated under reduced pressure to obtain a light yellow solid A17-3 (23 mg, 99% yield). LCMS (ESI) m / z = 343.2 [M+H] + .

[0401] Step 3:

[0402] To a solution of compound A17-3 (23 mg, 0.07 mmol) in N,N-dimethylformamide (2 mL) was added SM2 (15 mg, 0.03 mmol), HATU (15.5 mg, 0.04 mmol), and DIPEA (12.2 mg, 0.09 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 10 M aqueous ammonium bicarbonate) to afford A17 (11.4 mg, 45% yield) as a pale yellow solid. LCMS (ESI) m / z = 843.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.15(s,1H),10.29(s,1H),8.74(s,1H),8.32–8.30(m,3H),7.97(s,1H),7.89–7.81(m,6H),7.47–7.41(m,3H),7.2 4(bs,1H),5.19–5.14(m,1H),,4.19(s,3H),3.87–3.81(m,4H),3.53– 3.52(m,2H),2.95–2.89(m,3H),2.64–2.58(m,2H),2.10–2.04(m,1H).

[0403] Example 18 Synthesis of Compound A18:

[0404] Step 1:

[0405] To a solution of compound A18-1 (1.50 g, 5.57 mmol, Synthesis Reference Example 8) in 1,4-dioxane (15.0 mL) were added pinacol diboron (2.82 g, 11.15 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (455.21 mg, 557.43 μmol), and potassium acetate (1.37 g, 13.94 mmol) at room temperature. The reaction was stirred at 90°C for 12 h under argon. Solid impurities were removed by filtration, and the filtrate was concentrated. The product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to afford A18-2 (746 mg, 42.33% yield) as a yellow solid. LCMS (ESI) m / z = 317.2 [M+H] + .

[0406] Step 2:

[0407] 1-tert-Butyloxycarbonyl-3-(1-piperazinyl)azetidine (343.49 mg, 1.42 mmol) was dissolved in acetonitrile, and A18-2, copper acetate (377.66 mg, 1.90 mmol), triethylamine (191.68 mg, 1.90 mmol) and The mixture was added with 100 μg of 1-naphthenate-3-nitrogen zeolite (191.68 mg, 1.90 mmol) and stirred at 60°C for 3 h. After the reaction was completed, the mixture was directly dried and eluted with flash silica gel column chromatography (EA:MeOH = 10% to 10%) to give A18-3 (320 mg). LCMS (ESI) m / z = 430.2 [M+H] + .

[0408] Step 2:

[0409] A18-3 (40 mg) obtained in the previous step was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated to remove the solvent to obtain an oily product A18-4, which was used directly in the next step. LCMS (ESI) m / z = 330.18 [M+H] + .

[0410] Step 3:

[0411] A18-4 (30 mg, 96.46 μmol) obtained in the previous step was dissolved in N,N-dimethylformamide (1 mL), and SM2 (23 mg, 48.23 μmol), HATU (36.68 mg, 96.46 μmol), and DIPEA (18.70 mg, 144.70 μmol, 25.20 μL) were added sequentially. The reaction solution was stirred at room temperature overnight. After completion of the reaction, the reaction solution was separated and purified by reverse phase chromatography (acetonitrile / 0.1% formic acid aqueous solution = 2.3 / 1) to obtain A18 (10.2 mg, 26% yield) as a yellow solid. LCMS (ESI) m / z = 820.25 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),10.23(s,1H),8.76(s,1H),8.33(d,J=8.4Hz,1H),7.96–7.89(m,3H),7.68(d,J=8.4Hz,1H),7.61 –7.56(m,1H),7.36(d,J=2.4Hz,1H),7.19–7.17(m,4H),6.98–6.96(m,2H),3.72(t,J=6.8Hz,2H),3.19–3.17(m,4H),3.27–2.98(m,2H).

[0412] Example 19 Synthesis of Compound A19:

[0413] Compound A19 (5.6 mg, yield 34%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 788.21 [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.73(s,1H),8.64(s,1H),8.60(s,1H),8.31–8.29(m, 1H),8.01(s,1H),7.89–7.76(m,2H),7.66–7.63(m,2H),7.56–7.52(m,2H), 7.43–7.37(m,2H),7.29–7.24(m,2H),7.19–7.16(m,1H),7.04–7.01(1H),4 .51–4.32(m,2H),4.01–3.86(m,5H),3.91–3.86(m,4H),2.90–2.87(m,4H).

[0414] Example 20 Synthesis of Compound A20:

[0415] Step 1:

[0416] To a 100 mL solution of imidazo[1,2-a]pyridin-8-amine (5.56 g, 37.55 mmol) in dioxane was added di-tert-butyl dicarbonate (33.11 g, 150.21 mmol) at room temperature. The reaction mixture was stirred at 90°C for 16 h. Water was added to the reaction mixture, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to afford A20-1 (10.00 g, 90% yield) as a yellow solid. LCMS (ESI) m / z = 334.2 [M+H] + .

[0417] Step 2:

[0418] To a DMF solution (100 mL) of compound A20-1 (9.00 g, 25.92 mmol) was added N-iodosuccinimide (7.07 g, 31.10 mmol) at room temperature. The reaction mixture was stirred at 100°C for 16 h. The reaction mixture was washed with water and extracted with ethyl acetate. The organic phase was concentrated to remove the solvent and afforded a yellow solid, A20-2 (8.00 g, 90% yield). LCMS (ESI) m / z = 460.1 [M+H] + .

[0419] Step 3:

[0420] Compound A20-2 (8.00 g, 17.24 mmol), cesium carbonate (11.35 g, 34.49 mmol), trans-(1S,2S)-N,N-dimethylcyclohexanediamine (495.0 mg, 3.45 mmol), cuprous iodide (663.0 mg, 3.45 mmol), and 3-(4-methoxybenzyl)-dihydropyrimidine-2,4(1H,3H)-dione (4.49 g, 18.97 mmol) were dissolved in dioxane (100 mL) at room temperature. The reaction mixture was stirred at 80°C for 16 h. The solvent was removed by concentration, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to afford A20-3 (3.00 g, 27%) as a white solid. LCMS (ESI) m / z = 566.1 [M+H] + .

[0421] Step 4:

[0422] To a solution of compound A20-3 (1.11 g, 1.77 mmol) in 1,4-dioxane (5 mL) was added HCl (4.0 M in 1,4-dioxane, 5 mL). The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was directly dried to afford a yellow solid A20-4 (600.0 mg, 84% yield). LCMS (ESI) m / z = 366.2 [M+H] + .

[0423] Step 5:

[0424] To a solution of compound A20-4 (212.0 mg, 0.57 mmol) in N-methylpyrrolidone (2 mL) was added N-Boc-2-(2-bromoethoxy)ethanamine (250.5 mg, 0.92 mmol) and DIPEA (150.0 mg, 1.15 mmol) at room temperature. The reaction mixture was stirred at 80°C for 16 h. The reaction mixture was washed with water and extracted with ethyl acetate. The organic phase was concentrated to remove the solvent and afforded A20-5 (111.0 mg, 34% yield) as a yellow solid. LCMS (ESI) m / z = 553.1 [M+H] + .

[0425] Step 6:

[0426] Trifluoroacetic acid (3 mL) and trifluoromethanesulfonic acid (1.5 mL) were added to compound A20-5 (111.0 mg, 0.18 mmol) at 0°C, and the reaction mixture was stirred at 25°C for 16 h. The reaction mixture was adjusted to pH ~8 with saturated potassium bicarbonate and purified by reverse phase chromatography (acetonitrile / 10 M aqueous ammonium bicarbonate) to afford A20-6 (30.0 mg, 50%) as a white solid. LCMS (ESI) m / z = 333.3 [M+H] + .

[0427] Step 7:

[0428] To a solution of compound A20-6 (13.0 mg, 0.035 mmol) in N,N-dimethylformamide (1 mL) were added SM2 (12.2 mg, 0.021 mmol), HATU (12.1 mg, 0.032 mmol), and DIPEA (8.3 mg, 0.064 mmol). The reaction was stirred at room temperature for 2 h. The reaction solution was separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous formic acid = 2.3 / 1) to afford A20 (5.0 mg, 27% yield) as a yellow solid. LCMS (ESI) m / z = 833.2 [M+H] +.1H NMR (400MHz, DMSO-d6) δ10.34(s,1H),10.24(s,1H),8.75(s,1H),8.33(d,J=2.8Hz,2H),8.11( d,J=2.8Hz,1H),8.00(s,1H),7.92(d,J=8.4Hz,1H),7.85(dd,J=8.4,2.4Hz,1H),7.55(d,J=9. 2Hz,1H),7.51–7.44(m,3H),7.40(s,1H),6.79–6.75(m,1H),6.27–6.25(m,1H),5.94–5.92(m, 1H),3.94(s,3H),3.80–3.72(m,4H),3.65–3.53(m,2H),3.52–3.49(m,4H),2.84–2.81(m,2H).

[0429] Example 21 Synthesis of Compound A21:

[0430] Step 1:

[0431] Compound A21-1 (3.31 g, 0.41 mmol, synthesis reference patent WO2022125790) and compound 1-(N-Boc-aminoethyl)piperazine (180.9 mg, 0.81 mmol) were dissolved in dioxane solution (4 mL) and added Molecular sieves (200.0 mg), cesium carbonate (396.2 mg, 1.22 mmol), and RuPhos Pd G3 (33.9 mg, 0.041 mmol). The reaction solution was stirred at 100°C for 12 h under argon protection. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound A21-2 (171.0 mg, yellow solid). LCMS (ESI) m / z = 578.2 [M+H] + .

[0432] Step 4:

[0433] Compound A21-2 (171.0 mg, 0.30 mmol) was dissolved in trifluoroacetic acid (2 mL), and trifluoromethanesulfonic acid (1 mL) was added. The reaction solution was stirred at 25°C for 16 h. The pH of the reaction solution was adjusted to 5-6 with saturated sodium bicarbonate solution. The reaction solution was separated and purified by reverse phase chromatography (acetonitrile / 10 M aqueous ammonium bicarbonate) to obtain compound A21-3 (100.0 mg, brown solid). LCMS (ESI) m / z = 358.3 [M+H] + .

[0434] Step 5:

[0435] To a solution of compound A21-3 (20.7 mg, 0.058 mmol) in N,N-dimethylformamide (2 mL) were added SM2 (15.0 mg, 0.029 mmol), HATU (16.5 mg, 0.043 mmol), and DIPEA (11.2 mg, 0.087 mmol). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was separated and purified by reverse phase chromatography (methanol / 10 M aqueous ammonium bicarbonate) to afford A21 (7.0 mg, 28% yield) as a yellow solid. LCMS (ESI) m / z = 857.9 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.68(s,1H),10.24(s,1H),8.75(s,1H),8.46–8.23(m, 3H),8.02(s,1H),7.98–7.78(m,3H),7.55–7.39(m,3H),7.24(s,1H),6.87(t,J=7 .2Hz,1H),6.58(d,J=7.6Hz,1H),3.98(s,3H),3.81–3.79(m,2H),3.61–3.53(m, 4H),3.54–3.48(m,6H),2.90–2.84(m,1H),2.73–2.70(m,2H),2.66–2.58(m,1H).

[0436] Example 22 Synthesis of Compound A22:

[0437] To a solution of compound A21-3 (22.5 mg, 0.063 mmol) in N,N-dimethylformamide (2 mL) were added SM1 (15.0 mg, 0.031 mmol), HATU (17.9 mg, 0.047 mmol), and DIPEA (12.2 mg, 0.094 mmol). The reaction was stirred at room temperature for 4 h. The reaction solution was separated and purified by reverse phase chromatography (methanol / 10 M aqueous ammonium bicarbonate) to afford A22 (19.0 mg, 74% yield). LCMS (ESI) m / z = 815.9 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),10.20(s,1H),8.76(s,1H),8.39–8.29(m, 2H),7.98–7.82(m,6H),7.63–7.53(m,1H),7.49(s,1H),7.37(d,J=2.0Hz,1H),7. 20(t,J=8.8Hz,2H),6.85(t,J=6.8Hz,1H),6.54(d,J=7.6Hz,1H),3.79–3.70(m,2 H),3.59–3.35(m,10H),2.89–2.82(m,1H),2.69–2.64(m,2H),2.64–2.56(m,1H).

[0438] Example 23 Synthesis of Compound A23:

[0439] Step 1:

[0440] To a solution of 4-bromo-1H-imidazole (5.0 g, 34.02 mmol) in N,N-dimethylformamide (70 mL) at room temperature were added cesium carbonate (22.17 g, 68.04 mmol) and tert-butyl 4-methanesulfonyloxypiperidine-1-carboxylate (9.5 g, 34.02 mmol). The reaction mixture was heated to 100°C and stirred for 16 h under argon. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous formic acid) to afford A23-1 (1.5 g, 13% yield) as a yellow solid. LCMS (ESI) m / z = 331.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.75(d,J=1.4Hz,1H),7.49(d,J=1.5Hz,1H),4.28–4.20(m,1H),4 .14–4.02(m,2H),2.84(bs,2H),1.95(s,1H),1.91(s,1H),1.82–1.69(m,2H),1.44(s,9H).

[0441] Step 2:

[0442] To a 1,4-dioxane solution (20 mL) of compound A23-1 (1.7 g, 5.15 mmol) was added 3-(4-methoxybenzyl)-dihydropyrimidine-2,4(1H,3H)-dione (1.33 g, 5.66 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (732.2 mg, 5.15 mmol), cesium carbonate (3.35 g, 10.30 mmol), and cuprous iodide (196.09 mg, 1.03 mmol) at room temperature. The reaction mixture was stirred at 110°C for 16 h. The solvent was removed by concentration, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to afford A23-2 (2.2 g, 91%) as a yellow solid. LCMS (ESI) m / z = 484.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.21(d,J=8.2Hz,2H),6.84(d,J=7.7Hz,2H),4.82(s,2H),4.21(t,J=12.0Hz,1H),4. 10–3.99(m,4H),3.71(s,3H),2.83(t,J=6.4Hz,3H),1.95(d,J=12.3Hz,2H),1.81–1.63(m,2H),1.41(s,9H).

[0443] Step 3:

[0444] To compound A23-2 (1.0 g, 2.07 mmol) was added trifluoroacetic acid (5 mL) and trifluoromethanesulfonic acid (1 mL) at 0°C, and the reaction mixture was stirred at 25°C for 24 h. The reaction mixture was adjusted to pH ~8 with saturated potassium bicarbonate and purified by reverse phase chromatography (acetonitrile / 10 M aqueous ammonium bicarbonate) to afford A23-3 (150 mg, 27%) as a white solid. LCMS (ESI) m / z = 264.0 [M+H] + .

[0445] Step 4:

[0446] To a solution of compound A23-3 (150.0 mg, 0.56 mmol) in N-methylpyrrolidone (6 mL) were added N-tert-butyloxycarbonyl-bromoethylamine (255.3 mg, 1.14 mmol) and DIPEA (736.3 mg, 5.7 mmol) at room temperature. The reaction mixture was stirred at 80°C for 16 h. Water was added to the reaction mixture, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to afford A23-4 (77 mg, 33% yield) as a yellow solid. LCMS (ESI) m / z = 407.2 [M+H]+ . 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),7.70–7.60(m,0.5H),7.31–7.20(m,1H),6.69–6.64(m,1H),4.06–3.97(m,2H),3.04(q,J=6.6H z,2H),2.95(d,J=11.2Hz,2H),2.64(t,J=6.7Hz,1H),2.36(t,J=6.8Hz,2H),2.08(t,J=11.6Hz,2H),1.97–1.79(m,4H),1.37(s,9H).

[0447] Step 5:

[0448] At room temperature, hydrochloric acid (4.0 M, 1,4-dioxane solution) (2 mL) was added to compound A23-4 (77.0 mg, 0.19 mmol), and the reaction mixture was stirred at 25°C for 2 h. The reaction mixture was concentrated to remove the solvent to give A23-5 (78 mg), a yellow solid. LCMS (ESI) m / z = 307.1 [M+H] + .

[0449] Step 6:

[0450] To a solution of compound A23-5 (13.3 mg, 0.043 mmol) in N,N-dimethylformamide (1 mL) were added SM2 (15.0 mg, 0.029 mmol), HATU (13.2 mg, 0.034 mmol), and DIPEA (18.7 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous formic acid = 2.3 / 1) to afford A23 (20.0 mg, 87% yield) as a yellow solid. LCMS (ESI) m / z = 807.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.32(s,1H),10.19(s,1H),8.72(s,1H),8.31(d,J=8.4Hz 1H),8.25(t,J=5.2Hz,1H),7.96(s,1H),7.87(d,J=8.6Hz,1H),7.83(dd,J1=8.4Hz,J2=2. 2Hz,1H),7.64(d,J=1.6Hz,1H),7.47–7.37(m,2H),7.33(d,J=1.6Hz,1H),7.21(s,1H),4. 02(t,J=6.6Hz,2H),3.96(s,3H),3.46-3.40(m,2H),3.01(d,J=11.2Hz,2H),2.64(t,J=6. 8Hz,2H),2.62–2.55(m,3H),2.20–2.15(m,2H),2.02(d,J=12.0Hz,2H),1.91–1.81(m,2H).

[0451] Example 24 Synthesis of Compound A24:

[0452] Step 1:

[0453] To a solution of compound A24-1 (60.0 mg, 0.21 mmol) in N-methylpyrrolidone (1 mL) were added N-tert-butyloxycarbonyl-bromoethylamine (95.6 mg, 0.42 mmol) and DIPEA (137.8 mg, 1.07 mmol) at room temperature. The reaction mixture was stirred at 80°C for 16 h. Water was added to the reaction mixture, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to afford A24-2 (50 mg, 55% yield) as a yellow solid. LCMS (ESI) m / z = 425.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),6.99(s,1H),6.69(t,J=5.8Hz,1H),3.78(t,J=6.8Hz,2H),3.31–3.29 (m,4H),3.06(q,J=6.4Hz,2H),2.72(t,J=6.8Hz,2H),2.48–2.46(m,4H),2.36(t,J=6.9Hz,2H),1.37(s,9H).

[0454] Step 2:

[0455] At room temperature, HCl (4M in dioxane, 2 mL) was added to compound A24-2 (77.0 mg, 0.19 mmol), and the reaction mixture was stirred at 25°C for 2 h. The reaction mixture was concentrated to remove the solvent to give A24-3 (50 mg) as a yellow solid. LCMS (ESI) m / z = 325.2 [M+H] + .

[0456] Step 3:

[0457] To a solution of compound A24-3 (14.0 mg, 0.043 mmol) in N,N-dimethylformamide (1 mL) were added SM2 (15.0 mg, 0.029 mmol), HATU (13.2 mg, 0.034 mmol), and DIPEA (18.7 mg, 0.14 mmol). The reaction was stirred at room temperature for 2 h. The reaction solution was separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous formic acid = 2.3 / 1) to afford A24 (14.0 mg, 58% yield) as a yellow solid. LCMS (ESI) m / z = 825.6 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.60(s,1H),10.20(s,1H),8.72(s,1H),8.35-8.25(m,2H),7.99( s,1H),7.88(d,J=8.6Hz,1H),7.83(dd,J1=8.4Hz,J2=2.2Hz,1H),7.45–7.37(m,2H),7.21( s,1H),7.01(s,1H),7.19–6.81(m,2H),3.94(s,3H),3.79(t,J=6.8Hz,2H),3.78–3.69(m,1 H),3.47–3.42(m,2H),3.39(t,J=5.0Hz,5H),2.73(t,J=6.8Hz,2H),2.56(t,J=5.4Hz,4H).

[0458] Example 25 Synthesis of Compound A25:

[0459] Compound A25 (10.0 mg, yield 41%) was synthesized according to the synthesis method of Compound A24 described in Example 24. LCMS (ESI) m / z = 783.1 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ10.58(s,1H),10.15(s,1H),8.71(s,1H),8.33–8.20(m,2H),7.94–7.84(m,3H),7.84–7.75(m,2H),7.59–7.44(m,1H), 7.32(d,J=2.0Hz,1H),7.16(t,J=8.8Hz,2H),6.98(s,1H),3.77(t,J=6.8Hz,2H),3.45–3.33(m,6H),2.71(t,J=6.8Hz,2H),2.59–2.51(m,6H).

[0460] Example 26 Synthesis of Compound A26:

[0461] Step 1:

[0462] To a solution of compound A18-1 (250.0 mg, 0.92 mmol, Synthesis Reference Example 8) in N,N-dimethylformamide and triethylamine (2 mL / 2 mL) were added tert-butyl 3-butynylcarbamate (157.2 mg, 0.92 mmol), cuprous iodide (35.4 mg, 0.18 mmol), and bistriphenylphosphine palladium dichloride (65.2 mg, 0.092 mmol) at room temperature. The reaction mixture was heated to 80°C and stirred for 8 h under argon. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous formic acid) to afford A26-1 (129 mg, 38% yield) as a yellow solid. LCMS (ESI) m / z = 358.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),7.40(d,J=8.6Hz,2H),7.31(d,J=8.6Hz,2H),7.01(t,J=6.0Hz,1H) ,3.79(t,J=6.6Hz,2H),3.14(q,J=6.6Hz,2H),2.70(t,J=6.6Hz,2H),2.53(q,J=6.6Hz,2H),1.38(s,9H).

[0463] Step 2:

[0464] At room temperature, HCl (4.0 M in 1,4-dioxane, 2 mL) was added to compound A26-1 (125.0 mg, 0.34 mmol), and the reaction mixture was stirred at 25°C for 2 h. The reaction mixture was concentrated to remove the solvent to give A26-2 (100 mg, 98%) as a yellow solid. LCMS (ESI) m / z = 258.0 [M+H] + .

[0465] Step 3:

[0466] To a solution of compound A26-2 (14.8 mg, 0.057 mmol) in N,N-dimethylformamide (1 mL) were added SM2 (15.0 mg, 0.029 mmol), HATU (12.1 mg, 0.031 mmol), and DIPEA (18.7 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 10 M aqueous ammonium bicarbonate solution = 2.3 / 1) to afford A26 (16.0 mg, 73% yield) as a yellow solid. LCMS (ESI) m / z = 758.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),10.18(s,1H),8.72(s,1H),8.36–8.27(m,2H),7.96(s,1H),7.87(d,J=8.6Hz,1H),7.81(dd,J1=8.5Hz,J2 =2.2Hz,1H),7.45–7.38(m,4H),7.36–7.30(m,2H),7.22(bs,1H),3.90( s,3H),3.80(t,J=6.6Hz,2H),3.53(q,J=6.6Hz,2H),2.71–2.67(m,4H).

[0467] Example 27 Synthesis of Compound A27:

[0468] Step 1:

[0469] Acrylic acid (2.42 g, 33.60 mmol) was added to a toluene solution (25.0 mL) of p-toluidine (3.00 g, 28.00 mmol) at room temperature. The reaction was stirred at 100°C for 12 h. The reaction mixture was cooled to room temperature, and urea (8.41 g, 139.99 mmol) and acetic acid (25.0 mL) were added. The reaction mixture was heated to 110°C and stirred for 12 h. The toluene was removed by concentration under reduced pressure, and the pH was adjusted to ~8 with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the layers separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The product was isolated and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to afford A27-1 (1.78 g, 31.13% yield) as a yellow solid. LCMS (ESI) m / z = 204.9 [M+H] + .

[0470] Step 2:

[0471] To a solution of compound A27-1 (500.00 mg, 2.45 mmol) in acetonitrile (5.0 mL) were added N-bromosuccinimide (522.89 mg, 2.94 mmol) and azobisisobutyronitrile (80.41 mg, 489.66 μmol) at room temperature. The reaction was stirred at 80°C for 4 h. The solvent was removed by concentration under reduced pressure, and the product was isolated and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to afford A27-2 (345 mg, 24.85% yield) as a yellow solid. LCMS (ESI) m / z = 283.01 / 284.1 [M+H] + .

[0472] Step 3:

[0473] To a solution of compound A27-2 (150.00 mg, 529.81 μmol) in N,N-dimethylformamide (5.0 mL) were added tert-butyl (piperidin-4-ylmethyl)carbamate (113.54 mg, 529.81 μmol), DIPEA (205.42 mg, 1.59 mmol), and potassium iodide (17.59 mg, 105.96 μmol, 5.64 μL) at room temperature. The reaction was allowed to react at 90°C for 12 h. Water was added to the reaction solution, extracted with ethyl acetate, and the layers separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The product was isolated and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to afford A27-3 (118 mg, 53.47% yield) as a pale yellow solid. LCMS (ESI) m / z = 417.2 [M+H].

[0474] Step 4:

[0475] To a solution of compound A27-3 (20.00 mg, 48.02 μmol) in dichloromethane (6.0 mL) was added trifluoroacetic acid (1.5 mL) at room temperature. The reaction was stirred at 25°C for 2 h. The solvent was concentrated under reduced pressure to afford A27-4 (16 mg, 100% yield) as a yellow solid. LCMS (ESI) m / z = 317.1 [M+H] + .

[0476] Step 5:

[0477] To a solution of compound A27-4 (16.00 mg, 48.02 μmol) in N,N-dimethylformamide (2.0 mL) were added SM2 (15.00 mg, 28.91 μmol), HATU (21.98 mg, 57.81 μmol), and DIPEA (22.41 mg, 173.44 μmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. Reverse phase preparative (acetonitrile / 10 M aqueous ammonium bicarbonate solution = 1.5 / 1) separation and purification afforded A27 (5.45 mg, 23.07% yield) as a white solid. LCMS (ESI) m / z = 817.56 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),10.17(s,1H),8.71(s,1H),8.30(d,J=8.4Hz,1H),7.96( s,1H),7.92(d,J=6.0Hz,1H),7.88–7.73(m,2H),7.47–7.36(m,2H),7.34–7.24(m,4H),7.22(s, 1H),3.91(s,3H),3.87–3.81(m,2H),3.77(t,J=6.4Hz,2H),3.43(s,2H),3.19(t,J=6.4Hz,2H), 2.71–2.53(m,2H),2.51–2.49(m,1H),2.20–2.11(m,2H),1.87–1.84(m,2H),1.59–1.57(m,2H).

[0478] Example 28 Synthesis of Compound A28:

[0479] Compound A28 (10.55 mg, yield 45.44%) was synthesized according to the synthesis method of Compound A27 described in Example 27. LCMS (ESI) m / z=803.5 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.36(s,1H),10.18(s,1H),8.72(s,1H),8.30(d,J=8.8Hz,1H),7. 96(s,1H),7.90(d,J=7.6Hz,1H),7.86–7.75(m,2H),7.49–7.37(m,2H),7.30(q,J=8.8Hz,4 H),7.22(s,1H),3.92(s,3H),3.83(bs,2H),3.78(t,J=6.8Hz,2H),3.47(s,2H),3.33(s,1H ),2.70(t,J=6.8Hz,4H),2.14(t,J=8.8Hz,2H),1.83–1.79(m,2H),1.55(q,J=10.8Hz,2H).

[0480] Example 29 Synthesis of Compound A29:

[0481] Step 1:

[0482] To a solution of compound A29-1 (100.00 mg, 363.23 μmol, synthesis reference patent WO2020132561) in N,N-dimethylformamide (5.0 mL) were added tert-butyl (2-bromoethyl)carbamate (81.40 mg, 363.23 μmol) and DIPEA (140.83 mg, 1.09 mmol) at room temperature. The reaction was allowed to react at 90°C for 12 h. Water was added to the reaction solution, extracted with ethyl acetate, and the layers separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The product was isolated and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to afford A29-2 (30 mg, 19.74% yield) as a pale yellow solid. LCMS (ESI) m / z = 419.3 [M+H] + .

[0483] Step 2:

[0484] To a solution of compound A29-2 (29.00 mg, 69.30 μmol) in dichloromethane (2.0 mL) was added HCl (4 M in dioxane, 1.0 mL) at room temperature. The reaction was stirred at 25°C for 2 h. The solvent was concentrated under reduced pressure to afford A29-3 (30 mg, 100% yield) as a yellow solid. LCMS (ESI) m / z = 319.2 [M+H] + .

[0485] Step 3:

[0486] To a solution of compound A29-3 (30.00 mg, 69.30 μmol) in N,N-dimethylformamide (2.0 mL) were added SM2 (15.00 mg, 28.91 μmol), HATU (21.98 mg, 57.81 μmol), and DIPEA (22.41 mg, 173.44 μmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. Reverse phase preparative (acetonitrile / 10 M aqueous ammonium bicarbonate solution = 1.5 / 1) separation and purification afforded A29 (14.25 mg, 58.97% yield) as a pale yellow solid. LCMS (ESI) m / z = 819.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),10.18(s,1H),8.72(s,1H),8.37–8.23(m,2H),8.08(d,J=2.8Hz, 1H),7.99(s,1H),7.89(d,J=8.8Hz,1H),7.83(dd,J1=8.4Hz,J2=2.0Hz,1H),7.51(dd,J1=8.8Hz,J2=2.8 Hz,1H),7.42(td,J1=8.8Hz,J2=6.8Hz,2H),7.21(s,1H),6.91(s,1H),6.88(d,J=9.2Hz,1H),3.94(s,3H ),3.70(t,J=6.8Hz,2H),3.53(bs,4H),3.49–3.41(m,2H),2.70(t,J=6.8Hz,2H),2.55(d,J=6.8Hz,6H).

[0487] Example 30 Synthesis of Compound A30:

[0488] Step 1:

[0489] To a solution of 2-bromo-5-iodopyridine (5.00 g, 17.44 mmol) in dimethyl sulfoxide (50 mL) was added potassium carbonate (4.87 g, 34.87 mmol), cuprous iodide (670.9 mg, 3.49 mmol), L-proline (405.5 mg, 3.49 mmol), and 1-(N-Boc-aminoethyl)piperazine (4.40 g, 19.18 mmol) at room temperature. The reaction mixture was heated to 80°C and stirred under argon for 4 h. The reaction mixture was washed with water and extracted with ethyl acetate. The organic phase was then dried to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to afford A30-1 (6.00 g, 90%) as a white solid. LCMS (ESI) m / z = 385.1 [M+H] + .

[0490] Step 2:

[0491] Compound A30-1 (500.0 mg, 1.30 mmol), cesium carbonate (845.5 mg, 2.60 mmol), trans-(1S,2S)-N,N-dimethylcyclohexanediamine (37.0 mg, 0.26 mmol), cuprous iodide (49.0 mg, 0.26 mmol), and 3-(4-methoxybenzyl)-dihydropyrimidine-2,4(1H,3H)-dione (395.0 mg, 1.69 mmol) were dissolved in dioxane (5 mL) at room temperature. The reaction mixture was stirred at 80°C for 4 h. The solvent was removed by concentration, and the residue was separated and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain A30-2 (400.0 mg, 57%) as a white solid. LCMS (ESI) m / z = 539.2 [M+H] + .

[0492] Step 3:

[0493] Trifluoroacetic acid (5 mL) and trifluoromethanesulfonic acid (1 mL) were added to compound A30-2 (400.0 mg, 0.74 mmol) at 0°C, and the reaction mixture was stirred at 25°C for 16 h. The reaction mixture was adjusted to pH ≈ 8 with saturated aqueous potassium bicarbonate solution and purified by reverse phase chromatography (acetonitrile / 10 M aqueous ammonium bicarbonate solution) to afford A30-3 (100.0 mg, 42%) as a white solid. LCMS (ESI) m / z = 319.1 [M+H] + .

[0494] Step 4:

[0495] To a solution of compound A30-3 (15.4 mg, 0.048 mmol) in N,N-dimethylformamide (1 mL) were added SM2 (15.0 mg, 0.029 mmol), HATU (13.2 mg, 0.034 mmol), and DIPEA (18.7 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous formic acid = 2.3 / 1) to afford A30 (3.9 mg, 16% yield) as a yellow solid. LCMS (ESI) m / z = 819.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.45(s,1H),10.23(s,1H),8.77(s,1H),8.31(d,J=2.8Hz,2H),8.12 (d,J=2.8Hz,1H),8.00(s,1H),7.93(d,J=8.4Hz,1H),7.85(dd,J1=8.4Hz,J2=2.4Hz,1H),7.5 7(d,J=9.2Hz,1H),7.52–7.44(m,3H),7.26(s,1H),3.98(s,3H),3.96–3.94(m,2H),3.47–3.4 2(m,2H),3.30–3.22(m,4H),3.24(s,3H),2.68(t,2H),2.55–2.50(m,4H),2.06–2.01(m,2H).

[0496] Example 31 Synthesis of Compound A31:

[0497] Step 1:

[0498] 2-Fluoro-5-pyridineboronic acid (600 mg, 4.26 mmol) was dissolved in acetonitrile, and tert-butyl 2,4-dicarbonyl-1H-pyrimidine-3-carboxylate (903.58 mg, 4.26 mmol, synthesis reference WO2021255212), copper acetate monohydrate (170.03 mg, 851.62 μmol), and triethylamine (860.14 mg, 8.52 mmol) were added sequentially. The reaction system was stirred at 60°C for 2 h. After completion of the reaction, the crude product was concentrated under reduced pressure and purified by flash silica gel column chromatography (PE:EA = 50% to 100%) to afford A31-1 (320 mg). LCMS (ESI) m / z = 308.1 [M+H] + .

[0499] Step 2:

[0500] A31-1 (300 mg, 976.32 μmol) was dissolved in DMSO (1 mL), and 1-(N-Boc-aminoethyl)piperazine (447.78 mg, 1.95 mmol) and triethylamine (197.22 mg, 1.95 mmol) were added sequentially. The mixture was stirred at 100°C for 2 h. After completion of the reaction, water (10 mL) and ethyl acetate (20 mL) were added. The organic phase was separated, dried over sodium sulfate, and concentrated under reduced pressure to afford crude product A31-2, which was directly used in the next step. LCMS (ESI) m / z = 317.1 [M+H] + .

[0501] Step 3:

[0502] A31-2 obtained in the previous step was dissolved in HCl (4.0M in dioxane, 2 mL) and stirred at room temperature for 1 h. The reaction solution was concentrated to remove the solvent to obtain a white solid A31-3, which was used directly in the next step. LCMS (ESI) m / z = 317.2 [M+H] + .

[0503] Step 4:

[0504] A31-3 (20 mg, 63.22 μmol) obtained in the previous step was dissolved in N,N-dimethylformamide (1 mL), and SM2 (16.40 mg, 31.61 μmol), HATU (18.03 mg, 47.41 μmol), and DIPEA (12.26 mg, 94.83 μmol, 16.52 μL) were added sequentially. The reaction solution was stirred at room temperature overnight. The reaction solution was separated and purified by reverse phase chromatography (acetonitrile / 0.1% formic acid aqueous solution = 2.3 / 1) to obtain A31 (2 mg, 9% yield) as a yellow solid. LCMS (ESI) m / z = 817.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.21(s,1H),8.74(s,1H),8.36–8.29(m,2H),8 .14(d,J=2.4Hz,1H),8.02(s,1H),7.91(d,J=8.4Hz,1H),7.85(dd,J1=8.2Hz,J2=2.6Hz 1H),7.47–7.41(m,2H),7.24(s,1H),7.01(s,1H),6.95(d,J=9.2Hz,1H),5.67(d,J =8.0Hz,1H),3.97(s,3H),3.61–3.59(m,4H),3.51–3.46(m,2H),2.59–2.53(m,6H).

[0505] Example 32 Synthesis of Compound A32:

[0506] Step 1:

[0507] Compound A32-1 (440.0 mg, 1.07 mmol, synthesis reference patent WO2021188948) was dissolved in N-methylpyrrolidone solution (3 mL), and tert-butyl (2-(2-bromoethoxy)ethyl)carbamate (353.4 mg, 1.32 mmol) and DIPEA (227.1 mg, 1.76 mmol) were added. The reaction solution was microwave-treated at 130°C for 1 h. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL*3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound A32-2 (306.0 mg, yellow solid). LCMS (ESI) m / z = 553.2 [M+H].

[0508] Step 2:

[0509] At room temperature, compound A32-2 (306.0 mg, 0.55 mmol) was dissolved in trifluoroacetic acid (6 mL), and trifluoromethanesulfonic acid (2 mL) was added. The reaction solution was stirred at 25°C for 16 h. The reaction solution was adjusted to pH ≈ 5 with saturated sodium bicarbonate. The reaction solution was separated and purified by reverse phase chromatography (acetonitrile / 10 M aqueous ammonium bicarbonate) to obtain compound A32-3 (76.0 mg, white solid). LCMS (ESI) m / z = 333.40 [M+H] + .

[0510] Step 3:

[0511] To a solution of compound A32-3 (19.2 mg, 0.058 mmol) in N,N-dimethylformamide (2 mL) were added SM2 (15.0 mg, 0.029 mmol), HATU (16.5 mg, 0.043 mmol), and DIPEA (11.2 mg, 0.087 mmol). The reaction was stirred at room temperature for 16 h. The reaction solution was separated and purified by reverse phase chromatography (methanol / 10 M aqueous ammonium bicarbonate) to afford A32 (7.0 mg, 29% yield) as a white solid. LCMS (ESI) m / z = 833.5 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.22(s,1H),8.75(s,1H),8.52(s,1H),8.40–8.28(m,2H),8.13( t,J=5.6Hz,1H),7.96(s,1H),7.89–7.78(m,3H),7.52-7.40(m,2H),7.26(s,3H),6.86(dd ,J=7.6,2.0Hz,1H),6.77(d,J=2.0Hz,1H),4.33(t,J=4.8Hz,2H),3.91(s,3H),3.85(t,J= 4.8Hz,2H),3.77(t,J=6.4Hz,2H),3.60(t,J=6.0Hz,2H),3.50–3.44(m,2H),2.81(bs,2H).

[0512] Example 33 Synthesis of Compound A33:

[0513] Step 1:

[0514] A33-1 (200 mg, 569.55 μmol, synthesis reference WO2020173440) was dissolved in DMSO (2 mL), and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (112.92 mg, 569.55 μmol) and DIPEA (368.05 mg, 2.85 mmol, 496.03 μL) were added sequentially and stirred at room temperature overnight. After the reaction was completed, water (10 mL) and ethyl acetate (20 mL) were added to the system. The organic phase was separated, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by flash silica gel column chromatography (PE:EA = 40% to 100%) to obtain A33-2 (30 mg). LCMS (ESI) m / z = 469.1 [M+H] + .

[0515] Step 2:

[0516] A33-2 obtained in the previous step was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 h. The reaction solution was concentrated to remove the solvent to obtain an oily product A33-3, which was used directly in the next step. LCMS (ESI) m / z = 369.1 [M+H] + .

[0517] Step 3:

[0518] A33-3 (23.58 mg, 64 μmol) obtained in the previous step was dissolved in N,N-dimethylformamide (1 mL). SM2 (20.86 mg, 42.24 μmol), HATU (36.50 mg, 96.00 μmol), and DIPEA (24.81 mg, 192.00 μmol, 33.44 μL) were added sequentially. The reaction solution was stirred at room temperature for 2 h. The reaction solution was separated and purified by reverse phase chromatography (acetonitrile / 0.1% formic acid aqueous solution = 2.3 / 1) to obtain A33 (12.2 mg, 21% yield) as a yellow solid. LCMS (ESI) m / z = 869.2 [M+H] + . 1 H NMR (400MHz, CD3OD-d4) δ8.62(s,1H),8.39(d,J=8.2Hz,1H),7.96(s,1H),7.85–7.81(m,3H),7.75(dd,J1=8.4Hz,J2=2.4Hz,1H),7.49–7.45(m,1 H),7.38–7.31(m,3H),5.19–5.14(m,1H),4.61(s,1H),4.24–4.16(m,6H ),3.94(s,3H),3.60–3.52(m,4H),2.91–2.75(m,3H),2.17–2.16(m,1H).

[0519] Example 34 Synthesis of Compound A34:

[0520] Step 1:

[0521] To a solution of A34-1 (63.00 mg, 167.38 μmol, synthesis reference patent CN112079866) in N,N-dimethylformamide (2.0 mL) were added tert-butyl 3-(methylamino)azetidine-1-carboxylate (46.76 mg, 251.07 μmol) and DIPEA (64.90 mg, 502.15 μmol) at room temperature. The reaction was allowed to proceed at 90°C for 16 h. Water was added to the reaction solution, extracted with ethyl acetate, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The product was separated and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain a yellow solid A34-2 (37 mg, yield 47.38%). LCMS (ESI) m / z = 467.1 [M+H] + .

[0522] Step 2:

[0523] To a solution of compound A34-2 (37.00 mg, 79.31 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (1.0 mL) at room temperature. The reaction was stirred at 25°C for 2 h. The solvent was concentrated under reduced pressure to afford A34-3 (30 mg, 100% yield), a brown solid. LCMS (ESI) m / z = 367.2 [M+H] + .

[0524] Step 3:

[0525] To a solution of compound A34-3 (30.00 mg, 61.79 μmol) in N,N-dimethylformamide (2.0 mL) at room temperature were added SM2 (15.00 mg, 28.91 μmol), HATU (21.98 mg, 57.81 μmol), and DIPEA (22.41 mg, 173.44 μmol). The reaction was stirred at room temperature for 2 h. Reverse phase preparative (acetonitrile / 10 M aqueous ammonium bicarbonate solution = 1.5 / 1) separation and purification afforded A34 (21.91 mg, 86.67% yield) as a pale yellow solid. LCMS (ESI) m / z = 867.1 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),10.08(s,1H),8.70(s,1H),8.29(d,J=8.4Hz,1H),7.90(s,1H),7.80(dd, J1=8.4Hz,J2=2.4Hz,1H),7.71(dd,J1=19.2Hz,J2=7.2Hz,2H),7.53(t,J=7.6Hz,1H),7.47–7.30(m,2H),7.30– 7.16(m,2H),5.12(dd,J1=13.2Hz,J2=5.2Hz,1H),4.54–4.29(m,2H),3.99-3.95(m,2H),3.91-3.89(m,1H),3.8 6(s,3H),3.65(s,2H),3.51-3.49(m,1H),3.03–2.82(m,1H),2.70–2.55(m,2H),2.26(s,3H),2.07-2.03(m,1H).

[0526] Example 35 Synthesis of Compound A35:

[0527] Compound A35 (11.6 mg, yield 46.8%) was synthesized according to the synthesis method of Compound A8 described in Example 8. LCMS (ESI) m / z = 787.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.24(d,J=8.0Hz,1H),10.13(s,1H),8.71(s,1H),8.30(d,J =8.0Hz,1H),7.92–7.84(m,3H),7.55(t,J=8.0Hz,3H),7.35–7.31(m,1H),7.22–7.08 (m,4H),7.00–6.87(m,2H),3.68(t,J=7.2Hz,2H),3.58(d,J=7.2Hz,2H),3.40(s,2H) ,3.28–3.07(m,4H),2.70–2.64(m,2H),1.87–1.77(m,2H),1.70(s,2H),1.58(s,2H).

[0528] Example 36 Synthesis of Compound A36:

[0529] Compound A36 (14.5 mg, yield 58%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 829.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.24(d,J=8.0Hz,1H),10.03(d,J=4.0Hz,1H),8.68(d,J=4.0Hz,1H),8.33–8. 26(m,1H),7.89(s,1H),7.83–7.77(m,1H),7.45–7.34(m,2H),7.21(s,1H),7.17–7.08(m,3H),6.96(d, J=8.0Hz,1H),6.90(d,J=8.0Hz,1H),3.82(s,3H),3.72–3.63(m,2H),3.50(d,J=8.0Hz,1H),3.38–3.35 (m,1H),3.31–3.06(m,5H),3.05–2.96(m,1H),2.70–2.63(m,2H),1.84–1.72(m,2H),1.70–1.50(m,4H).

[0530] Example 37 Synthesis of Compound A37:

[0531] Compound A37 (18.19 mg, yield 72.43%) was synthesized according to the synthesis method of Compound A8 described in Example 8. LCMS (ESI) m / z = 787.5 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.23(s,1H),10.13(s,1H),8.73(s,1H),8.42(d,J=8.8Hz,1H),8.30(d, J=8.3Hz,1H),7.97–7.78(m,5H),7.61-7.53(m,1H),7.34(d,J=2.0Hz,1H),7.22–7.09(m,4H),6. 94(d,J=8.8Hz,2H),4.52–4.43(m,1H),3.69(t,J=6.8Hz,2H),3.18–3.14(m,2H),3.11(m,2H),2. 68(t,J=6.8Hz,2H),2.28–2.23(m,2H),1.93–1.88(m,2H),1.75–1.73(m,2H),1.70–1.68(m,2H).

[0532] Example 38 Synthesis of Compound A38:

[0533] Compound A38 (18.57 mg, yield 77.46%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 829.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),10.16(s,1H),8.72(s,1H),8.30(d,J=8.4Hz,1H),8.11(d,J=7. 6Hz,1H),7.94(s,1H),7.82(dd,J1=6.0Hz,J1=2.4Hz,1H),7.75(d,J=8.4Hz,1H),7.50–7.36(m,2H),7. 22(s,1H),7.13(d,J=8.4Hz,2H),6.94(d,J=8.8Hz,2H),4.42(m,1H),3.93(s,3H),3.69(t,J=6.4Hz,2 H),3.24–2.97(m,4H),2.68(t,J=6.4Hz,2H),2.32-2.27(m,2H),1.87-1.82(m,2H),1.76–1.58(m,4H).

[0534] Example 39 Synthesis of Compound A39:

[0535] Compound A39 (9.0 mg, yield 36%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 801.1 [M+H]+ . 1 H NMR (400MHz, DMSO-d6) δ10.26(s,1H),10.14(s,1H),8.74(s,1H),8.33(d,J=8.4H z,1H),7.97–7.82(m,3H),7.66–7.48(m,1H),7.44–7.31(m,3H),7.25–7.09(m,4H ),6.93(d,J=8.8Hz,2H),4.59(s,1H),3.71(t,J=6.4Hz,2H),3.20–3.03(m,4H),2 .99(s,3H),2.70(t,J=6.8Hz,2H),2.11–2.02(d,J=9.8Hz,4H),1.74–1.53(m,4H).

[0536] Example 40 Synthesis of Compound A40:

[0537] first step:

[0538] Compound A40-1 (269.0 mg, 0.74 mmol, synthesis reference patent WO2020147702) was dissolved in tetrahydrofuran (5 mL), and sodium hydride (119.1 mg, 2.98 mmol) was added at 0°C under argon protection. The reaction solution was stirred at 0°C under argon protection for 10 minutes. Iodomethane (316.9 mg, 2.23 mmol) was added, and the reaction solution was stirred at room temperature under argon protection for 2 hours. Water (50 mL) was added to the reaction solution, and dichloromethane (50 mL*3) was added. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound A40-2 (380.0 mg, yellow solid, crude product). LCMS (ESI) m / z = 376.3 [M+H] + .

[0539] Step 2:

[0540] Compound A40 (11.0 mg, yield 45%) was synthesized according to the synthesis method of Compound A8 described in Example 8. LCMS (ESI) m / z = 843.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.22(s,1H),10.03(s,1H),8.68(s,1H),8.28(d,J=8. 4Hz,1H),7.93–7.72(m,2H),7.48–7.29(m,2H),7.20(s,1H),7.17–6.98(m,3H), 6.98–6.76(m,3H),4.24–4.05(m,1H),3.76(s,3H),3.70–3.63(m,2H),3.14–2.9 1(m,6H),2.76(s,1H),2.72–2.60(m,2H),2.15–1.79(m,4H),1.77–1.39(m,4H).

[0541] Example 41 Synthesis of Compound A41:

[0542] Compound A41 (11 mg, yield 45.2%) was synthesized according to the synthesis method of Compound A8 described in Example 8. LCMS (ESI) m / z = 773.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),10.17(s,1H),8.72(s,1H),8.30(d,J=8. 4Hz,1H),7.97–7.85(m,3H),7.67(d,J=8.4Hz,2H),7.58–7.54(m,1H),7.33(d,J =2.0Hz,1H),7.21–7.15(m,4H),6.94(d,J=8.8Hz,2H),4.13(s,2H),3.79(s,2H ),3.69(t,J=6.8Hz,2H),3.20–3.13(m,4H),2.67(t,J=6.8Hz,2H),1.83(s,4H).

[0543] Example 42 Synthesis of Compound A42:

[0544] Compound A42 (9.4 mg, yield 39.8%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 815.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),10.06(s,1H),8.69(s,1H),8.29(d,J =8.4Hz,1H),7.89(s,1H),7.81(dd,J1=8.4Hz,J2=2.2Hz,1H),7.46–7.34(m, 2H),7.29–7.19(m,2H),7.12(d,J=8.8Hz,2H),7.01–6.89(m,3H),3.84(s,3H ),3.76–3.62(m,6H),3.22–3.03(m,4H),2.67(t,J=6.6Hz,2H),1.78(s,4H).

[0545] Example 43 Synthesis of Compound A43:

[0546] Compound A43 (16.2 mg, yield 67.8%) was synthesized according to the synthesis method of Compound A8 described in Example 8. LCMS (ESI) m / z = 759.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.20(s,1H),10.12(s,1H),8.71(s,1H),8.30(d,J=8.0Hz,1H),7.93–7.85(m,3H),7.58–7.52( m,3H),7.33(d,J=2.0Hz,1H),7.20–7.06(m,4H),6.50–6.38(m,2H),3.89–3.54(m,10H),2.70–2.64(m,2H),2.14(s,2H).

[0547] Example 44 Synthesis of Compound A44:

[0548] Compound A44 (11.6 mg, yield 48.2%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 801.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.22(d,J=8.0Hz,1H),10.04(s,1H),8.69(d,J=4.0Hz,1H),8.32–8.26(m,1H),7.90(s,1H),7.83–7.76(m,1H),7.46 –7.34(m,2H),7.21(s,1H),7.17–7.06(m,3H),6.54-6.44(m,2H),3.86 –3.65(m,9H),3.56–3.29(m,4H),2.70–2.63(m,2H),2.17–2.06(m,2H).

[0549] Example 45 Synthesis of Compound A45:

[0550] Step 1:

[0551] To a solution of 2-chloro-5-iodopyrimidine (1.00 g, 4.16 mmol) in N,N-dimethylformamide and DIEA (10 mL / 2 mL) was added 1-(N-Boc-aminoethyl)piperazine (77.5 mg, 0.26 mmol) at room temperature. The reaction mixture was heated to 80°C and stirred for 2 h. The reaction mixture was washed with water and extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to afford A45-1 (1.18 g, 65%) as a white solid. LCMS (ESI) m / z = 434.1 [M+H] + .

[0552] Step 2:

[0553] Compound A45-1 (1.18 g, 2.72 mmol), cesium carbonate (1.77 g, 5.45 mmol), trans-(1S,2S)-N,N-dimethylcyclohexanediamine (1.77 g, 0.54 mmol), cuprous iodide (103.0 mg, 0.54 mmol), and 3-(4-methoxybenzyl)-dihydropyrimidine-2,4(1H,3H)-dione (637.5 mg, 2.72 mmol) were dissolved in dioxane (15 mL) at room temperature. The reaction mixture was stirred at 80°C for 16 h. The solvent was removed by concentration, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to afford A45-2 (1.20 g, 81%) as a white solid. LCMS (ESI) m / z = 540.1 [M+H] + .

[0554] Step 3:

[0555] To a solution of compound A45-2 (300.0 mg, 0.56 mmol) in trifluoroacetic acid (3 mL) was added trifluoromethanesulfonic acid solution (3 mL), and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 10 M aqueous ammonium bicarbonate solution = 2.3 / 1) to afford A45-3 (100.0 mg, 56% yield) as a white solid. LCMS (ESI) m / z = 340.3 [M+H] + .

[0556] Step 4:

[0557] To a solution of compound A45-3 (15.4 mg, 0.048 mmol) in N,N-dimethylformamide (1 mL) were added SM2 (15.0 mg, 0.029), HATU (13.2 mg, 0.034 mmol), and DIPEA (18.7 mg, 0.14 mmol). The reaction was stirred at room temperature for 3 h. The reaction solution was separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous formic acid = 2.3 / 1) to afford A45 (5.8 mg, 24% yield) as a yellow solid. LCMS (ESI) m / z = 820.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.47(s,1H),10.23(s,1H),8.76(s,1H),8.30(s,2H), 8.38-8.32(m,2H),8.04(s,1H),7.92(d,J=8.8Hz,1H),7.85(dd,J1=8.4Hz,J2=2 .4Hz,1H),7.48–7.44(m,2H),7.25(s,1H),3.96(s,3H),3.83–3.80(m,4H),3.7 4(t,J=6.8Hz,2H),3.49–3.47(m,2H),2.76(t,J=6.8Hz,2H), 2.58–2.51(m,2H).

[0558] Example 46 Synthesis of Compound A46:

[0559] Compound A46 (15.0 mg, yield 61%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 799.5 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.29(s,1H),10.18(s,1H),8.74(s,1H),8.47(d,J=7.6Hz,1H),8.29(d,J =8.4Hz,1H),7.95(d,J=8.4Hz,2H),7.91–7.80(m,3H),7.45(q,J=8.0Hz,1H),7.25(s,1H),7.16(d, J=8.8Hz,2H),6.97(d,J=9.2Hz,2H),4.51–4.44(m,1H),3.72(t,J=6.4Hz,2H),3.24–3.14(m,2H), 3.14–3.03(m,2H),2.71(t,J=6.8Hz,2H),2.27–2.22(m,2H),1.93–1.88(m,2H),1.80–1.62(m,4H).

[0560] Example 47 Synthesis of Compound A47:

[0561] Step 1:

[0562] To a solution of 1-(N-Boc-aminoethyl)piperazine (2.7 g, 11.7 mmol) in dimethyl sulfoxide (15 mL) at room temperature were added 4-bromoiodobenzene (3 g, 10.6 mmol), potassium carbonate (2.93 g, 21.2 mmol), cuprous iodide (404 mg, 2.12 mmol), and L-proline (244 mg, 2.12 mmol). The reaction mixture was heated to 80°C and stirred under argon for 16 h. Water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:3) to afford A47-1 (2.8 g, 69% yield) as a white solid. LCMS (ESI) m / z = 384.9 [M+H] + .

[0563] Step 2:

[0564] To a solution of compound A47-1 (400 mg, 1.04 mmol) in dioxane (10 mL) and water (1 mL) at room temperature were added 2,6-bis(phenylmethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridine (456 mg, 10.6 mmol), cesium carbonate (678 mg, 2.08 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (85 mg, 0.1 mmol). The reaction mixture was heated to 100°C under argon and stirred for 16 h. Water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:2) to afford A47-2 (298 mg, 48% yield) as a white solid. LCMS (ESI) m / z = 595.2 [M+H] + .

[0565] Step 3:

[0566] To a solution of compound A47-2 (298 mg, 0.5 mmol) in methanol (5 mL) was added 10% palladium on carbon (50 mg, 0.05 mmol) at room temperature. The atmosphere was replaced with hydrogen three times, and the mixture was heated to 35°C and stirred for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford A47-3 (153 mg, 73% yield) as a white solid. LCMS (ESI) m / z = 417.1 [M+H] + .

[0567] Step 4:

[0568] To a solution of compound A47-3 (30 mg, 0.07 mmol) in dichloromethane (2 mL) was added HCl (4 M in dioxane, 0.5 mL) at room temperature. The reaction was stirred at 30°C for 1 h. The reaction solution was concentrated under reduced pressure to afford a light yellow solid A47-4 (23 mg, 99% yield). LCMS (ESI) m / z = 317.2 [M+H] + .

[0569] Step 5:

[0570] To a solution of compound A47-4 (23 mg, 0.07 mmol) in N,N-dimethylformamide (2 mL) were added SM2 (15 mg, 0.03 mmol), HATU (14 mg, 0.04 mmol), and DIPEA (12.2 mg, 0.09 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 10 M aqueous ammonium bicarbonate) to afford A47 (13.3 mg, 54.2% yield) as a pale yellow solid. LCMS (ESI) m / z = 817.1 [M+H] + .1 H NMR(400MHz,DMSO-d6)δ10.77(s,1H),10.19(s,1H),8.71(s,1H),8.34–8.27(m,2H),7.97(s,1H),7 .89(d,J=8.8Hz,1H),7.82(dd,J1=8.0Hz,J2=2.0Hz,1H),7.46–7.38(m,2H),7.21(s,1H),7.06(d,J= 8.0Hz,2H),6.92(d,J=8.0Hz,2H),3.93(s,3H),3.76–3.70(m,1H),3.49–3.41(m,2H),3.20–3.12(m, 4H),2.69–2.63(m,2H),2.62–2.57(m,4H),2.57–2.53(m,2H),2.18–2.08(m,1H),2.06–1.96(m,1H).

[0571] Example 48 Synthesis of Compound A48:

[0572] Step 1:

[0573] Compound A48-1 was synthesized according to the synthesis method of compound A8 described in Example 8. LCMS (ESI) m / z=313.1 [M+H] + .

[0574] Step 2:

[0575] To a solution of A48-1 (400 mg, 1.28 mmol) in N,N-dimethylformamide (4 mL) was added DIPEA (496.54 mg, 3.84 mmol, 669.20 μL) and 3-N-tert-butoxycarbonylaminocyclobutylamine (441.12 mg, 2.56 mmol) at room temperature. The reaction mixture was stirred at 80°C for 4 h. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methane = 20:1) to afford A48-2 (150 mg, 30.1% yield) as a white solid. LCMS (ESI) m / z = 389.0 [M+H] + .

[0576] Step 3:

[0577] To a solution of A48-2 (60 mg, 154.46 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1.49 g, 13.07 mmol, 1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was directly concentrated under reduced pressure to give a crude colorless oil, A48-3 (60 mg), which was used directly in the next step. LCMS (ESI) m / z = 289.1 [M+H] + .

[0578] Step 4:

[0579] Compound A48 (10 mg, yield 43.8%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 789.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),10.18(s,1H),8.72(s,1H),8.32(d,J=7.8Hz,1H),.8.25(d,J=7.8Hz,1H),7.94(s,1H),7.86–7.71(m,2H), 7.46–7.37(m,2H),7.23(s,6H),4.44(m,1H),3.93(s,3H),3.76(t,J=6.6 Hz,2H),3.58(t,J=7.0Hz,2H),2.93(t,J=7.0Hz,2H),2.74–2.54(m,6H).

[0580] Example 49 Synthesis of Compound A49:

[0581] Compound A49 (5.0 mg, yield 21%) was synthesized according to the synthesis method of compound A27 described in Example 27. LCMS (ESI) m / z = 801.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),10.08(s,1H),8.70(s,1H),8.29(d,J=8. 4Hz,1H),7.89(s,1H),7.81(d,J=8.4Hz,1H),7.47–7.38(m,1H),7.37–7.30(m, 1H),7.28–7.19(m,6H),4.05(s,2H),4.00(s,2H),3.82(s,3H),3.76(t,J=6.6H z,2H),3.49(s,2H),3.29(s,2H),3.24(d,J=7.4Hz,2H),2.69(t,J=6.6Hz,2H).

[0582] Example 50 Synthesis of Compound A50:

[0583] Compound A50 (5.5 mg, yield 24.2%) was synthesized according to the synthesis method of Compound A6 described in Example 6. LCMS (ESI) m / z = 784.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),10.17(s,1H),8.71(s,1H),8.32(d,J=8.0Hz,1H),8.28(d,J=8.0Hz,1H),7.94(s,1H),7.85–7.73(m,2H) ,7.47–7.26(m,6H),7.22(s,1H),4.72(m,1H),3.93(s,3H),3.80(t,J=6 .6Hz,2H),3.38–3.34(m,1H),2.70(t,J=6.6Hz,2H),2.47–2.38(m,4H).

[0584] Example 51 Synthesis of Compound A51:

[0585] Compound A51 (5.0 mg, yield 22%) was synthesized according to the synthesis method of Compound A6 described in Example 6. LCMS (ESI) m / z = 784.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.45(s,1H),10.21(s,1H),8.75(s,1H),8.35–8.30(m,J=7. 6Hz,2H),7.97(s,1H),7.85(d,J=8.4Hz,1H),7.78(d,J=8.4Hz,1H),7.50–7.43(m,J=7 .6Hz,4H),7.38(s,1H),7.35(s,1H),7.25(s,1H),4.75–4.70(m,1H),3.96(s,3H),3.8 4(t,J=6.4Hz,2H),3.38–3.34(m,1H),2.76–2.74(t,J=6.4Hz,2H),2.49–2.45(m,4H).

[0586] Example 52 Synthesis of Compound A52:

[0587] Compound A52 (13 mg, yield 55.6%) was synthesized according to the synthesis method of Compound A6 described in Example 6. LCMS (ESI) m / z = 742.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),10.18(s,1H),8.73(s,1H),8.63(d,J=7.6Hz,1H),8.32( d,J=7.6Hz,1H),7.94–7.82(m,5H),7.61–7.53(m,1H),7.43–7.24(m,5H),7.17(t,J=8.9Hz,2H ),4.77–4.65(m,0.7H),4.48–4.35(m,0.3H),3.84–3.75(m,2H),3.38–3.34(m,0.7H),3.05–2. 95(m,0.3H),2.74–2.62(m,3H),2.55–2.51(m,1H),2.48–2.37(m,1.4H),2.34–2.22(m,0.6H).

[0588] Example 53 Synthesis of Compound A53:

[0589] Compound A53 (6.0 mg, yield 27%) was synthesized according to the synthesis method of Compound A6 described in Example 6. LCMS (ESI) m / z = 742.23 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.46(s,1H),10.21(s,1H),8.77(s,1H),8.62(d,J =7.2Hz,1H),8.37–8.33(m,1H),7.95–7.83(m,6H),7.60–7.56(m,1H),7.48 –7.42(m,1H),7.37–7.31(m,3H),7.22–7.17(m,2H),4.74–4.72(m,1H),3.8 5(t,J=6.4Hz,2H),3.31–3.29(m,1H),2.74–2.65(m,3H),2.51–2.34(m,3H).

[0590] Example 54 Synthesis of Compound A54:

[0591] Step 1:

[0592] To a solution of tert-butyl 7-azaspiro[3.5]nonane-2-carbamate (200.0 mg, 0.89 mmol) in dimethyl sulfoxide (2 mL) was added 2-fluoro-5-iodopyridine (215.6 mg, 0.89 mmol) and DIPEA (1.3 g, 2.69 mmol) at room temperature. The reaction mixture was stirred at 110°C for 4 h. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous formic acid) to afford A54-1 (284 mg, 71%) as a yellow solid. LCMS (ESI) m / z = 444.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.21(d,J=2.4Hz,1H),7.70(dd,J1=9.0Hz,J2=2.4Hz,1H),7.11(d,J=8.0Hz,1H),6.73(d,J=9.0Hz,1H),3.98–3.88 (m,1H),3.47–3.41(m,2H),3.39–3.34(m,2H),2.13-2.08(m,2H),1.68–1.63(m,2H),1.52(t,J=5.6Hz,2H),1.49–1.43(m,2H),1.37(s,9H).

[0593] Step 2:

[0594] To a solution of compound A54-1 (280 mg, 0.63 mmol) in 1,4-dioxane (10 mL) were added 3-(4-methoxybenzyl)-dihydropyrimidine-2,4(1H,3H)-dione (162.7 mg, 0.69 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (89.8 mg, 0.63 mmol), cesium carbonate (411.5 mg, 1.26 mmol), and cuprous iodide (24.0 mg, 0.12 mmol) at room temperature. The reaction mixture was stirred at 110°C for 14 h. Water was added to the reaction mixture, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to remove the solvent. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to afford A54-2 (270 mg, 77%) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ8.03(d,J=2.6Hz,1H),7.46(dd,J1=9.0Hz,J2=2.8Hz,1H),7.21(d,J=8.2 Hz,2H),7.11(d,J=7.9Hz,1H),6.86–6.81(m,3H),4.78(s,2H),3.94(q,J=8.0Hz,1H),3.72(s,3H ),3.70–3.68(m,2H),3.46(t,J=3.6Hz,2H),3.38t,J=3.76Hz,2H),2.87(t,J=6.6Hz,2H),2.12(t ,J=9.6Hz,2H),1.67(t,J=10.0Hz,2H),1.55(t,J=6.0Hz,2H),1.48(t,J=6.0Hz,2H),1.37(s,9H).

[0595] Step 3:

[0596] Trifluoroacetic acid (1 mL) and trifluoromethanesulfonic acid (0.2 mL) were added to compound A54-2 (220.0 mg, 0.40 mmol) at 0°C, and the reaction mixture was stirred at 25°C for 14 h. The reaction mixture was adjusted to pH ≈ 8 with saturated potassium bicarbonate and purified by reverse phase chromatography (acetonitrile / 10 M aqueous ammonium bicarbonate) to afford A54-3 (100 mg, 75%) as a white solid. LCMS (ESI) m / z = 330.1 [M+H] + .

[0597] Step 4:

[0598] To a solution of compound A54-3 (19.0 mg, 0.057 mmol) in N,N-dimethylformamide (1 mL) were added SM2 (15.0 mg, 0.029 mmol), HATU (13.2 mg, 0.034 mmol), and DIPEA (18.7 mg, 0.14 mmol). The reaction was stirred at room temperature for 2 h. The reaction solution was separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous formic acid = 2.3 / 1) to afford A54 (13.7 mg, 57% yield) as a yellow solid. LCMS (ESI) m / z = 830.6 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.33(s,1H),10.17(s,1H),8.72(s,1H),8.30(d,J=8.5Hz,1H),8.12(d,J=7.4Hz,1H), 8.04(d,J=2.6Hz,1H),7.94(s,1H),7.82(dd,J1=8.4Hz,J2=2.2Hz,1H),7.75(d,J=8.6Hz,1H),7.49–7.39(m,3H) ,7.22(s,1H),6.85(d,J=9.0Hz,2H),4.47–4.37(m,1H),3.93(s,3H),3.69(t,J=6.6Hz,2H),3.54–3.52(m,2H), 3.48–3.45(m,2H),2.69(t,J=6.6Hz,2H),2.29–2.24(m,2H),1.85–1.79(m,2H),1.64–1.62(m,2H),1.58–1.54(m 2H).

[0599] Example 55 Synthesis of Compound A55:

[0600] Compound A55 (5.7 mg, yield 22%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 788.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),10.16(s,1H),8.73(s,1H),8.44(d,J=7.4Hz,1H),8.30(d,J=8.4Hz,1H),8 .04(d,J=2.7Hz,1H),7.93-7.81(m,5H),7.58–7.51(m,1H),7.47(dd,J=9.0,2.6Hz,1H),7.34(d,J=2.0Hz,1H),7. 17(t,J=8.6Hz,2H),6.85(d,J=9.0Hz,1H),4.45(q,J=8.0Hz,1H),3.69(t,J=6.6Hz,2H),3.53–3.50(m,2H),3.45 –3.43(m,2H),2.69(t,J=6.8Hz,2H),2.29–2.24(m,2H),1.94–1.89(m,2H),1.67–1.62(m,2H),1.59–1.57(m,2H).

[0601] Example 56 Synthesis of Compound A56:

[0602] Step 1:

[0603] To a mixed solution of compound A18-2 (443.00 mg, 1.40 mmol) in methanol (20.0 mL) and water (10.0 mL) were added sodium periodate (449.55 mg, 2.10 mmol) and ammonium acetate (1.08 g, 14.01 mmol) at room temperature. The reaction was stirred at 25°C for 12 h. Solid impurities were removed by filtration, and the filtrate was concentrated. The product was isolated and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to afford A56-1 (285 mg, 86.92% yield) as a white solid. LCMS (ESI) m / z = 235.1 [M+H] + .

[0604] Step 2:

[0605] To a mixed solution of compound A56-1 (250.00 mg, 1.07 mmol) in dimethyl sulfoxide (7.0 mL) and acetonitrile (30.0 mL) at room temperature were added 2-azaspiro[3.5]nonan-7-one (446.11 mg, 3.20 mmol), copper acetate (250 mg, 1.38 mmol), and triethylamine (1.08 g, 10.68 mmol). The reaction was stirred at 25°C for 12 h. The reaction mixture was filtered to remove solid impurities, the filtrate was concentrated, water was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The product was separated and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain a green solid A56-3 (256 mg, yield 73.20%). LCMS (ESI) m / z = 328.1 [M+H] + .

[0606] Step 3:

[0607] To a mixed solution of compound A56-3 (58.00 mg, 177.17 μmol) in methanol (5.0 mL) and acetonitrile (2.0 mL) at room temperature were added ammonium acetate (68.21 mg, 885.83 μmol) and sodium cyanoborohydride (33.40 mg, 531.50 μmol). The reaction was stirred at 25°C for 12 h. The solvent was removed by concentration under reduced pressure, and the product was isolated and purified using reverse phase preparative (acetonitrile / aqueous formic acid 0.1% = 25%) to afford A56-4 (15 mg, 25.78% yield) as a light green solid. LCMS (ESI) m / z = 328.2 [M+H] + .

[0608] Step 4:

[0609] To a solution of compound A56-4 (15.00 mg, 45.67 μmol) in N,N-dimethylformamide (2 mL) were added SM1 (5.00 mg, 10.49 μmol), HATU (7.97 mg, 20.97 μmol), and DIPEA (8.13 mg, 62.91 μmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. Reverse phase preparative (acetonitrile / 10 M aqueous ammonium bicarbonate solution = 1.5 / 1) separation and purification afforded A56 (6.36 mg, 77.05% yield) as a white solid. LCMS (ESI) m / z = 787.51 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.23(s,1H),10.15(s,1H),8.73(s,1H),8.30(d,J=8.4Hz,1H),8.04(d,J=8.0H z,1H),7.96–7.86(m,3H),7.83(d,J=8.8Hz,2H),7.61–7.46(m,1H),7.34(s,1H),7.18(d,J=8.4Hz,2H), 7.10(d,J=8.0Hz,2H),6.43(d,J=8.4Hz,2H),3.79(bs,1H),3.67(t,J=6.8Hz,2H),3.59(s,2H),3.51(s, 2H), 2.67(t,J=6.8Hz,2H),1.99–1.95(m,2H),1.82–1.80(m,2H),1.66–1.60(m,2H),1.50–1.43(m,2H).

[0610] Example 57 Synthesis of Compound A57:

[0611] Compound A57 (6.29 mg, yield 78.72%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 829.01 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.24(s,1H),10.19(s,1H),8.72(s,1H),8.31(d,J=8.8Hz,1H), 7.96(s,1H),7.89–7.76(m,3H),7.50–7.38(m,2H),7.22(s,1H),7.10(d,J=8.0Hz,2H),6 .42(d,J=8.0Hz,2H),3.93(s,3H),3.82(bs,1H),3.67(t,J=6.4Hz,2H),3.58(s,2H),3.5 2(s,2H),2.67(t,J=6.8Hz,2H),1.94–1.83(m,4H),1.70–1.64(m,2H),1.46–1.43(m,2H).

[0612] Example 58 Synthesis of Compound A58:

[0613] Step 1:

[0614] Compound A58-1 (157.0 mg, 0.40 mmol, Synthesis Reference Example 8) was dissolved in a mixture of acetic acid (2 mL) and water (0.4 mL). Sodium cyanate (52.4 mg, 0.81 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain compound A58-2 (200.0 mg, yellow solid, crude product). LCMS (ESI) m / z = 433.1 [M+H] + .

[0615] Step 2:

[0616] Compound A58-2 (174.0 mg, 0.40 mmol) was dissolved in tetrahydrofuran (4 mL) and potassium trimethylsilanol was added to adjust the pH to ≈ 9. The reaction solution was stirred at room temperature for 1 h. The reaction solution was adjusted to weak acidity with acetic acid and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain compound A58-3 (167.0 mg, yellow solid, crude product). LCMS (ESI) m / z = 401.2 [M+H] + .

[0617] Step 3:

[0618] Compound A58-3 (80.0 mg, 0.20 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1.5 mL) was added. The reaction mixture was stirred at 25°C for 2 h. The reaction mixture was concentrated to remove the solvent to give A58-4 (100.0 mg, yellow solid, crude product, trifluoroacetate salt). LCMS (ESI) m / z = 301.3 [M+H] + .

[0619] Step 7:

[0620] To a solution of compound A58-4 (23.9 mg, 0.058 mmol) in N,N-dimethylformamide (2 mL) were added SM2 (15.0 mg, 0.029 mmol), HATU (16.5 mg, 0.043 mmol), and DIPEA (11.2 mg, 0.087 mmol). The reaction was stirred at room temperature for 3 h. The reaction solution was separated and purified by reverse phase chromatography (acetonitrile / 10 M aqueous ammonium bicarbonate) to afford A58 (10.0 mg, 43% yield) as a yellow solid. LCMS (ESI) m / z = 800.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.26(s,1H),10.21(s,1H),8.75(s,1H),8.33(d,J=8.4Hz,1H),8.17(d,J =7.6Hz,1H),7.97(s,1H),7.85(dd,J1=8.4Hz,J2=2.4Hz,1H),7.79(d,J=8.4Hz,1H),7.51–7.36(m, 2H),7.25(s,1H),7.18-7.06(m,2H),6.51–6.36(m,2H),4.48–4.28(m,1H),3.96(s,3H),3.91(s,2H ),3.80(s,2H),3.69(t,J=6.4Hz,2H),2.70(t,J=6.8Hz,2H),2.60–2.55(m,2H),2.33–2.28(m,2H).

[0621] Example 59 Synthesis of Compound A59:

[0622] Compound A59 (14.5 mg, yield 61%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 758.96 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.26(s,1H),10.20(s,1H),8.76(s,1H),8.50(d,J=7.2Hz,1H),8. 33(d,J=8.4Hz,1H),8.00-7.77(m,5H),7.61–7.53(m,1H),7.37(d,J=2.0Hz,1H),7.27–7.17 (m,2H),7.13(d,J=8.0Hz,2H),6.45(d,J=8.4Hz,2H),4.41–4.35(m,1H),3.92(s,2H),3.81 (s,2H),3.69(t,J=6.4Hz,2H),2.70(t,J=6.8Hz,2H),2.63–2.55(m,2H),2.36–2.31(m,2H).

[0623] Example 60 Synthesis of Compound A60:

[0624] Compound A60 (21.0 mg, yield 88%) was synthesized according to the synthesis method of compound A54 described in Example 54. LCMS (ESI) m / z = 760.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.36(s,1H),10.20(s,1H),8.76(s,1H),8.49(d,J=7.2Hz,1H),8.3 3(d,J=8.4Hz,1H),8.04(d,J=2.4Hz,1H),7.99–7.82(m,5H),7.65–7.47(m,2H),7.37(d,J=2 .0Hz,1H),7.20(t,J=8.8Hz,2H),6.43(d,J=8.8Hz,1H),4.41–4.39(m,1H),4.05(s,2H),3.9 4(s,2H),3.71(t,J=6.4Hz,2H),2.72(t,J=6.8Hz,2H),2.61–2.56(m,2H),2.41–2.25(m,2H).

[0625] Example 61 Synthesis of Compound A61:

[0626] Compound A61 (7.82 mg, yield 47.31%) was synthesized according to the synthesis method of compound A54 described in Example 54. LCMS (ESI) m / z = 788.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.33(s,1H),10.15(s,1H),8.73(s,1H),8.30(d,J=8.4Hz,1H),8 .10–7.97(m,2H),7.92–7.80(m,5H),7.62–7.43(m,2H),7.34(d,J=2.4Hz,1H),7.23–7.09( m,2H),6.41(d,J=8.8Hz,1H),3.87–3.74(m,1H),3.74–3.65(m,4H),3.63(s,2H),2.70(t, J=6.8Hz,2H),1.99–1.96(m,2H),1.82–1.80(m,2H),1.66–1.61(m,2H),1.52–1.44(m,2H).

[0627] Example 62 Synthesis of Compound A62:

[0628] Compound A62 (10.0 mg, yield 42%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 758.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),10.20(s,1H),8.76(s,1H),8.50(d,J=7.6Hz,1H),8.33 (d,J=8.8Hz,1H),8.00-7.78(m,5H),7.58(t,J=7.6Hz,1H),7.37(d,J=2.0Hz,1H),7.26–7.13( m,3H),6.64(d,J=8.0Hz,1H),6.40(s,1H),6.34(d,J=8.4Hz,1H),4.44–4.39(m,1H),3.92(s, 2H),3.80(s,2H),3.78–3.74(m,2H),2.74–2.69(m,2H),2.62–2.56(m,2H),2.40–2.33(m,2H).

[0629] Example 63 Synthesis of Compound A63:

[0630] Step 1:

[0631] Compound A63-1 (4.00 g, 14.86 mmol, Synthesis Reference Example 8) and compound pinacol diboron (7.52 g, 29.73 mmol) were dissolved in dioxane solution (40 mL), and potassium acetate (3.65 g, 37.16 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.21 g, 1.49 mmol) were added. The reaction solution was stirred at 90°C for 16 h. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 mL x 3). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound A63-2 (3.45 g, brown solid). LCMS (ESI) m / z = 317.3 [M+H] + .

[0632] Step 2:

[0633] Compound A63-2 (3.45 g, 10.91 mmol) was dissolved in a mixture of methanol (100 mL) and water (50 mL). Sodium periodate (3.50 g, 16.37 mmol) and ammonium acetate (8.40 g, 109.12 mmol) were added. The reaction mixture was stirred at 25°C for 12 h. The reaction mixture was concentrated to obtain a crude product. The crude product was separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous formic acid) to obtain A63-3 (0.40 g, white solid). LCMS (ESI) m / z = 235.2 [M+H] + .

[0634] Step 3:

[0635] Compound A63-3 (50.0 mg, 0.21 mmol) was dissolved in acetonitrile (2 mL) and dimethyl sulfoxide (0.2 mL), and tert-butyl N-2-azaspiro[3.3]hept-6-ylcarbamate (45.4 mg, 0.21 mmol), copper acetate (34.1 mg, 0.28 mmol), and triethylamine (216.2 mg, 2.14 mmol) were added. The reaction solution was stirred at 25°C for 16 h. The reaction solution was concentrated, water (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL*3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound A63-4 (45 mg, yellow solid). LCMS (ESI) m / z = 401.3 [M+H] + .

[0636] Step 4:

[0637] At room temperature, compound A63-4 (91.0 mg, 0.23 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1.5 mL) was added, and the reaction solution was stirred at 25°C for 2 h. The reaction solution was concentrated to remove the solvent to give A63-5 (100.0 mg, yellow solid, crude product, trifluoroacetate salt). LCMS (ESI) m / z = 301.3 [M+H] + .

[0638] Step 5:

[0639] To a solution of compound A63-5 (25.4 mg, 0.061 mmol) in N,N-dimethylformamide (2 mL) were added A63-6 (15.0 mg, 0.031 mmol, synthesis reference patent WO2008063525), HATU (17.5 mg, 0.046 mmol), and N,N-diisopropylethylamine (11.9 mg, 0.092 mmol). The reaction was stirred at room temperature for 16 h. The reaction solution was separated and purified by reverse phase chromatography (acetonitrile / 10 M aqueous ammonium bicarbonate) to afford A63 (10.0 mg, 42% yield) as a yellow solid. LCMS (ESI) m / z = 771.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),10.19(s,1H),8.73(s,1H),8.49(d,J=7.2Hz,1H),8.29(d,J=8 .4Hz,1H),7.94(d,J=8.8Hz,2H),7.91–7.80(m,3H),7.45(q,J=8.0Hz,1H),7.24(s,1H),7.19(t,J=8. 0Hz,1H),6.71–6.57(m,1H),6.40(t,J=2.0Hz,1H),6.33(d,J=8.4Hz,1H),4.41–4.39(m,1H),3.91(s, 2H),3.80(s,2H),3.76(t,J=6.4Hz,2H),2.71(t,J=6.8Hz,2H),2.62–2.64(m,2H),2.35–2.31(m,2H).

[0640] Example 64 Synthesis of Compound A64:

[0641] Step 1:

[0642] To a solution of compound A64-1 (100.00 mg, 370.26 μmol, Synthesis Reference Example 8) in 1,4-dioxane (2.0 mL) were added tert-butyl (2-(3-oxopiperazin-1-yl)ethyl)carbamate (180.17 mg, 740.51 μmol), tris(dibenzylideneacetone)dipalladium (67.81 mg, 74.05 μmol), and cesium carbonate (361.91 mg, 1.11 mmol) at room temperature. The reaction was stirred at 100°C for 12 h under argon. Solid impurities were removed by filtration, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to afford A64-2 (81 mg, 50.59% yield) as a pale yellow solid. LCMS (ESI) m / z = 433.2 [M+H] + .

[0643] Step 2:

[0644] To a solution of compound A64-2 (20.00 mg, 46.25 μmol) in dichloromethane (3.0 mL) was added a 1,4-dioxane solution (4 M, 1.0 mL) of hydrochloric acid at room temperature. The reaction was stirred at 25°C for 2 h. The solvent was concentrated under reduced pressure to afford A64-3 (15 mg, 97.59% yield) as a yellow solid. LCMS (ESI) m / z = 333.3 [M+H] + .

[0645] Step 3:

[0646] To a solution of compound A64-3 (15.00 mg, 46.25 μmol) in N,N-dimethylformamide (2.0 mL) were added SM1 (8.00 mg, 16.78 μmol), HATU (12.76 mg, 33.55 μmol), and DIPEA (13.01 mg, 100.7 μmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. Reverse phase preparative (acetonitrile / 10 M aqueous ammonium bicarbonate solution = 1.5 / 1) separation and purification afforded A64 (10.78 mg, 81.21% yield) as a white solid. LCMS (ESI) m / z = 791.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.50(s,1H),10.17(s,1H),8.73(s,1H),8.44(d,J=2.8Hz, 1H),8.38–8.27(m,2H),7.97–7.74(m,7H),7.63–7.47(m,1H),7.34(d,J=2.4Hz,1H), 7.17(t,J=9.2Hz,2H),3.88(t,J=4.4Hz,2H),3.83(t,J=6.8Hz,2H),3.49–3.40(m,2 H),3.35(s,2H),2.88(t,J=5.6Hz,2H),2.73(t,J=6.8Hz,2H),2.62(t,J=6.4Hz,2H).

[0647] Example 65 Synthesis of Compound A65:

[0648] Compound A65 (10.28 mg, yield 76.29%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 803.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),10.16(s,1H),8.70(s,1H),8.43(d,J=2 .4Hz,1H),8.34(t,J=6.0Hz,1H),8.26(d,J=8.4Hz,1H),7.94–7.77(m,7H),7. 42(q,J=8.0Hz,1H),7.21(s,1H),3.86–3.79(m,4H),3.45(q,J=6.0Hz,2H),3. 35(s,2H),2.88(t,J=5.2Hz,2H),2.73(t,J=6.8Hz,2H),2.62(t,J=6.8Hz,2H).

[0649] Example 66 Synthesis of Compound A66:

[0650] Compound A66 (6.0 mg, yield 39%) was synthesized according to the synthesis method of compound A58 described in Example 58. LCMS (ESI) m / z = 803.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),10.19(s,1H),8.75(s,1H),8.33(d,J=8.4Hz,1H), 8.22(t,J=5.6Hz,1H),8.13(d,J=2.8Hz,1H),7.95–7.88(m,3H),7.83(d,J=8.8Hz,2H),7. 60–7.52(m,2H),7.36(d,J=2.4Hz,1H),7.20(d,J=8.8Hz,2H),7.07(d,J=9.2Hz,1H),3.68 -3.56(m,2H),3.46–3.42(m,2H),2.72(d,J=6.6Hz,2H)),2.48–2.35(m,3H),1.23(s,4H).

[0651] Example 67 Synthesis of Compound A67:

[0652] Compound A67 (7.0 mg, yield 49%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 815.2 [M+H] +. 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),10.19(s,1H),8.75(s,1H),8.33(d,J=8.4Hz,1H),8. 22(t,J=5.6Hz,1H),8.13(d,J=2.8Hz,1H),7.95–7.88(m,3H),7.83(d,J=8.8Hz,2H),7.60–7 .52(m,2H),7.36(d,J=2.4Hz,1H),7.20(d,J=8.8Hz,2H),7.07(d,J=9.2Hz,1H),3.74(d,J= 6.6Hz,2H),3.46–3.42(m,2H),2.72(d,J=6.6Hz,2H),2.45–2.43(m,3H),0.98–0.82(m,4H).

[0653] Example 68 Synthesis of Compound A68:

[0654] Step 1:

[0655] To a solution of tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (1 g, 4.71 mmol) and 1-(6-fluoropyridin-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (1.41 g, 4.28 mmol) in dimethyl sulfoxide (DMSO) (7 mL) was added DIPEA (608.81 mg, 4.71 mmol, 820.49 μL) at room temperature. The reaction mixture was stirred at 150°C under microwave conditions for 2 h. The reaction mixture was quenched with saturated brine and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methane = 50:1) to afford A68-1 (1.5 g, 53.7% yield) as a yellow solid. LCMS (ESI) m / z = 522.1 [M+H] + .

[0656] Step 2:

[0657] To a solution of A68-1 (1 g, 1.92 mmol) in dichloromethane (7 mL) was added HCl (4 M in dioxane, 3.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give a crude yellow solid A68-2 (1 g), which was used directly in the next step. LCMS (ESI) m / z = 422.1 [M+H] + .

[0658] Step 3:

[0659] To a solution of A68-2 (1 g, 2.37 mmol) in dichloromethane (10 mL) were added DIPEA (306.63 mg, 2.37 mmol, 413.24 μL), acetic acid (284.95 mg, 4.75 mmol), N-tert-butoxycarbonyl-2-aminoacetaldehyde (566.50 mg, 3.56 mmol), and sodium triacetoxyborohydride (1.51 g, 7.12 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by pouring into saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methane = 50:1) to afford A68-3 (1.1 g, 82.1% yield) as a yellow oil. LCMS (ESI) m / z = 565.2 [M+H] + .

[0660] Step 4:

[0661] A68-3 (300 mg, 531.28 μmol) was dissolved in trifluoromethanesulfonic acid solution (2 mL) and trifluoroacetic acid solution (2 mL) at room temperature. The reaction solution was stirred at room temperature for 16 h. The pH of the reaction solution was adjusted to 6 with saturated sodium carbonate solution in an ice bath. The resulting solution was directly purified by reverse phase column chromatography to obtain A68-4 (130 mg, 71.0% yield) as a white solid. LCMS (ESI) m / z = 345.0 [M+H] + .

[0662] Step 5:

[0663] To a solution of A68-4 (21.67 mg, 62.91 μmol) in N,N-dimethylformamide (3 mL) were added DIPEA (12.20 mg, 94.37 μmol, 16.44 μL), SM1 (15 mg, 31.46 μmol), and HATU (23.92 mg, 62.91 μmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was separated and purified by preparative HPLC to afford A68 (15 mg, 59.3% yield) as a white solid. LCMS (ESI) m / z = 802.9 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.35(s,1H),10.18(s,1H),8.72(s,1H),8.32–8.29(m,2H), 8.04(s,1H),7.92–7.87(m,3H),7.87–7.79(m,2H),7.59–7.53(m,2H),7.34(d,J=2.0H z,1H),7.16(t,J=8.6Hz,2H),6.87(bs,1H),3.69(t,J=6.8Hz,2H),3.49(s,2H),3.29– 3.22(m,4H),3.02(s,2H),2.88(s,2H),2.69(t,J=6.8Hz,2H),0.56(d,J=21.2Hz,4H).

[0664] Example 69 Synthesis of Compound A69:

[0665] Compound A69 (15 mg, yield 59.9%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 814.9 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),10.16(s,1H),8.70(s,1H),8.30–8.19(m,2H) ,8.03(d,J=2.8Hz,1H),7.90(d,J=8.8Hz,2H),7.85–7.75(m,3H),7.52–7.36(m,2H), 7.21(s,1H),6.80(d,J=9.1Hz,2H),3.68(t,J=6.8Hz,2H),3.48(s,2H),3.30–3.29( m,4H),3.01(s,2H),2.87(t,J=7.0Hz,2H),2.69(t,J=6.8Hz,2H),0.61–0.50(m,4H).

[0666] Example 70 Synthesis of Compound A70:

[0667] Step 1:

[0668] To a solution of compound A70-1 (400.00 mg, 1.27 mmol, Synthesis Reference Example 8) in dimethyl sulfoxide (3.0 mL) were added 3-methylhydroxyazetidine hydrochloride (234.58 mg, 1.90 mmol), cuprous iodide (48.20 mg, 0.25 mmol), L-proline (58.26 mg, 0.51 mmol), and potassium carbonate (524.69 mg, 3.80 mmol) at room temperature. The reaction was stirred at 90°C for 12 h. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was separated and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The compound was isolated and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain A70-2 (203 mg, 58.27% yield) as a yellow solid. LCMS (ESI) m / z = 276.2 [M+H] + .

[0669] Step 2:

[0670] To a solution of compound A70-2 (150.00 mg, 544.86 μmol) in dimethyl sulfoxide (3.0 mL) at room temperature were added methylsulfonyl chloride (74.90 mg, 653.83 μmol) and triethylamine (165.40 mg, 1.63 mmol). The reaction was stirred at 25°C for 12 h. Water was added to the reaction solution, extracted with dichloromethane, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain a crude product. The crude product was slurried in dichloromethane and filtered to obtain A70-3 (113 mg, 56.69% yield) as a yellow solid. LCMS (ESI) m / z = 354.2 [M+H] +.

[0671] Step 3:

[0672] To a solution of compound A70-3 (93.00 mg, 263.16 μmol) in N,N-dimethylformamide (3.0 mL) were added 3-N-tert-butyloxycarbonylaminocyclobutylamine (67.98 mg, 394.74 μmol) and DIPEA (102.03 mg, 789.49 μmol) at room temperature. The reaction was stirred at 100°C for 12 h. Water was added to the reaction solution, extracted with dichloromethane, and the layers separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The product was isolated and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to afford A70-4 (42 mg, 37.16% yield) as a yellow solid. LCMS (ESI) m / z = 430.3 [M+H] + .

[0673] Step 4:

[0674] To a solution of compound A70-4 (21.00 mg, 49.01 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (1.0 mL) at room temperature. The reaction was stirred at 25°C for 2 h. The solvent was concentrated under reduced pressure to afford A70-5 (17 mg, 100% yield), a brown solid. LCMS (ESI) m / z = 330.3 [M+H] + .

[0675] Step 5:

[0676] To a solution of compound A70-5 (17.00 mg, 49.01 μmol) in N,N-dimethylformamide (2.0 mL) were added SM1 (10.00 mg, 20.97 μmol), HATU (15.95 mg, 41.94 μmol), and DIPEA (8.13 mg, 61.91 μmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. Reverse phase preparative (acetonitrile / 10 M aqueous ammonium bicarbonate solution = 1.5 / 1) separation and purification afforded A70 (8.93 mg, 54.09% yield) as a pale yellow solid. LCMS (ESI) m / z = 787.9 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.24(s,1H),10.18(s,1H),8.73(s,1H),8.60(d,J=6.8Hz,1H),8.30(d, J=8.4Hz,1H),7.95–7.80(m,5H),7.60–7.48(m,1H),7.34(d,J=2.4Hz,1H),7.17(t,J=8.8Hz,2H) ,7.09(d,J=8.4Hz,2H),6.40(d,J=8.4Hz,2H),4.47-4.45(m,1H),3.89(d,J=6.8Hz,2H),3.66(t, J=6.8Hz,2H),3.58(t,J=6.4Hz,2H),3.48–3.46(m,2H),3.02(t,J=7.2Hz,2H),2.76–2.62(m,5H).

[0677] Example 71 Synthesis of Compound A71:

[0678] Compound A71 (9.27 mg, yield 56.70%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 800.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),10.17(s,1H),8.71(s,1H),8.59(d,J=7.2Hz,1H),8.26( d,J=8.4Hz,1H),7.92(d,J=8.4Hz,2H),7.88–7.78(m,3H),7.42(q,J=8.0Hz,1H),7.21(s,1H), 7.09(d,J=8.8Hz,2H),6.46–6.34(m,2H),4.47–4.42(m,1H),3.88(t,J=7.2Hz,2H),3.66(t,J= 6.8Hz,2H),3.58(t,J=6.8Hz,2H),3.48–3.46(m,2H),3.02(t,J=7.2Hz,2H),2.74–2.62(m,5H).

[0679] Example 72 Synthesis of Compound A72:

[0680] Compound A72 (10.8 mg, yield 45.6%) was synthesized according to the synthesis method of compound A58 described in Example 58. LCMS (ESI) m / z = 787.98 [M+H] + .1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),10.18(s,1H),8.73(s,1H),8.59(d,J=8.0Hz,1H),8.30(d,J =8.0Hz,1H),7.94–7.81(m,5H),7.59–7.50(m,1H),7.34(s,1H),7.22–7.10(m,3H),6.61–6.58(m,1 H),6.35(d,J=4.0Hz,1H),6.29(d,J=8.0Hz,1H),4.52–4.42(m,1H),3.88(t,J=4.0Hz,2H),3.73(t ,J=8.0Hz,2H),3.58(t,J=8.0Hz,2H),3.48–3.43(m,2H),3.03(t,J=4.0Hz,2H),2.71–2.64(m,5H).

[0681] Example 73 Synthesis of Compound A73:

[0682] Compound A73 (12.8 mg, yield 53%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 800.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),10.17(s,1H),8.71(s,1H),8.59(d,J=8.0Hz,1H),8.26(d,J=8.0Hz,1H) ,7.92(d,J=8.8Hz,2H),7.87–7.79(m,3H),7.46–7.38(m,1H),7.21(s,1H),7.15(t,J=8.0Hz,1H),6.60(dd,J1= 7.2Hz,J2=2.0Hz,1H),6.35(t,J=4.0Hz,1H),6.28(dd,J=7.8,2.0Hz,1H),4.53–4.42(m,1H),3.88(t,J=4.0Hz, 2H),3.73(t,J=4.0Hz,2H),3.59(t,J=4.0Hz,2H),3.46–3.42(m,2H),3.03(t,J=8.0Hz,2H),2.71–2.65(m,5H).

[0683] Example 74 Synthesis of Compound A74:

[0684] Step 1:

[0685] To a mixed solution of compound A74-1 (100.00 mg, 427.32 μmol, synthesis reference patent WO2020150385) in dimethyl sulfoxide (3.0 mL) and acetonitrile (15.0 mL) at room temperature were added A63-3 (145.70 mg, 640.98 μmol), copper acetate (100.00 mg, 500.88 μmol), and triethylamine (432.41 mg, 4.27 mmol). The reaction was stirred at 25°C for 12 h. The reaction mixture was filtered to remove solid impurities, the filtrate was concentrated, water was added, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The product was separated and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain a green solid A74-2 (56 mg, yield 31.54%). LCMS (ESI) m / z = 416.2 [M+H] + .

[0686] Step 2:

[0687] Compound A77 (9.55 mg, yield 65.36%) was synthesized according to the synthesis method of compound A8 described in Example 8. LCMS (ESI) m / z = 774.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),10.18(s,1H),8.73(s,1H),8.62(d,J=7.2Hz,1H),8.30(d,J=8.4Hz ,1H),7.99–7.79(m,5H),7.67–7.48(m,1H),7.34(d,J=2.4Hz,1H),7.17(t,J=8.0Hz,3H),6.61(d,J=8.0Hz 1.2Hz,1H),6.38(t,J=2.4Hz,1H),6.36–6.26(m,1H),4.47–4.62(m,1H),3.84(t,J=6.8Hz,2H),3.74(t ,J=6.8Hz,2H),3.70–3.59(m,3H),3.55(t,J=6.8Hz,2H),3.17(t,J=7.2Hz,2H),2.68(t,J=6.8Hz,2H).

[0688] Example 75 Synthesis of Compound A75:

[0689] Step 1:

[0690] To a solution of 2,6-bis(benzyloxy)-3-bromopyridine (500.00 mg, 1.35 mmol) in toluene (15.0 ml) were added tert-butyl 3-oxo-1-piperazinecarboxylate (405.62 mg, 2.03 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (96.05 mg, 675.24 μmol), cuprous iodide (128.60 mg, 675.24 μmol), and potassium carbonate (559.95 mg, 4.05 mmol) at room temperature. The reaction was stirred at 120°C for 12 h. The reaction mixture was filtered to remove solid impurities, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:2) to afford A75-1 (368 mg, 63.01% yield) as a yellow solid. LCMS (ESI) m / z = 490.1 [M+H] + .

[0691] Step 2:

[0692] To a solution of compound A75-1 (300.00 mg, 612.79 μmol) in dichloromethane (12.0 mL) was added HCl (4 Min dioxane, 3.0 mL) at room temperature. The reaction was stirred at 25°C for 2 h. The solvent was removed by concentration under reduced pressure. Methanol (5.0 mL), 1-tert-butyloxycarbonyl-3-azetidinone (419.77 mg, 2.45 mmol), and sodium cyanoborohydride (231.13 mg, 3.68 mmol) were added. The reaction was stirred at 25°C for 12 h. The solvent was removed by concentration under reduced pressure. The product was isolated and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to afford A75-2 (266 mg, 95.47% yield) as a white solid. LCMS (ESI) m / z = 455.2 [M+H] + .

[0693] Step 3:

[0694] To a solution of compound A75-2 (266.01 mg, 488.40 μmol) in dichloromethane (15.0 mL) was added trifluoroacetic acid (3.0 mL) at room temperature. The reaction was stirred at 25°C for 2 h. The solvent was removed by concentration under reduced pressure. Dichloromethane (25.0 mL), N-tert-butoxycarbonyl-2-aminoacetaldehyde (126.23 mg, 792.98 μmol), and sodium triacetoxyborohydride (224.09 mg, 1.06 mmol) were added. The reaction was stirred at 25°C for 12 h. The solvent was removed by concentration under reduced pressure. The product was isolated and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to afford A75-3 (226 mg, 72.74% yield) as a yellow solid. LCMS (ESI) m / z = 498.3 [M+H] + .

[0695] Step 4:

[0696] To a solution of compound A75-3 (300.00 mg, 510.46 μmol) in methanol (30.0 mL) was added reducing palladium on carbon (10%, 150 mg, 10% w / w) at room temperature. The reaction was stirred at 25°C for 12 h under hydrogen (1.0 atm). Solid impurities were removed by filtration and purified by reverse transpiration (methanol / water 0.01% formic acid = 1:1) to afford A75-4 (58 mg, 27.75% yield) as a purple solid. LCMS (ESI) m / z = 410.1 [M+H] + .

[0697] Step 5:

[0698] To a solution of compound A75-4 (30.00 mg, 73.26 μmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (1.0 mL) at room temperature. The reaction was stirred at 25°C for 2 h. The solvent was concentrated under reduced pressure to afford A75-5 (25 mg, 100% yield), a brown solid. LCMS (ESI) m / z = 310.2 [M+H] + .

[0699] Step 6:

[0700] To a solution of compound A75-5 (20.00 mg, 58.21 μmol) in N,N-dimethylformamide (2.0 mL) were added SM1 (9 mg, 18.87 μmol), HATU (14.35 mg, 37.75 μmol), and DIPEA (14.64 mg, 113.24 μmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. Reverse phase preparative (acetonitrile / 10 M aqueous ammonium bicarbonate solution = 1.5 / 1) separation and purification afforded A75 (9.56 mg, 65.94% yield) as a white solid. LCMS (ESI) m / z = 768.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.85(s,1H),10.16(s,1H),8.73(s,1H),8.30(d,J=8.4Hz,1H),8.22(t ,J=5.6Hz,1H),7.96–7.85(m,3H),7.81(d,J=8.8Hz,2H),7.62–7.48(m,1H),7.34(d,J=2.0Hz,1H ),7.17(t,J=8.8Hz,2H),4.92(bs,1H),3.45–3.42(m,2H),3.34–3.20(m,4H),3.06–2.93(m,3H) ,2.94-2.89(m,2H),2.82–2.65(m,1H),2.64–2.52(m,3H),2.39–2.20(m,1H),1.91–1.74(m,1H).

[0701] Example 76 Synthesis of Compound A76:

[0702] Compound A76 (13 mg, yield 54.8%) was synthesized according to the synthesis method of Compound A6 described in Example 6. LCMS (ESI) m / z = 753.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.42(s,1H),10.20(s,1H),8.95(s,1H),8.73(s,1H),8.29(d,J=8.4Hz,1H),7.93–7.78(m,5H),7.55(m,1 H),7.40(m,1H),7.39–7.32(m,3H),7.28(m,1H),7.17(t,J=8.8Hz,2H),3.80(t,J=6.6Hz,2H),2.70(t,J=6.6Hz,2H),2.44(s,6H).

[0703] Example 77 Synthesis of Compound A77:

[0704] Compound A77 (13 mg, yield 55.3%) was synthesized according to the synthesis method of Compound A6 described in Example 6. LCMS (ESI) m / z = 765.9 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.42(s,1H),10.19(s,1H),8.94(s,1H),8.71(s,1H),8.25(d,J=8.4Hz,1H),7.91(d,J=8.8Hz,2H),7.84–7.78(m,3 H),7.47–7.39(m,2H),7.38–7.32(m,2H),7.28(m,1H),7.21(s,1H),6.88(s,1H),3.80(t,J=6.6Hz,2H),2.70(t,J=6.6Hz,2H),2.44(s,6H).

[0705] Example 78 Synthesis of Compound A78:

[0706] Compound A78 (18.0 mg, yield 53%) was synthesized according to the synthesis method of compound A26 described in Example 26. LCMS (ESI) m / z = 758.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.42(s,1H),10.14(s,1H),8.72(s,1H),8.29(d,J=8.4Hz,1H),7.88(dd,J=8.6,2.5Hz,3H),7.76(d,J=8.6H z,2H),7.63–7.45(m,2H),7.43–7.25(m,5H),7.17(t,J=9.0Hz,2H),3.79(t,J=6.6Hz,2H),2.70(t,J=6.6Hz,2H),2.03–1.88(m,12H).

[0707] Example 79 Synthesis of Compound A79:

[0708] Compound A79 (18.0 mg, yield 53%) was synthesized according to the synthesis method of compound A26 described in Example 26. LCMS (ESI) m / z = 758.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.40(s,1H),10.14(s,1H),8.72(s,1H),8.44(s,1H),8.29(d,J=8.4Hz,1H),7.88(dd,J1=8.6Hz,J2=2.2Hz,3H),7.7 6(d,J=8.8Hz,2H),7.62–7.47(m,2H),7.39–7.25(m,4H),7.24-7.09(m ,3H),3.78(t,J=6.6Hz,2H),2.70(t,J=6.6Hz,2H),2.03–1.89(m,12H).

[0709] Example 80 Synthesis of Compound A80:

[0710] Compound A80 (17.0 mg, yield 70%) was synthesized according to the synthesis method of Compound A30 described in Example 30. LCMS (ESI) m / z=836.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.58(s,1H),10.18(s,1H),8.72(s,1H),8.30(d,J=8.4Hz,1H),8.12(d,J =7.4Hz,1H),7.94(s,1H),7.82(dd,J1=8.6Hz,J2=2.2Hz,1H),7.74(d,J=8.4Hz,1H),7.42(d,J=8.2 Hz,2H),7.22(s,1H),6.97(s,1H),4.42(q,J=8.0Hz,1H),3.93(s,3H),3.78(t,J=6.8Hz,2H),3.3-3 .25(m,4H),2.72(t,J=6.8Hz,2H),2.27(t,J=9.4Hz,2H),1.83(t,J=9.8Hz,2H),1.71–1.66(m,4H).

[0711] Example 81 Synthesis of Compound A81:

[0712] Compound A81 (16.0 mg, yield 64%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 794.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.17(s,1H),8.73(s,1H),8.45(d,J=7.4Hz,1H),8.30(d,J= 8.4Hz,1H),7.92–7.82(m,5H),7.58–7.50(m,1H),7.34(d,J=2.2Hz,1H),7.17(t,J=9. 2Hz,2H),6.97(s,1H),4.49–4.39(m,1H),3.78(t,J=6.8Hz,2H),3.30–3.27(m,4H),2. 72(t,J=6.8Hz,2H),2.24(t,J=9.8Hz,2H),1.89(t,J=10.0Hz,2H),1.70–1.61(m,4H).

[0713] Example 82 Synthesis of Compound A82:

[0714] Step 1:

[0715] Compound A54-3 (60.0 mg, 0.18 mmol) was dissolved in tetrahydrofuran (2 mL) and triethylamine (36.9 mg, 0.36 mmol) and di-tert-butyl dicarbonate (59.6 mg, 0.27 mmol) were added. The reaction solution was stirred at 25°C for 2 h. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound A82-1 (45.0 mg, white solid). LCMS (ESI) m / z = 430.4 [M+H] + .

[0716] Step 2:

[0717] At room temperature, compound A82-1 (40.0 mg, 0.093 mmol) was dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (60.7 mg, 0.19 mmol) and iodomethane (19.8 mg, 0.14 mmol) were added. The reaction solution was stirred at 25°C for 3 h. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound A82-2 (70.0 mg, yellow solid, crude product). LCMS (ESI) m / z = 444.1 [M+H] + .

[0718] Step 3:

[0719] At room temperature, compound A82-2 (70.0 mg, crude product) was dissolved in dichloromethane (2 mL), and hydrogen chloride (4.0 M in dioxane, 1 mL) was added. The reaction solution was stirred at 25°C for 2 h. The reaction solution was concentrated to remove the solvent to give A82-3 (50.0 mg, yellow solid, crude product, hydrochloride salt). LCMS (ESI) m / z = 344.3 [M+H] + .

[0720] Step 4:

[0721] To a solution of compound A82-3 (23.9 mg, 0.063 mmol) in N,N-dimethylformamide (2 mL) were added SM1 (15.0 mg, 0.031 mmol), HATU (17.9 mg, 0.047 mmol), and N,N-diisopropylethylamine (12.2 mg, 0.094 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 10 M aqueous ammonium bicarbonate) to afford A82 (14.0 mg, 55% yield) as a yellow solid. LCMS (ESI) m / z = 802.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.18(s,1H),8.76(s,1H),8.47(d,J=7.2Hz,1H),8.33(d,J=8.8Hz,1H),8.08(d,J=2.8Hz,1 H),7.98–7.81(m,5H),7.66–7.53(m,1H),7.50(dd,J1=8.8Hz,J2=2.8Hz,1H),7.37(d,J=2.4Hz,1H),7.20(t,J=8.8Hz ,2H),6.89(d,J=9.2Hz,1H),4.50(p,J=8.0Hz,1H),3.71(t,J=6.8Hz,2H),3.62–3.52(m,2H),3.52–3.42(m,2H),3.07 (s,3H),2.85(t,J=6.8Hz,2H),2.27(t,J=10.0Hz,2H),1.92(t,J=10.0Hz,2H),1.74–1.64(m,2H),1.64–1.55(m,2H).

[0722] Example 83 Synthesis of Compound A83:

[0723] Step 1:

[0724] Acrylonitrile (2.26 g, 42.68 mmol) and basic alumina (21.8 g, 213.4 mmol) were added to a solution of benzyl 4-aminopiperidine-1-carboxylate (5 g, 21.34 mmol) in ethanol (50 mL) at room temperature. The reaction was stirred at room temperature for 48 h. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to afford A83-1 as a colorless oil (6 g, 97.8% yield). LCMS (ESI) m / z = 288.3 [M+H] + .

[0725] Step 2:

[0726] Under ice bath, to a solution of A83-1 (6 g, 20.9 mmol) in ethanol (50 mL) was added cyanogen bromide (2.65 g, 25.0 mmol) and sodium acetate (3.43 g, 41.76 mmol). The reaction was stirred at room temperature for 24 h. Ethyl acetate (200 mL) was added to the reaction solution and washed with saturated brine (2*60 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain A83-2 (6.3 g, yield 96.5%) as a colorless oil. LCMS (ESI) m / z = 312.8 [M+H] + .

[0727] Step 3:

[0728] A83-2 (6.3 g, 20.1 mmol) was dissolved in 6N HCl (33.6 mL) and heated to 100°C for 4 h. The reaction mixture was concentrated to remove most of the solvent, and the pH was adjusted to 8 with saturated sodium bicarbonate. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 10 mM aqueous ammonium bicarbonate) to afford A83-3 (2.8 g, 70.3% yield) as a white solid.

[0729] Step 4:

[0730] To a solution of A83-3 (1.5 g, 7.6 mmol) in dichloromethane (60 mL) were added 1-Boc-3-azetidinone (1.43 g, 8.36 mmol), glacial acetic acid (1.36 g, 22.8 mmol), and sodium triacetoxyborohydride (4.83 g, 22.8 mmol) at room temperature, and the mixture was stirred at room temperature for 16 h. The reaction solution was washed with saturated sodium bicarbonate solution (50 mL) and saturated brine (50 mL), and then dried over anhydrous sodium sulfate. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol = 30:1) to obtain A83-4 (0.4 g, 15% yield) as a pale yellow solid. LCMS (ESI) m / z = 353.1 [M+H] + .

[0731] Step 5:

[0732] To a dichloromethane solution (2 mL) of A83-4 (130 mg, 0.37 mmol) was added trifluoroacetic acid (1 mL) at room temperature. The reaction was stirred at room temperature for 1 h. The reaction solution was directly concentrated under reduced pressure to afford A83-5 (93 mg, 99% yield). LCMS (ESI) m / z = 253.1 [M+H] + .

[0733] Step 6:

[0734] To A83-5 (93 mg, 0.37 mmol) in methanol (5 mL) were added N-tert-butoxycarbonyl-2-aminoacetaldehyde (70 mg, 0.44 mmol), glacial acetic acid (66 mg, 1.1 mmol), and sodium cyanoborohydride (70 mg, 1.1 mmol) at room temperature. The reaction was stirred at room temperature for 16 h. Ethyl acetate (50 mL) was added to the reaction solution, which was washed with saturated sodium bicarbonate solution (20 mL) and saturated brine (20 mL), and then dried over anhydrous sodium sulfate. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to give A83-6 (120 mg, 82.3% yield) as a light yellow solid. LCMS (ESI) m / z = 396.2 [M+H] + .

[0735] Step 7:

[0736] To a dichloromethane solution (2 mL) of A83-6 (30 mg, 0.076 mmol) was added trifluoroacetic acid (1 mL) at room temperature. The reaction was stirred at room temperature for 1 h. The reaction solution was directly concentrated under reduced pressure to afford A83-7 (22 mg, 99% yield). LCMS (ESI) m / z = 296.1 [M+H] + .

[0737] Step 8:

[0738] To a solution of compound A83-7 (22 mg, 0.07 mmol) in N,N-dimethylformamide (2 mL) were added SM1 (15 mg, 0.03 mmol), HATU (16 mg, 0.04 mmol), and N,N-diisopropylethylamine (12 mg, 0.09 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 10 mM aqueous ammonium bicarbonate) to afford A83 (14.7 mg, 61.9% yield) as a pale yellow solid. LCMS (ESI) m / z = 754.5 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.17(s,1H),10.06(s,1H),8.73(s,1H),8.30(d,J=8.0Hz,1H),8.26–8.20(m,1H ),7.92–7.86(m,3H),7.83–7.78(m,2H),7.59–7.50(m,1H),7.34(d,J=4.0Hz,1H),7.22–7.10(m,2H),4.0 7–3.97(m,1H),3.46–3.40(m,2H),3.30–3.25(m,2H),3.24–3.16(m,2H),2.86–2.80(m,1H),2.78–2.69(m ,4H),2.55–2.51(m,2H),2.46(t,J=4.0Hz,2H),1.83–1.74(m,2H),1.72–1.60(m,2H),1.53–1.46(m,2H).

[0739] Example 84 Synthesis of Compound A84:

[0740] Compound A84 (2.6 mg, yield 15%) was synthesized according to the synthesis method of compound A54 described in Example 54. LCMS (ESI) m / z = 775.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),10.18(s,1H),8.73(s,1H),8.63(d,J=8.0Hz,1H),8.30(d,J=8.0 Hz,1H),8.02(d,J=4.0Hz,1H),7.94–7.81(m,6H),7.58–7.47(m,2H),7.34(d,J=2.2Hz,1H),7.17(t,J= 8.0Hz,2H),6.41(d,J=8.0Hz,1H),4.59–4.51(m,1H),3.96(t,J=8.0Hz,2H),3.82–3.79(m,2H),3.69(t ,J=6.8Hz,2H),3.64–3.61(m,1H),3.56(t,J=6.8Hz,2H),3.16(t,J=6.8Hz,2H),2.69(t,J=6.8Hz,2H).

[0741] Example 85 Synthesis of Compound A85:

[0742] Compound A85 (5.8 mg, yield 35.3%) was synthesized according to the synthesis method of compound A83 described in Example 83. LCMS (ESI) m / z = 782.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.20(s,1H),10.08(s,1H),8.76(s,1H),8.33(d,J=8.0Hz,1H),8.26– 8.24(m,1H),7.94–7.90(m,3H),7.85–7.83(m,2H),7.62–7.53(m,1H),7.37(d,J=2.4Hz,1H),7. 24–7.15(m,2H),4.11–3.80(m,2H),3.43–3.38(m,3H),3.30(t,J=6.8Hz,2H),3.0–2.90(m,4H), 2.50–2.40(m,3H),2.31–2.15(m,2H),2.03–1.91(m,2H),1.77–1.60(m,4H),1.58–1.37(m,4H).

[0743] Example 86 Synthesis of Compound A86:

[0744] Compound A86 (2.8 mg, yield 17.2%) was synthesized according to the synthesis method of compound A56 described in Example 56. LCMS (ESI) m / z = 774.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),10.19(s,1H),8.73(s,1H),8.63(d,J=8.0Hz,1H ),8.30(d,J=8.0Hz,1H),7.92–7.83(m,5H),7.58–7.51(m,1H),7.34(d,J=2.2Hz,1H),7 .19–7.15(m,2H),7.12–7.10(m,2H),6.44–6.42(m,2H),4.56–4.51(m,1H),3.84(t,J=7 .0Hz,2H),3.68–3.60(m,5H),3.56–3.53(m,2H),3.17–3.13(m,2H),2.69–2.65(m,2H).

[0745] Example 87 Synthesis of Compound A87:

[0746] Compound A87 (2.5 mg, yield 15.1%) was synthesized according to the synthesis method of compound A54 described in Example 54. LCMS (ESI) m / z = 789.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.47(s,1H),10.20(s,1H),8.76(s,1H),8.49(d,J=8. 0Hz,1H),8.35(s,2H),8.33(d,J=8.0Hz,1H),7.96–7.86(m,5H),7.62–7.54(m,1 H),7.37(d,J=2.2Hz,1H),7.22–7.17(m,2H),4.52–4.46(m,1H),3.79–3.69(m,6 H),2.75–2.69(m,2H),2.36–2.26(m,2H),1.95–1.90(m,2H),1.66–1.58(m,4H).

[0747] Example 88 Synthesis of Compound A88:

[0748] At room temperature, compound A88-1 (9.0 mg, 19.61 μmol, synthesis method reference ACS Medicinal Chemistry Letters (2015), 6(6), 630-634) was added with A54-3 (9.69 mg, 29.42 μmol), HATU (15 mg, 39.23 μmol) and DIPEA (8 mg, 58.84 μmol). The reaction solution was stirred at 26°C for 16 h. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:20) to obtain a yellow oil A88 (6 mg, yield 39%). LCMS (ESI) m / z = 770.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.37(s,1H),10.17(s,1H),8.75(s,1H),8.47(d,J=7.6Hz,1H),8.31(d,J=8.4Hz,1H ),8.07(d,J=2.8Hz,1H),7.95–7.91(m,3H),7.89–7.86(m,3H),7.67–7.63(m,1H),7.56–7.49(m,1H),7.38–7 .33(m,2H),7.24–7.17(m,1H),6.89(d,J=9.2Hz,1H),3.84–3.71(m,2H),3.57–3.54(m,2H),3.50–3.47(m,2H ),2.72(t,J=6.8Hz,2H),2.27(t,J=9.6Hz,2H),1.91(t,J=10.0Hz,2H),1.68–1.65(m,2H),1.64–1.61(m,2H).

[0749] Example 89 Synthesis of Compound A89:

[0750] Step 1:

[0751] To a solution of tert-butyl 2-bromothiazole-5-carbamate (5.0 g, 17.91 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (1.07 g, 26.87 mmol, 60% purity) at 0°C. The reaction was stirred at 0°C for 2 hours. Methyl 3-bromopropionate (3.29 g, 19.70 mmol) and sodium iodide (1.34 g, 8.96 mmol) were added sequentially to the solution, and the reaction was heated to 45°C and stirred for 16 hours. LCMS analysis indicated that the reaction was complete. The reaction was cooled to room temperature and quenched with saturated aqueous ammonium chloride. The organic phase was extracted with ethyl acetate and dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by reverse phase column chromatography to afford A89-1 (3.5 g, 53.5% yield) as a yellow solid. LCMS (ESI) m / z = 364.9 / 366.9 [M+H] + .

[0752] Step 2:

[0753] Compound A89-2 (160 mg, yield 74.4%) was synthesized according to the synthesis method of compound A58 described in Example 58. LCMS (ESI) m / z=275.9 / 277.9 [M+H] + .

[0754] Step 3:

[0755] Compound A89 (5.1 mg, yield 31.9%) was synthesized according to the synthesis method of Compound A6 described in Example 6. LCMS (ESI) m / z = 761.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H),10.20(s,1H),8.98(s,1H),8.73(s,1H),8.30(d,J=8.4Hz,1H),7.93–7.86(m,3H),7.84–7.78(m,2 H),7.71(s,1H),7.59–7.50(m,1H),7.34(d,J=2.0Hz,1H),7.21–7.13(m,2H),4.04(t,J=6.8Hz,2H),2.80(t,J=6.8Hz,2H),2.48(s,6H).

[0756] Example 90 Synthesis of Compound A90:

[0757] Compound A90 (10.09 mg, yield 67.74%) was synthesized according to the synthesis method of compound A54 described in Example 54. LCMS (ESI) m / z = 789.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),10.18(s,1H),8.73(s,1H),8.60(d,J=6.8Hz,1H),8.30(d,J= 8.4Hz,1H),8.00(d,J=2.8Hz,1H),7.95–7.81(m,5H),7.60–7.50(m,1H),7.47(dd,J1=8.8Hz,J2=2. 4Hz,1H),7.34(d,J=2.0Hz,1H),7.17(t,J=8.8Hz,2H),6.38(d,J=8.8Hz,1H),4.52–4.42(m,1H),4. 01–3.97(m,2H),3.68(t,J=6.8Hz,2H),3.63–3.53(m,4H),3.03(t,J=6.8Hz,2H),2.75–2.65(m,5H).

[0758] Example 91 Synthesis of Compound A91:

[0759] Step 1:

[0760] At room temperature, to a solution of methyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (3.76 g, 17.72 mmol, synthesis reference WO2023067388A1) in N,N-dimethylacetamide (14 mL) were added tert-butyl N,N-bis(2-chloroethyl)carbamate (5.39 g, 22.27 mmol) and DIPEA (5.19 g, 7 mL). The reaction solution was heated to 110°C under argon and stirred for 4 h. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain a yellow liquid A91-1 (0.83 g, yield 32%). LCMS (ESI) m / z = 353.4 [M+H] + .

[0761] Step 2:

[0762] To compound A91-1 (0.83 g, 2.35 mmol) was added 1% sodium hydroxide solution (2.5 mL), and the reaction mixture was stirred at 100°C for 16 h. The reaction mixture was adjusted to a pH of 4-5 with 3M hydrochloric acid solution, and the resulting solution was directly separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous formic acid) to afford A91-2 (268 mg, 34% yield) as a yellow oil. LCMS (ESI) m / z = 339.3 [M+H] + .

[0763] Step 5:

[0764] To a toluene solution (5 mL) of A91-2 (268 mg, 0.79 mmol) at room temperature were added diphenylphosphoryl azide (240 mg, 0.87 mmol, 0.19 mL) and triethylamine (96 mg, 0.95 mmol, 0.13 mL). The reaction mixture was heated to 70°C and stirred for 1 h under argon. Benzyl alcohol (94 mg, 0.87 mmol, 0.09 mL) and triethylamine (96 mg, 0.95 mmol, 0.13 mL) were added. The reaction mixture was stirred at 80°C under argon for 6 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain A91-3 (228 mg, 65% yield) as a white solid. LCMS (ESI) m / z = 444.3 [M+H] + .

[0765] Step 6:

[0766] To a methanol solution (5 mL) of compound A91-3 (228 mg, 0.51 mmol) was added 10% palladium on carbon (167 mg). The atmosphere was replaced with hydrogen three times at room temperature, and the reaction was stirred at room temperature for 16 h. The reaction solution was filtered and concentrated under reduced pressure to afford A91-4 (133 mg, 84% yield) as a white solid. LCMS (ESI) m / z = 309.3 [M+H] + .

[0767] Step 7:

[0768] To a solution of compound A91-4 (133 mg, 0.43 mmol) in ethanol (2 mL) at room temperature were added acrylonitrile (34 mg, 0.64 mmol, 0.04 mL) and triethylamine (130 mg, 1.29 mmol, 0.18 mL). The reaction mixture was heated to 90°C and stirred under argon for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was added with water and extracted with dichloromethane. The residue was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound A91-5 (155 mg, 100% yield). LCMS (ESI) m / z = 362.4 [M+H] + .

[0769] Step 8:

[0770] To a solution of compound A91-5 (155 mg, 0.43 mmol) in ethanol (3 mL) was added sodium acetate (56 mg, 0.68 mmol) and cyanogen bromide (75 mg, 0.68 mmol) at room temperature. The reaction mixture was stirred at room temperature under argon for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was added with water and extracted with dichloromethane. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a yellow solid, crude product A91-6 (121 mg, 73% yield). LCMS (ESI) m / z = 388.4 [M+H] + .

[0771] Step 9:

[0772] 6M hydrochloric acid (2 mL) was added to compound A91-6 (121 mg, 0.31 mmol), and the reaction mixture was stirred at 100°C for 4 h. The reaction mixture was concentrated under reduced pressure to give crude compound A91-7 (105 mg, 100% yield). LCMS (ESI) m / z = 307.3 [M+H] + .

[0773] Step 10:

[0774] To a solution of compound A91-7 (95 mg, 0.31 mmol) in methanol (2 mL) and acetic acid (0.3 mL) at room temperature were added N-tert-butyloxycarbonyl-2-aminoacetaldehyde (99 mg, 0.62 mmol) and sodium cyanoborohydride (39 mg, 0.62 mmol). The reaction mixture was stirred at room temperature under argon for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford a white solid, crude product A91-8 (60 mg, 43% yield). LCMS (ESI) m / z = 450.2 [M+H] + .

[0775] Step 11:

[0776] To a solution of compound A91-8 (40 mg, 0.09 mmol) in dichloromethane (2 mL) was added HCl (1 mL, 4.0 M in 1,4-dioxane), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was directly spin-dried to give crude product A91-9 (35 mg, 100% yield). LCMS (ESI) m / z = 350.3 [M+H] + .

[0777] Step 12:

[0778] To a solution of compound A91-9 (24 mg, 0.06 mmol) in N,N-dimethylformamide (2 mL) were added SM2 (15 mg, 0.03 mmol), HATU (18 mg, 0.05 mmol), and DIPEA (12 mg, 0.09 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous formic acid) to afford A91 (7 mg, 28% yield) as a yellow solid. LCMS (ESI) m / z = 807.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.20(s,1H),9.86(s,1H),8.76(s,1H),8.36–8.29(m,1H),8.29–8.18(m,1H),7.98–7.87(m,3H),7.87–7.79(m,2H) ,7.65–7.51(m,1H),7.37(d,J=2.4Hz,1H),7.26–7.12(m,2H),3.36–3 .27(m,6H),2.51–2.29(m,10H),2.11–1.92(m,6H),1.70–1.51(m,2H).

[0779] Example 92 Synthesis of Compound A92:

[0780] Compound A92 (21 mg, yield 67%) was synthesized according to the synthesis method of compound A91 described in Example 91. LCMS (ESI) m / z = 766.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.20(s,1H),10.09(s,1H),8.76(s,1H),8.32(d,J=7.8Hz,1H),8.24(t,J=7.2Hz,1H),7.93–7.88(m ,3H),7.84–7.80(m,2H),7.61–7.53(m,1H),7.36(d,J=2.4Hz,1H),7.26–7.12(m,2H),3.36–3.27(m,6H),2.51–2.29(m,10H).

[0781] Example 93 Synthesis of Compound A93:

[0782] Compound A93 (10 mg, yield 38%) was synthesized according to the synthesis method of compound A8 described in Example 8. LCMS (ESI) m / z = 805.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),10.21(s,1H),8.77(s,1H),8.49(d,J=7.6Hz,1H),8.3 9–8.29(m,1H),7.99–7.84(m,5H),7.67–7.52(m,1H),7.38(d,J=2.0Hz,1H),7.28–7.15(m,3 H),7.15–7.06(m,2H),4.59–4.39(m,1H),3.78(t,J=6.8Hz,2H),,3.08–2.97(m,2H),2.97–2 .86(m,2H),2.73(t,J=6.8Hz,2H),2.34–2.21(m,2H),1.99–1.86(m,2H),1.85–1.67(m,4H).

[0783] Example 94 Synthesis of Compound A94:

[0784] Compound A94 (7.0 mg, yield 34.0%) was synthesized according to the synthesis method of Compound A8 described in Example 8. LCMS (ESI) m / z = 817.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.30(s,1H),10.17(s,1H),8.73(s,1H),8.44(d,J=7.6Hz,1H),8.30(d ,J=8.4Hz,1H),7.94–7.82(m,5H),7.60–7.50(m,1H),7.34(d,J=2.0Hz,1H),7.21–7.13(m,2H), 6.92–6.86(m,2H),6.82–6.78(m,1H),4.49–4.40(m,1H),3.77(s,3H),3.73(t,J=6.8Hz,2H),2. 94–2.79(m,4H),2.69(t,J=6.8Hz,2H),2.27–2.17(m,2H),1.91–1.82(m,2H),1.75–1.64(m,4H).

[0785] Example 95 Synthesis of Compound A95:

[0786] Compound A95 (9.0 mg, yield 43.7%) was synthesized according to the synthesis method of Compound A8 described in Example 8. LCMS (ESI) m / z = 817.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.20(s,1H),10.17(s,1H),8.73(s,1H),8.45(d,J=7.6Hz,1H),8.30(d,J=8.4Hz,1 H),7.94–7.82(m,5H),7.59–7.50(m,1H),7.34(d,J=2.0Hz,1H),7.21–7.13(m,2H),7.01(d,J=8.6Hz,1H),6. 61–6.58(m,1H),6.51–6.46(m,1H),4.51–4.40(m,1H),3.77(s,3H),3.49(t,J=6.4Hz,2H),3.23–3.16(m,2H ),3.13–3.06(m,2H),2.64(t,J=6.4Hz,2H),2.23(t,J=9.8Hz,2H),1.88(t,J=9.8Hz,2H),1.75–1.62(m,4H).

[0787] Example 96 Synthesis of Compound A96:

[0788] Compound A96 (10.09 mg, yield 67.74%) was synthesized according to the synthesis method of Example 8. LCMS (ESI) m / z = 805.6 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),10.16(s,1H),8.73(s,1H),8.44(d,J=7.6Hz,1H),8.3 0(d,J=8.8Hz,1H),7.98–7.76(m,5H),7.62–7.48(m,1H),7.34(d,J=2.4Hz,1H),7.25–7.11(m ,3H),6.89–6.73(m,2H),4.51–4.39(m,1H),3.62(t,J=6.8Hz,2H),3.25–3.16(m,2H),3.15– 3.08(s,2H),2.68(t,J=6.8Hz,2H),2.26–2.15(m,2H),1.95–1.83(m,2H),1.75–1.58(m,4H).

[0789] Example 97 Synthesis of Compound A97:

[0790] Step 1:

[0791] To a solution of alkynol (300 mg, 4.28 mmol) in tetrahydrofuran (5 mL) at room temperature were added triethylamine (866 mg, 8.56 mmol) and p-toluenesulfonyl chloride (979 mg, 5.14 mmol). The reaction mixture was stirred at room temperature for 2 h under argon. Water was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford A97-1 (700 mg, 73% yield) as a colorless liquid. LCMS (ESI) m / z = 225.3 [M+H] + .

[0792] Step 2:

[0793] At room temperature, 2-oxyylidene-1-[4-(piperazin-1-yl)phenyl]hexahydropyrimidin-4-one (120 mg, 0.39 mmol, synthesis reference WO2023017446A1), sodium iodide (116 mg, 0.77 mmol) and potassium carbonate (160 mg, 1.16 mmol) were added to a solution of compound A97-1 (130 mg, 0.58 mmol) in N,N-dimethylformamide (3 mL). The reaction mixture was stirred at 80°C under argon for 16 h. Water was added to the reaction mixture, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain A97-2 (90 mg, 71% yield) as a white solid. LCMS (ESI) m / z = 327.2 [M+H] + .

[0794] Step 3:

[0795] To a solution of compound A97-2 (23 mg, 0.07 mmol) in N,N-dimethylformamide (2 mL) were added SM3 (40 mg, 0.07 mmol, synthesis method referenced SM5), cuprous iodide (3 mg, 0.01 mmol), triethylamine (22 mg, 0.21 mmol), and tetrakis(triphenylphosphine)palladium (17 mg, 0.01 mmol) at room temperature. The reaction mixture was stirred at room temperature under argon for 3 h. The reaction mixture was filtered, and the filtrate was separated and purified by reverse phase chromatography (acetonitrile / 10 mM ammonium bicarbonate solution) to afford A112 (17 mg, 31% yield) as a yellow solid. LCMS (ESI) m / z = 757.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.33(s,1H),10.06(s,1H),9.75(s,1H),8.73(s,1H),8.3 0(d,J=8.4Hz,1H),8.03–7.96(m,1H),7.95–7.83(m,2H),7.71–7.52(m,2H),7.41– 7.33(m,2H),7.28–7.16(m,4H),7.10–7.03(m,3H),3.99–3.88(m,4H),3.75–3.69( m,4H),3.59–3.46(m,2H),3.42–3.20(m,1H),3.14–2.96(m,4H),2.77–2.66(m,2H).

[0796] Example 98 Synthesis of Compound A98:

[0797] Step 1:

[0798] To a solution of dihydro-1-(3-iodophenyl)-2,4(1H,3H)-pyrimidinedione (1.00 g, 3.16 mmol, synthesis reference WO2023080732A1) in 1,4-dioxane (15.0 mL) were added neopentyl glycol diborate (3.57 g, 15.82 mmol), palladium acetate (142.2 mg, 632.72 μmol), and potassium acetate (931.3 mg, 9.49 mmol) at room temperature. The reaction was stirred at 110°C for 16 h under argon. Solid impurities were removed by filtration, and the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to afford A98-1 (500 mg, 67% yield) as a yellow solid. LCMS (ESI) m / z = 235.2 [M+H] + .

[0799] Step 2:

[0800] 1-Boc-piperazine (374 mg, 2.01 mmol) was dissolved in acetonitrile, and A98-1 (470.0 mg, 2.01 mmol), copper acetate (729.29 mg, 4.02 mmol), triethylamine (406.46 mg, 4.02 mmol) and The mixture was added with 1% zeolite (191.68 mg, 1.90 mmol) and stirred at 26°C for 16 h. After completion of the reaction, the mixture was directly dried and eluted with flash silica gel column chromatography (EA:MeOH = 10% to 10%) to afford A98-2 (300 mg, 54% yield). LCMS (ESI) m / z = 375.3 [M+H] + .

[0801] Step 3:

[0802] At room temperature, A98-2 (250.0 mg, 667.28 μmol) was dissolved in dichloromethane (10 mL), and a 4 M solution of HCl in dioxane (5 mL) was added. The reaction was stirred at 26°C for 2 h. The solvent was removed by concentration under reduced pressure to afford A98-3 (200 mg, 96% yield) as a yellow solid. LCMS (ESI) m / z = 275.1 [M+H] + .

[0803] Step 4:

[0804] To a solution of compound A98-3 (150.0 mg, 546.81 μmol) in N,N-dimethylformamide (5 mL) at 0°C were added propargyl bromide (59 mg, 492.13 μmol) and DIPEA (141.5 mg, 1.09 mmol). The reaction mixture was heated to 0°C and stirred for 4 h. Water was added to the reaction mixture, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:2) to afford A98-4 (100.0 mg, 58% yield) as a yellow solid. LCMS (ESI) m / z = 313.2 [M+H] + .

[0805] Step 5:

[0806] Compound A98-4 (32 mg, 102.44 μmol), SM3 (57.24 mg, 102.44 μmol), triethylamine (20.7 mg, 204.89 μmol), cuprous iodide (3.9 mg, 20.49 μmol), and Pd(PPh3)4 (23.7 mg, 20.49 μmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature. The reaction mixture was stirred at 80°C for 4 h. The reaction mixture was washed with water and extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to afford A98 (10.0 mg, 13% yield) as a white solid. LCMS (ESI) m / z = 743.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),10.02(s,1H),8.73(s,1H),8.30(d,J=8.4Hz,1H),8.01(s ,1H),7.89(dd,J1=8.4Hz,J2=2.0Hz,1H),7.85(d,J=8.4Hz,1H),7.61–7.52(m,1H),7.37–7.32(m ,2H),7.24–7.18(m,3H),7.08(d,J=7.6Hz,1H),6.92(s,1H),6.84(d,J=8.4Hz,1H),6.75(d,J=7 .6Hz,1H),3.78–3.75(t,J=6.8Hz,2H),3.64–3.60(m,2H),3.23–3.20(m,4H),2.75–2.71(m,4H).

[0807] Example 99 Synthesis of Compound A99:

[0808] Compound A99 (9.56 mg, yield 7.5%) was synthesized according to the synthesis method of compound A97 described in Example 97. LCMS (ESI) m / z = 743.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),10.02(s,1H),8.73(s,1H),8.30(d,J=8.4Hz,1H),8.04(s,1H),7.89(dd,J1=8.4Hz,J2=2.0Hz,1H),7.83(d,J= 8.8Hz,2H),7.57–7.54(m,1H),7.34–7.32(m,2H),7.17–7.06(m,5H),6.95 (d,J=8.8Hz,2H),3.71(t,J=6.8Hz,2H),3.19(bs,4H),2.72–2.68(m,6H).

[0809] Example 100 Synthesis of Compound A100:

[0810] Compound A100 (10.09 mg, yield 67.74%) was synthesized according to the synthesis method of compound A97 described in Example 97. (15 mg, yield 11.0%). LCMS (ESI) m / z = 757.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),9.97(s,1H),8.69(s,1H),8.27(d,J=8.4Hz,1H), 7.91(s,1H),7.87(d,J=8.4Hz,1H),7.80(d,J=8.0Hz,1H),7.58–7.48(m,1H),7.33(s,1H ),7.28(t,J=7.6Hz,1H),7.22–7.10(m,3H),7.02–6.97(m,1H),6.89(s,1H),6.84–6.79( m,1H),6.74–6.68(m,1H),3.74(t,J=6.8Hz,2H),3.18–3.12(m,4H),2.70–2.60(m,10H).

[0811] Example 101 Synthesis of Compound A101:

[0812] Step 1:

[0813] Compound A101-1 (60 mg, crude) was synthesized according to the synthesis method of compound A68-2 described in Example 68. LCMS (ESI) m / z=331.5 [M+H] + .

[0814] Step 2:

[0815] At room temperature, potassium carbonate (250.99 mg, 1.82 mmol) was added to an ethanol solution (4 mL) of A101-3 (100 mg, 605.36 μmol, synthesis method reference Bioorganic & Medicinal Chemistry Letters (2017), 27 (18), 4440-4445) and SM4 (218.40 mg, 605.36 μmol, synthesis reference ACS Medicinal Chemistry Letters (2015), 6 (6), 630-634). The reaction solution was heated to 80 ° C and stirred for 16 h. LCMS detection showed that the reaction was complete, and the reaction solution was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography to obtain a yellow solid A101-4 (140 mg, yield 49.9%). LCMS (ESI) m / z = 463.2 [M+H] + .

[0816] Step 3:

[0817] To a solution of A101-4 (26 mg, 56.17 μmol) in dichloromethane (2 mL) was added thionyl chloride (13.37 mg, 112.34 μmol, 8.19 μL) at room temperature. The reaction mixture was heated to 40°C and stirred for 2 h. LCMS confirmed the reaction was complete, and the reaction mixture was concentrated to afford A101-5 (28 mg, crude) as a yellow solid. LCMS (ESI) m / z = 481.3 [M+H] + .

[0818] Step 4:

[0819] To a solution of A101-5 (26 mg, 54.02 μmol) and A101-2 (23.95 mg, 54.02 μmol, TFA) in N,N-dimethylformamide (3 mL) was added N,N-diisopropylethylamine (34.91 mg, 270.09 μmol, 47.04 μL) at room temperature. The reaction mixture was heated to 45°C and stirred for 16 h. LCMS confirmed the reaction was complete. The reaction mixture was filtered and the filtrate was purified by HPLC to afford A101 (8 mg, 19.1% yield) as a white solid. LCMS (ESI) m / z = 775.4 [M+H]+ . 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),9.85(s,1H),8.65(s,1H),8.28(d,J=8.4Hz,1H),8.0 2–7.98(m,1H),7.89–7.83(m,1H),7.76(d,J=8.4Hz,2H),7.58–7.44(m,2H),7.33–7.31(m,1 H),7.22(d,J=8.4Hz,2H),7.19–7.12(m,2H),6.39(d,J=8.8Hz,1H),3.97(t,J=7.6Hz,2H),3 .75–3.64(m,4H),3.41(s,2H),3.26–3.20(m,1H),2.69(t,J=6.8Hz,2H),2.46–2.18(m,8H).

[0820] Example 102 Synthesis of Compound A102:

[0821] Compound A102 (7 mg, yield 9.1%) was synthesized according to the synthesis method of compound A101 described in Example 101. LCMS (ESI) m / z = 763.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),9.91(s,1H),8.70(s,1H),8.33(d,J=8.4Hz,1H),7.90(dd,J 1=8.4Hz,J2=2.0Hz,1H),7.71(s,1H),7.57–7.54(m,1H),7.36–7.32(m,2H),7.22(t,J=8.0Hz,1H), 7.17–7.15(m,4H),6.93(d,J=8.8Hz,2H),6.59(dd,J1=8.8Hz,J2=2.0Hz,1H),4.06(t,J=6.0Hz,2H) ,3.72(t,J=6.8Hz,2H),3.12(bs,4H),2.72(t,J=6.8Hz,2H),2.50–2.35(m,6H),1.98–1.94(m,2H).

[0822] Example 103 Synthesis of Compound A103:

[0823] Compound A103 (10.0 mg, yield 50.9%) was synthesized according to the synthesis method of compound A101 described in Example 101. LCMS (ESI) m / z = 789.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),9.89(s,1H),8.68(s,1H),8.31(d,J=8.4Hz,1 H),7.87(dd,J1=8.6Hz,J2=2.2Hz,1H),7.71(s,1H),7.56–7.49(m,1H),7.33–7.26( m,3H),7.21–7.08(m,6H),6.59–6.55(m,1H),4.13–4.08(m,2H),3.77(t,J=6.6Hz,2 H),3.07–3.00(m,2H),2.77–2.73(m,2H),2.69(t,J=6.6Hz,2H),1.74–1.65(m,4H).

[0824] Example 104 Synthesis of Compound A104:

[0825] Step 1:

[0826] To a solution of compound SM4 (1.0 g, 2.077 mmol) in methanol (20 mL) were added 1-(4-nitrophenyl)guanidine nitrate (660.5 mg, 3.05 mmol) and potassium carbonate (957.7 mg, 6.93 mmol) at room temperature. The reaction was stirred at 70°C for 12 h. Solid impurities were removed by filtration, and the filtrate was concentrated and purified on a silica gel column to afford A104-1 as a yellow solid (183 mg, 13.82% yield). LCMS (ESI) m / z = 478.1 [M+H] + .

[0827] Step 2:

[0828] Compound A104-2 (135 mg, yield 78.71%) was synthesized according to the synthesis method of compound A64-1 described in Example 64. LCMS (ESI) m / z=477.8 [M+H] + .

[0829] Step 3:

[0830] To a solution of compound A104-2 (108 mg, 0.24 mmol) in dichloromethane (5 mL) at room temperature were added 3-bromopropionyl chloride (41.3 mg, 0.24 mmol) and N,N-diisopropylethylamine (93.5 mg, 0.72 mmol). The reaction mixture was stirred at 25°C for 12 h. The reaction mixture was concentrated and purified by forward column chromatography to afford A104-3 (53.6 mg, 38.14% yield). LCMS (ESI) m / z = 581.6 / 583.7 [M+H] + .

[0831] Step 4:

[0832] To a solution of compound A104-3 (53.6 mg, 0.096 mmol) in N,N-dimethylformamide (3 mL) at room temperature were added 2-oxyylidene-1-[4-(piperazin-1-yl)phenyl]hexahydropyrimidin-4-one (52.71 mg, 0.192 mmol) and N,N-diisopropylethylamine (37.2 mg, 0.288 mmol). The reaction mixture was stirred at 25°C for 12 h. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 0.1% formic acid aqueous solution = 2.3 / 1) to afford A104 (7.72 mg, 10.0% yield) as a yellow solid. LCMS (ESI) m / z = 775.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.99(s,1H),9.79(s,1H),8.63(s,1H),8.27( d,J=8.4Hz,1H),7.87(dd,J1=8.4Hz,J2=2.0Hz,1H),7.71(d,J=8.8Hz,2H),7.60–7.4 8(m,3H),7.31(d,J=2.0Hz,1H),7.21–7.11(m,4H),6.98–6.91(m,2H),3.69(t,J=6.4 Hz,2H),3.17–3.12(m,4H),2.74–2.64(m,4H),2.61–2.56(m,4H),2.54–2.51(m,2H).

[0833] Example 105 Synthesis of Compound A105:

[0834] Compound A105 (8.0 mg, yield 40.1%) was synthesized according to the synthesis method of Compound A6 described in Example 6. LCMS (ESI) m / z = 782.5 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.33(s,1H),10.14(s,1H),8.69(s,1H),8.44(d,J=7.6Hz,1H),8.24(d,J=8.4Hz,1H),8.04(d,J =2.8Hz,1H),7.94–7.89(m,2H),7.86–7.82(m,2H),7.81–7.77(m,1H),7.51–7.40(m,3H),7.15(d,J=2.4Hz,1H),7.06(t, J=7.6Hz,1H),6.98(d,J=8.4Hz,1H),6.85(d,J=9.2Hz,1H),4.85(bs,1H),4.50–4.42(m,1H),3.79(bs,1H),3.69(t,J=6. 8Hz,2H),3.55–3.41(m,4H),3.30(s,3H),2.69(t,J=6.8Hz,2H),2.28–2.19(m,2H),1.93-1.83(m,2H),1.67–1.55(m,4H).

[0835] Example 106 Synthesis of Compound A106:

[0836] Step 1:

[0837] To a solution of methyl 2-bromo-3-methyl-3H-imidazole-4-carboxylate (1.0 g, 4.57 mmol) in ethanol (20 mL) was added sodium borohydride (504 mg, 13.7 mmol) and calcium chloride (1.52 g, 13.7 mmol) at room temperature. The reaction mixture was stirred at 26°C for 16 h. The reaction mixture was filtered and concentrated. The crude product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to afford A106-1 (750 mg, 86% yield) as a white solid. LCMS (ESI) m / z = 191.2 [M+H] + .

[0838] Step 2:

[0839] Compound A106-1 (600 mg, 3.14 mmol), cesium carbonate (2.05 g, 6.28 mmol), tetrakistriphenylphosphine palladium (362 mg, 314 μmol), and SM6 (1.8 g, 3.77 mmol) were dissolved in dioxane / H₂O = 10 / 1 (20 mL) at room temperature. The reaction mixture was stirred at 90°C for 16 h under argon protection. The reaction mixture was concentrated to remove the solvent, and the residue was separated and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain A106-2 (1.0 g, 58%) as a white solid. LCMS (ESI) m / z = 543.2 [M+H] + .

[0840] Step 3:

[0841] At room temperature, compound A106-2 (600 mg, 1.11 mmol) was dissolved in dichloromethane (10 mL). Thionyl chloride (2 mL) was slowly added dropwise and stirred at 26°C for 2 h. The reaction mixture was concentrated to remove the solvent to obtain A106-3 (400 mg, 64%) as a yellow solid. LCMS (ESI) m / z = 561.1 [M+H] + .

[0842] Step 4:

[0843] To a solution of A106-3 (30 mg, 53.44 μmol) in N,N-dimethylformamide (10 mL) were added DIPEA (13.8 mg, 106.87 μmol) and 2-oxyylidene-1-[4-(piperazin-1-yl)phenyl]hexahydropyrimidin-4-one (16.6 mg, 53.44 μmol) at room temperature. The reaction mixture was stirred at 70°C for 2 h. Saturated brine was added to the reaction mixture, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain A106 (9 mg, 21% yield) as a white solid. LCMS (ESI) m / z = 799.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.28(s,1H),10.17(s,1H),8.74(s,1H),8.34(d,J=8.4Hz,1H),7.9 7(d,J=8.4Hz,2H),7.90(dd,J1=8.0Hz,J2=2.4Hz,1H),7.65(d,J=8.4Hz,2H),7.59–7.51(m, 1H),7.36(d,J=2.4Hz,1H),7.22–7.16(m,4H),6.96(d,J=9.2Hz,2H),3.75(s,3H),3.72(t,J =6.8Hz,2H),3.59–3.56(m,2H),3.19–3.16(m,4H),2.70(t,J=6.8Hz,2H),2.68–2.64(m,2H).

[0844] Example 107 Synthesis of Compound A107:

[0845] Step 1:

[0846] To a solution of tert-butyl 5,6-dihydroimidazo[1,5-A]pyrazine-7(8H)-carboxylate (200 mg, 0.90 mmol) in tetrahydrofuran (2 mL) was added n-butyl lithium (1.6 M in hexanes, 0.67 mL, 1.07 mmol) at -78°C under argon. The reaction mixture was stirred at -78°C under argon for 1 hour. Iodine (273 mg, 1.07 mmol) in tetrahydrofuran (1 mL) was slowly added dropwise and stirred for 1 hour after the addition was complete. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford A107-1 (150 mg, 48% yield) as a yellow solid. LCMS (ESI) m / z = 450.1 [M+H] + .

[0847] Step 2:

[0848] To a mixed solution of compound A107-1 (44 mg, 0.13 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) at room temperature were added SM6 (60 mg, 0.13 mmol), cesium carbonate (82 mg, 0.25 mmol), and tetrakis(triphenylphosphine)palladium (7 mg, 0.006 mmol). The reaction mixture was heated to 90°C and stirred under argon for 16 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford A107-2 (44 mg, 53% yield) as a yellow solid. LCMS (ESI) m / z = 654.1 [M+H] + .

[0849] Step 3:

[0850] To a solution of compound A107-2 (44 mg, 0.07 mmol) in dichloromethane (2 mL) was added HCl (4 M in dioxane, 1 mL) at room temperature. The reaction was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to afford a pale yellow solid A107-3 (40 mg, 100% yield, crude product). LCMS (ESI) m / z = 554.2 [M+H] + .

[0851] Step 4:

[0852] To a solution of 1-(4-bromophenyl)dihydropyrimidine-2,4(1H,3H)-dione (1 g, 3.72 mmol) in dimethyl sulfoxide (6 mL) were added ethanolamine (454 mg, 7.43 mmol), L-proline (428 mg, 3.72 mmol), potassium carbonate (1.54 g, 11.15 mmol), and cuprous iodide (142 mg, 0.74 mmol) at room temperature. The reaction mixture was heated to 90°C under argon and stirred for 16 h. The reaction mixture was purified by reverse phase separation to afford A107-4 (95 mg, 10% yield) as a yellow solid. LCMS (ESI) m / z = 250.2 [M+H] + .

[0853] Step 5:

[0854] To a solution of compound A107-4 (85 mg, 0.34 mmol) in dichloromethane (1 mL) were added imidazole (46 mg, 0.68 mmol), triphenylphosphine (179 mg, 0.68 mmol), and iodine (173 mg, 0.68 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford A107-5 (72 mg, 59% yield) as a yellow solid. LCMS (ESI) m / z = 360.1 [M+H]+ .

[0855] Step 6:

[0856] To a solution of compound A107-5 (40 mg, 0.11 mmol) in N,N-dimethylformamide (1 mL) at room temperature were added sodium iodide (17 mg, 0.11 mmol), DIPEA (22 mg, 0.17 mmol), and A107-3 (33 mg, 0.06 mmol). The reaction mixture was heated to 80°C and stirred under argon for 12 h. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous formic acid) to afford A107 (6 mg, 8% yield) as a pale yellow solid. LCMS (ESI) m / z = 785.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.23(s,1H),10.09(s,1H),8.73(s,1H),8.39–8.26(m,1H),8.00–7.83(m ,3H),7.75–7.65(m,2H),7.65–7.51(m,1H),7.36(d,J=2.4Hz,1H),7.28–7.12(m,2H),7.10–6.98( m,2H),6.79(s,1H),670–6.58(m,2H),5.59(t,J=5.6Hz,1H),4.19(t,J=5.2Hz,2H),3.78(s,2H),3 .68(t,J=6.4Hz,2H),3.31–3.20(m,2H),2.97–2.84(m,2H),2.82–2.72(m,2H),2.72–2.63(m,2H).

[0857] Example 108 Synthesis of Compound A108:

[0858] Compound A108 (15.8 mg, yield 17.6%) was synthesized according to the synthesis method of compound A101 described in Example 101. LCMS (ESI) m / z = 748.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.26(s,1H),9.38(s,1H),8.53(s,1H),8.23(d,J=8.5Hz,1 H),7.86–7.80(m,1H),7.59–7.50(m,1H),7.45(d,J=8.0Hz,2H),7.30–7.27(m,1H),7 .21–7.12(m,4H),6.98–6.91(m,2H),6.61–6.56(m,2H),5.18(t,J=5.6Hz,1H),3.70 (t,J=6.8Hz,2H),3.20–3.13(m,6H),2.71–2.65(t,J=6.8Hz,2H),2.61–2.55(m,6H).

[0859] Example 109 Synthesis of Compound A109:

[0860] Compound A109 (15.0 mg, yield 59.6%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 772.5 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.72(s,1H),8.45(d,J=8.0Hz,1H),8.38–8.34(m,1H),8 .04–8.02(m,1H),7.92–7.90(m,2H),7.86–7.83(m,2H),7.71–7.66(m,1H),7.58–7.52(m,1H),7 .48–7.44(m,1H),7.18–7.15(m,2H),6.87–6.82(m,1H),4.51–4.40(m,1H),3.71–3.67(m,2H), 3.53–3.39(m,4H),2.71–2.67(m,3H),2.26–2.18(m,2H),1.91–1.86(m,1H),1.66–1.52(m,4H).

[0861] Example 110 Synthesis of Compound A110:

[0862] Compound A110 (13.46 mg, yield 43.09%) was synthesized according to the synthesis method of compound A54 described in Example A54. LCMS (ESI) m / z = 802.16 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.33(s,1H),10.17(s,1H),8.73(s,1H),8.44(d,J=7.6Hz,1H),8.30( d,J=8.4Hz,1H),7.95–7.81(m,6H),7.61–7.49(m,1H),7.34(d,J=2.0Hz,1H),7.22–7.13(m,2H) ,6.75(s,1H),4.51–4.40(m,1H),3.72–3.61(m,1H),3.57–3.48(m,3H),3.47–3.42(m,2H),2.7 5–2.66(m,2H),2.24(t,J=10.0Hz,2H),2.10(s,3H),1.88(t,J=10.0Hz,2H),1.69–1.53(m,4H).

[0863] Example 111 Synthesis of Compound A111:

[0864] Step 1:

[0865] To a solution of 2-bromo-1H-imidazole (500 mg, 3.4 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (1.4 g, 10.2 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (980 mg, 4.1 mmol) at room temperature. The reaction was stirred at room temperature for 16 h. A spectrophotometer indicated complete reaction of the starting material. Water was added, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:20) to afford A111-1 as a colorless oil (1 g, 96.3% yield). LCMS (ESI) m / z = 305.4 [M+H] + .

[0866] Step 2:

[0867] To a solution of SM6 (200 mg, 0.42 mmol) in 1,4-dioxane (10 mL) and water (1 mL) at room temperature were added A111-1 (128 mg, 0.42 mmol), tetrakis(triphenylphosphine palladium) (48.5 mg, 0.04 mmol), and cesium carbonate (273 mg, 0.84 mmol). The atmosphere was replaced with argon three times, and the temperature was raised to 100°C with stirring for 16 hours. Water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:5) to obtain A111-2 (120 mg, 43.5% yield) as a yellow solid. LCMS (ESI) m / z = 657.6 [M+H] + .

[0868] Step 3:

[0869] To a solution of A111-2 (120 mg, 0.18 mmol) in tetrahydrofuran (3 mL) was added 1.0 M tetrabutylammonium fluoride (0.4 mL, 0.4 mmol) at room temperature and the mixture was stirred for 3 h. LCMS confirmed the complete reaction. Water was added, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:3) to afford A111-3 (85 mg, 85.7% yield) as a yellow solid. LCMS (ESI) m / z = 543.1 [M+H] + .

[0870] Step 4:

[0871] To a dichloromethane solution (3 mL) of A111-3 (85 mg, 0.15 mmol) was added triphenylphosphine (82 mg, 0.3 mmol), imidazole (21 mg, 0.3 mmol), and iodine (80 mg, 0.3 mmol) at room temperature. The mixture was stirred at room temperature for 2 h, then water was added and extracted with dichloromethane. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:3) to afford A111-4 (60 mg, 58.7% yield) as a yellow solid. LCMS (ESI) m / z = 653.2 [M+H] + .

[0872] Step 5:

[0873] To a solution of A111-4 (60 mg, 0.09 mmol) in N,N-dimethylformamide (3 mL) were added 2-oxyylidene-1-[4-(piperazin-1-yl)phenyl]hexahydropyrimidin-4-one (25 mg, 0.09 mmol) and DIPEA (36 mg, 0.27 mmol) at room temperature. The mixture was heated to 80°C and stirred for 16 h. LCMS analysis indicated a yield of approximately 30%. The reaction mixture was filtered, and the crude product was purified by reverse phase chromatography (acetonitrile / 10 mM aqueous ammonium bicarbonate) to afford A111 (7.6 mg, 10.3% yield) as a yellow solid. LCMS (ESI) m / z = 799.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),10.11(s,1H),8.71(s,1H),8.30(d, J=8.8Hz,1H),7.97–7.92(m,2H),7.88–7.82(m,1H),7.63–7.51(m,3H),7. 38–7.32(m,2H),7.21–7.07(m,4H),6.97(s,1H),6.91–6.85(m,2H),4.21– 4.14(m,2H),3.67(t,J=6.8Hz,2H),3.10–2.99(m,4H),2.70–2.63(m,4H).

[0874] Example 112 Synthesis of Compound A112:

[0875] Compound A112 (6 mg, yield 23%) was synthesized according to the synthesis method of compound A16 described in Example A16. LCMS (ESI) m / z = 802.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),10.21(s,1H),8.76(s,1H),8.49(d,J=7.6Hz,1H), 8.33(d,J=8.4Hz,1H),7.96–7.85(m,4H),7.61–7.54(m,1H),7.42–7.36(m,2H),7.22–7.2 1(m,2H),6.71(d,J=8.8Hz,1H),4.51–4.45(m,1H),3.71-3.64(m,1H),3.54–3.39(m,5H), 2.81-2.72(m,2H),2.29–2.26(m,2H),2.23(s,3H),1.93–1.88(m,2H),1.67–1.61(m,4H).

[0876] Example 113 Synthesis of Compounds A113 and A114:

[0877] Step 1:

[0878] A113-1 (3 g, 10.4 mmol, synthesis reference WO2019032743A1) and 5-bromo-2-iodopyridine (2.96 g, 10.41 mmol) were dissolved in DMA (80 mL). Zinc powder (676 mg, 10.41 mmol), 1,1'-bis(diphenylphosphino)ferrocene) nickel dichloride (711 mg, 1.1 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (558.09 mg, 2.08 mmol), and sodium iodide (780 mg, 5.21 mmol) were added sequentially under argon protection. The mixture was stirred at 60°C for 2 h. After completion of the reaction, the mixture was directly dried and purified by flash silica gel column chromatography (EA:PE = 10% to 50%) to give A113-2 (320 mg). LCMS (ESI) m / z = 318.2 [M+H] + .

[0879] Step 2:

[0880] A113-2 (700 mg, 2.2 mmol), 3-(4-methoxybenzyl)-dihydropyrimidine-2,4(1H,3H)-dione (772 mg, 3.3 mmol), cesium carbonate (1.08 g, 3.3 mmol), (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (156 mg, 1.1 mmol), cuprous iodide (209 mg, 1.1 mmol), and dioxane (10 mL) were added to a microwave reaction vial. The mixture was then microwaved at 120°C for 2 h under argon protection. After completion of the reaction, the mixture was directly dried and purified by flash silica gel column chromatography (EA:PE = 50% to 100%) to afford A113-3 (600 mg). LCMS (ESI) m / z = 471.5 [M+H] + .

[0881] Step 3:

[0882] A113-3 (400 mg) was dissolved in trifluoroacetic acid (4 mL), and trifluoromethanesulfonic acid (2 mL) was slowly added dropwise and stirred at room temperature for 3 h. After completion of the reaction, the reaction was quenched with ice water, and saturated sodium bicarbonate was added to adjust the pH of the system to 7-8. The reaction was extracted twice with ethyl acetate, and the aqueous phase was directly subjected to reverse phase medium pressure to obtain A113-4 (150 mg). LCMS (ESI) m / z = 261.2 [M+H] + .

[0883] Step 4:

[0884] A113-4 (50 mg, 0.19 mmol) was dissolved in tetrahydrofuran (5 mL), and Dess-Martin periodinane (162 mg, 0.38 mmol) was added and stirred at room temperature overnight. After completion of the reaction, the product was directly dried and purified by flash silica gel column chromatography (EA:PE = 50% to 100%) to afford A113-5 (49 mg). LCMS (ESI) m / z = 259.2 [M+H] + .

[0885] Step 5:

[0886] A113-6 (49 mg, 0.18 mmol) was dissolved in methanol (2 mL), and 3-N-tert-butyloxycarbonylaminocyclobutylamine (39 mg, 0.22 mmol), sodium triacetoxyborohydride (120 mg, 0.56 mmol), and 1 drop of acetic acid were added sequentially. The mixture was stirred at 50°C overnight. After completion, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was dried and purified by flash silica gel column chromatography (EA:PE = 50% to 100%) to afford the cis-product (10 mg) and the trans-product (5 mg). LCMS (ESI) m / z = 415.5 [M+H] + .

[0887] Step 6:

[0888] The product from the previous step was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was directly dried and used for the next step. LCMS (ESI) m / z = 315.2 [M+H] + .

[0889] Step 7:

[0890] The compound was synthesized according to the synthesis method of compound A1 described in Example 1, and the trans product A113 (4 mg, yield 24.6%) was obtained after separation and purification. LCMS (ESI) m / z = 774.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),10.23(s,1H),8.76(s,1H),8.55(d,J=8.4Hz,1H),8.34(d,J=8.4Hz,1H),7.96–7.87(m,5H),7.70 –7.68(m,1H),7.60–7.56(m,1H),7.37–7.32(m,2H),7.22–7.19(m,2H),3.84(t,J=6.8Hz,2H),2.74(t,J=6.8Hz,2H),1.28–1.25(m,4H).

[0891] Cis product A114 (2 mg, yield 12.3%). LCMS (ESI) m / z = 774.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),10.25(s,1H),8.79(s,1H),8.67(d,J=8.4Hz,1H),8. 57(d,J=8.4Hz,1H),8.36(d,J=8.8Hz,1H),7.97–7.89(m,5H),7.73–7.70(m,1H),7.62–7.58 (m,1H),7.40–7.34(m,2H),7.24–7.21(m,2H),3.86(t,J=6.8Hz,2H),3.52–3.49(m,2H),3. 29–3.26(m,1H),3.19(bs,1H),2.78(t,J=6.8Hz,2H),2.38–2.32(m,3H),2.23–2.20(m,2H).

[0892] Example 114 Synthesis of Compound A115:

[0893] Compound A115 (10.0 mg, yield 50.6%) was synthesized according to the synthesis method of compound A6 described in Example 6. LCMS (ESI) m / z = 793.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),10.08(s,1H),8.67(s,1H),8.43(d,J=7.6Hz,1H),8.18(d,J=8.2Hz,1H),8.04(d,J=2.8H z,1H),7.95–7.88(m,2H),7.85–7.80(m,2H),7.56–7.44(m,2H),7.39–7.35(m,1H),7.21–7.10(m,2H),7.07–7.03(m,1H),6.85 (d,J=9.1Hz,1H),4.50–4.39(m,1H),3.69(t,J=6.8Hz,2H),3.56–3.48(m,2H),3.47–3.42(m,2H),2.69(t,J=6.8Hz,2H),2.28– 2.19(m,2H),2.04–1.96(m,1H),1.92–1.85(m,2H),1.66–1.62(m,2H),1.60–1.56(m,2H),1.03–0.97(m,2H),0.78–0.60(m,2H).

[0894] Example 115 Synthesis of Compound A116:

[0895] Compound A116 (9.3 mg, yield 45.6%) was synthesized according to the synthesis method of compound A6 described in Example 6. LCMS (ESI) m / z = 754.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),10.12(s,1H),8.72(s,1H),8.44(d,J=8.0Hz,1H),8.32–8.27(m,1H),8.0 4(d,J=2.8Hz,1H),7.93(d,J=8.8Hz,2H),7.84(d,J=8.8Hz,2H),7.82–7.76(m,1H),7.68–7.62(m,1H),7.57–7.4 4(m,2H),7.33(d,J=7.8Hz,1H),7.15(s,2H),6.88–6.82(m,1H),4.51–4.40(m,1H),3.69(t,J=8.0Hz,2H),3.55– 3.48(m,2H),3.47–3.30(m,2H),2.69(t,J=8.0Hz,2H),2.28–2.19(m,2H),1.94–1.83(m,2H),1.69–1.53(m,4H).

[0896] Example 116 Synthesis of Compound A117:

[0897] Step 1:

[0898] Compound A117-1 (1.5 g, 5.30 mmol, Synthesis Reference Example 8) and neopentyl glycol diboronate (7.18 g, 31.79 mmol) were dissolved in a dioxane solution (15 mL), and potassium acetate (1.56 g, 15.89 mmol) and palladium acetate (594.74 mg, 2.65 mmol, 271.57 μL) were added. The reaction solution was stirred at 110°C for 16 h. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 mL*3). The organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound A117-2 (0.3 g, 22.8% yield). LCMS (ESI) m / z = 249.1 [M+H] + .

[0899] Step 2:

[0900] Compound A117-3 (100 mg, hydrochloride) was synthesized according to the synthesis method of compound A63-5 described in Example 63. LCMS (ESI) m / z=289.4 [M+H] + .

[0901] Step 3:

[0902] Compound A117 (5 mg, 5.5% yield) was synthesized according to the synthesis method of compound A98 described in Example 98. LCMS (ESI) m / z=771.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),9.98(s,1H),8.69(s,1H),8.27(d,J=8.4Hz,1H),7.94–7.90(m ,1H),7.88–7.84(m,1H),7.80(d,J=8.4Hz,1H),7.58–7.50(m,1H),7.34–7.32(m,1H),7.28(t,J=8.0 Hz,1H),7.20–7.11(m,2H),7.08(d,J=8.4Hz,1H),6.99(d,J=7.6Hz,1H),6.86–6.84(m,1H),6.83–6. 79(m,1H),3.78–3.70(m,1H),3.52–3.43(m,1H),3.16–3.06(m,4H),2.73–2.57(m,10H),2.06(s,3H).

[0903] Example 117 Synthesis of Compound A118:

[0904] Compound A118 (16 mg, yield 48%) was synthesized according to the synthesis method of compound A6 described in Example 6. LCMS (ESI) m / z = 768.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.37(s,1H),10.12(s,1H),8.72(s,1H),8.46(d,J=7.6Hz,1H),8.27–8.16(m,1 H),8.08(d,J=2.8Hz,1H),8.01–7.91(m,2H),7.91–7.81(m,2H),7.69–7.61(m,1H),761–7.42(m,2H),7. 27–7.05(m,2H),6.97–6.79(m,1H),4.58–4.36(m,1H),3.73(t,J=6.4Hz,2H),3.63–3.51(m,2H),3.51–3 .42(m,2H),2.73(t,J=6.8Hz,2H),2.41(s,3H),2.34–2.19(m,2H),2.00–1.86(m,2H),1.75–1.54(m,4H).

[0905] Example 118 Synthesis of Compound A119:

[0906] Compound A119 (2.0 mg, yield 8.0%) was synthesized according to the synthesis method of compound 4 described in Example 4. LCMS (ESI) m / z = 786.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),10.15(s,1H),8.73(s,1H),8.44(d,J=8.0Hz,1H),8.28(d,J=8. 0Hz,1H),8.03(d,J=2.7Hz,1H),7.91–7.82(m,5H),7.66–7.63(m,1H),7.50–7.46(m,3H),7.42–7.40(m ,1H),7.13(d,J=2.2Hz,1H),6.85(d,J=12Hz,1H),4.48–4.42(m,1H),3.69(t,J=8Hz,2H),3.53–3.50( m,2H),3.46–3.42(m,2H),2.71–2.68(m,3H),2.26–2.22(m,2H),1.91–1.86(m,2H),1.66–1.58(m,4H).

[0907] Example 119 Synthesis of Compound A120:

[0908] Step 1:

[0909] Iron powder (11.17 g, 200 mmol) was added to a solution of 2-bromo-5-nitropyridine (8.1 g, 40 mmol) in acetic acid (30 mL) at room temperature, and the reaction was stirred at 90°C for 2 h. The reaction solution was filtered, concentrated under reduced pressure, and water was added. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain A120-1 (6 g, 86% yield) as a brown solid. LCMS (ESI) m / z = 173.1 [M+H] + .

[0910] Step 2:

[0911] At room temperature, compound A120-1 (4.85 g, 22.04 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.8 g, 2.2 mmol) were dissolved in N,N-dimethylacetamide solution (50 mL) and stirred continuously at 65°C under argon protection. In another conical flask, 1-Boc-3-iodoazetidine (18.72 g, 66.13 mmol), elemental iodine (560 mg, 2.2 μmol), and zinc powder (4.3 g, 66.13 μmol) were dissolved in N,N-dimethylacetamide solution (50 mL). The reaction solution was stirred at room temperature for 2 h, then added to another reaction system, heated to 85°C, and stirred continuously overnight. The reaction mixture was added with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:20) to obtain a yellow oil A120-2 (3 g, yield 54%). LCMS (ESI) m / z = 250.3 [M+H] + .

[0912] Step 3:

[0913] To a solution of compound A120-2 (900 mg, 3.61 mmol) in ethanol (20 mL) was added methyl allylate (932 mg, 10.83 mmol) and triethylamine (731 mg, 7.22 mmol) at room temperature. The mixture was stirred at 100°C for 16 h. The mixture was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to afford A120-3 (1 g, 82% yield) as a brown solid. LCMS (ESI) m / z = 336.2 [M+H] + .

[0914] Step 4:

[0915] Compound A120-3 (1.0 g, 2.86 mmol) was dissolved in a mixture of acetic acid (20 mL) and water (0.4 mL). Sodium cyanate (930 mg, 14.31 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give compound A120-4 (1.0 g, yellow solid, crude product). LCMS (ESI) m / z = 379.3 [M+H] + .

[0916] Step 5:

[0917] Compound A120-4 (400 mg, 1.02 mmol) was dissolved in tetrahydrofuran (10 mL) and potassium trimethylsilanol was added to adjust the pH to ≈ 9. The reaction solution was stirred at room temperature for 1 h. The reaction solution was adjusted to weak acidity with acetic acid and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain compound A120-5 (250.0 mg, yellow solid, crude product). LCMS (ESI) m / z = 347.2 [M+H] +

[0918] Step 6:

[0919] Compound A120-5 (300.0 mg, 866.10 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 25°C for 2 h. The reaction mixture was concentrated to remove the solvent to give A120-6 (250.0 mg, yellow solid, crude product, trifluoroacetate salt). LCMS (ESI) m / z = 247.2 [M+H] + .

[0920] Step 7:

[0921] Compound A120-6 (213 mg, 864.92 μmol) was dissolved in dichloromethane, and 1-tert-butyloxycarbonyl-3-azetidinone (296 mg, 1.73 mmol) and acetic acid (2.52 mg, 42.20 μmol) were added sequentially. The mixture was stirred at 26°C for 1 hour, and then sodium acetate borohydride (367 mg, 1.73 μmol) was added. After the reaction was completed, the mixture was directly dried and washed with flash silica gel column chromatography (EA:MeOH = 10% to 10%) to obtain A120-7 (200 mg, yield 57%). LCMS (ESI) m / z = 402.4 [M+H] + .

[0922] Step 8:

[0923] Compound A120-7 (40 mg, 99.64 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at 25°C for 2 h. The reaction mixture was concentrated to remove the solvent to give A120-8 (30.0 mg, yellow solid, crude product, trifluoroacetate salt). LCMS (ESI) m / z = 302.3 [M+H] + .

[0924] Step 9:

[0925] To a solution of compound A120-8 (15 mg, 31.46 μmol) in N,N-dimethylformamide (5 mL) were added SM1 (14.22 mg, 47.18 μmol), HATU (23.9 mg, 62.91 μmol), and DIPEA (4.0 mg, 31.46 μmol) at room temperature. The reaction mixture was stirred at 26°C for 16 h. Water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:20) to afford A120 (4 mg, 16% yield) as a yellow oil. LCMS (ESI) m / z = 760.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),10.23(s,1H),8.76(s,1H),8.56(d,J=2.4Hz,1H),8.33(d,J=8 .4Hz,1H),7.95–7.90(m,3H),7.73(dd,J1=8.4Hz,J2=2.6Hz,1H),7.62–7.54(m,2H),7.60–7.54(m,1 H),7.44(d,J=8.4Hz,1H),7.37(d,J=2.4Hz,1H),7.22–7.18(m,2H),4.42–4.40(m,1H),4.12–4.08(m ,2H),3.86–3.78(m,4H),3.72–3.67(m,2H),3.60–3.54(m,1H),3.40–3.35(m,4H),2.77–2.74(m,2H).

[0926] Example 120 Synthesis of Compound A121:

[0927] Step 1:

[0928] To a solution of ethyl imidazole-4-carboxylate (1.0 g, 7.14 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (314 mg, 7.85 mmol) at zero degrees Celsius. The reaction was stirred for 0.5 h, and 2-(trimethylsilyl)ethoxymethyl chloride (1.42 g, 8.52 mmol) was added. The reaction was stirred at room temperature for 3 h. The mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate, and concentrated. The product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to afford A121-1 (1.1 g, 57.01% yield) as a white solid. LCMS (ESI) m / z = 271.21 [M+H] + .

[0929] Step 2:

[0930] To a solution of compound A121-1 (1.0 g, 3.70 mmol) in carbon tetrachloride (5 mL) were added N-bromosuccinimide (658 mg, 3.70 mmol) and azobisisobutyronitrile (30.36 mg, 0.18 mmol) at room temperature. The reaction was stirred at 60°C for 3 h. The reaction mixture was filtered and the filtrate was concentrated. The product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to afford A121-2 (1.02 mg, 78.95% yield) as a white solid. LCMS (ESI) m / z = 348.9 [M+H] + .

[0931] Step 3:

[0932] To a solution of compound A121-2 (1.0 g, 2.86 mmol) in ethanol (20 mL) at room temperature were added sodium borohydride (650 mg, 17.18 mmol) and calcium chloride (1.91 g, 17.8 mmol). The reaction was stirred at 25°C for 12 h. The reaction mixture was filtered, the filtrate concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to afford A121-3 (721 mg, 81.96% yield) as a white solid. LCMS (ESI) m / z = 307.0 [M+H] + .

[0933] Step 4:

[0934] To a solution of compound A121-3 (300 mg, 0.98 mmol) in dichloromethane (5 mL) was added thionyl chloride (2 mL) at room temperature. The reaction was stirred at 25°C for 3 h. The reaction solution was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to afford A121-4 (120 mg, 37.73% yield) as a white solid. LCMS (ESI) m / z = 325.2 [M+H] + .

[0935] Step 5:

[0936] Compound A121-5 (42 mg, yield 97.69%) was synthesized according to the synthesis method of compound A5-2 described in Example A5. LCMS (ESI) m / z = 563.1 [M+H] + .

[0937] Step 6:

[0938] At room temperature, compound A121-5 (142.38 mg, 251.75 μmol), SM6 (100 mg, 0.21 mmol), cesium carbonate (205.06 mg, 0.63 mmol), and tetrakistriphenylphosphine palladium (48.46 mg, 0.04 mmol) were dissolved in dioxane (5 mL) and ethanol (0.2 mL). The reaction mixture was stirred at 90°C for 8 h. The reaction mixture was filtered and the filtrate was concentrated to remove the solvent. The residue was separated and purified by silica gel column chromatography (dichloromethane / methanol = 30:1) to obtain A121-6 (53 mg, 27.53%) as a yellow solid. LCMS (ESI) m / z = 915.2 [M+H] + .

[0939] Step 7:

[0940] A121-6 (30 mg, 0.03 mmol) obtained in the previous step was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 12 h. The reaction solution was separated and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous formic acid = 2.3 / 1) to afford A121 (12.2 mg, 21% yield) as a yellow solid. LCMS (ESI) m / z = 785.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.2(s,1H),10.30(s,1H),10.07(s,1H),8.73(s,1H ),8.34(d,J=8.4Hz,1H),7.98–7.85(m,5H),7.64–7.52(m,1H),7.36(d,J=2. 0Hz,1H),7.26–7.05(m,5H),6.96(d,J=8.9Hz,3H),3.72(t,J=6.8Hz,2H),3. 62–3.44(m,2H),3.23–3.08(m,4H),2.70(t,J=6.8Hz,2H),2.67–2.56(m,4H).

[0941] Example 121 Synthesis of Compound A122:

[0942] Compound A122 (8.25 mg, yield 49.73%) was synthesized according to the synthesis method of compound A54 described in Example 54. LCMS (ESI) m / z = 784.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),10.10(s,1H),8.69(s,1H),8.47(d,J=7.6Hz,1H),8.3 0(d,J=8.8Hz,1H),8.09–8.04(m,1H),7.99–7.80(m,4H),7.62–7.39(m,3H),7.18(s,2H),6.8 8(d,J=8.8Hz,1H),6.74(s,1H),4.57–4.43(m,1H),3.81(s,3H),3.72(t,J=6.8Hz,2H),3.60– 3.45(m,4H),2.72(t,J=6.8Hz,2H),2.32–2.19(m,2H),1.99–1.82(m,2H),1.71–1.52(m,4H).

[0943] Example 122 Synthesis of Compound A123:

[0944] Compound A123 (2.0 mg, yield 4.2%) was synthesized according to the synthetic method of compound A98 described in Example 98. LCMS (ESI) m / z = 743.4 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),10.14(s,1H),8.74(s,1H),8.31(d,J=8. 4Hz,1H),7.88–7.83(m,3H),7.61–7.54(m,1H),7.43(d,J=8.4Hz,2H),7.36(d,J =2.2Hz,1H),7.28–7.15(m,3H),6.93(s,1H),6.87(d,J=8.4Hz,1H),6.76(d,J= 7.8Hz,1H),3.78(t,J=6.6Hz,2H),3.61(s,2H),3.22(s,4H),2.72–2.70(m,6H).

[0945] Example 124 Synthesis of Compound A124:

[0946] Compound A124 (4.0 mg, yield 8.4%) was synthesized according to the synthetic method of compound A98 described in Example 98. LCMS (ESI) m / z = 743.4 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),10.12(s,1H),8.70(s,1H),8.28(d,J=8.0Hz,1H),7.91–7.86(m,3H),7.68–7.61(m,1H),7.40(d,J=8.0 Hz,2H),7.33(d,J=2.2Hz,1H),7.19–7.14(m,4H),6.95(d,J=8.0Hz,2H),3.70(t,J=6.6Hz,2H),3.57(s,2H),3.18(bs,4H),3.19–3.16(m,6H).

[0947] Example 124 Synthesis of Compound A125:

[0948] Compound A125 (7 mg, yield 14.2%) was synthesized according to the synthesis method of compound A101 described in Example 101. LCMS (ESI) m / z = 749.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),9.92(s,1H),8.71(s,1H),8.33(d,J=8.4Hz,1H),7.90(dd,J1= 8.4Hz, J2=2.0Hz,1H),7.71(s,1H),7.60–7.52(m,1H),7.36–7.33(m,2H),7.24–7.18(m,4H),6.89(b s,1H),6.83–6.80(m,1H),6.75–6.73(m,1H),6.60(dd,J1=8.0Hz,J2=2.0Hz,1H),4.17(bs,2H),3.75 (t,J=6.8Hz,2H),3.17–3.15(m,4H),2.79(t,J=6.8Hz,2H),2.70(t,J=6.8Hz,2H),2.66–2.64(m,4H).

[0949] Example 125 Synthesis of Compound A126:

[0950] Compound A126 (20.0 mg, yield 18%) was synthesized according to the synthesis method of compound A98 described in Example 98. LCMS (ESI) m / z = 714.3 [M+H]+ .LCMS (ESI) m / z = 819.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.38(s,1H),10.04(s,1H),8.72(s,1H),8.28(d, J=8.4Hz,1H),8.03–8.01(m,1H),7.88–7.82(m,2H),7.61–7.53(m,1H),7. 38–7.26(m,5H),7.19–7.16(m,3H),7.11–7.07(m,1H),3.74–3.70(m,4H), 3.68–3.63(m,1H),3.59(s,2H),3.42–3.38(m,2H),2.65(t,J=6.8Hz,2H).

[0951] Example 126 Synthesis of Compound A127:

[0952] Compound A127 (20 mg, 6.8% yield) was synthesized according to the synthesis method of compound A98 described in Example 98. LCMS (ESI) m / z = 728.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),9.95(s,1H),8.69(s,1H),8.27(d,J=8.4Hz,1H),7.91–7.88(m,1H) ,7.86–7.79(m,2H),7.58–7.50(m,1H),7.34–7.31(m,1H),7.30–7.25(m,1H),7.22–7.13(m,3H),7.00(d,J =7.2Hz,1H),6.92–6.89(m,1H),6.86–6.81(m,1H),6.73–6.69(m,1H),3.75(t,J=6.8Hz,2H),3.54–3.46( m,2H),3.06–2.99(m,2H),2.91-2.84(m,1H),2.68(t,J=6.8Hz,2H),2.02–1.94(m,2H),1.78–1.68(m,2H).

[0953] Example 127 Synthesis of Compound A128:

[0954] Step 1:

[0955] To a solution of 5-chloro-2-iodobenzoic acid (5 g, 17.70 mmol) in dichloromethane (50 mL) was added N,N-dimethylformamide (1 mL) and thionyl chloride (4.21 g, 35.40 mmol) at room temperature. The reaction mixture was stirred at 40°C under argon for 3 h. The reaction mixture was concentrated and washed twice with toluene. The residue was dissolved in dichloromethane (20 mL), and methoxymethylamine (1.9 g, 19.47 mmol) and pyridine (5.6 g, 70.81 mol, 5.70 mL) were added. The reaction mixture was stirred at room temperature under argon for 12 h. Water was added, the mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield A128-1 (5.23 g, 91% yield) as a white solid. LCMS (ESI) m / z = 326.1 [M+H] + .

[0956] Step 2:

[0957] To a dichloromethane solution (100 mL) of compound A128-1 (5.23 g, 16.07 mmol) at room temperature were added N-Boc-aminopropyne (2.74 g, 17.67 mmol), cuprous iodide (306 mg, 1.61 mmol), and bistriphenylphosphine palladium dichloride (1.13 g, 1.61 mmol). Under argon, triethylamine (7.72 g, 76.31 mmol) was slowly added dropwise to the reaction mixture at 0°C. After addition, the mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to afford A128-2 (2.88 g, 51% yield) as an orange solid. LCMS (ESI) m / z = 353.2 [M+H] + .

[0958] Step 3:

[0959] To a solution of 2-bromopyridine (4.51 g, 28.57 mmol) in tetrahydrofuran (65 mL) was slowly added dropwise n-butyllithium (1.57 g, 24.49 mmol, 9.8 mL, 2.5 M n-hexane) under argon at -78°C. The reaction mixture was stirred at -78°C for 0.5 h, followed by the addition of A128-2 (2.88 g, 8.16 mmol). The temperature was raised to -40°C and stirring continued for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford A128-3 (1.26 g, 42% yield) as a yellow solid. LCMS (ESI) m / z = 371.3 [M+H] + .

[0960] Step 4:

[0961] To a dichloromethane solution (12 mL) of compound A128-3 (1.2 g, 3.24 mmol) was added formic acid (0.4 mL) and mercuric sulfate (288 mg, 0.97 mmol) under argon at 0°C. The reaction mixture was stirred at 0°C for 2 h. Saturated sodium bicarbonate was added to the reaction mixture, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford A128-4 (168 mg, 13% yield) as a brown oil. LCMS (ESI) m / z = 389.4 [M+H] + .

[0962] Step 5:

[0963] Compound A128-4 (168 mg, 0.43 mmol) was dissolved in HCl (4 M in dioxane, 3 mL) at room temperature. The reaction was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain A128-5 (100 mg, 86% yield) as a brown oil. LCMS (ESI) m / z = 271.2 [M+H] + .

[0964] Step 6:

[0965] To a toluene solution (2 mL) of compound A128-5 (100 mg, 0.37 mmol) was added N,N-dimethylformamide dimethyl acetal (1 mL) at room temperature. The reaction mixture was stirred at 110°C for 2 h. The reaction mixture was concentrated under reduced pressure to afford a brown solid A128-6 (80 mg, 66% yield). LCMS (ESI) m / z = 326.3 [M+H] + .

[0966] Step 7:

[0967] To a solution of compound A128-6 (47 mg, 0.14 mmol) in ethanol (2 mL) was added p-guanidinobenzoic acid (62 mg, 0.29 mmol) and potassium carbonate (50 mg, 0.36 mmol) at room temperature. The reaction mixture was stirred at reflux at 80°C for 14 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford A128-7 (37 mg, 58% yield) as a white solid. LCMS (ESI) m / z = 442.3 [M+H] + .

[0968] Step 8:

[0969] To a solution of compound A128-7 (26 mg, 0.06 mmol) in N,N-dimethylformamide (2 mL) were added A54-3 (39 mg, 0.12 mmol), HATU (34 mg, 0.09 mmol), and DIPEA (23 mg, 0.18 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was separated and purified by reverse phase chromatography (acetonitrile / 10 mM ammonium bicarbonate solution) to afford A128 (2 mg, 5% yield) as a white solid. LCMS (ESI) m / z = 753.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.37(s,1H),10.13(s,1H),8.74(s,1H),8.63–8.39(m,2H),8.25 (d,J=8.4Hz,1H),8.20–8.02(m,2H),8.02–7.80(m,6H),7.58–7.39(m,3H),6.88(d,J=9.2 Hz,1H),5.03–4.82(m,1H),4.63–4.35(m,1H),3.99–3.82(m,1H),3.78–3.68(m,2H),3.58 –3.52(m,2H),2.78–2.66(m,2H),2.33–2.17(m,2H),2.01–1.81(m,2H),1.73–1.54(m,4H).

[0970] Example 128 Synthesis of Compound A129:

[0971] Compound A129 (2 mg, yield 4%) was synthesized according to the synthesis method of compound A98 described in Example 98. LCMS (ESI) m / z = 771.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),10.01(s,1H),8.72(s,1H),8.30(d,J= 8.4Hz,1H),7.97(s,1H),7.94–7.86(m,1H),7.86–7.77(m,1H),7.65–7.50(m ,1H),7.41–7.27(m,2H),7.27–7.12(m,3H),7.08–6.93(m,3H),3.85–3.66(m ,1H),3.62–3.45(m,1H),2.97–2.83(m,4H),2.81–2.59(m,10H),2.13(s,3H).

[0972] Example 129 Synthesis of Compound A130:

[0973] Compound A130 (39.2 mg, yield 32.7%) was synthesized according to the synthesis method of compound A98 described in Example 98. LCMS (ESI) m / z = 744.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.48(s,1H),9.99(s,1H),8.69(s,1H),8.26(d,J=8.8Hz, 1H),8.04(d,J=4.0Hz,1H),7.96–7.93(m,1H),7.89–7.80(m,2H),7.58–7.50(m,1H) ,7.35–7.28(m,2H),7.20–7.10(m,2H),7.05–7.01(m,1H),6.76–6.73(m,1H),6.70– 6.66(m,1H),3.85–3.77(m,2H),3.60(s,2H),3.56–3.47(m,4H),2.69–2.61(m,6H).

[0974] Example 130 Synthesis of Compound A131:

[0975] Compound A131 (24.6 mg, yield 36.94%) was synthesized according to the synthesis method of compound A98 described in Example 98. LCMS (ESI) m / z = 744.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.44(s,1H),9.99(s,1H),8.70(s,1H),8.27(d,J=8.4Hz,1H),8.16(s,1H),8.06–7.93(m,2H),7.90–7.79(m,2H),7.59– 7.47(m,1H),7.35–7.27(m,3H),7.19–7.10(m,2H),7.08–7.01(m,1H),3 .78(t,J=6.8Hz,2H),3.62(s,2H),3.28–3.24(m,4H),2.74–2.66(m,6H).

[0976] Example 131 Synthesis of Compound A132:

[0977] Step 1:

[0978] To a toluene solution (3 mL) of SM5 (230 mg, 411.63 μmol) and tert-butyl 3-oxo-1-piperazinecarboxylate (164.85 mg, 823.27 μmol) were added potassium carbonate (142.23 mg, 1.03 mmol), cuprous iodide (31.36 mg, 164.65 μmol, 5.58 μL), and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (58.55 mg, 411.63 μmol) at room temperature. The reaction was heated to 110°C and stirred under argon for 16 h. LCMS confirmed the reaction was complete. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography to afford A132-1 (200 mg, 76.9% yield) as a yellow solid. LCMS (ESI) m / z = 631.2 [M+H] + .

[0979] Step 2:

[0980] To a solution of A132-1 (200 mg, 316.92 μmol) in dichloromethane (3 mL) was added hydrogen chloride (4.0 M in dioxane, 1 mL) at room temperature. The reaction was stirred at room temperature for 2 h. LCMS confirmed the reaction was complete, and the reaction solution was concentrated to afford A132-2 (200 mg, crude) as a yellow solid. LCMS (ESI) m / z = 531.3 [M+H] + .

[0981] Step 3:

[0982] Compound A132-3 (300 mg, 94.4% yield) was synthesized according to the synthesis method of compound A68-1 described in Example 68. LCMS (ESI) m / z=333.2 [M+H] + .

[0983] Step 4:

[0984] To a solution of A132-3 (200 mg, 601.77 μmol) in tetrahydrofuran (2 mL) was added aqueous hydrochloric acid (4 M, 752.21 μL) at room temperature. The reaction mixture was heated to 50°C and stirred for 3 h. LCMS confirmed the reaction was complete. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography to obtain an off-white solid A132-4 (90 mg, 51.9% yield). LCMS (ESI) m / z = 289.3 [M+H] + .

[0985] Step 5:

[0986] To a solution of A132-2 (210 mg, 395.51 μmol) and dichloromethane (4 mL) were added N,N-diisopropylethylamine (51.12 mg, 395.51 μmol, 68.89 μL), A132-4 (171.04 mg, 593.27 μmol), acetic acid (47.46 mg, 791.03 μmol), and sodium acetate borohydride (167.65 mg, 791.03 μmol) at room temperature. The reaction was stirred at room temperature for 1 h. LCMS confirmed the reaction was complete. The reaction solution was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by HPLC to afford A132 (32 mg, 10.0% yield) as a yellow solid. LCMS (ESI) m / z = 803.4 [M+H] + .1HNMR (400MHz, DMSO-d6) δ10.35(s,1H),9.95(s,1H),8.67(s,1H),8.28(d,J=8.4Hz,1H),8.06(d,J=2.7Hz,1H) ,7.87–7.83(m,1H),7.82–7.78(m,2H),7.59–7.52(m,1H),7.51–7.46(m,1H),7.32(d,J=2.1Hz,1H),7.28–7.24(m ,2H),7.19–7.12(m,2H),6.88(d,J=9.2Hz,1H),4.35–4.27(m,2H),3.70(t,J=6.8Hz,2H),3.63–3.57(m,2H),3.31 –3.29(m,2H),2.90–2.81(m,4H),2.70(t,J=6.8Hz,2H),2.62–2.54(m,1H),1.95–1.86(m,2H),1.48–1.35(m,2H).

[0987] Example 132 Synthesis of Compound A133:

[0988] Step 1:

[0989] Compound A133-1 (2.3 g, 55.8% yield) was synthesized according to the synthesis method of compound A6-2 described in Example 6. LCMS (ESI) m / z=196.3 [M+H] + .

[0990] Step 2:

[0991] Compound A133 (8 mg, 6.3% yield) was synthesized according to the synthesis method of compound A98 described in Example 98. LCMS (ESI) m / z=714.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),9.93(s,1H),8.68(s,1H),8.26(d,J=8.5Hz,1H),7.89–7.7 7(m,3H),7.59–7.49(m,1H),7.33(d,J=2.1Hz,1H),7.26(t,J=7.9Hz,1H),7.20–7.09(m,3H),6.93 –6.89(m,1H),6.61–6.57(m,1H),6.41–6.38m,1H),6.32–6.28(m,1H),3.97(t,J=7.6Hz,2H),3.7 1(t,J=6.8Hz,2H),3.63–3.57(m,2H),3.0–2.92(m,1H),2.81–2.76(m,2H),2.66(t,J=6.8Hz,2H).

[0992] Example 133 Synthesis of Compound A134:

[0993] Compound A134 (10.0 mg, yield 50.9%) was synthesized according to the synthesis method of compound A16 described in Example 16. LCMS (ESI) m / z = 789.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),10.10(s,1H),8.70(s,1H),8.30(t,J=5.6Hz,1H),8.20 (d,J=8.2Hz,2H),7.94(d,J=8.6Hz,2H),7.85(d,J=8.6Hz,2H),7.58–7.50(m,1H),7.41–7.38( m,1H),7.19–7.15(m,2H),7.08(s,1H),7.02(s,1H),3.81(t,J=6.8Hz,2H),3.46–3.40(m,6H) ,2.75(t,J=6.8Hz,2H),2.59–2.56(m,6H),2.05–1.99(m,1H),1.04–1.02(m,2H),0.72(s,2H).

[0994] Example 134 Synthesis of Compound A135:

[0995] Compound A135 (9 mg, yield 36%) was synthesized according to the synthesis method of compound A75 described in Example 75. LCMS (ESI) m / z = 803.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.60(s,0.5H),10.03(s,1H),8.68(s,1H),8.29–8.12(m,1H),8.01–7.79(m,2H),7.63–7.48(m,1H),7.4 8–7.34(m,3H),727–7.12(m,2H),7.12–6.95(m,2H),3.81(t,J=6.8Hz,2H),3.02(s,3H),2.75(t,J=6.8Hz,2H),2.66–2.55(m,2H).

[0996] Example 135 Synthesis of Compound A136:

[0997] Compound A136 (9 mg, 54.5% yield) was synthesized according to the synthesis method of compound A75 described in Example 75. LCMS (ESI) m / z=796.6 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.24(s,1H),10.00(s,1H),8.65(s,1H),8.17(d,J=8.2Hz,1H),7.91–7.8 6(m,2H),7.56–7.46(m,1H),7.41–7.32(m,3H),7.18–7.07(m,4H),7.05–7.05(m,1H),6.94–6.85(m ,2H),3.68(t,J=6.8Hz,2H),3.61–3.42(m,2H),3.30–3.23(m,2H),3.18–3.01(m,4H),2.99(s,3H), 2.67(t,J=6.8Hz,2H),2.62–2.52(m,4H),2.03–1.94(m,1H),1.01–0.95(m,2H),0.74–0.60(m,2H).

[0998] Example 136 Synthesis of Compound A137:

[0999] Compound A137 (8 mg, yield 31%) was synthesized according to the synthesis method of compound A75 described in Example 75. LCMS (ESI) m / z = 749.4 [M+H] + .1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),10.24(s,1H),8.89(d,J=5.2Hz,1H),8.80(s,1H),8.53–8.38(m,2H),8.17(d,J=5.2 Hz,1H),8.07(d,J=2.4Hz,1H),8.01–7.92(m,2H),7.92–7.83(m,2H),7.63–7.54(m,1H),7.54–7.42(m,2H),7.11(t,J=7.2H z,1H),8.01(d,J=8.0Hz,1H),6.88(d,J=9.2Hz,1H),4.60–4.34(m,1H),3.72(t,J=6.8Hz,2H),3.61–3.51(m,2H),3.51–3. 45(m,2H),3.31(s,1H),2.73(t,J=6.4Hz,2H),2.33–2.21(m,2H),1.98–1.83(m,2H),1.72–1.64(m,2H),1.64–1.56(m,2H).

[1000] Example 137 Synthesis of Compound A138:

[1001] Compound A138 (4 mg, yield 15%) was synthesized according to the synthesis method of compound A75 described in Example 75. LCMS (ESI) m / z = 737.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.35(s,1H),10.23(s,1H),8.87(d,J=4.8Hz,1H),8.80(s,1H),8.58(s,1H),8.47(d,J=7.6Hz,1H),8 .21(d,J=5.2Hz,1H),8.07(d,J=2.8Hz,1H),7.99–7.92(m,2H),7.92–7.85(m,2H),7.74–7.65(m,1H),7.62–7.53(m,1H),7.53 –7.47(m,1H),7.40–7.33(m,1H),7.26–7.16(m,1H),6.93–6.83(m,1H),4.59–4.38(m,1H),3.72(t,J=6.4Hz,2H),3.62–3.51( m,2H),3.51–3.44(m,2H),2.73(t,J=6.8Hz,2H),2.33–2.19(m,2H),1.98–1.85(m,2H),1.74–1.65(m,2H),1.64–1.55(m,2H).

[1002] Example 138 Synthesis of Compound A139:

[1003] Compound A139 (1 mg, yield 2%) was synthesized according to the synthesis method of compound A26 described in Example 26. LCMS (ESI) m / z = 780.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.44(s,1H),10.09(s,1H),8.73(s,1H),8.34(d,J=8.4Hz,1H),7.99–7.85(m,3H),7.76–7.67(m,2H),7.64–7.54(m,1H), 7.54–7.47(m,2H),7.41–7.32(m,3H),7.25–7.14(m,2H),6.82(s,1H),4. 31–4.16(m,2H),3.93–3.77(m,6H),3.03–2.89(m,2H),2.77–2.71(m,2H).

[1004] Example 139 Synthesis of Compound A140:

[1005] Step 1:

[1006] To a solution of tert-butyl 3-(bromomethyl)azetidine-1-carboxylate (600 mg, 2.4 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL) and stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to afford A140-1 as a pale yellow oil (360 mg, 100% yield). The crude product was used directly in the next reaction.

[1007] Step 2:

[1008] To a solution of A140-1 (360 mg, 2.4 mmol) in acetonitrile (10 mL) were added A98-1 (450 mg, 1.92 mmol), copper acetate (436 mg, 2.4 mmol), triethylamine (728 mg, 7.2 mmol) and The mixture was stirred at room temperature for 3 h after adding 300 mg of molecular sieves. LCMS confirmed the complete reaction. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1:20) to afford A140-2 (120 mg, 15.4% yield) as a yellow solid. LCMS (ESI) m / z = 338.4 [M+H] + .

[1009] Step 3:

[1010] To a solution of m-nitrofluorobenzene (10 g, 70.9 mmol) in dimethyl sulfoxide (60 mL) were added potassium carbonate (19.6 g, 142 mmol) and benzyl piperazine-1-carboxylate (15.6 g, 70.9 mmol) at room temperature. The mixture was heated to 100°C and stirred for 16 hours. Water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:10) to afford A140-3 (4.8 g, 19.8% yield) as a yellow solid.

[1011] Step 4:

[1012] To a solution of A140-3 (4.8 g, 14.0 mmol) in ethanol (50 mL) and water (10 mL) at room temperature were added reduced iron powder (3.93 g, 70.0 mmol) and ammonium chloride (3.76 g, 70.0 mmol). The temperature was raised to 80°C and stirred for 3 h. The reaction solution was filtered through celite and concentrated under reduced pressure. Water was added to the residue, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:5) to afford A140-4 (4 g, 91.3% yield) as a yellow solid. LCMS (ESI) m / z = 311.5 [M+H] + .

[1013] Step 5:

[1014] To a solution of A140-4 (1 g, 3.2 mmol) in isopropanol (10 mL) was added cyanamide (270 mg, 6.4 mmol) and p-toluenesulfonic acid monohydrate (916 mg, 4.8 mmol) at room temperature. The mixture was heated to 80°C and stirred for 16 hours. LCMS analysis indicated a yield of approximately 60%. The reaction mixture was concentrated, and the residue was added with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to afford an off-white solid, A140-5 (580 mg, 51.1% yield). LCMS (ESI) m / z = 353.5 [M+H] + .

[1015] Step 6:

[1016] To a methanol solution (20 mL) of A140-5 (580 mg, 1.64 mmol) was added potassium carbonate (567 mg, 4.1 mmol) and SM4 (592 mg, 1.64 mmol) at room temperature. The mixture was heated to 70°C and stirred for 16 h. LCMS confirmed the complete reaction. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1:60) to afford A140-6 (560 mg, 52.4% yield) as a yellow solid. LCMS (ESI) m / z = 652.2 [M+H] + .

[1017] Step 7:

[1018] To A140-6 (200 mg, 0.30 mmol) was added concentrated hydrochloric acid (0.25 mL, 3 mmol) at room temperature, and the mixture was heated to 100°C with stirring for 4 hours. LCMS analysis confirmed the complete reaction of the starting material. Saturated sodium bicarbonate was added to the reaction solution to adjust the pH to 8, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:20) to afford A140-7 (100 mg, 62.9% yield) as a yellow solid. LCMS (ESI) m / z = 517.2 [M+H] + .

[1019] Step 8:

[1020] To a solution of A140-7 (50 mg, 0.09 mmol) in N,N-dimethylformamide (5 mL) was added A140-2 (49 mg, 0.14 mmol) and N,N-diisopropylethylamine (37.5 mg, 0.27 mmol) at room temperature. The mixture was heated to 80°C and stirred for 6 hours. LC-MS analysis indicated a yield of approximately 50%. The reaction mixture was filtered, and the crude product was purified by reverse phase chromatography (acetonitrile / 10 mM aqueous ammonium bicarbonate) to afford A140 (23 mg, 30.7% yield) as a yellow solid. LCMS (ESI) m / z = 774.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),9.72(s,1H),8.66(s,1H),8.29(d,J=8.8Hz,1H),7.88–7 .82(m,1H),7.62–7.51(m,2H),7.33(d,J=4.0Hz,1H),7.24–7.20(m,1H),7.19–7.10(m,4H),6. 63–6.57(m,2H),6.39–6.36(m,1H),6.32–6.28(m,1H),3.99–3.92(m,2H),3.50–3.45(m,2H),3 .51–3.44(m,2H),3.18–3.09(m,4H),3.02–2.93(m,1H),2.70–2.62(m,4H),2.58–2.52(m,4H).

[1021] Example 140 Synthesis of Compound A141:

[1022] Compound A141 (1.21 mg, yield 4%) was synthesized according to the synthesis method of compound A126 described in Example 125. LCMS (ESI) m / z = 775.5 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.33(s,1H),9.74(s,1H),8.68(s,1H),8.35(d,J=7.8Hz,1H),7.87(dd,J1=7.8Hz,J2= 2.4Hz,1H),7.60–7.52(m,1H),7.37(s,1H),7.34(d,J=7.8Hz,1H),7.24–7.16(m,3H),7.09(t,J=7.4Hz,1H),6.9 8–6.96(m,1H),6.90(bs,1H),6.84–6.82(m,1H),6.75–6.73(m,1H),6.10–6.08(m,1H),4.00–3.96(m,2H),3.76( t,J=6.8Hz,2H),3.54–3.51(m,2H),3.21–3.18(m,4H),3.05–2.95(m,1H),2.72–2.67(m,4H),2.56–2.52(m,4H).

[1023] Example 141 Synthesis of Compound A142:

[1024] Compound A142 (6.7 mg, yield 15%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 793.4 [M+H] + .1H NMR (400MHz, DMSO-d6) δ10.36(s,1H),10.09(s,1H),8.69(s,1H),8.45(d,J=8.4Hz,1H),8.18(d,J=8.4Hz,1H),8.07(d,J=2.4Hz,1 H),7.96–7.93(m,2H),7.87–7.84(m,2H),7.63–7.60(m,1H),7.51–7.46(m,3H),7.43–7.38(m,2H),6.91–6.87(m,2H),4.51–4.45(m 1H),3.72(t,J=6.8Hz,2H),3.54–3.46(m,4H),2.72(t,J=6.8Hz,2H),2.2 9–2.24(m,2H),1.98–1.88(m,3H),1.86–1.60(m,4H),1.03–0.97(m,2H).

[1025] Example 142 Synthesis of Compound A143:

[1026] Compound A143 (9.56 mg, yield 16.76%) was synthesized according to the synthesis method of compound A132 described in Example 131. LCMS (ESI) m / z = 773.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),9.85(s,1H),8.67(s,1H),8.30(d,J=8.4Hz,1H),8.02(s,1H),7.85(dd,J1=8.4Hz, J2=2.0Hz,1H),7.59–7.47(m,2H),7.33(d,J=2.0Hz,1H),7.28–7.13(m,4H),6.91(d,J=7.6Hz,1H),6.85(d,J=2.0Hz,1H), 6.77(dd,J=8.0,2.4Hz,1H),6.67(dd,J1=7.6Hz,J2=2.0Hz,1H),3.73(t,J=6.8Hz,2H),3.70–3.55(m,4H),3.14–2.96(m,1 H),2.68(t,J=6.8Hz,2H),2.65–2.55(m,2H),2.34–2.18(m,1H),1.77–1.68(m,2H),1.46–1.32(m,2H),1.33–1.11(m,2H).

[1027] Example 143 Synthesis of Compound A144:

[1028] Compound A144 (4.26 mg, yield 16.12%) was synthesized according to the synthesis method of compound A56 described in Example 56. LCMS (ESI) m / z = 733.8 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.33(s,1H),9.87(s,1H),8.67(s,1H),8.29(d,J=8.4Hz,1H),7.84(d d,J1=8.4Hz,J2=2.0Hz,1H),7.65(d,J=2.8Hz,1H),7.60–7.48(m,1H),7.37–7.07(m,10H),6.5 7(dd,J1=8.0Hz,J2=2.4Hz,1H),4.10(t,J=5.8Hz,2H),3.75(t,J=6.8Hz,2H),3.05(s,1H),2.9 7–2.71(m,4H),2.67(t,J=6.8Hz,2H),2.58–2.53(m,1H),2.31–2.21(m,1H),1.81–1.72(m,1H).

[1029] Example 144 Synthesis of Compound A145:

[1030] Compound A145 (15.0 mg, yield 42.6%) was synthesized according to the synthesis method of compound A139 described in Example 138. LCMS (ESI) m / z = 780.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),10.07(s,1H),8.70(s,1H),8.30(d,J=8.4Hz,1H),7.97–7.84(m,3H),7.67(d,J=8.4Hz,2H),7.58–7.50(m,1H ),7.44–7.31(m,5H),7.19–7.14(m,2H),6.79(s,1H),4.22–4.19(m,2H), 3.85(s,2H),3.80–3.77(m,4H),2.96–2.93(m,2H),2.69(t,J=6.6Hz,2H).

[1031] Example 145 Synthesis of Compound A146:

[1032] Compound A146 (14.3 mg, yield 18.4%) was synthesized according to the synthesis method of compound A101 described in Example 101. LCMS (ESI) m / z = 719.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.29(s,1H),9.85(s,1H),8.66(s,1H),8.28(d,J=8.8Hz,1H), 7.89–7.82(m,2H),7.70–7.65(m,1H),7.56–7.47(m,1H),7.32–7.24(m,2H),7.20–7.06( m,3H),6.97–6.92(m,1H),6.87–6.84(m,1H),6.78–6.73(m,1H),6.73–6.68(m,1H),3.72 (t,J=8.0Hz,2H),3.53(s,2H),3.15–3.05(m,4H),2.69–2.64(m,2H),2.58–2.52(m,4H).

[1033] Example 146 Synthesis of Compound A147:

[1034] Compound A147 (22.0 mg, yield 42.7%, yellow solid) was synthesized according to the synthesis method of compound A101 described in Example 101. LCMS (ESI) m / z=733.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),9.82(s,1H),8.69(s,1H),8.32(d,J=8.4Hz,1H),7.89(dd,J 1=8.4Hz,J2=2.2Hz,2H),7.76(s,1H),7.67(d,J=8.2Hz,1H),7.32–7.51(m,1H),7.35(d,J=2.2Hz,1 H),7.29–7.14(m,4H),6.95–6.89(m,2H),6.83(dd,J1=8.0Hz,J2=2.4Hz,1H),6.77–6.71(m,1H),3. 77(t,J=4.0Hz,2H)3.18–3.16(m,2H),2.82–2.78(m,2H),2.71(t,J=6.6Hz,2H),2.64–2.60(m,6H).

[1035] Example 147 Synthesis of Compound A148:

[1036] Compound A148 (5.8 mg, yield 7.7%) was synthesized according to the synthesis method of compound A101 described in Example 101. LCMS (ESI) m / z = 755.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.29(s,1H),9.78(s,1H),8.63(s,1H),8.18(d,J=8.0Hz,1H),7.70(t,J=2.2Hz,1H),7. 56–7.47(m,1H),7.38–7.30(m,2H),7.21–7.10(m,4H),7.04(d,J=1.8Hz,1H),6.88–6.85(m,1H),6.81–6.76(m,1H ),6.73–6.69(m,1H),6.59–6.53(m,1H),4.12(t,J=6.0Hz,2H),3.73(t,J=8.0Hz,2H),3.16–3.09(m,4H),2.77(t, J=6.0Hz,2H),2.67(t,J=6.0Hz,2H),2.64–2.60(m,4H),2.02–1.94(m,1H),1.00–0.93(m,2H),0.73–0.56(m,2H).

[1037] Example 148 Synthesis of Compound A149:

[1038] Compound A149 (6.0 mg, yield 27%) was synthesized according to the synthesis method of compound A106 described in Example 106. LCMS (ESI) m / z = 806.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.61(s,1H),10.12(s,1H),8.74(s,1H),8.34(d,J=8.4Hz,1 H),7.98–7.96(m,2H),7.92–7.89(m,1H),7.66–7.63(m,2H),7.63–7.54(m,1H),7.36( d,J=2.4Hz,1H),7.22–7.18(m,1H),7.02(s,1H),6.91(s,1H),3.82(t,J=6.8Hz,2H),3 .75(s,3H),3.58(s,2H),3.42–3.38(m,4H),2.75(t,J=6.8Hz,2H),2.57–2.54(m,4H).

[1039] Example 149 Synthesis of Compound A150:

[1040] Step 1:

[1041] To a solution of p-iodoaniline (5 g, 22.83 mmol) in ethanol (35 mL) was slowly added 66% nitric acid (2.29 g, 23.97 mmol, 1.62 mL) and cyanamide (1.92 g, 45.66 mmol) in water (2 mL) at 0°C. The reaction mixture was heated to 80°C and stirred for 16 h. The reaction mixture was concentrated under reduced pressure to remove ethanol (20 mL). The residue was stirred at 0°C for 1 h, filtered, and the solid was washed with a small amount of cold ethanol. The solid was then pulled dry using an oil pump to obtain a light yellow solid A150-1 (3.4 g, 57% yield). LCMS (ESI) m / z = 262.1 [M+H] + .

[1042] Step 2:

[1043] To a solution of compound A150-1 (1.82 g, 6.98 mmol) in ethanol (34 mL) were added SM4 (1.68 g, 4.66 mmol) and potassium carbonate (1.61 g, 11.64 mmol) at room temperature. The reaction mixture was heated to 70°C and stirred for 16 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a brown solid SM5 (2 g, 77% yield). LCMS (ESI) m / z = 559.2 [M+H] + .

[1044] Step 3:

[1045] To a solution of compound SM5 (2 g, 3.58 mmol) in 1,4-dioxane (40 mL) at room temperature were added neopentyl glycol diboronate (4.85 g, 21.48 mmol), palladium acetate (402 mg, 1.79 mmol), and potassium acetate (1.05 g, 10.74 mmol). The reaction mixture was heated to 110°C under argon and stirred for 16 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford SM6 as a yellow solid (2.3 g, 94% yield, 70% purity). LCMS (ESI) m / z = 477.3 [M+H] + .

[1046] Step 4:

[1047] To a solution of compound SM6 (800 mg, 1.17 mmol) in acetonitrile (16 mL) at room temperature were added 1-Boc-piperazine (1.53 g, 8.22 mmol), copper acetate (308 mg, 1.17 mmol), triethylamine (356 mg, 3.52 mmol) and Molecular sieves (1.6 g). The reaction mixture was heated to 65°C and stirred for 4 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a yellow solid A150-2 (320 mg, yield 44%). LCMS (ESI) m / z = 617.4 [M+H] + .

[1048] Step 5:

[1049] To a solution of compound A150-2 (320 mg, 0.52 mmol) in dichloromethane (6 mL) was added hydrogen chloride (4 M in dioxane, 3 mL) at room temperature. The reaction was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was added with saturated aqueous sodium bicarbonate (10 mL). The residue was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford A150-3 (205 mg, 76% yield) as a yellow solid. LCMS (ESI) m / z = 516.3 [M+H] + .

[1050] Step 6:

[1051] To a solution of compound A150-5 (50 mg, 0.10 mmol) in ethanol (2 mL) at room temperature were added A132-4 (56 mg, 0.19 mmol) and magnesium sulfate (233 mg, 1.93 mmol). The reaction mixture was heated to 80°C and stirred under argon for 16 h. After cooling to room temperature, sodium cyanoborohydride (18 mg, 0.29 mmol) was added, and the reaction mixture was stirred at room temperature under argon for 16 h. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by reverse phase chromatography (acetonitrile / 10 mM ammonium bicarbonate solution) to afford A150 (7 mg, 9% yield) as a yellow solid. LCMS (ESI) m / z = 780.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.36(s,1H),9.61(s,1H),8.61(s,1H),8.27(d,J=8.4Hz,1H),8.08(d,J =2.8Hz,1H),7.92–7.82(m,1H),7.65(d,J=8.8Hz,1H),7.62–7.54(m,1H),7.54–7.46(m,1H),7.3 3(d,J=2.0Hz,1H),7.25–7.11(m,2H),6.98–6.85(m,3H),4.42–4.26(m,2H),3.73(t,J=6.8Hz,2H ),3.15–3.03(m,4H),2.91–2.78(m,2H),2.77–2.62(m,6H),1.97–1.83(m,2H),1.53–1.35(m,2H).

[1052] Example 150 Synthesis of Compound A151:

[1053] Compound A151 (9.01 mg, yield 32.17%) was synthesized according to the synthesis method of compound A132 described in Example 131. LCMS (ESI) m / z = 759.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),9.88(s,1H),8.69(s,1H),8.32(d,J=8.4Hz,1H),8.07(s, 1H),7.89(dd,J=8.4,2.0Hz,1H),7.60–7.45(m,2H),7.35(d,J=2.0Hz,1H),7.28–7.06(m,4H),6 .95(d,J=7.6Hz,1H),6.90–6.86(m,1H),6.80(dd,J1=8.0Hz,J2=2.4Hz,1H),6.75–6.64(m,1H), 3.80–3.51(m,6H),3.19–3.04(m,1H),2.75–2.67(m,4H),1.75–1.69(m,2H),1.35–1.21(m,2H).

[1054] Example 151 Synthesis of Compound A152:

[1055] Compound A152 (5.3 mg, yield 23%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 766.4 [M+H] + .1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),10.25(s,1H),8.92(d,J=4.8Hz,1H),8.80(s,1H),8.51(s,1H),8.45 (d,J=7.8Hz,1H),8.18(d,J=8.2Hz,2H),8.06(d,J=5.6Hz,1H),7.94(d,J=8.6Hz,2H),7.88(d,J=8.6Hz,2H ),7.51–7.43(m,1H),6.92(bs,1H),6.87(d,J=6.8Hz,1H),4.51(m,1H),3.72(t,J=4.8Hz,2H),3.55–3.53( m,2H),3.48–3.45(m,2H),2.72(t,J=6.8Hz,2H),2.29–2.24(m,2H),1.94–1.89(m,2H),1.68–1.60(m,4H).

[1056] Example 152 Synthesis of Compound A153:

[1057] Compound A153 (30.0 mg, yield 72.8%, yellow solid) was synthesized according to the synthesis method of compound A101 described in Example 101. LCMS (ESI) m / z = 733.2 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),9.87(s,1H),8.68(s,1H),8.31(d,J=8.4H z,1H),7.87(dd,J1=8.4Hz,J2=2.2Hz,1H),7.71(s,1H),7.56–7.49(m,1H),7.34 –7.26(m,2H),7.23–7.10(m,4H),7.01–6.93(m,2H),6.61–6.55(m,1H),4.13–4. 10(m,2H),3.76–3.69(m,1H),3.52–3.46(m,1H),2.9–2.57(m,12H),2.10(s,3H).

[1058] Example 153 Synthesis of Compound A154:

[1059] Compound A154 (9 mg, yield 23%) was synthesized according to the synthesis method of compound A150 described in Example 149. LCMS (ESI) m / z = 809.3 [M+H]. 1H NMR (400MHz, DMSO-d6) δ10.61(s,1H),9.97(s,1H),8.69(s,1H),8.31(d,J=8.4Hz,1H),7.90–7.82 (m,2H),7.61–7.55(m,1H),7.35(d,J=2.4Hz,1H),7.30–7.28(m,2H),7.21–7.17(m,2H),7.01(s,1 H),3.91–3.88(m,2H),3.81(t,J=6.8Hz,2H),3.65–3.62(m,2H),3.34(s,2H),3.04–2.98(m,2H),2 .91–2.89(m,2H),2.75(t,J=6.4Hz,2H),2.63–2.57(m,1H),1.96–1.93(m,2H),1.59–1.51(m,2H).

[1060] Example 154 Synthesis of Compound A155:

[1061] Compound A155 (22.0 mg, yield 58.3%, yellow solid) was synthesized according to the synthesis method of compound A101 described in Example 101. LCMS (ESI) m / z = 747.5 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),9.79(s,1H),8.66(s,1H),8.29(d,J=8.4Hz ,1H),7.86(dd,J1=8.4Hz,J2=2.2Hz,1H),7.76(s,1H),7.62–7.60(m,1H),7.57–7 .50(m,1H),7.32(d,J=2.2Hz,1H),7.24–7.13(m,4H),7.01–6.96(m,2H),6.89–6. 87(m,1H),3.76–3.69(m,1H),3.52–3.46(m,1H),2.85–2.62(m,14H),2.11(s,3H).

[1062] Example 155 Synthesis of Compound A156:

[1063] Compound A156 (8.6 mg, yield 16.8%) was synthesized according to the synthesis method of compound A18 described in Example 18. LCMS (ESI) m / z = 714.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.29(s,1H),9.98(s,1H),8.70(s,1H),8.28(d,J=8.8Hz,1H ),7.97(s,1H),7.89–7.78(m,2H),7.60–7.49(m,1H),7.36–7.26(m,2H),7.20–7.08(m ,3H),7.07–7.01(m,1H),6.82–6.73(m,1H),6.58–6.50(m,1H),4.31–4.21(m,2H),3.9 0–3.70(m,4H),3.51–3.42(m,1H),2.83–2.72(m,1H),2.71–2.62(m,1H),1.99(s,3H).

[1064] Example 156 Synthesis of Compound A157:

[1065] Compound A157 (9 mg, yield 22%) was synthesized according to the synthesis method of compound A101 described in Example 101. LCMS (ESI) m / z = 795.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.61(s,1H),10.30(s,1H),8.76(s,1H),8.33(d,J=8.4Hz,1H),8.26–8.09(m,1H),8.03–7.77(m,2H),7.77–7.48(m ,2H),7.36(s,1H),7.27–7.10(m,2H),7.02(s,1H),4.58(s,2H),3.93– 3.75(m,2H),3.75–3.58(m,2H),2.84–2.70(m,2H),2.70–2.56(m,6H).

[1066] Example 157 Synthesis of Compound A158:

[1067] Compound A158 (5.04 mg, yield 17.73%) was synthesized according to the synthesis method of compound A48 described in Example 48. LCMS (ESI) m / z = 788.3 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),10.28(s,1H),8.76(s,1H),8.33(d,J =8.4Hz,1H),8.18(d,J=2.0Hz,1H),7.90–7.85(m,2H),7.64–7.57(m,2H),7. 36(d,J=2.0Hz,1H),7.21–7.15(m,4H),6.96–6.94(m,1H),4.58(s,2H),3.7 3–3.67(m,4H),3.15–3.14(m,4H),2.70(t,J=6.8Hz,2H),2.66–2.63(m,6H).

[1068] Example 158 Synthesis of Compound A159:

[1069] Compound A159 (5.0 mg, 31%) was synthesized according to the synthesis method of compound A107 described in Example 107. LCMS (ESI) m / z = 785.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),9.86(s,1H),8.66(s,1H),8.30(d,J=8.4Hz,1H),8.04(d,J=2.8Hz,1H ),7.89–7.86(m,1H),7.81–7.79(m,2H),7.70–7.68(m,3H),7.63(s,1H),7.55(s,1H),7.49–7.46(m,1H),7.3 2(d,J=2.0Hz,1H),7.19–7.15(m,2H),6.85(d,J=9.2Hz,1H),4.32–4.28(m,2H),3.90(d,J=7.2Hz,2H),3.70– 7.67(m,2H),2.83–2.77(m,2H),2.71–2.67(m,2H),2.10–1.97(m,1H),1.59–1.56(m,2H),1.23–1.19(m,2H).

[1070] Example 159 Synthesis of Compound A160:

[1071] Compound A160 (10.0 mg, yield 24.5%) was synthesized according to the synthesis method of compound A107 described in Example 107. LCMS (ESI) m / z = 757.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.35(s,1H),9.90(s,1H),8.70(s,1H),8.06(d,J=2.8Hz,1H),7 .93–7.91(m,1H),7.84–7.82(m,2H),7.77–7.71(m,3H),7.64(s,1H),7.55(s,1H),7.49– 7.46(m,2H),7.35(d,J=2.0Hz,1H),7.20–7.17(m,2H),6.46(d,J=8.8Hz,1H),4.32(d,J= 7.6Hz,2H),4.08–4.04(m,2H),3.81–3.78(m,2H),3.73–3.69(m,2H),2.74–2.73(m,2H).

[1072] Example 160 Synthesis of Compound A161:

[1073] Compound A161 (2.0 mg, yield 7.5%) was synthesized according to the synthesis method of compound A6 described in Example 6. LCMS (ESI) m / z = 742.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.30(s,1H),9.96(s,1H),8.70(s,1H),8.48(s,1H),8.28(d ,J=8.4Hz,1H),7.95–7.94(m,1H),7.87–7.78(m,2H),7.58–7.50(m,1H),7.35–7.26(m ,2H),7.19–7.14(m,3H),7.03–6.95(m,3H),3.53–3.47(m,1H),3.06–3.03(m,2H),2.8 3–2.64(m,4H),2.33–2.31(m,1H),2.12(s,3H),2.07–1.98(m,3H),1.85–1.79(m,2H).

[1074] Example 161 Synthesis of Compound A162:

[1075] Compound A162 (20.0 mg, yield 29.6%, yellow solid) was synthesized according to the synthesis method of compound A101 described in Example 101. LCMS (ESI) m / z = 748.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.81 (s, 1H), 8.66 (s, 1H), 8.34 (s, 3H), 8.29 (d, J = 8.4Hz, 1H),8.20(s,2H),7.86(dd,J1=8.4Hz,J2=2.2Hz,1H),7.76(s,1H),7.63–7.60(m, 1H),7.57–7.48(m,1H),7.32(d,J=2.2Hz,1H),7.23(t,J=7.8Hz,1H),7.17–7.13( m,2H),6.88(d,J=7.6Hz,1H),2.96–2.93(m,4H),2.82–2.60(m,10H),2.13(s,3H).

[1076] Example 162 Synthesis of Compound A163:

[1077] Compound A163 (3 mg, 9.3% yield) was synthesized according to the synthesis method of compound A101 described in Example 101. LCMS (ESI) m / z=773.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),9.86(s,1H),8.70(s,1H),8.32(d,J=8.4Hz,1H ),7.91–7.86(m,2H),7.68–7.62(m,1H),7.60–7.51(m,1H),7.36–7.32(m,1H),7.27( t,J=7.6Hz,1H),7.22–7.13(m,3H),6.99–6.88(m,3H),3.79–3.70(m,1H),3.63(s,2H ),3.56–3.47(m,1H),3.04(s,4H),2.83–2.64(m,6H),2.09(s,3H),1.84–1.73(m,4H).

[1078] Example 163 Synthesis of Compound A164:

[1079] Step 1:

[1080] To a solution of p-iodoaniline (10 g, 45.66 mmol) in ethanol (70 mL) was slowly added 66% nitric acid (4.58 g, 47.94 mmol, 3.25 mL) and cyanamide (3.84 g, 91.31 mmol) in water (4 mL) at 0°C. The reaction mixture was heated to 80°C and stirred for 16 h. The reaction mixture was concentrated under reduced pressure to remove ethanol (50 mL). The residue was stirred at 0°C for 1 h, filtered, and the solid was washed with a small amount of cold ethanol. The solid was then pumped dry to afford A164-1 (7.93 g, 67% yield) as a pale yellow solid. LCMS (ESI) m / z = 262.2 [M+H] + .

[1081] Step 2:

[1082] To a solution of compound A164-1 (868 mg, 3.33 mmol) in ethanol (14 mL) were added SM4 (1 g, 2.77 mmol) and potassium carbonate (958 mg, 6.93 mmol) at room temperature. The reaction mixture was heated to 70°C and stirred for 16 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford A164-2 (1.29 g, 83% yield) as a brown solid. LCMS (ESI) m / z = 559.3 [M+H] + .

[1083] Step 3:

[1084] To a solution of compound A164-2 (500 mg, 0.89 mmol) in 1,4-dioxane (10 mL) at room temperature were added 3-hydroxyazetidine hydrochloride (294 mg, 2.68 mmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (75 mg, 0.09 mmol), and sodium tert-butoxide (258 mg, 2.68 mmol). The reaction mixture was heated to 100°C under argon and stirred for 4 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford A164-3 (210 mg, 47% yield) as a yellow solid. LCMS (ESI) m / z = 504.2 [M+H] + .

[1085] Step 4:

[1086] To a solution of compound A164-3 (200 mg, 0.40 mmol) and triethylamine (1.2 g, 11.91 mmol) in dimethyl sulfoxide (4 mL) was added a solution of sulfur trioxide (632 mg, 3.97 mmol) in dimethyl sulfoxide (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature under argon for 16 h. Water was added to the reaction mixture, which was then extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford A164-4 (100 mg, 50% yield) as a yellow solid. LCMS (ESI) m / z = 502.4 [M+H] + .

[1087] Step 5:

[1088] To a solution of compound A164-4 (56 mg, 0.11 mmol) in ethanol (2 mL) at room temperature were added 2-oxyylidene-1-[3-(piperazin-1-yl)phenyl]hexahydropyrimidin-4-one (26 mg, 0.09 mmol) and magnesium sulfate (224 mg, 1.86 mmol). The reaction mixture was heated to 80°C and stirred under argon for 16 h. After cooling to room temperature, sodium cyanoborohydride (18 mg, 0.28 mmol) was added, and the reaction mixture was stirred at room temperature under argon for 16 h. Water was added to the reaction mixture, which was then extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by reverse phase chromatography (acetonitrile / 10 mM ammonium bicarbonate solution) to afford A164 (5 mg, 7% yield) as a yellow solid. LCMS (ESI) m / z = 760.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),9.83(s,1H),8.69(s,1H),8.33(d,J=8.8Hz,1H),7 .97–7.82(m,1H),7.64–7.50(m,1H),7.36(d,J=2.0Hz,1H),7.33–7.25(m,3H),7.22–7.1 6(m,3H),7.13(s,1H),7.01(s,2H),6.96–6.90(m,1H),6.89–6.81(m,1H),6.27–6.08(m, 1H),4.61–4.55(m,1H),4.35–4.20(m,1H),3.79(t,J=6.8Hz,2H),2.73(t,J=6.4Hz,2H).

[1089] Example 164 Synthesis of Compound A165:

[1090] Compound A165 (5 mg, yield 7%) was synthesized according to the synthesis method of compound A141 described in Example 140. LCMS (ESI) m / z = 789.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.45(s,1H),9.74(s,1H),8.68(s,1H),8.35(d,J=8.4Hz,1H),8.23(s, 2H),7.89–7.87(m,1H),7.60–7.52(m,1H),7.37–7.35(m,2H),7.20–7.15(m,2H),7.10(t,J=8.0H z,1H),6.98–6.96(m,1H),6.11–6.08(m,1H),3.40–3.98(m,2H),3.84–3.78(m,1H),3.62–3.51( m,1H),3.54–3.51(m,2H),3.05–2.95(m,5H),2.84–2.70(m,4H),2.61–2.59(m,4H),2.15(s,3H).

[1091] Example 165 Synthesis of Compound A166:

[1092] Compound A166 (15.4 mg, yield 10.3%) was synthesized according to the synthesis method of compound A132 described in Example 131. LCMS (ESI) m / z = 789.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),9.95(s,1H),8.67(s,1H),8.28(d,J=8.8Hz,1H),8.02(d,J=4.0H z,1H),7.89–7.80(m,3H),7.59–7.51(m,1H),7.49–7.45(m,1H),7.32(d,J=2.2Hz,1H),7.30–7.25(m,2 H),7.17(t,J=8.0Hz,2H),6.51(d,J=8.0Hz,1H),3.80–3.57(m,6H),3.41–3.35(m,2H),3.28–3.21(m,2 H),3.14–3.05(m,1H),2.92–2.85(m,2H),2.70(t,J=8.0Hz,2H),2.31–2.20(m,1H),1.98–1.87(m,1H).

[1093] Example 166 Synthesis of Compound A167:

[1094] Compound A167 (12.4 mg, yield 50.9%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 812.6 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),10.04(s,1H),8.65(s,1H),8.42(d,J=8.0Hz,1H),8.25(d,J=8.0Hz,1H),8.05–8.0 3(m,1H),7.94–7.90(m,2H),7.86–7.81(m,2H),7.56–7.45(m,2H),7.40–7.36(m,1H),7.20–7.11(m,2H),6.85(d,J=8.0Hz ,1H),6.66(d,J=4.0Hz,1H),4.70–4.63(m,1H),4.51–4.43(m,1H),3.73–3.66(m,2H),3.55–3.48(m,2H),3.48–3.40(m,2 H),2.73–2.66(m,2H),2.27–2.21(m,2H),1.93–1.85(m,2H),1.67–1.62(m,2H),1.61–1.55(m,2H),1.23(d,J=6.0Hz,6H).

[1095] Example 167 Synthesis of Compound A168:

[1096] Compound A168 (96 mg, yield 26%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 810.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.35(s,1H),10.08(s,1H),8.70(s,1H),8.46(d,J=7.6Hz,1H),8.32(d,J=8.8Hz,1H),8.07 (d,J=2.8Hz,1H),7.97–7.95(m,2H),7.88–7.86(m,2H),7.57–7.54(m,2H),7.53–7.49(m,1H),7.21–7.17(m,1H),6. 87(s,1H),4.52–4.46(m,1H),3.95–3.92(m,1H),3.72(t,J=6.8Hz,2H),3.57–3.54(m,2H),3.52–3.48(m,2H),2.88– 2.86(m,2H),2.27(t,J=10.0Hz,2H),1.93(t,J=9.6Hz,2H),1.68–1.65(m,2H),1.64–1.62(m,2H),0.76–0.68(m,4H).

[1097] Example 168 Synthesis of Compound A169:

[1098] Compound A169 (9.0 mg, yield 20.5%, yellow solid) was synthesized according to the synthesis method of compound A132 described in Example 131. LCMS (ESI) m / z = 775.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),9.94(s,1H),8.67(s,1H),8.28(d,J=8.4Hz,1H),8.03 (d,J=2.6Hz,1H),7.87–7.79(m,3H),7.59–7.48(m,2H),7.32(d,J=2.2Hz,1H),7.27–7.25(m, 2H),7.18-–7.14(m,2H),6.43(d,J=8.8Hz,1H),4.05(t,J=8.0Hz,2H),3.87–3.84(m,2H),3. 72–3.63(m,3H),3.49–3.43(m,1H),3.22–3.17(m,2H),2.84–2.77(m,2H),2.71–2.06(m,3H).

[1099] Example 169 Synthesis of Compound A170:

[1100] Compound A170 (4.65 mg, yield 15.22%) was synthesized according to the synthesis method of compound A101 described in Example 101. LCMS (ESI) m / z = 745.18 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.26(s,1H),9.84(s,1H),8.66(s,1H),8.29(d,J=8.4Hz,1H),7.99(s,1H),7.88(dd, J1=8.4Hz, J2=2.0Hz,1H),7.67–7.42(m,2H),7.33(d,J=2.4Hz,1H),7.24(t,J=8.0Hz,1H),7.14(t,J=8.0Hz,2 H),6.91(d,J=7.6Hz,1H),6.55–6.48(m,1H),6.46–6.42(m,1H),6.40–6.35(m,1H),3.79–3.64(m,4H),3.64–3 .52(m,1H),3.27–3.15(m,3H),3.14–3.04(m,2H),3.02–2.90(m,2H),2.68(t,J=6.8Hz,2H),1.94–1.71(m,2H).

[1101] Example 170 Synthesis of Compound A171:

[1102] Compound A171 (6.0 mg, yield 13.2%) was synthesized according to the synthesis method of compound A132 described in Example 131. LCMS (ESI) m / z = 802.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.25(s,1H),9.94(s,1H),8.67(s,1H),8.42(s,2H),8.28(d,J=8 .4Hz,1H),7.89–7.78(m,3H),7.87–7.78(m,2H),7.62–7.48(m,1H),7.32(d,J=2.2Hz,1H) ,7.27(d,J=8.8Hz,2H),7.18–7.13(m,3H),6.96(d,J=9.0Hz,2H),3.78–3.67(m,4H),3.62 –3.60(m,2H),2.90–2.87(m,2H),2.7–2.66(m,4H),1.94–1.91(m,2H),1.59–1.50(m,2H).

[1103] Example 171 Synthesis of Compound A172:

[1104] Compound A172 (15.0 mg, yield 46.2%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 811.6 [M+H]. 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),10.09(s,1H),8.70(s,1H),8.42(d,J=7.4Hz,1H),8.26(d,J=8.0Hz,1H), 8.04(d,J=2.8Hz,1H),7.93(d,J=8.8Hz,2H),7.84(d,J=8.8Hz,2H),7.69–7.67(m,1H),7.57–7.43(m,2H),7.22 (s,1H),7.17–7.12(m,2H),6.85(d,J=9.0Hz,1H),4.50–4.42(m,1H),3.69(t,J=6.6Hz,2H),3.52–3.50(m,2H), 3.45–3.43(m,4H),2.72(t,J=6.6Hz,2H),2.26–2.21(m,2H),2.08(s,6H),1.91–1.86(m,2H),1.65–1.57(m,4H).

[1105] Example 172 Synthesis of Compound A173:

[1106] Compound A173 (20.3 mg, yield 64.4%) was synthesized according to the synthesis method of Compound A1 described in Example 1. LCMS (ESI) m / z = 853.7 [M+H]. 1H NMR (400MHz, DMSO-d6) δ10.32(s,1H),10.08(s,1H),8.70(s,1H),8.42(d,J=7.4Hz,1H),8.27(d,J=8.0 Hz,1H),8.04(d,J=2.8Hz,1H),7.93(d,J=8.8Hz,2H),7.84(d,J=8.8Hz,2H),7.71–7.68(m,1H),7.57–7. 45(m,2H),7.28(s,1H),7.17–7.12(m,2H),6.85(d,J=9.0Hz,1H),4.50–4.40(m,1H),3.69(t,J=6.6Hz,2 H),3.55–3.43(m,10H),2.69(t,J=6.6Hz,2H),2.30–2.21(m,6H),1.91–1.86(m,2H),1.65–1.57(m,4H).

[1107] Example 173 Synthesis of Compound A174:

[1108] Compound A174 (6.0 mg, yield 13.2%) was synthesized according to the synthesis method of compound A132 described in Example 131. LCMS (ESI) m / z = 781.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.61(s,1H),9.84(s,1H),8.67(s,1H),8.28(d,J=8 .4Hz,1H),7.89–7.88(m,1H),7.74(s,1H),7.62–7.55(m,2H),7.34(d,J=2.2 Hz,1H),7.21–7.17(m,3H),7.02(s,1H),3.91(bs,2H),3.86(bs,2H),3.81(t ,J=6.6Hz,2H),2.88–2.85(m,2H),2.75(t,J=6.6Hz,2H),2.59–2.57(m,6H).

[1109] Example 174 Synthesis of Compound A175:

[1110] Compound A175 (13.7 mg, yield 21.6%) was synthesized according to the synthesis method of compound A132 described in Example 131. LCMS (ESI) m / z = 773.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.31(s,1H),9.72(s,1H),8.63(s,1H),8.26(d,J=8.8Hz, 1H),7.88–7.84(m,1H),7.59–7.48(m,3H),7.31(d,J=4.0Hz,1H),7.21–7.13(m,3H) ,7.06–7.00(m,2H),6.98–6.94(m,1H),3.78–3...

Claims

1. A compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof: in, represents a single bond or a double bond; X 1 is CH, CD or N; R 3 is H, D, C1-C6 alkyl or optionally substituted C1-C6 alkyl; R 4 is H or C1-C6 alkyl; X 2 N, CH or CD; X 3 CR 2 or N; R 2 H, D, cyano, halogen, -OR 2-7 、-P(=O)(R 2-1 )2, -S(=O)2R 2-2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; R 2-1 and R 2-2 Each is independently an optionally substituted C1-C6 alkyl; R 2-7 is optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; R 1 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; R 1-1 and R 1-2 Each is independently halogen, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy; A is -R A1 C(=O)-、-R A2 CH2-、-R A2 CD2-, -R A2 CHD-, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene, or optionally substituted heterocycloalkylene; R A1 and R A2 each independently is optionally substituted aryl, optionally substituted heteroarylene, optionally substituted cycloalkylene or optionally substituted heterocycloalkylene; L is the connecting chain; B is optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene or optionally substituted heterocycloalkylene; And the compound represented by formula (I) is not any of the following compounds:

2. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: represents a single bond or a double bond; X 1 is CH, CD or N; R 3 is H, D, C1-C6 alkyl or optionally substituted C1-C6 alkyl; R 4 is H; X 2 N, CH or CD; X 3 CR 2 or N; R 2 H, D, cyano, halogen, -OR 2-7 ,-P(=O)(R 2-1 )2, -S(=O)2R 2-2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; R 2-1 and R 2-2 Each is independently an optionally substituted C1-C6 alkyl; R 2-7 is optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; R 1 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; R 1-1 and R 1-2 Each is independently halogen, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy; A is -R A1 C(=O)-、-R A2 CH2-、-R A2 CD2-, -R A2 CHD-, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene, or optionally substituted heterocycloalkylene; R A1 and R A2 each independently is optionally substituted aryl, optionally substituted heteroarylene, optionally substituted cycloalkylene or optionally substituted heterocycloalkylene; L is the connecting chain; B is optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene or optionally substituted heterocycloalkylene; And the compound represented by formula (I) is not any of the following compounds:

3. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: represents a single bond or a double bond; X 1 is CH, CD or N; R 3 is H, D, C1-C6 alkyl or optionally substituted C1-C6 alkyl; R 4 is H; X 2 N, CH or CD; X 3 CR 2 or N; R 2 H, D, halogen, -OR 2-7 ,-P(=O)(R 2-1 )2, -S(=O)2R 2-2 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; R 2-1 and R 2-2 Each is independently an optionally substituted C1-C6 alkyl; R 2-7 is optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; R 1 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; R 1-1 and R 1-2 Each is independently halogen, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkoxy; A is -R A1 C(=O)-、-R A2 CH2-、-R A2 CD2-, -R A2 CHD-, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene, or optionally substituted heterocycloalkylene; R A1 and R A2 each independently is optionally substituted aryl, optionally substituted heteroarylene, optionally substituted cycloalkylene or optionally substituted heterocycloalkylene; L is the connecting chain; B is optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene or optionally substituted heterocycloalkylene; And the compound represented by formula (I) is not any of the following compounds:

4. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: represents a single bond or a double bond; X 1 is CH or N; R 3 is H or C1-C6 alkyl; R 4 is H or C1-C6 alkyl; X 2 N or CH; X 3 CR 2 or N; R 2 is H, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, saturated C3-C 11 Cycloalkyl, saturated 3-11-membered heterocycloalkyl, -P(=O)(R 2-1 )2, -S(=O)2R 2-2 、-OR 2-7 , by one or more R 2-3 Substituted C1-C6 alkyl, one or more R 2-4 Substituted C1-C6 alkoxy, one or more R 2-5 Substituted saturated C3-C 11 Cycloalkyl or one or more R 2-6 Substituted saturated 3-11 membered heterocycloalkyl, wherein the saturated 3-11 membered heterocycloalkyl and one or more R 2-6 In the 3-11-membered heterocycloalkyl in the substituted saturated 3-11-membered heterocycloalkyl, the types of heteroatoms are independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3; R 2-1 and R 2-2 Each is independently a C1-C6 alkyl group; R 2-7 is saturated C3-C 11 Cycloalkyl; R 2-3 and R 2-4 Each is independently -N(R 2-3-1 )2. Saturated C3-C 11 Cycloalkyl, saturated 3-11 membered heterocycloalkyl, 2-3-2 Substituted saturated C3-C 11 Cycloalkyl or one or more R 2-3-3 Substituted saturated 3-11 membered heterocycloalkyl, wherein the saturated 3-11 membered heterocycloalkyl and one or more R 2-3-3 In the 3-11-membered heterocycloalkyl in the substituted saturated 3-11-membered heterocycloalkyl, the types of heteroatoms are independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3; R 2-3-1 are independently H or C1-C6 alkyl; R 2-3-2 and R 2-3-3 Each is independently a C1-C6 alkyl group; R 2-5 and R 2-6 Each independently C1-C6 alkyl; R 1 C6-C 10 Aryl, 5-10 membered heteroaryl, saturated C3-C 11 Cycloalkyl, saturated 3-11 membered heterocycloalkyl, 1-1 Substituted C6-C 10 Aryl, one or more R 1-2 substituted 5-10 membered heteroaryl, substituted by one or more R 1-3 Substituted saturated C3-C 11 Cycloalkyl or one or more R 1-4 A substituted saturated 3-11-membered heterocycloalkyl, wherein the type of heteroatoms in the saturated 3-11-membered heterocycloalkyl is selected from one or more of N, O, S and C(═O), and the number of heteroatoms is 1, 2 or 3, and the 5-10-membered heteroaryl and the substituted 5-10-membered heteroaryl are substituted with one or more R 1-2 In the 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; R 1-1 , R 1-2 , R 1-3 and R 1-4 Each is independently halogen, C1-C6 alkyl or C1-C6 alkoxy; A is -R A1 C(=O)-、-R A2 CH2-、C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 11 Cycloalkylene, saturated 3-11 membered heterocycloalkylene, By one or more R A3 Substituted C6-C 10 Arylene or one or more R A4 The saturated 3-11-membered heterocycloalkylene group has a heteroatom selected from one or more of N, O, S and C(=O), and the number of heteroatoms is 1, 2 or 3. The 5-10-membered heteroarylene group and the saturated 3-11-membered heterocycloalkylene group are substituted with one or more R A4 In the 5-10 membered heteroarylene group in the substituted 5-10 membered heteroarylene group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; R A1 and R A2 Each independently is C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 11 Cycloalkylene, saturated 3-11 membered heterocycloalkylene, A1-1 Substituted C6-C 10 Arylene or one or more R A1-2 substituted 5-10 membered heteroarylene, wherein the 5-10 membered heteroarylene and one or more R A1-2 In the 5-10 membered heteroarylene group in the substituted 5-10 membered heteroarylene group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; in the 3-11 membered heterocycloalkylene group, the type of heteroatoms is selected from one or more of N, O, S and C(═O), and the number of heteroatoms is 1, 2 or 3; R A1-1 and R A1-2 are independently CN, -P(=O)(R A3-1 )2, C1-C6 alkyl or C1-C6 alkoxy; Ring C1 is a partially unsaturated 3-8 membered heterocyclic ring or is replaced by one or more R C1 A partially unsaturated 3-8 membered heterocyclic ring substituted with one or more R C1 In the 3-8-membered heterocyclic ring of the substituted partially unsaturated 3-8-membered heterocyclic ring, the types of heteroatoms are independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3; R C1 are independently C1-C6 alkyl; R A3 and R A4 are independently CN, -P(=O)(R A3-1 )2, C1-C6 alkyl or C1-C6 alkoxy; R A3-1 are independently C1-C6 alkyl; L is -(CH2)n-, n is any integer from 1 to 18, and one or more -(CH2)- in -(CH2)n- are replaced by one or more of the following groups: -NR L1 -、-O-、-S-、-CR L6 R L7 -、-C(=O)-、 Saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, C6-C 10 Arylene, 5-10 membered heteroarylene, By one or more R L2 Substituted saturated C3-C 12 Cycloalkylene, one or more R L3 Substituted saturated 3-12 membered heterocycloalkylene, substituted by one or more R L4 Substituted C6-C 10 Arylene or one or more R L5 The substituted 5-10 membered heteroarylene group, the saturated 3-12 membered heterocycloalkylene group and one or more R L3 In the 3-12-membered heterocycloalkyl in the substituted saturated 3-12-membered heterocycloalkylene, the types of heteroatoms are independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3, and the 5-10-membered heteroarylene and the one or more R L5 In the substituted 5-10 membered heteroarylene group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; R L1 is H or C1-C6 alkyl; Ring C2 is a benzene ring or a 5-6 membered heteroaromatic ring, wherein the type of heteroatoms in the 5-6 membered heteroaromatic ring is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Ring C3 is a partially unsaturated C3-C7 carbocyclic ring or a partially unsaturated 3-7-membered heterocyclic ring, wherein the type of heteroatoms in the partially unsaturated 3-7-membered heterocyclic ring is selected from one or more of N, O, S and C(═O), and the number of heteroatoms is 1, 2 or 3; Ring C4 is a saturated C3-C7 carbocyclic ring or a saturated 3-7-membered heterocyclic ring, wherein the type of heteroatoms in the saturated 3-7-membered heterocyclic ring is selected from one or more of N, O, S and C(═O), and the number of heteroatoms is 1, 2 or 3; R L2 and R L3 Each is independently CN, OH, halogen, C1-C6 alkyl, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl; R L4 and R L5 Each is independently a C1-C6 alkyl group; R L6 is H or C1-C6 alkyl; R L7 is a C1-C6 alkyl group; B is C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, B1 Substituted C6-C 10 Arylene or one or more R B2 substituted 5-10 membered heteroarylene, wherein the 5-10 membered heteroarylene and one or more R B2 In the 5-10 membered heteroarylene group in the substituted 5-10 membered heteroarylene group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; in the saturated 3-12 membered heterocycloalkylene group, the type of heteroatoms is independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3; Y1, Y2, Y3 and Y4 are each independently CH2 or C(=O); Y5 for NY 5-1 , O or S, Y 5-1 is H or C1-C6 alkyl; Ring C5, Ring C6, Ring C7, Ring C8 and Ring C9 are each independently a benzene ring or a 5-6-membered heteroaromatic ring, wherein the type of heteroatoms in the 5-6-membered heteroaromatic ring is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Ring C 10 is a partially unsaturated C3-C7 carbocyclic ring or a partially unsaturated 3-7-membered heterocyclic ring, wherein the type of heteroatoms in the partially unsaturated 3-7-membered heterocyclic ring is selected from one or more of N, O, S and C(═O), and the number of heteroatoms is 1, 2 or 3; R B1 and R B2 Each is independently halogen, cyano, -P=O(C1-C6 alkyl)2, -C(=O)NH2, C1-C6 alkyl, C1-C6 alkoxy, B1-1 Substituted C1-C6 alkyl or one or more R B1-2 Substituted C1-C6 alkoxy; R B1-1 and R B1-2 are each independently a halogen; Furthermore, the compound as shown in formula (I) satisfies one or both of the following conditions: i: B is L is -(CH2)n-, n is any integer from 1 to 18, At least one -(CH2)- in -(CH2)n- is replaced by a saturated C3-C 12 Cycloalkylene, saturated 3-5 membered heterocycloalkylene, saturated 7-12 membered heterocycloalkylene, C6-C 10 Arylene, 6-10 membered heteroarylene, By one or more R L2 Substituted saturated C3-C 12 Cycloalkylene, one or more R L3 Substituted saturated 3-12 membered heterocycloalkylene, substituted by one or more R L4 Substituted C6-C 10 Arylene or one or more R L5 substituted 5-10 membered heteroarylene; Alternatively, at least two -(CH2)- in -(CH2)n- are replaced by the following groups: saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, C6-C 10 Arylene, 5-10 membered heteroarylene, By one or more R L2 Substituted saturated C3-C 12 Cycloalkylene, one or more R L3 Substituted saturated 3-12 membered heterocycloalkylene, substituted by one or more R L4 Substituted C6-C 10 Arylene or one or more R L5 substituted 5-10 membered heteroarylene; ii: B is C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, B1 Substituted C6-C 10 Arylene or one or more R B2 Substituted 5-10 membered heteroarylene, ring C 5-1 5-6 membered heteroaromatic ring in the same ring C5, ring C 5-2 A 5-6 membered heteroaromatic ring in the same ring C5.

5. The compound of formula (I) according to claim 1 or 2, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: represents a single bond or a double bond; X 1 is CH or N; R 3 is H or C1-C6 alkyl; R 4 is H; X 2 N or CH; X 3 CR 2 or N; R 2 is H, cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, saturated C3-C 11 Cycloalkyl, saturated 3-11-membered heterocycloalkyl, -P(=O)(R 2-1 )2, -S(=O)2R 2-2 、-OR 2-7 , by one or more R 2-3 Substituted C1-C6 alkyl, one or more R 2-4 Substituted C1-C6 alkoxy, one or more R 2-5 Substituted saturated C3-C 11 Cycloalkyl or one or more R 2-6 Substituted saturated 3-11 membered heterocycloalkyl, wherein the saturated 3-11 membered heterocycloalkyl and one or more R 2-6 In the 3-11-membered heterocycloalkyl in the substituted saturated 3-11-membered heterocycloalkyl, the types of heteroatoms are independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3; R 2-1 and R 2-2 Each is independently a C1-C6 alkyl group; R 2-7 is saturated C3-C 11 Cycloalkyl; R 2-3 and R 2-4 Each is independently -N(R 2-3-1 )2. Saturated C3-C 11 Cycloalkyl, saturated 3-11 membered heterocycloalkyl, 2-3-2 Substituted saturated C3-C 11 Cycloalkyl or one or more R 2-3-3 Substituted saturated 3-11 membered heterocycloalkyl, wherein the saturated 3-11 membered heterocycloalkyl and one or more R 2-3-3 In the 3-11-membered heterocycloalkyl in the substituted saturated 3-11-membered heterocycloalkyl, the types of heteroatoms are independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3; R 2-3-1 are independently H or C1-C6 alkyl; R 2-3-2 and R 2-3-3 Each is independently a C1-C6 alkyl group; R 2-5 and R 2-6 Each independently C1-C6 alkyl; R 1 C6-C 10 Aryl, 5-10 membered heteroaryl, saturated C3-C 11 Cycloalkyl, saturated 3-11 membered heterocycloalkyl, 1-1 Substituted C6-C 10 Aryl or one or more R 1-2 The saturated 3-11-membered heterocycloalkyl group has a heteroatom selected from one or more of N, O, S and C(=O), and the number of heteroatoms is 1, 2 or 3. The 5-10-membered heteroaryl group and the saturated 3-11-membered heterocycloalkyl group have a heteroatom selected from one or more of N, O, S and C(=O), and the number of heteroatoms is 1, 2 or 3. 1-2 In the 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; R 1-1 and R 1-2 Each is independently halogen, C1-C6 alkyl or C1-C6 alkoxy; A is -R A1 C(=O)-、-R A2 CH2-、C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 11 Cycloalkylene, saturated 3-11 membered heterocycloalkylene, By one or more R A3 Substituted C6-C 10 Arylene or one or more R A4 The saturated 3-11-membered heterocycloalkylene group has a heteroatom selected from one or more of N, O, S and C(=O), and the number of heteroatoms is 1, 2 or 3. The 5-10-membered heteroarylene group and the saturated 3-11-membered heterocycloalkylene group are substituted with one or more R A4 In the 5-10 membered heteroarylene group in the substituted 5-10 membered heteroarylene group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; R A1 and R A2 Each independently is C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 11 Cycloalkylene, saturated 3-11 membered heterocycloalkylene, A1-1 Substituted C6-C 10 Arylene or one or more R A1-2 substituted 5-10 membered heteroarylene, wherein the 5-10 membered heteroarylene and one or more R A1-2 In the 5-10 membered heteroarylene group in the substituted 5-10 membered heteroarylene group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; in the 3-11 membered heterocycloalkylene group, the type of heteroatoms is selected from one or more of N, O, S and C(═O), and the number of heteroatoms is 1, 2 or 3; R A1-1 and R A1-2 are independently CN, -P(=O)(R A3-1 )2, C1-C6 alkyl or C1-C6 alkoxy; Ring C1 is a partially unsaturated 3-8 membered heterocyclic ring or is replaced by one or more R C1 A partially unsaturated 3-8 membered heterocyclic ring substituted with one or more R C1 In the 3-8-membered heterocyclic ring of the substituted partially unsaturated 3-8-membered heterocyclic ring, the types of heteroatoms are independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3; R C1 are independently C1-C6 alkyl; R A3 and R A4 are independently CN, -P(=O)(R A3-1 )2, C1-C6 alkyl or C1-C6 alkoxy; R A3-1 are independently C1-C6 alkyl; L is -(CH2)n-, n is any integer from 1 to 18, and one or more -(CH2)- in -(CH2)n- are replaced by one or more of the following groups: -NR L1 -, -O-, -S-, -C(=O)-, Saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, C6-C 10 Arylene, 5-10 membered heteroarylene, By one or more R L2 Substituted saturated C3-C 12 Cycloalkylene, one or more R L3 Substituted saturated 3-12 membered heterocycloalkylene, substituted by one or more R L4 Substituted C6-C 10 Arylene or one or more R L5 The substituted 5-10 membered heteroarylene group, the saturated 3-12 membered heterocycloalkylene group and one or more R L3 In the 3-12-membered heterocycloalkyl in the substituted saturated 3-12-membered heterocycloalkylene, the types of heteroatoms are independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3, and the 5-10-membered heteroarylene and the one or more R L5 In the substituted 5-10 membered heteroarylene group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; R L1 is H or C1-C6 alkyl; Ring C2 is a benzene ring or a 5-6 membered heteroaromatic ring, wherein the type of heteroatoms in the 5-6 membered heteroaromatic ring is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Ring C3 is a partially unsaturated C3-C7 carbocyclic ring or a partially unsaturated 3-7-membered heterocyclic ring, wherein the type of heteroatoms in the partially unsaturated 3-7-membered heterocyclic ring is selected from one or more of N, O, S and C(═O), and the number of heteroatoms is 1, 2 or 3; Ring C4 is a saturated C3-C7 carbocyclic ring or a saturated 3-7-membered heterocyclic ring, wherein the type of heteroatoms in the saturated 3-7-membered heterocyclic ring is selected from one or more of N, O, S and C(═O), and the number of heteroatoms is 1, 2 or 3; R L2 and R L3 Each is independently CN, OH, halogen, C1-C6 alkyl, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl; R L4 and R L5 Each is independently a C1-C6 alkyl group; B is C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, B1 Substituted C6-C 10 Arylene or one or more R B2 substituted 5-10 membered heteroarylene, wherein the 5-10 membered heteroarylene and one or more R B2 In the 5-10 membered heteroarylene group in the substituted 5-10 membered heteroarylene group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; in the saturated 3-12 membered heterocycloalkylene group, the type of heteroatoms is independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3; Y1, Y2, Y3 and Y4 are each independently CH2 or C(=O); Y5 for NY 5-1 , O or S, Y 5-1 is H or C1-C6 alkyl; Ring C5, Ring C6, Ring C7, Ring C8 and Ring C9 are each independently a benzene ring or a 5-6-membered heteroaromatic ring, wherein the type of heteroatoms in the 5-6-membered heteroaromatic ring is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Ring C 10 is a partially unsaturated C3-C7 carbocyclic ring or a partially unsaturated 3-7-membered heterocyclic ring, wherein the type of heteroatoms in the partially unsaturated 3-7-membered heterocyclic ring is selected from one or more of N, O, S and C(═O), and the number of heteroatoms is 1, 2 or 3; R B1 and R B2 Each independently represents halogen, cyano, -P=O(CH3)2, C1-C6 alkyl, C1-C6 alkoxy, B1- 1 Substituted C1-C6 alkyl or one or more R B1-2 Substituted C1-C6 alkoxy; R B1-1 and R B1-2 are each independently a halogen; Furthermore, the compound as shown in formula (I) satisfies one or both of the following conditions: i: B is L is -(CH2)n-, n is any integer from 1 to 18, and at least one -(CH2)- in -(CH2)n- is replaced by the following groups: saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, C6-C 10 Arylene, 5-10 membered heteroarylene, By one or more R L2 Substituted saturated C3-C 12 Cycloalkylene, one or more R L3 Substituted saturated 3-12 membered heterocycloalkylene, substituted by one or more R L4 Substituted C6-C 10 Arylene or one or more R L5 substituted 5-10 membered heteroarylene; ii: B is C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, B1 Substituted C6-C 10 Arylene or one or more R B2 Substituted 5-10 membered heteroarylene, ring C 5-1 5-6 membered heteroaromatic ring in the same ring C5, ring C 5-2 Same ring as C5.

6. The compound of formula (I) according to any one of claims 1 to 3, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: represents a single bond or a double bond; X 1 is CH or N; R 3 is H or C1-C6 alkyl; R 4 is H; X 2 N or CH; X 3 CR 2 or N; R 2 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, saturated C3-C 11 Cycloalkyl, saturated 3-11-membered heterocycloalkyl, -P(=O)(R 2-1 )2, -S(=O)2R 2-2 、-OR 2-7 , by one or more R 2-3 Substituted C1-C6 alkyl, one or more R 2-4 Substituted C1-C6 alkoxy, one or more R 2-5 Substituted saturated C3-C 11 Cycloalkyl or one or more R 2-6 Substituted saturated 3-11 membered heterocycloalkyl, wherein the saturated 3-11 membered heterocycloalkyl and one or more R 2-6 In the 3-11-membered heterocycloalkyl in the substituted saturated 3-11-membered heterocycloalkyl, the types of heteroatoms are independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3; R 2-1 and R 2-2 Each is independently a C1-C6 alkyl group; R 2-7 is saturated C3-C 11 Cycloalkyl; R 2-3 and R 2-4 Each is independently -N(R 2-3-1 )2. Saturated C3-C 11 Cycloalkyl, saturated 3-11 membered heterocycloalkyl, 2-3-2 Substituted saturated C3-C 11 Cycloalkyl or one or more R 2-3-3 Substituted saturated 3-11 membered heterocycloalkyl, wherein the saturated 3-11 membered heterocycloalkyl and one or more R 2-3-3 In the 3-11-membered heterocycloalkyl in the substituted saturated 3-11-membered heterocycloalkyl, the types of heteroatoms are independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3; R 2-3-1 are independently H or C1-C6 alkyl; R 2-3-2 and R 2-3-3 Each is independently a C1-C6 alkyl group; R 2-5 and R 2-6 Each independently C1-C6 alkyl; R 1 C6-C 10 Aryl, 5-10 membered heteroaryl, saturated C3-C 11 Cycloalkyl, saturated 3-11 membered heterocycloalkyl, 1-1 Substituted C6-C 10 Aryl or one or more R 1-2 The saturated 3-11-membered heterocycloalkyl group has a heteroatom selected from one or more of N, O, S and C(=O), and the number of heteroatoms is 1, 2 or 3. The 5-10-membered heteroaryl group and the saturated 3-11-membered heterocycloalkyl group have a heteroatom selected from one or more of N, O, S and C(=O), and the number of heteroatoms is 1, 2 or 3. 1-2 In the 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; R 1-1 and R 1-2 Each is independently halogen, C1-C6 alkyl or C1-C6 alkoxy; A is -R A1 C(=O)-、-R A2 CH2-、C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 11 Cycloalkylene, saturated 3-11 membered heterocycloalkylene, By one or more R A3 Substituted C6-C 10 Arylene or one or more R A4 The saturated 3-11-membered heterocycloalkylene group has a heteroatom selected from one or more of N, O, S and C(=O), and the number of heteroatoms is 1, 2 or 3. The 5-10-membered heteroarylene group and the saturated 3-11-membered heterocycloalkylene group are substituted with one or more R A4 In the 5-10 membered heteroarylene group in the substituted 5-10 membered heteroarylene group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; R A1 and R A2 Each independently is C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 11 Cycloalkylene, saturated 3-11 membered heterocycloalkylene, A1-1 Substituted C6-C 10 Arylene or one or more R A1-2 substituted 5-10 membered heteroarylene, wherein the 5-10 membered heteroarylene and one or more R A1-2 In the 5-10 membered heteroarylene group in the substituted 5-10 membered heteroarylene group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; in the 3-11 membered heterocycloalkylene group, the type of heteroatoms is selected from one or more of N, O, S and C(═O), and the number of heteroatoms is 1, 2 or 3; R A1-1 and R A1-2 are independently CN, -P(=O)(R A3-1 )2, C1-C6 alkyl or C1-C6 alkoxy; Ring C1 is a partially unsaturated 3-8 membered heterocyclic ring or is replaced by one or more R C1 A partially unsaturated 3-8 membered heterocyclic ring substituted with one or more R C1 In the 3-8-membered heterocyclic ring of the substituted partially unsaturated 3-8-membered heterocyclic ring, the types of heteroatoms are independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3; R C1 are independently C1-C6 alkyl; R A3 and R A4 are independently CN, -P(=O)(R A3-1 )2, C1-C6 alkyl or C1-C6 alkoxy; R A3-1 are independently C1-C6 alkyl; L is -(CH2)n-, n is any integer from 1 to 18, and one or more -(CH2)- in -(CH2)n- are replaced by one or more of the following groups: -NR L1 -, -O-, -S-, -C(=O)-, Saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, C6-C 10 Arylene, 5-10 membered heteroarylene, By one or more R L2 Substituted saturated C3-C 12 Cycloalkylene, one or more R L3 Substituted saturated 3-12 membered heterocycloalkylene, substituted by one or more R L4 Substituted C6-C 10 Arylene or one or more R L5 The substituted 5-10 membered heteroarylene group, the saturated 3-12 membered heterocycloalkylene group and one or more R L3 In the 3-12-membered heterocycloalkyl in the substituted saturated 3-12-membered heterocycloalkylene, the types of heteroatoms are independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3, and the 5-10-membered heteroarylene and the one or more R L5 In the substituted 5-10 membered heteroarylene group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; R L1 is H or C1-C6 alkyl; Ring C2 is a benzene ring or a 5-6 membered heteroaromatic ring, wherein the type of heteroatoms in the 5-6 membered heteroaromatic ring is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Ring C3 is a partially unsaturated C3-C7 carbocyclic ring or a partially unsaturated 3-7-membered heterocyclic ring, wherein the type of heteroatoms in the partially unsaturated 3-7-membered heterocyclic ring is selected from one or more of N, O, S and C(═O), and the number of heteroatoms is 1, 2 or 3; Ring C4 is a saturated C3-C7 carbocyclic ring or a saturated 3-7-membered heterocyclic ring, wherein the type of heteroatoms in the saturated 3-7-membered heterocyclic ring is selected from one or more of N, O, S and C(═O), and the number of heteroatoms is 1, 2 or 3; R L2 and R L3 Each is independently CN, OH, halogen, C1-C6 alkyl, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl; R L4 and R L5 Each is independently a C1-C6 alkyl group; B is C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, B1 Substituted C6-C 10 Arylene or one or more R B2 substituted 5-10 membered heteroarylene, wherein the 5-10 membered heteroarylene and one or more R B2 In the 5-10 membered heteroarylene group in the substituted 5-10 membered heteroarylene group, the type of heteroatoms is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; in the saturated 3-12 membered heterocycloalkylene group, the type of heteroatoms is independently selected from one or more of N, O, S and C(═O), and the number of heteroatoms is independently 1, 2 or 3; Y1, Y2, Y3 and Y4 are each independently CH2 or C(=O); Y5 for NY 5-1 , O or S, Y 5-1 is H or C1-C6 alkyl; Ring C5, Ring C6, Ring C7, Ring C8 and Ring C9 are each independently a benzene ring or a 5-6-membered heteroaromatic ring, wherein the type of heteroatoms in the 5-6-membered heteroaromatic ring is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Ring C 10 is a partially unsaturated C3-C7 carbocyclic ring or a partially unsaturated 3-7-membered heterocyclic ring, wherein the type of heteroatoms in the partially unsaturated 3-7-membered heterocyclic ring is selected from one or more of N, O, S and C(═O), and the number of heteroatoms is 1, 2 or 3; R B1 and R B2 Each independently represents halogen, C1-C6 alkyl, C1-C6 alkoxy, or one or more R B1-1 Substituted C1-C6 alkyl or one or more R B1-2 Substituted C1-C6 alkoxy; R B1-1 and R B1-2 are each independently a halogen; Furthermore, the compound as shown in formula (I) satisfies one or both of the following conditions: i: B is L is -(CH2)n-, n is any integer from 1 to 18, and at least one -(CH2)- in -(CH2)n- is replaced by the following groups: saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, C6-C 10 Arylene, 5-10 membered heteroarylene, By one or more R L2 Substituted saturated C3-C 12 Cycloalkylene, one or more R L3 Substituted saturated 3-12 membered heterocycloalkylene, substituted by one or more R L4 Substituted C6-C 10 Arylene or one or more R L5 substituted 5-10 membered heteroarylene; ii: B is C6-C 10 Arylene, 5-10 membered heteroarylene, saturated C3-C 12 Cycloalkylene, saturated 3-12 membered heterocycloalkylene, B1 Substituted C6-C 10 Arylene or one or more R B2 Substituted 5-10 membered heteroarylene, ring C 5-1 5-6 membered heteroaromatic ring in the same ring C5, ring C 5-2 Same ring as C5.

7. The compound of formula (I) as described in any one of claims 1, 2, 4 and 5, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1)R 2 -H, -CN, -F, -Cl, -CH3, cyclopropyl, -OCH3, (2) B is: Wherein the c side is connected to L; in scheme ii, B is the aforementioned group except Any group other than .

8. The compound of formula (I) according to claim 4, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: It meets one or more of the following conditions: In the condition ii described in (1), L is: Among them, side b is connected to B; Xa1 is O or -NR L1 -, R L1 is H or C1-C6 alkyl; Xa2 is R M is a C1-C6 alkyl group, and ring C4 is a saturated C3-C6 carbocyclic ring or a saturated 3-6-membered heterocyclic ring, wherein the type of heteroatoms in the saturated 3-6-membered heterocyclic ring is selected from one or more of N, O, S and C(═O), and the number of heteroatoms is 1, 2 or 3; Ring A1 and Ring A2 are saturated 3-12 membered nitrogen-containing heterocyclic rings or are replaced by one or more R L3 Substituted saturated 3-12-membered nitrogen-containing heterocyclic ring, R L3 independently CN, OH, halogen, C1-C6 alkyl, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl, the 3-12 membered nitrogen-containing heterocycle in the saturated 3-12 membered nitrogen-containing heterocycle or the 3-12 membered nitrogen-containing heterocycle in the substituted saturated 3-12 membered nitrogen-containing heterocycle is independently a 3-6 membered monocyclic nitrogen-containing heterocycle, a 7-12 membered spirocycle or a 7-12 membered bridged nitrogen-containing heterocycle, wherein the heteroatom may be selected from one or more of O, S and C(=O) in addition to N, and the number of heteroatoms is 1, 2 or 3; Ring A3 is independently a saturated C3-C 12 A carbon ring or one or more R L2 Substituted saturated C3-C 12 Carbon ring, R L2 are independently CN, OH, halogen, C1-C6 alkyl, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl, the saturated C3-C 12 Carbocyclic or substituted saturated C3-C 12 C3-C in carbon ring 12 The carbocyclic ring is independently a C3-C6 monocyclic carbocyclic ring or a C5-C 12 spirocyclic carbocyclic ring; Ring A4 is independently a 5-10 membered heteroaromatic ring or is substituted by one or more R L5 Substituted 5-10 membered heteroaromatic ring, R L5 are independently C1-C6 alkyl; the 5-10 membered heteroaromatic ring and one or more R L5 In the 5-10 membered heteroaromatic ring of the substituted 5-10 membered heteroaromatic ring, the types of heteroatoms are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Ring A5 is independently Ring C2 is a benzene ring or a 5-6 membered heteroaromatic ring, wherein the type of heteroatoms in the 5-6 membered heteroaromatic ring is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Ring C3 is a partially unsaturated 3-7 membered nitrogen-containing heterocyclic ring, wherein the heteroatoms in the partially unsaturated 3-7 membered nitrogen-containing heterocyclic ring, in addition to N, may also be selected from one or more of O, S and C(=O), and the number of heteroatoms is 1, 2 or 3; n1a is independently any integer from 0 to 8; n2a is independently any integer from 0 to 3; n3a is independently any integer from 0 to 5; Preferably: Among them, side b is connected to B; (2) In the condition i, L is G1 or G2: G1： Among them, side b is connected to B; Xa1 is O or -NR L1 -, R L1 is H or C1-C6 alkyl; Ring A1 and Ring A2 are saturated 3-12 membered nitrogen-containing heterocyclic rings or are replaced by one or more R L3 Substituted saturated 3-12-membered nitrogen-containing heterocyclic ring, R L3 independently CN, OH, halogen, C1-C6 alkyl, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl, the 3-12 membered nitrogen-containing heterocycle in the saturated 3-12 membered nitrogen-containing heterocycle or the 3-12 membered nitrogen-containing heterocycle in the substituted saturated 3-12 membered nitrogen-containing heterocycle is independently a 4-membered monocyclic nitrogen-containing heterocycle, a 7-12 membered spirocyclic nitrogen-containing heterocycle or a 7-12 membered bridged nitrogen-containing heterocycle, wherein the heteroatom may be selected from one or more of O, S and C(=O) in addition to N, and the number of heteroatoms is 1, 2 or 3; Ring A3 is independently a saturated C3-C 12 A carbon ring or one or more R L2 Substituted saturated C3-C 12 Carbon ring, R L2 are independently CN, OH, halogen, C1-C6 alkyl, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl, the saturated C3-C 12 Carbocyclic or substituted saturated C3-C 12 C3-C in carbon ring 12 The carbocyclic ring is independently a C3-C6 monocyclic carbocyclic ring, a C7-C 12 Spirocyclic carbocyclic or C7-C 12 Bridged carbon ring; Ring A5 is independently Ring C2 is a benzene ring or a 5-6 membered heteroaromatic ring, wherein the type of heteroatoms in the 5-6 membered heteroaromatic ring is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; Ring C3 is a partially unsaturated 3-7 membered nitrogen-containing heterocyclic ring, wherein the heteroatoms in the partially unsaturated 3-7 membered nitrogen-containing heterocyclic ring, in addition to N, may also be selected from one or more of O, S and C(=O), and the number of heteroatoms is 1, 2 or 3; n2a is independently any integer from 0 to 3; n3a is independently any integer from 0 to 5; G2： Among them, side b is connected to B; Xa1 is O or -NR L1 -, R L1 is H or C1-C6 alkyl; Xa2 is R M is a C1-C6 alkyl group, and ring C4 is a saturated C3-C6 carbocyclic ring or a saturated 3-6-membered heterocyclic ring, wherein the type of heteroatoms in the saturated 3-6-membered heterocyclic ring is selected from one or more of N, O, S and C(═O), and the number of heteroatoms is 1, 2 or 3; Ring A1 and Ring A2 are saturated 3-12 membered nitrogen-containing heterocyclic rings or are replaced by one or more R L3 Substituted saturated 3-12-membered nitrogen-containing heterocyclic ring, R L3 independently CN, OH, halogen, C1-C6 alkyl, C3-C7 cycloalkyl or 3-7 membered heterocycloalkyl, the 3-12 membered nitrogen-containing heterocycle in the saturated 3-12 membered nitrogen-containing heterocycle or the 3-12 membered nitrogen-containing heterocycle in the substituted saturated 3-12 membered nitrogen-containing heterocycle is independently a 3-6 membered monocyclic nitrogen-containing heterocycle or a 5-12 membered spirocyclic nitrogen-containing heterocycle, wherein the heteroatom may be selected from one or more of O, S and C(=O) in addition to N, and the number of heteroatoms is 1, 2 or 3; Ring A4 is independently a 5-10 membered heteroaromatic ring or is substituted by one or more R L5 Substituted 5-10 membered heteroaromatic ring, R L5 are independently C1-C6 alkyl; the 5-10 membered heteroaromatic ring and one or more R L5 In the 5-10 membered heteroaromatic ring of the substituted 5-10 membered heteroaromatic ring, the types of heteroatoms are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; n2a is independently any integer from 0 to 3.

9. The compound of formula (I) according to claim 4, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: It meets one or more of the following conditions: In the condition ii described in (1), L is Wherein, n1 is any integer from 1 to 8, n2 is any integer from 1 to 3, n3 is any integer from 1 to 5, and side b is connected to B; Preferably Side b is connected to B; (2) In the condition i, L is G1 or G2: G1： Wherein, n1 is any integer from 1 to 8, n2 is any integer from 1 to 3, n3 is any integer from 1 to 5, and side b is connected to B; G2： The b side is connected to B.

10. The compound of formula (I) according to claim 2 or 5, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, characterized in that: L is wherein n1 is any integer from 1 to 8, n2 is any integer from 1 to 3, n3 is any integer from 1 to 5, and the side b is connected to B; preferably, in scheme i, L is any of the above groups except Any other group other than Preferably, L is: Wherein the b side is connected to B; Preferably, in scheme i, L is the aforementioned group except Any other group.

11. The compound of formula (I) according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1)R 3 is H or methyl; (2)R 2 -H, -F, -Cl, -CH3, cyclopropyl, -OCH3, (3) A is Side a is connected to L; (4) L is: wherein n1 is any integer from 1 to 8, n2 is any integer from 1 to 3, n3 is any integer from 1 to 5, and the side b is connected to B; preferably, in scheme i, L is any of the above groups except Any other group other than (5) B is: Wherein the c side is connected to L; in scheme ii, B is the aforementioned group except Any group other than .

12. The compound of formula (I) according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, characterized in that: L is: Wherein the b side is connected to B; Preferably, in scheme i, L is the aforementioned group except Any other group.

13. The compound of formula (I) according to claim 4, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: It meets one or more of the following conditions: In condition ii described in (1), -ALB- is G11 or G12: G11： G12： The d side is connected; (2) In scheme i, -ALB- is: The d side is connected.

14. The compound of formula (I) according to claim 2 or 5, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, characterized in that: -ALB- is: The d side is Preferably, in Scheme ii, -ALB- is the aforementioned group except Any other group except 15. The compound of formula (I) according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, characterized in that: (1)-ALB- is: The d side is Preferably, in Scheme ii, -ALB- is the aforementioned group except Any other group except (2) for: (3) for 16. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: The compound represented by formula (I) is any one of the following compounds:

17. A pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1 to 16, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

18. Use of a compound of formula (I) according to any one of claims 1 to 16, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17 in the preparation of an AURKA inhibitor or degrader.

19. Use of a compound of formula (I) according to any one of claims 1 to 16, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17 in the preparation of a medicament for treating and / or preventing a disease associated with AURKA, preferably, the disease associated with AURKA is neuroblastoma, retinoblastoma, colorectal cancer, breast cancer, lung cancer, kidney cancer or blood cancer.

20. Use of a compound of formula (I) as described in any one of claims 1 to 16, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 17 in the preparation of a medicament for treating and / or preventing a disease mediated by an AURKA inhibitor or degrader, preferably, the disease mediated by the AURKA inhibitor or degrader is neuroblastoma, retinoblastoma, colorectal cancer, breast cancer, lung cancer, kidney cancer or blood cancer.

21. Use of a compound of formula (I) as described in any one of claims 1 to 16, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 17 in the preparation of a medicament for treating and / or preventing neuroblastoma, retinoblastoma, colorectal cancer, breast cancer, lung cancer, kidney cancer or blood cancer.

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