A bifunctional compound for degrading receptor tyrosine kinase and its application

Abstract

The present invention belongs to the field of biomedicine, and specifically relates to a bifunctional compound for degrading receptor tyrosine kinase or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof, which degrades receptor tyrosine kinase, especially discoidin domain receptors (DDRs), regulates downstream key proteins and further plays a role in treating related diseases, and shows outstanding ability to inhibit tumor cell proliferation. The PROTAC compound developed by the present invention has a novel structure, excellent biological activity, and can safely and effectively inhibit or degrade DDR1. The compound can effectively degrade or inhibit receptor tyrosine kinase, especially DDR1 and / or DDR2, and can be used to treat diseases related to DDR1 and other RTK homeostasis imbalance. The present invention further recruits receptor tyrosine kinase target proteins to specific E3 ligases and completes ubiquitination labeling and degradation, which can be used to prepare drugs for preventing, diagnosing or treating receptor tyrosine kinase (RTK) related diseases or conditions.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and particularly relates to a bifunctional compound for degrading receptor tyrosine kinases or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof. Such compounds regulate downstream key proteins by degrading receptor tyrosine kinases, especially discoidin domain receptors (DDRs), and further play a role in treating related diseases, and show outstanding ability to inhibit the proliferation of tumor cells. Background Art

[0002] Receptor Tyrosine Kinases (RTKs) are located on the cell surface and are receptors with high affinity for various signaling molecules such as growth factors, cytokines, and hormones. As an important part of the tyrosine kinase family, receptor tyrosine kinases participate in cell signal transduction by catalyzing the phosphorylation of downstream protein tyrosine. Currently, more than fifty RTKs are known and can be divided into 20 different subfamilies, including the epidermal growth factor receptor subfamily, vascular endothelial growth factor receptor subfamily, hepatocyte growth factor receptor subfamily, etc. They play very important roles in controlling cell proliferation, migration, differentiation, and metabolism processes respectively. In terms of protein structure, RTKs are composed of three parts, including the extracellular domain (ECD) of the ligand-binding site, the hydrophobic α-helix transmembrane domain, and the intracellular domain containing tyrosine protein kinase activity, and the intracellular domain can be further divided into the juxtamembrane domain, tyrosine kinase domain, and carboxyl terminus. (Trenker and Jura, Curr Opin Cell Biol. 2020, 63:174–185.) Under normal physiological conditions, non-activated receptor tyrosine kinases exist in monomer form; when their extracellular domain binds to signaling molecules, the receptor molecule monomers dimerize or oligomerize on the cell membrane, the tyrosine residues in the intracellular domain are phosphorylated, the function of the kinase is activated, and a signal complex is formed at its end. The phosphorylated tyrosine site in the intracellular domain becomes the binding site for intracellular downstream signaling proteins, and the bound downstream signaling proteins are activated, expanding the information through different signal transduction pathways, causing a series of biochemical reactions in the cell, or causing a comprehensive response of the cell through multiple pathways of the information matrix, thereby controlling processes such as cell proliferation, migration, differentiation, and apoptosis (Lemmon MA, Schlessinger J. Cell. 2010; 141:1117–34).

[0003] Dysregulation of RTK signals can lead to various abnormal states of cells. RTK dysregulation plays an important role in the development and regulation of cancer cells. RTK mutations will activate a series of downstream associated reactions, disrupt the balance between cell growth / proliferation and cell death, and trigger tumorigenesis driven by RTK dysregulation. In human cancers, the main mechanisms leading to constitutive RTK activation dysregulation include gain-of-function mutations, genomic amplification, chromosomal rearrangements, autocrine activation, and kinase domain duplications. Many experiments have demonstrated that the tyrosine kinase family is closely related to the incidence of tumors. Inhibiting receptor tyrosine kinases is an effective measure for cancer treatment. Therefore, RTKs have become important targets for developing tumor treatment methods. Many RTK inhibitors based on small molecule compounds or monoclonal antibodies have been developed into drugs for treating various tumors (Punit S. Oncogene 2021, 40(24):4079-4093). Compared with traditional chemotherapy drugs, RTK inhibitors (TKIs) have the advantages of high selectivity and few side effects. However, this type of signal transduction inhibitor can only block some signal pathways of tumor cells, and the compensatory mechanisms of other signal pathways often weaken the treatment effect. In addition, the application of the targeted drug TKI may lead to tumor drug resistance, greatly reducing the treatment effect. The molecular mechanisms of tyrosine kinase inhibitor resistance include overexpression and mutation of kinases, drug uptake, drug binding, drug efflux mediated by ATP-binding cassette transporters, defects in DNA repair mechanisms, activation of abnormal signal pathways, epigenetic modifications, and the tumor microenvironment, etc. Therefore, it is urgently necessary to develop new methods and technical means for treating various diseases caused by RTK dysregulation.

[0004] Discoidin domain receptors (DDRs), as a member of receptor tyrosine kinases (RTKs), play an important role in the signal transduction pathways that control cell proliferation and differentiation. The dysregulation of DDRs is closely related to various diseases, including cancer, neurodegeneration, chronic inflammation, and fibrosis, etc. DDRs can promote the malignant proliferation of tumor cells and are related to the invasion and metastasis of tumor cells. In-depth research on DDR regulation means can open up a new way for the clinical prevention and treatment of diseases such as tumors. According to research, members of the DDR family, including DDR1 and DDR2, are widely expressed in various tissues. Among them, DDR1 is mainly expressed in epithelial cells, smooth muscle cells, fibroblasts, oligodendrocytes, and macrophages in the lung, kidney, colon, and brain, while DDR2 is mainly expressed in fibroblasts, myofibroblasts, smooth muscle cells, and chondrocytes in the kidney, skin, lung, heart, and connective tissues.

[0005] DDRs are composed of three main structural domains, namely the extracellular ligand-binding region, the transmembrane region, and the intracellular tyrosine kinase region. Among them, the extracellular domain consists of a discoidin domain and a discoidin-like domain that can bind to the ligand collagen; the transmembrane domain includes the extracellular juxtamembrane domain and the transmembrane helix region, which can mediate collagen-independent receptor dimerization (Yeung DA, Jmol Biol. 2019; 431: 368-390); the intracellular domain includes the intracellular juxtamembrane domain and the catalytic tyrosine kinase domain. In addition, DDRs have an activation mechanism different from other RTKs. They require collagen-binding stimulation to initiate downstream pathways, leading to autophosphorylation. The activation process of DDRs is collagen-specific, that is, DDR1 and DDR2 require different types of collagen for activation. DDR1 preferentially binds to collagens I-V and VIII, and has a lower affinity for type X collagen. Studies have shown that the functions of DDR1 are mainly achieved through three pathways, namely the classical collagen-DDR1 signaling pathway, which depends on the kinase activity of DDR1 and directly affects downstream molecules such as Shc, Nck2, and Shp-2; or, the non-classical DDR1 signaling pathway that depends on collagen binding but not on the kinase activity of DDR1; or, it can function without depending on collagen stimulation or the kinase activity of DDR1.

[0006] Studies have shown that DDR1 is expressed in a variety of tumors such as lung cancer, breast cancer, brain tumors, ovarian cancer, esophageal cancer, head and neck tumors, liver cancer, and testicular cancer, and its high expression is closely related to poor tumor prognosis (Rammal H, Front Pharmacol. 2016; 7: 55). For example, in the cancer tissues of patients with non-small cell lung cancer, the expression of DDR1 is positively correlated with mortality, and both the expression and phosphorylation levels of DDR1 are significantly increased in lung cancer tissues. Immunohistochemical analysis of 171 cases of non-small cell lung cancer showed that the positive rate of DDR1 in aggressive non-small cell lung cancer was as high as 61% (Yang SH. Oncol Rep. 2010; 24: 311-319). At the same time, DDR1 can promote the proliferation and growth of a variety of malignant tumor cells. For example, in human colon cancer and breast cancer, DDR1 can upregulate the anti-apoptotic protein Bcl-xL by activating the downstream signaling proteins Ras / Raf / ERK and the PI3K / Akt pathway, thereby enabling cancer cells to survive under toxic stress conditions (Matadag SP. Medicinal Chemistry Research, 2021, 30(3): 535-551).

[0007] Activated DDR1 by native type IV collagen can induce an increase in the expression of CD9 in breast cancer MDA-MB-231 cell line, which in turn leads to the migration of cancer cells; it also induces the secretion and invasion of matrix metalloproteinase-2 and metalloproteinase-9 through DDR1- and Src-dependent pathways, increasing their cellular expression levels. The activation of DDR1 plays an important role in the invasive ability and metabolic activities of breast cancer cells. Similarly, the upregulation of these two metalloproteinases caused by DDR1 is also a prerequisite for the metastasis and invasion of liver cancer cells (Lee, JH. Sci. Rep. 2018, 8, 1). In addition, in vivo and in vitro experiments have shown that DDRs are involved in the differentiation of tumor cells; furthermore, they also promote cell malignant transformation, tumor invasion, and metastasis by disrupting signal transduction in the normal cell-matrix, which can help tumors establish a barrier around them to prevent T cell infiltration and killing of tumor cells. Studies have shown that DDR1 can increase the invasive and migratory abilities of non-small cell lung cancer cells by promoting epithelial-mesenchymal transition; DDR1 can also inhibit the anti-tumor immune response by regulating T cells, CD4+, and CD8+, thereby promoting the growth of breast cancer (Zhong, X. Oncol Rep. 2019; 42(6):2844-2854); DDR1 can weaken the clearance of cancer cells by the immune system through its effect on the tumor microenvironment; DDR1 can make the extracellular matrix (ECM) highly ordered during tumor development, affecting the infiltration of immune cells and weakening their ability to kill tumor cells. Another study has shown that in a mouse model with DDR1 knockout, the infiltration of T cells in the tumor is improved and the growth of the tumor is inhibited. It can be inferred that DDR1 gene knockout or inhibition of DDR1 protein is a potential method to block the anti-immune surveillance ability of tumors. DDR1 may become a new target for tumor immunotherapy (Sun X, Nature, 2021, 599(7886):673-678). Preclinical studies have suggested that DDR1 inhibitors exhibit broad anti-tumor activity in mouse models of tumor xenografts derived from patients with non-small cell lung cancer, gastric cancer, esophageal cancer, liver cancer, breast cancer, and colorectal cancer.

[0008] In addition to their role in tumorigenesis, DDRs are also key mediators of the secretion of a variety of inflammatory cytokines and are dysregulated in a variety of inflammatory diseases, including osteoarthritis, organ fibrosis, atherosclerosis, etc. (Leitinger, B. Int. Rev. Cell Mol. Biol. 2014, 310, 39-87). DDR1 is also associated with fibrotic lesions in the liver, kidney, lung tissue, and blood vessels. Studies have confirmed that DDR1 not only directly stimulates the secretion of inflammatory factors but also enhances the effects of other pro-inflammatory cytokines and bacterial products (Matsuyama, W. J. Immunol. 2004, 172, 2332–2340). In various kidney disease models, inhibition of DDR expression can prevent inflammatory changes and fibrosis in the kidney. Experiments have confirmed that DDR1 deficiency can effectively reduce bleomycin-induced lung inflammation and pulmonary fibrosis (Avivi-Green, C. Am. J. Respir. Crit. Care Med. 2006, 174, 420–427). In a model of anti-glomerular basement membrane glomerulonephritis characterized by prominent inflammation and unilateral ureteral obstruction, it was found that inhibition of DDR1 expression could reduce the migration of inflammatory cells and impede fibrosis formation (Guerrot, D. Am. J. Pathol. 2011, 179, 83).

[0009] As unique members of the RTKs family, DDRs, especially DDR1, are closely associated with the occurrence and development of cancer, inflammation, fibrosis, and neurodegenerative diseases, and are regarded as potentially important targets for intervening in the treatment of these diseases. The regulation and inhibition of RTKs are usually achieved through small molecule inhibitors that antagonize the kinase activity within cells or antibody drugs that neutralize and interfere with the function of the extracellular domain. Similarly, DDR1 inhibitors can also be classified into monoclonal antibody types that act on the extracellular binding region and small molecule inhibitors that act on the intracellular kinase domain and affect downstream signaling pathways. The latter can be further divided into multi-target RTK inhibitors and selective DDR1 inhibitors. Because of the high homology in the structure of the kinase ATP-binding region among some members of the RTKs family, especially between DDRs and c-Kit, Bcr-Abl kinases, many RTK multi-target kinase inhibitors have certain DDR1 inhibitory activity. For example, multi-target inhibitors Imatinib, Dasatinib, and Nilotinib can inhibit collagen-induced DDR1 autophosphorylation. Currently, a variety of marketed Bcr-Abl inhibitors, such as Ponatinib, Bosutinib, and Bafetinib, exhibit strong DDR1 inhibitory activity. In addition, the p38 MAPK inhibitor Doramapimod, the B-Raf / VGFR dual-target inhibitor Sorafenib, and the c-Met / VEGFR-2 dual-target inhibitor Foretinib kinase inhibitor have a strong binding affinity for the DDR1 kinase domain. In recent years, a considerable number of highly selective DDR1 inhibitors rationally designed based on the three-dimensional molecular structure of DDR and small molecules have been discovered and developed, many of which have potential application prospects in tumors, neurodegenerative diseases, Alzheimer's disease, dry eye syndrome, inflammatory, and fibrotic diseases (William AD Biomolecules. 2021, 11(11): 1671). The parent nucleus structural types included in DDR1 small molecule inhibitors are urea, quinazoline, isoquinoline, tetrahydroisoquinoline, 1H-indole, spiroindoline, and triheterospirodecone, etc. (WO2017 / 038870, WO2016064970A1, WO2015060373A1, CN108276388A, WO2017137334A1, WO2017 / 038871).

[0010] Although the bioactivities of these DDR inhibitors have been confirmed by many experiments, like most other RTK inhibitors, these small molecule drugs rely on competitive occupation of the ATP-binding domain and long-term application can cause cell drug resistance. At the same time, RTKs have both kinase catalytic functions and non-catalytic functions in other domains. Simply relying on the competitive occupation of small molecule inhibitors cannot offset all the functions of RTKs. Therefore, it is urgently necessary to find means to more effectively regulate the functions of DDR1 and other RTKs.

[0011] In the past decade or so, great attention has been paid to the method of regulating the protein level in eukaryotic cells by the ubiquitin-proteasome system (UPS). The UPS negatively regulates signal functions by efficiently and specifically inducing protein degradation. It can degrade 80%-90% of the ubiquitinated proteins in cells. It plays an extremely important role in maintaining the levels of various proteins in cells and is involved in almost all life activities such as regulating the cell cycle, proliferation, apoptosis, metastasis, gene expression, and signal transduction. The ubiquitin protein composed of 76 amino acids is a highly conserved protein that is ubiquitous in eukaryotic cells. The ubiquitination of proteins initiates the degradation of substrate proteins, and this process is carried out under the coordinated action of ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and E3 ubiquitin ligase. First, ubiquitin is linked to E1 through the formation of a high-energy thioester bond between the carboxyl group on its C-terminal glycine and the essential cysteine thiol on ubiquitin activating enzyme E1, becoming activated ubiquitin; second, the activated ubiquitin is transferred from ubiquitin activating enzyme E1 to ubiquitin conjugating enzyme E2; finally, under the action of E3 ubiquitin ligase, the ubiquitin molecule linked to ubiquitin conjugating enzyme E2 is covalently linked to the substrate protein through an isopeptide bond. After the substrate protein is ubiquitinated, it can be transported to the 26S proteasome or enter the lysosome for digestion and degradation. The specific recognition ability of E3 ubiquitin ligase for substrate proteins determines the specificity of ubiquitin-mediated protein degradation.

[0012] The Proteolytic Targeting Chimera (PROTAC) technology utilizes the intracellular ubiquitin-proteasome system to degrade specific proteins. This technology constructs a bifunctional compound by linking a small molecule ligand that can bind to a specific target protein through a linker fragment and a ligand for an E3 ubiquitin ligase. By optimizing the linking position and the length of the linker, the ligands at both ends of the PROTAC molecule simultaneously bind to the target protein and the E3 ubiquitin ligase, forming a ternary complex of target protein-PROTACs-E3 ligase, which then promotes the ubiquitination labeling of the target protein and is subsequently degraded by the proteasome system. Due to the characteristics of the formation of the ternary complex, the target protein ligands used in the PROTAC technology do not need to have strong target binding activity, thus enabling targeting of target proteins that are not druggable by traditional inhibitors, such as scaffold proteins and transcription factors, etc.; additionally, since the overall degradation of the target protein helps to overcome the problem of drug resistance of small molecule inhibitors; the PROTAC molecule acts in a catalytic mechanism and cycles repeatedly. The degradation induced by PROTAC is event-driven rather than occupancy-driven. After forming the complex and completing ubiquitin transfer, the drug dissociates and transfers to the next target in an enzymatic manner. To a certain extent, it can achieve maintaining effective drug activity at a low dose. The technical difficulty of PROTAC lies in the relationship between target protein degradation and generation rate, the ability of the target protein to bind ubiquitin, the conformation and site of the connection of the target protein ligand and the E3 ubiquitin ligase ligand, the modification of the length and composition of the linker, and the concentration, etc., which have an impact on the formation and stability of the ternary complex, so it is more challenging to regulate. Among the known more than 600 E3 ubiquitin ligases, only a limited number are actually applied to the design of PROTAC compounds, including CRBN class, VHL class, MDM2 class, cIAP1 class. These E3 ubiquitin ligases confer substrate specificity to achieve ubiquitination of target proteins. The Von Hippel-Lindau (VHL) tumor suppressor in common E3 ubiquitin ligases consists of elongin B and C, Cul2, and Rbx1, and its main substrate is hypoxia-inducible factor 1 (HIF-1). For the ligand study of the E3 ubiquitin ligase VHL, the crystal structure of its complex was obtained, thus confirming that small molecule compounds can mimic the main substrate of the transcription factor HIF-1 (CN108601764A). During application, the binding of the ligand of VHL to the E3 ubiquitin ligase is relatively weak, which easily causes incomplete degradation of the target protein and leads to off-target effects. Another important E3 ligase, Cereblon (CRBN), is a protein encoded by the human CRBN gene. The CRBN homologous genes are highly conserved, indicating its importance in physiology. Cereblon forms an E3 ubiquitin ligase complex with damage-specific DNA-binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of Cullin-1 (ROC1).This complex can ubiquitinate a series of proteins. Considering the binding ability of the phthalimide structural unit to CRBN, this structural unit is often used as an E3 ligase recruitment ligand to hijack CRBN to degrade target proteins. So far, there are many experimental drugs developed using the PROTAC technology, including nuclear receptor degraders, kinase degraders, transcription factor degraders, etc. PROTACs targeting RTK can block kinase matrix signal transduction, prevent inactivated kinases from transmitting oncogene signals through their scaffold functions, and result in continuous loss of function of RTK. Existing RTK degraders can degrade kinases including wild-type or mutant EGFR, HER2, c-MET, etc. The present invention designs and develops degraders targeting tyrosine kinase receptors with unique structures, especially PROTAC degraders targeting DDR1. Such compounds can treat related diseases by degrading abnormal tyrosine kinase receptors, and thus have great clinical significance. Summary of the Invention

[0013] The first technical problem to be solved by the present invention is to provide a bifunctional compound for degrading receptor tyrosine kinases or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof. Such compounds regulate downstream key proteins and further play a role in treating related diseases by degrading specific receptor tyrosine kinases, especially discoidin domain receptors (DDRs), and show prominent ability to inhibit the proliferation of tumor cells;

[0014] The second technical problem to be solved by the present invention is to provide a preparation method and application of the bifunctional compound for degrading receptor tyrosine kinases.

[0015] To solve the above technical problems, a bifunctional compound of the present invention has a structure shown as X-L-Y, and the X, L, and Y parts are covalently connected; wherein,

[0016] The X part is a ligand that can bind to receptor tyrosine kinases, preferably a ligand that can bind to discoidin domain receptors (DDRs); more preferably a ligand that can bind to DDR1 in the discoidin domain receptor family;

[0017] The Y part is a ligand that can bind to E3 ubiquitin ligase, preferably a ligand that can bind to E3 ligase Cereblon (CRBN); more preferably a ligand that can bind to Von Hippel-Lindau tumor suppressor;

[0018] The L part is a linking group connecting the X part and the Y part.

[0019] Specifically, for the bifunctional compound, the X moiety is selected from the structures shown as X1-X6 below, where the wavy line indicates the position where the X moiety is covalently bonded to the L moiety;

[0020]

[0021] Among them,

[0022] the R 1 is selected from H, F or Cl;

[0023] the R 2 is selected from H, -OR 3 , -NHR 3 , F, Cl or Br;

[0024] Preferably, in the -NHR 3 , the R 3 is selected from H, C1-4 straight-chain or branched-chain alkyl, or C1-4 straight-chain or branched-chain alkyl in which any hydrogen atom is substituted by fluorine, or ArCO-; where the Ar is selected from H, halogen, C1-4 straight-chain or branched-chain alkyl, C1-4 straight-chain or branched-chain alkoxy, 5-8-membered aromatic ring group substituted by C1-4 straight-chain or branched-chain amino;

[0025] Preferably, the Ar is preferably phenyl substituted by H, halogen, C1-4 straight-chain or branched-chain alkyl, C1-4 straight-chain or branched-chain alkoxy or C1-4 straight-chain or branched-chain amino;

[0026] the R 6 is selected from H, F, Cl, OR 7 or NHR 7 ;

[0027] Preferably, in the NHR 7 , the R 7 is selected from H, C1-4 straight-chain or branched-chain alkyl;

[0028] the A 1 is selected from O or NH;

[0029] the A 2 is selected from N or CH;

[0030] the M 1 is selected from NR 3 , CH 2 , O, CO or Cy 1 ;

[0031] the M 2 is selected from NH, O, CO or Cy 1 ;

[0032] the Cy 1Selected from substituted or unsubstituted 4- to 7-membered carbocyclic heteromonocycles, substituted or unsubstituted 5- to 10-membered carbocyclic fused rings, substituted or unsubstituted 4- to 7-membered monocyclic alkyls, substituted or unsubstituted 5- to 10-membered fused alkyls, substituted or unsubstituted 7- to 10-membered bridged alkyls, or substituted or unsubstituted 5- to 8-membered aromatic ring groups;

[0033] Preferably, in the Cy 1 the substitution includes being optionally substituted by 0 to 3 substituents selected from H, F, Cl, OH, COOH, CN, NH 2 , carbonyl, C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, hydroxy-substituted C1-4 straight-chain or branched alkyl, or C1-4 alkoxy;

[0034] Preferably, in the Cy 1 the heteromonocycle and the heterofused ring contain 0 to 4 heteroatoms selected from O, S, and N; the aromatic ring group contains 0 to 3 heteroatoms selected from N, S, and O;

[0035] More preferably, the Cy 1 is selected from piperidine, piperazine, pyrimidine, pyrazine, pyridazine, benzene, pyrazole, imidazole, triazole, 2,2-difluoropiperidine, 2,2-difluoropiperazine, 2,2,3,3-tetrafluoropiperazine, 2,2,5,5-tetrafluoropiperazine, or 2,2,6,6-tetrafluoropiperazine.

[0036] Specifically, for the bifunctional compound, the Y part is a VHL ligand, and the Y part is selected from the structures shown in Y1 - Y3, where the asterisk (×) position indicates the position where the Y part is covalently bonded to the L part;

[0037]

[0038] wherein,

[0039] the R 4 is selected from H, C1-C5 straight-chain or branched alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl;

[0040] Preferably, the heterocycloalkyl contains 1 to 3 heteroatoms selected from O, N, and S;

[0041] Preferably, the R 4 is selected from isopropyl, tert-butyl, cyclohexyl, or tetrahydropyranyl;

[0042] The R 5 is selected from C1-C5 straight-chain or branched alkyl, C3-C6 substituted cycloalkyl;

[0043] Preferably, the R 5 is selected from methyl, ethyl, isopropyl, or 1-fluorocyclopropyl;

[0044] The said E 1 is selected from NH, NR 3 , CH 2 or Cy 2 ;

[0045] Preferably, the said Cy 2 is selected from a substituted or unsubstituted 4- to 7-membered carbocyclic monocyclic ring or a substituted or unsubstituted 5- to 8-membered aromatic ring group;

[0046] Preferably, the said aromatic ring group and carbocyclic monocyclic ring are substituted by 0 to 3 substituents selected from H, F, Cl, OH, COOH, CN, NH 2 , carbonyl, a C1-4 straight-chain or branched-chain alkyl group, a halogen-substituted C1-4 straight-chain or branched-chain alkyl group, a hydroxy-substituted C1-4 straight-chain or branched-chain alkyl group or a C1-4 alkoxy group;

[0047] Preferably, the said carbocyclic monocyclic ring contains 0 to 4 heteroatoms selected from O, S, N; the said aromatic ring group contains 0 to 3 heteroatoms selected from N, S, O;

[0048] Preferably, the said Cy 2 is selected from piperidine, piperazine, azetidine or 1,2,3-triazole;

[0049] The said E 2 is selected from O, NH, or Cy 3 ;

[0050] Preferably, the said Cy 3 is selected from a 4- to 7-membered carbocyclic monocyclic ring;

[0051] Preferably, the said Cy 3 is selected from piperidine, piperazine or azetidine.

[0052] Specifically, for the said bifunctional compound, the Y moiety is a ligand of the E3 ligase Cereblon (CRBN), and the Y moiety is selected from piperidine-2,6-dione compounds, thalidomide or its derivatives, lenalidomide or its derivatives, pomalidomide or its derivatives.

[0053] Specifically, for the said bifunctional compound, the Y moiety has the structures shown in Y4 - Y8 below, where the asterisk (×) position indicates the position where the Y moiety is covalently bonded to the L moiety;

[0054]

[0055] Among them,

[0056] Among them D 1 、D 2 、D 3, D 4 Independently selected from 0 to 2 N, CH or CR 6 ;

[0057] Preferably, said D 1 , D 2 , D 3 , D 4 Are independently CH or CR 6 ; or, when said D 1 , D 2 , D 3 or D 4 At least one of them is CH or CR 6 When, the remaining said D 1 , D 2 , D 3 or D 4 At least one of them is N;

[0058] Specifically, for example, when said D 1 Is CH or CR 6 When, said D 2 , D 3 , D 4 At least one of them is N; or, when said D 2 Is CH or CR 6 When, said D 2 , D 3 , D 4 At least one of them is N; or, when D 3 Is CH or CR 6 When, said D 1 , D 2 , D 4 At least one of them is N; or, when D 4 Is CH or CR 6 When, said D 1 , D 2 , D 3 At least one of them is N;

[0059] Said D 5 Is selected from -(CH 2 )q-, -CF 2 , CO, -W 1 W 2 - or -W 1 W 2 W 3 -; where q is arbitrarily selected from natural numbers 0 - 5; said W 1 , W 2 or W 3independently selected from CR 7 R 8 、N, NH, CO or CF 2 ; wherein said W 1 is connected to W 2 , W 2 is connected to W 3 respectively independently by a covalent single bond or double bond; said R 7 or R 8 are independently selected from H or a C1-4 straight or branched alkyl group;

[0060] said D 6 is selected from CH 2 , CO or is a covalent bond;

[0061] said D 11 is selected from NR 7 or is a covalent bond;

[0062] Specifically, D 6 and D 11 can both be absent, that is, they are directly connected by a covalent bond at the same time;

[0063] said D 12 is selected from CH or N; when D 12 is CH, its configuration can be R or S;

[0064] In said Y8, at least one of said D 7 , D 8 , D 9 , D 10 is N or a covalent bond, and the rest are independently selected from N, O, S or CH 2 ;

[0065] said E 3 , R 6 are independently connected to D 1 , D 2 , D 3 or D 4 by a covalent bond, and the D 1 , D 2 , D 3 or D 4 at the connection site is CH or CR 6 C;

[0066] Preferably, said E 3 is selected from NH, CH 2 , CF 2 , O, -CH=CH-, -C≡C-, -Cy 4 or Cy 4 -Cy 5 ;

[0067] Preferably, the R 6 is selected from H, F, Cl, OR 7 or NHR 7 ;

[0068] The Cy 4 is selected from 4- to 7-membered carbocyclic monocycles, 5- to 10-membered carbocyclic fused rings, 4- to 7-membered monocyclic alkyl groups, 5- to 10-membered fused ring alkyl groups, 7- to 10-membered bridged ring alkyl groups or 5- to 8-membered aromatic ring groups;

[0069] Preferably, the aromatic ring group, monocyclic alkyl group, carbocyclic monocycle, carbocyclic fused ring are optionally substituted with 0 to 3 substituents selected from H, F, Cl, OH, COOH, CN, NH 2 , carbonyl, C1-4 straight or branched chain alkyl groups, halogen-substituted C1-4 straight or branched chain alkyl groups, hydroxy-substituted C1-4 straight or branched chain alkyl groups or C1-4 alkoxy groups;

[0070] Preferably, the heterocyclic monocycles, heterocyclic fused rings contain 0 to 4 heteroatoms selected from O, S, N; the aromatic ring group contains 0 to 3 heteroatoms selected from N, S, O;

[0071] Preferably, the Cy 4 is selected from optionally substituted piperidine, piperazine or azetidine;

[0072] The Cy 5 is connected to Cy 4 by a covalent bond; its structure is selected from 4- to 7-membered carbocyclic monocycles, 5- to 10-membered carbocyclic fused rings, 4- to 7-membered monocyclic alkyl groups, 5- to 10-membered fused ring alkyl groups, 7- to 10-membered bridged ring alkyl groups or 5- to 8-membered aromatic ring groups;

[0073] Preferably, the aromatic ring group, monocyclic alkyl group, carbocyclic monocycle, carbocyclic fused ring are optionally substituted with 0 to 3 substituents selected from H, F, Cl, OH, COOH, CN, NH 2 , carbonyl, C1-4 straight or branched chain alkyl groups, halogen-substituted C1-4 straight or branched chain alkyl groups, hydroxy-substituted C1-4 straight or branched chain alkyl groups or C1-4 alkoxy groups;

[0074] Preferably, the heterocyclic monocycles, heterocyclic fused rings contain 0 to 4 heteroatoms selected from O, S, N; the aromatic ring group contains 0 to 3 heteroatoms selected from N, S, O;

[0075] Preferably, the Cy5 is selected from optionally substituted azetidine, piperidine or piperazine.

[0076] Specifically, for the bifunctional compound, the L part is a covalent bond directly connecting the X part and the Y part;

[0077] Or,

[0078] The L part is selected from -O-, -C=O, -OCO-, -CH 2 (CH 2 ) n CO-, -CH 2 (CH 2 ) n -, -CONHCH 2 (CH 2 ) n CO-, -COCH 2 (CH 2 ) n CO-, -O(CH 2 ) n -, -O(CH 2 ) n CO-, -O(CH 2 ) n NH-, -NH(CH 2 ) n CO-, -CH 2 CH 2 N(R 3 )CO-, -CH 2 OCH 2 CO-, -CH 2 Ar 1 CO-, where the Ar 1 is selected from a benzene ring, a thiophene ring or 1H-pyrrole; n is optionally a natural number from 0 to 14;

[0079] Or,

[0080] The L part is selected from the structures shown below, where the wavy line indicates the position of covalent bonding of the L part to the X part, and the asterisk (×) position indicates the position of covalent bonding to the Y part;

[0081]

[0082]

[0083]

[0084] Wherein,

[0085] The T 1 is selected from O, CH 2 or CO;

[0086] The T 2 is selected from O, CH 2 , CF 2 , NH or CO;

[0087] The T3 , T 7 are each independently selected from N, CH;

[0088] Said T 4 is selected from CH 2 or CO;

[0089] Said T 5 , T 6 are each independently selected from CH 2 , CF 2 or CO;

[0090] Said T 8 is selected from O, CH 2 , CF 2 , NH or CO;

[0091] Said T 9 is selected from O, NH or CH 2 ;

[0092] Said Ar 2 is selected from phenyl, imidazolyl or pyrazolyl;

[0093] Said R 8 is selected from H, C1-4 straight-chain or branched-chain alkyl;

[0094] m is arbitrarily selected from natural numbers 0-2, n is arbitrarily selected from natural numbers 0-12, p is arbitrarily selected from natural numbers 1-6, q is arbitrarily selected from natural numbers 0-5, r is arbitrarily selected from natural numbers 0-3.

[0095] Specifically, for the said bifunctional compound, the compound is selected from any one of the structures in Table 1 below.

[0096] Table 1 Compound Structures

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127] The present invention also discloses a pharmaceutical composition for degrading receptor tyrosine kinase, comprising the bifunctional compound or a pharmaceutically acceptable salt, stereoisomer, enantiomer, solvate, polymorph, isotope-labeled compound or prodrug thereof.

[0128] Specifically, compounds containing chiral centers in the compound form different stereoconfigurations and can thus exist in more than one stereoisomeric form. The stereoisomers involved in the present invention exist in optically pure form, such as greater than 95% ee, or in the form of a mixture thereof, including racemic mixtures. These optically pure isomers can be prepared by starting asymmetric synthesis with optically pure starting materials or by chiral resolution.

[0129] Specifically, for the pharmaceutical composition, the pharmaceutical composition further comprises at least one bioactive agent;

[0130] Preferably, the bioactive agent comprises at least one of an anticancer agent, an immunomodulator, an immune checkpoint inhibitor, a kinase inhibitor or an anti-inflammatory agent.

[0131] The present invention also discloses a method for preparing a pharmaceutical composition of the compound or its pharmaceutically acceptable salt, stereoisomer, enantiomer, solvate, polymorph, isotopically labeled compound or prodrug, which can be completed in the traditional manner of the prior art.

[0132] The present invention also discloses the use of the bifunctional compound or the pharmaceutical composition for preparing a preparation for degrading or inhibiting receptor tyrosine kinase.

[0133] Specifically, the receptor tyrosine kinase comprises wild-type or locally variant discoidin domain receptor (DDR), especially DDR1 and / or DDR2.

[0134] The present invention also discloses the use of the bifunctional compound or the pharmaceutical composition for preparing a drug for preventing, diagnosing or treating receptor tyrosine kinase (RTK)-related diseases or disorders.

[0135] Specifically, the receptor tyrosine kinase (RTK)-related diseases or disorders include cancers, immune-related diseases, fibrotic diseases, neurodegenerative diseases or inflammatory diseases related to abnormal expression of DDR1 or DDR2.

[0136] Specifically, the abnormal expression is overexpression or hyperactivity.

[0137] Specifically, the cancers include gastric cancer, intestinal cancer, esophageal cancer, head and neck cancer, lung cancer, liver cancer, brain cancer, breast cancer, colorectal cancer, skin cancer, thyroid cancer, prostate cancer, soft tissue cancer, endometrial cancer, uterine cancer, testicular cancer, cervical cancer, ovarian cancer, fallopian tube tumor, leukemia, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, renal cell carcinoma, bladder cancer, kidney cancer, pancreatic cancer, lymphoma, non-Hodgkin's lymphoma, melanoma, myeloproliferative disease, sarcoma, angiosarcoma, peripheral neuroepithelioma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma or schwannoma.

[0138] Specifically, the inflammatory and immune-related diseases include rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, axial spondyloarthritis, psoriasis, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, recurrent aphthous ulcer, Kawasaki disease, spondyloarthritis, neuromyelitis optica, Behcet's disease, lupus nephritis, familial Mediterranean fever, ulcerative colitis, autoimmune hepatitis, asthma, arteriosclerosis or Crohn's disease, etc.

[0139] Specifically, the neurodegenerative diseases include Alzheimer's disease, amyotrophic lateral sclerosis, ataxia-telangiectasia, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's chorea, cerebellar atrophy, multiple sclerosis, Parkinson's disease, primary lateral sclerosis, spinal muscular atrophy, cerebral ischemia, spastic paraplegia or myasthenia gravis.

[0140] For the pharmaceutical preparation of the present invention, the addition of the bifunctional compound as an active ingredient, or a bifunctional compound with a desired structure can also be selected as the sole active ingredient.

[0141] For the pharmaceutical preparation of the present invention, a preparation type suitable for oral administration, injection administration or inhalation administration can be selected. For those skilled in the art, the following dosage forms can contain the active ingredient to prepare the required pharmaceutical preparation.

[0142] To prepare a suitable pharmaceutical preparation of the present invention, a pharmaceutically acceptable carrier can be solid or liquid. Solid forms of the preparation include powders, tablets, pills, capsules, cachets, and dispersible granules. The solid carrier can be one or more substances that also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrants, or encapsulating materials.

[0143] In the powder, the carrier is a finely divided solid, which is mixed with the finely divided active ingredient.

[0144] In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in a suitable proportion and compressed into the desired shape and size. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, waxes of low melting point, cocoa butter, and the like.

[0145] Liquid preparations include solutions, suspensions, and emulsions, for example, aqueous solutions or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions of water-polyethylene glycol.

[0146] Thus, the medicaments for use in the present invention can be formulated in total for parenteral administration (such as injection, such as rapid bolus injection or continuous infusion), and can be present in the form of unit doses together with added preservatives in ampoules, pre-filled syringes, small-volume infusion bags or multi-dose containers. The composition can take the form of a suspension, solution or emulsion in an oily or aqueous carrier, and can contain formulation ingredients such as suspending agents, stabilizers and / or dispersing agents. Additionally, the active ingredient can be in the form of a powder, which can be obtained by sterile solid aseptic separation or by freeze-drying from a solution, for reconstitution with a suitable carrier such as sterile, pyrogen-free water shortly before use.

[0147] An aqueous solution suitable for oral administration can be prepared by dissolving the active ingredient in water and adding the required coloring agents, flavoring agents, stabilizers and thickening agents.

[0148] An aqueous suspension suitable for oral administration can be prepared by dispersing the subdivided active ingredient in water containing a viscous substance such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

[0149] Also included are solid preparations designed to be converted shortly before use into liquid preparations for oral administration. Such liquid preparations include solutions, suspensions, and emulsions. In addition to the active ingredient, such preparations can contain coloring agents, flavoring agents, stabilizers, buffering agents, artificial and natural sweeteners, dispersing thickening agents, solubilizing agents, and the like.

[0150] Administration to the respiratory tract can also be achieved by an aerosol, wherein the active ingredient is contained in a pressurized package together with a suitable propellant. Suitable propellants include chlorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gases. The aerosol can also suitably contain a surfactant such as lecithin. The dose of the medicament can be controlled by a metering valve.

[0151] Alternatively, the active ingredient may be in the form of a dry powder, for example, a powder mixture of the compound with a suitable powder matrix such as lactose, starch, starch derivatives such as hydroxypropyl methylcellulose, and polyvinylpyrrolidone (PVP). The powder carrier can conveniently form a gel in the nasal cavity. The powder composition may be in unit dose form, for example, in capsules or cartridges (such as gelatin capsules or cartridges), or in blister packs from which the powder can be administered via an inhaler.

[0152] As an alternative, when needed, a composition suitable for sustained release of the active ingredient can be applied.

[0153] In the therapeutic use of the pharmaceutical preparation, the daily dose of the compound can be according to the conventional dose. These doses can vary according to the needs of the patient, the severity of the disease being treated, and the compound used. Generally, treatment is started with a smaller dose less than the optimal dose of the compound, and thereafter, this dose is increased in small amounts to achieve the best effect. For convenience, if necessary, the total daily dose can be further subdivided into multiple administrations within a day.

[0154] The PROTAC compounds developed in the present invention have novel structures, excellent biological activities, and can safely and effectively inhibit or degrade DDR1. The compounds can effectively degrade or inhibit receptor tyrosine kinases, especially DDR1 and / or DDR2, and can be used to treat diseases related to the imbalance of DDR1 and other RTK homeostasis. The present invention further recruits the receptor tyrosine kinase target protein to a specific E3 ligase and completes ubiquitination labeling and degradation, and can be used to prepare drugs for preventing, diagnosing, or treating receptor tyrosine kinase (RTK)-related diseases or disorders. BRIEF DESCRIPTION OF THE DRAWINGS

[0155] In order to make the content of the present invention easier to be clearly understood, the following further describes the present invention in detail according to the specific embodiments of the present invention and in combination with the drawings, wherein,

[0156] Figure 1 shows the inhibitory effects of different compounds of the present invention on MKN45 tumor cells;

[0157] Figure 2 shows the inhibitory effects of different compounds of the present invention on SNU5 tumor cells;

[0158] Figure 3 shows the immunoblot experiment of the degradation activity of different compounds of the present invention on DDR1 in tumor cells MKN45;

[0159] Figure 4 shows the measurement of the degradation activity of different compounds of the present invention on DDR1 in tumor cells MKN45;

[0160] Figure 5Growth inhibition curve of the representative compound TPD12140 of the present invention on subcutaneous transplanted tumors in mice and body weight change curve;

[0161] Figure 6 Research results on the mechanism of degradation of the target protein DDR1 by the representative compound TPD12140 of the present invention. Detailed implementation manners

[0162] The present invention will be further described below in conjunction with the examples and their accompanying drawings. These examples are only for more detailed specific descriptions and should not be construed as limiting the present invention in any form. The present invention can be implemented in many different ways defined and covered by the claims.

[0163] Although many of the materials and operating methods used in the present invention are well known in the art, the present invention is still described in as much detail as possible herein. In the following text, unless otherwise specified, the materials and operating methods used are well known in the art. Unless otherwise defined, all terms (including technical terms and scientific terms) used in the present invention have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention pertains. The target compounds of the present invention were synthesized using the methods shown in the reaction flowcharts. The products were confirmed for their structures and purities by nuclear magnetic resonance, mass spectrometry, and liquid chromatography. Unless otherwise specified, the starting materials used to prepare the compounds of the present invention by the synthetic methods were obtained from commercial sources or could be prepared according to known methods in the art or described herein.

[0164] General synthesis of compounds: In view of the present disclosure or by the illustrative methods shown in the following general schemes, the compounds of the present disclosure were prepared using methods known to those skilled in the art. If desired, suitable protecting groups can be used in the synthesis in any of the general schemes. It should be understood that the embodiments and examples are not intended to limit the scope of the present disclosure, and the claims presented herein are intended to cover all embodiments and examples, whether or not explicitly presented herein.

[0165] Example 1: Synthesis of compound TPD005305

[0166] This example is used to prepare the synthetic compound TPD005305, and the specific synthetic route is as follows:

[0167]

[0168] Compound 1 (20 g, 139 mol) was added to a 250 mL single-necked flask, and triethyl orthoformate (70 mL) was added. The temperature was raised to 100 °C and stirred for 2 hours. The reaction solution was cooled to room temperature, methyl tert-butyl ether was added and filtered, and the filter cake was washed with methyl tert-butyl ether and dried to obtain compound 2 (23 g, yellow solid). The calculated yield was 82.7%.

[0169] Add compound 2 (5 g, 25 mmol), methyl 5-amino-2-methoxybenzoate (4.5 g, 25 mmol) and isopropanol (50 mL) into a 100 mL single-necked flask, and stir at room temperature for 3 hours. Filter the reaction solution, wash the filter cake with methyl tert-butyl ether, and dry to obtain compound 3 (8 g, yellow solid). Calculate the yield: 95%.

[0170] Add diphenyl ether (80 mL) into a 100 mL single-necked flask, and heat up to 240 °C. Add compound 3 (8 g, 23.9 mmol) in portions, stir for 30 minutes. Let the reaction solution cool to room temperature, add methyl tert-butyl ether and filter. Wash the filter cake with methyl tert-butyl ether and dry to obtain the crude product of compound 4 (4.5 g, brown solid).

[0171] Add phosphorus oxychloride (50 mL) and compound 4 (4.5 g, crude) into a 100 mL single-necked flask, heat up to 100 °C and stir for 2 hours. Let the reaction solution cool to room temperature, and concentrate to remove phosphorus oxychloride. Add methyl tert-butyl ether and filter. Wash the filter cake with methyl tert-butyl ether and dry to obtain compound 5 (1 g, brown solid). Calculate the yield: 16.7% in two steps.

[0172] Add compound 6 (2 g, 6.4 mmol), compound 5 (1.6 g, 6.4 mmol), cesium carbonate (4.2 g, 12.7 mmol) and N,N-dimethylformamide (20 mL) into a 100 mL single-necked flask, heat up to 100 °C and stir overnight. Let the reaction solution cool to room temperature, pour it into water, extract with ethyl acetate (30 mL × 3). Wash the organic phase, dry and concentrate. Purify the crude product by column chromatography to obtain compound 7 (1 g, yellow solid). Calculate the yield: 29.8%.

[0173] Add lithium aluminum hydride (144 mg, 3.8 mmol) and anhydrous tetrahydrofuran (10 mL) into a 100 mL three-necked flask. Under nitrogen protection, add a tetrahydrofuran solution (5 mL) of compound 7 (1 g, 1.9 mmol) dropwise at 0 °C. After the addition is complete, stir at room temperature for 1 hour. Quench the reaction solution with sodium sulfate decahydrate and filter. Wash the filter cake with dichloromethane:methanol (20:1), and concentrate the filtrate to obtain compound 8 (500 mg, yellow solid). Calculate the yield: 52.6%.

[0174] In a 50 mL three-necked flask, add compound 8 (500 mg, 1 mmol), N,N-dimethylformamide (10 mL), and sodium hydride (200 mg, 5 mmol) under nitrogen protection. Stir at room temperature for 30 minutes, and then add 2-(2-bromoethoxy)tetrahydro-2H-pyran (250 mg, 1.2 mmol). Stir overnight at room temperature. Pour the reaction mixture into ammonium chloride solution to quench the reaction, extract with dichloromethane (20 mL × 3), dry and concentrate the organic phase to obtain compound 9 (230 mg, yellow solid). Calculate the yield: 36.6%.

[0175] In a 50 mL single-necked flask, add compound 9 (1.2 g, 1.9 mmol), methanol (10 mL), and 2N hydrochloric acid (10 mL). Stir at room temperature for 2 hours. Pour the reaction mixture into water, adjust the pH to 7 - 8 with sodium carbonate solution, filter, and dry the filter cake to obtain compound 10 (700 mg, yellow solid). Calculate the yield: 90%.

[0176] In a 100 mL three-necked flask, add compound 10 (400 mg, 0.73 mmol), triethylamine (148 mg, 1.5 mmol), and dichloromethane (10 mL). Dropwise add methanesulfonyl chloride (126 mg, 1.1 mmol) at 0 °C. After addition, stir at room temperature for 2 hours. Pour the reaction mixture into water, extract with ethyl acetate (10 mL × 3), dry and concentrate the organic phase to obtain the crude product of compound core 1 (400 mg, yellow liquid).

[0177] Take a solution of compound 11 (15 g, 74.6 mmol), ethyl acrylate (8.96 g, 89.6 mmol), and potassium tert-butoxide (12.5 g, 112 mmol) in tetrahydrofuran (150 mL). Stir at room temperature overnight. Quench the reaction mixture with 1N HCl (100 mL), and extract with ethyl acetate (50 mL × 2). Wash the combined organic phase with water (50 mL), dry over anhydrous sodium sulfate, and purify by column chromatography to obtain compound 12 (6.5 g, 30%).

[0178] Add sodium hydroxide (1.8 g, 45.3 mmol) to a methanol solution (60 mL) of compound 12 (6.5 g, 22.6 mmol). Stir at room temperature overnight. Rotavaporize the reaction mixture, dilute with water, adjust the pH to 6 with 1N hydrochloric acid, and extract with ethyl acetate (30 mL × 3). Dry the combined organic phase over anhydrous sodium sulfate and rotavaporize to obtain compound 13 (2 g, 32%).

[0179] In a 100 mL single-necked flask, compound 13 (150 mg, 0.55 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (257 mg, 0.55 mmol), 1-hydroxybenzotriazole (111.4 mg, 0.82 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (158 mg, 0.82 mmol), N,N-diisopropylethylamine (248 mg, 1.9 mmol), and dichloromethane (5 mL) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was washed with water, dried, and concentrated. The crude product was purified by preparative plate to obtain compound 14 (230 mg, yellow solid), and the calculated yield was 61.2%.

[0180] In a 100 mL single-necked flask, compound 14 (230 mg, 0.34 mmol), hydrochloric acid / ethyl acetate (2N, 5 mL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to obtain compound 15 (200 mg, yellow solid), and the calculated yield was 96%.

[0181] In a 100 mL single-necked flask, compound 15 (200 mg, 0.32 mmol), core 1 (200 mg, 0.32 mmol), sodium iodide (97 mg, 0.64 mmol), potassium carbonate (89 mg, 0.64 mmol), and N,N-dimethylformamide (10 mL) were added, and the mixture was stirred at 80 °C for 3 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate (10 ml × 3). The organic phase was washed with water, dried, and concentrated. The crude product was purified by high-pressure preparation to obtain compound TPD005305 (50 mg, yellow solid), and the calculated yield was 14%. LCMS (ESI) m / z calcd. for C60H69FN8O10S [M+H] + 1112.5; found 1112.7. It can be seen that the compound structure is correct.

[0182] Example 2: Synthesis of compound TPD005313

[0183] This example is used to prepare and synthesize compound TPD005313, and the specific synthesis route is as follows:

[0184]

[0185] The compound core 1 (200 mg, 0.32 mmol), compound 2 (109.8 mg, 0.48 mmol), sodium iodide (97 mg, 0.64 mmol) and potassium carbonate (88.6 mg, 0.67 mmol) synthesized according to the method steps in Example 1 were stirred in a solution of DMF (5 ml) at 100 °C overnight. After the reaction was completed, the reaction solution was added to ice water (20 ml), extracted with EA (10 ml × 2), the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude compound 3 as a yellow solid (200 mg, yield 82.6%).

[0186] Compound 3 (200 mg, 0.26 mmol) was dissolved in DCM (5 ml), TFA (5 ml) was added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was rotary evaporated to obtain the yellow solid of compound 4 (160 mg, yield 92.4%).

[0187] Compound 4 (80 mg, 0.12 mmol) and compound 4-1 (40.4 mg, 0.15 mmol) were dissolved in NMP (5 ml), DIEA (31 mg, 0.24 mmol) was added at room temperature, and the reaction solution was reacted at 100 °C overnight. The reaction solution was prepared by high pressure to obtain the yellow solid of compound TPD005313 (4 mg, yield 3.6%). LCMS (ESI) m / z calcd. for C50H51FN7O9 [M+H] + 912.4; found 912.5. It can be seen that the compound structure is correct.

[0188] Example 3: Synthesis of compound TPD005315

[0189] This example is used to prepare and synthesize compound TPD005315, and the specific synthesis route is as follows:

[0190]

[0191] Compound 1 (10 g, 42.2 mmol), benzyl 4-hydroxypiperidine-1-carboxylate (10 g, 42.2 mmol) and potassium carbonate

[0192] (12.5 g, 90.9 mmol) were dissolved in DMF (100 ml) and stirred at 50 °C overnight. After the reaction was completed, the reaction solution was added to ice water (200 ml), extracted with EA (100 ml × 2), the organic layer was dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography to obtain the yellow solid of compound 2 (6 g, yield 36.3%).

[0193] Compound 2 (6 g, 16.5 mmol) was dissolved in methanol, palladium on carbon (1 g) was added, and the mixture was stirred overnight at room temperature under 20 Psi of hydrogen. After filtration and evaporation of the solvent, a yellow solid of compound 3 (2.2 g, yield 55.7%) was obtained.

[0194] Compound Core1 (100 mg, 0.16 mmol) and compound 3 (62 mg, 0.24 mmol) were dissolved in DMF (2 ml), NaI (48 mg, 0.32 mmol) and potassium carbonate (44.3 mg, 0.32 mmol) were added, and the reaction was carried out overnight at 100 °C. After completion of the reaction, the reaction mixture was poured into water, extracted with EA (10 ml × 2), the organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and the solvent was evaporated to give a crude yellow solid of compound 4 (110 mg, yield 88%).

[0195] Compound 4 (110 mg, 0.14 mmol) was dissolved in EA (2 ml), 4N HCl / EA (2 ml) was added, and the reaction was carried out at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated under vacuum and the product was prepared by high-pressure chromatography to give a yellow solid of compound 5 (10 mg, yield 10%).

[0196] Compound 5 (10 mg, 0.015 mmol) and compound 5-1 (5 mg, 0.018 mmol) were dissolved in NMP (2 ml), DIEA (4 mg, 0.03 mmol) was added at room temperature, and the reaction mixture was stirred overnight at 100 °C. The reaction mixture was prepared by high-pressure chromatography to give a yellow solid of compound TPD005315 (1 mg, yield 7.3%). LCMS (ESI) m / z calcd.for C51H53FN7O10

[0197] [M+H] + 942.4; found 942.5. It can be seen that the structure of the compound is correct.

[0198] Example 4: Synthesis of compound TPD005316

[0199] This example is used to prepare and synthesize compound TPD005316, and the specific synthesis route is as follows:

[0200]

[0201] Compound 1 (10 g, 45.4 mmol), tert-butyl (2-bromoethyl)carbamate (12.16 g, 54.5 mmol) and potassium carbonate (12.5 g, 90.9 mmol) were dissolved in DMF (100 ml), and stirred overnight at 50 °C. After the reaction was completed, the reaction solution was added to ice water (200 ml), and extracted with EA (100 ml × 2). The organic layer was dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography to obtain compound 2 as a yellow solid (6 g, yield 36.3%).

[0202] Compound 2 (6 g, 16.5 mmol) was dissolved in methanol, palladium on carbon (1 g) was added, and the reaction was carried out overnight at room temperature under 20 Psi of hydrogen. After filtration and evaporation, a yellow solid of compound 3 was obtained (2.2 g, yield 59.4%).

[0203] Compound Core1 (100 mg, 0.16 mmol) prepared in Example 1 and compound 3 (62 mg, 0.24 mmol) were dissolved in DMF (2 ml), NaI (48 mg, 0.32 mmol) and potassium carbonate (44.3 mg, 0.32 mmol) were added, and the reaction was carried out overnight at 100 °C. After the reaction was completed, the reaction solution was poured into water, and extracted with EA (10 ml × 2). The organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain a crude yellow solid of compound 4 (102 mg, yield 84.2%).

[0204] Compound 4 (102 mg, 0.13 mmol) was dissolved in EA (2 ml), 4N HCl / EA (2 ml) was added, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated under vacuum to obtain a yellow solid of compound 5 (80 mg, yield 90%).

[0205] Compound 5 (80 mg, 0.12 mmol) and compound 4-1 (40.4 mg, 0.14 mmol) were dissolved in NMP (2 ml), DIEA (31 mg, 0.24 mmol) was added at room temperature, and the reaction solution was reacted overnight at 100 °C. The reaction solution was prepared by high pressure to obtain a yellow solid of compound TPD005316 (2 mg, yield 1.8%). LCMS (ESI) m / z calcd.for C49H50FN8O9[M+H] + 913.4; found 913.3. It can be seen that the compound structure is correct.

[0206] Example 5: Synthesis of compound TPD005317

[0207] This example is used to prepare and synthesize compound TPD005317, and the specific synthesis route is as follows:

[0208]

[0209] Compound 1 (450 mg, 1.63 mmol), tert-butyl glycinate (256.3 mg, 1.96 mmol) and DIEA (420.6 mg, 3.26 mmol) were stirred in DMF (10 ml) at 100 °C overnight. After completion of the reaction, the reaction mixture was added to ice water (30 ml), and extracted with EA (20 ml × 2). The organic layer was dried with Na 2 SO 4 dried and concentrated to obtain crude yellow solid compound 2 (610 mg, yield 101.3%).

[0210] Compound 2 (300 mg, 0.78 mmol) was dissolved in DCM (5 ml), TFA (5 ml) was added, and the reaction was carried out at room temperature for 2 hours. The reaction mixture was rotary evaporated to obtain a yellow solid of compound 3 (280 mg, crude).

[0211] The aforementioned compound Core1 (100 mg, 0.16 mmol) and N-BOC-piperazine (59.7 mg, 0.32 mmol) were dissolved in DMF (5 ml), NaI (48 mg, 0.32 mmol) and potassium carbonate (44.3 mg, 0.32 mmol) were added, and the reaction was carried out at 80 °C overnight. After completion of the reaction, the reaction mixture was poured into water and extracted with EA (10 ml × 2). The organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, rotary evaporated to dryness with DCM:MeOH = 10:1, and purified by preparative plate to obtain a yellow solid of compound 4 (54 mg, yield 47.3%).

[0212] Compound 4 (54 mg, 0.75 mmol) was dissolved in (2 ml) DCM, TFA (0.4 ml) was added, and the reaction was carried out at room temperature for 1 hour. After completion of the reaction, the solvent was rotary evaporated under vacuum to obtain a yellow solid of compound 5 (80 mg, yield 90%).

[0213] Compound 5 (80 mg, 0.13 mmol) and compound 3 (66 mg, 0.2 mmol) were dissolved in DMF (2 ml), HATU (76 mg, 0.2 mmol) and TEA (26 mg, 0.26 mmol) were added at room temperature, and the reaction mixture was reacted at 100 °C overnight. The reaction mixture was prepared by high pressure to obtain a yellow solid of compound TPD005317 (17 mg, yield 14.1%). LCMS (ESI) m / z calcd.for C49H48FN8O10 [M+H] + 927.3; found 927.2. It can be seen that the compound structure is correct.

[0214] Example 6: Synthesis of Compound TPD005401

[0215] This example is used to prepare the synthetic compound TPD005401, and the specific synthetic route is as follows:

[0216]

[0217] In a 250 ml three-necked flask, compound 1 (10.0 g, 0.05 mol), 4-aminophenol (7.33 g, 0.07 mol) and N,N-dimethylformamide (100 ml) were added. After dissolution, N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (25.5 g, 0.07 mol) and N,N-diisopropylethylamine (17.3 g, 0.13 mol) were added, and the mixture was stirred at room temperature overnight. The reaction was quenched with water, and the mixture was extracted with ethyl acetate three times. The combined organic phase was washed with water three times, once with saturated brine, dried over sodium sulfate, and concentrated by rotary evaporation. The crude product was triturated with dichloromethane, filtered, and the filter cake was dried to obtain compound 2 (9.00 g, white solid) with a yield of 64.3%.

[0218] In a 250 ml single-necked flask, compound 2 (10.0 g, 0.03 mol), 7-benzyloxy-4-chloro-6-methoxyquinoline 5-amino-2-methoxybenzoate (8.70 g, 0.03 mol), cesium carbonate (21.0 g, 0.06 mol) and dimethyl sulfoxide (100 ml) were added. The reaction mixture was stirred at 120 °C overnight, quenched with water, extracted with ethyl acetate three times, washed once with water, once with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. The crude product was purified by column chromatography using petroleum ether / ethyl acetate (1:1) and dichloromethane / methanol (20:1 - 10:1) to obtain compound 3 (10 g, brown solid) with a yield of 48.3%.

[0219] In a 250 ml hydrogenation flask, compound 3 (8.00 g, 0.013 mol), palladium on carbon (3.00 g), tetrahydrofuran (40 ml) and methanol (40 ml) were added. The air was displaced with hydrogen three times, and the mixture was stirred at 40 °C overnight under a hydrogen atmosphere of 20 Psi. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated by rotary evaporation to obtain compound 4 (6.00 g, yellow solid) with a yield of 88.9%.

[0220] In a 250 ml three-necked flask, compound 4 (7.00 g, 0.01 mol), pyridine (14.0 g, 0.18 mol), dichloromethane (35 ml) and tetrahydrofuran (35 ml) were added. Trifluoromethanesulfonic anhydride (26.0 g, 0.09 mol) was added dropwise at 0 °C, and the mixture was stirred at room temperature overnight. The reaction was quenched with water, and the mixture was extracted with dichloromethane three times. The combined organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. Purification by column chromatography (petroleum ether / ethyl acetate = 30:1 - 3:1) gave compound 5 (4.00 g, yellow solid) with a yield of 44.9%.

[0221] Compound 5 (100 mg, 0.16 mmol), 4-hydroxymethylpiperidine (40.0 mg, 0.35 mmol), tris(dibenzylideneacetone)dipalladium (30.0 mg, 0.03 mmol), 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (40.0 mg, 0.06 mmol), cesium carbonate (105 mg, 0.32 mmol) and 1,4-dioxane (10 ml) were added to a 20 ml reaction flask. The flask was purged with nitrogen and stirred at 100 °C overnight. The reaction was quenched by adding water, and the mixture was extracted with ethyl acetate three times. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 30:1 - 2:1) to give compound 6 (30.0 mg, yellow solid), yield: 31.8%.

[0222] Compound 6 (380 mg, 0.64 mmol), triethylamine (99.0 mg, 0.97 mmol), dichloromethane (5 ml) and methanesulfonyl chloride (89.0 mg, 0.78 mmol) were added to a 100 ml three-necked flask. The reaction mixture was stirred at 25 °C overnight. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane three times. The combined organic phases were washed once with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give compound core2 (320 mg, yellow solid), yield: 74.3%.

[0223] Compound core2 (200 mg, 0.30 mmol), tert-butyl 2-(piperidin-1-yl)acetate (723 mg, 0.36 mmol), potassium carbonate (83.0 mg, 0.60 mmol), sodium iodide (90.0 mg, 0.60 mmol) and N,N-dimethylformamide (20 ml) were added to a 100 ml single-necked flask. The reaction mixture was stirred at 100 °C overnight. The reaction was quenched by adding water, and the mixture was extracted with ethyl acetate three times. The combined organic phases were washed three times with water, once with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give compound 7 (200 mg, yellow solid), yield: 86.5%.

[0224] Compound 7 (400 mg, 0.52 mmol), dichloromethane (10 ml) and trifluoroacetic acid (2 ml) were added to a 100 ml single-necked flask. The reaction mixture was stirred at room temperature overnight, concentrated in vacuo, and triturated with methyl tert-butyl ether to give the crude compound 8 (400 mg, yellow solid).

[0225] In a 100 ml three-necked flask, compound 8 (500 mg, 0.70 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (492 mg, 1.05 mmol), and triethylamine (213 mg, 2.11 mmol) were added. It was dissolved in DCM (5 ml), 1-hydroxybenzotriazole (114 mg, 0.25 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (161 mg, 0.85 mmol) were added, and the mixture was stirred overnight at room temperature. The reaction was quenched with water, extracted 3 times with dichloromethane, the combined organic phases were washed 3 times with water, once with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by preparative HPLC to give compound TPD005401 (35 mg, yellow solid), yield: 4.7%. LCMS (ESI) m / z calcd. for C61H72FN10O8S [M+H] + 1122.5; found 1122.6. It can be seen that the structure of the compound is correct.

[0226] Example 7: Synthesis of compound TPD005402B

[0227] This example is used to prepare and synthesize compound TPD005402B, and the specific synthetic route is as follows:

[0228]

[0229] In a 100 ml single-necked flask, compound core2 (200 mg, 0.30 mmol) prepared according to the procedure in Example 6, tert-butyl piperidine-4-carboxylate (67.0 mg, 0.36 mmol), potassium carbonate (83.4 mg, 0.60 mmol), sodium iodide (90.0 mg, 0.60 mmol) and N,N-dimethylformamide (20 ml) were added. The reaction mixture was stirred at 80 °C overnight. The reaction was quenched with water, extracted 3 times with ethyl acetate, the combined organic phases were washed 3 times with water, once with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give compound 9 (100 mg, yellow solid), yield: 44.0%.

[0230] In a 100 ml single-necked flask, compound 9 (100 mg, 0.13 mmol), dichloromethane (10 ml) and trifluoroacetic acid (2 ml) were added. The reaction mixture was stirred at room temperature overnight, concentrated in vacuo, and triturated with methyl tert-butyl ether to give the crude product compound 10 (80 mg, yellow solid), yield: 92.3%.

[0231] In a 100 ml three-necked flask, compound 10 (95 mg, 0.15 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (102 mg, 0.22 mmol) and triethylamine (44.2 mg, 0.44 mmol) were added, dissolved in dichloromethane (10 ml). 1-Hydroxybenzotriazole (23.6 mg, 0.18 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (33.4 mg, 0.18 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction was quenched by adding water, and the mixture was extracted with dichloromethane three times. The combined organic phases were washed with water three times, once with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. The crude product was purified by preparative high pressure liquid chromatography to obtain compound TPD00542B (19 mg, yellow solid) with a yield of 11.7%. LCMS (ESI) m / z calcd. for C61H71FN9O8S [M+H] + 1107.5; found 1107.5. It can be seen that the structure of the compound is correct.

[0232] Example 8: Synthesis of compound TPD005406

[0233] This example is used to prepare and synthesize compound TPD005406. The specific synthesis route is as follows:

[0234]

[0235] A solution of compound 7 (10 g, 42.6 mmol), tert-butyl acrylate (8.17 g, 63.8 mmol) and potassium tert-butoxide (12.5 g, 112 mmol) in tetrahydrofuran (150 ml) was stirred at room temperature overnight. The reaction mixture was quenched with 1N HCl (100 ml) and extracted with ethyl acetate (50 ml × 2). The combined organic phases were washed with water (50 ml), dried over anhydrous sodium sulfate and purified by column chromatography to obtain compound 8 (5 g, 32.5%).

[0236] Palladium on carbon (1 g) was added to a methanol solution (50 ml) of compound 8 (5 g, 13.8 mmol), and the mixture was stirred at room temperature overnight in a hydrogen atmosphere (30 psi). The reaction mixture was filtered and concentrated by rotary evaporation to obtain compound 9 (1.5 g, 47.6%).

[0237] In a 100 ml single-necked flask, add compound core 2 (100 mg, 0.15 mmol), tert-butyl 3-(piperidine-4-yloxy)propionate (68.7 mg, 0.30 mmol), potassium carbonate (83.0 mg, 0.60 mmol), sodium iodide (90.0 mg, 0.60 mmol) and N,N-dimethylformamide (10 ml). Stir the reaction mixture at 100 °C overnight. Quench with water, extract 3 times with ethyl acetate, wash the combined organic phase 3 times with water, once with saturated brine, dry over anhydrous sodium sulfate, and concentrate in vacuo to obtain compound 10 (80 mg, yellow solid), yield: 66.7%.

[0238] In a 100 ml single-necked flask, add compound 7 (80 mg, 0.11 mmol), dichloromethane (10 ml) and trifluoroacetic acid (2 ml). Stir the reaction mixture at room temperature overnight, concentrate in vacuo, and triturate with methyl tert-butyl ether to obtain the crude compound 11 (50 mg, yellow solid).

[0239] In a 100 ml three-necked flask, add compound 11 (50 mg, 0.07 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (49 mg, 0.11 mmol) and triethylamine (21.3 mg, 0.2 mmol). Dissolve in DCM (2 ml), add 1-hydroxybenzotriazole (11.4 mg, 0.03 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (16.1 mg, 0.09 mmol), and stir at room temperature overnight. Quench with water, extract 3 times with dichloromethane, wash the combined organic phase 3 times with water, once with saturated brine, dry over anhydrous sodium sulfate, and concentrate in vacuo. Purify the crude product by preparative HPLC to obtain compound TPD005406 (10 mg, yellow solid), yield: 12.8%. LCMS (ESI) m / z calcd. for C63H75FN9O9S [M+H] + 1151.5;

[0240] found 1151.3. It can be seen that the structure of the compound is correct.

[0241] Example 9: Synthesis of compound TPD005407

[0242] This example is used to prepare and synthesize compound TPD005407. The specific synthesis route is as follows:

[0243]

[0244] To a solution of compound 12 (10 g, 42.6 mmol) in DMF (100 ml) was added NaH (3.8 g, 112 mmol) at 0 °C, and the mixture was stirred at room temperature for 1 h. A solution of tert-butyl bromoacetate (12.4 g, 63.8 mmol) in DMF (30 ml) was added to the above solution at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was quenched by pouring into ammonium chloride solution (500 ml), and extracted with ethyl acetate (500 ml × 2). The combined organic phases were washed with water (500 ml), dried over anhydrous sodium sulfate, and purified by column chromatography to give compound 8 (5 g, 33%).

[0245] To a solution of compound 13 (5 g, 13.8 mmol) in methanol (50 ml) was added palladium on carbon (1 g), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere (30 psi). The reaction mixture was filtered and concentrated in vacuo to give compound 14 (3 g, 80%).

[0246] Compound core 1 (100 mg, 0.15 mmol), tert-butyl 2-(piperidin-4-yloxy)acetate (64.5 mg, 0.30 mmol), potassium carbonate (83.0 mg, 0.60 mmol), sodium iodide (90.0 mg, 0.60 mmol) and N,N-dimethylformamide (10 ml) were added to a 100 ml single-necked flask. The reaction mixture was stirred at 100 °C overnight. The reaction was quenched by adding water, and extracted with ethyl acetate three times. The combined organic phases were washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, and concentrated in vacuo to give compound 15 (60 mg, yellow solid), yield: 50.8%.

[0247] Compound 7 (60 mg, 0.08 mmol), dichloromethane (10 ml) and trifluoroacetic acid (2 ml) were added to a 100 ml single-necked flask. The reaction mixture was stirred overnight at room temperature, concentrated in vacuo, and triturated with methyl tert-butyl ether to give crude compound 11 (40 mg, yellow solid).

[0248] In a 100 ml three-necked flask, compound 16 (50 mg, 0.06 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (49 mg, 0.11 mmol) and triethylamine (21.3 mg, 0.2 mmol) were added. It was dissolved with DCM (2 ml), 1-hydroxybenzotriazole (11.4 mg, 0.03 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (16.1 mg, 0.09 mmol) were added, and it was stirred overnight at room temperature. It was quenched with water, extracted 3 times with dichloromethane, the combined organic phase was washed 3 times with water, once with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. The crude product was purified by high-pressure preparation to obtain compound TPD005407 (10 mg, yellow solid), yield: 15.9%. LCMS (ESI) m / z calcd. for C62H73FN9O9S [M+H] + 1137.5; found 1137.3. It can be seen that the compound structure is correct.

[0249] Example 10: Synthesis of compound TPD005409

[0250] This example is used to prepare and synthesize compound TPD005409, and the specific synthesis route is as follows:

[0251]

[0252] Compound 5 (200 mg, 0.32 mmol), tert-butyl piperidine-4-carboxylate (131.6 mg, 0.71 mmol), BINAP (80.4 mg, 0.13 mmol), Pd(dba)2 (55.7 mg, 0.10 mmol) and cesium carbonate (210.4 mg, 0.65 mmol) were dissolved in 1,4-dioxane (5 ml), and reacted at 100 °C overnight. After the reaction was completed, the reaction solution was added to water (30 ml), and extracted with EA (10 ml × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated, and purified by preparative plate to obtain compound 6 as a yellow solid (50 mg, yield 23.6%).

[0253] Compound 6 (50 mg, 0.08 mmol) was dissolved in TFA (1 ml), and reacted overnight at room temperature. The solvent of the reaction solution was evaporated to dryness under vacuum to obtain compound 7 as a yellow solid (50 mg, yield 109.4%).

[0254] Compound 7 (50 mg, 0.08 mmol), core1 (58.5 mg, 0.13 mmol), HOBT (13.5 mg, 0.10 mmol), EDCI (19.2 mg, 0.10 mmol) and triethylamine (25.4 mg, 0.25 mmol) were dissolved in DMF (2 ml), and the reaction was carried out overnight at room temperature. After the reaction was completed, the reaction solution was added to water (30 ml), and extracted with EA (10 ml×3). The organic layer was dried over anhydrous sodium sulfate and concentrated, and purified by pre-HPLC to obtain the yellow solid of compound TPD005409 (10.5 mg, yield 12.5%). LCMS (ESI) m / z calcd. for C55H60FN8O8S [M+H] + 1011.4; found 1011.3. It can be seen that the compound structure is correct.

[0255] Example 11: Synthesis of compound TPD005410

[0256] This example is used to prepare and synthesize compound TPD005410, and the specific synthesis route is as follows:

[0257]

[0258] Compound 5 (200 mg, 0.32 mmol), tert-butyl 4-piperidineacetate oxalate (141.5 mg, 0.71 mmol), BINAP (80.4 mg, 0.13 mmol), Pd(dba)2 (55.7 mg, 0.10 mmol) and cesium carbonate (210.4 mg, 0.65 mmol) were dissolved in 1,4-dioxane (5 ml), and the reaction was carried out overnight at 100 °C. After the reaction was completed, the reaction solution was added to water (30 ml), and extracted with EA (10 ml×3). The organic layer was dried over anhydrous sodium sulfate and concentrated, and purified by preparative TLC to obtain the yellow solid of compound 8 (50 mg, yield 23.2%).

[0259] Compound 8 (50 mg, 0.07 mmol) was dissolved in TFA (1 ml), and the reaction was carried out overnight at room temperature. After the reaction was completed, the solvent was evaporated in vacuo to obtain the yellow solid of compound 9 (50 mg).

[0260] Compound 9 (50 mg, 0.08 mmol), core1 (52.7 mg, 0.12 mmol), HOBT (13.2 mg, 0.10 mmol), EDCI (18.8 mg, 0.10 mmol) and triethylamine (24.8 mg, 0.24 mmol) were dissolved in DMF (2 ml), and the reaction was carried out overnight at room temperature. After the reaction was completed, the reaction solution was added to water (30 ml), and extracted with EA (10 ml × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated, and purified by pre-HPLC to obtain the yellow solid of compound TPD005410 (6.5 mg, yield 7.7%). LCMS (ESI) m / z calcd. for C56H62FN8O8S [M+H] + 1024.4; found 1024.3. It can be seen that the compound structure is correct.

[0261] Example 12: Synthesis of Compound TPD005411

[0262] This example is used to prepare and synthesize compound TPD005411, and the specific synthesis route is as follows:

[0263]

[0264] Compound 5 (100 mg, 0.16 mmol), tert-butyl 2-(piperidin-4-yloxy)acetate (75.3 mg, 0.35 mmol), tris(dibenzylideneacetone)dipalladium (30.0 mg, 0.03 mmol), 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (40.0 mg, 0.06 mmol), cesium carbonate (105 mg, 0.32 mmol) and 1,4-dioxane (10 ml) were added to a 20 ml reaction flask. After purging with nitrogen, the mixture was stirred overnight at 100 °C. The reaction was quenched by adding water, and extracted with ethyl acetate three times. The combined organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 30:1 - 2:1) to obtain compound 21 (70.0 mg, yellow solid), and the yield was 63.6%.

[0265] Compound 21 (70 mg, 0.10 mmol), dichloromethane (10 ml) and trifluoroacetic acid (2 ml) were added to a 100 ml single-necked flask. The reaction solution was stirred overnight at room temperature, concentrated by rotary evaporation, and triturated with methyl tert-butyl ether to obtain the crude product of compound 22 (30 mg, yellow solid).

[0266] In a 100 ml three-necked flask, compound 22 (30 mg, 0.05 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (44.2 mg, 0.1 mmol), and triethylamine (20.2 mg, 0.2 mmol) were added. It was dissolved with DCM (2 ml), 1-hydroxybenzotriazole (27.2 mg, 0.2 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (38.4 mg, 0.2 mmol) were added, and the mixture was stirred overnight at room temperature. It was quenched with water, extracted 3 times with dichloromethane, the combined organic phase was washed 3 times with water, once with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. The crude product was purified by high-pressure preparation to obtain compound TPD005411 (10 mg, yellow solid), yield: 20%. LCMS (ESI) m / z calcd. for C56H62FN8O9S [M+H] + 1040.4; found 1040.4. It can be seen that the compound structure is correct.

[0267] Example 13: Synthesis of compound TPD005412

[0268] This example is used to prepare and synthesize compound TPD005412, and the specific synthesis route is as follows:

[0269]

[0270] In a 20 ml reaction flask, compound 5 (100 mg, 0.16 mmol), tert-butyl 3-(piperidin-4-yloxy)propionate (80 mg, 0.35 mmol), tris(dibenzylideneacetone)dipalladium (30.0 mg, 0.03 mmol), 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (40.0 mg, 0.06 mmol), cesium carbonate (105 mg, 0.32 mmol) and 1,4-dioxane (10 ml) were added. It was purged with nitrogen and stirred overnight at 100 °C. It was quenched with water, extracted 3 times with ethyl acetate, the combined organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 30:1 - 2:1) to obtain compound 23 (80.0 mg, yellow solid), yield: 70.8%.

[0271] In a 100 ml single-necked flask, compound 23 (80 mg, 0.11 mmol), dichloromethane (10 ml) and trifluoroacetic acid (2 ml) were added. The reaction solution was stirred overnight at room temperature, concentrated by rotary evaporation, and triturated with methyl tert-butyl ether to obtain the crude compound 22 (30 mg, yellow solid).

[0272] Compound 24 (30 mg, 0.05 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (44.2 mg, 0.1 mmol), and triethylamine (20.2 mg, 0.2 mmol) were added to a 100 ml three-necked flask, dissolved in DCM (2 ml), 1-hydroxybenzotriazole (27.2 mg, 0.2 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (38.4 mg, 0.2 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with dichloromethane three times, the combined organic phases were washed with water three times, saturated brine once, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by preparative HPLC to give compound TPD005412 (10 mg, yellow solid) with a yield of 20%. LCMS (ESI) m / z calcd. for C57H64FN8O9S [M+H] + 1054.4; found 1054.3. It can be seen that the structure of the compound is correct.

[0273] Example 14: Synthesis of Compound TPD005415

[0274] This example is used to prepare and synthesize compound TPD005415, and the specific synthesis route is as follows:

[0275]

[0276] Compound 5 (200 mg, 0.32 mmol), tert-butyl 3-aminopropionate (103.1 mg, 0.71 mmol), BINAP (80.4 mg, 0.13 mmol), Pd(dba)2 (55.7 mg, 0.10 mmol) and cesium carbonate (210.4 mg, 0.65 mmol) were dissolved in 1,4-dioxane (5 ml), and the reaction was carried out at 100 °C overnight. After the reaction was completed, the reaction mixture was added to water (30 ml), and extracted with EA (10 ml × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated, and purified by preparative TLC to give compound 8 as a yellow solid (50 mg, yield 25.2%).

[0277] Compound 10 (50 mg, 0.07 mmol) was dissolved in TFA (1 ml), and the reaction was carried out at room temperature overnight. After the reaction was completed, the solvent was removed in vacuo to give compound 11 as a yellow solid (50 mg, yield 110.1%).

[0278] Compound 11 (50 mg, 0.09 mmol), core1 (57.8 mg, 0.13 mmol), HOBT (14.5 mg, 0.11 mmol), EDCI (20.6 mg, 0.11 mmol) and triethylamine (27.2 mg, 0.27 mmol) were dissolved in DMF (2 ml), and the reaction was carried out overnight at room temperature. After the reaction was completed, the reaction solution was added to water (30 ml), and extracted with EA (10 ml × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated, and purified by pre-HPLC to obtain the yellow solid of compound TPD005415 (11 mg, yield 12.7%). LCMS (ESI) m / z calcd. for C52H56FN8O8S [M+H] + 970.4; found 970.3. It can be seen that the structure of the compound is correct.

[0279] Example 15: Synthesis of Compound TPD005417

[0280] This example is used to prepare and synthesize compound TPD005417, and the specific synthesis route is as follows:

[0281]

[0282] Compound 5 (200 mg, 0.32 mmol), tert-butyl glycinate (93.2 mg, 0.71 mmol), BINAP (80.4 mg, 0.13 mmol), Pd(dba)2 (55.7 mg, 0.10 mmol) and cesium carbonate (210.4 mg, 0.65 mmol) were dissolved in 1,4-dioxane (5 ml), and the reaction was carried out overnight at 100 °C. After the reaction was completed, the reaction solution was added to water (30 ml), and extracted with EA (10 ml × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated, and purified by preparative TLC to obtain the yellow solid of compound 12 (50 mg, yield 25.8%).

[0283] Compound 12 (50 mg, 0.08 mmol) was dissolved in TFA (1 ml), and the reaction was carried out overnight at room temperature. After the reaction was completed, the solvent was evaporated under vacuum to obtain the yellow solid of compound 13 (50 mg, yield 110.3%).

[0284] Compound 13 (50 mg, 0.09 mmol), core1 (59.3 mg, 0.14 mmol), HOBT (14.9 mg, 0.11 mmol), EDCI (21.1 mg, 0.11 mmol) and triethylamine (27.9 mg, 0.28 mmol) were dissolved in DMF (2 ml), and the reaction was carried out overnight at room temperature. After the reaction was completed, the reaction solution was added to water (30 ml), and extracted with EA (10 ml×3). The organic layer was dried over anhydrous sodium sulfate and concentrated, and purified by pre-HPLC to obtain the yellow solid of compound TPD005417 (10.1 mg, yield 11.5%). LCMS (ESI) m / z calcd. for C51H54FN8O8S [M+H] + 956.4; found 956.3. It can be seen that the compound structure is correct.

[0285] Example 16: Synthesis of compound TPD005420

[0286] This example is used to prepare and synthesize compound TPD005420, and the specific synthesis route is as follows:

[0287]

[0288] Compound 5 (200 mg, 0.32 mmol), 4-hydroxypiperidine (49.0 mg, 0.48 mmol), BINAP (80.4 mg, 0.13 mmol), Pd(dba)2 (55.7 mg, 0.10 mmol) and cesium carbonate (210.4 mg, 0.65 mmol) were dissolved in 1,4-dioxane (5 ml), and the reaction was carried out overnight at 100 °C. After the reaction was completed, the reaction solution was added to water (30 ml), and extracted with EA (10 ml×3). The organic layer was dried over anhydrous sodium sulfate and concentrated, and purified by preparative TLC to obtain the yellow solid of compound 14 (50 mg, yield 27.1%).

[0289] Compound 14 (250 mg, 0.44 mmol) was dissolved in DCM (10 ml), and Dess-Martin (371.6 mg, 0.88 mmol) was added in portions, and the reaction was carried out overnight at room temperature. After the reaction was completed, the reaction solution was added to water (30 ml), and extracted with DCM (10 ml×3). The organic layer was dried over anhydrous sodium sulfate and concentrated, and purified by preparative TLC to obtain the yellow solid of compound 15 (150 mg, yield 60.2%).

[0290] Compound 15 (150 mg, 0.26 mmol) and tert-butyl piperidine-4-carboxylate (146.6 mg, 0.79 mmol) were dissolved in DCM (5 ml) and titanium(IV) isopropoxide (1 ml), and the mixture was stirred at room temperature for 3 h. Sodium triacetoxyborohydride (167.9 mg, 0.79 mmol) was added, and the reaction was carried out overnight at room temperature. After completion of the reaction, the reaction mixture was added to water (30 ml), and the mixture was extracted with DCM (10 ml × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by preparative TLC to give compound 16 as a yellow solid (40 mg, yield 20.5%).

[0291] Compound 12 (70 mg, 0.09 mmol) was dissolved in TFA (1 ml), and the reaction was carried out overnight at room temperature. After completion of the reaction, the solvent was removed by rotary evaporation under vacuum to give compound 13 as a yellow solid (70 mg, yield 108.2%).

[0292] Compound 17 (70 mg, 0.10 mmol), core1 (71.8 mg, 0.15 mmol), HOBT (16.7 mg, 0.12 mmol), EDCI (23.6 mg, 0.12 mmol) and triethylamine (31.2 mg, 0.31 mmol) were dissolved in DMF (2 ml), and the reaction was carried out overnight at room temperature. After completion of the reaction, the reaction mixture was added to water (30 ml), and the mixture was extracted with EA (10 ml × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated, and the residue was purified by pre-HPLC to give compound TPD005420 as a yellow solid (10.3 mg, yield 9.1%). LCMS (ESI) m / z calcd. for C60H69FN9O8S [M+H] + 1094.5; found 1094.3. It can be seen that the structure of the compound is correct.

[0293] Example 17: Synthesis of Compound TPD005421

[0294] This example is used to prepare and synthesize compound TPD005421, and the specific synthesis route is as follows:

[0295]

[0296] Compound 5 (200 mg, 0.32 mmol), 4-hydroxypiperidine (81.8 mg, 0.71 mmol), BINAP (80.4 mg, 0.13 mmol), Pd(dba)2 (55.7 mg, 0.10 mmol) and cesium carbonate (210.4 mg, 0.65 mmol) were dissolved in 1,4-dioxane (5 ml), and the reaction was carried out at 100 °C overnight. After the reaction was completed, the reaction solution was added to water (30 ml), and extracted with EA (10 ml × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated, and purified by preparative plate to obtain compound 14 as a yellow solid (50 mg, yield 26.5%).

[0297] Compound 18 (500 mg, 0.86 mmol) and triethylamine (129.8 mg, 1.28 mmol) were dissolved in DCM (5 ml), and MsCl (117.6 mg, 1.03 mmol) was added dropwise at 0 °C, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was washed with water (2 ml), the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound 19 as a yellow solid (500 mg, yield 88.2%).

[0298] Compound 19 (300 mg, 0.45 mmol), tert-butyl piperidine-4-carboxylate (125.8 mg, 0.68 mmol), sodium iodide (135.8 mg, 0.91 mmol) and potassium carbonate (187.7 mg, 1.36 mmol) were dissolved in DMF (5 ml), and stirred at 80 °C overnight. After the reaction was completed, the reaction solution was added to water (30 ml), and extracted with EA (10 ml × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated, and purified by preparative plate to obtain compound 20 as a yellow solid (200 mg, yield 58.8%).

[0299] Compound 20 (200 mg, 0.27 mmol) was dissolved in TFA (2 ml), and the reaction was carried out at room temperature overnight. After the reaction was completed, the solvent was evaporated under vacuum to obtain compound 21 as a yellow solid (150 mg, yield 69.7%).

[0300] Dissolve compound 21 (100 mg, 0.14 mmol), the aforementioned compound core2 (68.4 mg, 0.22 mmol), HOBT (23.3 mg, 0.17 mmol), EDCI (33.1 mg, 0.17 mmol) and triethylamine (43.6 mg, 0.43 mmol) in DMF (2 ml), and react overnight at room temperature. After the reaction is completed, add the reaction solution to water (30 ml), extract with EA (10 ml × 3), dry the organic layer with anhydrous sodium sulfate and concentrate, and purify by pre-HPLC to obtain compound TPD005421 as a yellow solid (12.1 mg, yield 7.6%). LCMS (ESI) m / z calcd. for C55H59FN8O7S [M+H] + 994.4; found 994.3. It can be seen that the compound structure is correct.

[0301] Example 18: Synthesis of compound TPD005423

[0302]

[0303] Add compound core1 (300 mg, 0.45 mmol), tert-butyl azetidine-3-carboxylate (94.2 mg, 0.6 mmol), potassium carbonate (83.0 mg, 0.60 mmol), sodium iodide (90.0 mg, 0.60 mmol), and N,N-dimethylformamide (10 ml) to a 100 ml single-necked flask. Stir the reaction solution at 100 °C overnight. Quench with water, extract 3 times with ethyl acetate, wash the combined organic phase 3 times with water and 1 time with saturated brine, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain compound 7 (120 mg, yellow solid) Yield: 36.5%.

[0304] Add compound 35 (120 mg, 0.17 mmol), dichloromethane (10 ml) and trifluoroacetic acid (2 ml) to a 40 ml single-necked flask. Stir the reaction solution at room temperature overnight, evaporate to dryness, and triturate with methyl tert-butyl ether to obtain crude compound 36 (100 mg, yellow solid).

[0305] Add compound 8 (100 mg, 0.15 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (124 mg, 0.3 mmol) and triethylamine (50.5 mg, 0.5 mmol) into a 100 ml three-necked flask. Dissolve them with DCM (5 ml), add 1-hydroxybenzotriazole (114 mg, 0.25 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (161 mg, 0.85 mmol), and stir at room temperature overnight. Quench with water, extract with dichloromethane for 3 times, wash the combined organic phase with water for 3 times and with saturated brine for 1 time, dry over anhydrous sodium sulfate, and rotary evaporate to dryness. The crude product is purified by high-pressure preparation to obtain compound TPD005423 (10 mg, yellow solid), yield: 6.2%. LCMS (ESI) m / z calcd. for C59H67FN9O8S [M+H] + 1079.5; found 1079.4. It can be seen that the structure of the compound is correct.

[0306] Example 19: Synthesis of compound TPD005424

[0307]

[0308] Add compound int-A (600 mg, 0.9685 mmol), 4-Boc-aminopiperidine (387.94 mg, 1.937 mmol), cesium carbonate (631.11 mg, 1.937 mmol), BINAP (241.22 mg, 0.3874 mmol), Pd 2 (dba) 3 (177.37 mg, 0.1937 mmol) and 1,4-dioxane (30 ml) into a 100 ml three-necked flask in sequence. React at 100 °C for 16 hours under nitrogen protection. After the reaction is completed, cool the reaction solution to room temperature and concentrate to dryness. The residue is purified by silica gel column chromatography, and the eluent ratio is DCM / MeOH = 50 / 1 - 30 / 1 to obtain compound TPD5424-1 (440 mg, yellow solid, purity 84.226%), yield: 57.13%. LCMS (ESI) m / z calcd. for C 37 H 40 FN 5 O 6 [M+H] + 670.3; found 670.2. 1 H NMR (400 MHz, CDCl 3): δ = 9.34 (s, 1H), 8.81 (s, 1H), 8.46 (d, J = 5.3 Hz, 1H), 7.62 (d, J = 8.9 Hz, 2H), 7.52 - 7.45 (m, 4H), 7.16 (d, J = 8.9 Hz, 2H), 7.05 (t, J = 8.6 Hz, 2H), 6.43 (d, J = 5.2 Hz, 1H), 4.52 (s, 1H), 4.02 (s, 3H), 3.64 (d, J = 12.1 Hz, 2H), 2.83 (t, J = 11.0 Hz, 2H), 2.11 (d, J = 10.9 Hz, 2H), 1.74 - 1.71 (m, 2H), 1.68 - 1.65 (m, 4H), 1.47 (s, 9H).

[0309] Compound TPD5424 - 1 (440 mg, 0.657 mmol), DCM (8 ml) and TFA (4 ml) were added to a 50 ml three - necked flask. The reaction mixture was reacted at 20 °C for 4 hours. After the reaction was completed, the reaction solution was directly rotary - evaporated to obtain the crude compound TPD5424 - 2 (440 mg, yellow solid, purity 91.595%), yield: 89.73%. LCMS (ESI) m / z calcd. for C 32 H 32 FN 5 O 4 [M + H] + 570.2; found 570.2. It can be seen that the compound structure is correct.

[0310] Compound TPD5424 - 2 (300 mg, 0.563 mmol), monomethyl 1,1 - cyclopropanedicarboxylate (91 mg, 0.632 mmol), DMF (5 ml), HATU (300 mg, 0.790 mmol) and triethylamine (266 mg, 2.633 mmol) were successively added to a 50 ml three - necked flask. The reaction mixture was reacted at 20 °C for 16 hours. After the reaction was completed, the reaction solution was poured into saturated sodium bicarbonate aqueous solution (20 ml), and the aqueous phase was extracted three times with DCM (20 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with the eluent ratio of DCM / MeOH = 50 / 1 - 30 / 1 to obtain compound TPD5424 - 3 (250 mg, yellow solid, purity 97.596%), yield: 66.58%. LCMS (ESI) m / z calcd. for C 38 H 38 FN 5 O 7 [M + H] + 696.3; found 696.1. 1HNMR (400 MHz, CDCl 3 ): δ = 9.49 (s, 1H), 8.88 (d, J = 7.8 Hz, 1H), 8.76 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 7.69 - 7.63 (m, 2H), 7.53 (s, 1H), 7.49 - 7.46 (m, 3H), 7.20 - 7.15 (m, 2H), 7.09 - 7.01 (m, 2H), 6.48 (d, J = 5.6 Hz, 1H), 4.05 (s, 3H), 3.70 - 3.62 (m, 5H), 2.96 (t, J = 10.4 Hz, 2H), 2.13 - 2.11 (m, 2H), 1.88 - 1.64 (m, 8H), 1.59 - 1.56 (m, 2H). It can be seen that the structure of the compound is correct.

[0311] In a 50 ml three-necked flask, compound TPD5424 - 3 (100 mg, 0.1437 mmol), THF (2 ml), H 2 O (1 ml) and lithium hydroxide monohydrate (12.06 mg, 0.2874 mmol) were successively added. The reaction was carried out at 20 °C for 3 hours. The pH value of the reaction solution was adjusted to 8 with dilute hydrochloric acid, and then the mixture was extracted three times with ethyl acetate (5 ml). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product of compound TPD5424 - 5 (50 mg, yellow solid, purity 97.614%), yield: 49.83%. LCMS (ESI) m / z calcd. for C 37 H 36 FN 5 O 7 [M + H] + 682.26; found 682.2. It can be seen that the structure of the compound is correct.

[0312] In a 50 ml three-necked flask, 50 mg (0.0733 mmol) of compound TPD5424-4, 34.72 mg (0.0806 mmol) of compound TPD5424-5, 4 ml of DMF, 41.81 mg (0.1099 mmol) of HATU, and 22.25 mg (0.2199 mmol) of triethylamine were added successively. The reaction mixture was reacted at 20 °C for 16 hours. After the reaction was completed, the reaction solution was poured into saturated aqueous sodium bicarbonate solution (20 ml), and the aqueous phase was extracted three times with DCM (20 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the developing agent ratio was DCM / MeOH = 10 / 1, to obtain compound TPD005424 (26.6 mg, off-white solid, purity 97.557%), yield: 32.33%. LCMS(ESI) m / z calcd. for C 59 H 64 FN 9 O 9 S[M+H] + 1094.45; found 1094.7. 1 HNMR(400 MHz, DMSO-d 6 ): δ = 10.19 (s, 1H), 10.06 (s, 1H), 9.10 (d, J = 8.6 Hz, 1H), 8.96 (s, 1H), 8.68 (t, J = 5.9 Hz, 1H), 8.44 (d, J = 5.2 Hz, 1H), 7.74 (dd, J = 18.3, 8.3 Hz, 3H), 7.67 - 7.59 (m, 2H), 7.46 (s, 1H), 7.44 - 7.36 (m, 4H), 7.34 (s, 1H), 7.21 (d, J = 9.0 Hz, 2H), 7.15 (dd, J = 12.3, 5.5 Hz, 2H), 6.40 (d, J = 5.2 Hz, 1H), 5.15 (d, J = 3.5 Hz, 1H), 4.58 - 4.17 (m, 5H), 3.99 - 3.76 (m, 4H), 3.72 - 3.47 (m, 4H), 2.86 - 2.66 (m, 2H), 2.43 (s, 3H), 2.04 (d, J = 8.5 Hz, 1H), 1.96 - 1.65 (m, 5H), 1.47 (s, 4H), 1.29 (s, 4H), 0.95 (s 9H). It can be seen that the compound structure is correct.

[0313] Example 20: Synthesis of compound TPD005430

[0314]

[0315] In a 50 ml three-necked flask, compound TPD5488-1 (200 mg, 0.3421 mmol), triethylamine (103.85 mg, 1.0263 mmol) and dichloromethane (10 ml) were added successively. The temperature was lowered to 0 °C under nitrogen protection. Then methanesulfonyl chloride (58.78 mg, 0.51315 mmol) was added dropwise. After the addition was complete, the cold bath was removed and the temperature was allowed to rise to 20 °C naturally and the reaction was carried out for 1 hour. The reaction solution was poured into water (20 ml), and extracted three times with DCM (5 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain crude compound TPD5430-1 (220 mg, yellow solid, purity 83.913%), yield: 81.44%. LCMS (ESI) m / z calcd. for C 34 H 35 FN 4 O 7 S[M+H] + 663.22; found 663.1. It can be seen that the compound structure is correct.

[0316] In a 25 ml three-necked flask, compound TPD5430-2 (110 mg, 0.166 mmol), tert-butyl 3-acridinecarboxylate hydrochloride (38.58 mg, 0.1992 mmol), potassium carbonate (45.89 mg, 0.332 mmol), sodium iodide (49.8 mg, 0.332 mmol) and N,N-dimethylformamide (5 ml) were added successively. Under nitrogen protection, the reaction was carried out at 80 °C for 16 hours. The reaction solution was poured into water (20 ml). It was extracted three times with EA (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 15 / 1, to obtain compound TPD005430-2 (50 mg, yellow solid, purity 96.731%), yield: 40.24%. LCMS (ESI) m / z calcd. for C 41 H 46 FN 5 O 6 [M+H] + 724.34; found 724.4. 1 H NMR (400 MHz, CDCl 3): δ = 9.19 (s, 1H), 8.88 (s, 1H), 8.39 (d, J = 5.2 Hz, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.48 - 7.46 (m, 2H), 7.41 (s, 1H), 7.15 (t, J = 8.8 Hz, 3H), 7.05 (t, J = 6.4 Hz, 2H), 6.33 (d, J = 5.2 Hz, 1H), 3.96 (s, 3H), 3.66 - 3.57 (m, 2H), 3.56 - 3.48 (m, 3H), 3.28 - 3.18 (m, 4H), 2.52 - 2.48 (m, 2H), 2.29 - 2.21 (m, 1H), 2.16 - 2.10 (m, 1H), 1.73 - 1.68 (m, 5H), 1.54 - 1.49 (m, 2H), 1.46 (s, 9H). It can be seen that the structure of the compound is correct.

[0317] Compound TPD5488 - 2 (100 mg, 0.1382 mmol), dichloromethane (6 ml), and trifluoroacetic acid (3 ml) were added to a 50 ml three - necked flask. The reaction was carried out at 20 °C for 16 hours. It was concentrated to dryness to obtain the crude product of compound TPD5430 - 3 (90 mg, yellow solid, purity 79.272%), yield: 66.06%. LCMS (ESI) m / z calcd. for C 37 H 38 FN 5 O 6 [M + H] + 668.28; found 668.3. 1 H NMR (400 MHz, DMSO - d 6 ): δ = 14.78 (s, 1H), 10.32 (s, 1H), 10.00 (s, 1H), 8.57 (d, J = 6.8 Hz, 1H), 7.84 (d, J = 9.2 Hz, 2H), 7.66 - 7.62 (m, 2H), 7.54 (s, 1H), 7.33 (d, J = 9.2 Hz, 2H), 7.16 (t, J = 9.2 Hz, 2H), 6.90 (s, 1H), 6.71 (d, J = 6.8 Hz, 1H), 4.29 - 4.07 (m, 7H), 4.00 (s, 3H), 3.38 - 3.17 (m, 4H), 2.27 - 2.19 (m, 1H), 2.16 - 2.10 (m, 1H), 1.70 - 1.57 (m, 3H), 1.49 (d, J = 8.4 Hz, 4H). It can be seen that the structure of the compound is correct.

[0318] In a 25 ml three-necked flask, successively add compound TPD5430-3 (45 mg, 0.0674 mmol), N,N-dimethylformamide (3 ml), (2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (32.09 mg, 0.1011 mmol), HOBt (13.66 mg, 0.1011 mmol), EDCI (19.38 mg, 0.1011 mmol) and triethylamine (40.84 mg, 0.4044 mmol). Under nitrogen protection, react at 25 °C for 16 hours. Pour the reaction solution into water (10 ml). Extract three times with EA (3 ml). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. Purify the residue by preparative plate, with the eluent ratio of DCM / MeOH = 4 / 1, to obtain compound TPD005430 (6.65 mg, yellow solid, purity 97.127%), yield: 4.97%. LCMS (ESI) m / z calcd. for C 53 H 55 FN 8 O 7 S[M+H] + 967.39; found 967.7. 1 H NMR (400 MHz, DMSO_d 6 ): δ = 10.19 (s, 1H), 10.08 (s, 1H), 8.98 (s, 1H), 8.80 (br.s., 0.35H), 8.46 (br.s., 0.76H), 8.35 (br.s., 1H), 7.75 (d, J = 6.4 Hz, 2H), 7.65 (br.s., 2H), 7.47 - 7.43 (m, 2H), 7.38 (s, 3H), 7.21 - 7.14 (m, 4H), 6.94 (s, 1H), 6.27 (br.s., 1H), 5.12 (s, 1H), 4.42 - 4.25 (m, 4H), 3.90 (s, 3H), 3.56 - 3.44 (m, 6H), 3.23 (s, 1H), 3.15 (s, 3H), 2.51 (s, 3H), 2.20 (s, 1H), 2.06 - 1.96 (m, 3H), 1.90 - 1.85 (m, 1H), 1.55 - 1.35 (m, 7H), 1.24 (s, 2H). It can be seen that the compound structure is correct.

[0319] Example 21: Synthesis of compound TPD005431

[0320]

[0321] In a 25 ml single-necked flask, add tert-butyl 3-oxoazetidine-1-carboxylate (70 mg, 0.4065 mmol), compound TPD5431-1 (189.85 mg, 0.4065 mmol), sodium triacetoxyborohydride 258.46 mg, 1.2195 mmol), dichloroethane (6 ml) and glacial acetic acid (73.23 mg, 1.2195 mmol) in sequence. React at 50 °C for 16 hours. After the reaction is completed, pour the reaction solution into 10 ml of saturated ammonium chloride aqueous solution, extract three times with DCM (10 ml), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and purify the residue by preparative plate. The eluent is DCM / MeOH = 10 / 1 to obtain compound TPD5431-2 (210 mg, white solid, purity 89.921%), yield: 79.31%. LCMS (ESI) m / z calcd. for C 30 H 43 N 5 O 5 S[M+H] + 586.3; found 586.1. 1 HNMR (400 MHz, DMSO_d 6 ): δ = 8.99 (d, J = 6.2 Hz, 1H), 8.59 (t, J = 6.0 Hz, 1H), 7.51 - 7.31 (m, 4H), 5.07 (d, J = 2.8 Hz, 1H), 4.50 - 4.32 (m, 3H), 4.26 - 4.20 (m, 1H), 4.12 - 3.69 (m, 3H), 3.81 - 3.50 (m, 4H), 3.39 (br.s., 1H), 3.00 (br.s., 1H), 2.45 (d, J = 3.2 Hz, 3H), 2.13 - 1.79 (m, 2H), 1.36 (d, J = 3.2 Hz, 9H), 0.92 (s, 9H). It can be seen that the compound structure is correct.

[0322] Add compound TPD5431-2 (180 mg, 0.3073 mmol) and hydrogen chloride methanol solution (4N, 6 mL) to a 25 ml single-necked flask. React at 25 °C for 30 minutes. After the reaction is completed, concentrate under reduced pressure to obtain compound TPD5431-3 (185 mg, yellow solid, purity 85.380%), yield: 98.44%. LCMS (ESI) m / z calcd. for C 25 H 35 N 5 O 3 S[M+H] + 486.3; found 486.1. It can be seen that the compound structure is correct.

[0323] In a 25 ml single-necked flask, add compound TPD5488-1 (100 mg, 0.171 mmol), DCM (6 ml) and triethylamine (51.91 mg, 0.513 mmol). After cooling the temperature to 0 °C, add methanesulfonyl chloride (29.38 mg, 0.2565 mmol) dropwise. React at 0 °C for 1 hour. After the reaction is completed, pour it into water (10 ml), and extract with DCM (3 ml) three times. Combine the organic phases, wash with water, wash with brine, dry over saturated sodium sulfate, filter, and concentrate to dryness to obtain crude compound TPD5431 (50 mg, yellow oil, purity 40.853%), yield: 25.26%. LCMS (ESI) m / z calcd. for C 34 H 35 FN 4 O 7 S[M+H] + 663.2; found 229.2 and 663.1. It can be seen that the compound structure is correct.

[0324] In a 25 mL single-necked flask, add compound TPD5431-4 (70 mg, 0.1056 mmol), compound TPD5431-3 (102.57 mg, 0.2112 mmol), potassium carbonate (58.38 mg, 0.4224 mmol), sodium iodide (31.68 mg, 0.2112 mmol) and DMF (5 ml) in sequence. React at 80 °C for 16 hours. After the reaction is completed, cool to room temperature, pour it into water (10 ml), and extract with EA (5 ml) three times. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. The residue is prepared by high performance liquid chromatography, and the relevant parameters are as follows: chromatographic column: XBridge-1 5um 19-150mm; mobile phase: acetonitrile-water (0.1% ammonia water); gradient: 30-90 / 8 minutes, to obtain compound TPD005431 (11.2 mg, off-white solid, purity 95.035%), yield 9.56%. LCMS (ESI) m / z calcd. for C 58 H 66 FN 9 O 7 S[M / 2+H] + 526.7; found 526.9. 1 H NMR (400 MHz, DMSO_d 6): δ = 10.17 (s, 1H), 10.06 (s, 1H), 8.97 (d, J = 6.0 Hz, 1H), 8.59 (t, J = 5.9 Hz, 1H), 8.34 (d, J = 5.1 Hz, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.66 - 7.62 (m, 2H), 7.48 - 7.32 (m, 5H), 7.23 - 7.09 (m, 4H), 6.93 (s, 1H), 6.26 (d, J = 5.2 Hz, 1H), 5.14 (d, J = 10.2 Hz, 1H), 4.50 - 4.29 (m, 3H), 4.25 - 4.20 (m, 1H), 3.90 (s, 3H), 3.64 (d, J = 11.1 Hz, 1H), 3.58 - 3.41 (m, 6H), 3.22 - 3.10 (m, 3H), 3.00 (br.s., 1H), 2.62 - 2.56 (m, 1H), 2.44 (s, 3H), 2.39 - 2.32 (m, 2H), 2.20 - 2.14 (m, 1H), 2.10 - 1.97 (m, 3H), 1.93 - 1.85 (m, 1H), 1.55 - 1.43 (m, 4H), 1.42 - 1.33 (m, 2H), 1.23 (s, 1H), 0.96 - 0.79 (m, 9H). It can be seen that the structure of the compound is correct.

[0325] Example 22: Synthesis of Compound TPD005432

[0326]

[0327] Into a 100 ml three-necked flask were successively added compound int-A (1400 mg, 2.2579 mmol), 4-hydroxypiperidine (502.84 mg, 4.97134 mmol), Pd 2 (dba) 3 (413.85 mg, 0.45194 mmol), BINAP (562.82 mg, 0.9038 mmol), cesium carbonate (1472.51 mg, 4.5194 mmol) and dioxane (50 ml). The reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, water was added to the reaction solution, and it was extracted 3 times with EtOAc (100 ml). The combined organic layers were washed with brine (200 ml), dried over anhydrous sodium sulfate, filtered and evaporated to obtain a residue. The residue was purified by silica gel column chromatography, and the eluent and ratio were DCM / MeOH = 100 / 1 - 20 / 1, to obtain the product compound TPD5432-1 (595 mg, yellow solid, purity 85.651%), yield: 37.67%. LCMS (ESI) m / z calcd. for C 32 H31 FN 4 O 5 [M+H] + 571.23; found 571.2. It can be seen that the compound structure is correct.

[0328] Under nitrogen protection, oxalyl chloride (143.48 mg, 1.1304 mmol) and DCM (2 ml) were added to a 50 ml three-necked flask. The temperature was lowered to -78 °C, and a solution of DMSO (176.34 mg, 2.2608 mmol) in DCM (1 ml) was added dropwise. The resulting mixture was maintained at -78 °C for 0.5 h. Then, a solution of compound TPD5432-1 (430 mg, 0.7536 mmol) in DCM (2 ml) was added dropwise at -78 °C. The resulting mixture was maintained at -78 °C for 1 h. Then, TEA (228.77 mg, 2.2608 mmol) was added dropwise at -78 °C. The resulting mixture was allowed to warm up to 20 °C naturally and maintained for 0.5 h. After the reaction was completed, the reaction was quenched by adding saturated aqueous sodium bicarbonate. The mixture was extracted with DCM (20 ml × 3). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and evaporated to obtain a residue. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain the product compound TPD5432-2 (290 mg, yellow solid, purity 92.290%), yield: 62.46%. LCMS (ESI) m / z calcd. for C 32 H 29 FN 4 O 5 [M+H] + 569.21; found 569.0. 1 H NMR (400 MHz, CDCl 3 ): δ = 9.35 (s, 1H), 8.66 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 7.58 - 7.46 (m, 5H), 7.19 - 7.17 (m, 2H), 7.08 - 7.04 (m, 2H), 6.46 (d, J = 5.2 Hz, 1H), 4.07 (s, 3H), 3.57 - 3.54 (m, 4H), 2.72 - 2.69 (m, 4H), 1.75 - 1.65 (m, 4H). It can be seen that the compound structure is correct.

[0329] Add DCE (10 ml), compound TPD5432-2 (150 mg, 0.2638 mmol), tert-butyl 3-acridinecarboxylate hydrochloride (255.45 mg, 1.319 mmol), sodium triacetoxyborohydride (167.73 mg, 0.7913 mmol), and titanium(IV) isopropoxide (0.5 ml) into a 50-ml single-necked flask. Under nitrogen protection, the reaction solution is heated to 40 °C and reacted for 16 hours. After the reaction is completed, add water to the mixture, and the mixture is extracted 3 times with EtOAc (10 ml). The combined organic layers are washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered, and evaporated to obtain a residue. The residue is purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain the product compound TPD5432-3 (100 mg, yellow solid, purity 96.741%), yield: 51.67%. LCMS (ESI) m / z calcd. for C 40 H 44 FN 5 O 6 [M+H] + 710.33; found 710.5. It can be seen that the compound structure is correct.

[0330] Add compound TPD5432-3 (50 mg, 0.0704 mmol), DCM (2 ml), and trifluoroacetic acid (2 ml) into a 50-ml single-necked flask. Stir the resulting mixture at 20 °C for 2 hours. After the reaction is completed, rotary evaporate the mixture to obtain the crude product compound TPD5432-4 (46 mg, white solid, purity 92.176%), yield: 92.19%. LCMS (ESI) m / z calcd. for C 36 H 36 FN 5 O 6 [M+H] + 654.26; found 654.3. It can be seen that the compound structure is correct.

[0331] In a 50 ml single-necked flask, add compound TPD5432-4 (46 mg, 0.0704 mmol), HATU (40.15 mg, 0.1056 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (40.3 mg, 0.0704 mmol) and TEA (35.62 mg, 0.352 mmol) in sequence. Under nitrogen protection, react at 15 °C for 16 hours. After the reaction is completed, quench the reaction solution with water. Extract three times with ethyl acetate (10 ml). Wash the combined organic layers with brine (20 ml), dry over anhydrous sodium sulfate, filter and evaporate to obtain a residue. Purify the crude product by preparative HPLC (column: sunfire, 5 μm, 19 - 150 mm; detector: 254 nm; mobile phase: ACN / H 2 O (0.1% FA in H 2 O); gradient: 10 - 50 / 8 minutes; retention time: 7.0 minutes to obtain the product compound TPD005432 (23.5 mg, yellow solid, purity 97.684%), yield: 22.03%. LCMS (ESI) m / z calcd. for C 58 H 64 FN 9 O 8 S [M + H] + 1066.46; found 533.8 (half peak); 356.2 (one-third peak) 1 HNMR (400 MHz, DMSO_d 6): δ = 10.18 (s, 1H), 10.06 (s, 1H), 8.98 (s, 1H), 8.59 (t, J = 6.0 Hz, 1H), 8.43 (d, J = 5.2 Hz, 1H), 8.18 (s, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.64 (dd, J = 9.0, 5.1 Hz, 2H), 7.47 - 7.37 (m, 5H), 7.31 (s, 1H), 7.23 - 7.13 (m, 4H), 6.39 (d, J = 5.2 Hz, 1H), 4.57 (d, J = 9.4 Hz, 1H), 4.48 - 4.40 (m, 2H), 4.37 (s, 1H), 4.22 (dd, J = 15.7, 5.3 Hz, 1H), 3.94 (s, 3H), 3.67 - 3.64 (m, 2H), 3.44 - 3.37 (m, 2H), 3.22 (dd, J = 28.7, 6.4 Hz, 3H), 2.74 (t, J = 10.0 Hz, 2H), 2.45 (s, 3H), 2.30 (br.s., 1H), 2.15 - 1.75 (m, 5H), 1.48 (s, 4H), 1.36 (d, J = 9.0 Hz, 2H), 1.23 (s, 2H), 0.95 - 0.93 (m, 9H). It can be seen that the compound structure is correct.

[0332] Example 23: Synthesis of Compound TPD005436

[0333]

[0334] Into a 250 ml three-necked flask were successively added compound int-A (1.4 g, 2.2597 mmol), ethyl 4-piperidinecarboxylate (710.49 mg, 4.5194 mmol), cesium carbonate (1.472 g, 4.5194 mmol), BINAP (562.82 mg, 0.9038 mmol), Pd 2 (dba) 3 (413.85 mg, 0.4519) and 1,4-dioxane (70 ml). The reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated to dryness. The residue was purified by silica gel column chromatography with an eluent ratio of DCM / MeOH = 100 / 1 - 30 / 1 to obtain compound TPD5436-1 (660 mg, brown solid, purity 72.545%), yield: 33.81%. LCMS (ESI) m / z calcd. for C 35 H 35 FN 4 O 6 [M + H] +627.3; found 627.4. It can be seen that the compound has the correct structure.

[0335] In a 50 ml single-necked flask, compound TPD5436-1 (600 mg, 0.9574 mmol), lithium hydroxide monohydrate (80.35 mg, 1.9148 mmol) and methanol / water = 2:1 (10 ml) were successively added. The reaction was carried out at 20 °C for 4 hours. After the reaction was completed, it was concentrated to dryness to obtain crude compound TPD5436-2 (700 mg, brown solid), yield: 86.17%. LCMS (ESI) m / z calcd. for C 33 H 31 FN 4 O 6 [M+H] + 599.2; found 599.1. It can be seen that the compound has the correct structure.

[0336] In a 25 ml single-necked flask, compound TPD5436-2 (200 mg, 0.3341 mmol), ethyl 4-piperidinecarboxylate (63.03 mg, 0.4009 mmol), HATU (254.07 mg, 0.6682 mmol), triethylamine (101.43 mg, 0.6682 mmol) and DMF (5 ml) were successively added. The reaction was carried out at 20 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (6 ml), and extracted three times with EA (3 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 10 / 1 to obtain compound TPD5436-3 (200 mg, brown solid, purity 80.484%), yield: 65.31%. LCMS (ESI) m / z calcd. for C 41 H 44 FN 5 O 7 [M+H] + 738.3; found 738.2; 1 H NMR (400 MHz, DMSO_d 6): δ = 10.19 (s, 1H), 10.06 (s, 1H), 8.44 (d, J = 5.2 Hz, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.66 - 7.63 (m, 2H), 7.47 (s, 1H), 7.31 (s, 1H), 7.21 (d, J = 9.0 Hz, 2H), 7.18 - 7.13 (m, 2H), 6.40 (d, J = 5.2 Hz, 1H), 4.11 - 4.05 (m, 2H), 3.95 (s, 3H), 3.62 (d, J = 11.1 Hz, 2H), 3.24 - 3.06 (m, 2H), 2.92 - 2.83 (m, 3H), 2.79 - 2.68 (m, 4H), 2.65 - 2.59 (m, 1H), 1.89 - 1.70 (m, 6H), 1.47 (s, 4H), 1.21 - 1.17 (m, 3H). It can be seen that the structure of the compound is correct.

[0337] In a 50 ml single-necked flask, add compound TPD5436-3 (200 mg, 0.2711 mmol), lithium hydroxide monohydrate (22.75 mg, 0.5422 mmol) and methanol / water = 2:1 (3 ml) in sequence. React at 20 °C for 4 hours. After the reaction is completed, concentrate to dryness to obtain the crude compound TPD5436-4 (250 mg, brown solid), yield: 85.58%. LCMS (ESI) m / z calcd. for C 39 H 40 FN 5 O 7 [M + H] + 710.3; found 710.2. It can be seen that the structure of the compound is correct.

[0338] To a 25 mL single-necked flask, add compound TPD5436-4 (250 mg, 0.3522 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (197.38 mg, 0.4226 mmol), HATU (267.83 mg, 0.7044 mmol), triethylamine (71.28 mg, 0.7044 mmol) and DMF (5 mL) successively. React at 20 °C for 16 hours under nitrogen protection. After the reaction is completed, pour the reaction solution into water (6 mL), and extract three times with EA (3 mL). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. Purify the residue by preparative plate, with the eluent ratio of DCM / MeOH = 10 / 1, to obtain compound TPD005436 (31.2 mg, light yellow solid, purity 96.544%), yield: 7.47%. LCMS (ESI) m / z calcd. for C 61 H 68 FN 9 O 9 S[M+H] + 1122.5; found 1122.3; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 10.18 (s, 1H), 10.06 (s, 1H), 8.99 (s, 1H), 8.58 ((br.s., 1H), 8.44 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.66 - 7.63 (m, 2H), 7.47 (s, 1H), 7.44 - 7.38 (m, 4H), 7.31 (s, 1H), 7.21 (d, J = 8.9 Hz, 2H), 7.18 - 7.13 (m, 2H), 6.40 (d, J = 5.2 Hz, 1H), 5.14 (d, J = 3.3 Hz, 1H), 4.54 (d, J = 9.7 Hz, 1H), 4.45 - 4.31 (m, 3H), 4.35 (s, 1H), 4.25 - 4.20 (m, 1H), 4.03 (br.s., 1H), 3.95 (s, 3H), 3.68 - 3.61 (m, 4H), 3.07 - 3.02 (m, 1H), 2.83 - 2.67 (m, 4H), 2.45 (s, 3H), 2.08 - 1.87 (m, 3H), 1.81 - 1.62 (m, 6H), 1.47 (s, 5H), 1.23 (s, 1H), 0.95 - 0.92 (m, 9H). It can be seen that the structure of the compound is correct.

[0339] Example 24: Synthesis of Compound TPD005452

[0340]

[0341] Compound TPD5436-2 (300 mg, 0.5012 mmol), ethyl glycinate hydrochloride (83.95 mg, 0.6014 mmol), HATU (381.14 mg, 1.0024 mmol), triethylamine (101.43 mg, 1.0024 mmol) and DMF (5 ml) were successively added into a 25 ml single-necked flask. The reaction was carried out at 20 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (6 ml), and extracted three times with EA (3 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by a preparative plate with the eluent ratio of DCM / MeOH = 10 / 1 to obtain Compound TPD5452-1 (190 mg, brown solid, purity 90.489%), yield: 50.18%. LCMS (ESI) m / z calcd. for C 37 H 38 FN 5 O 7 [M+H] + 684.3; found 684.3; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 10.19 (s, 1H), 10.07 (s, 1H), 8.45 (d, J = 5.2 Hz, 1H), 8.32 (t, J = 5.9 Hz, 1H), 7.76 (d, J = 8.9 Hz, 1H), 7.67 - 7.63 (m, 2H), 7.48 (s, 1H), 7.34 (s, 1H), 7.23 - 7.21 (m, 2H), 7.18 - 7.14 (m, 2H), 6.40 (d, J = 5.2 Hz, 1H), 4.13 - 4.08 (m, 2H), 3.96 (s, 1H), 3.83 (d, J = 5.9 Hz, 1H), 3.62 (d, J = 11.5 Hz, 1H), 2.74 - 2.68 (m, 3H), 1.84 - 1.79 (m, 4H), 1.48 (s, 4H), 1.21 (t, J = 7.1 Hz, 1H). It can be seen that the structure of the compound is correct.

[0342] To a 50 ml single-necked flask were successively added compound TPD5436-3 (190 mg, 0.2779 mmol), lithium hydroxide monohydrate (23.32 mg, 0.5558 mmol), and methanol / water = 2:1 (3 ml). The reaction was carried out at 20 °C for 4 hours. After the reaction was completed, it was concentrated to dryness to obtain crude compound TPD5436-4 (200 mg, brown solid), with a yield of 76.90%. LCMS (ESI) m / z calcd. for C 35 H 34 FN 5 O 7 [M+H] + 656.2; found 656.2. It can be seen that the compound structure is correct.

[0343] To a 25 ml single-necked flask were successively added compound TPD5452-2 (100 mg, 0.1525 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (85.46 mg, 0.183 mmol), HATU (115.97 mg, 0.305 mmol), triethylamine (30.86 mg, 0.305 mmol), and DMF (5 ml). The reaction was carried out at 20 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (6 ml), and extracted three times with EA (3 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 6 / 1 to obtain compound TPD005452 (28.2 mg, light yellow solid, purity 95.282%), with a yield of 16.52%; LCMS (ESI) m / z calcd. for C 57 H 62 FN 9 O 9 S[M+H] + 1068.4; found 534.7; 1 H NMR (400 MHz, DMSO_d 6): δ = 10.18 (s, 1H), 10.06 (s, 1H), 8.94 (s, 1H), 8.67 (t, J = 6.4 Hz, 1H), 8.44 (d, J = 5.2 Hz, 1H), 8.23 (t, J = 5.6 Hz, 1H), 7.76 (d, J = 8.9 Hz, 1H), 7.70 - 7.63 (m, 3H), 7.46 (s, 1H), 7.44 - 7.37 (m, 4H), 7.33 (s, 1H), 7.23 - 7.21 (m, 2H), 7.18 - 7.13 (m, 2H), 6.40 (d, J = 5.2 Hz, 1H), 5.17 (d, J = 3.5 Hz, 1H), 4.54 (d, J = 9.5 Hz, 1H), 4.48 - 4.46 (m, 1H), 4.44 - 4.41 (m, 1H), 4.36 (br.s., 1H), 4.25 - 4.19 (m, 1H), 3.93 (s, 3H), 3.78 (d, J = 6.0 Hz, 1H), 3.69 - 3.63 (m, 4H), 2.67 (br.s., 2H), 2.43 (s, 3H), 2.01 - 1.84 (m, 6H), 1.47 (s, 4H), 1.23 (s, 1H), 0.94 - 0.92 (m, 9H). It can be seen that the structure of the compound is correct.

[0344] Example 25: Synthesis of Compound TPD005453

[0345]

[0346] Compound TPD5436 - 2 (300 mg, 0.5012 mmol), ethyl 5 - aminopentanoate hydrochloride (109.26 mg, 0.6014 mmol), HATU (381.14 mg, 1.0024 mmol), triethylamine (101.43 mg, 1.0024 mmol) and DMF (5 ml) were successively added to a 25 - ml single - necked flask. The reaction was carried out at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (6 ml), and extracted three times with EA (3 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 10 / 1, to obtain compound TPD5453 - 1 (110 mg, brown solid, purity 82.845%), yield: 25.06%. LCMS (ESI) m / z calcd. for C 40 H 44 FN 5 O 7 [M + H] + 726.32; found 726.2; 11H NMR (400 MHz, DMSO-d 6 ): δ = 10.18 (s, 1H), 10.06 (s, 1H), 8.44 (d, J = 5.2 Hz, 1H), 7.84 (t, J = 5.5 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.66 - 7.62 (m, 2H), 7.47 (s, 1H), 7.33 (s, 1H), 7.23 - 7.20 (m, 2H), 7.18 - 7.13 (m, 2H), 6.40 (d, J = 5.1 Hz, 1H), 4.08 - 4.03 (m, 2H), 3.95 (s, 3H), 3.62 (d, J = 11.1 Hz, 2H), 3.09 - 3.04 (m, 2H), 2.89 (s, 4H), 2.70 - 2.63 (m, 2H), 2.30 (s, 1H), 1.79 (br.s., 4H), 1.47 (s, 4H), 1.43 - 1.38 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H). It can be seen that the structure of the compound is correct.

[0347] The compound TPD5453-1 (110 mg, 0.1516 mmol), lithium hydroxide monohydrate (12.72 mg, 0.3032 mmol) and methanol / water = 2 / 1 (3 ml) were successively added to a 50 ml single-necked flask. The reaction was carried out at 25 °C for 4 hours. After the reaction was completed, it was concentrated to dryness to obtain the crude compound TPD5453-2 (110 mg, brown solid), yield: 90.50%. LCMS (ESI) m / z calcd. for C 38 H 40 FN 5 O 7 [M + H] + 698.3; found 698.2. It can be seen that the structure of the compound is correct.

[0348] In a 25 ml single-necked flask, add compound TPD5453-2 (100 mg, 0.1433 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (80.31 mg, 0.17196 mmol), HATU (108.97 g, 0.2866 mmol), triethylamine (29 mg, 0.2866 mmol) and DMF (3 ml) in sequence. React at 25 °C for 16 hours under nitrogen protection. After the reaction is completed, pour the reaction solution into water (6 ml), and extract it three times with EA (3 ml). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. Purify the residue by preparative plate, and the eluent ratio is DCM / MeOH = 8 / 1 to obtain compound TPD005453 (21.8 mg, light yellow solid, purity 97.007%), yield: 13.26%. LCMS(ESI) m / z calcd. for C 60 H 68 FN 9 O 9 S[M+H] + 1110.5; found 555.8 (half peak); 1 H NMR(400 MHz, DMSO_d 6): δ = 10.19 (s, 1H), 10.07 (s, 1H), 8.98 (s, 1H), 8.59 (t, J = 6.4 Hz, 1H), 8.44 (d, J = 5.2 Hz, 1H), 7.89 (d, J = 9.4 Hz, 1H), 7.83 (t, J = 5.4 Hz, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.66 - 7.63 (m, 2H), 7.47 (s, 1H), 7.43 - 7.37 (m, 4H), 7.32 (s, 1H), 7.22 (d, J = 8.9 Hz, 2H), 7.18 - 7.13 (m, 2H), 6.40 (d, J = 5.1 Hz, 1H), 5.16 (d, J = 3.4 Hz, 1H), 4.55 (d, J = 9.4 Hz, 1H), 4.47 - 4.41 (m, 2H), 4.36 (br.s., 1H), 4.24 - 4.19 (m, 1H), 3.95 (s, 3H), 3.66 - 3.60 (m, 4H), 3.06 - 3.04 (m, 2H), 2.67 - 2.66 (m, 2H), 2.44 (s, 3H), 2.31 - 2.24 (m, 2H), 2.16 - 2.10 (m, 1H), 2.08 - 1.99 (m, 2H), 1.94 - 1.87 (m, 1H), 1.79 (br.s., 4H), 1.47 (s, 4H), 1.42 - 1.35 (m, 2H), 1.23 (s, 1H), 0.94 (s, 9H). It can be seen that the compound structure is correct.

[0349] Example 26: Synthesis of Compound TPD005457

[0350]

[0351] Into a 25 ml single-necked flask, successively add compound int-A (200 mg, 0.3228 mmol), tert-butyl piperazine-1-carboxylate (132.27 mg, 0.7101 mmol), cesium carbonate (210.35 mg, 0.6456 mmol), dioxane (10 ml), Pd 2 (dba) 3 (59.12 mg, 0.0645 mmol) and 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (80.4 mg, 0.1291 mmol). React at 100 °C for 16 hours under nitrogen protection. After the reaction is completed, the reaction solution is cooled to room temperature and concentrated to dryness. The residue is purified by silica gel column chromatography, and the eluent ratio is DCM / MeOH = 100 / 1 - 50 / 1, to obtain compound TPD5457-1 (63.33 mg, yellow solid, purity 88.841%), yield: 53.16%. LCMS (ESI) m / z calcd. for C 36H 38 FN 5 O 6 [M+H] + 656.3; found 656.3; 1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.19 (s, 1H), 10.06 (s, 1H), 8.45 (d, J = 5.2 Hz, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.67 - 7.62 (m, 2H), 7.50 (s, 1H), 7.34 (s, 1H), 7.24 - 7.12 (m, 4H), 6.41 (d, J = 5.2 Hz, 1H), 3.96 (s, 3H), 3.53 (br.s., 4H), 3.18 - 3.01 (m, 4H), 1.49 - 1.37 (m, 13H). It can be seen that the structure of the compound is correct.

[0352] Compound TPD5457-1 (280 mg, 0.4270 mmol), DCM (2 ml), and TFA (2 ml) were added to a 25-ml single-necked flask. The reaction was carried out at 25 °C for 30 minutes. The reaction solution was concentrated to dryness to obtain crude compound TPD5457-2 (440 mg, white solid, purity 82.094%), and the yield was 94.24%. LCMS (ESI) m / z calcd. for C 31 H 30 FN 5 O 4 [M+H] + 556.2; found 556.1. It can be seen that the structure of the compound is correct.

[0353] Compound TPD5457-2 (300 mg, 0.54 mmol), ethyl 4-bromobutyrate (210.66 mg, 1.08 mmol), potassium carbonate (223.9 mg, 1.62 mmol), potassium iodide (8.96 mg, 0.054 mmol), and acetonitrile (30 mL) were added to a 100-ml single-necked flask. The reaction was carried out at 20 °C for 16 hours. The reaction solution was poured into water (50 ml), and extracted with EA (30 ml) three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 10 / 1 to obtain compound TPD5457-3 (100 mg, yellow solid, purity 98.017%), and the yield was 27.11%. LCMS (ESI) m / z calcd. for C 37 H 40 FN 5 O 6 [M+H] +670.3; found 670.1; 1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.19 (s, 1H), 10.06 (s, 1H), 8.44 (d, J = 5.2 Hz, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.69 - 7.58 (m, 2H), 7.48 (s, 1H), 7.31 (s, 1H), 7.24 - 7.09 (m, 4H), 6.40 (d, J = 5.2 Hz, 1H), 4.07 (q, J = 7.1 Hz, 2H), 3.95 (s, 3H), 3.14 (br.s., 4H), 2.56 (br.s., 4H), 2.38 - 2.32 (m, 4H), 1.82 - 1.65 (m, 2H), 1.48 (s, 4H), 1.19 (t, J = 7.1 Hz, 3H). It can be seen that the structure of the compound is correct.

[0354] In a 25 ml single-necked flask, compound TPD5457 - 3 (100 mg, 0.1493 mmol), EtOH (0.5 ml), H 2 O (0.5 ml) and lithium hydroxide monohydrate (9.4 mg, 0.2239 mmol) were successively added. The reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated to dryness to obtain crude compound TPD5457 - 4 (100 mg, white solid, purity 91.427%), yield: 94.44%. LCMS (ESI) m / z calcd. for C 35 H 36 FN 5 O 6 [M + H] + 642.3; found 642.1. It can be seen that the structure of the compound is correct.

[0355] In a 25 ml single-necked flask, add compound TPD5457-4 (110 mg, 0.1714 mmol), DMF (6 ml), TEA (34.69 mg, 0.3428 mmol), HATU (130.34 mg, 0.3428 mmol) and (2S,4R)-1-((S)-2-(12-azacyclic group)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (96.06 mg, 0.2056 mmol) in sequence. React at 25 °C for 16 hours. Pour the reaction solution into water (10 ml), and extract it 3 times with EA (5 ml). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. The residue is purified by a preparative plate, and the eluent ratio is DCM / MeOH = 6 / 1 to obtain compound TPD005457 (30.1 mg, off-white solid, purity 96.484%), yield: 16.04%. LCMS (ESI) m / z calcd. for C 57 H 64 FN 9 O 8 S[M+H] + 1054.5; found 1054.7; 1 H NMR (400 MHz, DMSO_d 6): δ = 10.19 (s, 1H), 10.06 (s, 1H), 8.98 (s, 1H), 8.58 (t, J = 5.9 Hz, 1H), 8.44 (d, J = 5.2 Hz, 1H), 7.92 (br.s., 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.88 - 7.83 (m, 2H), 7.48 (s, 1H), 7.44 - 7.37 (q, J = 8.3 Hz, 4H), 7.32 (s, 1H), 7.21 (d, J = 8.9 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 6.40 (d, J = 5.1 Hz, 1H), 5.15 (d, J = 3.2 Hz, 1H), 4.57 (d, J = 9.4 Hz, 1H), 4.47 - 4.12 (m, 2H), 4.36 (br.s., 1H), 4.25 - 4.19 (m, 1H), 3.98 - 3.92 (m, 3H), 3.71 - 3.61 (m, 2H), 3.15 (br.s., 4H), 2.56 (br.s., 2H), 2.44 (s, 4H), 2.39 - 2.27 (m, 3H), 2.22 (d, J = 7.1 Hz, 1H), 2.07 - 1.99 (m, 1H), 1.94 - 1.87 (m, 1H), 1.72 (br.s., 2H), 1.47 (s, 4H), 1.23 (s, 1H), 0.98 - 0.93 (m, 9H). It can be seen that the structure of the compound is correct.

[0356] Example 27: Synthesis of Compound TPD005488

[0357]

[0358] Compound int - A (600 mg, 0.9685 mmol), piperidine - 4 - methanol (245.4 mg, 2.1307 mmol), cesium carbonate (631.11 mg, 1.937 mmol), BINAP (241.22 mg, 0.3874 mmol), Pd 2 (dba) 3 (177.37 mg, 0.1937) and 1,4 - dioxane (30 ml) were successively added to a 100 - ml three - necked flask. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated to dryness. The residue was purified by silica gel column chromatography, and the eluent ratio was DCM / MeOH = 50 / 1 - 30 / 1, to obtain compound TPD5488 - 1 (360 mg, yellow solid, purity 63.777%), and the yield was 40.55%. LCMS (ESI) m / z calcd. for C 33 H 33 FN 4 O5 [M+H] + 585.2; found 585.1; 1 HNMR(400 MHz, CDCl 3 ): δ = 9.30 (s, 1H), 8.80 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.51 - 7.46 (m, 4H), 7.17 (d, J = 8.8 Hz, 2H), 7.07 - 7.03 (m, 2H), 6.43 (d, J = 5.2 Hz, 1H), 4.03 (s, 3H), 3.76 - 3.73 (m, 2H), 3.60 (d, J = 6.4 Hz, 2H), 2.74 - 2.68 (m, 2H), 1.92 - 1.89 (m, 2H), 1.75 - 1.53 (m, 8H). It can be seen that the structure of the compound is correct.

[0359] Oxalyl chloride (86.85 mg, 0.6842 mmol) and DCM (5 ml) were added to a 50 ml three-necked flask. Under nitrogen protection, the reaction solution was cooled to -78 °C, and then DMSO (106.91 mg, 1.3684 mmol) was added dropwise. After reacting at -78 °C for half an hour, a DCM (5 ml) solution of compound TPD5488-2 (200 mg, 0.3421 mmol) was added dropwise. After reacting at -78 °C for 1 hour, TEA (276.94 mg, 2.7368 mmol) was added dropwise. After the addition was completed, the cold bath was removed, and the reaction was allowed to warm up naturally for 1 hour. The reaction solution was poured into saturated sodium bicarbonate aqueous solution (20 ml), and extracted three times with DCM (20 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain crude compound TPD5488-2 (80 mg, yellow solid, purity 53.406%), yield: 21.43%. LCMS(ESI) m / z calcd. for C 33 H 31 FN 4 O 5 [M+H] + 583.2; found 583.0. It can be seen that the structure of the compound is correct.

[0360] Oxalyl chloride (5.51 g, 43.4 mmol) and DCM (80 ml) were added to a 250 ml three-necked flask. Under nitrogen protection, the reaction solution was cooled to -78 °C, and then DMSO (6.784 g, 86.8 mmol) was added dropwise. After reacting at -78 °C for half an hour, a DCM (20 ml) solution of compound 4-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (5, 21.7 mmol) was added dropwise. After reacting at -78 °C for 1 hour, TEA (17.47 g, 173.6 mmol) was added dropwise. After the addition was complete, the cold bath was removed, and the reaction was allowed to warm to room temperature for 1 hour. The reaction solution was poured into saturated aqueous sodium bicarbonate solution (100 ml), and the organic phase was separated. The aqueous phase was extracted twice with DCM (80 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the crude compound TPD5488-4 (4 g, light yellow oil, purity 90%), yield: 72.81%. LCMS (ESI) m / z calcd. for C 11 H 20 N 2 O 3 [M+H] + 229.2; found 229.2 and 247.2; 1 H NMR (400 MHz, DMSO-d 6 ): δ = 9.58 (s, 1H), 3.28 (br.s., 1H), 3.21 (s, 3H), 2.41 - 2.39 (m, 6H), 1.40 (s, 9H). It can be seen that the structure of the compound is correct.

[0361] Compound TPD5488-4 (1.76 g, 7.71 mmol), DCE (50 ml), 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (2 g, 7.71 mmol) and sodium triacetoxyborohydride (4.08 g, 19.2 mmol) were successively added to a 250 ml three-necked flask. Under nitrogen protection, the reaction was carried out at 20 °C for 16 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate solution (50 ml). The organic phase was separated. The aqueous phase was extracted twice with DCM (50 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with an eluent ratio of DCM / MeOH = 60 / 1 - 40 / 1 to obtain compound TPD5488-5 (1.78 g, white solid, purity 92.874%), yield: 42.21%. LCMS (ESI) m / z calcd. for C 24 H 33 N 5 O 5 [M+H] +472.3; found 472.1; 1 HNMR(400 MHz, CDCl 3 ): δ = 8.20 (s, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 6.80 (d, J = 7.9 Hz, 1H), 5.26 (dd, J = 13.3, 5.1 Hz, 1H), 4.33 (d, J = 15.4 Hz, 1H), 4.25 (br.s., 1H), 4.16 (d, J = 15.3 Hz, 1H), 3.46 (s, 4H), 3.29 (dd, J = 10.4, 5.1 Hz, 2H), 2.96 - 2.85 (m, 2H), 2.71 (t, J = 5.4 Hz, 2H), 2.48 - 2.32 (m, 5H), 2.27 - 2.17 (m, 1H), 1.48 (s, 9H). It can be seen that the structure of the compound is correct.

[0362] To a 50 ml single-necked flask were successively added compound TPD5488-5 (500 mg, 1.0581 mmol) and 1,4-dioxane solution of hydrogen chloride (10 ml, 4N). The reaction was carried out at 20 °C for 4 hours. After the reaction was completed, it was concentrated to dryness to obtain crude compound TPD5488-6 (480 mg, white solid), yield: 98.09%. LCMS (ESI) m / z calcd. for C 19 H 25 N 5 O 3 [M + H] + 372.2; found 372.0. It can be seen that the structure of the compound is correct.

[0363] To a 50 ml single-necked flask were successively added compound TPD5488-2 (80 mg, 0.1373 mmol), DCE (4 ml), compound TPD5488-6 (56.1 mg, 0.151 mmol) and sodium triacetoxyborohydride (87.3 mg, 0.4119 mmol). Under nitrogen protection, the reaction was carried out at 20 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 10 / 1, to obtain compound TPD005488 (15.6 mg, light yellow solid, purity 99.304%), yield: 12.02%. LCMS (ESI) m / z calcd. for C 52 H 56 FN 9 O 7 [M + H] + 938.4; found 938.4; 11H NMR (400 MHz, CDCl 3 ): δ = 9.38 (s, 1H), 8.80 (s, 1H), 8.46 (d, J = 5.3 Hz, 1H), 8.23 (br.s., 1H), 7.62 (d, J = 8.9 Hz, 2H), 7.54 - 7.44 (m, 4H), 7.37 (t, J = 7.7 Hz, 1H), 7.29 - 7.26 (m, 1H), 7.16 (d, J = 8.9 Hz, 2H), 7.05 (t, J = 8.6 Hz, 2H), 6.76 (d, J = 7.9 Hz, 1H), 6.43 (d, J = 5.3 Hz, 1H), 5.21 (dd, J = 13.2, 5.0 Hz, 1H), 4.39 - 4.30 (m, 2H), 4.02 (s, 3H), 3.71 (d, J = 11.5 Hz, 2H), 3.35 (br.s., 2H), 2.96 - 2.57 (m, 12H), 2.45 - 2.18 (m, 5H), 1.90 (d, J = 12.7 Hz, 3H), 1.80 - 1.61 (m, 6H), 1.59 - 1.44 (m, 3H). It can be seen that the structure of the compound is correct.

[0364] Example 28: Synthesis of Compound TPD005494

[0365]

[0366] Compound TPD5432 - 2 (550 mg, 0.9673 mmol), 1 - tert - butoxycarbonylpiperazine (900.8 mg, 4.8365 mmol), sodium triacetoxyborohydride (615.03 mg, 2.9019 mmol), titanium(IV) isopropoxide (1 ml), and DCE (10 ml) were successively added to a 50 - ml three - necked flask. The reaction mixture was stirred at 40 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, water was added to the reaction solution, and it was extracted 3 times with DCM (20 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered, and evaporated to obtain a residue. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain the product compound TPD5494 - 1 (800 mg, yellow solid, purity 80.329%), and the yield was 89.92%. LCMS (ESI) m / z calcd. for C 41 H 47 FN 6 O 6 [M + H] + 739.4; found 739.5; 1 1H NMR (400 MHz, CDCl 3): δ 9.21 (s, 1H), 8.68 (s, 1H), 8.40 (d, J = 5.2 Hz, 1H), 7.55 (d, J = 8.9 Hz, 2H), 7.49 - 7.33 (m, 4H), 7.10 (d, J = 8.9 Hz, 2H), 7.04 - 6.90 (m, 2H), 6.36 (d, J = 5.2 Hz, 1H), 3.95 (s, 3H), 3.73 - 3.65 (m, 3H), 3.39 - 3.38 (m, 5H), 2.74 (br.s., 8H), 2.51 (br.s., 4H), 1.61 - 1.60 (m, 6H), 1.40 (s, 9H). It can be seen that the structure of the compound is correct.

[0367] Add compound TPD5494 - 1 (500 mg, 0.6767 mmol), DCM (2.5 ml), and trifluoroacetic acid (2.5 ml) to a 25 - ml three - necked flask. React the resulting mixture at 20 °C for 3 hours. After the reaction is completed, directly evaporate to dryness to obtain the yellow solid product compound TPD5494 - 2 (400 mg, yellow solid, purity 90.161%), yield: 83.43%. LCMS (ESI) m / z calcd. for C 36 H 39 FN 6 O 4 [M + H] + 639.3; found 639.3. It can be seen that the structure of the compound is correct.

[0368] Add compound TPD54945 - 2 (400 mg, 0.6262 mmol), HATU (357.15 mg, 0.9393 mmol), monoethyl adipate (109.08 mg, 0.6262 mmol), and TEA (316.83 mg, 3.131 mmol) successively to a 25 - ml single - necked flask. Under nitrogen protection, react the reaction solution at 20 °C for 16 hours. After the reaction is completed, add water to the mixture, and extract the mixture with DCM (5 ml) three times. Wash the combined organic layers with brine (20 ml), dry over anhydrous sodium sulfate, filter, and evaporate to obtain a residue. Purify the residue by preparative TLC (DCM / MeOH = 10 / 1) to obtain the yellow solid product compound TPD5494 - 3 (50 mg, yellow solid, purity 95.357%), yield: 9.58%. LCMS (ESI) m / z calcd. for C 44 H 51 FN 6 O 7 [M + H] + 795.4; found 795.5. It can be seen that the structure of the compound is correct.

[0369] Add compound TPD5494-3 (50 mg, 0.0629 mmol), THF / MeOH / H 2 O = 1 / 1 / 1 (2 ml), and LiOH.H 2 O (5.28 mg, 0.1258 mmol) into a 25 ml single-necked flask. Stir the resulting mixture at 20 °C for 3 hours. After the reaction is completed, rotary evaporate the reaction solution to obtain the crude product compound TPD5494-4 (48 mg, white solid, purity 96.029%), yield: 95.55%. LCMS (ESI) m / z calcd. for C 42 H 47 FN 6 O 7 [M + H] + 767.3; found 767.5. It can be seen that the compound structure is correct.

[0370] Add DMF (5 ml), compound TPD5494-4 (48 mg, 0.0626 mmol), HATU (35.7 mg, 0.0939 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (35.84 mg, 0.0626 mmol) and TEA (31.67 mg, 0.313 mmol) into a 50 ml single-necked flask in sequence. Under nitrogen protection, react at 20 °C for 16 hours. After the reaction is completed, quench the reaction solution with water. Extract three times with ethyl acetate (10 ml). Wash the combined organic layers with brine (20 ml), dry over anhydrous sodium sulfate, filter and evaporate to obtain a residue. Purify the residue by preparative TLC (DCM / MeOH = 10 / 1) to obtain the yellow solid product compound TPD005494 (13.5 mg, yellow solid, purity 95.005%), yield: 17.41%. LCMS (ESI) m / z calcd. for C 64 H 75 FN 10 O 9 S [M + H] + 1079.5; found 1179.6; 1 H NMR (400 MHz, DMSO-_d 6): δ 10.18 (s, 1H), 10.05 (s, 1H), 8.98 (s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 8.43 (d, J = 5.2 Hz, 1H), 7.87 (d, J = 9.3 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.64 (dd, J = 8.9, 5.0 Hz, 2H), 7.51 - 7.34 (m, 5H), 7.32 (s, 1H), 7.25 - 7.10 (m, 4H), 6.39 (d, J = 5.2 Hz, 1H), 5.13 (d, J = 3.4 Hz, 1H), 4.55 (d, J = 9.3 Hz, 1H), 4.44 (dd, J = 15.5, 7.0 Hz, 2H), 4.35 (s, 1H), 4.21 (dd, J = 15.9, 5.2 Hz, 1H), 3.94 (s, 3H), 3.66 (s, 4H), 3.44 (s, 4H), 2.64 (d, J = 10.7 Hz, 2H), 2.45 (d, J = 5.5 Hz, 5H), 2.29 (s, 3H), 2.19 - 1.97 (m, 3H), 1.94 - 1.81 (m, 3H), 1.63 (d, J = 10.2 Hz, 2H), 1.47 (s, 9H), 1.23 (s, 1H), 0.94 (s, 9H). It can be seen that the structure of the compound is correct.

[0371] Example 29: Synthesis of Compound TPD005495

[0372]

[0373] Compound TPD5495-1 (2 g, 12.33 mmol), tert-butyl glycolate (1.63 g, 12.33 mmol), sodium methoxide (1.33 g, 24.66 mmol) and tetrahydrofuran (50 ml) were successively added to a 100 ml three-necked flask. The reaction was carried out at 20 °C for 48 hours under nitrogen protection. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride (100 ml). The mixture was extracted with ethyl acetate (100 ml) three times. The combined organic phases were washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain a residue. The residue was purified by silica gel column chromatography with an eluent ratio of PE / EtOAc = 50 / 1 - 15 / 1 to obtain compound TPD5495-2 (800 mg, colorless oil, purity 88.706%), yield: 19.55%. LCMS (ESI) m / z calcd. for C 16 H 22 O 5 [M + H] + 295.2; found 295.1 and 317.1 (plus Na); 11H NMR (400 MHz, CDCl 3 ): δ = 7.41 - 7.27 (m, 3H), 5.15 (s, 2H), 3.97 (s, 1H), 3.84 (t, J = 6.4 Hz, 1H), 2.70 (t, J = 6.4 Hz, 1H), 1.47 (s, 5H). It can be seen that the structure of the compound is correct.

[0374] Compound TPD5495 - 2 (200 mg, 0.68 mmol) and EA (2 ml) were added to a 50 ml single - necked flask. Pd / C (43 mg, 0.41 mmol) was further added, and the reaction mixture was stirred at 20 °C for 2 h under H 2 environment. The mixture was filtered and concentrated to dryness to obtain crude compound TPD5495 - 2 (100 mg, yellow solid, purity 90%), yield: 64.86%. LCMS (ESI) m / z calcd. for C 9 H 16 O 5 [M - H] - 203.1; found 203.2. It can be seen that the structure of the compound is correct.

[0375] Compound TPD5494 - 2 (172 mg, 0.27 mmol), compound TPD5494 - 2 (55 mg, 0.27 mmol), HATU (154 mg, 0.40 mmol), triethylamine (136 mg, 1.35 mmol) and DMF (5 ml) were successively added to a 50 ml single - necked flask. The reaction was carried out at 20 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (6 ml), and extracted three times with EA (6 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 5 / 1 to obtain compound TPD005495 - 4 (70 mg, light yellow solid, purity 90.63%), yield: 61.20%. LCMS (ESI) m / z calcd. for C 45 H 53 FN 6 O 8 [M + H] + 825.3; found 825.4 and 826.4; 1 1H NMR (400 MHz, DMSO - d 6): δ = 10.17 (s, 1H), 10.05 (s, 1H), 8.44 (d, J = 5.2 Hz, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.65 - 7.62 (m, 2H), 7.46 (s, 1H), 7.32 (s, 1H), 7.22 - 7.20 (m, 2H), 7.17 - 7.13 (m, 2H), 6.39 (d, J = 5.2 Hz, 1H), 3.96 (s, 5H), 3.67 - 3.63 (d, J = 11.3 Hz, 4H), 3.45 (m, 5H), 2.59 - 2.54 (t, J = 11.2 Hz, 8H), 1.88 (m, 2H), 1.64 - 1.62 (m, 2H), 1.47 (m, 4H), 1.47 (s, 4H), 1.42 (s, 9H). It can be seen that the compound structure is correct.

[0376] Compound TPD5495 - 4 (100 mg, 0.12 mmol), DCM (3 ml) and trifluoroacetic acid (1 ml) were successively added into a 50 ml single - necked flask. The reaction was carried out at 25 °C for 2 hours. After the reaction was completed, it was concentrated to dryness to obtain crude compound TPD5496 - 4 (90 mg, brown solid, purity 82.471%), yield: 79.62%. LCMS (ESI) m / z calcd. for C 4 H4 5 FN 6 O 8 [M + H] + 769.3; found 385.2 and 769.3. It can be seen that the compound structure is correct.

[0377] Compound TPD5495 - 5 (90 mg, 0.12 mmol), (2S,4R)-1 - ((S)-2 - amino - 3,3 - dimethylbutanoyl)-4 - hydroxy - N-(4-(4 - methylthiazol - 5 - yl)benzyl)pyrrolidine - 2 - carboxamide hydrochloride (74 mg, 0.13 mmol), HATU (67 mg, 0.18 mmol), triethylamine (59 mg, 0.59 mmol) and DMF (5 ml) were successively added into a 25 ml single - necked flask. The reaction was carried out at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (20 ml), and extracted three times with EA (20 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 8 / 1 to obtain compound TPD005496 (15.5 mg, light yellow solid, purity 97.458%), yield: 10.93%. LCMS (ESI) m / z calcd. for C 63 H 73 FN10 O 10 S[M+H] + 1181.5; found 1181.3; 1 H NMR(400MHz, DMSO_d 6 ): δ = 10.16(s, 1H), 10.05(s, 1H), 8.99(s, 1H), 8.59(br.s., 1H), 8.44(d, J = 4.9Hz, 1H), 7.74(d, J = 9.0Hz, 2H), 7.46(d, J = 8.4Hz, 3H), 7.40 - 7.38(m, 5H), 7.22(s, 1H), 7.17 - 7.13(m, 4H), 6.40(d, J = 4.7Hz, 1H), 5.14(s, 1H), 4.58(d, J = 9.2Hz, 1H), 4.39 - 4.35(m, 3H), 4.27 - 4.25(m, 2H), 3.94(s, 5H), 3.73 - 3.64(m, 6H), 3.46(s, 4H), 2.66 - 2.63(m, 4H), 2.49(s, 3H), 2.07(m, 2H), 2.02 - 1.82(m, 4H), 1.59(m, 3H), 1.47(s, 4H), 1.23(s, 1H), 0.93(s, 9H). It can be seen that the compound structure is correct.

[0378] Example 30: Synthesis of Compound TPD005496

[0379]

[0380] Compound TPD5432 - 2 (350 mg, 0.6156 mmol), tert - butyl piperidine - 4 - carboxylate hydrochloride (651.67 mg, 3.078 mmol), sodium triacetoxyborohydride (391.41, 1.8468 mmol), titanium(IV) isopropoxide (1.5 ml) and 1,2 - dichloroethane (5 ml) were successively added to a 25 - ml single - necked flask. The reaction was carried out at 40 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water (10 ml), and extracted three times with DCM (5 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with an eluent ratio of DCM / MeOH = 100 / 1 - 30 / 1 to obtain compound TPD5496 - 1 (500 mg, brown solid, purity 75.139%), yield: 82.72%. LCMS(ESI) m / z calcd. for C 42 H 48 FN 5 O 6 [M+H] +738.4; found 738.4; 1 HNMR(400MHz, DMSO_d 6 ): δ = 10.17(s, 1H), 10.06(s, 1H), 8.43(d, J = 5.2Hz, 1H), 7.75(d, J = 8.9Hz, 2H), 7.66 - 7.61(m, 2H), 7.46(s, 1H), 7.31(s, 1H), 7.23 - 7.19(m, 2H), 7.18 - 7.12(m, 2H), 6.39(d, J = 5.2Hz, 1H), 3.95(s, 3H), 3.65(d, J = 11.3Hz, 2H), 2.92 - 2.85(m, 4H), 2.64(t, J = 11.2Hz, 2H), 2.46 - 2.43(m, 2H), 1.84 - 1.76(m, 4H), 1.69 - 1.63(m, 4H), 1.47(s, 4H), 1.39(s, 10H). It can be seen that the structure of the compound is correct.

[0381] In a 50 ml single-necked flask, compound TPD5496-1 (450 mg, 0.6099 mmol), DCM (2 ml) and trifluoroacetic acid (2 ml) were added successively. The reaction was carried out at 25 °C for 2 hours. After the reaction was completed, it was concentrated to dryness to obtain crude compound TPD5496-2 (450 mg, brown solid), yield: 81.41%. LCMS(ESI) m / z calcd. for C 38 H 40 FN 5 O 6 [M + H] + 682.3; found 682.2. It can be seen that the structure of the compound is correct.

[0382] In a 25 ml single-necked flask, compound TPD5496-2 (450 mg, 0.6601 mmol), H-Y-ABU-OTBU hydrochloride (155.01 mg, 0.7921 mmol), HATU (501.98 mg, 1.3202 mmol), triethylamine (133.59 mg, 1.3202 mmol) and DMF (5 ml) were added successively. The reaction was carried out at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (20 ml), and extracted three times with EA (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography, and the eluent ratio was DCM / MeOH = 50 / 1 - 30 / 1 to obtain compound TPD5496-3 (250 mg, brown solid, purity 76.554%), yield: 35.24%. LCMS(ESI) m / z calcd. for C46 H 55 FN 6 O 7 [M+H] + 823.4; found 823.4. It can be seen that the compound structure is correct.

[0383] Compound TPD5496-3 (250 mg, 0.3038 mmol), DCM (3 ml) and trifluoroacetic acid (2 ml) were successively added to a 50 ml single-necked flask. The reaction was carried out at 25 °C for 2 hours. After the reaction was completed, it was concentrated to dryness to obtain crude compound TPD5496-4 (200 mg, brown solid), yield: 71.49%. LCMS (ESI) m / z calcd. for C 42 H 47 FN 6 O=[M+H] + 767.4; found 767.3. It can be seen that the compound structure is correct.

[0384] Compound TPD5496-4 (200 mg, 0.2608 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (146.16 mg, 0.3129 mmol), HATU (198.33 mg, 0.5216 mmol), triethylamine (52.78 mg, 0.5216 mmol) and DMF (5 ml) were successively added to a 25 ml single-necked flask. The reaction was carried out at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (20 ml), and extracted three times with EA (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 5 / 1 to obtain compound TPD005496 (10.4 mg, light yellow solid, purity 95.075%), yield: 3.22%. LCMS (ESI) m / z calcd. for C 64 H 75 FN 10 O 9 S[M+H] + 1179.5; found 590.4 (half peak); 1 H NMR (400 MHz, DMSO_d 6): δ = 10.20 (s, 1H), 10.05 (s, 1H), 8.99 (s, 1H), 8.57 (br.s., 1H), 8.45 (d, J = 4.9 Hz, 1H), 7.92 (d, J = 9.0 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.66 - 7.63 (m, 2H), 7.50 - 7.36 (m, 6H), 7.22 - 7.13 (m, 4H), 6.41 (d, J = 4.7 Hz, 1H), 5.14 (s, 1H), 4.55 (d, J = 9.2 Hz, 1H), 4.45 - 4.36 (m, 3H), 4.25 - 4.19 (m, 1H), 3.96 (s, 3H), 3.73 - 3.57 (m, 5H), 3.05 (s, 3H), 2.72 - 2.67 (m, 2H), 2.45 (s, 3H), 2.33 - 2.16 (m, 4H), 2.07 - 1.91 (m, 9H), 1.62 (s, 2H), 1.48 (s, 4H), 1.23 (br.s., 3H), 0.95 (s, 9H). It can be seen that the structure of the compound is correct.

[0385] Example 31: Synthesis of Compound TPD005505

[0386]

[0387] Compound int-A (300 mg, 0.4842 mmol), tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (274.03 mg, 0.7263 mmol), sodium carbonate (102.65 mg, 0.9684 mmol), Pd(dppf)Cl 2 (70.86 mg, 0.09684) and DMSO / H 2 O = 5 / 1 (6 ml) were successively added to a 25 ml three-necked flask. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water (20 ml), and extracted three times with EA (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with an eluent ratio of DCM / MeOH = 50 / 1 - 30 / 1 to obtain compound TPD5505-1 (350 mg, brown solid, purity 87.238%), yield: 87.48%. LCMS(ESI) m / z calcd. for C 40 H 41 FN 6 O 6 [M + H] +721.3; found 721.2; 1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.20 (s, 1H), 10.06 (s, 1H), 8.52 (d, J = 5.1 Hz, 1H), 8.44 (s, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 7.78 (d, J = 8.9 Hz, 2H), 7.67 - 7.62 (m, 3H), 7.26 (d, J = 9.0 Hz, 2H), 7.18 - 7.14 (m, 2H), 6.48 (d, J = 5.1 Hz, 1H), 4.48 - 4.40 (m, 2H), 4.10 - 4.05 (m, 6H), 2.07 - 2.04 (m, 2H), 1.92 - 1.82 (m, 2H), 1.48 (s, 4H), 1.43 (s, 9H). It can be seen that the compound structure is correct.

[0388] To a 50 ml single-necked flask were successively added compound TPD5505-1 (300 mg, 0.4162 mmol), DCM (4 ml) and trifluoroacetic acid (2 ml). The reaction was carried out at 25 °C for 2 hours. After the reaction was completed, it was concentrated to dryness to obtain crude compound TPD5505-2 (320 mg, brown solid), yield: 77.73%. LCMS (ESI) m / z calcd. for C 35 H 33 FN 6 O 4 [M + H] + 621.3; found 621.4. It can be seen that the compound structure is correct.

[0389] To a 25 ml single-necked flask were successively added compound TPD5505-2 (320 mg, 0.5156 mmol), monoethyl adipate (107.77 mg, 0.61872 mmol), HATU (392.09 mg, 1.0312 mmol), triethylamine (104.35 mg, 1.0312 mmol) and DMF (5 ml). The reaction was carried out at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (20 ml), and extracted three times with EA (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with an eluent ratio of DCM / MeOH = 50 / 1 - 30 / 1 to obtain compound TPD5505-3 (340 mg, brown solid, purity 94.211%), yield: 79.97%. LCMS (ESI) m / z calcd. for C 43 H 45 FN 6 O7 [M+H] + 777.3; found 777.4; 1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.23 (s, 1H), 10.04 (s, 1H), 8.60 (d, J = 5.5 Hz, 1H), 8.46 (s, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 7.80 (d, J = 9.0 Hz, 2H), 7.67 - 7.63 (m, 3H), 7.30 - 7.28 (m, 2H), 7.19 - 7.14 (m, 2H), 6.57 (d, J = 5.5 Hz, 1H), 4.54 - 4.50 (m, 2H), 4.08 - 4.03 (m, 6H), 3.17 (s, 2H), 2.38 (t, J = 6.9 Hz, 2H), 2.32 (t, J = 7.0 Hz, 2H), 2.12 - 2.06 (m, 2H), 1.99 - 1.93 (m, 1H), 1.86 - 1.80 (m, 1H), 1.58 - 1.54 (m, 4H), 1.48 (s, 4H), 1.18 (t, J = 7.1 Hz, 3H). It can be seen that the structure of the compound is correct.

[0390] In a 50 ml single-necked flask, compound TPD5505-3 (300 mg, 0.3862 mmol), lithium hydroxide monohydrate (32.41 mg, 0.7724 mmol) and methanol / water = 2 / 1 (3 ml) were added successively. The reaction was carried out at 25 °C for 2 hours. After the reaction was completed, it was concentrated to dryness to obtain the crude compound TPD5505-4 (300 mg, brown solid), yield: 85.24%. LCMS (ESI) m / z calcd. for C 41 H 41 FN 6 O 7 [M+H] + 749.3; found 749.2. It can be seen that the structure of the compound is correct.

[0391] To a 25-ml single-necked flask were successively added compound TPD5505-4 (300 mg, 0.4006 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (224.51 mg, 0.48072 mmol), HATU (304.64 mg, 0.8012 mmol), triethylamine (81.07 mg, 0.8012 mmol) and DMF (5 ml). The reaction was carried out at 25 °C for 16 h under nitrogen protection. After completion of the reaction, the reaction solution was poured into water (20 ml), and extracted three times with EA (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with an eluent ratio of DCM / MeOH = 50 / 1 to 30 / 1 to obtain compound TPD005505 (13.3 mg, white solid, purity 98.177%), yield: 2.80%. LCMS (ESI) m / z calcd. for C 63 H 69 FN 10 O 9 S[M+H] + 1161.5; found 1161.6; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 10.20 (s, 1H), 10.05 (s, 1H), 8.98 (s, 1H), 8.59 - 8.52 (m, 2H), 8.43 (s, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 7.88 (d, J = 9.4 Hz, 1H), 7.78 (d, J = 8.9 Hz, 2H), 7.67 - 7.60 (m, 3H), 7.43 - 7.37 (m, 5H), 7.26 (d, J = 9.0 Hz, 2H), 7.18 - 7.13 (m, 2H), 6.49 (d, J = 5.3 Hz, 1H), 5.13 (s, 1H), 4.57 - 4.51 (m, 3H), 4.46 - 4.41 (m, 2H), 4.35 (s, 1H), 4.24 - 4.19 (m, 1H), 4.04 (s, 4H), 3.65 (br.s., 2H), 3.23 - 3.17 (m, 1H), 2.70 (d, J = 25.1 Hz, 1H), 2.44 (s, 4H), 2.39 - 2.35 (m, 2H), 2.33 - 2.28 (m, 1H), 2.18 - 1.99 (m, 4H), 1.95 - 1.75 (m, 3H), 1.56 - 1.45 (m, 8H), 0.94 (s, 9H). It can be seen that the structure of the compound is correct.

[0392] Example 32: Synthesis of Compound TPD005706

[0393]

[0394] Compound TPD5706-1 (5 g, 21.3 mmol), tert-butyl acrylate (4.10 g, 31.95 mmol), potassium tert-butoxide (0.48 g, 4.26 mmol) and 1,4-dioxane (50 ml) were successively added to a 100 ml three-necked flask. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and poured into saturated ammonium chloride aqueous solution (100 ml), and extracted three times with EA (50 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain crude compound TPD5706-2 (1.4 g, yellow solid, purity 20.909%), yield: 3.76%. LCMS (ESI) m / z calcd. for C 20 H 29 NO 5 [M+H] + 364.2; found 308.1. It can be seen that the compound structure is correct.

[0395] Compound TPD5706-2 (1.4 g, 3.9 mmol), THF (15 ml), and Pd / C (0.14 g, 10% Pd, 50% wet) were successively added to a 50 ml single-necked flask. The reaction was carried out at 25 °C for 4 hours under hydrogen protection. After the reaction was completed, the reaction solution was filtered and concentrated to dryness to obtain crude compound TPD5706-3 (900 mg, brown oil, purity 37.009%), yield: 33.33%; LCMS (ESI) m / z calcd. for C 12 H 23 NO 3 [M+H] + 230.2; found 230.1; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 3.58 (t, J = 6.0 Hz, 2H), 3.29 - 3.25 (m, 1H), 3.13 (s, 2H), 2.87 (d, J = 12.0 Hz, 2H), 2.44 - 2.41 (m, 1H), 2.38 (t, J = 6.4 Hz, 2H), 1.78 - 1.74 (m, 2H), 1.40 (s, 9H), 1.26 - 1.17 (m, 2H). It can be seen that the compound structure is correct.

[0396] In a 100 ml three-necked flask, 800 mg (3.4886 mmol) of compound TPD5706-3, 2.161 g (3.4886 mmol) of int-A, 2.27331 g (6.9772 mmol) of cesium carbonate, 868.9 mg (1.3954 mmol) of BINAP, Pd 2 (dba) 3 (638.92 mg, 0.6977 mmol) and 40 ml of 1,4-dioxane were successively added. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated to dryness. The residue was purified by silica gel column chromatography, and the eluent ratio was DCM / MeOH = 150 / 1 to 30 / 1, to obtain compound TPD5706-4 (470 mg, brown solid, purity 72.189%), yield: 13.92%. LCMS (ESI) m / z calcd. for C 39 H 43 FN 4 O 7 [M + H] + 699.3; found 350.2 and 699.2; 1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.19 (s, 1H), 10.07 (s, 1H), 8.43 (d, J = 5.2 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.66 - 7.63 (m, 2H), 7.47 (s, 1H), 7.23 - 7.13 (m, 5H), 6.39 (d, J = 5.2 Hz, 1H), 3.95 (s, 3H), 3.66 (t, J = 6.0 Hz, 2H), 3.50 (s, 1H), 3.39 (s, 2H), 2.89 (t, J = 9.2 Hz, 2H), 2.44 (t, J = 6.0 Hz, 2H), 1.96 (s, 2H), 1.65 - 1.63 (m, 2H), 1.47 (s, 4H), 1.42 (s, 9H). It can be seen that the structure of the compound is correct.

[0397] In a 50 ml single-necked flask, 400 mg (0.5724 mmol) of compound TPD5706-4, 2 ml of DCM and 2 ml of trifluoroacetic acid were successively added. The reaction was carried out at 25 °C for 4 hours. After the reaction was completed, it was concentrated to dryness to obtain the crude product compound TPD5706-5 (380 mg, brown solid), yield: 57.95%. LCMS (ESI) m / z calcd. for C 35 H 35 FN 4 O 7 [M + H] +643.3; found 643.4. It can be seen that the compound has the correct structure.

[0398] In a 50 ml single-necked flask, the compound TPD5706-5 (100 mg, 0.1556 mmol), DCM (10 ml) and 1-chloro-N,N,2-trimethylallylamine (41.58 mg, 0.3112 mmol) were added successively. The mixture was stirred at 25 °C for 0.5 h. Then a DCM mixture of pyridine (36.92 mg, 0.4668 mmol) and 5-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (85.04 mg, 0.3112 mmol) was added. Under nitrogen protection, the reaction was carried out at 25 °C for 16 h. The reaction solution was poured into water (10 ml). The organic phase was separated, and the aqueous phase was extracted twice with DCM (5 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was prepared by high performance liquid chromatography, and the relevant parameters are as follows: chromatographic column: sunfire 5um 19-150 mm; mobile phase: acetonitrile-water (0.1% FA); gradient: 20-55 / 8 min, to obtain the compound TPD005706 (11.6 mg, yellow solid, purity 98.769%), yield: 7.97%. LCMS (ESI) m / z calcd. for C 48 H 44 FN 7 O 10 [M+H] + 898.3; found 449.6 and 898.3; 1 H NMR (400 MHz, DMSO_d 6): δ = 11.13 (s, 1H), 10.67 (s, 1H), 10.19 (s, 1H), 10.06 (s, 1H), 8.42 (d, J = 4.9 Hz, 1H), 8.28 (s, 1H), 8.24 (s, 0.5H), 7.93 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.66 - 7.63 (m, 2H), 7.45 (s, 1H), 7.25 - 7.13 (m, 5H), 6.38 (d, J = 4.8 Hz, 1H), 5.15 - 5.10 (m, 1H), 3.93 (s, 3H), 3.82 - 3.80 (m, 2H), 3.55 (br.s., 2H), 2.89 - 2.84 (m, 3H), 2.69 - 2.66 (m, 2H), 2.62 - 2.57 (m, 2H), 2.01 - 1.98 (m, 3H), 1.65 - 1.63 (m, 2H), 1.47 (s, 3H), 1.23 (s, 2H). It can be seen that the structure of the compound is correct.

[0399] Example 33: Synthesis of Compound TPD005714

[0400]

[0401] Compound TPD5714 - 1 (5 g, 28.6 mmol), palladium acetate (1.28 g, 5.72 mmol), dppf (3.17 g, 5.72 mmol), methanol (50 ml), triethylamine (10 ml) and DMF (150 ml) were successively added to a 500 ml autoclave. Carbon monoxide gas at 0.4 MPa was introduced, and the reaction was carried out at 80 °C for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness to obtain a residue. The residue was purified by silica gel column chromatography with an eluent ratio of DCM / MeOH = 80 / 1 - 60 / 1 to obtain compound TPD5714 - 2 (2.4 g, brown solid, purity 70%), yield: 38.11%. LCMS (ESI) m / z calcd. for C 5 H 6 N 4 O 2 [M + H] + 155.1; found 155.1; 1 H NMR (400 MHz, CDCl 3 ): δ = 8.83 (s, 1H), 6.02 (br.s, 2H), 4.06 (s, 3H). It can be seen that the structure of the compound is correct.

[0402] In a 100 ml single-necked flask, successively add compound TPD5714-2 (1.8 g, 7.82 mmol), ACN (30 ml), tert-butyl nitrite (4.84 g, 46.91 mmol) and dimethyl disulfide (7.36 g, 78.19 mmol). React at 60 °C for 16 hours under nitrogen protection. After the reaction is completed, the reaction solution is concentrated to dryness. The residue is purified by silica gel column chromatography, and the eluent ratio is PE / EA = 10 / 1 to 5 / 1, to obtain compound TPD5714-2 (800 mg, light yellow oil, purity 83.445%), yield: 32.68%. LCMS (ESI) m / z calcd. for C 9 H 16 O 5 [M-H] + 186.0; found 186.0; 1 H NMR (400 MHz, CDCl 3 ): δ = 8.95 (s, 1H), 4.08 (s, 3H), 2.83 (s, 3H). It can be seen that the structure of the compound is correct.

[0403] In a 50 ml single-necked flask, successively add compound TPD5494-3 (2 g, 10.80 mmol), piperidinemethanol (1.49 g, 12.94 mmol) and ACN (40 ml). React at 25 °C for 5 hours under nitrogen protection. After the reaction is completed, the reaction solution is poured into water (150 ml), and extracted three times with EA (80 ml). The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel column chromatography, and the eluent ratio is PE / EA = 5 / 1 to 1 / 1, to obtain compound TPD005714-4 (310 mg, light yellow solid, purity 79.48%), yield: 9.26%. LCMS (ESI) m / z calcd. for C 11 H 16 N 4 O 3 [M+H] + 253.1; found 253.2; 1 H NMR (400 MHz, CDCl 3 ): δ = 8.69 (s, 1H), 4.00 (s, 3H), 3.56 (d, J = 5.9 Hz, 2H), 3.06 (br.s, 2H), 1.91 - 1.85 (m, 3H), 1.49 - 1.41 (m, 1H), 1.35 - 1.23 (m, 3H). It can be seen that the structure of the compound is correct.

[0404] To a 50 ml single-necked flask were successively added compound TPD5714-4 (140 mg, 0.56 mmol), LiOH (47 mg, 1.11 mmol), and THF (3 ml), MeOH (3 ml), H 2 O (3 ml). The reaction was carried out at 25 °C for 2 hours. After the reaction was completed, the mixture was concentrated to dryness to obtain crude compound TPD5496-5 (81 mg, yellow solid, purity 88.152%), and the yield was 54.00%. LCMS (ESI) m / z calcd. for C 10 H14N 4 O 3 [M+H] + 239.1; found 239.1. It can be seen that the structure of the compound is correct.

[0405] To a 50 ml single-necked flask were successively added compound TPD5714-5 (170 mg, 0.71 mmol), int-B (347 mg, 0.71 mmol), HATU (407 mg, 1.07 mmol), TEA (369 mg, 2.85 mmol), and DMF (3 mL). The reaction was carried out at 25 °C for 16 hours. After the reaction was completed, the reaction solution was poured into water (10 ml), and extracted three times with EA (5 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. Compound TPD5496-6 (85 mg, brown solid, purity 88.183%) was obtained by high-pressure preparation, and the yield was 14.87%. LCMS (ESI) m / z calcd. for C 4 H4 5 FN 6 O 8 [M+H] + 707.3; found 707.4. It can be seen that the structure of the compound is correct.

[0406] To a 50 ml single-necked flask were successively added compound TPD5714-6 (70 mg, 0.10 mmol), Dess-Martin periodinane (63 mg, 0.15 mmol), and DCM (3 ml). The reaction was carried out at 25 °C for 0.5 hour. After the reaction was completed, the reaction solution was poured into saturated sodium bicarbonate solution (10 ml), and extracted three times with DCM (5 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. Crude compound TPD5714-7 (35 mg, brown solid, purity 65.428%) was obtained, and the yield was 32.83%. LCMS (ESI) m / z calcd. for C 4 H4 5 FN 6 O 8 [M+H]+ 705.3; found 705.1. It can be seen that the compound has the correct structure.

[0407] To a 25 ml single-necked flask were successively added compound TPD5714-7 (35 mg, 0.05 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione (18.8 mg, 0.05 mmol), sodium triacetoxyborohydride (21 mg, 0.09 mmol) and DCE (2 ml). The reaction was carried out at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into sodium bicarbonate (10 ml), and extracted three times with DCM (3 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 15 / 1, to obtain compound TPD005714 (3.0 mg, light yellow solid, purity 88.487%), yield: 5.23%. LCMS (ESI) m / z calcd. for C 54 H 51 FN 12 O 9 [M+H] + 1031.39; found 1031.60; 1 H NMR (400 MHz, CDCl 3 :CD 3 OD = 10:1): δ = 9.39 (s, 1H), 8.97 (s, 1H), 8.70 (d, J = 6.0 Hz, 1H), 7.76 - 7.73 (m., 4H), 7.56 - 7.49 (m, 3H), 7.23 - 7.19 (m, 2H), 7.15 - 7.11 (m, 1H), 7.08 - 7.02 (m, 2H), 6.76 - 6.72 (m, 1H), 5.36 - 5.34 (m, 1H), 4.19 (s, 3H), 3.70 - 3.62 (m, 2H), 3.39 - 3.35 (m, 4H), 3.17 - 3.14 (m, 2H), 2.83 - 2.80 (m, 4H), 2.64 - 2.61 (m, 1H), 2.16 - 2.08 (m, 3H), 2.05 - 1.99 (m, 3H), 1.74 - 1.69 (m, 4H), 1.63 - 1.56 (m, 4H). It can be seen that the compound has the correct structure.

[0408] Example 34: Synthesis of compound TPD005734

[0409]

[0410] In a 50 ml three-necked flask, compound TPD5735-6 (500 mg, 1.3199 mmol), 4-formyl-N-CBZ piperidine (359.04 mg, 1.45189 mmol) and 1,2-dichloroethane (8 ml) were added successively. Then sodium triacetoxyborohydride (839.22 mg, 3.9597 mmol) was added at room temperature. Then the reaction was carried out at 25 °C for 16 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate (20 ml), and extracted three times with DCM (5 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 20 / 1, to obtain crude compound TPD5734-6 (400 mg, yellow solid, purity 60%), yield: 31.7%. LCMS (ESI) m / z calcd. for C 31 H 35 N 5 O 6 [M+H] + 574.26; found 574.5. It can be seen that the compound structure is correct.

[0411] In a 50 ml three-necked flask, compound TPD5734-6 (800 mg, 1.3946 mmol), palladium hydroxide (300 mg) and ethyl acetate (20 ml) were added successively. Then the reaction was carried out at 30 °C under 20 psi hydrogen for 3 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to dryness to obtain crude compound TPD5734-7 (500 mg, yellow solid, purity 60%), yield: 48.95%. LCMS (ESI) m / z calcd. for C 23 H 29 N 5 O 4 [M+H] + 440.22; found 440.1. It can be seen that the compound structure is correct.

[0412] In a 25 ml three-necked flask, add int B (100 mg, 0.2056 mmol), triethylamine (83.22 mg, 0.8224 mmol), dichloromethane (3 ml), and tetrahydrofuran (3 ml). Then, at 0 °C, add dropwise a solution of acryloyl chloride (37.22 mg, 0.4112 mmol) in dichloromethane (0.5 ml). Then react at 0 °C for 2 hours. Pour the reaction solution into water (10 ml). Extract three times with DCM (3 ml). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. Purify the residue by preparative plate, with the eluent ratio of DCM / MeOH = 15 / 1, to obtain compound TPD5734-8 (50 mg, yellow solid, purity 99.242%), yield: 44.65%. LCMS (ESI) m / z calcd. for C 30 H 25 FN 4 O 5 [M+H] + 541.18; found 542.2; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 10.20 (s, 1H), 10.06 (s, 1H), 9.72 (s, 1H), 8.88 (s, 1H), 8.52 (s, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.66 - 7.63 (m, 2H), 7.61 (s, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.16 (t, J = 8.8 Hz, 2H), 6.90 - 6.83 (m, 1H), 6.47 (d, J = 5.2 Hz, 1H), 6.36 (d, J = 16.8 Hz, 1H), 5.81 (d, J = 11.2 Hz, 1H), 4.05 (s, 3H), 1.48 (s, 4H). It can be seen that the compound structure is correct.

[0413] In a 25 ml three-necked flask, successively add compound TPD5734-8 (45 mg, 0.0832 mmol), acetonitrile (3 ml), compound TPD5734-7 (36.57 mg, 0.0832 mmol), and DBU (38 mg, 0.2496 mmol). Under nitrogen protection, react at 25 °C for 16 hours. Pour the reaction solution into water (10 ml). Extract three times with DCM (3 ml). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. Purify the residue by preparative plate, with the eluent ratio of DCM / MeOH = 10 / 1, to obtain compound TPD005734 (10.2 mg, yellow solid, purity 97.581%), yield: 12.2%. LCMS (ESI) m / z calcd. for C53 H 54 FN 9 O 9 [M+H] + 980.40; found 980.3; 1 H NMR(400MHz, DMSO_d 6 ): δ = 11.09(s, 1H), 10.82(s, 1H), 10.20(s, 1H), 10.06(s, 1H), 8.92(s, 1H), 8.49(d, J = 4.8Hz, 1H), 7.77(d, J = 8.4Hz, 2H), 7.69 - 7.63(m, 3H), 7.59(s, 1H), 7.35(s, 1H), 7.27 - 7.23(m, 3H), 7.16(t, J = 8.8Hz, 2H), 6.45(d, J = 4.8Hz, 1H), 5.10 - 5.04(m, 1H), 4.05(s, 3H), 3.45(s, 3H), 3.05(br.s., 2H), 2.93 - 2.83(m, 2H), 2.64(br.s., 8H), 2.25(br.s., 2H), 2.01(br.s., 3H), 1.80(d, J = 10.4Hz, 2H), 1.63(br.s., 1H), 1.47(s, 4H), 1.31 - 1.24(m, 4H). It can be seen that the compound structure is correct.

[0414] Example 35: Synthesis of Compound TPD005735

[0415]

[0416] Compound TPD5735 - 4 (4g, 0.0145mol), 1 - tert - butoxycarbonylpiperazine (3.26g, 0.0174mol), triethylamine (2.93g, 0.029mol) and dimethyl sulfoxide (50ml) were successively added into a 100ml three - necked flask. Then the reaction was carried out at 90 °C for 16 hours. The reaction solution was poured into water (100ml), filtered, the filter cake was washed with a small amount of water, and the filter cake was purified by silica gel chromatography column, and the eluent and ratio were PE / EtOAc = 3 / 1 - 1 / 1, to obtain compound TPD5735 - 5 (2.5g, yellow solid, purity 98.803%), yield: 38.62%. LCMS(ESI) m / z calcd.for C 22 H 26 N 4 O 6 [M+H] + 443.19; found343.0, 387.0; 1 H NMR(400MHz, DMSO_d6 ): δ = 11.09 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.25 (d, J = 8.8 Hz, 1H), 5.10 - 5.06 (m, 1H), 3.47 (s, 8H), 2.93 - 2.84 (m, 1H), 2.61 - 2.50 (m, 2H), 2.03 - 1.99 (m, 1H), 1.43 (s, 9H). It can be seen that the structure of the compound is correct.

[0417] Compound TPD5735 - 5 (2.5 g, 0.0056 mol), ethyl acetate (10 ml) and ethyl acetate hydrochloride gas (50 ml) were successively added into a 100 - ml three - necked flask. Then the reaction was carried out at 25 °C for 16 hours. The reaction solution was filtered, and the filter cake was dried to obtain the crude product of compound TPD5735 - 6 (1.9 g, yellow solid, purity 75.193%), yield: 67.86%. LCMS (ESI) m / z calcd. for C 17 H 18 N 4 O 4 [M + H] + 343.13; found 343.0; 1 H NMR (400 MHz, DMSO - d 6 ): δ = 11.10 (s, 1H), 9.28 (s, 2H), 7.75 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.33 (d, J = 8.8 Hz, 1H), 5.12 - 5.07 (m, 1H), 3.57 (s, 4H), 3.21 (s, 4H), 2.93 - 2.84 (m, 1H), 2.67 - 2.53 (m, 2H), 2.04 - 1.99 (m, 1H). It can be seen that the structure of the compound is correct.

[0418] Compound int B (100 mg, 0.2056 mmol), triethylamine (83.22 mg, 0.8224 mmol), tetrahydrofuran (3 mL) and dichloromethane (3 ml) were successively added into a 25 - ml three - necked flask. Then a solution of chloroacetyl chloride (34.85 mg, 0.3084 mmol) in dichloromethane (0.5 mL) was added dropwise at 0 °C. Then the reaction was carried out at 0 °C for 2 hours. The reaction solution was poured into water (10 ml), and extracted three times with DCM (3 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 15 / 1, to obtain compound TPD5735 - 9 (70 mg, yellow solid, purity 98.963%), yield: 59.85%. LCMS (ESI) m / z calcd. for C29 H 24 ClFN 4 O 5 [M+H] + 563.14; found 563.0; 1 H NMR(400MHz, DMSO_d 6 ): δ = 10.19(s, 1H), 10.05(s, 1H), 9.84(s, 1H), 8.79(s, 1H), 8.52(d, J = 5.2Hz, 1H), 7.77(d, J = 8.8Hz, 2H), 7.66 - 7.63(m, 3H), 7.25(d, J = 8.8Hz, 2H), 7.15(t, J = 8.8Hz, 2H), 6.48(d, J = 4.8Hz, 1H), 4.53(s, 2H), 4.06(s, 3H), 1.48(s, 4H). It can be seen that the compound structure is correct.

[0419] Into a 25 ml three-necked flask, compound TPD5735 - 9 (65 mg, 0.1155 mmol), compound TPD5734 - 7 (50.76 mg, 0.1155 mmol), potassium carbonate (31.88 mg, 0.231 mmol), potassium iodide (1.92 mg, 0.01155 mmol) and acetonitrile (3 ml) were added successively. Then the reaction was carried out at 25 °C for 16 hours. The reaction solution was filtered and concentrated to dryness. The residue was purified by preparative plate with the eluent ratio of DCM / MeOH = 15 / 1 to obtain compound TPD005735 (8.85 mg, yellow solid, purity 95.813%), yield: 7.62%. LCMS(ESI) m / z calcd.for C 52 H 52 FN 9 O 9 [M+H] + 966.39, 967.39; found 966.3, 967.3; 1 H NMR(400MHz, DMSO_d 6): δ = 11.09 (s, 1H), 10.27 (s, 1H), 10.20 (s, 1H), 10.06 (s, 1H), 8.86 (s, 1H), 8.51 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.69 - 7.63 (m, 4H), 7.35 (s, 1H), 7.28 - 7.24 (m, 3H), 7.16 (t, J = 9.2 Hz, 2H), 6.47 (d, J = 5.2 Hz, 1H), 5.10 - 5.05 (dd, J = 5.2, 5.6 Hz, 1H), 4.09 (s, 3H), 3.45 (s, 4H), 3.21 (s, 2H), 2.92 - 2.85 (m, 3H), 2.67 - 2.55 (m, 5H), 2.30 - 2.25 (m, 4H), 2.03 - 2.00 (m, 1H), 1.82 (d, J = 10.4 Hz, 2H), 1.62 (br.s., 1H), 1.48 (s, 4H), 1.30 - 1.22 (m, 3H). It can be seen that the structure of the compound is correct.

[0420] Example 36: Synthesis of Compound TPD005736

[0421]

[0422] Compound TPD5736 - 1 (5 g, 0.027 mmol), benzyl 4 - formylpiperidine - 1 - carboxylate (6.68 g, 0.027 mmol), sodium triacetoxyborohydride (11.44 g, 0.054 mmol) and dichloroethane (100 ml) were successively added to a 100 - ml single - necked flask. The reaction was carried out at 15 °C for 16 hours. After the reaction was completed, the reaction system was poured into water (50 ml), and extracted three times with dichloromethane (50 ml). After combining the organic phases, they were successively washed with water (50 ml) and saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the eluent ratio was PE / EA = 10 / 1 - 3 / 1, to obtain compound TPD5736 - 2 (6.2 g, colorless oil, purity 93.260), yield: 51.48%. LCMS (ESI) m / z calcd. for C 24 H 36 N 2 O 4 [M + H] + 417.3; found 417.2; 1 H NMR (400 MHz, CDCl 3): δ = 7.41 - 7.28 (m, 5H), 5.12 (s, 2H), 4.16 (s, 2H), 2.78 (d, J = 11.3 Hz, 4H), 2.24 - 2.07 (m, 3H), 1.94 (t, J = 10.9 Hz, 2H), 1.82 (d, J = 10.6 Hz, 2H), 1.75 - 1.63 (m, 4H), 1.60 (s, 1H), 1.43 (s, 9H), 1.08 (d, J = 11.7 Hz, 2H). It can be seen that the structure of the compound is correct.

[0423] Compound TPD5736-2 (2.0 g, 4.8 mmol), THF (40 ml) and palladium on carbon (0.4 g, 10% content, 50% water content) were successively added to a 100 ml single-necked flask. The system was reacted at 15 °C for 16 hours under 1 atm of hydrogen. After the reaction was completed, it was filtered through diatomaceous earth and washed with THF. The filtrate was concentrated under reduced pressure to obtain compound TPD5736-3 (1.2 g, white solid, purity 55.619%), yield: 50.00%. LCMS (ESI) m / z calcd. for C 16 H 30 N 2 O 2 [M + H] + 283.2; found 283.1; 1 H NMR (400 MHz, CDCl 3 ): δ = 3.06 (d, J = 12.1 Hz, 2H), 2.80 (d, J = 11.5 Hz, 2H), 2.58 (td, J = 12.1, 2.0 Hz, 2H), 2.19 - 2.14 (m, 1H), 2.12 (d, J = 7.1 Hz, 2H), 1.92 (t, J = 11.3 Hz, 2H), 1.82 (d, J = 10.0 Hz, 2H), 1.74 - 1.88 (m, 4H), 1.82 - 1.57 (m, 3.8 Hz, 1H), 1.43 (s, 8H), 1.12 - 1.02 (m, 2H). It can be seen that the structure of the compound is correct.

[0424] Add compound TPD5736-3 (562.36 mg, 1.991 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-isoindole-1,3-dione (500 mg, 1.810 mmol), DIEA (701.85 mg, 5.431 mmol) and DMSO (5 ml) into a 40 ml single-necked flask. React at 100 °C for 16 hours. After the reaction is completed, cool to room temperature, then pour into cold water (20 ml), filter, and purify the filter cake through a silica gel chromatography column. The eluent ratio is PE / EA = 5 / 1 - 2 / 1 to obtain compound TPD5736-4 (750 mg, yellow solid, purity 91.595%), yield: 70.46%. LCMS (ESI) m / z calcd. for C 29 H 38 N 4 O 6 [M+H] + 539.3; found 229.2 and 539.1; 1 H NMR (400 MHz, CDCl 3 ): δ = 8.25 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.05 - 7.02 (m, 1H), 4.96 - 4.92 (m, 1H), 4.02 - 3.86 (m, 2H), 2.98 - 2.92 (m, 2H), 2.88 - 2.73 (m, 4H), 2.26 - 2.06 (m, 4H), 1.97 (t, J = 10.8 Hz, 2H), 1.86 (t, J = 13.1 Hz, 4H), 1.77 - 1.53 (m, 4H), 1.44 (s, 9H), 1.29 - 1.21 (m, 2H). It can be seen that the compound structure is correct.

[0425] Add compound TPD5736-4 (500 mg, 0.928 mmol) and HCl / EA (4N, 20 ml) into a 50 ml single-necked flask. React at 20 °C for 16 hours, then raise the temperature to 60 °C and react for another 8 hours. After the reaction is completed, concentrate the system under reduced pressure to dryness to obtain compound TPD5736-5 (450 mg, yellow solid, purity 85.053%), yield: 79.45%. LCMS (ESI) m / z calcd. for C 25 H 30 N 4 O 6 [M+H] + 483.2; found 483.0. It can be seen that the compound structure is correct.

[0426] In a 25 ml single-necked flask, add compound TPD5736-5 (100 mg, 0.2072 mmol), int-C (103.71 mg, 0.2072 mmol), HATU (157.57 mg, 0.4144 mmol), triethylamine (41.93 mg, 0.4144 mmol) and DMF (3 ml) successively. React at 25 °C for 16 hours under nitrogen protection. After the reaction is completed, pour the reaction solution into water (3 ml), and extract it three times with EA (1 ml). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. The residue is purified by a preparative plate, and the developing agent ratio is DCM / MeOH = 10 / 1, to obtain compound TPD005736 (25 mg, yellow solid, purity 97.359%), yield: 12.16%. LCMS (ESI) m / z calcd. for C 53 H 53 FN 8 O 9 [M+H] + 965.4; found 965.3; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 11.09 (s, 1H), 10.20 (s, 1H), 10.06 (s, 1H), 8.51 (d, J = 5.2 Hz, 1H), 8.40 (s, 1H), 7.79 - 7.64 (m, 6H), 7.54 (s, 1H), 7.31 - 7.13 (m, 6H), 6.52 (d, J = 4.8 Hz, 1H), 5.09 - 5.04 (m, 1H), 4.40 (s, 2H), 4.05 (d, J = 12.4 Hz, 2H), 3.98 (s, 3H), 3.00 - 2.88 (m, 5H), 2.14 (s, 2H), 1.99 (s, 2H), 1.90 (s, 2H), 1.79 (d, J = 12.8 Hz, 4H), 1.68 (br.s., 2H), 1.47 (s, 4H), 1.23 - 1.16 (m, 5H). It can be seen that the structure of the compound is correct.

[0427] In a 50 ml three-necked flask, compound int-A (500 mg, 0.807 mmol), zinc cyanide (189.52 mg, 1.614 mmol), tetrakis(triphenylphosphine)palladium (93.25 mg, 0.0807 mmol) and N,N-dimethylformamide (10 ml) were added successively. Then the reaction was carried out at 110 °C for 3 hours. The reaction solution was poured into water (30 ml), and extracted three times with EA (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography, and the eluent and ratio were PE / EtOAc = 3 / 1 - 1 / 1, to obtain compound int-C-1 (250 mg, yellow solid, purity 98.176%), yield: 61.26%. LCMS (ESI) m / z calcd. for C 28 H 21 FN 4 O 4 [M+H] + 497.15; found 497.6; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 10.23 (s, 1H), 10.49 (s, 1H), 8.66 (d, J = 4.8 Hz, 1H), 8.57 (s, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.77 (s, 1H), 7.66 - 7.63 (m, 2H), 7.28 (d, J = 8.8 Hz, 2H), 7.16 (t, J = 8.8 Hz, 2H), 6.66 (d, J = 5.2 Hz, 1H), 4.08 (s, 3H), 1.48 (s, 4H). It can be seen that the compound structure is correct.

[0428] In a 50 ml single-necked flask, compound int-C-1 (250 mg, 0.5035 mmol), ethanol (5 ml) and ammonia water (3 ml) were added successively. Then Raney nickel (100 mg) was added. Then the reaction was carried out at 20 °C under a hydrogen balloon for 4 hours. The reaction solution was filtered, and the filtrate was concentrated to dryness to obtain compound int-C (150 mg, white solid, purity 99.425%), yield: 59.19%. LCMS (ESI) m / z calcd. for C 28 H 25 FN 4 O 4 [M+H] + 501.19; found 501.4; 1 H NMR (400 MHz, DMSO_d 6): δ = 10.18 (br.s., 1H), 10.05 (br.s., 1H), 8.51 (d, J = 5.2 Hz, 1H), 7.80 (s, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.66 - 7.63 (m, 2H), 7.50 (s, 1H), 7.23 (d, J = 8.8 Hz, 2H), 7.15 (t, J = 8.8 Hz, 2H), 6.50 (d, J = 5.2 Hz, 1H), 3.96 (s, 3H), 3.86 (s, 2H), 1.47 (s, 4H). It can be seen that the structure of the compound is correct.

[0429] Example 37: Synthesis of Compound TPD005745

[0430]

[0431] Into a 50 ml three-necked flask were successively added 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (200 mg, 0.7241 mmol), tert-butyl 2-(piperidin-1-yl)acetate, DIEA (280.75 mg, 2.1723 mmol) and DMSO solution (10 ml). The reaction was carried out at 90 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, and the reaction solution was poured into saturated sodium bicarbonate aqueous solution (20 ml) to precipitate a yellow solid. The yellow solid was filtered and dissolved in dichloromethane, dried over anhydrous sodium sulfate and concentrated to dryness to obtain compound TPD5745-13 (280 mg, yellow solid, purity 60.632%), yield: 79.50%. LCMS (ESI) m / z calcd. for C 23 H 28 N 4 O 6 [M + H] + 457.5; found 457.1. It can be seen that the structure of the compound is correct.

[0432] Into a 50 ml three-necked flask were successively added compound TPD5745-13 (200 mg, 0.4381 mmol) and 3N hydrogen chloride 1,4-dioxane solution (10 ml). The reaction was carried out at 15 °C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated to dryness to obtain compound TPD5745-14 (150 mg, yellow solid, purity 92.973%), yield: 79.50%. LCMS (ESI) m / z calcd. for C 19 H 20 N 4 O 6 [M + H] + 401.14; found 401.0. It can be seen that the structure of the compound is correct.

[0433] Add thionyl chloride (20 ml) to a 100 ml single-necked flask, and add compound TPD5745-9 (1 g, 0.0036 mol). Under nitrogen protection, the reaction solution is heated to 70 °C and reacted for 3 hours. The reaction solution is concentrated to dryness to obtain crude compound TPD5745-10 (0.9 g, light yellow oil, purity 93.903%), yield: 72.81%. LCMS (ESI) m / z calcd. for C 15 H 18 ClNO 3 [M-Cl + OCH 3 +H] + 292.35; found 292.0. It can be seen that the compound structure is correct.

[0434] Add int-B (450 mg, 0.925 mmol) and TEA (280.80 mg, 2.7750 mmol) to a 250 ml three-necked flask in DCM (55 ml). Under nitrogen protection, the reaction solution is cooled to 0 °C, and then compound TPD-5745-11 (410.37 mg, 1.3875 mmol) dissolved in DCM (5 ml) is added dropwise. After the addition is complete, the reaction is carried out at 15 °C for one and a half hours. The reaction solution is poured into saturated sodium bicarbonate aqueous solution (30 ml), and extracted three times with DCM (20 ml). The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel column chromatography, and the eluent ratio is DCM / MeOH = 50 / 1 to 30 / 1, to obtain compound TPD5745-11 (360 mg, white solid, purity 87.842%), yield: 45.84%. LCMS (ESI) m / z calcd. for C 42 H 40 FN 5 O 7 [M + H] + 746.29; found 764.4. It can be seen that the compound structure is correct.

[0435] Add compound TPD5745-11 (300 mg, 0.4023 mmol) and Pd(OH) 2 / C (100 mg, 10%) to ethyl acetate (5 ml) in a 50 ml single-necked flask. React at 15 °C for 6 hours. After the reaction is complete, concentrate to dryness to obtain crude compound TPD5745-12 (70 mg, white solid, purity 30.526%), yield: 8.68%. LCMS (ESI) m / z calcd. for C 19 H 25 N 5 O3 [M+H] + 612.67; found 612.1. It can be seen that the compound structure is correct.

[0436] In a 50 ml single-necked flask, compound TPD5745-12 (70 mg, 0.1144 mmol), HATU (65.25 mg, 0.1716 mmol), compound TPD5745-14 (45.8 mg, 0.1144 mmol) and TEA (57.88 mg, 0.572 mmol) were added successively. Under nitrogen protection, the reaction was carried out at 15 °C for 16 hours. After the reaction was completed, the reaction solution was quenched with water. It was extracted three times with ethyl acetate (10 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated to obtain a residue. The residue was purified by a preparative plate, and the eluent ratio was DCM / MeOH = 10 / 1, to obtain compound TPD005745 (23.5 mg, yellow solid, purity 97.684%), yield: 22.03%. LCMS (ESI) m / z calcd. for C 53 H 52 FN 9 O 10 [M+H] + 994.05; found 994.4; 1 H NMR (400 MHz, DMSO_d6): δ = 11.08 (s, 1H), 10.19 - 10.09 (m, 1H), 10.05 (br.s., 1H), 9.41 (br.s., 1H), 8.78 (s, 1H), 8.49 - 8.47 (m, 1H), 7.68 (br.s., 2H), 7.64 (br.s., 3H), 7.35 (s, 1H), 7.23 (s, 1H), 7.16 (br.s., 3H), 7.13 (br.s., 2H), 6.47 - 6.44 (m, 1H), 5.10 - 5.05 (m, 1H), 4.36 - 4.33 (m, 1H), 4.02 - 4.01 (m, 3H), 3.44 (s, 3H), 3.12 - 3.04 (m, 4H), 2.56 (br.s., 5H), 2.08 (br.s., 4H), 1.75 (m, 2H), 1.48 (s, 3H), 1.23 - 0.93 (m, 7H). It can be seen that the compound structure is correct.

[0437] Example 38: Synthesis of compound TPD005746

[0438]

[0439] To a 250 mL single-necked flask were successively added 1-Boc-piperazine (5.0 g, 26.7 mmol), 1-Cbz-4-piperidinecarboxaldehyde (6.6 g, 26.7 mmol), acetic acid (4.81 g, 80.1 mmol), and sodium triacetoxyborohydride (11.32 g, 53.4 mmol). The reaction was carried out at 20 °C for 16 h. After completion of the reaction, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution (200 mL). It was extracted three times with DCM (100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain a residue. The residue was purified by silica gel column chromatography with an eluent and ratio of DCM / MeOH = 60 / 1 to 40 / 1 to obtain compound TPD5746-10 (5.1 g, colorless oil, purity 85.387%), yield: 38.95%. LCMS (ESI) m / z calcd. for C 23 H 35 N 3 O 4 [M+H] + 418.2; found 418.0; 1 HNMR (400 MHz, CDCl 3 ): δ = 7.36 - 7.30 (m, 5H), 5.12 (s, 2H), 4.17 (br.s.2H), 3.40 (t, J = 4.8 Hz, 4H), 2.77 (br.s.2H), 2.33 (t, J = 4.8 Hz, 4H), 2.17 - 2.15 (m, 2H), 1.76 - 1.61 (m, 3H), 1.46 (s, 9H), 1.13 - 1.05 (m, 2H). It can be seen that the structure of the compound is correct.

[0440] To a 100 mL single-necked flask were added compound TPD5746-10 (1 g, 2.4 mmol), EA (20 mL), and palladium on carbon hydroxide (0.1 g, 10% palladium content, 50% water content). Hydrogen was introduced at 25 °C at 20 psi for 2 h. After filtration, it was concentrated to dryness to obtain compound TPD5746-11 (320 mg, gray solid, purity 43.468%), yield: 20.83%. LCMS (ESI) m / z calcd. for C 15 H 29 N 3 O 2 [M+H] + 284.2; found 284.1; 1 H NMR (400 MHz, DMSO_d 6): δ = 3.28 ((t, J = 5.2 Hz, 5H), 2.87 (d, J = 12.0 Hz, 2H), 2.45 - 2.35 (m, 2H), 2.28 - 2.21 (m, 4H), 2.07 (d, J = 7.0 Hz, 2H), 1.64 - 1.49 (m, 3H), 0.97 - 0.87 (m, 2H). It can be seen that the compound structure is correct.

[0441] In a 25 mL single-necked flask, compound TPD5746-11 (320 mg, 1.1251 mmol), DIEA (436.22 mg, 3.3753 mmol), DMSO (2 ml) and 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (310.78 mg, 1.1251 mmol) were added. The reaction was carried out at 100 °C for 16 hours. After cooling to room temperature, the reaction solution was poured into water (20 ml), and stirred for 10 minutes. Filtration was carried out, and the filter cake was washed with water and then purified by silica gel column chromatography. The eluent ratio was DCM / MeOH = 100 / 1 to 50 / 1, and compound TPD5746-12 (510 mg, yellow solid, purity 97.998%) was obtained, with a yield of 82.17%. LCMS (ESI) m / z calcd. for C 28 H 37 N 5 O 6 [M + H] + 540.3; found 540.1 and 484.1.

[0442] In a 25 mL single-necked flask, compound TPD5746-12 (260 mg, 0.4809 mmol) and dioxane solution of hydrogen chloride (3N, 10 ml) were added. The reaction was carried out at 25 °C for 2 hours. The reaction solution was concentrated to dryness, and compound TPD5746-13 (248 mg, yellow solid, purity 95.127%) was obtained, with a yield of 95.74%. LCMS (ESI) m / z calcd. for C 23 H 29 N 5 O 4 [M + H] + 440.22; found 440.1. It can be seen that the compound structure is correct.

[0443] In a 25 ml single-necked flask, 43 mg (0.0839 mmol) of compound TPD5746-13, 47.23 mg (0.0839 mmol) of compound TPD5735-9, 34.79 mg (0.0839 mmol) of potassium carbonate, 6 ml of acetonitrile and 1.39 mg (0.00839 mmol) of potassium iodide were added successively. The reaction was carried out at 25 °C for 16 hours. The reaction solution was poured into 10 ml of water, and extracted 3 times with 10 ml of EA. The combined organic phases were washed with water, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by a preparative plate. The eluent ratio was DCM / MeOH = 10 / 1, and compound TPD005746 (31.4 mg, yellow solid, purity 97.503%) was obtained with a yield of 37.78%. LCMS (ESI) m / z calcd. for C 52 H 52 FN 9 O 9 [M+H] + 966.4; found 966.4; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 11.10 (s, 1H), 10.22 (d, J = 4.9 Hz, 2H), 10.07 (s, 1H), 8.88 (s, 1H), 8.52 (t, J = 5.3 Hz, 1H), 7.79 (d, J = 8.9 Hz, 2H), 7.69 - 7.62 (m, 4H), 7.33 (s, 1H), 7.26 (d, J = 9.0 Hz, 3H), 4.12 (t, J = 8.9 Hz, 2H), 6.49 (d, J = 5.1 Hz, 1H), 5.11 - 5.06 (m, 1H), 4.11 - 4.05 (d, J = 19.4 Hz, 5H), 3.25 (s, 2H), 3.07 - 2.83 (m, 4H), 2.73

[0444] - 2.59 (m, 6H), 2.23 (d, J = 6.1 Hz, 2H), 2.10 - 1.92 (m, 2H), 1.83 (d, J = 12.6 Hz, 2H), 1.49 (s, 4H), 1.26 - 1.16 (m, 5H). It can be seen that the structure of the compound is correct.

[0445] Example 39: Synthesis of compound TPD005752m

[0446]

[0447] In a 100 ml three-necked flask, 4-(4-aminophenyl)piperazine-1-carboxylic acid tert-butyl ester (2 g, 7.2 mmol), 3-bromopiperidine-2,6-dione (2.76 g, 14.4 mmol), DIEA (1.86 g, 14.4 mmol) and DMF (20 ml) were added successively. The reaction was carried out at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (30 ml), and extracted three times with EA (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with the eluent ratio of DCM / MeOH = 100 / 1 - 30 / 1 to obtain compound TPD5752m-2 (1.1 g, green solid, purity 95.775%), yield: 37.50%. LCMS(ESI) m / z calcd.for C 20 H 28 N 4 O 4 [M+H] + 389.2; found 389.1; 1 H NMR(400 MHz, DMSO_d 6 ): δ = 10.77 (s, 1H), 6.78 - 6.76 (m, 2H), 6.62 - 6.60 (m, 2H), 5.45 (d, J = 7.4 Hz, 1H), 4.24 - 4.18 (m, 1H), 3.43 (br.s., 4H), 2.87 - 2.85 (m, 4H), 2.77 - 2.68 (m, 1H), 2.60 - 2.54 (m, 1H), 2.12 - 2.08 (m, 1H), 1.88 - 1.78 (m, 1H), 1.41 (s, 9H). It can be seen that the structure of the compound is correct.

[0448] In a 25 ml single-necked flask, compound TPD5752m-2 (250 mg, 0.6419 mmol), EA (1 ml) and HCl / EA (2 ml) were added successively. The reaction was carried out at 25 °C for 2 hours. After the reaction was completed, it was concentrated to dryness to obtain the crude compound TPD5752m-3 (250 mg, blue solid), yield: 75.14%. LCMS(ESI) m / z calcd.for C 15 H 20 N 4 O 2 [M+H] + 289.2; found 289.2. It can be seen that the structure of the compound is correct.

[0449] In a 100 ml three-necked flask, compound int-B (862.6 mg, 1.7731 mmol), TEA (717.68 mg, 7.0924 mmol) and DCM (10 ml) were added successively. After cooling to 0 °C, compound TPD5752m-4 (500 mg,

[0450] 3.5462 mmol) was added. The reaction was carried out at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to 0 °C and poured into water (30 ml), and extracted three times with DCM (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the crude compound TPD5752m-5 (480 mg, brown oil, purity 76.441%), yield: 17.51%. LCMS (ESI) m / z calcd. for C 31 H 28 ClFN 4 O 5 [M+H] + 591.2; found 591.2; 1 HNMR (400 MHz, DMSO_d 6 ): δ = 10.20 (s, 1H), 10.07 (s, 1H), 9.54 (s, 1H), 8.78 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 8.9 Hz, 2H), 7.67 - 7.62 (m, 3H), 7.26 - 7.24 (m, 2H), 7.19 - 7.13 (m, 3H), 4.03 (s, 3H), 3.73 (t, J = 6.6 Hz, 2H), 2.70 (t, J = 7.3 Hz, 2H), 2.10 - 2.06 (m, 2H), 1.48 (s, 4H). It can be seen that the structure of the compound is correct.

[0451] In a 50 ml three-necked flask, compound TPD5752m-5 (500 mg, 0.846 mmol), 4-hydroxymethylpiperidine (194.75 mg, 1.692 mmol), K 2 CO 3(233.85 mg, 1.692 mmol), KI (28.09 mg, 0.1692 mmol) and acetonitrile (10 ml). The reaction was carried out at 60 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and poured into water (10 ml), and extracted three times with EA (3 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with the eluent ratio of DCM / MeOH = 100 / 1 - 30 / 1 to obtain compound TPD5752m-6 (240 mg, brown solid, purity 97.264%), yield: 41.19%. LCMS (ESI) m / z calcd. for C 37 H 40 FN 5 O 6 [M + H] + 670.3; found 670.3; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 10.20 (s, 1H), 10.06 (s, 1H), 9.39 (s, 1H), 8.79 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 7.77 (d, J = 8.9 Hz, 1H), 7.66 - 7.63 (m, 3H), 7.27 - 7.23 (m, 2H), 7.18 - 7.13 (m, 3H), 4.44 (s, 1H), 4.03 (s, 2H), 3.22 - 3.17 (m, 4H), 2.97 (br.s., 2H), 2.55 - 2.54 (m, 2H), 1.82 (br.s., 2H), 1.67 - 1.64 (m, 3H), 1.48 (s, 3H), 1.36 - 1.34 (m, 2H), 1.17 (br.s., 2H). It can be seen that the structure of the compound is correct.

[0452] Oxalyl chloride (90.96 mg, 0.7166 mmol) and DCM (2 ml) were successively added to a 50 ml three-necked flask. After cooling to -78 °C, a solution of DMSO (111.79 mg, 1.4332 mmol) in DCM (1 ml) was added, and the mixture was stirred at -78 °C for 0.5 h. Then, a solution of compound TPD5752m-6 (240 mg, 0.3583 mmol) in DCM (2 ml) was added, and the mixture was stirred at -78 °C for 0.5 h. Finally, TEA (290.05 mg, 2.8664 mmol) was added, and the temperature was slowly restored to room temperature. The reaction was carried out for 1 h under nitrogen protection. After the reaction was completed, the reaction solution was poured into saturated NaHCO 3In a solution (6 ml), extract three times with DCM (3 ml). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness to obtain the crude compound TPD5752m-7 (240 mg, brown solid, purity 31.626%), yield: 31.73%. LCMS (ESI) m / z calcd. for C 37 H 38 FN 5 O 6 [M+H] + 668.3; found 668.3. It can be seen that the compound structure is correct.

[0453] Add compound TPD5752m-7 (160 mg, 0.2396 mmol), compound TPD5752m-3 (82.91 mg, 0.2875 mmol), sodium triacetoxyborohydride (101.56 mg, 0.4792 mmol) and DCE (3 ml) into a 25 ml single-necked flask in sequence. Under nitrogen protection, react at 25 °C for 16 hours. Pour the reaction solution into water (5 ml), and add an appropriate amount of saturated NaHCO 3 solution to make the reaction solution alkaline. Separate the organic phase, and extract the aqueous phase twice with DCM (5 ml). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. The residue is prepared by high performance liquid chromatography, and the relevant parameters are as follows: chromatographic column: XBridge-1 5um 19-150 mm; mobile phase: acetonitrile-water (0.1% NH 3 H 2 O); gradient: 40-80 / 8 minutes, to obtain compound TPD005752m (2.47 mg, gray solid, purity 87.474%), yield: 0.96%. LCMS (ESI) m / z calcd. for C 52 H 58 FN 9 O 7 [M+H] + 940.4; found 314.3 and 470.8 (one-third peak and half peak); 1 H NMR (400 MHz, CD 3OD): δ = 8.93 (s, 1H), 8.43 (d, J = 5.4 Hz, 1H), 7.73 - 7.70 (m, 3H), 7.58 - 7.54 (m, 2H), 7.23 - 7.21 (m, 2H), 7.09 - 7.05 (m, 2H), 6.89 - 6.87 (m, 2H), 6.73 - 6.71 (m, 2H), 6.56 (d, J = 5.3 Hz, 1H), 4.21 - 4.17 (m, 1H), 4.09 (s, 3H), 3.13 - 3.11 (m, 2H), 3.02 (br.s., 3H), 2.79 - 2.71 (m, 2H), 2.61 - 2.56 (m, 7H), 2.34 - 2.30 (m, 1H), 2.20 (t, J = 6.7 Hz, 1H), 2.03 - 1.97 (m, 3H), 1.92 - 1.88 (m, 1H), 1.85 - 1.81 (m, 2H), 1.64 (br.s., 3H), 1.30 (s, 9H). It can be seen that the compound structure is correct.

[0454] Example 40: Synthesis of Compound TPD005760

[0455]

[0456] Add int-H (280 mg, 0.87 mmol), benzyl 4-formylpiperidine-1-carboxylate (323 mg, 1.31 mmol), DCE (10 ml), sodium triacetoxyborohydride (554 mg, 2.61 mmol) and glacial acetic acid (157 mg, 2.61 mmol) into a 50 ml single-necked flask. React at 25 °C for 16 hours. Pour the reaction solution into saturated sodium bicarbonate aqueous solution (10 ml), and extract with dichloromethane (5 ml) three times. Combine the organic phases and wash them successively with water (10 ml) and saturated brine (10 ml). Then dry over anhydrous sodium sulfate, filter and concentrate to dryness to obtain the crude product, which is purified by silica gel column chromatography. The eluent ratio is PE / EA = 5 / 1 - 0 / 1, and compound TPD5760-1 (160 mg, white solid, purity 92.58%) is obtained, with a yield of 30.76%. LCMS (ESI) m / z calcd. for C 29 H 37 FN 6 O 4 [M + H] + 553.3; found 553.1; 1 H NMR (400 MHz, CDCl 3): δ = 7.90 (s, 1H), 7.37 - 7.28 (m, 6H), 6.36 (d, J = 8.4 Hz, 1H), 5.51 - 5.47 (m, 1H), 5.13 (s, 2H), 4.18 (br.s., 2H), 2.96 (d, J = 4.2 Hz, 4H), 2.91 - 2.85 (m, 3H), 2.84 - 2.72 (m, 4H), 2.56 (s, 4H), 2.40 - 2.29 (m, 1H), 2.23 (d, J = 7.0 Hz, 2H), 1.83 - 1.63 (m, 4H), 1.11 (d, J = 10.8 Hz, 2H). It can be seen that the compound structure is correct.

[0457] Add compound TPD5760-1 (160 mg, 0.35 mmol), EA (4 ml) and palladium on carbon hydroxide (40 mg, 10%) to a 250 ml single-necked flask. React under 1 atm hydrogen at 25 °C for 1 hour. After filtration, concentrate to dryness to obtain the crude compound TPD5760-2 (120 mg, brown oil, purity 39.10%), yield: 41.56%. LCMS (ESI) m / z calcd. for C 21 H 31 FN 6 O 2 [M + H] + 419.3; found 419.1. It can be seen that the compound structure is correct.

[0458] Add compound TPD5760-2 (55 mg, 0.13 mmol), compound TPD5735-9 (73.98 mg, 0.13 mmol), acetonitrile (5 ml), potassium carbonate (36.32 mg, 0.26 mmol) and potassium iodide (2 mg, 0.01 mmol) to a 25 mL single-necked flask. React at 25 °C for 16 hours. Pour the reaction solution into water (20 ml), extract with ethyl acetate (10 ml) three times, combine the organic phases, wash successively with water (20 ml) and saturated brine (20 ml), and then dry with anhydrous sodium sulfate. After filtration, purify by preparative plate, and the eluent ratio is DCM / MeOH = 10 / 1 to obtain compound TPD005760 (12.6 mg, off-white solid, purity 99.553%), yield 8.56%. LCMS (ESI) m / z calcd. for C 50 H 54 F 2 N 10 O 7 [M + H] + 945.4; found 945.4; 1 H NMR (400 MHz, DMSO_d 6): δ = 10.81 (s, 1H), 10.23 (d, J = 24.7 Hz, 2H), 10.06 (s, 1H), 8.86 (s, 1H), 8.51 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 8.9 Hz, 2H), 7.68 - 7.59 (m, 3H), 7.47 - 7.42 (m, 1H), 7.25 (d, J = 9.0 Hz, 2H), 7.19 - 7.11 (m, 2H), 6.50 - 6.46 (m, 2H), 5.20 (d, J = 7.5 Hz, 1H), 4.09 (s, 3H), 3.20 (s, 2H), 2.87 (d, J = 14.8 Hz, 6H), 2.80 (s, 3H), 2.56 (s, 2H), 2.45 - 2.32 (m, 2H), 2.26 (t, J = 9.1 Hz, 4H), 1.86 - 1.79 (m, 3H), 1.59 (br.s., 1H), 1.48 (s, 4H), 1.24 (d, J = 10.4 Hz, 4H). It can be seen that the compound structure is correct.

[0459] Example 41: Synthesis of Compound TPD005773

[0460]

[0461] Compound int - A (1.0 g, 1.61 mmol), tert - butyl glycinate (423 mg, 3.23 mmol), cesium carbonate (1051 mg, 3.23 mmol), XantPhos (187 mg, 0.323 mmol), Pd 2 (dba) 3 (148 mg, 0.16 mmol) and 1,4 - dioxane (50 ml) were successively added to a 250 - ml three - necked flask. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated to dryness. The residue was purified by silica gel column chromatography, and the eluent ratio was DCM / MeOH = 100 / 1 - 30 / 1, to obtain compound TPD5773 - 1 (680 mg, yellow solid, purity 98.573%), yield: 69.14%. LCMS (ESI) m / z calcd. for C 33 H 33 FN 4 O 6 [M + H] + 601.2; found 601.2; 1 HNMR (400 MHz, DMSO_d 6): δ = 10.16 (s, 1H), 10.06 (s, 1H), 8.34 (d, J = 5.2 Hz, 1H), 7.74 (d, J = 8.9 Hz, 2H), 7.66 - 7.63 (m, 2H), 7.39 (s, 1H), 7.20 - 7.13 (m, 4H), 6.73 (s, 1H), 6.28 (d, J = 5.2 Hz, 1H), 6.08 (t, J = 6.1 Hz, 1H), 3.99 - 3.97 (m, 5H), 1.47 (s, 4H), 1.44 (s, 9H). It can be seen that the structure of the compound is correct.

[0462] Compound TPD5773-1 (250 mg, 0.416 mmol), DCM (2 ml) and trifluoroacetic acid (1 ml) were successively added to a 50 ml single-necked flask. The reaction was carried out at 25 °C for 2 hours. After the reaction was completed, it was concentrated to dryness to obtain crude compound TPD5773-2 (250 mg, yellow solid), yield: 89.33%. LCMS (ESI) m / z calcd. for C 29 H 25 FN 4 O 6 [M + H] + 545.2; found 545.2. It can be seen that the structure of the compound is correct.

[0463] Compound TPD5773-2 (100 mg, 0.184 mmol), compound TPD5760-2 (77 mg, 0.184 mmol), HATU (105 mg, 0.275 mmol), triethylamine (37 mg, 0.367 mmol) and DMF (3 ml) were successively added to a 25 ml single-necked flask. The reaction was carried out at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (6 ml), and extracted three times with EA (2 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 10 / 1, to obtain compound TPD005773 (26.4 mg, off-white solid, purity 96.12%), yield: 14.65%. LCMS (ESI) m / z calcd. for C 50 H 54 F 2 N 10 O 7 [M + H] + 945.4; found 945.4; 1 H NMR (400 MHz, DMSO_d 6): δ = 10.81 (s, 1H), 10.17 (s, 1H), 10.06 (s, 1H), 8.36 (d, J = 5.3 Hz, 1H), 7.75 (d, J = 8.9 Hz, 2H), 7.66 - 7.63 (m, 2H), 7.48 - 7.43 (m, 1H), 7.40 (s, 1H), 7.21 - 7.13 (m, 4H), 6.97 (s, 1H), 6.50 (d, J = 8.3 Hz, 1H), 6.27 (d, J = 5.3 Hz, 1H), 5.98 (br.s., 1H), 5.20 (d, J = 9.6 Hz, 1H), 4.41 (d, J = 13.9 Hz, 1H), 4.14 - 4.07 (m, 2H), 4.00 (br.s., 4H), 3.06 (t, J = 12.0 Hz, 1H), 2.89 - 2.84 (m, 5H), 2.81 (s, 3H), 2.69 (t, J = 11.4 Hz, 1H), 2.56 (br.s., 1H), 2.43 - 2.30 (m, 2H), 2.21 (s, 2H), 2.04 - 1.73 (m, 5H), 1.47 (s, 4H), 1.23 (s, 2H), 1.14 (d, J = 12.6 Hz, 1H), 1.02 - 0.95 (m, 1H). It can be seen that the structure of the compound is correct.

[0464] Example 42: Synthesis of Compound TPD005774

[0465]

[0466] Compound TPD5773 - 1 (400 mg, 0.67 mmol), DCM (2 ml) and trifluoroacetic acid (1 ml) were successively added to a 50 ml single - necked flask. The reaction was carried out at 25 °C for 2 hours. After the reaction was completed, it was concentrated to dryness to obtain the crude compound TPD5773 - 2 (400 mg, yellow solid), yield: 72.60%. LCMS (ESI) m / z calcd. for C 29 H 25 FN 4 O 6 [M + H] + 545.2; found 545.0. It can be seen that the structure of the compound is correct.

[0467] In a 25 ml single-necked flask, sequentially add compound TPD5773-2 (350 mg, 0.64 mmol), 4-hydroxymethylpiperidine (111 mg, 0.964 mmol), EDCI (185 mg, 0.96 mmol), HOBT (130 mg, 0.96 mmol), triethylamine (195 mg, 1.93 mmol) and DCM (5 ml). React at 25 °C for 16 hours under nitrogen protection. After the reaction is completed, pour the reaction solution into water (6 ml), and extract three times with DCM (2 ml). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. The residue is purified by silica gel column chromatography with an eluent ratio of DCM / MeOH = 100 / 1 to 30 / 1 to obtain compound TPD5774-1 (240 mg, yellow solid, purity 96.292%), yield: 56.02%. LCMS (ESI) m / z calcd. for C 35 H 36 FN 5 O 6 [M+H] + 642.3; found 642.1; 1 HNMR (400 MHz, DMSO_d 6 ): δ = 10.17 (s, 1H), 10.07 (s, 1H), 8.35 (d, J = 5.2 Hz, 1H), 7.74 (d, J = 8.9 Hz, 2H), 7.66 - 7.63 (m, 2H), 7.39 (s, 1H), 7.21 - 7.13 (m, 4H), 6.97 (s, 1H), 6.27 (d, J = 5.2 Hz, 1H), 5.96 (t, J = 4.2 Hz, 1H), 4.54 (t, J = 5.2 Hz, 1H), 4.44 - 4.36 (m, 1H), 4.13 - 4.04 (m, 3H), 4.00 (s, 3H), 3.27 (t, J = 5.6 Hz, 3H), 3.17 (d, J = 4.7 Hz, 1H), 3.03 (t, J = 11.9 Hz, 1H), 2.65 (t, J = 11.7 Hz, 1H), 1.77 - 1.65 (m, 3H), 1.47 (s, 4H). It can be seen that the compound structure is correct.

[0468] In a 25 ml three-necked flask, sequentially add compound TPD5774-1 (190 mg, 0.30 mmol) and DCM (5 ml). After cooling to 0 °C, add Dess-Martin oxidant (251 mg, 0.59 mmol). React at 25 °C for 3 hours under nitrogen protection. After the reaction is completed, add saturated NaHCO 3The solution (3 ml) and water (5 ml) were extracted three times with DCM (3 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate with the eluent ratio of DCM / MeOH = 10 / 1 to obtain compound TPD5774-2 (90 mg, white solid, purity 84.277%), yield: 40.05%. LCMS (ESI) m / z calcd. for C 35 H 34 FN 5 O 6 [M+H] + 640.2; found 640.1; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 10.18 (s, 1H), 10.07 (s, 1H), 9.62 (s, 1H), 8.35 (d, J = 5.2 Hz, 1H), 7.74 (d, J = 8.9 Hz, 2H), 7.66 - 7.62 (m, 2H), 7.39 (s, 1H), 7.21 - 7.13 (m, 4H), 6.97 (s, 1H), 6.27 (d, J = 5.2 Hz, 1H), 5.95 (t, J = 4.3 Hz, 1H), 4.20 - 4.09 (m, 3H), 4.00 (s, 3H), 3.92 (d, J = 13.7 Hz, 1H), 3.27 - 3.16 (m, 2H), 3.01 - 2.92 (m, 1H), 2.68 - 2.60 (m, 1H), 1.99 - 1.87 (m, 2H), 1.60 - 1.53 (m, 1H), 1.47 (s, 4H). It can be seen that the structure of the compound is correct.

[0469] Compound TPD5774-2 (90 mg, 0.14 mmol), Int-I-5 (86 mg, 0.28 mmol), sodium triacetoxyborohydride (60 mg, 0.28 mmol), acetic acid (25 mg, 0.42 mmol) and DCE (3 ml) were successively added into a 25-ml single-necked flask. Under nitrogen protection, the reaction was carried out at 30 °C for 16 h. The reaction solution was poured into water (5 ml), and an appropriate amount of saturated NaHCO 3A solution was added to make the reaction solution alkaline. The organic phase was separated, and the aqueous phase was extracted twice with DCM (5 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was prepared by high performance liquid chromatography with the following parameters: Column: XBridge-15um 19-150mm; Mobile phase: acetonitrile-water (0.1% NH3H2O); Gradient: 10-55 / 8 min, to obtain compound TPD005774 (1.05 mg, white solid, purity 93.818%), Yield: 0.78%. LCMS (ESI) m / z calcd. for C 49 H 52 F 2 N 10 O 7 [M+H] + 931.4; found 931.4; 1 H NMR (400 MHz, CD 3 OD): δ = 8.41 (d, J = 6.9 Hz, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.67 (s, 1H), 7.58 - 7.54 (m, 2H), 7.45 - 7.38 (m, 1H), 7.31 (d, J = 8.9 Hz, 2H), 7.07 (t, J = 8.8 Hz, 2H), 6.85 (s, 1H), 6.68 (d, J = 6.8 Hz, 1H), 6.46 (d, J = 8.4 Hz, 1H), 4.29 (d, J = 6.1 Hz, 2H), 4.15 (s, 3H), 3.75 - 3.55 (m, 4H), 3.18 - 3.13 (m, 4H), 2.85 - 2.69 (m, 4H), 2.26 - 2.17 (m, 4H), 2.07 - 2.02 (m, 3H), 1.65 (s, 3H), 1.29 (s, 9H). It can be seen that the structure of the compound is correct.

[0470] Example 43: Synthesis of compound TPD005901

[0471]

[0472] In a 50 ml single-necked flask, successively add compound DMF (15 ml), compound TPD55901-1 (1 g, 3.90 mmol), 4-Boc-1-piperazineacetic acid (1.05 g, 4.29 mmol), HATU (2.22 g, 5.85 mmol) and DIEA (1.26 g, 9.75 mmol). React at 25 °C for 16 hours under nitrogen protection. After the reaction is completed, pour it into saturated sodium bicarbonate aqueous solution (60 ml), and extract three times with ethyl acetate (50 ml). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. The residue is purified by silica gel column chromatography, and the eluent ratio is DCM / MeOH = 50 / 1 to 30 / 1 to obtain compound TPD5901-1 (1 g, white solid, purity 98.733%), yield: 51.28%. LCMS (ESI) m / z calcd. for C 24 H 31 N 5 O 6 [M+H] + 486.2; found 486.1; 1 H NMR (400 MHz, CDCl 3 ): δ = 9.10 (s, 1H), 8.47 (s, 1H), 7.73 (dd, J = 7.7, 4.5 Hz, 2H), 7.50 (t, J = 7.8 Hz, 1H), 5.20 (dd, J = 13.3, 5.1 Hz, 1H), 4.42 (s, 2H), 3.54 - 3.47 (m, 4H), 3.21 (s, 2H), 2.93 - 2.75 (m, 2H), 2.61 (t, J = 4.8 Hz, 4H), 2.38 (dd, J = 13.1, 5.3 Hz, 1H), 2.28 - 2.14 (m, 1H), 1.47 (s, 9H). It can be seen that the compound structure is correct.

[0473] In a 20 ml single-necked flask, successively add compound TPD5901-2 (200 mg, 0.41 mmol) and 1,4-dioxane / HCl (4N, 10 ml). React at 25 °C for 4 hours. After the reaction is completed, concentrate to dryness to obtain the crude product compound TPD5901-3 (180 mg, brown solid), yield: 94.55%. LCMS (ESI) m / z calcd. for C 19 H 23 N 5 O 4 [M+H] + 386.2; found 386.1. It can be seen that the compound structure is correct.

[0474] In a 25 ml single-necked flask, add compound TPD5488-2 (100 mg, 0.17 mmol), compound TPD5901-3 (66 mg, 0.17 mmol), DCE (4 ml) and STAB (73 mg, 0.34 mmol) in sequence. React at 25 °C for 16 hours under nitrogen protection. After the reaction is completed, pour the reaction solution into saturated sodium bicarbonate aqueous solution (10 ml), and extract three times with DCM (10 ml). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. The residue is purified by a preparative plate, and the eluent ratio is DCM / MeOH = 10 / 1 to obtain compound TPD005901 (16.7 mg, light yellow solid, purity 95.093%), yield: 19.46%. LCMS (ESI) m / z calcd. for C 52 H 54 FN 9 O 8 [M+H] + 952.4; found 952.7; 1 H NMR (400 MHz, CDCl 3 ): δ = 9.52 (s, 1H), 9.33 (s, 1H), 8.84 (s, 1H), 8.54 (d, J = 2.8 Hz, 1H), 8.27 (s, 1H), 7.82 (d, J = 7.3 Hz, 2H), 7.72 (d, J = 7.0 Hz, 2H), 7.67 - 7.52 (m, 5H), 7.25 (d, J = 6.7 Hz, 2H), 7.13 (t, J = 7.4 Hz, 2H), 6.53 (d, J = 2.6 Hz, 1H), 5.30 (d, J = 13.3 Hz, 1H), 4.54 (s, 2H), 4.11 (s, 3H), 3.81 (d, J = 9.6 Hz, 2H), 3.28 (s, 2H), 3.09 - 2.88 (m, 2H), 2.79 (br.s., 6H), 2.64 (br.s., 3H), 2.56 - 2.28 (m, 5H), 2.00 (d, J = 12.5 Hz, 3H), 1.89 - 1.73 (m, 9H), 1.67 - 1.55 (m, 3H). It can be seen that the compound structure is correct.

[0475] Example 44: Synthesis of compound TPD005907

[0476]

[0477] In a 100 ml single-necked flask, 2.0 g (0.01 mol) of compound TPD5907-1, 2.20 g (0.01 mol) of benzyl-1-piperazine carbonate, 1.26 g (0.02 mol) of sodium cyanoborohydride and 30 ml of methanol were added successively. The reaction was carried out at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into 30 ml of water, and an appropriate amount of saturated NaHCO 3 solution was added to make the reaction solution alkaline. It was extracted three times with 30 ml of DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with an eluent ratio of DCM / MeOH = 100 / 1 to 30 / 1 to obtain 3.5 g of compound TPD5907-2 (colorless oil, purity 56.272%), and the yield was 49.00%. LCMS (ESI) m / z calcd. for C 22 H 33 N 3 O 4 [M+H] + 404.2; found 404.1. It can be seen that the compound structure is correct.

[0478] In a 100 ml single-necked flask, 1.5 g (0.0037 mol) of compound TPD5907-2, Pd(OH) 2 (3 g, 10%) and 25 ml of EA were added successively. The reaction was carried out at 50 °C for 16 hours under a hydrogen atmosphere. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with an eluent ratio of DCM / MeOH = 20 / 1 to 4 / 1 to obtain 0.75 g of compound TPD5907-3 (yellow solid), and the yield was 67.57%. LCMS (ESI) m / z calcd. for C 14 H 27 N 3 O 2 [M+H] + 270.21; found 270.1; 1H NMR (400 MHz, DMSO_d 6 ): δ = 3.93 (d, J = 11.1 Hz, 1H), 2.80 - 2.58 (m, 3H), 2.47 - 2.37 (m, 2H), 2.35 - 2.25 (m, 0H), 1.69 (d, J = 12.7 Hz, 1H), 1.38 (s, 4H), 1.29 - 1.17 (m, 1H).

[0479] In a 25 ml single-necked flask, compound TPD5907-3 (482 mg, 1.78 mmol), sm-1 (480 mg, 1.49 mmol), PEPPSI IHept-Cl (145 mg, 0.149 mmol), cesium carbonate (968 mg, 2.97 mmol) and 1,4-dioxane (25 ml) were added successively. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water (50 ml), and extracted three times with EA (50 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative silica gel column chromatography with an eluent ratio of DCM / MeOH = 50 / 1 to 20 / 1 to obtain compound TPD5907-4 (170 mg, yellow solid, purity 63.146%), yield: 14.68%. LCMS (ESI) m / z calcd. for C 27 H 37 N 5 O 5 [M+H] + 512.28; found 512.1. It can be seen that the structure of the compound is correct.

[0480] In a 25 ml single-necked flask, compound TPD5907-4 (170 mg, 0.27 mmol) and 4N HCl / 1,4-dioxane (8 ml) were added successively. The reaction was carried out at 25 °C for 2 hours. After the reaction was completed, it was concentrated to dryness to obtain the crude compound TPD5907-5 (180 mg, yellow solid). LCMS (ESI) m / z calcd. for C 22 H 29 N 5 O 3 [M+H] + 412.22; found 412.1. It can be seen that the structure of the compound is correct.

[0481] In a 25 ml single-necked flask, compound TPD5907-5 (177 mg, 0.43 mol), compound TPD5488-2 (250 mg, 0.43 mmol), sodium triacetoxyborohydride (1832 mg, 0.86 mmol) and DCE (8 ml) were added successively. The reaction was carried out at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (20 ml), and an appropriate amount of saturated NaHCO 3Solution was added to make the reaction solution alkaline. It was extracted twice with DCM (20 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was prepared by high performance liquid chromatography with the following parameters: Column: XBridge-1 5um 19-150mm; Mobile phase: acetonitrile-water (0.1% FA); Gradient: 10-55 / 8 min, to obtain compound TPD005907 (10.8 mg, yellow solid, purity 96.778%), yield: 2.49%. LCMS (ESI) m / z calcd. for C 55 H 60 FN 9 O 7 [M+H] + 978.46; found 489.7, 978.4; 1 H NMR (400 MHz, CD 3 OD): δ = 8.41 (d, J = 5.4 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.63 (s, 1H), 7.56 (dd, J = 8.9, 4.9 Hz, 2H), 7.48 (t, J = 6.9 Hz, 2H), 7.41 (s, 1H), 7.24 (dd, J = 19.1, 7.4 Hz, 3H), 7.07 (t, J = 8.7 Hz, 2H), 6.53 (d, J = 5.4 Hz, 1H), 5.17 (dd, J = 13.2, 5.1 Hz, 1H), 4.87 (s, 1H), 4.50 (d, J = 17.1 Hz, 2H), 4.03 (s, 3H), 3.74 (d, J = 9.6 Hz, 2H), 3.54 (s, 2H), 3.20 (s, 4H), 3.01-2.63 (m, 13H), 2.59-2.45 (m, 1H), 2.25-2.12 (m, 3H), 2.09-2.01 (m, 1H), 2.01-1.83 (m, 4H), 1.70-1.52 (m, 6H). It can be seen that the structure of the compound is correct.

[0482] Example 45: Synthesis of compound TPD005937

[0483]

[0484] To a 50 ml three-necked flask were successively added compound TPD5937-1 (400 mg, 1.24 mmol), PdCl 2 (PPh 3 ) 2(87 mg, 0.12 mmol), CuI (24 mg, 0.12 mmol), DMF (16 ml), propynyloxytrimethylsilane (238 mg, 1.86 mmol) and DIEA (320 mg, 2.48 mmol). React at 80 °C for 6 hours under nitrogen protection. After the reaction is completed, pour the reaction solution into water (10 ml), and extract six times with ethyl acetate (5 ml). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. Purify the residue by silica gel column chromatography with an eluent ratio of DCM / MeOH = 100 / 1 to 30 / 1 to obtain compound TPD5937-2 (250 mg, yellow solid, purity 95.746%), yield: 69.59%. LCMS (ESI) m / z calcd. for C 16 H 14 N 2 O 4 [M+H] + 299.1; found 299.0; 1 HNMR (400 MHz, DMSO_d 6 ): δ = 11.01 (s, 1H), 7.74 (d, J = 6.9 Hz, 1H), 7.69 - 7.66 (m, 1H), 7.54 (t, J = 7.6 Hz, 1H), 5.43 (t, J = 5.9 Hz, 1H), 5.17 - 5.13 (m, 1H), 4.35 - 4.33 (m, 2H), 3.16 (d, J = 5.2 Hz, 2H), 3.13 - 3.10 (m, 1H), 2.95 - 2.86 (m, 1H), 2.58 (d, J = 17.3 Hz, 1H), 2.46 - 2.38 (m, 1H), 2.03 - 1.97 (m, 1H). It can be seen that the compound structure is correct.

[0485] Add compound TPD5937-2 (800 mg, 2.68 mmol), Pd / C (800 mg, washed with ethanol to remove water) and ethanol (80 ml) to a 300 ml hydrogenation bottle. After introducing 20 - 40 psi of hydrogen, heat to 50 °C and react for 72 hours. After the reaction is completed, filter, and wash the filter cake with a large amount of ethanol. Concentrate the filtrate to dryness to obtain compound TPD5937-3 (220 mg, white solid, purity 54.175%), yield: 14.70%; LCMS (ESI) m / z calcd. for C 16 H 18 N 2 O 4 [M+H] + 303.1; found 303.0; 1 H NMR (400 MHz, DMSO_d 6): δ = 11.01 (s, 1H), 7.58 - 7.55 (m, 1H), 7.48 - 7.44 (m, 2H), 5.17 - 5.12 (m, 1H), 4.49 - 4.29 (m, 2H), 3.46 - 3.40 (m, 3H), 2.76 - 2.53 (m, 4H), 2.46 - 2.30 (m, 2H), 1.83 - 1.68 (m, 2H). It can be seen that the structure of the compound is correct.

[0486] Compound TPD5937 - 3 (290 mg, 0.96 mmol) and DCM (25 ml) were added to a 100 ml three - necked flask. Under nitrogen protection, the reaction solution was cooled to 0 °C, and then DMP (814 mg, 1.92 mmol) was added. The reaction was carried out at 30 °C for 3 hours. After the reaction was completed, the reaction solution was poured into a saturated sodium bicarbonate and sodium thiosulfate aqueous solution (50 ml). The organic phase was separated, and the aqueous phase was extracted three times with DCM (50 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the crude compound TPD5937 - 4 (52 mg, white solid, purity 87.420%), yield: 15.78%. LCMS (ESI) m / z calcd. for C 16 H 16 N 2 O 4 [M + H] + 301.1; found 301.0; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 11.02 (s, 1H), 9.73 (s, 1H), 7.59 - 7.56 (m, 1H), 7.52 - 7.40 (m, 2H), 5.16 - 5.12 (m, 1H), 4.54 - 4.31 (m, 2H), 2.98 - 2.86 (m, 4H), 2.61 (d, J = 17.5 Hz, 1H), 2.47 - 2.37 (m, 2H), 2.07 - 1.95 (m, 1H). It can be seen that the structure of the compound is correct.

[0487] In a 25 ml three-necked flask, 170 mg (0.29 mmol) of compound TPD5488-2, 3.4 ml of DCE, 60 mg (0.32 mmol) of tert-butyl piperazine-1-carboxylate, 53 mg (0.88 mmol) of glacial acetic acid, and 124 mg (0.58 mmol) of sodium triacetoxyborohydride were successively added. Under nitrogen protection, the reaction was carried out at 30 °C for 2 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate solution (10 ml). The organic phase was separated, and the aqueous phase was extracted three times with DCM (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 10 / 1, to obtain compound TPD5937-5 (120 mg, yellow solid, purity 97.751%), yield: 53.32%. LCMS(ESI) m / z calcd. for C 42 H 49 FN 6 O 6 [M+H] + 753.4; found 753.3; 1 H NMR(400 MHz, DMSO_d 6 ): δ = 10.21 - 10.02 (m, 2H), 8.43 (d, J = 5.2 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.66 - 7.62 (m, 2H), 7.46 (s, 1H), 7.31 (s, 1H), 7.25 - 7.11 (m, 4H), 6.39 (d, J = 5.2 Hz, 1H), 3.94 (s, 3H), 3.59 (d, J = 11.2 Hz, 2H), 3.33 (d, J = 3.2 Hz, 6H), 2.64 (t, J = 11.1 Hz, 2H), 2.31 (br.s., 4H), 2.21 (d, J = 6.8 Hz, 2H), 1.83 (d, J = 11.9 Hz, 2H), 1.71 (br.s., 1H), 1.47 (s, 4H), 1.40 (s, 9H), 1.33 - 1.21 (m, 2H). It can be seen that the structure of the compound is correct.

[0488] In a 25 ml single-necked flask, 90 mg (0.12 mmol) of compound TPD5937-5, 3 ml of dichloromethane, and 1.5 ml of trifluoroacetic acid were added successively. The reaction was carried out at 30 °C for 2 hours. After the reaction was completed, the pH was adjusted to 8 with saturated sodium bicarbonate. The organic phase was separated, and the aqueous phase was extracted three times with 10 ml of DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain compound TPD5937-6 (82 mg, yellow solid, purity 93.306%), yield: 98.16%. LCMS (ESI) m / z calcd. for C 37 H 41 FN 6 O 4 [M+H] + 653.3; found 653.4; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 10.13 (d, J = 48.7 Hz, 2H), 8.43 (d, J = 5.2 Hz, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.66 - 7.63 (m, 2H), 7.46 (s, 1H), 7.31 (s, 1H), 7.24 - 7.12 (m, 4H), 6.39 (d, J = 5.2 Hz, 1H), 3.94 (s, 3H), 3.58 (d, J = 11.5 Hz, 2H), 2.74 (s, 4H), 2.63 (t, J = 11.1 Hz, 2H), 2.32 (br.s., 4H), 2.17 (d, J = 7.1 Hz, 2H), 1.82 (d, J = 12.1 Hz, 2H), 1.70 (br.s., 1H), 1.48 (s, 4H), 1.35 - 1.24 (m, 3H). It can be seen that the structure of the compound is correct.

[0489] In a 25 ml three-necked flask, 82 mg (0.13 mmol) of compound TPD5488-2, 6 ml of DCE, 41 mg (0.14 mmol) of compound TPD5937-4, 23 mg (0.38 mmol) of glacial acetic acid, and 53 mg (0.25 mmol) of sodium triacetoxyborohydride were added successively. Under nitrogen protection, the reaction was carried out at 25 °C for 16 hours. The reaction solution was poured into 10 ml of saturated sodium bicarbonate aqueous solution. The organic phase was separated, and the aqueous phase was extracted three times with 10 ml of DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by a preparative plate, and the eluent ratio was DCM / MeOH = 10 / 1 to obtain compound TPD005937 (39 mg, yellow solid, purity 99.422%), yield: 32.96%. LCMS (ESI) m / z calcd. for C53 H 57 FN 8 O 7 [M+H] + 937.4; found 937.4; 1 H NMR(400 MHz, DMSO_d 6 ): δ = 11.02 (s, 1H), 10.13 (d, J = 49.4 Hz, 2H), 8.43 (d, J = 5.2 Hz, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.66 - 7.63 (m, 2H), 7.58 - 7.56 (m, 1H), 7.50 - 7.42 (m, 3H), 7.31 (s, 1H), 7.25 - 7.10 (m, 4H), 6.39 (d, J = 5.2 Hz, 1H), 5.17 - 5.13 (m, 1H), 4.51 - 4.31 (m, 2H), 3.94 (s, 3H), 3.58 (d, J = 11.1 Hz, 2H), 2.98 - 2.88 (m, 1H), 2.68 - 2.61 (m, 5H), 2.45 - 2.25 (m, 8H), 2.18 (d, J = 6.3 Hz, 2H), 2.05 - 2.00 (m, 1H), 1.82 - 1.75 (m, 4H), 1.47 (s, 4H), 1.30 - 1.19 (m, 6H). It can be seen that the structure of the compound is correct.

[0490] Example 46: Synthesis of Compound TPD005937 - Trifluoroacetate

[0491]

[0492] Compound TPD005937 (10 mg, 0.0097 mmol), DCM (2 ml), and TFA (1 ml) were successively added to a 25 - ml single - necked flask. The system was reacted at 30 °C for 10 minutes. After concentration to dryness, the product compound TPD005937 - TFA (7.4 mg, yellow solid, purity 96.678) was obtained, and the yield was 52.58%. LCMS (ESI) m / z calcd. for C 53 H 57 FN 8 O 7 [M+H] + 937.4; found 937.4; 1 H NMR(400 MHz, DMSO_d 6): δ = 11.04 (s, 1H), 10.33 (s, 1H), 10.02 (s, 1H), 8.73 (d, J = 6.6 Hz, 1H), 7.85 (d, J = 8.9 Hz, 2H), 7.67 - 7.61 (m, 4H), 7.52 - 7.47 (m, 3H), 7.35 (d, J = 9.0 Hz, 2H), 7.16 (t, J = 8.9 Hz, 2H), 6.74 (d, J = 6.6 Hz, 1H), 5.20 - 5.15 (m, 1H), 4.52 - 4.31 (m, 2H), 4.05 (s, 3H), 3.79 (d, J = 11.0 Hz, 2H), 3.06 - 2.90 (m, 4H), 2.84 (t, J = 11.5 Hz, 2H), 2.73 - 2.68 (m, 2H), 2.66 - 2.55 (m, 2H), 2.46 - 2.24 (m, 3H), 2.22 - 1.74 (m, 8H), 1.49 (d, J = 6.5 Hz, 4H), 1.37 (d, J = 11.2 Hz, 2H), 1.23 (s, 4H). It can be seen that the compound structure is correct.

[0493] Example 47: Synthesis of Compound TPD005972

[0494]

[0495] In a 50 ml single-necked flask, successively add compound DMSO (10 ml), compound TPD55972-1 (500 mg, 1.81 mmol), 4-N-(2-aminoethyl)-1-N-Boc-piperidine (500 mg, 2.17 mmol) and DIEA (468 mg, 3.62 mmol). React at 100 °C for 16 hours under nitrogen protection. After the reaction is completed, pour it into saturated sodium bicarbonate aqueous solution (30 ml), and extract three times with ethyl acetate (20 ml). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. The residue is purified by silica gel column chromatography, and the eluent ratio is DCM / MeOH = 100 / 1 - 60 / 1, to obtain compound TPD5972-2 (420 mg, yellow solid, purity 97.762%), yield: 46.62%. LCMS (ESI) m / z calcd. for C 24 H 31 N 5 O 6 [M + H] + 486.2; found 486.1; 1 HNMR (400 MHz, CDCl 3): δ = 11.10 (s, 1H), 7.63 - 7.56 (m, 1H), 7.10 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.79 (t, J = 4.7 Hz, 1H), 5.07 (dd, J = 12.9, 5.3 Hz, 1H), 3.42 - 3.28 (m, 8H), 2.95 - 2.80 (m, 1H), 2.65 - 2.56 (m, 3H), 2.43 - 2.34 (m, 4H), 2.09 - 1.96 (m, 1H), 1.37 (s, 9H). It can be seen that the compound structure is correct.

[0496] Compound TPD5972 - 2 (420 mg, 0.86 mmol) and HCl(g) / EA (4N, 10 ml) were successively added to a 20 ml single - necked flask. The reaction was carried out at 25 °C for 2 hours. After the reaction was completed, it was concentrated to dryness to obtain crude compound TPD5972 - 3 (360 mg, brown solid), yield: 97.87%. LCMS(ESI) m / z calcd. for C 19 H 23 N 5 O 4 [M + H] + 386.2; found 386.1. It can be seen that the compound structure is correct.

[0497] Compound TPD5488 - 2 (100 mg, 0.17 mmol), compound TPD5972 - 3 (79 mg, 0.21 mmol), DCE (4 ml) and STAB (73 mg, 0.34 mmol) were successively added to a 25 ml single - necked flask. The reaction was carried out at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into saturated sodium bicarbonate aqueous solution (10 ml), and extracted three times with DCM (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 10 / 1 to obtain compound TPD005972 (12.4 mg, yellow solid, purity 95.422%), yield: 7.23%. LCMS(ESI) m / z calcd. for C 52 H 54 FN 9 O 8 [M + H] + 952.4; found 952.7; 1 H NMR(400 MHz, CDCl 3): δ = 11.11 (s, 1H), 10.18 (s, 1H), 10.06 (s, 1H), 8.43 (d, J = 5.2 Hz, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.68 - 7.54 (m, 3H), 7.46 (s, 1H), 7.31 (s, 1H), 7.26 - 7.07 (m, 5H), 7.03 (d, J = 7.1 Hz, 1H), 6.77 (t, J = 4.6 Hz, 1H), 6.39 (d, J = 5.2 Hz, 1H), 5.08 (dd, J = 13.0, 5.4 Hz, 1H), 4.22 (t, J = 6.6 Hz, 1H), 3.94 (s, 4H), 3.59 (d, J = 11.3 Hz, 2H), 3.43 - 3.35 (m, 3H), 2.95 - 2.81 (m, 1H), 2.71 - 2.55 (m, 6H), 2.43 - 2.35 (m, 4H), 2.21 (d, J = 6.9 Hz, 2H), 2.06 - 1.97 (m, 1H), 1.83 (d, J = 11.4 Hz, 2H), 1.76 - 1.51 (m, 3H), 1.47 (s, 4H), 1.41 - 1.25 (m, 4H), 0.95 - 0.84 (m, 2H). It can be seen that the structure of the compound is correct.

[0498] Example 48: Synthesis of Compound TPD007022

[0499]

[0500] Compound 7022 - 1 (500 mg) was subjected to an amide condensation reaction with intermediate 7022 - 2 to obtain compound 7022 - 3. The product was prepared into its corresponding aldehyde derivative 7022 - 4 (100 mg) through an oxidation reaction. 25 ml of a single - necked flask was successively added with compound TPD7022 - 5 (81 mg), DCE (4 ml), and STAB (80 mg). The reaction was carried out at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into saturated sodium bicarbonate aqueous solution (10 ml), and extracted three times with DCM (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the developing agent ratio was DCM / MeOH = 10 / 1, to obtain compound TPD007022 (17 mg, yellow solid, purity 97%). LCMS (ESI) m / z calcd. for C48H49FN11O5 [M + H] + 877.4; found 877.7. It can be seen that the structure of the compound is correct.

[0501] Example 49: Synthesis of Compound TPD007026

[0502]

[0503] Compound 7026-1 (700 mg) was condensed with bromoacetamide to obtain compound 7026-2. This product was condensed with 4-hydroxymethylpiperidine under basic conditions to obtain 7026-3, and then its corresponding aldehyde derivative 7026-4 (90 mg) was prepared by an oxidation reaction. It was added to a 25-ml single-necked flask, and compound TPD7022-5 (75 mg), DCE (4 ml), and STAB (77 mg) were successively added. The reaction was carried out at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into saturated sodium bicarbonate aqueous solution (10 ml), and extracted three times with DCM (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by a preparative plate with the eluent ratio of DCM / MeOH = 10 / 1 to obtain compound TPD007022 (15 mg, pale yellow solid, purity 97%). LCMS (ESI) m / z calcd. for C48H48FN12O6 [M+H] + 907.4; found 907.6. It can be seen that the compound structure is correct.

[0504] Example 50: Synthesis of Compound TPD009004

[0505]

[0506] Compound 7022-1 (600 mg) was condensed with 9004-1 to obtain compound 9004-2. This product was hydrolyzed in lithium hydroxide solution to obtain 9004-3, which was added to a 25-ml single-necked flask, and compound VH032, DCM (5 ml), HOBt (5 mg), and EDCI were successively added. The reaction was carried out at 25 °C for 15 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into saturated sodium bicarbonate aqueous solution (10 ml), and extracted three times with DCM (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by a preparative plate with the eluent ratio of DCM / MeOH = 10 / 1 to obtain compound TPD009004 (19 mg, pale yellow solid, purity 96%). LCMS (ESI) m / z calcd. for C56H64FN12O5S [M+H] + 1035.5; found 1035.6. It can be seen that the compound structure is correct.

[0507] Example 51: Synthesis of Compound TPD009006

[0508]

[0509] Compound 9006-1 (500 mg) was reacted with EDCI and HOBt in DCM (10 ml), and subjected to an amide condensation reaction with 9004-1 to obtain compound 9006-2. This product was hydrolyzed in lithium hydroxide solution to obtain 9006-3, which was added to a 25-ml single-necked flask, and compound VH032, DCM (5 ml), HOBt (5 mg), and EDCI were added successively. The reaction was carried out at 25 °C for 17 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into saturated sodium bicarbonate aqueous solution (10 ml), and extracted three times with DCM (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 10 / 1 to obtain compound TPD009006 (13 mg, pale yellow solid, purity 98%). LCMS (ESI) m / z calcd. for C58H67FN13O6S [M+H] + 1092.5; found 1092.6. It can be seen that the compound structure is correct.

[0510] Example 52: Synthesis of Compound TPD10001

[0511]

[0512] Compound 10001-1 (550 mg) was reacted with DIAD and PPh3 in DCM (10 ml), and then 10001-2 was added for a condensation reaction to obtain compound 10001-3. This product was hydrolyzed in lithium hydroxide solution to obtain 10001-4, which was added to a 25-ml single-necked flask, and compound VH032, DCM (5 ml), HOBt (5 mg), and EDCI were added successively. The reaction was carried out at 25 °C for 19 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into saturated sodium bicarbonate aqueous solution (10 ml), and extracted three times with DCM (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 10 / 1 to obtain compound TPD10001 (11 mg, pale yellow solid, purity 98%). LCMS (ESI) m / z calcd. for C53H59N10O6S [M+H] + 963.4; found 963.6. It can be seen that the compound structure is correct.

[0513] Example 53: Synthesis of Compound TPD10013

[0514]

[0515] Compound 10001-4 (90 mg) was reacted with lenalidomide, HOBt (5 mg), and EDCI in DCM (5 ml). The mixture was stirred at 25 °C for 19 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into saturated aqueous sodium bicarbonate (10 ml), and extracted three times with DCM (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate with the eluent ratio of DCM / MeOH = 10 / 1 to obtain compound TPD10001 (17 mg, pale yellow solid, purity 96%). LCMS (ESI) m / z calcd. for C44H42N9O6 [M+H] + 792.3; found 792.5. It can be seen that the compound structure is correct.

[0516] Example 54: Synthesis of Compound TPD10040

[0517]

[0518] Compound 10040-4 (70 mg) was reacted with DIAD and PPh3 in DCM (7 ml), and then N-Boc-protected 4-hydroxypiperidine was added for condensation reaction to obtain 10040-2 which was deprotected by TFA / DCM. This product was added to a 25-ml single-necked flask, and compound 10040-3, potassium carbonate, and methanol were added in sequence. The reaction was carried out at 25 °C for 12 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into saturated aqueous sodium bicarbonate (10 ml), and extracted three times with DCM (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate with the eluent ratio of DCM / MeOH = 10 / 1 to obtain compound TPD10040 (9 mg, pale yellow solid, purity 98%). LCMS (ESI) m / z calcd. for C37H38Cl2FN8O5 [M+H] + 763.2; found 763.3. It can be seen that the compound structure is correct.

[0519] Example 55: Synthesis of Compound TPD10041

[0520]

[0521] Compound 10040-2 (90 mg) was reacted with STAB, 2,2-dimethoxyacetaldehyde in DCE (7 ml), and then the resulting crude product was deprotected in the HCl / THF system to obtain 10041-1. This product was added to a 25-ml single-necked flask, and compound 10041-2, STAB, and DCE were added successively. The reaction was carried out at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into saturated sodium bicarbonate aqueous solution (10 ml), and extracted three times with DCM (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 10 / 1 to obtain compound TPD10041 (7 mg, pale yellow solid, purity 98%). LCMS (ESI) m / z calcd. for C40H43Cl2FN9O5 [M+H] + 818.3; found 818.4. It can be seen that the compound structure is correct.

[0522] Example 56: Synthesis of Compound TPD10050

[0523]

[0524] Compound 10050-1 (100 mg) was reacted with NaH in anhydrous THF (9 ml), and then N-Boc-4-bromopiperidine was added. The resulting crude compound was reacted with TFA / DCM to deprotect and obtain 10050-2. This product was added to a 25-ml single-necked flask, and compound 10040-3, potassium carbonate, and methanol were added successively. The reaction was carried out at 25 °C for 12 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into saturated sodium bicarbonate aqueous solution (10 ml), and extracted three times with DCM (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 10 / 1 to obtain compound TPD10040 (11 mg, pale yellow solid, purity 96%). LCMS (ESI) m / z calcd. for C39H43ClN9O6S [M+H] + 800.3; found 800.3. It can be seen that the compound structure is correct.

[0525] Example 57: Synthesis of Compound TPD10051

[0526]

[0527] Compound 10050-1 (100 mg) was subjected to Swern oxidation to obtain compound 10051-1, which was reacted with STAB and 4-hydroxymethylpiperidine in DCE (7 ml) to prepare 10051-2, and then further subjected to Swern oxidation to obtain compound 10051-3. The product was added to a 25-ml single-necked flask, and compound 10041-2, STAB, and DCE were added successively. The reaction was carried out at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into saturated aqueous sodium bicarbonate (10 ml), and extracted three times with DCM (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 10 / 1 to obtain compound TPD10051 (9 mg, pale yellow solid, purity 98%). LCMS (ESI) m / z calcd. for C41H46ClN10O5S [M+H] + 825.4; found 825.5. It can be seen that the compound structure is correct.

[0528] Example 58: Synthesis of Compound TPD12001

[0529]

[0530] Compound TPD12001-1 (2 g, 10.8 mmol), NBS (2.88 g, 16.2 mmol), AIBN (0.18 g, 1.08 mmol), and CCl 4 (20 ml) were successively added to a 100-ml three-necked flask. The reaction was carried out at 80 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water (30 ml), and extracted three times with DCM (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain crude compound TPD12001-2 (3.1 g, yellow oil, purity 85.695%), yield: 92.59%. LCMS (ESI) m / z calcd. for C 8 H 7 BrClNO 2 [M+H] + 263.9, 263.9; found 264.1, 266.0; 1 H NMR (400 MHz, CDCl 3 ): δ = 8.48 (d, J = 5.0 Hz, 1H), 7.71 (d, J = 5.0 Hz, 1H), 5.05 (s, 2H), 4.02 (s, 3H). It can be seen that the compound structure is correct.

[0531] In a 100 ml three-necked flask, compound TPD12001-2 (3 g, 11.3 mmol), 3-amino-2,6-piperidinedione hydrochloride (2.23 g, 13.5 mmol), DIEA (2.92 g, 22.6 mmol) and DMF (30 ml) were added successively. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and poured into water (100 ml), and extracted three times with EA (50 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with the eluent ratio of DCM / MeOH = 100 / 1 - 30 / 1 to obtain compound TPD12001-3 (1.72 g, yellow solid, purity 92.354%), yield: 50.44%. LCMS(ESI) m / z calcd. for C 12 H 10 ClN 3 O 3 [M+H] + 280.0; found 280.1; 1 H NMR(400 MHz, DMSO_d 6 ): δ = 11.06 (s, 1H), 8.63 (d, J = 4.9 Hz, 1H), 7.80 (d, J = 4.9 Hz, 1H), 5.18 (dd, J = 13.3, 5.1 Hz, 1H), 4.60 (d, J = 18.2 Hz, 1H), 4.44 (d, J = 18.3 Hz, 1H), 2.95 - 2.87 (m, 1H), 2.63 - 2.58 (m, 1H), 2.49 - 2.42 (m, 1H), 2.05 - 2.01 (m, 1H). It can be seen that the compound structure is correct.

[0532] In a 25 ml three-necked flask, compound TPD12001-3 (500 mg, 1.79 mmol), 4-N-(2-aminoethyl)-1-N-BOC-piperidine (492 mg, 2.15 mmol), DIEA (462 mg, 3.58 mmol) and DMSO (10 ml) were added successively. The reaction was carried out at 140 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and poured into water (50 ml), and extracted three times with EA (30 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with the eluent ratio of DCM / MeOH = 100 / 1 - 30 / 1 to obtain compound TPD12001-4 (130 mg, yellow solid, purity 97.218%), yield: 14.93%. LCMS(ESI) m / z calcd. for C 23 H 32 N6 O 5 [M+H] + 473.3; found 473.3; 1 H NMR (400 MHz, DMSO-d 6 ): δ = 11.04 (s, 1H), 8.15 (d, J = 5.2 Hz, 1H), 6.82 (d, J = 5.2 Hz, 1H), 6.67 (t, J = 5.4 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.27 (d, J = 18.1 Hz, 1H), 4.15 (d, J = 18.0 Hz, 1H), 3.52 (dd, J = 13.1, 6.6 Hz, 2H), 2.96 - 2.84 (m, 2H), 2.64 - 2.54 (m, 2H), 2.39 - 2.29 (m, 8H), 2.08 - 2.03 (m, 2H), 1.39 (s, 9H). It can be seen that the structure of the compound is correct.

[0533] Compound TPD12001-4 (130 mg, 0.27 mmol), 1,4-dioxane (5 ml) and 4N HCl / 1,4-dioxane (3 ml) were successively added to a 25 ml single-necked flask. The reaction was carried out at 25 °C for 3 hours. After the reaction was completed, it was concentrated to dryness to obtain crude compound TPD12001-5 (140 mg, yellow solid), yield: 94.68%. LCMS (ESI) m / z calcd. for C 18 H 24 N 6 O 3 [M+H] + 373.2; found 373.2. It can be seen that the structure of the compound is correct.

[0534] Compound TPD12001-5 (70 mg, 0.19 mmol), compound TPD5488-2 (110 mg, 0.19 mmol), sodium triacetoxyborohydride (80 mg, 0.38 mmol), and DCE (3 ml) were successively added to a 25 ml single-necked flask. The reaction was carried out at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (15 ml), and an appropriate amount of saturated NaHCO 3 solution was added to make the reaction solution alkaline. It was extracted three times with DCM (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 8 / 1, to obtain compound TPD12001 (12.5 mg, light yellow solid, purity 96.23%), yield: 6.81%. LCMS (ESI) m / z calcd. for C51 H 55 FN 10 O 7 [M+H] + 940.1;found 940.2; 1 H NMR(400 MHz, DMSO-d 6 ): δ = 11.05 (s, 1H), 10.18 (s, 1H), 10.06 (s, 1H), 8.43 (d, J = 5.2 Hz, 1H), 8.16 (d, J = 5.1 Hz, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.66 - 7.63 (m, 2H), 7.46 (s, 1H), 7.31 (s, 1H), 7.21 (d, J = 9.0 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 7.02 (s, 1H), 6.83 (d, J = 5.2 Hz, 1H), 6.39 (d, J = 5.2 Hz, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.28 (d, J = 18.0 Hz, 1H), 4.16 (d, J = 17.9 Hz, 1H), 3.94 (s, 4H), 3.60 - 3.53 (m, 4H), 2.95 - 2.87 (m, 1H), 2.67 - 2.59 (m, 4H), 2.33 - 2.24 (m, 8H), 2.07 - 2.04 (m, 1H), 1.82 (d, J = 11.6 Hz, 2H), 1.70 (s, 1H), 1.47 (s, 4H), 1.32 (d, J = 14.9 Hz, 4H), 1.25 (d, J = 3.8 Hz, 2H). It can be seen that the structure of the compound is correct.

[0535] Example 59: Synthesis of Compound TPD12003

[0536]

[0537] Compound TPD12003-1 (3 g, 17.5 mmol), dimethyl sulfate (4.41 g, 35 mmol), and K were successively added to a 100 ml three-necked flask. 2 CO 3(7.26 g, 52.5 mmol) and DMF (40 ml). The reaction was carried out at 25 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (150 ml), and extracted three times with EA (80 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with the eluent ratio of PE / EtOAc = 20 / 1 - 5 / 1 to obtain compound TPD12003-2 (2.5 g, white solid, purity 93.222%), yield: 61.76%. LCMS (ESI) m / z calcd. for C 8 H 8 ClNO 2 [M + H] + 186.0; found 186.0; 1 H NMR (400 MHz, CDCl 3 ): δ = 8.88 (s, 1H), 7.25 (s, 1H), 3.94 (s, 3H), 2.63 (s, 3H). It can be seen that the structure of the compound is correct.

[0538] Compound TPD12003-2 (1.5 g, 8.1 mmol), NBS (2.16 g, 12.2 mmol), AIBN (0.13 g, 0.81 mmol) and CCl 4 (30 ml) were successively added to a 100 ml three-necked flask. The reaction was carried out at 80 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water (60 ml), and extracted three times with DCM (20 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain crude compound TPD12003-3 (2.4 g, yellow oil), yield: 33.33%. LCMS (ESI) m / z calcd. for C 8 H 7 BrClNO 2 [M + H] + 263.9, 265.9; found 263.9, 265.9. It can be seen that the structure of the compound is correct.

[0539] In a 100 ml three-necked flask, 2.4 g (9.1 mmol) of compound TPD12003-3, 1.8 g (10.9 mmol) of 3-amino-2,6-piperidinedione hydrochloride, 2.35 g (18.2 mmol) of DIEA and 30 ml of DMF were successively added. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and poured into water (100 ml). It was extracted three times with EA (50 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with an eluent ratio of DCM / MeOH = 100 / 1 to 30 / 1 to obtain compound TPD12003-4 (500 mg, light purple solid, purity 99.318%), yield: 19.78%. LCMS (ESI) m / z calcd. for C 12 H 10 ClN 3 O 3 [M+H] + 280.0; found 280.1; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 11.04 (s, 1H), 8.80 (s, 1H), 7.87 (s, 1H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.57 (d, J = 18.8 Hz, 1H), 4.44 (d, J = 18.7 Hz, 1H), 2.96 - 2.86 (m, 1H), 2.63 - 2.57 (m, 1H), 2.46 - 2.35 (m, 1H), 2.04 - 2.00 (m, 1H). It can be seen that the compound structure is correct.

[0540] In a 25 ml three-necked flask, 200 mg (0.72 mmol) of compound TPD12003-4, 197 mg (0.86 mmol) of 4-N-(2-aminoethyl)-1-N-BOC-piperidine, 185 mg (1.43 mmol) of DIEA and 5 ml of DMSO were successively added. The reaction was carried out at 120 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and poured into water (20 ml). It was extracted three times with EA (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with an eluent ratio of DCM / MeOH = 100 / 1 to 30 / 1 to obtain compound TPD12003-5 (100 mg, brown solid, purity 90.95%), yield: 26.86%. LCMS (ESI) m / z calcd. for C 23 H 32 N 6 O5 [M+H] + 473.2; found 473.2; 1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.96 (s, 1H), 8.35 (s, 1H), 7.09 (s, 1H), 6.59 (s, 1H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.32 (d, J = 17.4 Hz, 1H), 4.18 (d, J = 17.5 Hz, 1H), 3.46 - 3.42 (m, 2H), 3.31 (br.s, 4H), 2.94 - 2.85 (m, 1H), 2.60 - 2.51 (m, 2H), 2.38 - 2.31 (m, 6H), 1.97 - 1.92 (m, 1H), 1.39 (s, 9H). It can be seen that the structure of the compound is correct.

[0541] Compound TPD12003 - 5 (100 mg, 0.21 mmol), 1,4 - dioxane (1 ml) and 4N HCl / 1,4 - dioxane (2 ml) were successively added into a 25 - ml single - necked flask. Under nitrogen protection, the reaction was carried out at 25 °C for 2 hours. After the reaction was completed, it was concentrated to dryness to obtain the crude compound TPD12003 - 6 (100 mg, brown solid), yield: 95.50%. LCMS (ESI) m / z calcd. for C 18 H 24 N 6 O 3 [M+H] + 373.2; found 373.2. It can be seen that the structure of the compound is correct.

[0542] Compound TPD12003 - 6 (100 mg, 0.27 mmol), compound TPD5488 - 2 (156 mg, 0.27 mmol), sodium triacetoxyborohydride (114 mg, 0.54 mmol) and DCE (3 ml) were successively added into a 25 - ml single - necked flask. Under nitrogen protection, the reaction was carried out at 25 °C for 16 hours. After the reaction was completed, the reaction solution was poured into water (5 ml), and an appropriate amount of saturated NaHCO 3 solution was added to make the reaction solution alkaline. The organic phase was separated, and the aqueous phase was extracted twice with DCM (5 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 6 / 1 to obtain compound TPD12003 (16.1 mg, yellow solid, purity 98.655%), yield: 6.29%. LCMS (ESI) m / z calcd. for C 51 H 55 FN10 O 7 [M+H] + 939.4; found 939.4; 1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.97 (s, 1H), 10.19 (s, 1H), 10.06 (s, 1H), 8.43 (d, J = 5.2 Hz, 1H), 8.36 (s, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.66 - 7.63 (m, 2H), 7.46 (s, 1H), 7.31 (s, 1H), 7.21 (d, J = 8.9 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 7.08 (br.s, 1H), 6.60 (s, 1H), 6.39 (d, J = 5.2 Hz, 1H), 5.03 (dd, J = 13.2, 5.0 Hz, 1H), 4.33 (d, J = 17.4 Hz, 1H), 4.18 (d, J = 17.4 Hz, 1H), 3.94 (s, 3H), 3.59 (d, J = 11.1 Hz, 2H), 3.44 (s, 2H), 2.95 - 2.85 (m, 1H), 2.67 - 2.56 (m, 4H), 2.38 - 2.28 (m, 6H), 2.20 (br.s, 2H), 1.96 - 1.91 (m, 1H), 1.82 (d, J = 11.4 Hz, 2H), 1.70 (br.s, 1H), 1.47 (s, 4H), 1.34 - 1.23 (m, 6H). It can be seen that the compound structure is correct.

[0543] Example 60: Synthesis of Compound TPD12009

[0544]

[0545] Compound TPD12009-1 (50 mg, 0.18 mmol), tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (62 mg, 0.27 mmol), DMSO (5 ml) and DIEA (69 mg, 0.54 mmol) were successively added to a 25 ml single-necked flask. The reaction was carried out at 140 °C for 16 hours under nitrogen protection. After cooling the system to room temperature, it was poured into ice water (20 ml), and extracted three times with ethyl acetate (10 ml). The combined organic phases were washed successively with water (10 ml) and saturated brine (10 ml). Dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent was DCM / MeOH = 15 / 1, to obtain compound TPD12009-2 (10 mg, brown oil, purity 58.279%), yield: 6.88%. LCMS (ESI) m / z calcd. for C 23 H32 N 6 O 5 [M+H] + 473.2; found 473.1. It can be seen that the compound structure is correct.

[0546] Add compound TPD12009-2 (20 mg, 0.042 mmol), DCM (1 ml) and dioxane hydrochloride solution (2 ml, 4 M) to a 40 ml single-necked flask. After reacting at 30 °C for 1 hour, the system was rotary evaporated to dryness, and DCE (0.5 ml) and sodium triacetoxyborohydride (18 mg, 0.084 mmol) were added. React at 30 °C for 72 hours under nitrogen protection. Pour the system into saturated aqueous sodium bicarbonate solution (2 ml), and extract 3 times with DCM (2 ml). After combining the organic phases, wash successively with water (2 ml) and saturated brine (2 ml). Dry over anhydrous sodium sulfate, filter, and concentrate to dryness. The residue was purified by preparative plate, and the eluent was DCM / MeOH = 10 / 1 to obtain compound TPD12009 (2.4 mg, yellow solid, purity 83.866%), yield: 4.98%. LCMS (ESI) m / z calcd. for C 51 H 55 FN 10 O 7 [M+H] + 939.4; found 939.7; 1 H NMR (400 MHz, CD 3 OD): δ = 8.38 (d, J = 5.4 Hz, 1H), 8.24 (s, 1H), 7.71 (d, J = 8.9 Hz, 2H), 7.60 (s, 1H), 7.58 - 7.54 (m, 3H), 7.47 - 7.42 (m, 1H), 7.39 (s, 1H), 7.22 - 7.19 (m, 2H), 7.09 - 7.05 (m, 3H), 6.88 (d, J = 1.0 Hz, 1H), 6.50 (d, J = 5.4 Hz, 1H), 5.34 (t, J = 4.7 Hz, 2H), 5.41 - 5.27 (m, 1H), 4.02 (s, 3H), 3.69 (d, J = 11.2 Hz, 2H), 3.49 (d, J = 5.9 Hz, 2H), 3.13 - 3.10 (m, 1H), 2.78 - 2.73 (m, 4H), 2.59 - 2.55 (m, 2H), 2.39 (d, J = 7.0 Hz, 2H), 2.21 - 2.17 (m, 2H), 2.02 (d, J = 5.0 Hz, 2H), 1.92 (d, J = 8.7 Hz, 2H), 1.80 (br.s, 2H), 1.64 (s, 4H), 1.33 (s, 6H). It can be seen that the compound structure is correct.

[0547] Example 61: Synthesis of Compound TPD12013

[0548]

[0549] Compound TPD12013-1 (5.0 g, 33.1 mmol) and DCM (100 ml) were successively added to a 250 ml three-necked flask. After the system was cooled to 0 °C, m-CPBA (8.57 g, 49.6 mmol) was added. The reaction was carried out at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into saturated NaHCO 3 solution (100 ml), and extracted three times with DCM (50 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography, and the eluent ratio was DCM / MeOH = 100 / 1 - 30 / 1, to obtain Compound TPD12013-2 (6 g, yellow oil, purity 81.067%), yield: 87.92%. LCMS (ESI) m / z calcd. for C 8 H 9 NO 3 [M+H] + 168.1; found 168.1; 1 H NMR (400 MHz, CDCl 3 ): δ = 8.13 (d, J = 6.4 Hz, 1H), 7.24 - 7.20 (m, 1H), 7.15 (d, J = 7.9 Hz, 1H), 4.03 (s, 3H), 2.31 (s, 3H). It can be seen that the compound structure is correct.

[0550] Compound TPD12013-2 (6.0 g, 35.9 mmol), POCl 3 (27.52 g, 179.5 mmol) and DCE (60 ml) were successively added to a 100 ml three-necked flask. The reaction was carried out at 80 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated, adjusted to alkaline with saturated NaHCO 3 solution, and extracted three times with DCM (30 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography, and the eluent ratio was PE / EtOAc = 20 / 1 - 5 / 1, to obtain Compound TPD12013-3 (1.9 g, brown oil, purity 97.863%), yield: 27.86%. LCMS (ESI) m / z calcd. for C 8 H 8 ClNO 2 [M+H] +186.0; found 186.0; 1 H NMR (400 MHz, CDCl 3 ): δ = 7.90 (d, J = 1.8 Hz, 1H), 7.23 (d, J = 5.2 Hz, 1H), 3.89 (s, 3H), 2.32 (s, 3H). It can be seen that the structure of the compound is correct.

[0551] Into a 100 ml three-necked flask, compound TPD12013-3 (1.7 g, 9.2 mmol), NBS (2.46 g, 13.8 mmol), AIBN (0.15 g, 0.92 mmol) and CCl 4 (50 ml) were successively added. The reaction was carried out at 80 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water (100 ml), and extracted three times with DCM (50 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with an eluent ratio of PE / EtOAc = 50 / 1 - 30 / 1 to obtain compound TPD12013-4 (1.7 g, yellow oil, purity 97.915%), yield: 68.48%. LCMS (ESI) m / z calcd. for C 8 H 7 BrClNO 2 [M + H] + 263.9; found 264.0; 1 H NMR (400 MHz, CDCl 3 ): δ = 8.54 (d, J = 5.2 Hz, 1H), 7.54 (d, J = 5.2 Hz, 1H), 5.04 (s, 2H), 4.05 (s, 3H). It can be seen that the structure of the compound is correct.

[0552] Into a 100 ml three-necked flask, compound TPD12013-4 (1.7 g, 6.4 mmol), 3-amino-2,6-piperidinedione hydrochloride (1.26 g, 7.68 mmol), DIEA (1.65 g, 12.8 mmol) and DMF (30 ml) were successively added. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water (100 ml), and extracted three times with EA (50 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with an eluent ratio of DCM / MeOH = 100 / 1 - 30 / 1 to obtain compound TPD12013-5 (1 g, purple solid, purity 90.452%), yield: 50.00%. LCMS (ESI) m / z calcd. for C 12 H10 ClN 3 O 3 [M+H] + 280.0; found 280.1; 1 H NMR(400MHz, DMSO_d 6 ): δ = 11.06(s, 1H), 8.75(d, J = 5.3Hz, 1H), 7.81(d, J = 5.3Hz, 1H), 5.20(dd, J = 13.3, 5.1Hz, 1H), 4.58(d, J = 17.8Hz, 1H), 4.42(d, J = 17.8Hz, 1H), 2.98 - 2.89(m, 1H), 2.65 - 2.60(m, 1H), 2.55 - 2.44(m, 1H), 2.07 - 2.03(m, 1H). It can be seen that the compound structure is correct.

[0553] Compound TPD12013 - 5 (350 mg, 1.25 mmol), 4 - N-(2 - aminoethyl)-1 - N - BOC - piperidine (344.37 mg, 1.50 mmol), DIEA (323.49 mg, 2.50 mmol) and DMSO (5 ml) were successively added into a 25 ml three - necked flask. The reaction was carried out at 120 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water (10 ml), and extracted three times with EA (5 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 10 / 1, to obtain compound TPD12013 - 6 (240 mg, yellow solid, purity 57.007%), yield: 23.09%. LCMS(ESI) m / z calcd.for C 23 H 32 N 6 O 5 [M+H] + 473.2; found 473.3. It can be seen that the compound structure is correct.

[0554] Compound TPD12013 - 6 (240 mg, 0.5068 mmol), 1,4 - dioxane (2 ml) and 4N HCl / 1,4 - dioxane (4 ml) were successively added into a 25 ml single - necked flask. The reaction was carried out at 25 °C for 2 hours under nitrogen protection. After the reaction was completed, it was concentrated to dryness to obtain the crude product compound TPD12013 - 7 (240 mg, yellow solid), yield: 74.88%. LCMS(ESI) m / z calcd.for C 18 H 24 N 6 O 3[M+H] + 373.2; found 373.2. It can be seen that the compound structure is correct.

[0555] Into a 25 ml single-necked flask, successively add compound TPD12003-6 (100 mg, 0.27 mmol), compound TPD5488-2 (156 mg, 0.27 mmol), sodium triacetoxyborohydride (114 mg, 0.54 mmol) and DCE (3 ml). Under nitrogen protection, react at 25 °C for 16 hours. After the reaction is completed, pour the reaction solution into water (5 ml), and add an appropriate amount of saturated NaHCO 3 solution to make the reaction solution alkaline. Separate the organic phase, and extract the aqueous phase twice with DCM (5 ml). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. Purify the residue by preparative plate, and the developing agent ratio is DCM / MeOH = 6 / 1 to obtain compound TPD12003 (16.1 mg, yellow solid, purity 98.655%), yield: 6.29%. LCMS (ESI) m / z calcd. for C 51 H 55 FN 10 O 7 [M+H] + 939.4; found 470.2; 1 H NMR (400 MHz, DMSO_d 6): δ = 11.04 (s, 1H), 10.19 (s, 1H), 10.06 (s, 1H), 8.43 (d, J = 5.2 Hz, 1H), 8.25 (d, J = 5.7 Hz, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.66 - 7.62 (m, 2H), 7.46 (s, 1H), 7.31 (s, 1H), 7.21 (d, J = 8.9 Hz, 2H), 7.17 - 7.13 (m, 2H), 6.68 (d, J = 5.7 Hz, 1H), 6.57 (t, J = 5.2 Hz, 1H), 6.39 (d, J = 5.2 Hz, 1H), 5.13 (dd, J = 13.3, 5.0 Hz, 1H), 4.25 (d, J = 17.1 Hz, 1H), 4.14 (d, J = 17.2 Hz, 1H), 3.94 (s, 3H), 3.59 (d, J = 10.7 Hz, 4H), 3.32 (d, J = 5.9 Hz, 2H), 2.97 - 2.88 (m, 1H), 2.67 - 2.61 (m, 4H), 2.42 - 2.26 (m, 6H), 2.20 (d, J = 6.8 Hz, 2H), 2.07 - 1.99 (m, 1H), 1.82 (d, J = 12.1 Hz, 2H), 1.69 (br.s, 1H), 1.47 (s, 4H), 1.36 - 1.24 (m, 4H). It can be seen that the structure of the compound is correct.

[0556] Example 62: Synthesis of Compound TPD12068

[0557]

[0558] Compound int - N - 1 (5.0 g, 21.3 mmol) and THF (100 ml) were successively added to a 250 ml three - necked flask. After the system was cooled to 0 °C, NaH (1.70 g, 42.6 mmol) was added. The reaction was carried out at 0 °C for 1 hour under nitrogen protection. Then bromoacetonitrile (5.11 g, 42.6 mmol), potassium iodide (0.35 g, 2.13 mmol) and tetrabutylammonium bromide (0.69 g, 2.13 mmol) were successively added. The reaction was carried out at 25 °C for 15 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into saturated NH 4 Cl solution (300 ml), and extracted three times with EA (100 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography, and the eluent ratio was DCM / MeOH = 100 / 1 - 30 / 1, to obtain compound int - N - 2 (4.7 g, brown solid, purity 92.512%), yield: 74.65%. LCMS (ESI) m / z calcd. for C 14 H 15N 3 O 3 [M+H] + 274.1; found 274.1; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 7.39 - 7.32 (m, 5H), 5.11 (s, 2H), 4.46 (s, 2H), 4.08 (s, 2H), 3.69 (s, 2H), 3.47 (t, J = 5.5 Hz, 2H). It can be seen that the compound structure is correct.

[0559] Compound int-N-2 (5.0 g, 18.3 mmol), EtOH / NH 3 H 2 O = 10 / 1 (50 ml) and Raney nickel (1.07 g, 18.3 mmol) were successively added to a 100 ml single-necked flask. The reaction was carried out at 25 °C for 16 hours under a hydrogen (1 atm) atmosphere. After the reaction was completed, the reaction solution was filtered by suction, the filtrate was concentrated to dryness, and the residue was purified by silica gel column chromatography with an eluent ratio of DCM / MeOH = 50 / 1 to 30 / 1 to obtain compound int-N (2.0 g, brown oil, purity 94.845%), yield: 37.16%. LCMS (ESI) m / z calcd. for C 14 H 19 N 3 O 3 [M+H] + 278.1; found 278.2. It can be seen that the compound structure is correct.

[0560] Compound TPD12001-3 (670 mg, 2.40 mmol), int-N (664 mg, 2.40 mmol), DIEA (619 mg, 4.79 mmol) and DMSO (10 ml) were successively added to a 25 ml single-necked flask. The reaction was carried out at 145 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and poured into water (60 ml), and extracted three times with EA (20 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with an eluent ratio of DCM / MeOH = 100 / 1 to 30 / 1 to obtain compound TPD12068-1 (100 mg, brown solid, purity 93.032%), yield: 7.46%. LCMS (ESI) m / z calcd. for C 26 H 28 N 6 O 6 [M+H] + 521.2; found 521.3; 11H NMR (400 MHz, DMSO-d 6 ): δ = 11.04 (s, 1H), 8.14 (d, J = 5.1 Hz, 1H), 7.38 - 7.35 (m, 5H), 6.89 (t, J = 5.0 Hz, 1H), 6.83 (d, J = 5.2 Hz, 1H), 5.09 (s, 2H), 4.24 (d, J = 17.9 Hz, 1H), 4.13 (d, J = 17.9 Hz, 1H), 3.94 (s, 2H), 3.58 - 3.52 (m, 7H), 3.42 - 3.39 (m, 2H), 2.95 - 2.86 (m, 1H), 2.61 (d, J = 16.4 Hz, 1H), 2.35 - 2.24 (m, 1H), 2.07 - 2.02 (m, 1H). It can be seen that the structure of the compound is correct.

[0561] Compound TPD 12068-1 (100 mg, 0.38 mmol), EA (5 ml) and Pd(OH) 2 / C (54 mg, 10% wet) were successively added into a 25 ml single-necked flask. The reaction was carried out at 40 °C for 48 h under a hydrogen (1 atm) atmosphere. After the reaction was completed, the reaction solution was filtered by suction and concentrated to dryness to obtain the crude compound TPD12068-2 (30 mg, yellow oil, purity 92.378%), and the yield was 21.42%. LCMS (ESI) m / z calcd. for C 18 H 22 N 6 O 4 [M + H] + 387.2; found 387.2. It can be seen that the structure of the compound is correct.

[0562] Compound TPD12068-2 (30 mg, 0.078 mmol), compound TPD5488-2 (54 mg, 0.093 mmol), sodium triacetoxyborohydride (33 mg, 0.16 mmol), acetic acid (14 mg, 0.23 mmol) and DCE (3 ml) were successively added into a 25 ml single-necked flask. Under nitrogen protection, the reaction was carried out at 25 °C for 6 h. After the reaction was completed, the reaction solution was poured into water (15 ml), and an appropriate amount of saturated NaHCO 3The solution was made alkaline. The organic phase was separated, and the aqueous phase was extracted twice with DCM (5 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was prepared by high performance liquid chromatography with the following parameters: column: sunfire 5um 19 - 150mm; mobile phase: acetonitrile - water (0.1% FA); gradient: 15 - 40 / 6 min, to obtain compound TPD12068 (8.62 mg, yellow solid, purity 98.240%), yield: 11.08%. LCMS (ESI) m / z calcd. for C 51 H 53 FN 10 O 8 [M + H] + 953.4; found 477.3; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 11.06 (s, 1H), 10.18 (s, 1H), 10.06 (s, 1H), 8.43 (d, J = 5.1 Hz, 1H), 8.22 (s, 0.6H), 8.17 (d, J = 5.1 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.64 (dd, J = 8.8, 5.1 Hz, 2H), 7.46 (s, 1H), 7.32 (s, 1H), 7.21 (d, J = 8.8 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 6.87 (d, J = 5.8 Hz, 1H), 6.84 (d, J = 5.1 Hz, 1H), 6.39 (d, J = 5.1 Hz, 1H), 5.12 (dd, J = 13.2, 4.8 Hz, 1H), 4.26 (d, J = 18.0 Hz, 1H), 4.15 (d, J = 18.0 Hz, 1H), 3.94 (s, 3H), 3.58 (d, J = 8.0 Hz, 5H), 3.50 (d, J = 3.6 Hz, 3H), 2.97 (s, 2H), 2.93 - 2.87 (m, 1H), 2.67 - 2.60 (m, 5H), 2.36 - 2.29 (m, 1H), 2.24 (d, J = 6.6 Hz, 2H), 1.80 (d, J = 11.9 Hz, 2H), 1.69 (s, 1H), 1.47 (s, 4H), 1.35 - 1.23 (m, 3H). It can be seen that the structure of the compound is correct.

[0563] Example 63: Synthesis of compound TPD12081

[0564]

[0565] In a 100 ml three-necked flask, 2 g (10.09 mmol) of compound TPD12081-1, 30 ml of acetonitrile, 1.21 g (10.09 mmol) of bromoacetonitrile, and 2.07 g (15.13 mmol) of potassium carbonate were added successively. The reaction was carried out at 25 °C for 4 hours under nitrogen protection. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated to dryness, and the residue was purified by silica gel column chromatography with an eluent ratio of DCM / MeOH = 50 / 1 to 30 / 1 to obtain compound TPD12081-2 (1.6 g, yellow solid, purity 98.554%), and the yield was 66.00%. LCMS (ESI) m / z calcd. for C 12 H 19 N 3 O 2 [M+H] + 238.2; found 237.8; 1 HNMR (400 MHz, CDCl 3 ): δ = 4.15 - 4.09 (m, 2H), 3.60 (s, 2H), 3.38 - 3.25 (m, 2H), 2.83 - 2.81 (m, 2H), 2.47 - 2.44 (m, 1H), 1.61 - 1.58 (m, 1H), 1.46 (s, 9H). It can be seen that the structure of the compound is correct.

[0566] In a 50 ml single-necked flask, 1 g (4.21 mmol) of compound TPD12081-2, 10 ml of EtOH, 1 ml of ammonia water, and 0.49 g of Raney nickel were added successively. The reaction was carried out at 25 °C for 16 hours under 1 atm of hydrogen. After the reaction was completed, suction filtration was carried out, the filtrate was concentrated to dryness, and the residue was purified by silica gel column chromatography with an eluent ratio of DCM / MeOH = 50 / 1 to 10 / 1 to obtain compound TPD12081-3 (0.26 g, brown solid, purity 86.928%), and the yield was 21.43%. LCMS (ESI) m / z calcd. for C 12 H 23 FN 3 O 2 [M+H] + 242.18; found 242.2; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 4.00 - 3.99 (m, 2H), 3.80 (s, 2H), 3.15 - 3.06 (m, 3H), 2.75 - 2.65 (m, 3H), 2.34 - 2.27 (m, 2H), 1.55 - 1.53 (m, 2H), 1.39 (s, 9H). It can be seen that the structure of the compound is correct.

[0567] To a 25-ml single-necked flask were successively added compound TPD12081-3 (260 mg, 1.07 mmol), compound TPD12003-4 (330 mg, 1.18 mmol), DIEA (416 mg, 3.22 mmol), and DMSO (3 ml). Under nitrogen protection, the reaction was carried out at 120 °C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature. The reaction solution was poured into water (10 ml), and the aqueous phase was extracted three times with ethyl acetate (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 15 / 1, to obtain compound TPD12081-4 (100 mg, brown solid, purity 95.665%), yield: 18.37%. LCMS (ESI) m / z calcd. for C 24 H 32 N 6 O 5 [M+H] + 485.24; found 485.1; 1 H NMR (400 MHz, DMSO-d 6 ): δ = 10.96 (br.s, 1H), 8.35 (s, 1H), 7.04 (s, 1H), 6.56 (s, 1H), 5.02 (dd, J = 13.3, 5.1 Hz, 1H), 4.25 (dd, J = 58.9, 17.4 Hz, 2H), 3.95 (d, J = 5.9 Hz, 2H), 3.50 - 3.41 (m, 2H), 3.06 - 2.76 (m, 7H), 2.68 (t, J = 6.7 Hz, 2H), 2.36 - 2.23 (m, 3H), 2.09 - 1.84 (m, 2H), 1.58 (d, J = 7.8 Hz, 1H), 1.38 (s, 9H).

[0568] To a 25-ml single-necked flask were successively added compound TPD12081-4 (50 mg, 0.103 mmol) and HCl(g) / 1,4-dioxane (40 ml, 4N). The reaction was carried out at 25 °C for half an hour. The reaction solution was concentrated to dryness to obtain the crude product compound TPD12081-5 (40 mg, yellow solid), yield: 90%. LCMS (ESI) m / z calcd. for C 24 H 33 N 5 O 5 [M+H] + 385.2; found 385.1. It can be seen that the compound structure is correct.

[0569] To a 25 ml single-necked flask were successively added compound TPD5488-2 (100 mg, 0.18 mmol), DCE (4 ml), compound TPD12081-5 (69 mg, 0.18 mmol) and sodium triacetoxyborohydride (76 mg, 0.36 mmol). Under nitrogen protection, the reaction was carried out at 25 °C for 16 hours. After the reaction was completed, the reaction solution was poured into saturated aqueous sodium bicarbonate (10 ml), and the aqueous phase was extracted three times with DCM (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 10 / 1, to obtain compound TPD12081 (15.3 mg, yellow solid, purity 99.365%), yield: 8.90%. LCMS (ESI) m / z calcd. for C 52 H 55 FN 10 O 7 [M+H] + 951.4; found 952.4; 1 H NMR (400 MHz, CD 3 OD): δ = 8.56 - 8.32 (m, 3H), 7.72 (d, J = 8.9 Hz, 2H), 7.62 (s, 1H), 7.59 - 7.53 (m, 2H), 7.39 (s, 1H), 7.27 - 7.18 (m, 2H), 7.12 - 7.03 (m, 2H), 6.65 (s, 1H), 6.52 (d, J = 5.4 Hz, 1H), 5.05 (dd, J = 13.0, 4.7 Hz, 1H), 4.48 - 4.30 (m, 3H), 4.02 (s, 3H), 3.71 (br.s, 2H), 3.65 - 3.56 (m, 2H), 3.51 - 3.32 (m, 4H), 3.16 - 2.87 (m, 4H), 2.85 - 2.60 (m, 4H), 2.33 (br.s, 2H), 2.11 - 1.78 (m, 4H), 1.68 - 1.46 (m, 6H). It can be seen that the structure of the compound is correct.

[0570] Example 64: Synthesis of compound TPD12082

[0571]

[0572] In a 25 ml single-necked flask, add compound TPD12086-7 (50 mg, 0.13 mmol), compound TPD5488-2 (76 mg, 0.13 mmol), sodium triacetoxyborohydride (55 mg, 0.26 mmol) and DCE (3 ml) in sequence. Under nitrogen protection, react at 25 °C for 16 hours. After the reaction is completed, pour the reaction solution into water (15 ml), and add an appropriate amount of saturated NaHCO 3 solution to make the reaction solution alkaline. Separate the organic phase, and extract the aqueous phase twice with DCM (10 ml). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. The residue is prepared by high performance liquid chromatography, and the relevant parameters are as follows: chromatographic column: sunfire 5um 19-150 mm; mobile phase: acetonitrile-water (0.1% FA); gradient: 5-40 / 8 minutes, to obtain compound TPD12082 (9.44 mg, yellow solid, purity 98.466%), yield: 7.07%. LCMS (ESI) m / z calcd. for C 52 H 55 FN 10 O 7 [M+H] + 951.4; found 951.5; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 10.98 (s, 1H), 10.19 (s, 1H), 10.07 (s, 1H), 8.43 (d, J = 5.1 Hz, 1H), 8.37 (s, 1H), 8.22 (s, 1H), 7.76 (d, J = 8.6 Hz, 2H), 7.64 (dd, J = 8.4, 5.2 Hz, 2H), 7.46 (s, 1H), 7.32 (s, 1H), 7.25 - 7.13 (m, 5H), 6.59 (s, 1H), 6.39 (d, J = 5.1 Hz, 1H), 5.03 (dd, J = 13.1, 5.1 Hz, 1H), 4.33 (d, J = 17.2 Hz, 1H), 4.19 (d, J = 17.3 Hz, 1H), 3.94 (s, 3H), 3.66 (s, 3H), 2.97 - 2.84 (m, 6H), 2.67 - 2.57 (m, 4H), 2.36 - 2.26 (m, 4H), 1.98 - 1.79 (m, 5H), 1.70 (s, 1H), 1.47 (s, 4H), 1.35 - 1.23 (m, 4H). It can be seen that the compound structure is correct.

[0573] Example 65: Synthesis of compound TPD12083

[0574]

[0575] In a 50 ml single-necked flask, compound sm-1 (500 mg, 2.51 mmol), 2-bromoacetamide (415 mg, 3.01 mmol), potassium carbonate (1040 mg, 7.53 mmol) and acetonitrile (10 ml) were added successively. The reaction was carried out at 25 °C for 2 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (30 ml), and extracted three times with EA (30 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography, and the eluent ratio was DCM / MeOH = 100 / 1 to 30 / 1, to obtain compound TPD12083-3a (500 mg, white solid, purity 96.019%), yield: 74.65%. LCMS (ESI) m / z calcd. for C 12 H 21 N 3 O 3 [M+H] + 256.2; found 255.7; 1 HNMR (400 MHz, DMSO_d 6 ): δ = 7.16 (s, 1H), 7.01 (s, 1H), 3.94 (d, J = 5.7 Hz, 2H), 3.10 - 2.99 (m, 4H), 2.80 (dd, J = 41.5, 9.0 Hz, 2H), 2.30 (dd, J = 13.7, 6.4 Hz, 1H), 1.59 (d, J = 8.0 Hz, 1H), 1.38 (s, 9H). It can be seen that the compound structure is correct.

[0576] In a 25 ml single-necked flask, compound TPD12083-3a (200 mg, 0.78 mmol), compound TPD12003-4 (218 mg, 0.78 mmol), palladium acetate (35 mg, 0.156 mmol), Xant-Phos (90 mg, 0.156 mmol), cesium carbonate (381 mg, 1.17 mmol) and 1,4-dioxane (5 ml) were added successively. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water (30 ml), and extracted three times with EA (30 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative plate, and the eluent ratio was DCM / MeOH = 15 / 1, to obtain compound TPD12083-4 (57 mg, brown solid, purity 94.190%), yield: 13.78%. LCMS (ESI) m / z calcd. for C 24 H 30 N 6 O 6[M+H] + 499.2; found 499.2. It can be seen that the compound structure is correct.

[0577] Into a 25 ml single-necked flask, compound TPD12083-4 (57 mg, 0.114 mmol), 1,4-dioxane (2 ml) and 4N HCl / 1,4-dioxane (2 ml) were added successively. Under nitrogen protection, the reaction was carried out at 25 °C for 2 hours. After the reaction was completed, it was concentrated to dryness to obtain crude compound TPD12083-5 (60 mg, white solid), yield: 89.48%. LCMS(ESI) m / z calcd. for C 19 H 22 N 6 O 4 [M+H] + 399.2; found 399.2. It can be seen that the compound structure is correct.

[0578] Into a 25 ml single-necked flask, compound TPD12083-5 (60 mg, 0.15 mmol), compound TPD5488-2 (88 mg, 0.15 mmol), sodium triacetoxyborohydride (64 mg, 0.30 mmol) and DCE (3 ml) were added successively. Under nitrogen protection, the reaction was carried out at 25 °C for 6 hours. After the reaction was completed, the reaction solution was poured into water (15 ml), and an appropriate amount of saturated NaHCO 3 solution was added to make the reaction solution alkaline. The organic phase was separated, and the aqueous phase was extracted twice with DCM (5 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was prepared by high performance liquid chromatography, and the relevant parameters are as follows: chromatographic column: T3 5um 19-150mm; mobile phase: acetonitrile-water (0.1% FA); gradient: 20-35 / 7 minutes, to obtain compound TPD12083 (6.86 mg, yellow solid, purity 97.191%), yield: 4.38%. LCMS(ESI) m / z calcd. for C 52 H 53 FN 10 O 8 [M+H] + 965.4; found 965.1; 1 H NMR(400 MHz, DMSO_d 6): δ = 11.02 (s, 1H), 10.31 (s, 1H), 10.01 (s, 1H), 8.74 - 8.68 (m, 2H), 8.34 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.65 - 7.62 (m, 4H), 7.42 (s, 1H), 7.32 (d, J = 8.5 Hz, 2H), 7.16 (t, J = 8.9 Hz, 3H), 6.69 (br.s, 1H), 5.11 (dd, J = 13.0, 4.8 Hz, 1H), 4.55 (d, J = 18.2 Hz, 1H), 4.41 (d, J = 18.4 Hz, 1H), 4.04 (s, 3H), 3.77 (br.s, 4H), 3.65 - 3.56 (m, 3H), 2.81 (br.s, 3H), 2.67 - 2.57 (m, 1H), 2.33 - 2.25 (m, 5H), 2.03 - 1.91 (m, 6H), 1.62 (s, 1H), 1.48 (d, J = 16.1 Hz, 8H). It can be seen that the structure of the compound is correct.

[0579] Example 66: Synthesis of Compound TPD12086

[0580]

[0581] Compound int - O - 1 (10 g, 52.6 mmol), EtOH (200 ml) and 5 - (methoxymethylene) - 2,2 - dimethyl - 1,3 - dioxane - 4,6 - dione (10.77 g, 57.8 mmol) were successively added to a 500 ml three - necked flask. The reaction was refluxed for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and filtered by suction to obtain compound int - O - 2 (16 g, yellow solid, purity 99.855%), yield: 92.02%. LCMS (ESI) m / z calcd. for C 13 H 11 BrFNO 4 [M + H] + 344.0; found 286.0; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 11.23 (d, J = 14.0 Hz, 1H), 8.52 (d, J = 14.3 Hz, 1H), 8.06 (dd, J = 6.0, 2.8 Hz, 1H), 7.67 - 7.63 (m, 1H), 7.44 (t, J = 8.7 Hz, 1H), 1.68 (s, 6H). It can be seen that the structure of the compound is correct.

[0582] In a 250 ml single-necked flask, compound int-O-2 (8 g, 23.2 mmol) and diphenyl ether (80 ml) were added successively. The reaction was carried out at 240 °C for 15 minutes under nitrogen protection. The same operation was performed for another batch. After the reaction was completed, the reaction solution was cooled to room temperature, and compound int-O-3 (7.8 g, brown solid, purity 52.957%) was obtained by suction filtration, and the yield was 36.13%. LCMS (ESI) m / z calcd. for C 9 H 5 BrFNO[M+H] + 241.9; found 242.0, 244.0; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 11.90 (s, 1H), 7.99 - 7.91 (m, 1H), 7.86 (dd, J = 11.3, 6.3 Hz, 1H), 7.67 - 7.57 (m, 1H), 6.05 (dd, J = 13.9, 7.4 Hz, 1H). It can be seen that the structure of the compound is correct.

[0583] In a 250 ml three-necked flask, compound int-O-3 (7.8 g, 32.2 mmol), toluene (100 ml) and POCl 3 (14.81 g, 96.5 mmol) were added successively. The reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated, adjusted to alkaline with saturated NaHCO 3 solution, and extracted three times with DCM (100 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography, and the eluent ratio was PE / EtOAc = 50 / 1 - 30 / 1 to obtain compound int-O-4 (2.5 g, yellow solid, purity 98.538%), and the yield was 29.50%. LCMS (ESI) m / z calcd. for C 9 H 4 BrClFN[M+H] + 259.9; found 259.9, 262.0. It can be seen that the structure of the compound is correct.

[0584] In a 500 ml single-necked flask, successively add compound int-A-1 (20 g, 89.6 mmol), 4-aminophenol (13.69 g, 125.4 mmol), HATU (47.7 g, 125.4 mmol), DIEA (28.95 g, 224 mmol) and DMF (200 ml). React at 25 °C for 16 hours under nitrogen protection. After the reaction is completed, the reaction solution is concentrated to dryness. The residue is purified by silica gel column chromatography, and the eluent ratio is DCM / MeOH = 100 / 1 to 30 / 1 to obtain compound int-A-2 (24 g, brown oil, purity 82.759%), yield: 70.54%. LCMS (ESI) m / z calcd. for C 17 H 15 FN 2 O 3 [M+H] + 315.1; found 315.1; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 10.17 (s, 1H), 9.74 (s, 1H), 9.23 (s, 1H), 7.64 - 7.61 (m, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.16 - 7.12 (m, 2H), 6.70 (dd, J = 7.0, 5.1 Hz, 2H), 1.44 (d, J = 1.6 Hz, 4H). It can be seen that the compound structure is correct.

[0585] In a 100 ml three-necked flask, successively add compound int-O-4 (2 g, 7.7 mmol), int-A-2 (2.90 g, 9.24 mmol), cesium carbonate (5.02 g, 15.4 mmol) and DMSO (30 ml). React at 120 °C for 16 hours under nitrogen protection. After the reaction is completed, the reaction solution is cooled to room temperature, poured into water (100 ml), and extracted three times with EA (100 ml). The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel column chromatography, and the eluent ratio is PE / EtOAc = 5 / 1 to 2 / 1 to obtain compound int-O (1.0 g, brown oil, purity 96.582%), yield: 23.38%. LCMS (ESI) m / z calcd. for C 26 H 18 BrF 2 N 3 O 3 [M+H] + 538.1; found 538.1, 540.1; 1 H NMR (400 MHz, DMSO_d 6): δ = 10.22 (s, 1H), 10.05 (s, 1H), 8.70 (d, J = 5.1 Hz, 1H), 8.45 (d, J = 6.7 Hz, 1H), 8.17 (d, J = 9.4 Hz, 1H), 7.79 (d, J = 8.9 Hz, 2H), 7.64 (dd, J = 9.0, 5.1 Hz, 2H), 7.27 (d, J = 9.0 Hz, 2H), 7.16 (t, J = 8.9 Hz, 2H), 6.65 (d, J = 5.0 Hz, 1H), 1.47 (s, 4H). It can be seen that the structure of the compound is correct.

[0586] Compound TPD12086-1 (5 g, 25.1 mmol), sodium bicarbonate (4.22 g, 50.2 mmol) and DCM / H2O = 1 / 1 (100 ml) were successively added to a 250 ml three-necked flask. After the system was cooled to 0 °C, CbzCl (5.14 g, 30.1 mmol) was added. The reaction was carried out at 25 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (100 ml), and extracted three times with DCM (30 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography, and the eluent ratio was PE / EtOAc = 10 / 1 - 5 / 1, to obtain compound TPD12086-2 (5.7 g, yellow oil, purity 96%), yield: 65.74%. LCMS (ESI) m / z calcd. for C 18 H 24 N 2 O 4 [M + H] + 333.2; found 233.2, 355.2; 1 H NMR (400 MHz, CDCl 3 ): δ = 7.37 - 7.32 (m, 5H), 5.17 (s, 2H), 4.13 (d, J = 21.6 Hz, 3H), 3.99 (s, 1H), 3.44 (d, J = 12.2 Hz, 2H), 2.58 (dd, J = 15.0, 6.5 Hz, 1H), 1.61 (s, 1H), 1.41 (s, 9H). It can be seen that the structure of the compound is correct.

[0587] Compound TPD12086-2 (5.7 g, 17.1 mmol), DCM (30 ml) and trifluoroacetic acid (60 ml) were successively added to a 100 ml single-necked flask. Under nitrogen protection, the reaction was carried out at 25 °C for 2 hours. After the reaction was completed, it was concentrated to dryness to obtain the crude compound TPD12086-3 (6 g, brown oil), yield: 87.13%. LCMS (ESI) m / z calcd. for C 13 H16 N 2 O 2 [M+H] + 233.1; found 233.1. It can be seen that the compound structure is correct.

[0588] To a 250 ml single-necked flask were successively added compound TPD12086-3 (6 g, 25.8 mmol), bromoacetonitrile (3.71 g, 31.0 mmol), potassium carbonate (10.70 g, 77.4 mmol) and ACN (100 ml). The reaction was carried out at 25 °C for 3 hours under nitrogen protection. After the reaction was completed, the reaction solution was poured into water (300 ml), and extracted three times with EA (100 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with an eluent ratio of DCM / MeOH = 200 / 1 to 50 / 1 to obtain compound TPD12086-4 (5.4 g, brown oil, purity 92.063%), yield: 70.93%. LCMS(ESI) m / z calcd.for C 15 H 17 N 3 O 2 [M+H] + 272.1; found 272.2. It can be seen that the compound structure is correct.

[0589] To a 100 ml single-necked flask were successively added compound TPD12086-4 (4.4 g, 16.2 mmol), EtOH / NH 3 H 2 O = 10 / 1 (60 ml) and Raney nickel (2.85 g). The reaction was carried out at 40 °C for 16 hours under a hydrogen (1 atm) atmosphere. After the reaction was completed, the reaction solution was filtered by suction and concentrated to dryness. The residue was purified by silica gel column chromatography with an eluent ratio of DCM / MeOH = 50 / 1 to 30 / 1 to obtain compound TPD12086-5 (2 g, brown oil, purity 95.061%), yield: 42.59%. LCMS(ESI) m / z calcd.forC 15 H 21 N 3 O 2 [M+H] + 276.2; found 276.2; 1 H NMR(400MHz, DMSO_d 6): δ = 7.39 - 7.34 (m, 5H), 5.11 (s, 2H), 3.62 (d, J = 12.1 Hz, 1H), 3.51 (t, J = 15.4 Hz, 4H), 3.26 (d, J = 11.4 Hz, 3H), 2.40 - 2.31 (m, 4H), 1.41 (d, J = 8.4 Hz, 1H). It can be seen that the structure of the compound is correct.

[0590] Compound TPD12086 - 5 (500 mg, 1.82 mmol), compound TPD12003 - 4 (508 mg, 1.82 mmol), DIEA (469 mg, 3.63 mmol) and DMSO (5 ml) were successively added to a 25 ml three - necked flask. The reaction was carried out at 120 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature and poured into water (30 ml), and extracted three times with EA (30 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography, and the eluent ratio was DCM / MeOH = 50 / 1 - 30 / 1, to obtain compound TPD12086 - 6 (200 mg, brown solid, purity 86.411%), yield: 21.24%. LCMS(ESI) m / z calcd. for C 27 H 30 N 6 O 5 [M + H] + 519.2; found 519.1. It can be seen that the structure of the compound is correct.

[0591] Compound TPD12086 - 6 (80 mg, 0.15 mmol) and trifluoroacetic acid (2 ml) were successively added to a 25 ml single - necked flask. The reaction was carried out at 75 °C for 2 hours under nitrogen protection. After the reaction was completed, it was concentrated to dryness to obtain the crude product compound TPD12086 - 7 (100 mg, brown solid), yield: 54.50%. LCMS(ESI) m / z calcd. for C 19 H 24 N 6 O 3 [M + H] + 385.2; found 385.2. It can be seen that the structure of the compound is correct.

[0592] Compound int - O (250 mg, 0.46 mmol), 4 - hydroxymethylpiperidine (107 mg, 0.93 mmol), Pd 2 (dba) 3(43 mg, 0.046 mmol), BINAP (58 mg, 0.093 mmol), cesium carbonate (303 mg, 0.93 mmol) and 1,4-dioxane (10 ml). The reaction was carried out at 100 °C for 16 hours under nitrogen protection. The same operation was carried out for another five batches. After the reaction was completed, the reaction solution was cooled to room temperature and poured into water (1200 ml), and extracted three times with EA (50 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with the eluent ratio of DCM / MeOH = 50 / 1 - 30 / 1 to obtain compound TPD12086-8 (310 mg, yellow solid, purity 91.691%), yield: 17.82%. LCMS (ESI) m / z calcd. for C 32 H 30 F 2 N 4 O 4 [M+H] + 573.2; found 573.2; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 10.20 (s, 1H), 10.06 (s, 1H), 8.56 (d, J = 5.2 Hz, 1H), 7.86 (d, J = 13.5 Hz, 1H), 7.76 (d, J = 9.0 Hz, 2H), 7.66 - 7.63 (m, 2H), 7.45 (d, J = 8.5 Hz, 1H), 7.24 - 7.20 (m, 2H), 7.18 - 7.13 (m, 2H), 6.45 (d, J = 5.2 Hz, 1H), 4.54 (t, J = 5.3 Hz, 1H), 3.58 (d, J = 11.4 Hz, 2H), 3.33 (s, 1H), 2.77 (t, J = 11.1 Hz, 2H), 1.82 (d, J = 10.8 Hz, 2H), 1.58 (br.s, 1H), 1.47 (s, 4H), 1.38 - 1.23 (m, 3H). It can be seen that the structure of the compound is correct.

[0593] Oxalyl chloride (137 mg, 1.08 mmol) and DCM (4 ml) were successively added to a 50 ml three-necked flask. After cooling to -78 °C, a solution of DMSO (169 mg, 2.17 mmol) in DCM (2 ml) was added, and the mixture was stirred at -78 °C for 0.5 hour. Then, a solution of compound TPD12086-8 (310 mg, 0.54 mmol) in DCM (4 ml) was added, and the mixture was stirred at -78 °C for 0.5 hour. Finally, TEA (438 mg, 4.33 mmol) was added, and the temperature was slowly restored to room temperature, and the reaction was carried out for 1 hour under nitrogen protection. After the reaction was completed, the reaction solution was poured into saturated NaHCO 3In a solution (30 ml), extract three times with DCM (30 ml). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to dryness. The residue is purified by preparative plate with the eluent ratio of DCM / MeOH = 12 / 1 to obtain compound TPD12086-9 (180 mg, yellow solid, purity 95.968%), yield: 55.91%. LCMS (ESI) m / z calcd. for C 32 H 28 F 2 N 4 O 4 [M+H] + 571.2; found 571.3; 1 HNMR (400 MHz, DMSO-d 6 ): δ = 10.19 (s, 1H), 10.06 (s, 1H), 9.68 (s, 1H), 8.57 (d, J = 5.2 Hz, 1H), 7.87 (d, J = 13.4 Hz, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.64 (dd, J = 9.0, 5.1 Hz, 2H), 7.46 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 8.9 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 6.46 (d, J = 5.2 Hz, 1H), 3.52 - 3.49 (m, 2H), 2.94 (t, J = 10.3 Hz, 2H), 2.73 (s, 1H), 2.04 (d, J = 10.3 Hz, 2H), 1.77 - 1.68 (m, 2H), 1.47 (s, 4H). It can be seen that the structure of the compound is correct.

[0594] Add compound TPD12086-7 (50 mg, 0.13 mmol), compound TPD12086-9 (74 mg, 0.13 mmol), sodium triacetoxyborohydride (55 mg, 0.26 mmol) and DCE (3 ml) successively into a 25-ml single-necked flask. Under nitrogen protection, react at 25 °C for 16 hours. After the reaction is completed, pour the reaction solution into water (15 ml) and add an appropriate amount of saturated NaHCO 3Solution was added to make the reaction solution alkaline. The organic phase was separated, and the aqueous phase was extracted twice with DCM (10 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was prepared by high performance liquid chromatography with the following parameters: Column: sunfire 5um 19 - 150mm; Mobile phase: acetonitrile - water (0.1% FA); Gradient: 20 - 35 / 7 min, to obtain compound TPD12086 (13.26 mg, yellow solid, purity 98.425%), Yield: 10.68%. LCMS (ESI) m / z calcd. for C 51 H 52 F 2 N 10 O 6 [M + H] + 939.4; found 470.2; 939.1; 1 H NMR (400 MHz, DMSO_d 6 ): δ = 10.98 (s, 1H), 10.20 (s, 1H), 10.06 (s, 1H), 8.56 (d, J = 5.2 Hz, 1H), 8.38 (s, 1H), 8.22 (s, 2H), 7.86 (d, J = 13.4 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.64 (dd, J = 8.9, 5.1 Hz, 2H), 7.44 (d, J = 8.5 Hz, 1H), 7.23 - 7.13 (m, 5H), 6.59 (s, 1H), 6.45 (d, J = 5.2 Hz, 1H), 5.04 (dd, J = 13.2, 5.0 Hz, 1H), 4.33 (d, J = 17.4 Hz, 1H), 4.19 (d, J = 17.5 Hz, 1H), 3.71 (s, 3H), 2.98 - 2.84 (m, 6H), 2.79 - 2.74 (m, 4H), 2.41 - 2.22 (m, 4H), 1.93 - 1.83 (m, 5H), 1.73 (s, 1H), 1.47 (s, 4H), 1.33 - 1.23 (m, 4H). It can be seen that the structure of the compound is correct.

[0595] Example 67: Synthesis of Compound TPD12088

[0596]

[0597] To a 50 mL single-necked flask were successively added compound sm-1 (500 mg, 2.51 mmol), 2-bromoacetamide (415 mg, 3.01 mmol), potassium carbonate (1040 mg, 7.53 mmol), and acetonitrile (10 mL). The reaction was carried out at 25 °C for 2 h under nitrogen protection. After the reaction was completed, the reaction mixture was poured into water (30 mL), and extracted three times with EA (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with an eluent ratio of DCM / MeOH = 100 / 1 to 30 / 1 to obtain compound TPD12088-1 (410 mg, white solid, purity 92.085%), yield: 58.70%. LCMS (ESI) m / z calcd. for C 12 H 21 N 3 O 3 [M+H] + 256.2; found 255.8; 1 HNMR (400 MHz, DMSO-d 6 ): δ = 7.23 (s, 1H), 7.09 (s, 1H), 3.56 - 3.39 (m, 4H), 3.28 - 3.20 (m, 2H), 2.86 (s, 2H), 2.43 (dd, J = 13.9, 6.4 Hz, 1H), 1.43 (s, 9H), 1.38 (d, J = 8.5 Hz, 1H). It can be seen that the structure of the compound is correct.

[0598] To a 25 mL single-necked flask were successively added compound TPD12088-1 (410 mg, 1.60 mmol), compound TPD12003-4 (537 mg, 1.92 mmol), palladium acetate (72 mg, 0.32 mmol), Xant-Phos (185 mg, 0.32 mmol), cesium carbonate (782 mg, 2.40 mmol), and 1,4-dioxane (10 mL). The reaction was carried out at 100 °C for 16 h under nitrogen protection. After the reaction was completed, the reaction mixture was cooled to room temperature, poured into water (30 mL), and extracted three times with EA (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography with an eluent ratio of DCM / MeOH = 100 / 1 to 30 / 1 to obtain compound TPD12088-2 (200 mg, yellow solid, purity 93.691%), yield: 23.45%. LCMS (ESI) m / z calcd. for C 24 H 30 N 6 O 6 [M+H] +499.2; found 499.1; 1 H NMR (400 MHz, DMSO-d 6 ): δ = 11.03 (s, 1H), 10.44 (s, 1H), 8.70 (s, 1H), 8.32 (s, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.55 (d, J = 18.5 Hz, 1H), 4.40 (d, J = 18.5 Hz, 1H), 3.68 - 3.49 (m, 4H), 3.34 - 3.26 (m, 5H), 2.95 - 2.86 (m, 1H), 2.63 - 2.54 (m, 2H), 2.43 - 2.34 (m, 1H), 2.02 - 1.99 (m, 1H), 1.44 (s, 9H). It can be seen that the structure of the compound is correct.

[0599] Compound TPD12088 - 2 (200 mg, 0.40 mmol), 1,4 - dioxane (1 ml) and 4N HCl / 1,4 - dioxane (4 ml) were successively added to a 25 - ml single - necked flask. Under nitrogen protection, the reaction was carried out at 25 °C for 2 hours. After the reaction was completed, it was concentrated to dryness to obtain the crude compound TPD12088 - 3 (200 mg, off - white solid), yield: 102.57%. LCMS (ESI) m / z calcd. for C 19 H 22 N 6 O 4 [M + H] + 399.2; found 399.0. It can be seen that the structure of the compound is correct.

[0600] Compound TPD12088 - 3 (100 mg, 0.25 mmol), compound TPD12086 - 9 (143 mg, 0.25 mmol), sodium triacetoxyborohydride (106 mg, 0.50 mmol) and DCE (3 ml) were successively added to a 25 - ml single - necked flask. Under nitrogen protection, the reaction was carried out at 25 °C for 16 hours. After the reaction was completed, the reaction solution was poured into water (15 ml), and an appropriate amount of saturated NaHCO 3 solution was added to make the reaction solution alkaline. The organic phase was separated, and the aqueous phase was extracted twice with DCM (5 ml). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was prepared by high - performance liquid chromatography, and the relevant parameters are as follows: chromatographic column: sunfire 5um 19 - 150 mm; mobile phase: acetonitrile - water (0.1% FA); gradient: 20 - 35 / 7 minutes, to obtain compound TPD12088 (19.5 mg, yellow solid, purity 98.134%), yield: 7.73%. LCMS (ESI) m / z calcd. for C51 H 50 F 2 N 10 O 7 [M+H] + 953.4; found 953.2; 1 H NMR(400 MHz, DMSO_d 6 ): δ = 11.02 (s, 1H), 10.41 (s, 1H), 10.20 (s, 1H), 10.06 (s, 1H), 8.71 (s, 1H), 8.56 (d, J = 5.2 Hz, 1H), 8.33 (s, 1H), 8.19 (s, 0.7H), 7.86 (d, J = 13.5 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.64 (dd, J = 8.9, 5.1 Hz, 2H), 7.45 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 8.9 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 6.45 (d, J = 5.2 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.55 (d, J = 18.5 Hz, 1H), 4.41 (d, J = 18.5 Hz, 1H), 3.64 - 3.58 (m, 5H), 2.95 - 2.78 (m, 8H), 2.67 - 2.53 (m, 3H), 2.43 - 2.33 (m, 2H), 2.01 - 1.99 (m, 1H), 1.87 (dd, J = 20.3, 10.1 Hz, 3H), 1.78 (s, 1H), 1.47 (s, 4H), 1.34 - 1.32 (m, 2H). It can be seen that the compound structure is correct.

[0601] Example 68: Synthesis of Compound TPD12096

[0602]

[0603] Compound TPD12096-1 (2 g, 0.01 mol), bromoacetonitrile (1.44 g, 0.012 mol), K 2 CO 3 (4.15 g, 0.03 mol), and ACN (30 ml) were successively added to a 100 ml single-necked flask. The reaction was carried out at 25 °C for 16 hours under nitrogen protection. After the reaction w...

Claims

1. A bifunctional compound, characterized in that the compound is selected from any one of the following structures:

2. A pharmaceutical composition for degrading receptor tyrosine kinases, characterized in that it comprises the bifunctional compound according to claim 1, or a pharmaceutically acceptable salt of the bifunctional compound.

3. Use of the bifunctional compound according to claim 1 or the pharmaceutical composition according to claim 2 for the preparation of a preparation for degrading or inhibiting receptor tyrosine kinases.

4. The use according to claim 3, characterized in that the receptor tyrosine kinase includes wild-type or locally variant discoidin domain receptors.

5. The use according to claim 4, characterized in that the discoidin domain receptor is DDR1 and / or DDR2.

6. Use of the bifunctional compound according to claim 1 or the pharmaceutical composition according to claim 2 for the preparation of a drug for preventing, diagnosing or treating receptor tyrosine kinase-related diseases or disorders.

7. The use according to claim 6, characterized in that the receptor tyrosine kinase-related diseases or disorders are cancers, immune-related diseases, fibrotic diseases, neurodegenerative diseases or inflammatory diseases related to abnormal expression of DDR1 or DDR2.

8. The use according to claim 7, characterized in that the cancer is gastric cancer, intestinal cancer, esophageal cancer, head and neck cancer, lung cancer, liver cancer, brain cancer, colorectal cancer, skin cancer, thyroid cancer, soft tissue cancer, endometrial cancer, uterine cancer, testicular cancer, cervical cancer, ovarian cancer, fallopian tube tumor, leukemia, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, renal cell carcinoma, bladder cancer, kidney cancer, lymphoma, melanoma, myeloproliferative disease, sarcoma, peripheral neuroepithelioma, glioma, astrocytoma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma or schwannoma.

9. The use according to claim 8, characterized in that: the adenocarcinoma includes breast cancer, prostate cancer or pancreatic cancer; the lymphoma includes non-Hodgkin's lymphoma; the sarcoma includes angiosarcoma; the glioma includes oligodendroglioma or ganglioglioma.

10. The use according to claim 7, characterized in that the inflammatory diseases and immune-related diseases are rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, axial spondyloarthritis, psoriasis, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, recurrent aphthous ulcer, Kawasaki disease, spondyloarthritis, neuromyelitis optica, Behçet's disease, lupus nephritis, familial Mediterranean fever, ulcerative colitis, autoimmune hepatitis, asthma, arteriosclerosis or Crohn's disease.

11. The use according to claim 7, characterized in that The neurodegenerative disease is Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, cerebellar atrophy, multiple sclerosis, Parkinson's disease, primary lateral sclerosis, spinal muscular atrophy, cerebral ischemia, spastic paraplegia or myasthenia gravis.

Images