A compound for treating thrombotic disorders

Abstract

This invention relates to a compound for treating thrombotic diseases. Specifically, this invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, or its enantiomer, diastereomer, transtransferase, racemic mixture, polymorph thereof, solvate thereof, or isotopically labeled derivative thereof. The compound of this invention specifically binds to the SH3 domain protein of Src kinase, interfering with the binding of integrin αIIbβ3 to Src kinase, thereby selectively inhibiting outward-to-inward signal transduction without affecting inward-to-outward signal transduction. This allows the compound of this invention to exert antithrombotic effects without affecting normal physiological hemostasis, avoiding bleeding side effects, and thus becoming a new generation of effective drugs for the prevention and treatment of thrombosis-related cardiovascular and cerebrovascular diseases.

Description

Technical Field

[0001] This invention relates to the field of pharmaceuticals, and more specifically to a compound for treating thrombotic diseases. Background Technology

[0002] Currently, cardiovascular and cerebrovascular thrombotic diseases such as myocardial infarction and cerebral infarction have become the leading causes of death and health, characterized by high morbidity and mortality. According to the World Health Organization, approximately 12 million people die prematurely from cardiovascular and cerebrovascular diseases each year. The mortality rate from cardiovascular and cerebrovascular diseases is the highest among all diseases, accounting for about one-third of all deaths globally each year. Platelets play a crucial role in the formation of cardiovascular and cerebrovascular thrombosis. When vascular endothelial damage or atherosclerotic plaque ruptures, platelets activate and, through adhesion, extension, and aggregation, lead to pathological thrombosis, causing ischemic necrosis of the heart and brain tissue in the affected blood vessel distribution area. This can severely endanger the patient's life. Therefore, antiplatelet therapy has become the first-line treatment for cardiovascular and cerebrovascular thrombotic diseases. The most direct cause of pathological thrombosis in thrombotic diseases is the abnormal activation and aggregation of platelets. The common pathway for platelet aggregation and thrombosis induced by various platelet agonists in the body is mediated by integrin αIIbβ3 (GPIIb / IIIa). Therefore, integrin αIIbβ3 has become an ideal target for antiplatelet therapy. However, the current challenge with antithrombotic drugs is that while they fight thrombosis, they also inhibit normal physiological hemostasis, often leading to bleeding side effects.

[0003] Integrin αIIbβ3 belongs to the integrin family. Integrins are a class of transmembrane proteins widely distributed in cells, mediating cell-cell interactions (through binding to cadherins and selectins) and cell-extracellular matrix interactions (through binding to extracellular matrix components such as fibronectin, collagen, and laminin). They participate in a series of physiological and pathological processes, including cell signal transduction, adhesion, extension, tumor migration, hemostasis, and thrombosis. Integrins are heterodimers formed by α and β subunits. Currently, 18 α subunits have been identified in mammals, forming 24 different integrins with 8 β subunits. Among them, integrin β3 can form two integrins with αIIb and αv subunits: αIIbβ3 and αvβ3. Integrin αIIbβ3 is mainly expressed on the surface of platelets and megakaryocytes. It is the main membrane receptor on the platelet surface and plays an important role in thrombosis and hemostasis. Integrin αvβ3 is widely distributed in the body, such as in endothelial cells, osteoclasts, tumor cells, smooth muscle cells, and fibroblasts, and mediates a variety of pathophysiological processes such as angiogenesis, bone resorption, and tumor metastasis.

[0004] Integrin αIIbβ3 is a transmembrane heterodimer composed of two subunits, αIIb and β3, linked by non-covalent bonds. It is primarily expressed on the surface of platelets and megakaryocytes and is a major membrane receptor on the platelet surface, mediating bidirectional platelet signal transduction. Therefore, it plays a crucial role in platelet activation, maintaining normal platelet function, and thrombus formation. Platelet activators such as thrombin and ADP, upon interaction with their corresponding receptors, induce conformational changes in integrin αIIbβ3, leading to increased affinity for its ligands, such as soluble fibrinogen. This process is an inside-out signal transduction, marked by unstable platelet adhesion, binding to free fibrinogen, and reversible aggregation. When integrin αIIbβ3 is activated and binds to its ligands, it activates outside-in signal transduction, marked by stable platelet adhesion, extension, irreversible aggregation, and fibrin clot retraction. Ultimately, this promotes platelet aggregation and the formation of relatively stable thrombi, thus completing the physiological or pathological processes of hemostasis and thrombosis. The current consensus is that hemostasis and thrombosis require the joint participation of inward-to-outward and outward-to-inward signal transduction. The pathological process of thrombosis requires the increase of platelet emboli under the condition of resisting high blood flow impact. Therefore, thrombosis is relatively more dependent on outward-to-inward signal transduction.

[0005] Integrin αIIbβ3 serves as the final common pathway mediating platelet activation, aggregation, and thrombus formation, making it a primary target for antithrombotic drug research. In fact, significant progress has been made in research targeting integrin αIIbβ3 for antithrombotic drugs, currently focusing primarily on integrin αIIbβ3 receptor antagonists, which have achieved good clinical efficacy. Currently, three integrin αIIbβ3 receptor antagonist antiplatelet drugs are approved by the U.S. Food and Drug Administration (FDA) for clinical antithrombotic therapy: abciximab, etibactate, and tirofiban. These αIIbβ3 receptor antagonists specifically exert their antithrombotic effect by interfering with the interaction between integrin αIIbβ3 and its ligand. However, this strategy still has significant limitations. αIIbβ3 receptor antagonists block bidirectional signal transduction by preventing integrin αIIbβ3 from binding to its ligand, meaning that while exerting their antithrombotic effect, they also affect normal hemostatic function. Clinical trial retrospectives show that approximately 2% of patients treated with integrin αIIbβ3 antagonists experienced severe intracranial hemorrhage, about 15% experienced gastrointestinal bleeding, and about 5-10% experienced peritoneal hemorrhage. Additionally, approximately 60-80% of patients experienced significant bleeding at the femoral artery puncture site. Similar to classic antithrombotic drugs like aspirin and clopidogrel, integrin αIIbβ3 antagonists, while exerting effective antithrombotic effects, also increase the risk of bleeding, which is currently the most common and significant side effect of antithrombotic drugs. Therefore, the selection of antithrombotic drug dosages in clinical practice must also consider the contribution of bleeding side effects, making it difficult to achieve better antithrombotic effects by simply increasing the dosage. Therefore, developing a new generation of antithrombotic drugs that do not affect normal hemostasis may potentially achieve stronger antithrombotic efficacy with lower risk, representing the future direction of antithrombotic drug development.

[0006] Integrin β3 is a major subunit that binds to intracellular platelet signaling molecules and regulates bidirectional signal transduction. The interaction between its intracellular segment and signaling molecules in regulating bidirectional signal transduction has attracted widespread attention. Recent research suggests that selectively inhibiting the outward-to-inward signal transduction of integrin αIIbβ3 can suppress pathological thrombus formation without inducing spontaneous bleeding. Therefore, to achieve a more rational antithrombotic strategy, a scientifically sound approach should avoid directly antagonizing the αIIbβ3 receptor and instead selectively regulate outward-to-inward signal transduction by interfering with the interaction between integrin β3 and intracellular platelet signaling molecules, thus achieving effective antithrombotic effects while preserving physiological hemostasis as much as possible. Therefore, the key issue currently is finding a clinically applicable method. The most feasible approach is a small-molecule interference strategy, which selectively regulates the outward-to-inward signal transduction of human platelet integrin while largely not affecting the inward-to-outward signal transduction of platelet integrin, achieving a truly effective antithrombotic strategy without compromising normal hemostasis.

[0007] Integrin αIIbβ3 bidirectional signal transduction consists of two interconnected yet distinct signaling pathways. Recent research has significantly advanced the regulation of bidirectional signal transduction by the cytoplasmic segment of integrin β3 through interactions with cytoplasmic signaling proteins. For example, β3-endonexin, ILK, talin head domain, and kindlin-3 are involved in inward-to-outward signal transduction regulation; while c-Src, Gα13, Talin, VPS33B, Shc, JAM-A, and Dok-1 are involved in outward-to-inward signal transduction regulation. Among these, the function and mechanism of the interaction between platelet integrin β3 and c-Src are the most clearly understood. c-Src, constitutively bound to the RGT sequence at the tail of integrin β3, undergoes kinase activity modulation upon activation, subsequently phosphorylating downstream signaling molecules. This is the most fundamental regulatory pathway for outward-to-inward signal transduction. It has been confirmed that defects in Src family genes such as c-Src, Hck, Fgr, and Lyn (especially c-Src) or the action of Src kinase inhibitors affect integrin β3. T762A Mutations and β3 Δ760-762Deletion mutations can inhibit outward-to-inward signaling-mediated platelet function. The three terminal amino acids RGT in the β3 subunit directly interact with c-Src, and synthetically produced RGT peptides can specifically interfere with the interaction between integrin β3 and c-Src in platelets, selectively inhibiting outward-to-inward signal transduction. Therefore, the β3 / c-Src interaction plays a crucial role in platelet integrin αIIbβ3-mediated outward-to-inward signal transduction, a consensus in the academic community. Targeting the β3 / c-Src interaction with synthetic molecules to selectively inhibit outward-to-inward signal transduction has the potential to develop into a new generation of antithrombotic drugs.

[0008] In a resting state, platelets have approximately 80,000 integrin αIIbβ3 on their membrane surface. Upon activation, platelet α granules release integrin αIIbβ3, and the intracellular conduit system opens, allowing integrin to translocate to the membrane, increasing its quantity and enhancing hemostasis. Integrin αIIbβ3 is composed of αIIb and β3 subunits linked non-covalently. The αIIb subunit has a molecular weight of 140 kDa and consists of a heavy chain (containing 871 amino acids) and a light chain (containing 137 amino acids) linked by disulfide bonds. The β3 subunit has a molecular weight of 105 kDa and is a transmembrane polypeptide composed of 762 amino acids. Both αIIb and β3 subunits consist of a relatively long extracellular segment, a transmembrane α-helix, and a relatively short intracellular segment. The extracellular segment of the integrin can bind to ligands such as fibrinogen and vWF factor. Its ligand binding ability is not only regulated by the extracellular segment but is also regulated by the extracellular, transmembrane, and intracellular components. Electron microscopy revealed that the extracellular segments of both subunits each have an N-terminal "head" that binds to a ligand, which connects to a longer C-terminal "leg" and then to the transmembrane segment and the cytoplasmic segment.

[0009] Further crystal diffraction revealed that the "head" of the α subunit consists of a β-propeller-like domain composed of seven leaf-like folds, and the "leg" is composed of the "thigh," "Calf-1," and "Calf-2" domains, with the knee of the leg formed between the "thigh" and "Calf-1" domains. The "head" of the β subunit consists of a βA domain and an immunoglobulin-like "Hybrid" domain, and the "leg" consists of a PSI (plexin-semaphorin-integrin) domain, four EGF (epidermal growth factor) domains, and a β-tail domain, with the knee of the leg formed between the "EGF-1" and "EGF-2" domains. When integrin is at rest, both subunits are in a "V"-shaped flexed position, bringing the subunit head close to the cell membrane and obscuring the ligand binding site, resulting in low affinity of integrin αIIbβ3 for ligands. When platelet agonists such as thrombin and adenosine diphosphate (ATP) interact with their corresponding receptors on the platelet membrane, a series of signal transductions occur. The ankle protein head binds to the cytoplasmic proximal segment of integrin β3, disrupting the salt bridge between αIIbR995 and β3D723, which maintains the resting state of αIIbβ3. The spatial conformation of integrin αIIbβ3 changes from a "flexed" to an "extended" state. The ligand binding site is exposed, increasing ligand affinity. This process is called "inside-out" signaling, functionally manifested in platelet binding of soluble fibrinogen, initial platelet adhesion, and phase I aggregation. Following conformational changes, integrin αIIbβ3 receptors cluster, aggregate and bind to kinases and anchoring proteins, leading to a series of signal transductions including calcium influx, protein tyrosine phosphorylation, and cytoskeletal protein remodeling. This process is called "outside-in" signaling, functionally manifested as stable platelet adhesion and extension, phase II aggregation, and fibrin clot retraction. Integrin αIIbβ3 fulfills its role in thrombosis and hemostasis through this bidirectional signal transduction. Inside-out signaling initiates initial integrin activation, initial adhesion, and reversible aggregation, essentially achieving hemostasis. Outside-in signaling, on the other hand, enables platelet extension, irreversible aggregation, and the formation of a strong fibrin clot, playing a more significant role in thrombosis.

[0010] The cytoplasmic segment of integrin αIIbβ3 is short, but it can bind to many intracellular proteins and kinases, playing a crucial role in regulating integrin αIIbβ3 signal transduction. Proteins interacting with the β3 cytoplasmic segment include cytoskeletal proteins such as ankle protein, α-actin, filament protein, and myosin. Kinases include the Src kinase family, integrin-linked kinase (ILK), and focal adhesion kinase (FAK). Regulatory proteins include β3-inlin and cell adhesion protein-1. In recent years, the role of Src kinase in the bidirectional signal transduction of integrin αIIbβ3, especially in the outward-to-inward signal transduction, has attracted considerable interest. Src kinase is a member of the SFK (Src family of kinase proteins) family, which contains nine members. Src, Fyn, and Yes are widely distributed in various tissues of the body and play important regulatory roles in cell growth, development, and differentiation. When mice lack these three kinases, developmental defects lead to embryonic death. The Src kinase consists of SH3, SH2, a kinase domain, and a C-terminal domain from the N-terminus to the C-terminus. Csk kinase binds to the SH2 domain and phosphorylates Y527 at the C-terminus of the Src kinase, thus maintaining the Src kinase in a closed conformation and keeping it inactive. Upon certain signal stimulation, Csk kinase can leave the SH2 domain of the Src kinase, leading to dephosphorylation of Y527 and phosphorylation of Y416, thereby activating the Src kinase and enabling it to phosphorylate downstream substrates and participate in cellular signal transduction.

[0011] Current research shows that the SH3 domain of Src kinase constitutively binds to the three amino acids of the RGT at the C-terminus of integrin β3. In the resting state, platelets form a complex of β3-Src(SH3)-Src(SH2)-Csk, which forms the basis of integrin αIIbβ3 outward-inward signal transduction. When mouse platelets lack Src kinase, integrin αIIbβ3 outward-inward signal transduction is inhibited, and this transduction is also significantly inhibited by Src kinase inhibitors. During integrin-activated outward-inward signal transduction, Src kinase interacts with the RGT sequence at the C-terminus of β3, and phosphorylation of the β3 cytoplasmic segments Y747 and Y759 occurs, becoming a crucial event in outward-inward signal transduction. When αIIbβ3Δ759 was transfected into CHO cells, the outward-inward signaling was significantly suppressed compared to αIIbβ3-transfected CHO cells. In mice, knocking out the integrin αIIbβ3-RGT sequence significantly impaired the outward-inward signaling, and phosphorylation of Y747 and Y759 was inhibited. Ablooglu, AJ, et al. established transgenic mice containing integrin αIIbβ3Δ759, i.e., RGT knockout mice. Results showed that, compared to control mice, RGT knockout mice exhibited suppressed platelet extension on solid-phase fibrinogen; fibrin clot retraction was also inhibited; and Y747 phosphorylation was impaired. However, the binding of free fibrinogen to PAR4 and glycoprotein VI as agonists remained unaffected. In vivo experiments confirmed that RGT knockout mice could avoid thrombosis induced by FeCl3 stimulation of the carotid artery; in tail-cutting experiments, some mice experienced prolonged bleeding time, but no spontaneous bleeding, postoperative hemorrhage, bloody stools, hematuria, or anemia occurred. Knocking out the RGT sequence of integrin αIIbβ3 can affect αIIbβ3 signal transduction involving c-Src kinase, thus preventing arterial thrombosis; it inhibits the outward-inward signal transduction of integrin αIIbβ3, while only partially affecting the inward-outward signal transduction.

[0012] Experimental studies have shown that synthesizing an oligopeptide mimicking the C-terminal RGT sequence of integrin β3 (RGT peptide) and modifying it with tetradecanoylation (Myr-RGT peptide) enables the oligopeptide to penetrate cell membranes. When the RGT peptide is applied to human platelets, the adhesion, extension, aggregation, and free fibrinogen binding capacity of platelets are observed, relating to the outward-to-inward and inward-to-outward signal transduction functions of integrin αIIbβ3. The tetradecanoylated RGT peptide dose-dependently inhibits the stable adhesion and extension of normal human platelets on solid-phase fibrinogen; co-incubation of Myr-RGT peptide with platelets inhibits fibrin clot retraction. Furthermore, Myr-RGT peptide inhibits phase II (irreversible) platelet aggregation induced by ADP, thrombin, and ristocetine, but has little effect on phase I (reversible) aggregation. After incubation with Myr-RGT peptide, thrombin stimulation significantly reduces CD62P expression on the platelet membrane surface. These results indicate that treatment with Myr-RGT peptide inhibits the outward-to-inward signal transduction of platelet integrin αIIbβ3. Conversely, platelet functions mediated by integrin αIIbβ3 inward-to-outward signal transduction remain unaffected, including platelet aggregation and free fibrinogen binding. These studies demonstrate that Myr-RGT peptide treatment does not block the inward-to-inward signal transduction pathway of integrin αIIbβ in platelets, and that a synthetic peptide mimicking the terminal three amino acid (RGT) sequence of the integrin β3 cytoplasmic segment can selectively inhibit outward-to-inward signal transduction without affecting inward-to-inward signal transduction (CN200610117991.7). The inventors’ recent research results further confirm that the artificially synthesized RGT peptide inhibits platelet thrombus formation under high shear stress in a fluid state, and prove that this artificially synthesized RGT peptide targeting the c-SrcSH3 domain does not directly affect the activity of c-Src, and therefore does not affect the activity of other intracellular c-Src that are not located in the integrin β3 signaling pathway (201811037039.5).

[0013] The Myr-RGT assay elucidated that the binding of the interfering integrin αIIbβ3RGT sequence to the SH3 domain of Src kinase selectively inhibits outward-to-inward signal transduction, laying the foundation for applied research. However, due to the low efficacy of the mimic peptides, their in vivo application is difficult, becoming a major obstacle to drug development and clinical application. Therefore, there is an urgent need to explore and find a batch of new small molecule compounds that can target this binding site and be applied in vivo with sufficient efficiency. Thus, the potential of developing a new generation of antithrombotic drugs lies in the artificial synthesis of small molecule compounds that target the β3 / c-Src interaction to selectively inhibit outward-to-inward signal transduction without affecting inward-to-outward signal transduction.

[0014] In summary, the biggest challenge in the development of antithrombotic drugs lies in separating the concurrent platelet thrombosis and hemostasis, specifically inhibiting the outward-to-inward and inward-to-outward signal transduction of platelets. While some studies have found that certain oligopeptides or peptides can selectively inhibit outward-to-inward platelet signaling (related to thrombosis) while having less impact on inward-to-outward signaling (related to hemostasis), these mimic peptides have poor membrane permeability and low utilization efficiency, making them difficult to apply in vivo and resulting in poor drug-likeness. This poses a significant obstacle to their pharmaceuticalization and clinical application. Currently, there are no reports of inhibitors targeting the protein-protein interaction between β3 and c-Src proteins.

[0015] Therefore, there is a need in this field to develop a drug that targets Src kinase, interferes with the binding of integrin αIIbβ3 to Src kinase, and thus selectively inhibits outward-to-inward signal transduction without affecting inward-to-outward signal transduction. This would allow the drug to have antithrombotic effects without affecting normal physiological hemostasis, avoiding bleeding side effects, and also enable the drug to have multiple therapeutic effects by targeting integrins. Summary of the Invention

[0016] The purpose of this invention is to provide a novel compound that can prevent thrombosis without affecting normal physiological hemostasis.

[0017] In a first aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, or a diastereomer thereof, or a transisomer thereof, or a racemic mixture thereof, or a polymorph thereof, or a solvate thereof, or an isotopically labeled derivative thereof:

[0018]

[0019] Z 1 For N or CR 1 ;

[0020] Z 2 For N or CR 2 ;

[0021] Z 3 For N or CR 3 ;

[0022] Z 4 For N or CR 4 ;

[0023] The condition is Z 1 Z 2 Z 3 and Z 4 0, 1, or two independent elements are each N;

[0024] R 1 R 2 R 3 and R 4 Each is independently hydrogen, hydroxyl, amino, C1-C6 alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C3-C 10 Cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, G a -OR a -OC(O)R d -OC(O)NR b R c -SR a -S(O)2R d -S(O)2NR b R c -C(O)R d -C(O)OR a -C(O)NR b R c -NR b R c -N(R) e )C(O)R d -N(R) e )S(O)2R d -N(R) e )C(O)OR d -N(R) e )C(O)NR b R c -N(R) e )S(O)2NR b R c -(C1-C6 alkylene)-G a -(C1-C6 alkylene)-OR a -(C1-C6 alkylene)-OC(O)R d -(C1-C6 alkylene)-OC(O)NR b R c -(C1-C6 alkylene)-S(O)2R d -(C1-C6 alkylene)-S(O)2NR b R c -(C1-C6 alkylene)-C(O)R d -(C1-C6 alkylene)-C(O)OR a -(C1-C6 alkylene)-C(O)NR b R c -(C1-C6 alkylene)-NRb R c -(C1-C6 alkylene)-N(R) e )C(O)R d -(C1-C6 alkylene)-N(R) e )S(O)2R d -(C1-C6 alkylene)-N(R) e )C(O)OR a -(C1-C6 alkylene)-N(R) e )C(O)NR b R c -(C1-C6 alkylene)-N(R) e )S(O)2NR b R c -(C1-C6 alkylene)-CN, substituted or unsubstituted C6-C 16 aryl, substituted or unsubstituted 5-16 heteroaryl, substituted or unsubstituted C6-C 16 Aryl-C1-C4 alkyl-, substituted or unsubstituted 5-16-membered heteroaryl-C1-C4 alkyl-, wherein the substitution refers to one or more (preferably 1, 2, 3 or 4) hydrogens on the group being independently substituted by substituents selected from the group consisting of: C1-C6 alkyl, halogen, C1-C6 haloalkyl, C3-C6 cycloalkyl; or, Z 3 For CR 3 Z 4 For CR 4 R 3 and R 4 The linkage forms a C6-C12 aromatic ring; or, Z 1 For CR 1 Z 2 For CR 2 R 1 and R 2 The linkage forms a C6-C12 aromatic ring;

[0025] R 5 -CN, -C(O)OR a -C(O)NR b R c -N(R) e )C(O)R d ;

[0026] X is independently -NR x -, -O-, or -S-; where R x It is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C6-C 12 Aryl, 5-12 heteroaryl, Gb -(C1-C6 alkylene)-G b ;

[0027] Y can be -NH-, -O-, or -S- independently;

[0028] R 6 It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, G b ;

[0029] R a R b R c and R e Each of the following is independently hydrogen, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G b C1-C6 alkyl, C3-C8 cycloalkyl, C6-C12 aryl, 5-12 heteroaryl, or C1-C6 alkyl substituted with one substituent, wherein the substituent is -OR z1 -NR z1 R z2 -C(O)OR z1 -C(O)NR z1 R z2 -S(O)2R z1 -S(O)2NR z1 R z2 and G b ;

[0030] R d It is C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, G b C1-C6 alkyl, or C1-C6 alkyl substituted with one substituent selected from -OR z1 -NR z1 R z2 -C(O)OR z1 -C(O)NR z1 R z2 -S(O)2R z1 -S(O)2NR z1 R z2 and G b ;

[0031] R z1 and R z2 Each is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;

[0032] G a and G b Each independently is C6-C 12Aryl, 5-12 membered heteroaryl, 3-10 membered heterocyclic, C3-C 10 cycloalkyl, or C3-C 10 Cycloalkenyl groups, and each of them is independently unsubstituted or surrounded by 1, 2, 3, 4, or 5 R groups. v replace;

[0033] R v It can be C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, -CN, oxo, or -OR. h -OC(O)R i -OC(O)NR j R k -SR h -S(O)2R h -S(O)2NR j R k -C(O)R h -C(O)-5-12-membered monocyclic heterocyclic ring, -C(O)-5-12-membered monocyclic heteroaryl ring, -C(O)OR h -C(O)NR j R k -NR j R k -N(R) h )C(O)R i -N(R) h )S(O)2R i -N(R) h )C(O)OR i -N(R) h )C(O)NR j R k -(C1-C6 alkylene)-OR h -(C1-C6 alkylene)-OC(O)R i -(C1-C6 alkylene)-OC(O)NR j R k -(C1-C6 alkylene)-S(O)2R h -(C1-C6 alkylene)-S(O)2NR j R k -(C1-C6 alkylene)-C(O)R h -(C1-C6 alkylene)-C(O)OR h -(C1-C6 alkylene)-C(O)NR j R k -(C1-C6 alkylene)-NR j R k-(C1-C6 alkylene)-N(R) h )C(O)R i -(C1-C6 alkylene)-N(R) h )S(O)2R i -(C1-C6 alkylene)-N(R) h )C(O)OR i -(C1-C6 alkylene)-N(R) h )C(O)NR j R k 、 or -(C1-C6 alkylene)-CN;

[0034] R z1 R z2 Each is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;

[0035] R h R j R k Each is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; and R i Each time it appears, it is independently a C1-C6 alkyl or a C1-C6 haloalkyl;

[0036] R i It is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0037] The heterocycles and heteroaryl heterocycles each have 1 to 4 (preferably 1, 2, 3 or 4) heteroatoms selected from N, O and S.

[0038] In another preferred embodiment, Z 1 For N or CR 1 .

[0039] In another preferred embodiment, Z 2 For N or CR 2 .

[0040] In another preferred embodiment, Z 3 For N or CR 3 .

[0041] In another preferred embodiment, Z 4 For N or CR 4 .

[0042] In another preferred embodiment, R 1 R 2 R 3 and R 4 At least one is not hydrogen.

[0043] In another preferred embodiment, Z1 Z 2 Z 3 and Z 4 At least one is not N.

[0044] In another preferred embodiment, R 1 R 2 R 3 and R 4 Each of these elements independently comprises hydrogen, hydroxyl, amino, C1-C4 alkyl-O-, C6-C12 aryl-O-, 5-12 heteroaryl-O-, C6-C16 aryl, C1-C4 alkyl-substituted C6-C16 aryl, halogen-substituted C6-C16 aryl, C1-C4 alkyl-substituted 5-16 heteroaryl, halogen-substituted 5-16 heteroaryl, 5-16 heteroaryl, C3-C8 cycloalkyl-O-, halogen, C3-C8 cycloalkenyl, halogenated or unsubstituted C3-C8 cycloalkyl, C6-C 16 aryl-C1-C4 alkyl-, 5-12-membered heteroaryl-C1-C4 alkyl-, benzo-C5-C8 cycloalkyl, benzo-C5-C8 cycloalkenyl; or, Z 3 For CR 3 Z 4 For CR 4 R 3 and R 4 The linkage forms a C6-C12 aromatic ring; or, Z 1 For CR 1 Z 2 For CR 2 R 1 and R 2 They connect to form C6-C12 aromatic rings.

[0045] In another preferred embodiment, R 1 R 2 R 3 and R 4 Each of the following groups is independently hydrogen, hydroxyl, amino, C1-C4 alkoxy, C1-C4 alkyl-substituted naphthyl, C6-C 12 Aryl, 5-16 membered heteroaryl, halogen-substituted naphthyl (preferably monohalogen-substituted naphthyl), C3-C8 cycloalkyl-O-, C6-C 12 aryl-O-, 5-12-membered heteroaryl-O-, anthracene-, halogen, phenylpyranyl, C3-C8 cycloalkenyl, dihalogenated or unsubstituted C3-C8 cycloalkyl, C6-C 12 Aryl-C1-C4 alkyl-, benzo-C5-C6 cycloalkyl-; or, Z 3 For CR 3 Z 4 For CR 4 R3 and R 4 The linkage forms a C6-C12 aromatic ring; or, Z 1 For CR 1 Z 2 For CR 2 R 1 and R 2 They connect to form C6-C12 aromatic rings.

[0046] In another preferred embodiment, R 1 R 2 R 3 and R 4 Each of these can be independently represented by hydrogen, hydroxyl, amino, methoxy, monomethylnaphthyl, isoquinolinyl, quinolinyl, monohalonaphthyl, phenyl, naphthyl, cyclopentyl-O-, cyclohexyl-O-, anthraceneyl, halogen (such as bromine), phenylpyranyl, etc. Cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, benzocyclopentyl, benzocycloheptenyl, dihalocyclohexyl, pyridyl, pyridyl-O-; or, Z 3 For CR 3 Z 4 For CR 4 R 3 and R 4 The linkage forms a benzene ring; or, Z 1 For CR 1 Z 2 For CR 2 R 1 and R 2 They connect to form a benzene ring.

[0047] In another preferred embodiment, the C1-C4 alkyl-substituted naphthyl group is a C1-C4 alkyl monosubstituted naphthyl group.

[0048] In another preferred embodiment, the naphthyl group is... In another preferred embodiment, the monomethylnaphthyl group is...

[0049] In another preferred embodiment, the isoquinolinyl group is...

[0050] In another preferred embodiment, the quinolinyl group is...

[0051] In another preferred embodiment, the monohalonaphthyl group is...

[0052] In another preferred embodiment, the anthracene group is...

[0053] In another preferred embodiment, the structure of the phenylpyranyl group is as follows:

[0054] In another preferred embodiment, the benzocyclopentyl group is...

[0055] In another preferred embodiment, the dihalosubstituted cyclohexyl group is...

[0056] In another preferred embodiment, the cycloheptyl group is...

[0057] In another preferred embodiment, the benzocycloheptenyl group is...

[0058] In another preferred embodiment, the substitution refers to the independent substitution of one or more (preferably 1, 2, 3 or 4) hydrogens on a group by a substituent.

[0059] In another preferred embodiment, the C6-C16 aryl group is a C6-C12 aryl group.

[0060] In another preferred embodiment, the 5-16-membered heteroaryl group is a 5-12-membered heteroaryl group.

[0061] As used in this article, For substitution sites.

[0062] In another preferred embodiment, X is independently -NR. x -, -O-, or -S-; where R x It can be hydrogen, C1-C6 alkyl, C6-C12 aryl, or 5-12 heteroaryl.

[0063] In another preferred embodiment, X is independently -NR. x -、-O-、or -S-;R x It can be hydrogen, methyl, propyl, or phenyl.

[0064] In another preferred embodiment, R a It is a C1-C6 alkyl group.

[0065] In another preferred embodiment, R a It is an ethyl group.

[0066] In another preferred embodiment, R b R c and R e Each is independently hydrogen or C1-C6 alkyl.

[0067] In another preferred embodiment, R b R c and Re Each is independently hydrogen or methyl.

[0068] In another preferred embodiment, R d It is a C1-C6 alkyl group.

[0069] In another preferred embodiment, R d It is a methyl group.

[0070] In another preferred embodiment, R 5 -CN, -C(O)OR a -C(O)NR b R c -N(R) e )C(O)R d Among them, R a It is a C1-C6 alkyl group; R b R c and R e Each is independently hydrogen or C1-C6 alkyl; R d It is a C1-C6 alkyl group.

[0071] In another preferred embodiment, R 5 -CN, -C(O)OR a -C(O)NR b R c -N(R) e )C(O)R d Among them, R a It is a C1-C4 alkyl group; R b R c and R e Each is independently hydrogen or C1-C4 alkyl; R d It is a C1-C4 alkyl group.

[0072] In another preferred embodiment, Y is independently -NH- or -S-.

[0073] In another preferred embodiment, R 6 It can be hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl.

[0074] In another preferred embodiment, R 6 It is hydrogen or ethyl.

[0075] In another preferred embodiment, the compound has one or more features selected from the group consisting of:

[0076] R 1 R 2 R 3 and R 4Each of these can be independently hydrogen, hydroxyl, amino, methoxy, monomethylnaphthyl, isoquinolinyl, quinolinyl, monohalonaphthyl, phenyl, naphthyl, cyclopentyl-O-, cyclohexyl-O-, anthraceneyl, halogen (such as bromine), phenylpyranyl, Cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, benzocyclopentyl, benzocycloheptenyl, dihalocyclohexyl, pyridyl, pyridyl-O-; or, Z 3 For CR 3 Z 4 For CR 4 R 3 and R 4 The linkage forms a benzene ring; or, Z 1 For CR 1 Z 2 For CR 2 R 1 and R 2 The linkage forms a benzene ring;

[0077] X is independently -NR x -、-O-、or -S-;R x It can be hydrogen, methyl, propyl, or phenyl.

[0078] R a It is a C1-C6 alkyl group;

[0079] R b R c and R e Each is independently hydrogen or a C1-C6 alkyl group;

[0080] R d It is a C1-C6 alkyl group;

[0081] R 5 -CN, -C(O)OR a -C(O)NR b R c -N(R) e )C(O)R d Among them, R a It is a C1-C4 alkyl group; R b R c and R e Each is independently hydrogen or C1-C4 alkyl; R d It is a C1-C4 alkyl group;

[0082] Y can be -NH- or -S- independently;

[0083] R 6 It can be hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl.

[0084] In another preferred embodiment, the compound is selected from the group consisting of:

[0085]

[0086]

[0087]

[0088] In a second aspect, the present invention provides a pharmaceutical composition comprising:

[0089] (a) A compound of Formula I as described in the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, or a diastereomer thereof, or a transisomer thereof, or a racemic mixture thereof, or a polymorph thereof, or a solvate thereof, or an isotopically labeled derivative thereof; and

[0090] (b) Pharmaceutically acceptable carriers.

[0091] In another preferred embodiment, the content of the compound represented by Formula I, or a pharmaceutically acceptable salt thereof, or its enantiomer, or its diastereomer, or its transisomer, or its racemic mixture, or its polymorph, or its solvate, or its isotopically labeled derivative, is 0.01-99.99 wt.%, preferably 0.1-99.9 wt.%, more preferably 1-99 wt.%, more preferably 5-95 wt.%, more preferably 10-90 wt.%, more preferably 20-80 wt.%, and most preferably 30-70 wt.%, based on the weight of the composition.

[0092] In another preferred embodiment, the pharmaceutical composition further comprises a drug for preventing and / or treating thrombosis.

[0093] In another preferred embodiment, the dosage form of the pharmaceutical composition is an oral preparation or a parenteral preparation (such as an injection or infusion).

[0094] In another preferred embodiment, the dosage form of the pharmaceutical composition is selected from the group consisting of: injections, capsules, tablets, pills, powders, granules, aerosols, suppositories, films, drop pills, and topical liniments.

[0095] In another preferred embodiment, the pharmaceutical composition is a controlled-release, sustained-release, or nano-formulation.

[0096] In a third aspect, the present invention provides the use of a compound of Formula I as described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, or a diastereomer thereof, or a transtransisomer thereof, or a racemic mixture thereof, or a polymorph thereof, or a solvate thereof, or an isotopically labeled derivative thereof, for the preparation of a composition or formulation, said composition or formulation for use in one or more of the following: (1) selectively inhibiting outward-inward signal transduction mediated by the interaction of integrin β3 with Src kinase; (2) preventing and / or treating diseases associated with outward-inward signal transduction mediated by the interaction of integrin β3 with Src kinase; (3) preventing and / or treating thrombosis.

[0097] In another preferred embodiment, the inhibition of integrin β3's interaction with Src kinase includes inhibiting the interaction between integrin β3 and the SH3 domain of Src kinase.

[0098] In another preferred embodiment, the selective inhibition of outward-to-inward signal transduction mediated by the interaction between integrin β3 and Src kinase means selectively inhibiting outward-to-inward signal transduction mediated by the interaction between integrin β3 and Src kinase without affecting inward-to-outward signal transduction.

[0099] In another preferred embodiment, the interaction between integrin β3 and Src kinase refers to the interaction between integrin β3 and c-Src kinase in platelets.

[0100] In another preferred embodiment, the integrin β3 is β3 of integrin αIIbβ3 and / or integrin αvβ3.

[0101] In another preferred embodiment, the diseases associated with outward-to-inward signal transduction mediated by the interaction of integrin β3 with Src kinase are selected from the group consisting of thrombosis, tumors, osteoporosis, endothelial cell-mediated angiogenesis, or combinations thereof.

[0102] In another preferred embodiment, the prevention and / or treatment of thrombosis achieves antithrombotic effects without affecting or improving bleeding. In yet another preferred embodiment, the improvement of bleeding includes inhibiting bleeding, not increasing the risk of bleeding, reducing the risk of bleeding, not causing bleeding side effects, and / or not affecting hemostatic function.

[0103] In another preferred embodiment, the hemostatic function includes platelet hemostatic function.

[0104] In another preferred embodiment, the hemostasis includes physiological hemostasis.

[0105] In another preferred embodiment, the thrombus is a cardiovascular or cerebrovascular disease thrombus, which is selected from the group consisting of: myocardial infarction thrombus, cerebral infarction thrombus, ischemic stroke, atherosclerotic thrombus, or a combination thereof.

[0106] In another preferred embodiment, the prevention and / or treatment of thrombosis includes one or more methods selected from the group consisting of:

[0107] (3-1) Inhibits the platelet stretching function on solid fibrinogen;

[0108] (3-2) Inhibits platelet aggregation, adhesion and / or stretching;

[0109] (3-3) Inhibits fibrin clot retraction;

[0110] (3-3) It does not affect the binding function of platelets to free fibrinogen.

[0111] In another preferred embodiment, the inhibition of platelet aggregation includes inhibiting one-phase or two-phase platelet aggregation.

[0112] In another preferred embodiment, the composition or formulation is a pharmaceutical composition or formulation.

[0113] In another preferred embodiment, the composition or formulation further includes a pharmaceutically acceptable carrier.

[0114] In another preferred embodiment, the composition or formulation further includes other antithrombotic drugs, other antitumor drugs, other osteoporosis treatment drugs, and / or other antiangiogenic drugs.

[0115] In another preferred embodiment, the dosage form of the composition or preparation is a tablet, injection, infusion, ointment, gel, solution, microsphere, or film.

[0116] A fourth aspect of the present invention provides a method for preventing and / or treating thrombosis, the method comprising the steps of:

[0117] Applying a compound of Formula I as described in the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, or a diastereomer thereof, or a transisomer thereof, or a racemic mixture thereof, or a polymorph thereof, or a solvate thereof, or an isotopically labeled derivative thereof, to a desired object to prevent and / or treat thrombosis.

[0118] In another preferred embodiment, the object is a human or non-human mammal (rodents, rabbits, monkeys, livestock, dogs, cats, etc.).

[0119] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0120] Figure 1 The results are from surface plasmon resonance (SPR) experiments on the compound.

[0121] Figure 2 The compound inhibits platelet stretching in a concentration-dependent manner. Detailed Implementation

[0122] Through long-term and in-depth research and extensive screening, the inventors unexpectedly discovered that a compound represented by Formula I can specifically bind to the SH3 domain protein of Src kinase, interfering with the binding of integrin αIIbβ3 to Src kinase. This selectively inhibits outward-to-inward signal transduction (related to thrombosis) without affecting inward-to-outward signal transduction (related to hemostasis). Therefore, the compound of this invention, while having antithrombotic effects, does not affect normal physiological hemostasis, avoiding bleeding side effects. Based on this, the inventors completed this invention.

[0123] the term

[0124] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0125] As used herein, the terms “comprising,” “including,” and “containing” are used interchangeably and include not only open-ended definitions but also semi-closed and closed definitions. In other words, the terms include “consisting of” and “substantially consisting of”.

[0126] As used in this article, "Src kinase" is a non-receptor tyrosine kinase.

[0127] As used in this article, “SH3”, “SH3 domain”, “SH3 domain protein”, and “SH3 protein” can be used interchangeably.

[0128] It should be understood that those skilled in the art can select the substituents and substitution patterns on the compounds of the present invention to produce chemically stable compounds that can be synthesized using techniques known in the art and the methods described below. If substituted by more than one (or more) substituent groups, it should be understood that these groups can be on the same carbon or on different carbons, as long as a stable structure is produced.

[0129] As used herein, the term “substitution” or “substituted” refers to a compound in which a hydrogen atom on a group is replaced by a non-hydrogen group, but the substitution must satisfy the valence requirement and the substitution produces a chemically stable compound, i.e., a compound that does not spontaneously undergo transformations such as cyclization or elimination.

[0130] As used in this article, "R1", "R1", and "R" are... 1 The meanings of "" are the same and they can be used interchangeably. Other similar definitions have the same meaning.

[0131] As used in this article, Indicates the linking site of a functional group.

[0132] As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of straight and branched groups. When an alkyl group is preceded by a carbon number qualifier (e.g., C1-C6 alkyl), it means that the alkyl group contains 1 to 6 carbon atoms. For example, C1-C6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms, and representative examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

[0133] As used herein, the term "alkylene" refers to a group formed by removing one hydrogen atom from an alkyl group, where the alkyl group is as defined above. Representative examples of C1-C6 alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, or similar groups.

[0134] As used herein, the term "alkenyl" refers to a straight-chain or branched carbon chain group having at least one carbon-carbon double bond. When an alkenyl group is preceded by a carbon number qualifier (e.g., C2-C6), it indicates that the alkenyl group contains 2-6 carbon atoms. For example, C2-C6 alkenyl refers to alkenyl groups containing 2-6 carbon atoms, including vinyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or similar groups.

[0135] As used herein, the term "alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group can be straight-chain or branched, or a combination thereof. When the alkynyl group is preceded by a carbon number qualifier (e.g., C2-C6 alkynyl), it indicates that the alkynyl group contains 2-6 carbon atoms. For example, the term "C2-C6 alkynyl" refers to a straight-chain or branched alkynyl group having 2-6 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups.

[0136] In this invention, the term "halogen" refers to F, Cl, Br, or I.

[0137] In this invention, the term "halogenated" refers to being replaced by a halogen.

[0138] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more (preferably 1, 2, 3 or 4) hydrogen atoms are replaced by a halogen, the alkyl group and the halogen being as defined above. When an alkyl group is preceded by a carbon number limit (e.g., C1-C6 haloalkyl), it means that the alkyl group contains 1 to 6 carbon atoms. For example, C1-C6 haloalkyl refers to a haloalkyl group containing 1 to 6 carbon atoms. Representative examples include, but are not limited to, -CF3, -CHF2, monofluoroisopropyl, difluorobutyl, or similar groups.

[0139] As used herein, the term "cycloalkyl" refers to a cyclic group having a saturated monocyclic, bicyclic, or polycyclic (fused, bridged, or spirocyclic) ring. When a cycloalkyl group is preceded by a carbon number limitation (e.g., C3-C12), it means that the cycloalkyl group has 3-12 ring carbon atoms. In some preferred embodiments, the term "C3-C8 cycloalkyl" refers to a saturated monocyclic or bicyclic alkyl group having 3-8 ring carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar groups. "Spirocycloalkyl" refers to a bicyclic or polycyclic group in which monocyclic rings share a carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. "Fused cycloalkyl" refers to an all-carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. "Bridged cycloalkyl" refers to a polycyclic aromatic hydrocarbon group in which any two rings share two non-directly bonded carbon atoms. These groups may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. The cycloalkane ring of the cycloalkyl group may be fused to an aromatic ring, but the bonding site must be located on the cycloalkane ring, not on the aromatic ring.

[0140] The following are representative examples of cycloalkyl groups, including but not limited to:

[0141]

[0142] As used herein, the term "cycloalkenyl" refers to a cycloalkyl group having one or more double bonds on its cycloalkane ring, but the double bonds cannot form a ring with a conjugated π-electron system, and the linkage site is located on a carbon atom of one of the double bonds. The cycloalkyl group is as defined above, and the cycloalkenyl ring can be fused to an aromatic ring, but the linkage site cannot be on the aromatic ring.

[0143] As used herein, the term "halocycloalkyl" refers to a cycloalkyl group in which one or more (preferably 1, 2, 3, or 4) hydrogen atoms are replaced by a halogen, the cycloalkyl group and the halogen being as defined above. When a carbon number limitation is specified before the cycloalkyl group (e.g., C3-C8 haloalkyl), it means that the cycloalkyl group contains 3-8 cyclic carbon atoms. For example, C3-C8 haloalkyl refers to a halocycloalkyl group containing 3-6 carbon atoms. Representative examples include, but are not limited to, monofluorocyclopropyl, monochlorocyclobutyl, monofluorocyclopentyl, difluorocycloheptyl, or similar groups.

[0144] The term "alkoxy" refers to an RO- group, where R is an alkyl group, and the alkyl group is as defined above herein. When the alkoxy group is preceded by a carbon number qualifier, such as C1-C4 alkoxy groups, it means that the alkyl group in the alkoxy group has 1-4 carbon atoms. Representative examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, or similar groups.

[0145] As used herein, the term "haloalkoxy" refers to a haloalkyl group -O-, as defined above. For example, C1-C6 haloalkoxy refers to a haloalkoxy group containing 1-6 carbon atoms, and representative examples include, but are not limited to, monofluoromethoxy, monofluoroethoxy, difluorobutoxy, or similar groups.

[0146] The term "heterocycle," also known as a "heterocyclic alkane," refers to a fully saturated or partially unsaturated ring (including, but not limited to, 3-7 membered monocyclic rings, 7-11 membered bicyclic rings, or 8-16 membered tricyclic systems), in which at least one heteroatom is present in a ring containing at least one carbon atom. When a heterocycle is preceded by a number, it refers to the number of ring atoms in the heterocycle; for example, a 3-16 membered heterocycle refers to a heterocycle with 3-16 ring atoms. Each heterocycle containing heteroatoms may have one or more (e.g., 1, 2, 3, or 4) heteroatoms, each independently selected from nitrogen, oxygen, or sulfur atoms, wherein the nitrogen or sulfur atom can be oxidized or quaternized. Heterocycles can be attached to any heteroatom or carbon atom residue in a ring or ring system molecule. Typical monocyclic heterocyclic alkanes include, but are not limited to, azathiobutane rings, oxacyclobutane rings, imidazoline rings, imidazoline rings, tetrahydrofuran rings, piperidine rings, piperazine rings, 2-oxopiperazine rings, 2-oxopiperidine rings, 4-piperidinone rings, tetrahydropyran rings, morpholine rings, thiomorpholine rings, thiomorpholine sulfoxide rings, thiomorpholine sulfone rings, 1,3-dioxane rings, and tetrahydro-1,1-dioxothiophene rings. Polycyclic heterocyclic alkanes include spirocyclic, fused, and bridged heterocyclic rings; the spirocyclic, fused, and bridged heterocyclic rings involved may optionally be connected to other rings via single bonds, or may be further cyclically linked to other cycloalkane rings or heterocyclic rings via any two or more atoms on the ring.

[0147] The term "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic ring (i.e., a ring sharing adjacent carbon atom pairs) with a conjugated π-electron system. It is an aromatic cyclic hydrocarbon. When the aromatic ring is preceded by a carbon number limit, such as a C6-C12 aromatic ring, it means that the aromatic ring has 6-12 ring carbon atoms, such as benzene and naphthalene rings. The aromatic ring can be fused to other rings (including saturated or unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur. The point of connection to the parent ring must be on a carbon atom of a ring with a conjugated π-electron system. Representative examples of aromatic rings are as follows, including but not limited to: benzene rings, naphthalene rings, anthracene rings, or similar rings.

[0148] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon pairs) group with a conjugated π-electron system. It is an aromatic cyclic hydrocarbon compound group. When the aryl group is preceded by a carbon number limit, such as C6-C12 aryl, it means that the aryl group has 6-12 ring carbon atoms, for example, phenyl and naphthyl. The aryl ring can be fused to other cyclic groups (including saturated or unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur. The point of attachment to the parent group must be on a carbon atom of a ring with a conjugated π-electron system. The following are representative examples of aryl groups, including but not limited to:

[0149]

[0150] The term "heteroaryl" refers to an aromatic heterocyclic group having one to several (preferably 1, 2, 3, or 4) heteroatoms. These heteroatoms can be monocyclic (monocyclic) or polycyclic (bicyclic, tricyclic, or polycyclic) fused together or covalently linked. Each heterocycle containing a heteroatom may have one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen. When a member is specified before "heteroaryl," it refers to the number of ring atoms in the heteroaryl group. For example, a 5-12 member heteroaryl refers to a heteroaryl group having 5-12 ring atoms. Representative examples include, but are not limited to: pyrrole, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, and tetrazolyl. The heteroaromatic ring can be fused to other cyclic groups (including saturated or unsaturated rings), and the point of connection to the parent group must be on the heteroaromatic ring.

[0151] As used herein, the term "amino" means -NH2, either alone or as part of other substituents.

[0152] As used herein, the term "nitro" means -NO2, either alone or as part of other substituents.

[0153] As used herein, the term "hydroxyl" means -OH, either alone or as part of other substituents.

[0154] In this specification, all substituents should be interpreted as unsubstituted unless explicitly described herein as "substituted". The term "substituted" means that one or more hydrogen atoms on a particular group are replaced by a particular substituent. The particular substituent is the substituent described accordingly above, or the substituent appearing in the various examples. Preferably, the substitution refers to the substitution of one or more (preferably 1, 2, 3, 4, or 5) hydrogen atoms on a ring or group by a substituent selected from the group consisting of: C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 haloalkyl, C3-C8 halocycloalkyl, halogen, nitro, -CN, hydroxyl, mercapto, amino, C1-C4 carboxyl, C2-C4 ester, C2-C4 amide, C1-C8 alkoxy, C1-C8 alkylthio, C1-C8 haloalkoxy, C1-C8 haloalkylthio, C6-C12 aryl, 5-10 heteroaryl, 5-10 heterocyclic alkyl. Unless otherwise specified, any substituted group may have a substituent selected from a particular group at any substituted site of the group, and the substituents may be the same or different at each position.

[0155] In this invention, the term "prevention" refers to a method of preventing the onset of a disease and / or its accompanying symptoms or protecting a subject from acquiring a disease. As used herein, "prevention" also includes delaying the onset of a disease and / or its accompanying symptoms and reducing the subject's risk of contracting the disease.

[0156] The “treatment” described in this invention includes delaying and halting disease progression, or eliminating disease, and does not require 100% inhibition, eradication, or reversal. In some embodiments, compared to levels observed in the absence of the compositions, packaging, food or health supplement packaging, or active ingredient combinations described in this invention, the compositions or pharmaceutical compositions of this invention alleviate, inhibit, and / or reverse related diseases (such as tumors) and their complications by, for example, at least about 10%, at least about 30%, at least about 50%, or at least about 80%.

[0157] Active ingredients

[0158] As used herein, "compound of the present invention," "compound of Formula I," "compound of Formula I," "compound of Formula I of the present invention," or "compound of Formula I of the present invention" are used interchangeably to refer to a compound having Formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, or a diastereomer thereof, or a transisomer thereof, or a racemic mixture thereof, or a polymorph thereof, or a solvate thereof, or an isotopically labeled derivative thereof.

[0159]

[0160] The definitions of each group are as described in the first aspect of this invention above. It should be understood that this term also includes mixtures of the above-described components.

[0161] In another preferred embodiment, the compound is preferably the compound prepared in the examples.

[0162] The term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are salts formed by the compounds of the present invention with acids, including (but not limited to): inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid. A preferred class of salts are metal salts formed by the compounds of the present invention with bases, including (but not limited to): inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and sodium phosphate; and organic bases such as ammonia, triethylamine, and diethylamine.

[0163] The compounds of Formula I described in this invention can be converted into their pharmaceutically acceptable salts by conventional methods. For example, a solution of the corresponding acid can be added to a solution of the above-mentioned compound, and after complete salt formation, the solvent can be removed to obtain the corresponding salt of the compound described in this invention.

[0164] Preparation method

[0165] The preparation methods of the compounds represented by Formula I of the present invention are described in more detail below, but these specific methods do not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0166] Typically, the preparation process of the compounds of the present invention is as follows, wherein the raw materials and reagents used can be purchased commercially unless otherwise specified.

[0167] By way of example, the compound represented by Formula I of the present invention is prepared as follows:

[0168] Overall plan:

[0169]

[0170] The method for preparing compounds of general formula IA is given in the scheme. Among them, Z... 1 Z 2 Z3 Z 4 X, Y and R 5 The definition is as described above.

[0171] Synthesis I-2: The substrate (Formula I-1), a brominating agent, and an initiator are reacted in an organic solvent. Examples of the brominating agent include, but are not limited to, elemental bromine, inorganic bromides (hydrobromic acid, sodium bromide, etc.), N-bromosuccinimide (NBS), perbromopyridine hydrobromide (PHP), dibromohydantoin (DBDMH), and tetrabromocycloketone (TBCO), with NBS being preferred. Examples of the initiator include, but are not limited to, organic peroxides such as cyclohexanone peroxide, benzoyl peroxide (BPO), and tert-butyl hydroperoxide, and azo initiators such as azobisisobutyronitrile and azobisisoheptanenitrile, with BPO being preferred. Examples of organic solvents include acetonitrile, chloroform, and carbon tetrachloride, with chloroform being preferred. Examples of reaction temperatures include from room temperature to reflux, with reflux being preferred.

[0172] Synthesis of I-3: I-2 is reacted with sodium azide in an organic solvent. The organic solvent is, for example, but not limited to, N,N-dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile, dioxane, etc., preferably N,N-dimethylformamide (DMF). Examples of reaction temperatures include from -20°C to reflux, preferably room temperature.

[0173] Synthesis of I-4: I-4 is prepared from I-3 using conventional methods well-known in the art. Depending on the specific substrate, a Pd / C catalytic hydrogenation reaction or a staudinger reaction is preferred. The organic solvent is, for example, but not limited to, N,N-dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile, dioxane, methanol, and ethanol, preferably THF. Examples of reaction temperatures range from room temperature to reflux, preferably room temperature or reflux temperature.

[0174] Synthesis IA: The substrate (Formula I-4), 1H-pyrazole-1-methylimidazolium hydrochloride (when Y is defined as NH), is reacted with a base in an organic solvent. Examples of the base include, but are not limited to, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydrogen hydride (NaH), triethylamine, diisopropylethylamine, pyridine, 1,5-diazabicyclo[5.4.0]undec-5-ene, 4-dimethylaminopyridine (DMAP), preferably potassium carbonate; the organic solvent includes, but is not limited to, N,N-dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile, dioxane, dichloromethane (DCM), dichloroethane (DCE), chloroform, methanol, ethanol, etc., preferably acetonitrile. Examples of reaction temperatures include from room temperature to reflux, preferably room temperature. Alternatively, the substrate (Formula I-4), thiourea (when Y is defined as S), can be placed in an organic solvent and heated for reaction. The organic solvent may include, but is not limited to, methanol, ethanol, N,N-dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile, dioxane, dichloromethane (DCM), dichloroethane (DCE), chloroform, etc., with ethanol being preferred. Examples of reaction temperatures include those ranging from room temperature to reflux, with reflux being preferred.

[0175] Synthesis 1-1 has the following route:

[0176] Route A:

[0177]

[0178] Route A provides a method for preparing compounds of general formula 1-2-1.

[0179] Close the indole ring, where Z 1 Z 2 Z 3 Z 4 and R 5 The definition is consistent with the previous text.

[0180] Synthesis of 1-1-A: The substrate, CuI, ethyl acetoacetate, and tetrazolium acetic acid are placed in an organic solvent with a base. Examples of the base include, but are not limited to, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydrogen hydride (NaH), triethylamine, diisopropylethylamine, pyridine, 1,5-diazabicyclo[5.4.0]undec-5-ene, 4-dimethylaminopyridine (DMAP), preferably potassium carbonate; the organic solvent includes, but is not limited to, dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile, dioxane, etc., preferably DMSO. Examples of reaction temperatures include from 50 degrees to reflux, preferably 100 degrees.

[0181] Route C:

[0182]

[0183] Route C provides a method for preparing compounds of general formula 1-2-3.

[0184] Methylation---Alkylation

[0185] Among them, Z 1 Z 2 Z 3 Z 4 and R 5 The definition is consistent with the previous text.

[0186] Synthesis of A-1: ​​At -60°C, the substrate and base are placed in an organic solvent, and iodomethane is added dropwise. Examples of the base include, but are not limited to, lithium diisopropylamino (LDA), n-butyllithium (n-BuLi), etc., with LDA preferred; the organic solvent includes, but is not limited to, tetrahydrofuran (THF), acetonitrile, dichloromethane (DCM), etc., with THF preferred. Examples of reaction temperatures include from -60°C to reflux, preferably -60°C, followed by stirring at room temperature.

[0187] Synthesis of 1-1-C: A-1, AlCl3, and acetyl chloride are placed in an organic solvent. The organic solvent may be, for example but not limited to, acetonitrile, dichloromethane (DCM), dichloroethane (DCE), chloroform, etc., with DCM being preferred. Examples of reaction temperatures include from 0 degrees to reflux, with 0 degrees being preferred.

[0188] The synthesis routes 1-4 are as follows:

[0189] Route D:

[0190]

[0191] The method for preparing compound of general formula 1-4-1 is given in route D.

[0192] Closing the indole ring --- methylation --- deprotection

[0193] The definitions of Z1, Z2, Z3, Z4 and R5 are consistent with those in the previous text.

[0194] Synthesis of D-1: The substrate, ethyl 4-(tert-butoxycarbonylamino)-3-oxobutyrate, tetrazolium acetic acid, cuprous iodide, and a base are placed in an organic solvent. Examples of the base include, but are not limited to, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydrogen hydride (NaH), triethylamine, diisopropylethylamine, pyridine, 1,5-diazabicyclo[5.4.0]undecyl-5-ene, 4-dimethylaminopyridine (DMAP), preferably potassium carbonate; the organic solvent includes, but is not limited to, dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile, dioxane, etc., preferably DMSO. Examples of reaction temperatures include from 50 degrees to reflux, preferably 100 degrees.

[0195] Synthesis of D-2: D-1, the methylating agent, and a base are placed in an organic solvent. Examples of the methylating agent include, but are not limited to, iodomethane, dimethyl sulfate, diazomethane, etc., with iodomethane being preferred. Examples of the base include, but are not limited to, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydrogen hydride (NaH), triethylamine, diisopropylethylamine, pyridine, 1,5-diazabicyclo[5.4.0]undec-5-ene, 4-dimethylaminopyridine (DMAP), with cesium carbonate being preferred; the organic solvent includes, but is not limited to, dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile, dioxane, etc., with DMSO being preferred. Examples of reaction temperatures include from 0 degrees Celsius to reflux, with room temperature being preferred.

[0196] Synthesis of 1-4-D: Using 1-3 as a substrate, it is prepared according to conventional deprotection methods well known in the art. The preferred deprotection agent is trifluoroacetic acid (TFA), and the preferred solvent is DCM.

[0197] The optimal reaction conditions and reaction time for each individual step can be varied depending on the specific reactants used and the substituents present in all reactants. Unless otherwise specified, solvents, temperatures, and other reaction conditions can be readily selected by those skilled in the art. Specific steps are provided in the Synthesis Examples section. The reaction can be further processed in a conventional manner, for example by removing the solvent from the residue and further purifying it according to methods generally known in the art, such as, but not limited to, crystallization, distillation, extraction, grinding, and chromatography. Unless otherwise stated, the starting materials and reactants are commercially available or can be prepared by those skilled in the art from commercially available materials using methods described in the chemical literature.

[0198] Routine experiments, including appropriate adjustment of reaction conditions, reactants and sequence in synthetic routes, protection of arbitrary chemical functional groups (which may not be adapted to reaction conditions), and deprotection at appropriate points in the reaction sequence of the method, are all included within the scope of this invention. Appropriate protecting groups and methods for protecting and deprotecting different substituents using such appropriate protecting groups are well known to those skilled in the art; examples of which can be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd Edition), John Wiley & Sons, NY (1999), which are incorporated herein by reference in their entirety. The synthesis of the compounds of this invention can be carried out by methods similar to those described in the synthetic schemes described above and in the specific examples.

[0199] If the starting materials are not commercially available, they may be prepared by steps selected from: standard organic chemistry techniques, techniques similar to those used to synthesize known structural analogs, or techniques similar to those described in the foregoing embodiments or synthesis examples. When an optically active form of the compounds of the present invention is desired, it may be obtained by performing one of the steps described herein using optically active starting materials (e.g., asymmetric induction via appropriate reaction steps), or by resolving a mixture of stereoisomers of the compound or intermediates using standard steps (e.g., chromatographic separation, recrystallization, or enzymatic resolution).

[0200] Similarly, when pure geometric isomers of the compounds of the present invention are required, they can be obtained by performing one of the above steps using pure geometric isomers as starting materials, or by using standard steps, such as chromatographic separation to resolve mixtures of geometric isomers of the compounds or intermediates.

[0201] Src and c-Src

[0202] Src, an oncogene protein, was initially discovered in Rous sarcoma retrovirus, and subsequently, v-Src, a highly conserved and homologous variant of it, was found to be ubiquitous in cells.

[0203] The Src kinase family consists of proteins with protein tyrosine kinase (PTK) activity, with c-Src being an important component of the Src kinase family.

[0204] use

[0205] The present invention provides a use of the compound described herein for (1) selectively inhibiting outward-inward signal transduction mediated by the interaction between integrin β3 and Src kinase; (2) preventing and / or treating diseases related to outward-inward signal transduction mediated by the interaction between integrin β3 and Src kinase; and / or (3) preventing and / or treating thrombosis.

[0206] In another preferred embodiment, the inhibition of integrin β3's interaction with Src kinase includes inhibiting the interaction between integrin β3 and the SH3 domain of Src kinase.

[0207] In another preferred embodiment, the selective inhibition of outward-to-inward signal transduction mediated by the interaction between integrin β3 and Src kinase means selectively inhibiting outward-to-inward signal transduction mediated by the interaction between integrin β3 and Src kinase without affecting inward-to-outward signal transduction.

[0208] In another preferred embodiment, the interaction between integrin β3 and Src kinase refers to the interaction between integrin β3 and c-Src kinase in platelets.

[0209] In another preferred embodiment, the integrin β3 is β3 of integrin αIIbβ3 and / or integrin αvβ3.

[0210] In another preferred embodiment, the diseases associated with outward-to-inward signal transduction mediated by the interaction of integrin β3 with Src kinase include (but are not limited to): thrombosis, tumors, osteoporosis, endothelial cell-mediated angiogenesis, or combinations thereof.

[0211] In another preferred embodiment, the prevention and / or treatment of thrombosis includes antithrombotic therapy and improvement of bleeding.

[0212] In another preferred embodiment, the improvement of bleeding includes inhibiting bleeding, not increasing the risk of bleeding, reducing the risk of bleeding, not causing bleeding side effects, and / or not affecting hemostatic function.

[0213] In another preferred embodiment, the hemostatic function includes platelet hemostatic function.

[0214] In another preferred embodiment, the hemostasis includes physiological hemostasis.

[0215] In another preferred embodiment, the thrombus is a cardiovascular or cerebrovascular disease thrombus, which is selected from the group consisting of: myocardial infarction thrombus, cerebral infarction thrombus, ischemic stroke, atherosclerotic thrombus, or a combination thereof.

[0216] In another preferred embodiment, the prevention and / or treatment of thrombosis includes one or more methods selected from the group consisting of:

[0217] (3-1) Inhibits the platelet stretching function on solid fibrinogen;

[0218] (3-2) Inhibits platelet aggregation, adhesion and / or stretching;

[0219] (3-3) Inhibits fibrin clot retraction;

[0220] (3-3) It does not affect the binding function of platelets to free fibrinogen.

[0221] Compositions or formulations, combinations of active ingredients, and packaging and administration methods

[0222] The present invention also provides a composition comprising a compound of formula I of the present invention.

[0223] The compositions described in this invention are preferably pharmaceutical compositions. The compositions described in this invention may include pharmaceutically acceptable carriers.

[0224] As used herein, "pharmaceutically acceptable carrier" refers to one or more compatible solid, semi-solid, liquid, or gel fillers that are suitable for human or animal use and must have sufficient purity and sufficiently low toxicity. "Compatibility" refers to the ability of the components in a pharmaceutical composition and the active ingredient of the drug, as well as the interactions between them, to not significantly reduce the efficacy of the drug.

[0225] It should be understood that, in this invention, there are no particular limitations on the pharmaceutically acceptable carriers used. Materials commonly used in the art can be selected, or they can be prepared using conventional methods or purchased from the market. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting agents (such as sodium dodecyl sulfate), buffers, chelating agents, thickeners, pH adjusters, transdermal penetration enhancers, colorants, flavoring agents, stabilizers, antioxidants, preservatives, antibacterial agents, and pyrogen-free water, etc.

[0226] In this invention, the dosage forms of the compositions and formulations include, but are not limited to, oral formulations, injectable formulations, and topical formulations.

[0227] Representatively, the dosage forms of compounds and preparations include, but are not limited to: tablets, injections, infusions, ointments, gels, solutions, microspheres, and films.

[0228] Typically, the injectable is an intratumoral injectable.

[0229] Pharmaceutical formulations should be matched with the route of administration, preferably oral or injectable (e.g., intratumoral injection). When used, a therapeutically effective amount of the drug is administered to the desired subject (e.g., human or non-human mammal). As used herein, the term "therapeutically effective amount" refers to an amount that is functionally or activityably produced in humans and / or animals and is acceptable to humans and / or animals. Those skilled in the art will understand that the "therapeutically effective amount" can vary depending on the form of the pharmaceutical composition, the route of administration, the excipients used, the severity of the disease, and whether it is used in combination with other drugs.

[0230] In one administration method, the safe and effective daily dose of the first active ingredient is generally at least about 0.1 mg, and in most cases does not exceed about 2500 mg. Preferably, this dose is 1 mg to 500 mg; the safe and effective dose of the second active ingredient is generally at least about 0.01 mg, and in most cases does not exceed 2500 mg. Preferably, this dose range is 0.1 mg to 2500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of a skilled physician's expertise.

[0231] The main advantages of this invention include

[0232] 1. This invention unexpectedly developed a compound represented by Formula I. The compound of this invention can specifically bind to the SH3 domain protein of Src kinase, interfering with the binding of integrin αIIbβ3 to Src kinase, thereby selectively inhibiting outward-to-inward signal transduction without affecting inward-to-outward signal transduction. Thus, the compound of this invention can have antithrombotic effects without affecting normal physiological hemostasis, avoiding the occurrence of bleeding side effects, and can become a new generation of effective drugs for the prevention and treatment of thrombosis-related cardiovascular and cerebrovascular diseases.

[0233] 2. The compounds of this invention are small molecule compounds, which have the advantages of good drug-like properties and low side effects.

[0234] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0235] Example

[0236] Example 1: Preparation of compound SYY-C001

[0237]

[0238] Step 1:

[0239] Under mechanical stirring, 2-methoxy-3-chloro-5-nitropyridine (37.0 g, 196.2 mmol) was added to ethanol (500 mL), followed by iron powder (40.0 g, 716.2 mmol), ammonium chloride (40.0 g, 747.8 mmol), and water (100 mL) at room temperature. The mixture was heated to 90 °C and reacted for 5 hours. TLC showed that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated to approximately 150 mL. Ethyl acetate was added, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography to give a gray solid C001-1 (30.5 g, 98% yield).

[0240] Step 2:

[0241] C001-1 (30.5 g, 192.3 mmol) was dissolved in acetonitrile (400 ml), cooled to 0 °C, and NIS (47.1 g, 209.4 mmol, dissolved in 300 ml acetonitrile) was added dropwise, maintaining the temperature at 0–2 °C, and the addition was completed over 1 hour. TLC monitoring showed that a small amount of the starting material remained unreacted. The reaction mixture was then extracted with saturated sodium bicarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give a brown solid C001-2 (38.0 g, 69% yield).

[0242] Step 3:

[0243] Add 1,4-dioxane / triethylamine (640 ml / 160 ml) to a 2.0 L three-necked flask, bubble under nitrogen for 30 minutes, then add substrate C001-2 (38.0 g, 133.6 mmol), Pd(PPh3)2Cl2 (9.8 g, 13.36 mmol), CuI (5.1 g, 26.78 mmol), and TBAF.3H2O (63.1 g, 200.0 mmol) at room temperature. Purge with nitrogen three times, then add 1-(trimethylsilyl)propyne (20 ml, 133.6 mmol), heat to 80 °C and react for 2 hours. Add 1-(trimethylsilyl)propyne (20 ml, 133.6 mmol) and continue reacting at 80 °C overnight. Monitor by TLC (after the starting material has reacted completely). The reaction solution was concentrated, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give a dark brown solid C001-3 (30.5 g).

[0244] Step 4:

[0245] Potassium tert-butoxide (52.2 g, 465.2 mmol) was dissolved in dry DMF (400 mL). A crude C001-3 solution (30.5 g, 155.1 mmol) in DMF (200 mL) was added dropwise at room temperature. After the addition was complete, the mixture was stirred overnight at room temperature, and the reaction was monitored by TLC until complete. The reaction solution was extracted with water and ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give a brownish-yellow solid C001-4 (20.0 g, two-step yield 76%).

[0246] Step 5:

[0247] C001-4 (5.0 g, 25.43 mmol) was dissolved in 20 mL of dry DMF. Under nitrogen atmosphere, the mixture was cooled to approximately 0 °C, and sodium hydride solid (915 mg, 38.13 mmol) was added in portions. After the addition was complete, the mixture was allowed to return to room temperature and react for half an hour. Then, it was cooled to approximately 0 °C again, and a solution of 7.2 g (50.72 mmol) in DMF (5 mL) was added dropwise. After the addition was complete, the mixture was allowed to react at 0 °C for another hour. TLC analysis showed that the reaction proceeds were complete. The reaction solution was quenched with ice water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain a yellow solid C001-5 (4.5 g, 83% yield).

[0248] Step 6:

[0249] C001-5 (4.0 g, 18.99 mmol) was dispersed in acetonitrile (40 mL) and cooled to approximately 0 °C under nitrogen protection. NBS (3.4 g, 19.10 mmol) was added in portions. After the addition was complete, the reaction was continued at 0 °C for another half hour. The reaction mixture was monitored by TLC to confirm complete reaction of the starting material. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain a pale yellow solid C001-6 (4.0 g, yield 73%).

[0250] Step 7:

[0251] C001-6 (1.08 g, 3.73 mmol) was dissolved in tetrahydrofuran (15 mL). Under nitrogen protection, the solution was cooled to -70 °C, and n-butyllithium solution (2.2 mL, 5.50 mmol, 2.5 M) was added dropwise over approximately half an hour. Ethyl cyanoformate (554 mg, 5.59 mmol) was then added, and the reaction was continued for another half hour. TLC was used to confirm the completeness of the reaction. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain a white solid C001-7 (490 mg, 50% yield).

[0252] Step 8:

[0253] C001-7 (490 mg, 1.73 mmol) and NBS (308 mg, 1.73 mmol) were dissolved in carbon tetrachloride (10 mL), and BPO (59 mg, 0.17 mmol) was added at room temperature. The mixture was heated to 80 °C and reacted for 2 h. The reaction was confirmed by TLC to be complete. The reaction solution was cooled to room temperature and purified by silica gel column chromatography to give an off-white solid C001-8 (350 mg, yield 56%).

[0254] Step 9:

[0255] C001-8 (170 mg, 0.47 mmol) and sodium azide (34 mg, 0.52 mmol) were heated to 60 °C and reacted for 3 hours in DMF (3 mL). The reaction mixture was monitored by TLC to ensure complete reaction of the starting materials. The reaction solution was cooled to room temperature, water was added, and the mixture was filtered to obtain a white solid C001-9, which was directly added to the next step of the reaction.

[0256] Step 10:

[0257] Crude C001-9 was dissolved in tetrahydrofuran (5 mL) and water (1 mL). Triphenylphosphine (325 mg, 1.24 mmol) was added at room temperature. The reaction mixture was heated to 60 °C and reacted for 3 hours. The reaction was confirmed to be complete by LC-MS. The reaction mixture was concentrated, and the crude product was purified by silica gel column chromatography to obtain a white solid C001-10 (80 mg, 57% yield in two steps). LC-MS: m / z = 298.1 [M+H] + .

[0258] Step 11:

[0259] C001-10 (80 mg, 0.27 mmol) was dissolved in methanol (3 mL) and ethyl acetate (3 mL). Palladium hydroxide (80 mg) was added at room temperature. After three gas purgings, the mixture was heated to 60 °C and reacted for 2 hours. TLC analysis showed the reaction proceeded completely. The reaction solution was cooled to room temperature, filtered through a diatomaceous earth filter, and the filtrate was concentrated to give a white solid, C001-11 (45 mg). LCMS: m / z = 264.2 [M+H] + .

[0260] Step 12:

[0261] C001-11 (45 mg, 0.17 mmol) and pyrazole formamidin hydrochloride (38 mg, 0.26 mmol) were dispersed in acetonitrile (3 mL), and DIPEA (88 mg, 0.68 mmol) was added. The mixture was reacted at room temperature for 2 days. TLC analysis showed that a small amount of the starting material had not reacted completely. The reaction solution was concentrated and purified to give an off-white solid (28 mg, two-step yield 34%). 1H NMR: (DMSO-d6,400MHz): δ1.36(s,3H),3.85(s,3H),3.92(s,3H),4.31(s,2H), 4.89(s,2H),6.75(s,1H),7.17-7.75(m,3H),8.04(s,1H),8.41(s,1H); LCMS: m / z= 306.2[M+H] + .

[0262] Example 2: Preparation of intermediates C-IN-002 and C-IN-003

[0263]

[0264] Step 1:

[0265] Under N2 protection, 2-amino-5-bromopyridine (30.0 g, 173.40 mmol) was dissolved in DMF (200 mL). Trifluoroacetic acid (14.2 mL, 191.17 mmol) and NIS (43.0 g, 191.13 mmol) were added at room temperature. The mixture was heated to 50 °C and stirred for 3 hours. TLC showed complete consumption of the starting material. The reaction solution was cooled to room temperature and slowly poured into water. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with 10% Na2SO3 solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid IN-002-1 (45 g).

[0266] Step 2:

[0267] Under N2 protection, IN-002-1 (2.0 g, 6.69 mmol) and Et3N (1.2 mL, 8.63 mmol) were dissolved in THF (30 mL). Trimethylsilyrylpropyne (2.0 mL, 13.51 mmol) was added in portions at room temperature. After the addition was complete, PdCl2(PPh3)2 (240 mg, 0.34 mmol) and CuI (65 mg, 0.34 mmol) were added. After stirring at room temperature for 5 minutes, TBAF.3H2O (2.2 g, 6.97 mmol) was added, and the mixture was stirred at room temperature for 18 hours. TLC showed that the starting material reacted completely. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to give a yellow solid IN-002-2 (1.3 g, 67% yield in two steps). 1 H NMR (400MHz, CDCl3): δ2.12 (s, 3H), 5.08 (br, 1H), 7.56 (d, J = 2.4Hz, 1H), 8.01 (d, J = 2.4Hz, 1H). LCMS: m / z = 211.0 / 213.0 [M+H] + .

[0268] Step 3:

[0269] Under N2 protection, IN-002-2 (11.0 g, 52.12 mmol) and t-BuOK (17.6 g, 156.85 mmol) were dispersed in DMF (170 mL) and stirred at room temperature for 18 hours. The reaction was confirmed to be complete by TLC. The reaction solution was extracted with ethyl acetate after adding water (500 mL), and the organic phases were combined, washed with water, dried over saturated brine and anhydrous sodium sulfate, and concentrated to give a brown solid IN-002-3 (10.0 g). 1 HNMR (400MHz, CDCl3): δ2.55 (s, 3H), 6.15 (br, 1H), 7.94 (d, J = 2.0Hz, 1H), 8.24 (d, J = 1.8Hz, 1H), 10.66 (br, 1H); LCMS: m / z = 211.0 / 213.0 [M+H] + .

[0270] Step 4:

[0271] Under N2 protection, IN-002-3 (10.0 g, 47.38 mmol) was dissolved in DMF (100 mL). NaH (2.9 g, 72.50 mmol, 60%) was added in portions under an ice-water bath. After stirring for 15 minutes, MeI (6.0 mL, 96.38 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. TLC showed complete reaction of the starting material. The reaction mixture was slowly poured into water under an ice-water bath, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give a white solid IN-002-4 (9.0 g, 84% yield). 1 H NMR (400MHz, CDCl3): δ 2.46 (s, 3H), 3.76 (s, 3H), 6.16 (s, 1H), 7.89 (d, J = 2.0Hz, 1H), 8.25 (d, J = 2.0Hz, 1H); LCMS: m / z = 225.0 / 227.0 [M+H] + .

[0272] Step 5:

[0273] Under N2 protection, IN-002-4 (8.5 g, 37.76 mmol) was dissolved in THF (130 mL). The mixture was cooled to -65°C in a dry ice-acetone bath, and n-BuLi (18.2 mL, 45.5 mmol, 2.5 M) was slowly added dropwise. After stirring at -65°C for 1 hour, trimethyl borate (43.0 mL, 385.68 mmol) was added in one go. Stirring continued at -65°C for 1 hour, followed by slow warming to room temperature and stirring for 2 hours. TLC showed the disappearance of the starting material. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow solid IN-002-5 (8.0 g) (containing approximately 5–10% debrominated byproduct C-IN-002). LCMS: m / z = 191.1 [M+H] + Byproduct C-IN-002 LCMS: m / z = 147.2 [M+H] + .

[0274] Step 6:

[0275] Under N2 protection, IN-002-5 (7.2 g, 37.89 mmol) was dissolved in DCM (210 mL), and 30% H2O2 (13.0 mL, 129.58 mmol) was added. After stirring at room temperature for 0.5 hours, TLC showed that the starting material disappeared. Under ice-water bath, an aqueous solution of Na2SO3 (15.0 g, 119.01 mmol) (150 mL) was added, and the mixture was stirred for 0.5 hours. No blue color was observed on starch-KI test paper. The mixture was separated, the organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain a brown solid C-IN-003 (3.8 g, yield 62%). LCMS: m / z = 163.1 [M+H] + .

[0276] Example 3: Preparation of compound SYY-C002

[0277]

[0278] Step 1:

[0279] Under N2 protection, C-IN-002 (1.2 g, 8.21 mmol) was dissolved in DMF (20 mL), and NBS (1.46 g, 8.20 mmol) was added under ice-water bath. After reacting for 10 minutes, TLC showed that the starting material had reacted completely. The reaction solution was extracted with water and ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give a yellow solid C002-1 (1.5 g, yield 81%). 1H NMR (400MHz, CDCl3) δ2.48 (s, 3H), 3.83 (s, 3H), 7.10 (dd, J = 7.8, 4.8Hz, 1H), 7.76 (dd, J = 7.8, 1.5Hz, 1H), 8.29 (dd, J = 4.8, 1.5Hz, 1H).

[0280] Step 2:

[0281] Under N2 protection, C002-1 (1.5 g, 6.66 mmol) was dissolved in THF (30 mL), cooled to -65 °C, and n-BuLi (2.8 mL, 7.00 mmol, 2.5 M) was slowly added dropwise. After the addition was complete, the mixture was stirred at -65 °C for 1 hour, then ethyl cyanoformate (0.85 mL, 8.60 mmol) was added, and the mixture was stirred for another hour. The mixture was then allowed to warm naturally to room temperature and stirred for another hour. TLC showed that the reaction proceeds were completely reacted. The reaction solution was quenched with saturated ammonium chloride solution, and the layers were separated. The aqueous layer was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give a pale yellow solid C002-2 (1.0 g, yield 69%). 1 H NMR (400MHz, CDCl3): δ1.46(t,J=7.2Hz,3H), 2.83(s,3H),3.85(s,3H),4.41(q,J=7.2Hz,2H),7.18(dd,J=7.6,4.8Hz,1H),8.31 (dd,J=4.8,1.6Hz,1H),8.34(dd,J=7.8,1.6Hz,1H).LCMS: m / z=219.1[M+H] + .

[0282] Step 3:

[0283] Under N2 protection, CO02-2 (700 mg, 3.21 mmol) was dissolved in CCl4 (15 mL), and BPO (70%) (70 mg, 0.20 mmol) was added and stirred. After heating to 80 °C, NBS (580 mg, 3.26 mmol) was added, and the reaction was continued for 1.5 hours. TLC showed that the starting material had reacted completely. The reaction solution was cooled to room temperature, and the crude product was purified by silica gel column chromatography to give a yellow solid CO02-3 (800 mg, yield 84%). 1 H NMR (400MHz, CDCl3) δ1.49 (t, J = 7.2 Hz, 3H), 3.98 (s, 3H), 4.46 (q, J = 7.2 Hz, 2H), 5.19 (s, 2H), 7.24 (dd, J = 7.6, 4.8 Hz, 1H), 8.45-8.38 (m, 2H).

[0284] Step 4:

[0285] Under N2 protection, CO002-3 (500 mg, 1.68 mmol) was dissolved in DMF (10 mL), and NaN3 (220 mg, 3.38 mmol) was added at room temperature. The mixture was heated to 50 °C and stirred for 1 hour, then cooled to room temperature and stirred overnight. TLC showed that the starting material reacted completely. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain CO002-4 (437 mg), which was directly used in the next step.

[0286] Step 5:

[0287] Under N2 protection, CO02-4 (437 mg) was dissolved in THF / H2O (10 mL / 2 mL), and PPh3 (885 mg, 3.37 mmol) was added at room temperature. The mixture was heated to 50 °C and stirred for 2 hours. TLC showed that the starting material and intermediates disappeared. The reaction solution was cooled to room temperature and concentrated. The crude product was purified by silica gel column chromatography to obtain a pale yellow solid CO002-5 (350 mg, two-step yield 89%). 1 H NMR (400MHz, DMSO_d6): δ1.37(t,J=7.2Hz,3H),1.92(br,2H),3.90(s, 3H), 4.21 (s, 2H), 4.32 (q, J=7.2Hz, 2H), 7.26 (dd, J=8.0, 4.8Hz, 1H), 8.28 (dd, J= 8.0, 1.6Hz, 1H), 8.33 (dd, J=4.8, 1.6Hz, 1H). LCMS: m / z=234.1[M+H] + .

[0288] Step 6:

[0289] Under N2 protection, CO002-5 (250 mg, 1.07 mmol) and DIEA (831 mg, 6.43 mmol) were dispersed in MeCN (10 mL). After stirring until dissolved, 1H-1-methylformamidinium hydrochloride (315 mg, 2.15 mmol) was added. The mixture was stirred at room temperature for 18 hours, resulting in the precipitation of a large amount of solid. TLC showed that only a small amount of the starting material remained. The reaction solution was filtered, the filter cake was washed with acetonitrile, and dried to obtain a white solid SYY-C002 (220 mg, yield 75%). 1H NMR(400MHz, DMSO_d6)δ1.39 (t,J=7.2Hz,3H),3.92(s,3H),4.37(q,J=7.2Hz,2H),4.99(s,2H),7.23-7.87(m,5H), 8.34(dd,J=7.6,1.6Hz,1H),8.42(dd,J=4.4,1.6Hz,1H).LCMS: m / z=276.2 [M+H] + .

[0290] Example 4: Preparation of compound SYY-C003

[0291]

[0292] Step 1:

[0293] Under N2 protection, C-IN-003 (1.9 g, 11.71 mmol) was dissolved in DMF (20 mL). NaH (60%) (705 mg, 17.63 mmol) was added in an ice bath, and the mixture was stirred for 15 minutes. Then, MeI (2.0 g, 14.1 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. TLC showed that the starting material reacted completely. The reaction mixture was slowly added to water in an ice bath, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give C003-1 (1.9 g). LCMS: m / z = 177.1 [M+H] + .

[0294] Step 2:

[0295] Under N2 protection, C003-1 (1.90 g) was dissolved in DMF (20 mL), and NBS (1.92 g, 10.78 mmol) was added under ice bath conditions. After stirring for 5 minutes, TLC showed that the starting material had reacted completely. The reaction solution was added to water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain a yellow solid C003-2 (2.30 g, 77% yield in two steps).

[0296] Step 3:

[0297] Under N2 protection, C003-2 (2.3 g, 9.02 mmol) was dissolved in THF (45 mL), cooled to -65 °C, and n-BuLi (2.5 M) (4.3 mL, 10.75 mmol, 2.5 M) was slowly added dropwise. After the addition was complete, the mixture was stirred at -65 °C for 1 hour. Ethyl cyanoformate (1.2 mL, 12.14 mmol) was added, and the mixture was stirred for another hour. The mixture was then allowed to warm naturally to room temperature and stirred for another hour. TLC showed that the reaction proceeds were completely reacted. The reaction mixture was quenched with saturated ammonium chloride solution, and the layers were separated. The aqueous layer was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give a pale yellow solid C003-3 (800 mg, yield 36%). 1 H NMR (400MHz, CDCl3): δ1.46(t,J=7.2Hz,3H),2.80(s,3H),3.81(s,3H),3.93(s,3H),4.41(q,J=7.2Hz,2H),7.90(d,J=2.8Hz,1H),8.07(d,J=2.8Hz, 1H).LCMS: m / z=249.1[M+H] + .

[0298] Step 4:

[0299] Under N2 protection, CO03-3 (600 mg, 2.42 mmol) was dissolved in CCl4 (20 mL), and BPO (70%) (70 mg, 0.20 mmol) was added at room temperature. The mixture was heated to 80 °C, and NBS (480 mg, 2.70 mmol) was added. The reaction was continued for 1.5 hours, and TLC showed that the starting material had reacted completely. The reaction solution was cooled to room temperature, and the crude product was purified by silica gel column chromatography to give a yellow solid CO03-4 (700 mg, yield 88%). 1 H NMR (400MHz, CDCl3) δ1.49(t,J=7.2Hz, 3H),3.93(s,3H),3.94(s,3H),4.46(q,J=7.2Hz,2H),5.16(s,2H),7.92(d,J=2.8Hz, 1H), 8.18 (d, J = 2.8Hz, 1H).

[0300] Step 5:

[0301] Under N2 protection, C003-4 (450 mg, 1.38 mmol) was dissolved in DMF (10 mL), and NaN3 (180 mg, 2.77 mmol) was added at room temperature. The mixture was heated to 50 °C and stirred for 1 hour, then cooled to room temperature and stirred overnight. TLC showed that the starting material reacted completely. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain C003-5 (398 mg).

[0302] Step 6:

[0303] Under N2 protection, CO03-5 (398 mg) was dissolved in THF / H2O (10 mL / 2 mL), and PPh3 (723 mg, 2.76 mmol) was added at room temperature. The mixture was heated to 50 °C and stirred for 2 hours. TLC showed that the starting material and intermediates disappeared. The reaction solution was cooled to room temperature and concentrated. The crude product was purified by silica gel column chromatography to give a pale yellow solid CO003-6 (250 mg, yield 69%). 1 H NMR (400MHz, DMSO_d6): δ1.37(t,J=7.2Hz,3H),1.94(,2H),3.85(s,3H),3.86 (s,3H),4.16(s,2H),4.30(q,J=7.2Hz,2H),7.78(d,J=2.8Hz,1H),8.07(d,J=2.8Hz,1H).LCMS: m / z=264.1[M+H] + .

[0304] Step 7:

[0305] Under N2 protection, CO003-6 (250 mg, 0.95 mmol) and DIEA (491 mg, 3.8 mmol) were dispersed in MeCN (10 mL). After stirring until dissolved, 1H-1-methylformamidin hydrochloride (279 mg, 1.90 mmol) was added. The mixture was stirred at room temperature for 18 hours, and a large amount of solid precipitated. TLC showed that only a small amount of the reaction solution remained. The mixture was filtered, the filter cake was washed with acetonitrile, and dried to obtain a white solid SYY-C003 (200 mg, yield 69%). 1 H NMR (400MHz, DMSO_d6): δ 1.39 (t, J=7.2Hz, 3H), 3.88 (s, 6H), 4.36 (q, J=7.2Hz, 2H), 4.95 (s, 2H), 7.49 (br, 3H), 7.82(d,J=2.8Hz,1H),8.17(d,J=2.8Hz,1H),8.39(br,1H).LCMS: m / z=306.1[M+H] + .

[0306] Example 5: Preparation of intermediate C-IN-001

[0307]

[0308] Step 1:

[0309] C001-4 (23.0 g, 116.97 mmol) was dissolved in methanol (300 mL), and palladium hydroxide (10.0 g) was added. The mixture was purged with hydrogen three times and heated to 50°C for 4 hours. TLC analysis showed that the reaction was essentially complete. The reaction solution was cooled to room temperature, filtered through a diatomaceous earth sieve, and the filtrate was concentrated to obtain a pale yellow solid IN-001-5 (25 g).

[0310] Step 2:

[0311] Under nitrogen protection, IN-001-5 (16.9 g, 104.20 mol) was dissolved in dry THF (170 ml), cooled in an ice-water bath, and 60% NaH (7.5 g, 187.5 mmol) was added in portions at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 0.5 hours, cooled in an ice-water bath, and iodomethane (29.6 g, 208.54 mmol) was added dropwise at 0 °C over 30 minutes. After the addition was complete, the reaction was continued for 1 hour. The reaction was monitored by TLC until the starting material was completely reacted. Water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was added to 40 ml of a mixed solvent (PE / EA = 20 / 1). The mixture was stirred for 1 hour and filtered to obtain a brownish-yellow solid C-IN-001 (11.5 g, yield 63%).

[0312] Example 6: Preparation of compounds SYY-C004 and SYY-C005

[0313]

[0314] Step 1:

[0315] C-IN-001 (1.0 g, 5.67 mmol) was dissolved in acetonitrile (10 mL), cooled to approximately 0°C in an ice-water bath, and NIS (1.28 g, 5.69 mmol) was added in portions. The reaction solution was reacted at 0°C for 1 hour, and TLC showed that the reaction was complete. Water was added dropwise to the reaction solution, and the mixture was stirred at 0°C for 10 minutes. The mixture was filtered, the filter cake was washed, and dried to obtain a yellow solid C004-1 (1.7 g, crude product).

[0316] Step 2:

[0317] C004-1 (900 mg, crude) was dissolved in DMF (15 mL), and zinc cyanide (525 mg, 4.47 mmol) and Pd(PPh3)4 (344 mg, 0.30 mmol) were added at room temperature. After purging with nitrogen three times, the mixture was heated to 130°C and reacted for 5 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give a white solid C004-2 (280 mg, two-step yield 47%). LCMS: m / z = 202.1 [M+H] + .

[0318] Step 3:

[0319] C004-2 (193 mg, 0.96 mmol), NBS (171 mg, 0.96 mmol), and BPO (35 mg, 0.14 mmol) were dispersed in carbon tetrachloride (10 mL). The mixture was heated to 80°C for 2 h under nitrogen protection, and the reaction proceeded to completion as determined by TLC. The reaction solution was cooled to room temperature and concentrated. The crude product was purified by silica gel column chromatography to obtain a white solid C004-3 (255 mg, 95% yield). LCMS: m / z = 280.0 / 282.0 [M+H] + .

[0320] Step 4:

[0321] C004-3 (627 mg, 2.24 mmol) was dissolved in DMF (5 mL), and sodium azide (218 mg, 3.35 mmol) was added at room temperature. The mixture was heated to 60°C and reacted for 4 hours. The reaction was confirmed to be complete by TLC. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid C004-4 (500 mg, crude product). LCMS: m / z = 243.1 [M+H] + .

[0322] Step 5:

[0323] C004-4 (500 mg, 2.06 mmol) was dissolved in THF (10 mL) and water (2 mL). Triphenylphosphine (881 mg, 3.36 mmol) was added at room temperature, and the mixture was heated to 60°C for 3 hours. The reaction was confirmed to be complete by LCMS. The reaction solution was cooled to room temperature, concentrated to a minimum, extracted with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified to give a yellow solid C004-5 (110 mg, 23% yield in two steps). LCMS: m / z = 217.2 [M+H] + .

[0324] Step 6:

[0325] C004-5 (80 mg, 0.37 mmol) was dispersed in acetonitrile (3 mL), and after the addition of DIEA (191 mg, 1.48 mmol), the solution became clear. Then, pyrazole formamidin hydrochloride (60 mg, 0.41 mmol) was added. After the addition was complete, the reaction solution was reacted at room temperature for 2 days, and a solid precipitated. The reaction solution was filtered and dried to obtain an off-white solid SYY-C004 (50 mg, yield 52%). 1 H NMR: (DMSO-d6, 400MHz): δ3.80 (s, 3H), 3.91 (s, 3H), 4.80 (s, 2H), 6.80 (d, J=8.8Hz, 1H), 7.50 (br, 4H), 8.06 (d, J=8.8Hz, 1H). LCMS: m / z=259.1[M+H] + .

[0326] Step 7:

[0327] C004-4 (100 mg, 0.41 mmol) was dispersed in ethanol (2 mL), and hydrogen peroxide (0.5 mL) was added at room temperature. Then, potassium hydroxide aqueous solution (0.5 mL, 1.0 mmol, 2 M) was added in a single batch, and the mixture was heated to 80°C and reacted for 2 hours. The reaction was confirmed to be complete by TLC and LCMS. The reaction solution was cooled to room temperature, extracted with water and ethyl acetate, washed with saturated sodium sulfite aqueous solution, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified to give a white solid C005-1 (60 mg, yield 56%). LCMS: m / z = 261.1 [M+H] + .

[0328] Step 8:

[0329] C005-1 (60 mg, 0.23 mmol) was dispersed in methanol (5 mL), and palladium on carbon (10%, 60 mg) was added. The mixture was purged with hydrogen three times, heated to 60°C, and reacted for 1 hour. The reaction was monitored by TLC to ensure complete reaction. The reaction solution was cooled to room temperature, filtered through a diatomaceous earth filter, washed, and the filtrate concentrated. The crude product was purified to give a pale yellow solid, C005-2 (42 mg, overall yield 78%). LCMS: m / z = 235.1 [M+H] + .

[0330] Step 9:

[0331] C005-2 (40 mg, 0.17 mmol) was dispersed in acetonitrile (3 mL), and DIEA (88 mg, 0.68 mmol) and pyrazole formamidin hydrochloride (28 mg, 0.19 mmol) were added at room temperature. The mixture was reacted at room temperature for 2 days, and a white solid precipitated. The reaction solution was filtered, the filter cake was washed, and dried to obtain a white solid SYY-C005 (45 mg, yield 96%). 1 H NMR: (DMSO-d6, 400MHz): δ3.89 (s, 3H), 3.92 (s, 3H), 4.97 (s, 2H), 6.80 (d, J = 9.12Hz, 1H), 7.19(br,2H),7.90(s,1H),8.07(d,J=8.4Hz,1H),8.08(br,1H),8.53(s,1H),8.88(br,1H).LCMS:m / z=277.1[M+H] + .

[0332] Example 7: Preparation of intermediate C-IN-005

[0333]

[0334] Step 1:

[0335] Under nitrogen protection, C-IN-001 (16.6 g, 94.20 mmol) was dissolved in acetonitrile (170 ml), cooled in an ice-water bath, and NBS (16.8 g, 94.39 mmol) was added in portions at 0 °C over 30 minutes. After the addition was complete, the reaction was allowed to proceed at 0 °C for 0.5 hours, and TLC was used to determine the completeness of the reaction. The reaction solution was extracted with water and ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give a pale yellow solid IN-005-1 (13.7 g, 57% yield).

[0336] Step 2:

[0337] Under nitrogen protection, IN-005-1 (13.7 g, 53.70 mmol) was dissolved in 200 ml of dry THF. The mixture was cooled to -60 to -70 °C in a dry ice-acetone bath. Butyllithium (28.0 ml, 70.0 mmol, 2.5 mol / L) was added dropwise over 30 minutes. The reaction was continued at this temperature for 1 hour. Then, ethyl cyanoacetate (8.0 g, 80.73 mmol, diluted in 10 ml THF) was added dropwise. The reaction was continued at -60 to -70 °C for 1 hour, then slowly raised to room temperature for another 1 hour. TLC was used to confirm the complete reaction of the starting material. The reaction solution was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain a crude product. A 50 ml mixture of PE / EA (40 / 1) was added, and the mixture was stirred for 30 minutes. The mixture was filtered, and the filter cake was washed and dried to obtain a white solid, IN-005-2 (9.3 g, 70% yield).

[0338] Step 3:

[0339] Under nitrogen protection, IN-005-2 (2.0 g, 8.06 mmol) was dissolved in carbon tetrachloride (40 mL). NBS (1.43 g, 8.06 mmol) and BPO (195 mg, 0.81 mmol) were added at room temperature. The mixture was heated to 50 °C and reacted for 1.0 h. TLC analysis showed that the starting material was not completely reacted. NBS (143 mg, 0.8 mmol) was added again, and the reaction was continued at 50 °C for another 0.5 h. TLC analysis again showed that the starting material was not completely reacted. The reaction solution was cooled to room temperature, and the crude product was purified by silica gel column chromatography to give a yellow solid IN-005-3 (2.4 g, 91% yield). LCMS: m / z = 327.0 / 329.0 [M+H] + .

[0340] Step 4:

[0341] Under nitrogen protection, IN-005-3 (2.78 g, 8.50 mmol) was dissolved in DCM (40 ml), and TMSI (4.8 ml, 33.73 mmol, diluted in 5 ml DCM) was added dropwise at room temperature. After the addition was complete, the reaction was allowed to proceed at room temperature for 30 minutes, then heated to 40 °C and refluxed for 20 minutes. The reaction proceeded to TLC after the starting material had reacted completely. The reaction solution was cooled to room temperature, quenched with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give a yellow solid C-IN-005 (2.57 g, 97% yield). 1H NMR (400MHz, DMSO_d6): δ1.30 (t, J=7.2Hz, 3H), 2.57 (s, 3H), 3.65 (s, 3H), 4.31 (q, J=7.2Hz, 2H), 8.40 (s, 1H), 10.63 (br,1H).LCMS: m / z=313.0 / 315.0[M+H] + .

[0342] Example 8: Preparation of compound SYY-C006

[0343]

[0344] Step 1:

[0345] Under nitrogen protection, C-IN-005 (1.72 g, 5.49 mmol) was dissolved in DCM (50 ml), and N,N-diisopropylethylamine (2.83 g, 21.90 mmol) was added. The mixture was cooled to 0°C in an ice-water bath, and chloromethyl methyl ether (1.1 g, 13.66 mmol, diluted in 2 ml DCM) was added dropwise. After the addition was complete, the reaction was carried out at 40°C for 5 hours. TLC analysis showed that the starting material was not completely reacted. N,N-diisopropylethylamine (1.42 g, 10.99 mmol) and chloromethyl methyl ether (0.57 g, 7.08 mmol, diluted in 2 ml DCM) were added, and the mixture was heated to 40°C and reacted for 6 hours. The reaction solution was cooled to room temperature, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give a pale yellow solid C006-1 (860 mg, yield 44%). 1 H NMR (400MHz, CDCl3) δ7.89 (s, 1H), 6.01 (s, 2H), 4.38 (d, J = 7.2Hz, 2H), 3.63 (s, 3H), 3.20(s,3H),2.51(s,3H),1.40(t,J=7.2Hz,3H).LCMS: m / z=357.0 / 359.0[M+H] + .

[0346] Step 2:

[0347] C006-1 (500 mg, 1.40 mmol), NBS (250 mg, 1.40 mmol), and BPO (34 mg, 0.14 mmol) were dissolved in CCl4 (10 mL), and the mixture was heated to 80 °C and reacted for 1 hour. TLC analysis showed that the reaction proceeded completely. Silica gel column chromatography yielded a yellow solid, C006-2 (300 mg, 55% yield).

[0348] Step 3:

[0349] C006-2 (300 mg, 0.77 mmol) and NaN3 (75 mg, 1.15 mmol) were dissolved in DMF (6 mL), and the mixture was heated to 50 °C and reacted for 1.5 hours. LCMS analysis confirmed the reaction was complete. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain C006-3 (180 mg), which was used directly in the next step. LCMS: m / z = 354.0 / 356.0 [M+H] + .

[0350] Step 4:

[0351] C006-3 (180 mg, 0.51 mmol) was dissolved in methanol (10 ml), and 10% palladium hydroxide / carbon (150 mg) was added. The mixture was purged with hydrogen three times, heated to 60 °C, and reacted for 1 hour. The reaction was confirmed to be complete by TLC. The reaction solution was cooled to room temperature, filtered through a diatomaceous earth sieve, and the filtrate was concentrated to obtain a pink solid. This solid was neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was discarded. The aqueous phase was concentrated, and a slurry (DCM / MeOH = 10 / 1) was added. The mixture was filtered, and the filtrate was concentrated. The crude product was purified to obtain a white solid C006-4 (57 mg, yield 45%).

[0352] Step 5:

[0353] C006-4 (57 mg, 0.23 mmol), 1H-pyrazole-1-formamidinium hydrochloride (40 mg, 0.27 mmol), and DIEA (118 mg, 0.91 mmol) were dispersed in acetonitrile (4 ml) and reacted at room temperature for 2 days. The reaction solution was filtered, and the filter cake was washed with 1 ml of acetonitrile to give a white solid SYY-C006 (45 mg, yield 67%). 1 H NMR: (DMSO-d6, 400MHz): δ1.32(t,J=7.2Hz,3H),3.78(s,3H),4.35(q,J=7.2Hz,2H),4.77(s,2H), 6.23(d,J=9.6Hz,1H),7.46(br,3H),7.91(d,J=9.2Hz,1H),8.27(br,1H),10.36(br,1H).LCMS:m / z=292.2[M+H] + .

[0354] Example 9: Preparation of compounds SYY-C007 and SYY-C008

[0355]

[0356] Step 1:

[0357] C-IN-005 (450 mg, 1.44 mmol), bromocyclopentane (428 mg, 2.87 mmol), and potassium carbonate (595 mg, 4.31 mmol) were dissolved in DMF (10 mL). The mixture was heated to 80 °C and reacted for 4 hours. TLC analysis showed that the starting material was not completely reacted, so bromocyclopentane (214 mg, 1.44 mmol) was added, and the reaction was continued at 80 °C for another 2 hours. TLC analysis showed that the starting material was completely reacted. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give a yellow solid C008-1 (460 mg, 84% yield). 1 H NMR (400MHz, CDCl3) δ1.47(t,J=7.2Hz,3H),1.61-1.68(m,2H),1.86-1.95(d,4H),2.05 -2.14(m,2H),2.76(s,3H),3.66(s,3H),4.41(q,J=7.2Hz,2H),5.59-5.62(m,1H),7.71(s,1H).LCMS: m / z=381.0 / 383.0[M+H] + .

[0358] Step 2:

[0359] C008-1 (400 mg, 1.05 mmol), NBS (205 mg, 1.15 mmol), and BPO (25 mg, 0.10 mmol) were dissolved in CCl4 (10 mL), and the mixture was heated to 80 °C and reacted for 2 hours. The reaction was confirmed to be complete by TLC. The reaction solution was cooled to room temperature, concentrated, and the residue was purified by silica gel column chromatography to obtain a pale yellow solid C008-2 (515 mg).

[0360] Step 3:

[0361] C008-2 (510 mg, 1.11 mmol) and NaN3 (108 mg, 1.66 mmol) were dissolved in DMF (8 mL), and the mixture was heated to 50 °C and reacted for 1.5 h. TLC analysis showed the starting material was completely reacted. The reaction solution was cooled to room temperature, extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in a mixture of THF (12 mL) and water (4 mL), and PPh3 (434 mg, 1.65 mmol) was added. The mixture was reacted overnight at room temperature, and LCMS analysis showed the reaction was completely reacted. The reaction solution was concentrated, and the residue was subjected to column chromatography to give a yellow solid C008-3 (370 mg, yield 84%). LCMS: m / z = 379.0 / 81.0 [M-NH2] + .

[0362] Step 4:

[0363] C008-3 (110 mg, 0.28 mmol), 1H-pyrazole-1-formamidin hydrochloride (53 mg, 0.36 mmol), and DIEA (143 mg, 1.11 mmol) were dissolved in acetonitrile (3 ml) and reacted at room temperature for 2 days. A solid precipitated out. The mixture was filtered, and the filter cake was washed with 1 ml of acetonitrile to give a white solid SYY-C008 (91 mg, yield 75%). 1 H NMR(DMSO-d6, 400MHz) δ1.36(t,J=7.2Hz,3H),1.56-1.79(m,6H),1.99-2.11(m,2H),3.84(s,3H) ,4.31(q,J=7.2Hz,2H),4.88(s,2H),5.47(s,1H),7.45(br,3H),8.29-8.44(m,2H). LCMS: m / z=440.1[M+H] + .

[0364] Step 5:

[0365] C008-3 (200 mg, 0.50 mmol) was dissolved in methanol (5 ml), and palladium hydroxide / carbon (200 mg) was added. The mixture was purged with hydrogen three times and heated to 60 °C for 1 hour. The reaction was monitored by TLC until the starting material was completely reacted. The reaction solution was cooled to room temperature, filtered through a diatomaceous earth filter, and the filtrate was concentrated to obtain a pale yellow solid, C007-1 (145 mg).

[0366] Step 6:

[0367] C007-1 (145 mg, 0.46 mmol) 1H-pyrazole-1-formamidin hydrochloride (80 mg, 0.55 mmol) and DIEA (236 mg, 1.83 mmol) were dissolved in acetonitrile (6 ml) and reacted at room temperature for 2 days, resulting in the precipitation of a solid. The reaction solution was filtered, and the filter cake was washed with 1 ml of acetonitrile to give a white solid SYY-C007 (110 mg, 60% yield in two steps). 1 H NMR: (DMSO-d6,400MHz): δ1.36(t,J=7.2Hz,3H),1.54-1.77(m,6H),2.00-2.10(m,2H), 3.84(s,3H),4.31(q,J=7.2Hz,2H),4.89(s,2H),5.41-5.46(m,1H),6.68(d,J=8.9Hz, 1H),7.46(br,3H),7.96(d,J=8.9Hz,1H),8.37(br,1H).LCMS: m / z=360.2[M+H] + .

[0368] Example 10: Preparation of compound SYY-C009

[0369]

[0370] Step 1:

[0371] Under N2 protection, C-IN-003 (1.9 g, 8.54 mmol) was dissolved in DMF (30 mL). NaH (60%) (938 mg, 23.45 mmol) was added in an ice-water bath, and the mixture was stirred for 15 minutes. Then, MOMCl (1.0 mL, 13.17 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. TLC showed that the starting material reacted completely. The reaction mixture was slowly added to a saturated NH4Cl solution in an ice bath, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give a pale yellow oil, C009-1 (2.0 g, 83% yield). 1 H NMR (400MHz, CDCl3): δ2.43(d,J=0.8Hz,3H),3.53(s,3H),3.74(s,3H),5.17(s,2H),6.13(d,J= 1.0Hz, 1H), 7.52 (d, J = 2.4Hz, 1H), 8.08 (d, J = 2.4Hz, 1H).

[0372] Step 2:

[0373] Under N2 protection, C009-1 (2.0 g, 9.70 mmol) was dissolved in DMF (20 mL), and NBS (1.73 g, 9.70 mmol) was added under ice bath conditions. The mixture was stirred for 2 minutes, and TLC showed that the starting material reacted completely. The reaction solution was added to water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain a yellow semi-solid C009-2 (2.3 g, 83% yield). 1 H NMR (400MHz, CDCl3) δ2.43 (d, J = 0.8 Hz, 3H), 3.53 (s, 3H), 3.74 (s, 3H), 5.17 (s, 2H), 7.52 (d, J = 2.8 Hz, 1H), 8.10 (d, J = 2.8 Hz, 1H).

[0374] Step 3:

[0375] Under N2 protection, C009-2 (2.0 g, 7.01 mmol) was dissolved in THF (40 mL), cooled to -65 °C, and n-BuLi (2.5 M) (3.1 mL, 7.75 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at -65 °C for 1 hour. CNCOOEt (0.78 mL, 7.90 mmol) was then added, and the mixture was stirred for another hour. The mixture was then allowed to warm naturally to room temperature and stirred for 1 hour. TLC showed that the reaction proceeds were completely reacted. The reaction solution was quenched with saturated NH4Cl solution, and the layers were separated. The aqueous layer was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give a pale yellow solid C009-3 (800 mg, yield 41%).

[0376] Step 4:

[0377] Under N2 protection, C009-3 (300 mg, 1.08 mmol) was dissolved in CCl4 (10 mL), and BPO (70%) (20 mg, 0.058 mmol) was added at room temperature. The mixture was heated to 80 °C, and NBS (200 mg, 1.12 mmol) was added. The reaction was continued for 1 hour, and TLC showed that the starting material had reacted completely. The reaction solution was cooled to room temperature, and the crude product was directly precipitated by silica gel column chromatography to give a pale yellow solid C009-4 (340 mg, yield 88%). 1 H NMR (400MHz, CDCl3): δ1.48(t,J=7.2Hz,3H),3.55(s,3H),3.94(s,3H),4.45(q,J=7.2Hz,2H),5.17(s,2H),5.24(s,2H), 8.11(d,J=2.7Hz,1H), 8.24(d,J=2.8Hz,1H).

[0378] Step 5:

[0379] Under N2 protection, C009-4 (340 mg, 0.95 mmol) was dissolved in DMF (10 mL), and NaN3 (124 mg, 1.91 mmol) was added at room temperature. The mixture was heated to 50 °C and stirred for 1 hour, then stirred overnight at room temperature. TLC showed that the starting material reacted completely. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain C009-5 (306 mg, crude product).

[0380] Step 6:

[0381] Under N2 protection, C009-5 (306 mg, crude product) was dissolved in THF / H2O (8 mL / 1.6 mL), and PPh3 (500 mg, 1.91 mmol) was added at room temperature. The mixture was heated to 50 °C and stirred for 2 hours. TLC showed that the starting material and intermediates disappeared. The reaction solution was cooled to room temperature and concentrated. The crude product was purified by silica gel column chromatography to obtain a light brown solid C009-6 (190 mg, 68% yield in two steps).

[0382] Step 7:

[0383] Under N2 protection, C009-6 (190 mg, 0.65 mmol) and DIEA (418 mg, 3.23 mmol) were dispersed in acetonitrile (8 mL). After stirring until dissolved, 1H-1-methylformamidinium hydrochloride (191 mg, 1.30 mmol) was added and the mixture was stirred at room temperature for 18 hours. TLC showed that the starting material reacted completely (the product dissolved in acetonitrile, and no solid precipitated). The reaction solution was concentrated, and the crude product was purified to give a white solid C009-8 (190 mg, yield 88%).

[0384] Step 8:

[0385] Under N2 protection, C009-8 (190 mg, 0.57 mmol) was dissolved in MeCN / MeOH (8 mL / 1 mL), and HCl / dioxane (1.0 mL) was added. The mixture was stirred at room temperature for 3 hours, and TLC showed that the reaction proceeds were completely reacted (a large amount of solid precipitated). The reaction solution was filtered, the filter cake was washed with acetonitrile, and dried to give a white solid SYY-C009 hydrochloride (100 mg, yield 49%). 1 H NMR: (DMSO-d6, 400MHz): δ1.38 (t, J=7.2Hz, 3H), 3.85 (s, 3H), 4.33 (q, J=7.2Hz, 2H), 4.94 (d, J=4.8Hz, 2H), 7.40 (br, 6H), 7.76 (d, J=2.8Hz, 1H), 8.03 (d, J=2.8Hz, 1H).LCMS: m / z=292.2[M+H] + .

[0386] Example 11: Preparation of compound SYY-C010

[0387]

[0388] Step 1:

[0389] Under N2 protection, CO009-3 (400 mg, 1.44 mmol) was dissolved in DCM (10 mL), and HCl / dioxane (1 mL, 4 M) was added. The mixture was stirred for 18 hours, and TLC showed that the starting material reacted completely. The reaction solution was concentrated to obtain CO10-1 (334 mg, crude product), which was used directly in the next step.

[0390] Step 2:

[0391] Under N2 protection, CO10-1 (334 mg, crude product) was dissolved in DMF (10 mL), and K2CO3 (397 mg, 2.87 mmol) and bromocyclopentane (425 mg, 2.85 mmol) were added. After stirring at room temperature for 18 hours, TLC showed that about 2 / 3 of the starting material remained. K2CO3 (397 mg, 2.87 mmol) and bromocyclopentane (425 mg, 2.85 mmol) were added again, and the mixture was heated to 50 °C and stirred for 6 hours. TLC showed that the starting material had basically reacted completely. The reaction solution was cooled to room temperature, and water was slowly added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain CO10-2 (200 mg, two-step yield 46%).

[0392] Step 3:

[0393] Under N2 protection, CO10-2 (200 mg, 0.66 mmol) was dissolved in CCl4 (8 mL), and BPO (70%) (20 mg, 0.06 mmol) was added at room temperature. The mixture was heated to 80 °C, and NBS (118 mg, 0.66 mmol) was added. After reacting for another 2 hours, TLC showed that the starting material had completely reacted. The reaction solution was cooled to room temperature, and the crude product was directly precipitated by silica gel column chromatography to give a pale yellow solid CO10-3 (200 mg, yield 79%). 1 H NMR(400MHz,cdcl3)δ1.49(t,J=7.2Hz,3H),1.61-1.69(m,2H),1.83-1.89(m,2H),1.93-1.98(m,2H),4.45(q,J=7.2Hz, 2H),3.93(s,3H),4.80-4.87(m,1H),5.16(s,2H),7.90(d,J=2.8Hz,1H),8.13(d,J=2.8Hz,1H)

[0394] Step 4:

[0395] Under N2 protection, CO10-3 (200 mg, 0.52 mmol) was dissolved in DMF (10 mL), and NaN3 (70 mg, 1.08 mmol) was added at room temperature. The mixture was heated to 50 °C and stirred for 1 h, then stirred overnight at room temperature. TLC showed that the starting material reacted completely. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain CO10-4 (182 mg, crude product).

[0396] Step 5:

[0397] Under N2 protection, CO10-4 (182 mg, crude product) was dissolved in THF / H2O (6 mL / 1.2 mL), and PPh3 (275 mg, 1.05 mmol) was added at room temperature. The mixture was heated to 50 °C and stirred for 2 h. TLC showed that the starting material and intermediates disappeared. The reaction solution was cooled to room temperature and concentrated. The crude product was purified by silica gel column chromatography to obtain a light brown semi-solid CO10-5 (150 mg, 90% yield in two steps).

[0398] Step 6:

[0399] Under N2 protection, CO10-5 (150 mg, 0.47 mmol) and DIEA (305 mg, 2.36 mmol) were dispersed in MeCN (8 mL). After stirring until dissolved, 1H-1-methylformamidinium hydrochloride (140 mg, 0.95 mmol) was added. The mixture was stirred at room temperature for 18 h. TLC showed that the reaction proceeds were completely reacted (the product dissolved in acetonitrile, and no solid precipitated). The reaction solution was concentrated, and the crude product was purified by Pre-TLC to obtain a white, foamy solid SYY-C010 (150 mg, yield 88%). 1H NMR (DMSO-d6, 400MHz) δ1.39 (t, J = 7.2Hz, 3H), 1.58-1.65 (m, 2H), 1.69-1.82 (m, 4H), 1.88-2.00(m,2H),3.87(s,3H),4.35(q,J=7.2Hz,2H),4.88-4.91(m,1H),4.94(d,J= 5.2Hz,2H),7.46(br,3H),7.80(d,J=2.8Hz,1H),8.12(d,J=2.8Hz,1H),8.38(s,1H). LCMS: m / z=360.2[M+H] +

[0400] Example 12: Preparation of compound SYY-C014

[0401]

[0402] C-IN-008 (100 mg, 0.32 mmol), pyrazolium formamidin hydrochloride (52 mg, 0.35 mmol), and DIEA (165 mg, 1.28 mmol) were dispersed in acetonitrile (5 mL) and reacted overnight at room temperature with stirring. A white solid precipitated. The reaction solution was filtered, the filter cake was washed, and dried to give an off-white solid (50 mg, HPLC purity 75%). This was combined with the mother liquor, concentrated, and the crude product was purified by Pre-TLC to give a white solid (60 mg, yield 53%). 1 H NMR: (DMSO_d6,400MHz): δ1.33(t,J=7.2Hz,3H),3.88(s,3H),4.14(s,3H),4.36(q,J= 7.2Hz, 2H), 4.94 (s, 2H), 7.51-7.85 (m, 4H), 8.48 (d, J=2.0Hz, 1H), 8.61 (d, J=2.0Hz, 1H). LC-MS: m / z=356.1[M+H] + (93.17% purity, 220nm).

[0403] Example 13: Preparation of compound SYY-C015

[0404]

[0405] C-IN-010 (150 mg, 0.48 mmol), 1H-pyrazole-1-formamidinium hydrochloride (92 mg, 0.63 mmol), and DIEA (187 mg, 1.45 mmol) were dispersed in acetonitrile (4 ml) and reacted overnight at room temperature, resulting in the precipitation of a large amount of solid. The reaction solution was filtered, the filter cake was washed with 1 ml of acetonitrile, and dried to give a white solid SYY-C015 (135 mg, yield 79%). 1 H NMR: (DMSO-d6, 400MHz): δ1.37 (t, J=7.2Hz, 3H), 3.85 (s, 3H), 4.35 (q, J=7.2Hz,2H),4.93(s,2H),7.27-7.65(m,4H),7.93-7.96(m,2H),8.39(br,1H).LC-MS: m / z=355.1[M+H]+(98.96% purity,254nm)

[0406] Example 14: Preparation of compound SYY-C016

[0407]

[0408] Step 1

[0409] o-Bromoaniline (10.0 g, 58.13 mmol), ethyl acetoacetate (45.39 g, 0.35 mol), Cs₂CO₃ (37.88 g, 0.12 mol), tetrazolium acetic acid (1.49 g, 11.63 mmol), and cuprous iodide (1.11 g, 5.83 mmol) were dispersed in 50 mL of DMSO solution. The reaction was carried out under nitrogen protection at 100 °C for 3 hours, and TLC showed complete reaction. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain a pale yellow solid C₀₁₆₁ (8.2 g, yield 69%). LC-MS: m / z = 204.1 [M+H] + .

[0410] Step Two:

[0411] Under ice bath conditions, 60% NaH (885 mg, 22.1 mmol) was added to a 20 mL solution of CO16-1 (2.0 g, 9.84 mmol) in DMF. The mixture was stirred for 15 min, then iodomethane (3.14 g, 22.1 mmol) was added, and the mixture was stirred for 30 min. TLC showed that the reaction was complete. The reaction solution was quenched with ice water, and a solid precipitated. The solid was filtered, the filter cake was dissolved in DCM, dried over anhydrous sodium sulfate, and concentrated by filtration to obtain CO16-2 (2.1 g, crude product). 1 H NMR (CDCl3, 400Hz): δ 8.15-8.17 (m, 1H), 7.24-7.31 (m, 3H), 4.43 (q, J = 7.2Hz, 2H), 3.68 (s, 3H), 2.78 (s, 3H), 1.49 (t, J = 7.2Hz, 3H).LC-MS: m / z=218.2[M+H] +

[0412] Step 3:

[0413] C016-2 (1.0 g, 4.6 mmol) was dissolved in carbon tetrachloride (10 mL). NBS (0.82 g, 4.6 mmol) and BPO (56 mg, 0.23 mmol) were added at room temperature, and the mixture was heated under reflux for 2 hours. TLC showed the reaction was complete. The reaction solution was filtered, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography to give a pale yellow solid C016-3 (1.0 g, 72% yield in two steps). LC-MS: m / z = 296.0 [M+H] +

[0414] Step Four:

[0415] C016-3 (1.5 g, 5.06 mmol) was dissolved in DMF (5 mL), and sodium azide (494 mg, 7.60 mmol) was added at room temperature. The system was heated to 60°C and reacted for 2 h. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow solid C016-4 (1.3 g, crude product). LC-MS: m / z = 281.1 [M + Na] +

[0416] Step 5:

[0417] C016-4 (1.5 g, 5.81 mmol) was dissolved in methanol (20 mL), and Pd / C (150 mg) was added. The reaction was carried out overnight at room temperature, and LC-MS showed that the reaction was complete. The reaction solution was filtered through a diatomaceous earth sieve, and the filtrate was concentrated to obtain a pale yellow solid. The solid was slurried with DCM, filtered, and the filter cake was washed and dried to obtain a white solid C016-5 (1.0 g, crude product). LC-MS: m / z = 216.1 [M+H] +

[0418] Step Six:

[0419] C016-5 (150 mg, crude) was dispersed in acetonitrile (5 mL), and DIPEA (336 mg, 2.60 mmol) and pyrazole formamidin hydrochloride (104 mg, 0.71 mmol) were added. The mixture was stirred overnight at room temperature, and a white precipitate was obtained by filtration. The reaction solution was filtered, and the filter cake was washed and dried to give a white solid (120 mg, 50% yield in three steps). 1 H NMR: (DMSO-d6, 400MHz): δ1.39(t,J=7.2Hz,3H),3.86(s,3H),4.36(q,J=7.2Hz,2H),4.94(d,J=4.8 Hz,2H),7.24-7.78(m,6H),8.03(d,J=7.6Hz,1H),8.29-8.35(m,1H).LC-MS: m / z=275.2[M+H] + (99.35% purity, 220nm)

[0420] Example 15: Preparation of compound SYY-C017

[0421]

[0422] C-IN-012 (300 mg, 0.96 mmol) was dispersed in acetonitrile (5 mL), and DIPEA (503 mg, 3.86 mmol) and pyrazole formamidin hydrochloride (155 mg, 1.06 mmol) were added. The mixture was stirred at a warm temperature overnight, and a white precipitate was obtained by filtration. The reaction solution was filtered, and the filter cake was washed and dried to give a white solid SYY-C017 (100 mg, yield 29%). 1 H NMR: (DMSO-d6, 400MHz): δ1.37 (t, J=7.2Hz, 3H), 3.85 (s, 3H), 4.37 (q, J=7.2Hz, 2H), 4.91 (s, 2H), 7.08-7.89 (m, 6H), 8.14 (d, J=2.0Hz, 1H). LC-MS: m / z= 353.1[M+H] +

[0423] Example 16: Preparation of compound SYY-C020

[0424]

[0425] Step 1:

[0426] Under nitrogen protection, 2-amino-6-chloropyridine (5.0 g, 38.89 mmol) was dissolved in DMF (50 mL), and the solution was heated to approximately 0°C in an ice-water bath. NBS (7.3 g, 40.78 mmol) was added in portions. After the addition was complete, the mixture was stirred for 18 minutes. TLC showed that the starting material had reacted completely. The reaction solution was slowly added to water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give an off-white solid CO20-1 (8.0 g, crude product).

[0427] Step 2:

[0428] Under N2 protection, CO20-1 (8.0 g, crude product) was dissolved in DMF (80 mL), and NIS (10.5 g, 46.67 mmol) was added at room temperature. The mixture was heated to 90 °C and stirred for 1 h. TLC showed that the starting material had basically reacted completely. The reaction solution was cooled to room temperature, and water was slowly added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a dark brown solid, CO20-2 (11.4 g, crude product).

[0429] Step 3:

[0430] Under N2 protection, CO20-2 (6.2 g, crude), CuI (345 mg, 1.81 mmol), Cs2CO3 (11.8 g, 36.22 mmol), ethyl acetoacetate (14.0 mL, 110.70 mmol), and tetrazolium acetic acid (463 mg, 3.61 mmol) were dispersed in DMSO (80 mL). The mixture was heated to 110 °C and stirred for 2 h. TLC showed that the starting materials reacted almost completely. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain a dark brown solid, CO20-3 (5.6 g, crude).

[0431] Step 4:

[0432] Under N2 protection, 5.6 g of crude CO20-3 was dissolved in 60 mL of DMF. NaH (60%) (1.06 g, 26.50 mmol) was added in portions under ice bath conditions. After stirring for 15 min, MeI (1.3 mL, 20.88 mmol) was added, and the mixture was stirred at room temperature for 0.5 h. TLC showed that the starting material reacted completely. The reaction mixture was slowly added to a saturated ammonium chloride solution under ice bath conditions. Extraction was performed with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give a yellow solid CO20-4 (2.7 g, 44% yield in four steps). LCMS: m / z = 331.0 [M+H] +

[0433] Step 5:

[0434] Under N2 protection, CO20-4 (620 mg, 1.87 mmol) was dissolved in THF (20 mL), and the solution was cooled to -65 °C. n-BuLi (2.5 M) (2.3 mL, 5.75 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at -65 °C for 0.5 h. TLC showed that the reaction proceeds were completely reacted. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain a yellow solid CO20-5 (470 mg, 99% yield). 1 H NMR (400MHz, CDCl3) δ1.46 (t, J = 7.2Hz, 3H), 2.81 (s, 3H), 3.82 (s, 3H), 4.40 (q, J=7.2Hz,2H),7.18(d,J=8.2Hz,1H),8.26(d,J=8.2Hz,1H).LCMS: m / z=253.1[M+H] +

[0435] Step 6:

[0436] Under N2 protection, CO2O-5 (230 mg, 0.91 mmol) was dissolved in CCl4 (6 mL), and BPO (70%) (20 mg, 0.058 mmol) was added at room temperature. The mixture was heated to 80 °C, and NBS (163 mg, 0.92 mmol) was added. The reaction was continued for 2 h, and TLC showed that the starting material had reacted completely. The reaction solution was cooled to room temperature, and the crude product was purified by silica gel column chromatography to give a pale yellow solid CO2O-6 (185 mg, yield 61%). 1 HNMR (400MHz, CDCl3) δ1.48 (t, J=7.2Hz, 3H), 3.95 (s, 3H), 4.45 (q, J=7.2Hz, 2H), 5.16 (s, 2H), 7.24 (d, J=8.4Hz, 1H), 8.34 (d, J=8.4Hz, 1H)

[0437] Step 7:

[0438] Under N2 protection, CO20-6 (185 mg, 0.56 mmol) was dissolved in DMF (10 mL), and NaN3 (85 mg, 1.31 mmol) was added at room temperature. The mixture was heated to 50 °C and stirred for 1 h, then stirred overnight at room temperature. TLC showed that the starting material reacted completely. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain CO20-7 (164 mg, crude product), which was used directly in the next step.

[0439] Step 8:

[0440] Under N2 protection, CO20-7 (164 mg, 0.56 mmol) was dissolved in THF / H2O (6 mL / 1.2 mL), and PPh3 (293 mg, 1.12 mmol) was added at room temperature. The mixture was heated to 50 °C and stirred for 2 h. TLC showed that the starting material and intermediates disappeared. Silica gel column chromatography of the reaction solution yielded a light brown semi-solid CO20-8 (130 mg, 87% yield in two steps).

[0441] Step 9:

[0442] Under N2 protection, CO20-8 (130 mg, 0.49 mmol) and DIEA (314 mg, 2.43 mmol) were dispersed in acetonitrile (8 mL). After stirring until dissolved, 1H-1-methylformamidinium hydrochloride (144 mg, 0.98 mmol) was added. The mixture was stirred at room temperature (after which solids precipitated) for 48 h. TLC showed that the starting material was completely consumed. The reaction solution was filtered, the filter cake was washed with acetonitrile, and dried to obtain a white solid SYY-C020 (100 mg, yield 67%). 1H NMR (400MHz, DMSO_d6): δ1.38(t,J=7.2Hz,3H),3.86(s,3H),4.37(q,J=7.2Hz,2H),4.97(s,2H),7.41(d,J= 8.4Hz,1H),7.43-7.64(m,3H),8.35(d,J=8.4Hz,1H),8.38-8.41(m,1H).LCMS: m / z=310.1[M+H] +

[0443] Example 17: Preparation of compound SYY-C022

[0444]

[0445] Step 1:

[0446] 4-Amino-2-bromopyridine (3.3 g, 19.07 mmol) and TFA (2.4 g, 21.05 mmol) were dissolved in DMF (30 mL), and NIS (4.7 g, 20.89 mmol) was added at room temperature. The mixture was heated to 50°C and reacted for 2 h. The reaction mixture was monitored by TLC to ensure complete reaction of the starting materials. The reaction solution was cooled to room temperature, poured into ice water, neutralized with saturated sodium carbonate aqueous solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain CO22-1 (2.3 g) and CO22-1-1 (2.6 g).

[0447] C022-1: 1 H NMR: (CDCl3, 400MHz): δ4.75 (s, 2H), 6.80 (s, 1H), 8.33 (s, 1H).

[0448] C022-1-1: 1 H NMR: (CDCl3, 400MHz): δ5.01 (s, 2H), 6.49 (d, J = 5.6Hz, 1H), 7.88 (d, J = 5.6Hz, 1H).

[0449] Step 2:

[0450] C022-1 (2.3 g, 7.69 mmol), ethyl acetoacetate (6.0 g, 46.10 mmol), tetrazolium acetic acid (176 mg, 1.37 mmol), cuprous iodide (147 mg, 0.77 mmol), and cesium carbonate (5.0 g, 15.35 mmol) were dispersed in DMSO (50 mL). The mixture was heated to 150 °C for 7 h under nitrogen protection, and the reaction proceeded to completion as determined by TLC. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed, diluted with water, extracted with ethyl acetate, filtered through diatomaceous earth, separated, washed with water, combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain a brownish-yellow solid, C022-2 (560 mg, yield 26%). LCMS: m / z = 283.0 / 285.0 [M+H] +

[0451] Step 3:

[0452] C022-2 (560 mg, 1.98 mmol) was dissolved in DMF (10 mL). Under nitrogen protection, the mixture was cooled to approximately 0 °C, and 60% sodium hydride (95 mg, 2.38 mmol) was added in portions. After the addition was complete, the mixture was brought back to room temperature and stirred for 30 minutes. Then, it was cooled to approximately 0 °C again, and a solution of iodomethane (295 mg, 2.08 mmol) in DMF (2 mL) was added dropwise. After the addition was complete, the mixture was reacted at 0 °C for 30 minutes. TLC analysis showed that the reaction proceeds were complete. The reaction solution was quenched with ice water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain a pale brownish-yellow solid C022-3 (530 mg, 90% yield). 1 H NMR (400MHz, CDCl3): δ1.46 (t, J= 7.2Hz, 3H), 2.79 (s, 3H), 3.69 (s, 3H), 4.42 (q, J=7.2Hz, 2H), 7.41 (s, 1H), 9.05 (s, 1H). LCMS: m / z=297.0 / 299.0[M+H] +

[0453] Step 4:

[0454] CO22-3 (530 mg, 1.78 mmol), NBS (317 mg, 1.78 mmol), and BPO (44 mg, 0.18 mmol) were dispersed in carbon tetrachloride (30 mL) and heated to reflux for 2 h. TLC was used to detect the remaining trace amount of starting material. The reaction solution was cooled to room temperature and purified directly by silica gel column chromatography to give a white solid CO22-4 (410 mg, yield 61%).

[0455] Step 5:

[0456] C022-4 (410 mg, 1.09 mmol) was dissolved in DMF (10 mL), and sodium azide (107 mg, 1.65 mmol) was added. The mixture was stirred overnight at room temperature, and TLC was used to confirm the complete reaction of the starting material. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow-brown solid C022-5 (crude product, good TLC purity), which was directly added to the next reaction.

[0457] Step 6:

[0458] C022-5 (the crude product from the previous step, theoretically calculated at 1.09 mmol) was dissolved in THF (15 mL) and water (3 mL). Triphenylphosphine (430 mg, 1.64 mmol) was added at room temperature. The reaction mixture was heated to 60°C and reacted for 2 h. TLC analysis showed that the reaction proceeds were complete. The reaction mixture was cooled to room temperature, concentrated, dissolved in ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give an off-white solid C022-6 (250 mg, two-step yield 74%). 1 H NMR (400MHz, DMSO_d6): δ1.37(t,J=7.2Hz,3H),1.90(br,2H),3.84(s,3H),4.17(s,2H),4.33(q,J=7.2Hz,2H),7.94(s,1H),8.88(s,1H). LCMS: m / z=312.1[M+H] +

[0459] Step 7:

[0460] C022-6 (100 mg, 0.32 mmol) was dispersed in acetonitrile (3 mL), and DIEA (165 mg, 1.28 mmol) was added. The mixture did not dissolve upon stirring. Methanol (1 mL) was added, and the reaction solution became clear. Pyrazole formamidin hydrochloride (94 mg, 0.64 mmol) was added, and the reaction solution was stirred at room temperature over the weekend. A solid precipitated from the reaction solution. The solid was filtered, and the filter cake was washed with acetonitrile and dried to give an off-white solid (73 mg, 65% yield). 1 H NMR: (DMSO-d6, 400MHz): δ1.39(t,J=7.2Hz,3H),3.86(s,3H),4.38(q,J=7.2Hz,2H),4.94(d,J=4.0Hz,2H),7.46(br,3H), 8.06(s,1H),8.38(s,1H),8.96(s,1H).LCMS: m / z=354.1[M+H] + (98.07% purity, 220 nm).

[0461] Example 18: Preparation of compound SYY-C023

[0462]

[0463] Step 1:

[0464] C-IN-010 (200 mg, 0.64 mmol), phenylboronic acid (157 mg, 1.29 mmol), PdCl2 (dppf) dichloromethane complex (52 mg, 0.06 mmol), and sodium carbonate (266 mg, 2.51 mmol) were dissolved in a mixed solvent of dioxane (20 ml) and water (5 ml). The mixture was heated to 100 °C and reacted for 2 h. The reaction was confirmed to be complete by LCMS. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was purified by Pre-TLC (DCM / MeOH = 10 / 1) to obtain 220 mg of brown oil. 0.5 ml of DCM was added, followed by 5 ml of PE. The mixture was stirred for 30 min, filtered, and the filter cake was washed and dried to obtain a yellow solid C023-1 (55 mg, crude product).

[0465] Step 2:

[0466] C023-1 (55 mg, 0.18 mmol), 1H-pyrazole-1-formamidin hydrochloride (40 mg, 0.27 mmol), and DIEA (92 mg, 0.71 mmol) were dissolved in acetonitrile (4 ml) and reacted at room temperature for 1 day, resulting in the precipitation of a solid. The reaction solution was filtered, and the filter cake was washed with 1 ml of acetonitrile to give a white solid (54 mg, two-step yield 24%). 1 H NMR: (DMSO-d6, 400MHz): δ1.41(t,J=7.2Hz,3H), 3.93(s,3H), 4.38(q,J=7.2Hz,2H), 4.96(s,2H), 7.22-7.71(m,7H),7.76-7.82(m,2H),7.94(s,1H),8.09(d,J=8.4Hz,1H),8.30(br,1H).LC-MS:m / z=351.2[M+H] + (99.66% purity, 254nm)

[0467] Example 19: Preparation of compounds SYY-C024 and SYY-C025

[0468]

[0469] Step 1:

[0470] C-IN-010 (600 mg, 1.93 mmol), cyclopenten-1-ylboronic acid (432 mg, 3.86 mmol), Pd(dppf)Cl2 (157 mg, 0.19 mmol), and sodium carbonate (798 mg, 7.53 mmol) were dissolved in a mixed solvent of 1,4-dioxane (30 mL) and water (10 mL). The mixture was heated to 100 °C for 2 h under nitrogen protection, and the reaction was monitored for completeness by LC-MS. The reaction solution was cooled to room temperature, extracted with water and ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to crude silica gel column chromatography (DCM / MeOH = 80 / 1) to give a yellow solid C024-1 (510 mg, 89% yield). LC-MS: m / z = 282.2 [M-NH2] +

[0471] Step 2:

[0472] C024-1 (100 mg, 0.34 mmol), 1H-pyrazole-1-formamidin hydrochloride (74 mg, 0.50 mmol), and DIEA (173 mg, 1.34 mmol) were dissolved in acetonitrile (6 ml) and reacted at room temperature for 1 day, resulting in the precipitation of a solid. The reaction solution was filtered, and the filter cake was washed with 1 ml of acetonitrile and dried to give a pale yellow solid SYY-C024 (87 mg, yield 76%). 1 H NMR: (DMSO-d6, 400MHz): δ1.39 (t, J=7.2Hz, 3H), 1.94-2.06 (m, 2H), 2.52-2.56 (m,1H),2.72-2.82(m,2H),3.87(s,3H),4.36(q,J=7.2Hz,2H),4.92(s,2H),6.35(s ,1H),7.07-7.72(m,6H),7.95(d,J=8.4Hz,1H),8.29(br,1H).LCMS: m / z=341.2[M+H] + (98.08% purity, 254nm).

[0473] Step 3:

[0474] CO24-1 (200 mg, 0.67 mmol) was dissolved in methanol (10 mL), and palladium / carbon (200 mg) was added at room temperature. The mixture was purged with hydrogen three times and heated to 50 °C for 1.5 h. LCMS analysis confirmed the reaction was complete. The reaction solution was cooled to room temperature, filtered through a diatomaceous earth liner, and the filtrate was concentrated. The crude product was purified by Pre-TLC (DCM / MeOH = 10 / 1) to give a white solid CO25-1 (140 mg, 70% yield). LCMS: m / z = 284.1 [M-NH2]. +

[0475] Step 4:

[0476] C025-1 (70 mg, 0.23 mmol), 1H-pyrazole-1-formamidin hydrochloride (52 mg, 0.35 mmol) and DIEA (121 mg, 0.94 mmol) were dissolved in acetonitrile (6 ml) and reacted at room temperature for 1 day. A solid precipitated out. The mixture was filtered, and the filter cake was washed with 1 ml of acetonitrile to give a pale yellow solid (44 mg, yield 55%). 1 H NMR:(DMSO-d6,400MHz): δ1.38(t,J=7.2Hz,3H),1.56-1.88(m,6H),2.00-2.12(m,2H),3.07-3.15(m,1H),3.83 (s,3H),4.35(q,J=7.2Hz,2H),4.91(s,2H),7.16-7.92(m,7H).LCMS: m / z=343.2[M+H] + (99.39% purity, 220nm).

[0477] Example 20: Preparation of compound SYY-C026

[0478]

[0479] Step 1:

[0480] IN-008-7 (210 mg, 0.62 mmol) was dissolved in methanol (5 ml), and 10% Pd(OH)₂ / C (210 mg) was added at room temperature. The mixture was purged with hydrogen three times, and the temperature was raised to 60 °C for 1 h, monitored by TLC (after the starting material had completely reacted). The reaction solution was cooled to room temperature, filtered through a diatomaceous earth liner, and the filtrate was concentrated. The crude product was purified by Pre-TLC (DCM / MeOH = 7 / 1) to give a white solid CO₂₆₁ (106 mg, yield 73%). LCMS: m / z = 234.1 [M + H] +

[0481] Step 2:

[0482] C026-1 (100 mg, 0.43 mmol), 1H-pyrazole-1-formamidin hydrochloride (75 mg, 0.51 mmol), and DIEA (221 mg, 1.71 mmol) were dispersed in acetonitrile (4 mL) and methanol (2 mL). The mixture was reacted at room temperature for 2 days, resulting in the precipitation of a solid. The reaction solution was filtered, the filter cake was washed with acetonitrile, and dried to give a white solid SYY-C026 (36 mg, yield 31%). 1H NMR: (DMSO-d6, 400MHz): δ1.34 (t, J=7.2Hz, 3H), 3.88 (s, 3H), 4.37 (q, J=7.2 Hz, 2H), 4.95 (s, 2H), 7.25-7.65 (m, 4H), 8.08 (d, J=8.4Hz, 1H), 8.31 (br, 1H), 8.55 (d, J=4.4Hz, 1H). LCMS: m / z=276.2[M+H] + (97.63% purity, 220nm)

[0483] Example 21: Preparation of compound SYY-C028

[0484]

[0485] Step 1:

[0486] C-IN-011 (1.21 g, 4.1 mmol), phenylboronic acid (100 g, 8.2 mmol), Pd(dppf)Cl2 (355 mg, 0.41 mmol), and sodium carbonate (870 mg, 8.2 mmol) were dispersed in a mixed solvent of Dioxane (100 ml) and water (5 ml). The mixture was heated to 100 °C and reacted for 2 h until complete. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and purified by pre-TLC of the crude product to give a yellow solid C028-1 (800 mg, yield 67%).

[0487] Step 2:

[0488] C028-1 (378 mg, 1.29 mmol) was dissolved in carbon tetrachloride (100 mL), and NBS (229 mg, 1.28 mmol) and BPO (31 mg, 0.12 mmol) were added. The mixture was heated to 70 °C and reacted for 3 h. TLC showed that the starting material disappeared. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The pre-TLC purified yellow solid C028-2 (273 mg, yield 57%) was obtained.

[0489] Step 3:

[0490] C028-2 (273 mg, 0.73 mmol) was dissolved in DMF (5 mL), and sodium azide (72 mg, 1.10 mmol) was added at room temperature. The system was heated to 60°C and reacted for 2 h. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow oily C028-3 (200 mg, crude product).

[0491] Step 4:

[0492] C028-3 (200 mg, 0.60 mmol) was dissolved in MeOH (10 mL), and Pd / C (50 mg) was added at room temperature. The mixture was heated to 40 °C and reacted for 5 h under a hydrogen atmosphere. TLC showed that the reaction was complete. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated into a pale yellow oily C028-4 (130 mg, crude product).

[0493] Step 5:

[0494] C028-4 (130 mg, crude), 1H-pyrazole-1-formamidinium hydrochloride (68 mg, 0.46 mmol), and DIEA (217 mg, 1.68 mmol) were dispersed in acetonitrile (5 mL) and reacted at room temperature for 18 h, resulting in the precipitation of a solid. The reaction solution was filtered, the filter cake was washed with 1 mL of acetonitrile, and dried to give a white solid (50 mg, 24% yield in two steps). 1 H NMR: (DMSO-d6,400MHz): δ1.40(t,J=7.2Hz,3H),3.89(s,3H),4.39(q,J=7.2Hz,2H), 4.95(s,2H),7.24-7.80(m,10H),8.28-8.36(m,2H).LC-MS: m / z=351.2[M+H] +

[0495] Example 22: Preparation of compound SYY-C029

[0496]

[0497] Step 1:

[0498] 1-Naphthylamine (9.34 g, 65.23 mmol), NBS (11.61 g, 65.23 mmol), and acetic acid (4.11 g, 68.49 mmol) were dispersed in acetonitrile (200 mL) and reacted at room temperature for 18 h. TCL showed the starting material disappeared, and two new spots appeared. The reaction solution was diluted with ethyl acetate, washed with saturated Na₂CO₃ aqueous solution, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain CO₂₉₁ (7.0 g, 48% yield).

[0499] Step 2:

[0500] C029-1 (7.0 g, 31.52 mmol), ethyl acetoacetate (24.61 g, 189.12 mmol), tetrazolium acetic acid (807 mg, 6.30 mmol), cuprous iodide (600 mg, 3.15 mmol), and cesium carbonate (20.54 g, 63.04 mmol) were dispersed in DMSO (100 mL). The mixture was reacted at 100°C for 3 h under nitrogen protection, and the starting material disappeared according to TCL. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain C029-2 (1.2 g, 15% yield).

[0501] Step 3:

[0502] C029-2 (1.2 g, 4.74 mmol) was dissolved in DMF (10 mL). 60% sodium hydride (284 mg, 7.11 mmol) was added at 0 °C, and the mixture was stirred for 30 min. Iodomethane (1.0 g, 7.11 mmol) was then added, and the reaction was continued at 0 °C for 2 h. TLC showed the disappearance of the starting material. The reaction mixture was quenched with ice water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain solid C029-3 (350 mg, yield 28%).

[0503] Step 4:

[0504] CO29-3 (350 mg, 1.31 mmol), NBS (233 mg, 1.31 mmol), and BPO (45 mg, 0.13 mmol) were dissolved in carbon tetrachloride and reacted at 80 °C for 2 hours. TLC showed that the reaction was complete. The reaction solution was concentrated to obtain CO29-4 (crude product), which was used directly in the next step.

[0505] Step 5:

[0506] C029-4 (crude product) and NaN3 (128 mg, 1.97 mmol) were dispersed in DMF (10 mL) and reacted at 70 °C for 2 h. TLC showed that the starting material disappeared. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain C029-5 (crude product), which was used directly in the next step.

[0507] Step 6:

[0508] C029-5 (crude product) was dissolved in methanol (10 mL), and 10% Pd / C (300 mg) was added at room temperature. The mixture was purged with hydrogen three times and reacted at room temperature for 48 h. TLC showed the disappearance of the starting material. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography to obtain solid C029-6 (80 mg, three-step yield 22%).

[0509] Step 7:

[0510] C029-6 (80 mg, 0.28 mmol), 1H-pyrazole-1-formamidin hydrochloride (45 mg, 0.31 mmol), and DIPEA (145 mg, 1.12 mmol) were dispersed in acetonitrile (5 mL) and reacted at room temperature for 18 h, resulting in the precipitation of a solid. The reaction solution was filtered, and the filter cake was washed and dried to give a white solid SYY-C029 (25 mg, yield 27%).

[0511] 1 H NMR: (DMSO-d6, 400MHz): δ1.42(t,J=7.2Hz,3H),4.29(s,3H),4.41(q,J=7.2Hz,2H),5.02(s,2H),7.24- 7.76(m,7H),8.06(d,J=8.0Hz,1H),8.23(d,J=8.8Hz,1H),8.70(d,J=8.4Hz,1H).LC-MS: m / z=325.2[M+H] +

[0512] Example 23: Preparation of compound SYY-C030

[0513]

[0514] C018-4 (300 mg, 1.02 mmol) and 1H-pyrazole-1-formamidin hydrochloride (165 mg, 1.12 mmol) were dissolved in CH3CN (5 mL), and DIPEA (516 mg, 4.08 mmol) was added. The mixture was stirred overnight at room temperature, and TLC showed that the reaction was complete. During the concentration of the reaction solution, a solid precipitated out. The mixture was filtered, and the filter cake was washed with acetonitrile to give a white solid SYY-C030 (260 mg, yield 76%). 1 HNMR: (DMSO-d6, 400MHz): δ1.39 (t, J=7.2Hz, 3H), 4.38 (q, J=7.2Hz, 2H), 4.55 (d, J=4.0Hz, 2H), 6.95-7.49 (m, 6H), 7.51-7.60 (m, 2H),7.62-7.72(m,3H),8.11-8.17(m,2H).LC-MS: m / z=337.1[M+H] + (99.57% purity, 220nm)

[0515] Example 24: Preparation of compound SYY-C031

[0516]

[0517] C018-2 (470 mg, 1.31 mmol) was dissolved in EtOH (5 ml), and thiourea (110 mg, 1.45 mmol) was added at room temperature. The mixture was heated to 80 °C and stirred for 2 h. TLC showed that the reaction was complete. The reaction solution was concentrated, and the crude product was purified by pre-TLC to give a solid (110 mg, yield 24%). 1 H NMR: (DMSO-d6, 400MHz): δ1.40 (t, J=7.2Hz, 3H), 4.40 (q, J=7.2Hz, 2H), 4.75 (s, 2H), 7.01 (d, J=8.0Hz, 1H), 7.28-7.33 (m, 2H), 7,53-7.55(m,2H),7.68-7.71(m,3H),8.11(d,J=8.0Hz,1H),8.98(br,2H).LC-MS: m / z=354.1[M+H] + (93.59% purity, 254nm).

[0518] Example 25: Preparation of compound SYY-C032

[0519]

[0520] Step 1:

[0521] C-IN-004 (400 mg, 0.99 mmol), 2-aminooxazole (168 mg, 2.00 mmol), and DIEA (322 mg, 2.49 mmol) were dissolved in dichloromethane (10 mL). The mixture was stirred at room temperature for 2 days. TLC analysis showed the remaining starting material and the formation of new spots. The reaction solution was purified by silica gel column chromatography to give an off-white solid C033-1 (85 mg, yield 21%). LCMS: m / z = 409.0 / 412.0 [M+H] +

[0522] Step 2:

[0523] C033-1 (85 mg, 0.21 mmol) was dissolved in methanol (10 mL), and palladium on carbon (85 mg) was added. After three purgings with hydrogen, the mixture was heated to 60°C and reacted for 2 h. The reaction was confirmed to be complete by TLC. The reaction solution was cooled to room temperature, filtered through a diatomaceous earth liner, and the filtrate was concentrated. The crude product was neutralized with saturated sodium carbonate aqueous solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Pre-TLC to give a white solid SYY-C032 (40 mg, yield 58%). 1H NMR: (CD3OD, 400MHz): δ1.00(t,J=7.2Hz,3H),1.46(t,J=7.2Hz,3H),3.21(q,J=7.2Hz,2H),4.01(s,3H),3.79(s,3H),4.40(q,J=7.2Hz,2H),5.25 (s,2H),6.72(d,J=8.8Hz,1H),7.81(d,J=8.8Hz,1H).LCMS:m / z=335.2[M+H] + (96.30% purity, 220nm)

[0524] Example 26: Preparation of compound SYY-C034

[0525]

[0526] Step 1:

[0527] Under nitrogen protection, 4-amino-3-iodopyridine (4.00 g, 18.18 mmol), ethyl acetoacetate (14.20 g, 109.11 mmol), tetrazolium acetate (415 mg, 3.24 mmol), cuprous iodide (347 mg, 1.82 mmol), and cesium carbonate (1.18 g, 3.62 mmol) were dispersed in DMSO (80 mL) and reacted at 150 °C for 7 h. The reaction mixture was monitored by TLC to ensure complete reaction of the starting materials. The reaction solution was cooled to room temperature, filtered through a diatomaceous earth liner, washed, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give a brownish-yellow solid C034-1 (2.1 g, 57% yield). LCMS: m / z = 205.1 [M+H] +

[0528] Step 2:

[0529] C034-1 (1.0 g, 4.90 mmol) was dispersed in DMF (10 mL). Under nitrogen protection, the mixture was cooled to approximately 0 °C, and 60% sodium hydride (255 mg, 6.38 mmol) was added in portions. After the addition was complete, the mixture was allowed to return to room temperature for half an hour. The mixture was then cooled again to 0 °C, and a solution of iodomethane (765 mg, 5.39 mmol) in DMF (5 mL) was added dropwise. After the addition was complete, the mixture was allowed to continue reacting at 0 °C for another half hour. TLC analysis confirmed complete reaction of the starting material. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain a light brown solid, C034-2 (630 mg, yield 59%). LCMS: m / z = 219.1 [M+H] +

[0530] Step 3:

[0531] C034-2 (510 mg, 2.34 mmol) was dissolved in trifluoroacetic acid (5 mL), and NBS (749 mg, 4.21 mmol) was added. The reaction mixture was stirred overnight at room temperature, and TLC was used to confirm the complete reaction of the starting material. The reaction mixture was concentrated at room temperature to obtain C034-3 (crude product), which was directly added to the next reaction step.

[0532] Step 4:

[0533] C034-3 (the crude product from the previous step, theoretically calculated at 2.34 mmol) was dissolved in DMF (5 mL), cooled to approximately 0°C in an ice bath, neutralized with DIEA, and then NaN3 (183 mg, 2.81 mmol) was added. The reaction mixture was heated to 40°C and reacted for 2 h. LCMS analysis confirmed the reaction was complete. The reaction mixture was cooled to room temperature, poured into water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain a brownish-yellow viscous oil, C034-4 (320 mg, two-step yield 53%). LCMS: m / z = 260.1 [M+H] +

[0534] Step 5:

[0535] C034-4 (320 mg, 1.23 mmol) was dissolved in a mixed solvent of THF (15 mL) and water (3 mL). Triphenylphosphine (486 mg, 1.85 mol) was added at room temperature, and the mixture was heated to 60 °C for 2 h. The reaction was confirmed to be complete by TLC and LCMS. The reaction solution was cooled to room temperature, and the solvent was concentrated to a minimum. The solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Pre-TLC to give a grayish-white solid C034-5 (230 mg, 80% yield). LC-MS: No reaction observed.

[0536] Step 6:

[0537] C034-5 (55 mg, 0.24 mmol) was dispersed in acetonitrile (5 mL), and DIEA (122 mg, 0.94 mmol) was added. After stirring and dissolving, pyrazole formamidin hydrochloride (69 mg, 0.47 mmol) was added at room temperature. After the addition was complete, the reaction solution was heated to 25 °C and reacted for 3 days, resulting in the precipitation of a solid. The reaction solution was filtered, and the filter cake was washed and dried to give a white solid (36 mg, yield 55%). 1H NMR: (CD3OD, 400MHz): δ1.50(t,J=7.2Hz,3H),3.95(s,3H), 4.51(q,J=7.2Hz,2H),5.05(s,2H),7.65(d,J=6.0Hz,1H), 8.38(d,J=6.0Hz,1H), 9.23(s,1H).LCMS:m / z=276.1[M+H] + (99.12% purity, 220nm)

[0538] Example 27: Preparation of compound SYY-C035

[0539]

[0540] Step 1:

[0541] Under nitrogen protection, 3-amino-4-iodopyridine (3.0 g, 13.64 mmol) was dissolved in DMSO (50 mL), and ethyl acetoacetate (10.6 g, 81.45 mmol), tetrazolium acetic acid (349 mg, 2.732 mmol), cuprous iodide (260 mg, 1.37 mmol), and cesium carbonate (8.9 g, 27.32 mmol) were added. After the addition was complete, the mixture was heated to 150 °C and reacted for 7 h. The reaction mixture was monitored by TLC to ensure the starting material was completely reacted. The reaction solution was cooled to room temperature, filtered through a diatomaceous earth filter, and the filtrate was extracted with water and ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography (DCM / MeOH = 15 / 1) to give a yellow solid CO35-1 (1.96 g, 71% yield). LCMS: m / z = 205.1 [M+H] +

[0542] Step 2:

[0543] Under nitrogen protection, CO35-1 (1.0 g, 4.90 mmol) was dissolved in 15 ml of dry DMF. The solution was cooled in an ice-water bath, and 60% NaH (206 mg, 5.15 mmol) was added in portions at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 0.5 h, then cooled to 0 °C. Iodomethane (731 mg, 5.15 mmol) was added dropwise. After the addition was complete, the reaction was continued for 20 min, and TLC was used to monitor the reaction progress. The reaction solution was quenched with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography (DCM / MeOH = 100 / 1) to give a yellow solid CO35-2 (485 mg, yield 45%). LCMS: m / z = 219.1 [M+H] +

[0544] Step 3:

[0545] C035-2 (436 mg, 2.00 mmol) was dissolved in TFA (10 ml), and NBS (374 mg, 2.10 mmol) was added. The reaction was carried out overnight at room temperature. TLC showed that a small amount of starting material had not reacted completely, so NBS (36 mg, 0.20 mmol) was added, and the reaction was continued at room temperature for 3 hours. TLC showed that the starting material had reacted completely. The reaction solution was concentrated at room temperature to obtain C035-3 (crude product), which was directly used in the next step.

[0546] Step 4:

[0547] C035-3 (crude product, 2.00 mmol theoretically) was dissolved in DMF (10 ml), and the pH was adjusted to neutral with DIEA. Then, NaN3 (195 mg, 3.00 mmol) was added, and the mixture was heated to 50 °C for 2 h. LC-MS analysis confirmed the reaction was complete. The reaction solution was cooled to room temperature, extracted with water and ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give a yellow solid C035-4 (345 mg, 67% yield in two steps). LC-MS: m / z = 260.1 [M+H] +

[0548] Step 5:

[0549] C035-4 (340 mg, 1.31 mmol) and PPh3 (516 mg, 1.97 mmol) were dissolved in a mixed solvent of THF (12 ml) and water (4 ml) and reacted overnight at room temperature, monitored by LCMS (after the starting material had reacted completely). The reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by pre-TLC (DCM / MeOH = 15 / 1) to give a pale yellow solid C035-5 (210 mg, yield 69%). LCMS: m / z = 234.1 [M+H] +

[0550] Step 6:

[0551] C035-5 (100 mg, 0.43 mmol), 1H-pyrazole-1-formamidin hydrochloride (95 mg, 0.65 mmol), and DIEA (222 mg, 1.72 mmol) were dissolved in acetonitrile (6 mL) and reacted at room temperature for 36 h. A solid precipitated from the reaction solution, which was filtered, and the filter cake was washed and dried to give a white solid SYY-C035 (105 mg, yield 89%). 1H NMR: (DMSO-d6, 400MHz): δ1.39(t,J=7.2Hz,3H),3.98(s,3H),4.37(q,J=7.2Hz,2H),4.98(s,2H), 7.52(br,3H),7.90(dd,J=6.0,1.2Hz,1H),8.35(d,J=6.0Hz,1H),8.42(br,1H),9.03 (d,J=1.2Hz,1H).LCMS: m / z=276.2[M+H] + (95.94% purity, 220nm)

[0552] Example 28: Preparation of compound SYY-C036

[0553]

[0554] Step 1:

[0555] Under N2 protection, C-IN-003 (1.5 g, 9.25 mmol) was dissolved in DMF (20 mL). NaH (60%) (560 mg, 14.00 mmol) was added in an ice bath, and the mixture was stirred for 15 min. Then, MeI (0.7 mL, 11.24 mmol) was added, and the mixture was stirred at room temperature for 0.5 h. TLC showed that the starting material reacted completely. The reaction mixture was slowly poured into water in an ice bath, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give a pale yellow solid C036-1 (1.0 g, 62% yield).

[0556] Step 2:

[0557] Under N2 protection, CO36-1 (1.0 g, 5.67 mmol) was dissolved in DMF (20 mL), and NIS (1.28 g, 5.69 mmol) was added under ice bath conditions. The mixture was stirred for 2 min, and TLC showed that the starting material disappeared. Water was slowly added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow solid, CO36-2 (1.5 g, crude product).

[0558] Step 3:

[0559] Under N2 protection, CO36-2 (1.3 g, crude product) was dissolved in NMP (13 mL), and CuCN (3.0 g, 34.42 mmol) was added at room temperature. The mixture was heated to 110 °C and stirred for 14 h. TLC showed that the starting material was basically completely reacted. The reaction solution was cooled to room temperature, and ethyl acetate and NH3·H2O / NH4Cl aq (1:3) were added. The layers were separated, the aqueous layer was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was concentrated and purified by silica gel column chromatography to obtain CO36-3 (415 mg, two-step yield 42%).

[0560] Step 4:

[0561] Under N2 protection, CO36-3 (300 mg, 1.49 mmol) was dissolved in carbon tetrachloride (4 mL), and BPO (70%) (20 mg, 0.06 mmol) was added at room temperature. The mixture was heated to 80 °C, and NBS (300 mg, 1.49 mmol) was added. The reaction was continued for 2 h, and TLC showed that the starting material had reacted completely. The reaction solution was cooled to room temperature, and the crude product was purified by silica gel column chromatography to give a pale yellow solid CO36-4 (376 mg, 90% yield). 1 H NMR (400MHz, CDCl3) δ3.92 (s, 3H), 3.95 (s, 3H), 4.75 (s, 2H), 7.46 (d, J = 2.8Hz, 1H), 8.22 (d, J = 2.8Hz, 1H)

[0562] Step 5:

[0563] Under N2 protection, CO36-4 (376 mg, 1.34 mmol) was dissolved in DMF (10 mL), and NaN3 (233 mg, 3.58 mmol) was added at room temperature. The mixture was heated to 50 °C and stirred for 1 h, then cooled to room temperature and stirred overnight. TLC showed that the starting material reacted completely. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain CO36-5 (300 mg, crude product).

[0564] Step 6:

[0565] Under nitrogen protection, CO36-5 (300 mg, crude product) was dissolved in MeOH (30 mL). H2O2 (30%) (30 mL) and KOH solution (15 mL, 2 M) were added at room temperature. The mixture was heated to 50 °C and stirred for 1 h. TLC showed complete reaction of the starting material. The reaction solution was cooled to room temperature, and the pH was adjusted to approximately 5 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with water and 10% Na2SO3 solution, dried over anhydrous sodium sulfate, and concentrated to give a white solid CO36-6 (270 mg, two-step yield 77%). 1H NMR (400MHz, DMSO_d6): δ3.81 (s, 3H), 3.89 (s, 3H), 5.03 (s, 2H), 7.39 (s, 2H), 7.79 (d, J = 2.8Hz, 1H), 8.13 (d, J = 2.8Hz, 1H). LCMS: m / z = 261.1 [M+H] +

[0566] Step 7:

[0567] Under N2 protection, CO36-6 (150 mg, 0.58 mmol) was dissolved in a mixed solvent of MeOH / THF (10 mL / 10 mL). Pd / C (10%) (50 mg) was added at room temperature, and the mixture was heated to 40 °C and stirred for 1 h. TLC showed that the starting material reacted completely. The reaction solution was cooled to room temperature, filtered through a diatomaceous earth filter, and the filter cake was washed with THF and MeOH. The filtrate was concentrated, and the residue was slurried with petroleum ether and ethyl acetate, filtered, and a white solid, CO36-7 (90 mg, crude product), was obtained. LCMS: m / z = 235.1 [M+H] +

[0568] Step 8:

[0569] Under N2 protection, CO36-7 (90 mg, crude product) and DIEA (245 mg, 1.90 mmol) were dispersed in acetonitrile (6 mL). After stirring until dissolved, 1H-1-methylformamidinium hydrochloride (113 mg, 0.77 mmol) was added, and the mixture was stirred at room temperature for 18 h. A large amount of solid precipitated, and TLC showed that the starting material was completely consumed. The reaction solution was filtered, the filter cake was washed with acetonitrile, and dried to give a white solid SYY-C036 (80 mg, 50% yield in two steps). 1 H NMR ((DMSO-d6, 400MHz): δ3.89 (s, 6H), 4.84 (s, 2H), 7.28 (br, 3H), 7.75 (s, 1H), 7.85 (s, 2H), 8.12 (s, 1H), 9.0 (br, 1H). LCMS: m / z=277.1[M+H] +

[0570] Example 29: Preparation of compounds SYY-C037 and SYY-C039

[0571]

[0572] Step 1:

[0573] Under nitrogen protection, C-IN-012 (650 mg, 2.09 mmol) was dissolved in a mixed solvent of Dioxane (13 ml) and water (4 ml). At room temperature, Pd(dppf)Cl2 dichloromethane complex (172 mg, 0.21 mmol), cyclopenten-1-ylboronic acid (588 mg, 5.25 mmol), and Na2CO3 (668 mg, 6.31 mmol) were added. The mixture was heated to 100 °C and stirred for 3 h. TLC showed the disappearance of the starting material. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give a brown solid C037-1 (430 mg, 69% yield).

[0574] Step 2:

[0575] C037-1 (150 mg, 0.50 mmol) and DIEA (323 mg, 2.50 mmol) were dispersed in acetonitrile (3 mL), stirred until dissolved, and then 1H-1-methylformamidinium hydrochloride (147 mg, 1.00 mmol) was added. The mixture was stirred at room temperature for 20 h. The reaction solution was filtered, the filter cake was washed with acetonitrile, and dried to give a light brown solid SYY-C037 (30 mg, yield 18%). 1 H NMR (400MHz, DMSO_d6)δ1.40(t,J=7.2Hz,3H),1.94-2.05(m,2H),2.53-2.55(m,2H), 2.70-2.77(m,2H),3.85(s,3H),4.36(q,J=7.2Hz,2H),4.92(d,J=4.4Hz,2H),6.2 6(s,1H),7.42(br,3H),7.57-7.60(m,2H),8.03(s,1H),8.26-8.33(m,1H).LCMS: m / z=341.2[M+H] + (88.84% purity, 254nm)

[0576] Step 3:

[0577] Under a hydrogen atmosphere, CO37-1 (250 mg, 0.84 mmol) was dissolved in methanol (6 mL), and 10% Pd / C (200 mg) was added at room temperature. The mixture was heated to 40 °C and stirred for 4 h. LCMS showed that the starting material disappeared. The reaction solution was filtered, the filter cake was washed with methanol, the filtrate was concentrated, and pre-TLC purification yielded a pale pink solid CO39-1 (200 mg, yield 79%). 1H NMR (400MHz, DMSO_d6): δ1.40(t,J=7.2Hz,3H),1.50-1.63(m,2H),1.64-1.74(m,2H), 1.79-1.82(m,2H),2.02-2.09(m,2H),3.07-3.14(m,1H),3.84(s,3H),4.26-4.38(m,4H), 5.68(br,2H),7.18(d,J=8.5Hz,1H),7.50(d,J=8.5Hz,1H),7.90(s,1H)

[0578] Step 4:

[0579] C039-1 (100 mg, 0.33 mmol) and DIEA (213 mg, 1.65 mmol) were dispersed in acetonitrile (3 mL), stirred until dissolved, and then 1H-1-methylformamidinium hydrochloride (100 mg, 0.68 mmol) was added. The mixture was stirred at room temperature for 40 h, and a large amount of solid precipitated. The reaction solution was filtered, the filter cake was washed with acetonitrile, and dried to give a white solid SYY-C039 (50 mg, yield 44%). 1 H NMR (400MHz, DMSO_d6): δ1.39 (t, J = 7.2Hz, 3H), 1.53-1.62 (m, 2H),1.64-1.74(m,2H),1.75-1.84(m,2H),2.02-2.10(m,2H),3.09-3.13(m,1H),3.83 (s,3H),4.35(q,J=7.2Hz,2H),4.91(s,2H),7.23(dd,J=8.8,1.6Hz,1H),7.28-7.80(m, 4H),7.90(s,1H),8.21(br,1H).LCMS: m / z=343.2[M+H] + (99.27purity, 220nm).

[0580] Example 30: Preparation of compound SYY-C040

[0581]

[0582] Step 1:

[0583] Under nitrogen protection, C-IN-010 (280 mg, 0.90 mmol) was dissolved in a mixed solvent of 1,4-Dioxane (30 ml) and water (10 ml). At room temperature, Pd(dppf)Cl2 dichloromethane complex (74 mg, 0.091 mmol), 2-naphthoboric acid (389 mg, 2.26 mmol), and Na2CO3 (288 mg, 2.72 mmol) were added sequentially. The mixture was heated to 100 °C and stirred for 1.5 h. TLC showed the disappearance of the starting material. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain a dark brown solid, which was then purified by Pre-TLC to obtain a pale yellow solid C040-1 (220 mg, yield 68%).

[0584] Step 2:

[0585] Under nitrogen protection, CO40-1 (150 mg, 0.42 mmol) was dissolved in acetonitrile (3 mL), and DIEA (272 mg, 2.10 mmol) and 1H-1-methylformamidinium hydrochloride (123 mg, 0.84 mmol) were added. The mixture was stirred at room temperature for 40 h, and a large amount of solid precipitated. The reaction solution was filtered, the filter cake was washed with acetonitrile, and dried to give an off-white solid SYY-C040 (120 mg, yield 72%). 1 H NMR (400MHz, DMSO_d6): δ1.42(t,J=7.2Hz,3H),3.91(s,3H),4.40(q, J=7.2Hz,2H),5.00(s,2H),7.38(dd,J=8.0,0.8Hz,1H),7.43-7.74(m,6H),7.77(s, 1H),7.84(d,J=8.4Hz,1H),8.00(dd,J=17.6,8.4Hz,2H),8.14-8.76(m,3H)LCMS: m / z=401.2[M+H] +

[0586] Example 31: Preparation of compound SYY-C041

[0587]

[0588] Step 1:

[0589] Under nitrogen protection, C-IN-010 (280 mg, 0.90 mmol) was dissolved in a mixed solvent of 1,4-Dioxane (30 ml) and water (10 ml). At room temperature, Pd(dppf)Cl2 dichloromethane complex (74 mg, 0.091 mmol), 2-naphthoboric acid (389 mg, 2.26 mmol), and Na2CO3 (288 mg, 2.72 mmol) were added sequentially. The mixture was heated to 100 °C and stirred for 1.5 h. TLC showed the disappearance of the starting material. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain a dark brown solid, which was then purified by Pre-TLC to obtain a pale yellow solid C041-1 (220 mg, yield 68%).

[0590] Step 2:

[0591] Under nitrogen protection, CO41-1 (150 mg, 0.42 mmol) was dissolved in acetonitrile (3 ml), and DIEA (272 mg, 2.10 mmol) and 1H-1-methylformamidinium hydrochloride (123 mg, 0.84 mmol) were added. The mixture was stirred at room temperature for 40 h, and a large amount of solid precipitated. The reaction solution was filtered, the filter cake was washed with acetonitrile, and dried to give an off-white solid SYY-C041 (150 mg, yield 89%). 1 H NMR(400MHz, DMSO_d6)δ1.42(t,J=7.2Hz,3H),3.98 (s,3H),4.40(q,J=7.2Hz,2H),4.98(s,2H),7.18-7.72(m,5H),7.77(dd,J=8.4,1.2Hz, 1H),7.96-8.05(m,4H),8.11-8.14(m,2H),8.34-8.47(br,2H).LCMS: m / z=401.2[M+H] + .

[0592] Example 32: Preparation of compound SYY-C042

[0593]

[0594] Step 1:

[0595] C-IN-015 (300 mg, 0.96 mmol) was dissolved in a mixed solvent of 1,4-dioxane (30 ml) and water (10 ml). At room temperature, 1-naphthoboric acid (331 mg, 1.92 mmol), PdCl2(dppf) dichloromethane complex (79 mg, 0.10 mmol), and sodium carbonate (398 mg, 3.76 mmol) were added. The mixture was purged with nitrogen three times and heated to 100 °C for 2 h. TLC analysis confirmed complete reaction of the starting material. The reaction solution was cooled to room temperature, extracted with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give a white solid C042-1 (183 mg, 53% yield).

[0596] Step 2:

[0597] CO42-1 (116 mg, 0.32 mmol) was dissolved in dichloromethane (3 mL), cooled to 0 °C in an ice-water bath, and PBr3 (88 mg, 0.33 mmol, diluted in 0.5 mL DCM) was added dropwise under nitrogen protection. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 h, and the reaction was monitored by TLC to confirm the completeness of the reaction. The reaction solution was diluted with 3 mL DCM, and saturated sodium bicarbonate solution was added dropwise until neutral. The mixture was separated, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a pink solid CO42-2 (129 mg, crude product).

[0598] Step 3:

[0599] Under nitrogen protection, CO42-2 (129 mg, crude product) was dissolved in ethanol (5 ml), and thiourea (21 mg, 0.28 mmol) was added at room temperature. The mixture was heated to 80 °C and reacted for 1.0 h. TLC was used to detect the complete reaction of the starting material. The reaction solution was cooled to room temperature, and a large amount of solid precipitated out. The mixture was stirred for 20 min, filtered, and the filter cake was washed with ethanol to obtain a white solid SYY-C042 (60 mg, two-step yield 45%). 1 H NMR: (DMSO-d6, 400MHz): δ1.42(t,J=7.2Hz,3H),3.92(s,3H), 4.40(q,J=7.2Hz,2H),5.18(s,2H),7.39(dd,J=8.4,1.2Hz,1H),7.45-7.66(m,4H), 7.76(s,1H),7.86(d,J=8.4Hz,1H),7.98-8.04(m,2H),8.14(d,J=8.4Hz,1H),9.25(br,3H).LCMS: m / z=418.1[M+H] + (99.17% purity, 220nm).

[0600] Example 33: Preparation of compound SYY-C043

[0601]

[0602] Step 1:

[0603] C-IN-015 (400 mg, 1.28 mmol) was dissolved in a mixed solvent of 1,4-Dioxane (30 ml) and water (10 ml). 2-Naphthoboric acid (441 mg, 2.56 mmol), PdCl2(dppf) dichloromethane complex (105 mg, 0.13 mmol), and sodium carbonate (531 mg, 5.01 mmol) were added at room temperature. The mixture was purged with nitrogen three times and heated to 100 °C for 2 h. TLC showed complete reaction of the starting material. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography (PE / EA = 3 / 1) to give a pale yellow solid C043-1 (361 mg, yield 79%).

[0604] Step 2:

[0605] C043-1 (150 mg, 0.42 mmol) was dissolved in dichloromethane (4 mL), cooled to 0°C in an ice-water bath, and PBr3 (113 mg, 0.42 mmol, diluted in 0.5 mL DCM) was added dropwise under nitrogen protection. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 h, and the reaction was monitored by TLC to confirm the completeness of the reaction. The reaction solution was diluted with 3 mL DCM, and the pH was adjusted to neutral by adding saturated sodium bicarbonate solution. The mixture was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a yellow solid C043-2 (176 mg, crude product).

[0606] Step 3:

[0607] Under nitrogen protection, CO43-2 (176 mg, crude product) was dissolved in ethanol (5 ml), and thiourea (32 mg, 0.42 mmol) was added at room temperature. The mixture was heated to 80 °C and reacted for 1.0 h. TLC was used to detect the complete reaction of the starting material. The reaction solution was cooled to room temperature, and a large amount of solid precipitated out. The mixture was stirred for 20 min, filtered, the filter cake was washed with ethanol, and dried to obtain a white solid SYY-C043 (120 mg, two-step yield 69%). 1HNMR: (DMSO-d6, 400MHz): δ1.42 (t, J=7.2Hz, 3H), 3.99 (s, 3H), 4.38 (q, J=7.2Hz, 2H), 5.17 (s, 2H), 7.47-7.62 (m, 2H), 7.77 (dd, J=8.4, 1.2Hz, 1H),7.93-8.15(m,6H),8.34(s,1H),9.26(br,3H).LCMS: m / z=418.2[M+H] + (99.27% ​​purity, 254nm).

[0608] Example 34: Preparation of compound SYY-C045

[0609]

[0610] Step 1:

[0611] C-IN-015 (200 mg, 0.64 mmol) and benzyl borate (210 mg, 0.96 mmol) were dissolved in dioxane (10 mL), followed by the addition of saturated sodium carbonate aqueous solution (3 mL) and PdCl2(dppf) dichloromethane complex (45 mg, 0.06 mmol). The mixture was purged with nitrogen three times and heated to 80°C for 2 h. TLC analysis confirmed complete reaction of the starting material. The reaction solution was cooled to room temperature, extracted with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give a pale yellow solid C045-1 (130 mg, 63% yield). LCMS: m / z = 306.1 [M-17] +

[0612] Step 2:

[0613] C045-1 (130 mg, 0.40 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 °C in an ice-water bath, and a solution of PBr3 (108 mg, 0.40 mmol) in dichloromethane (2 mL) was added dropwise under nitrogen protection. After the addition was complete, the reaction was carried out at 0 °C for half an hour, and the reaction was confirmed to be complete by TLC. The reaction solution was quenched with ice water, neutralized with sodium bicarbonate, separated, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow solid C045-2 (140 mg, crude product).

[0614] Step 3:

[0615] C045-2 (140 mg, 0.36 mmol) and thiourea (25 mg, 0.33 mmol) were dispersed in ethanol (3 mL) and heated to 80°C for 2 h. The reaction was confirmed to be complete by TLC. The reaction solution was cooled to room temperature, and no solid precipitated. The solution was concentrated to a minimum volume and slurryed with acetonitrile, precipitating a solid. The solid was filtered, and the filter cake was washed and dried to give 106 mg of an off-white solid. The crude product was dissolved in ethanol (1 mL) by heating and stirring overnight, precipitating a solid. The solid was filtered, and the filter cake was washed with cold ethanol and dried to give a white solid SYY-C045 (60 mg, two-step yield 39%). 1 H NMR: (DMSO-d6, 400MHz): 1.37 (t, J=7.2Hz, 3H), 3.84 (s, 3H), 4.07 (s, 2H), 4.33 (q, J=7.28Hz, 2H), 5.11 (s, 2H), 7.12-7.30(m,6H),7.53(s,1H),7.91(d,J=8.4Hz,1H),9.21(br,3H).LCMS: m / z=382.1[M+H] + (94.28% purity, 220nm)

[0616] Example 35: Preparation of compound SYY-C046

[0617]

[0618] Step 1:

[0619] Cycloheptanone (2.00 g, 17.83 mmol) and p-toluenesulfonyl hydrazine (3.32 g, 17.83 mmol) were dispersed in ethanol (10 mL) and heated to reflux for 1 h. The reaction was confirmed to be complete by TLC. The reaction solution was concentrated to dryness to give a white solid CO46-1 (5.0 g, crude product).

[0620] Step 2:

[0621] C046-1 (2.8 g, crude) was dissolved in n-hexane (30 mL) and TMEDA (30 mL). Under nitrogen protection, the mixture was cooled to -70°C, and n-butyllithium solution (15 mL, 37.5 mmol, 2.5 M) was added dropwise. After the addition was complete, the mixture was stirred at -70°C for 1 h, then heated to room temperature and stirred for another 1 h. The reaction mixture was then cooled to -70°C again, and isopropyl borate ester (7.06 g, 37.92 mmol) was added dropwise. After the addition was complete in about 15 min, the mixture was stirred for another 1 h, then slowly heated to room temperature and stirred overnight. The reaction mixture was quenched with saturated ammonium chloride aqueous solution, extracted with MTBE, filtered through a diatomaceous earth liner, washed with saturated brine of organic phase, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain a colorless oil (1.5 g, two-step yield 38%).1 H NMR (400MHz, CDCl3): δ1.27 (s, 12H), 1.45-1.52 (m, 4H), 1.73-1.79 (m, 2H), 2.22-2.29 (m, 4H), 6.79 (t, J = 6.0Hz, 1H).

[0622] Step 3:

[0623] Under nitrogen protection, C-IN-010 (500 mg, 1.61 mmol) was dissolved in a mixed solvent of Dioxane (20 ml) and water (2 ml). Pd(dppf)Cl2 (130 mg, 0.16 mmol), cyclopenten-1-ylboronic acid (538 mg, 2.42 mmol), and Na2CO3 (512 mg, 4.83 mmol) were added at room temperature. The mixture was heated to 100 °C and stirred for 3 h. LC-MS showed the starting material had disappeared. The reaction solution was cooled to room temperature, extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give CO46-3 (250 mg, 48% yield). LC-MS: m / z = 310.2 [M-NH2]. + .

[0624] Step 4:

[0625] C046-3 (100 mg, 0.31 mmol) and DIEA (160 mg, 1.24 mmol) were dissolved in acetonitrile (5 mL), and 1H-1-methylformamidin hydrochloride (90 mg, 0.62 mmol) was added at room temperature, and the mixture was stirred for 2 days. The reaction solution was filtered, the filter cake was washed with acetonitrile, and dried to give a solid (80 mg, 70% yield). 1 H NMR: (DMSO-d6, 400MHz): δ1.38 (t, J=7.2Hz, 3H), 1.50-1.58 (m, 2H), 1.59-1.69 (m, 2H), 1.79-1.86 (m, 2H), 2.25-2.35 (m, 2H),2.64-2.68(m,2H),3.85(s,3H),4.35(q,J=7.2Hz,2H),4.92(s,2H),6.19(t,J= 6.8Hz, 1H), 7.20-7.64 (m, 5H), 7.92 (d, J=8.4Hz, 1H), 8.27 (br, 1H). LC-MS: m / z= 369.2[M+H] +

[0626] Example 36: Preparation of compound SYY-C047

[0627]

[0628] Under a hydrogen atmosphere, SYY-C046 (40 mg, 0.11 mmol) was dissolved in methanol (10 mL), and 10% Pd / C (10 mg) was added at room temperature. The mixture was heated to 50 °C and stirred for 2 h. LC-MS showed that the starting material disappeared. The reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was concentrated to give a white solid (36 mg, yield 88%). 1 H NMR:(DMSO-d6,400MHz): δ1.38(t,J=7.2Hz,3H),1.51-1.92(m,12H),2.73-2.87(m,1H),3.82(s,3H),4.35 (q,J=7.2Hz,2H),4.91(d,J=1.6Hz,2H),7.07-7.60(m,5H),7.90(d,J=8.0Hz,1H), 8.18-8.27(m,1H).LC-MS: m / z=371.2[M+H] +

[0629] Example 37: Preparation of compound SYY-C048

[0630]

[0631] Step 1:

[0632] Under nitrogen protection, C-IN-010 (400 mg, 1.29 mmol) was dissolved in a mixed solvent of 1,4-Dioxane (20 ml) and water (2 ml). Pd(dppf)Cl2 (104 mg, 0.13 mmol), cyclopenten-1-ylboronic acid (324 mg, 2.58 mmol), and Na2CO3 (410 mg, 3.87 mmol) were added at room temperature. The mixture was heated to 100 °C and stirred for 3 h. LC-MS showed the starting material had disappeared. The reaction solution was cooled to room temperature, extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give C048-1 (350 mg, 87% yield). LC-MS: m / z = 296.2 [M-NH2] + .

[0633] Step 2:

[0634] C048-1 (100 mg, 0.32 mmol) and DIEA (165 mg, 1.28 mmol) were dissolved in acetonitrile (5 mL). 1H-1-methylformamidinium hydrochloride (52 mg, 0.35 mmol) was added at room temperature, and the mixture was stirred for 4 days. The reaction was confirmed to be complete by LCMS. The reaction solution was filtered, the filter cake was washed with acetonitrile, and dried to give a solid (30 mg, yield 26%). 1H NMR:(DMSO-d6, 400MHz): δ1.38(t,J=7.2Hz,3H),1.59-1.70(m,2H),1.72-1.83(m,2H),2.17-2.27(m, 2H),2.45-2.49(m,2H),3.85(s,3H),4.35(d,J=7.2Hz,2H),4.92(s,2H),6.21-6.27(m, 1H), 7.01-7.50 (m, 4H), 7.59 (s, 1H), 7.93 (d, J = 8.4Hz, 1H), 8.23 ​​(br, 1H). LC-MS: m / z = 355.2 [M-NH2] +

[0635] Example 38: Preparation of compound SYY-C049

[0636]

[0637] Step 1:

[0638] Under a hydrogen atmosphere, CO48-1 (100 mg, 0.32 mmol) was dissolved in methanol (5 mL), and 10% Pd / C (20 mg) was added at room temperature. The mixture was heated to 50 °C and stirred for 2 h. LC-MS showed that the starting material disappeared. The reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was concentrated to obtain CO49-1 (crude product). LC-MS: m / z = 298.2 [M-NH2] + .

[0639] Step 2:

[0640] 049-1 (100 mg, 0.32 mmol) and DIEA (165 mg, 1.28 mmol) were dissolved in acetonitrile (5 mL), and 1H-1-methylformamidinium hydrochloride (52 mg, 0.35 mmol) was added at room temperature. The mixture was stirred for 2 days, and the reaction was confirmed to be complete by LCMS. The reaction solution was filtered, the filter cake was washed with acetonitrile, and dried to give solid SYY-C049 (43 mg, yield 38%). 1H NMR: (DMSO-d6,400MHz): δ1.31-1.90(m,13H),2.56-2.71(m,1H),3.83(s,3H),4.35(q,J= 7.2Hz,2H),4.91(d,J=4.8Hz,2H),7.11-7.57(m,5H),7.91(d,J=8.0Hz,1H), 8.24-8.30(m,1H).LC-MS: m / z=357.2[M-NH2] +

[0641] Example 39: Preparation of compounds SYY-C050 and SYY-C051

[0642]

[0643] Step 1:

[0644] C-IN-015 (400 mg, 1.28 mmol) was dissolved in a mixed solvent of 1,4-Dioxane (30 ml) and water (10 ml). Cyclohexene-1-ylboronic acid (323 mg, 2.56 mmol), PdCl2(dppf)dichloromethane complex (105 mg, 0.13 mmol), and sodium carbonate (531 mg, 5.01 mmol) were added at room temperature. The mixture was purged with nitrogen three times and heated to 100 °C for 2 h. TLC showed complete reaction. The reaction solution was cooled to room temperature, extracted with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography (PE / EA = 3 / 1) to give a pale yellow solid C051-1 (367 mg, 91% yield).

[0645] Step 2:

[0646] C051-1 (180 mg, 0.57 mmol) was dissolved in DCM (5 ml). Under nitrogen protection, the solution was cooled to 0°C in an ice-water bath, and PBr3 (155 mg, 0.57 mmol, diluted in 0.5 ml DCM) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 h, and the reaction was monitored for completeness by TLC. The reaction solution was diluted with DCM, and the solution was adjusted to neutral by adding saturated NaHCO3 solution. The mixture was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid C051-2 (188 mg, crude product).

[0647] Step 3:

[0648] Under nitrogen protection, C051-2 (188 mg, 0.50 mmol) was dissolved in ethanol (5 ml), and thiourea (26 mg, 0.34 mmol) was added at room temperature. The mixture was heated to 80 °C and reacted for 1.0 h. TLC was used to detect the complete reaction of the starting material. The reaction solution was cooled to room temperature, and no solid precipitated. The reaction solution was concentrated, and 1.0 ml of ethanol was added to dissolve it. 3 ml of MTBE was added dropwise, and the mixture was stirred at room temperature for 10 min. A large amount of solid precipitated. The mixture was stirred for 20 min, filtered, and the filter cake was washed with (ethanol / MTBE = 1 / 3) to obtain a white solid SYY-C051 (58 mg, two-step yield 27%). 1 H NMR:(DMSO-d6,400MHz):1.38 (t,J=7.2Hz,3H),1.61-1.68(m,2H),1.73-1.80(m,2H),2.18-2.24(m,2H),2.43-2.49 (m,2H),3.87(s,3H),4.35(q,J=7.2Hz,2H),5.11(s,2H),6.24(s,1H),7.37(dd,J=8.4, 1.2Hz,1H),7.58(s,1H),7.92(d,J=8.4Hz,1H),9.22(br,4H).LCMS: m / z=372.2[M +H] + (93.10% purity, 254nm)

[0649] Step 4:

[0650] C051-1 (140 mg, 0.45 mmol) was dissolved in methanol (5 ml), and Pd / C (56 mg) was added. The mixture was reacted at room temperature for 1.5 h, and the reaction was monitored by TLC until the reaction was complete. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a white solid C050-1 (140 mg, crude product).

[0651] Step 5:

[0652] C050-1 (114 mg, 0.36 mmol) was dissolved in dichloromethane (5 ml). Under nitrogen protection, the solution was cooled to 0°C in an ice-water bath, and phosphine tribromide (98 mg, 0.36 mmol, diluted in 0.5 ml dichloromethane) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 hour, and TLC was used to determine the completeness of the reaction. The reaction solution was then diluted with dichloromethane, and the pH was adjusted to neutral by adding saturated sodium bicarbonate solution. The mixture was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow solid C050-2 (128 mg, crude product).

[0653] Step 6:

[0654] Under nitrogen protection, CO50-2 (128 mg, 0.34 mmol) was dissolved in ethanol (5 ml), and thiourea (23 mg, 0.30 mmol) was added at room temperature. The mixture was heated to 80 °C and reacted for 1.0 h. TLC was used to detect the complete reaction of the starting material. The reaction solution was cooled to room temperature, and no solid precipitated. The reaction solution was concentrated, and 0.5 ml of ethanol was added to dissolve the solid. 1.5 ml of MTBE was added dropwise, and the mixture was stirred at room temperature for 10 min. A large amount of solid precipitated. The mixture was stirred for another 20 min, filtered, and the filter cake was washed with ethanol / MTBE = 1 / 3 to obtain a white solid (119 mg, three-step yield 71%). 1 H NMR: (DMSO-d6, 400MHz): 1.24-1.53 ​​(m, 8H), 1.72-1.84 (m 5H), 2.59-2.66 (m, 1H), 3.85 (s, 3H), 4.34 (q, J=7.2Hz, 2H), 5.12 (s,2H),7.15(dd,J=8.4,1.2Hz,1H),7.44(s,1H),7.90(d,J=8.4Hz,1H),9.17(br,2H), 9.31(br,2H).LCMS: m / z=374.2[M+H] + (99.02% purity, 220nm)

[0655] Example 40: Preparation of compounds SYY-C052 and SYY-C053

[0656]

[0657] Step 1:

[0658] C-IN-015 (650 mg, 2.08 mmol) was dissolved in a mixed solvent of 1,4-Dioxane (30 ml) and water (10 ml). At room temperature, boronic acid ester (700 mg, 3.15 mmol), Pd(dppf)Cl2 dichloromethane complex (170 mg, 0.21 mmol), and sodium carbonate (862 mg, 8.13 mmol) were added. The mixture was purged with nitrogen three times and heated to 100 °C for 2 h. TLC showed complete reaction. The reaction solution was cooled to room temperature, extracted with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography (PE / EA = 3 / 1) to give a yellow solid C052-1 (614 mg, 90% yield).

[0659] Step 2:

[0660] C052-1 (250 mg, 0.76 mmol) was dissolved in DCM (5 ml). Under nitrogen protection, the solution was cooled to 0°C in an ice-water bath. PBr3 (206 mg, 0.76 mmol, diluted in 0.5 ml DCM) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 hour. TLC showed that the reaction was complete. The reaction solution was then diluted with DCM, and the pH was adjusted to neutral by adding saturated NaHCO3 solution. The mixture was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain yellow oil C052-2 (400 mg, crude product).

[0661] Step 3:

[0662] Under nitrogen protection, C052-2 (400 mg, 1.02 mmol) was dissolved in ethanol (5 ml), and thiourea (42 mg, 0.55 mmol) was added at room temperature. The mixture was heated to 80 °C and reacted for 1.0 h. TLC was used to detect the complete reaction of the starting material. The reaction solution was cooled to room temperature, and no solid precipitated. The reaction solution was concentrated, and 2.0 ml of ethanol was added to dissolve the solid. 6.0 ml of methyl tert-butyl ether was added dropwise, and the mixture was stirred at room temperature for 10 min. A large amount of solid precipitated. The mixture was stirred for another 20 min, filtered, and the filter cake was washed with ethanol / MTBE = 1 / 3 and dried to give a white solid SYY-C052 (67 mg, two-step yield 23%). 1 H NMR: (DMSO-d6,400MHz):1.38(t,J=7.2Hz,3H),1.49-1.57(m,2H),1.59-1.68(m,2H), 1.80-1.86(m,2H),2.26-2.33(m,2H),2.64-2.67(m,2H),3.87(s,3H),4.34(q,J=7.2Hz, 2H), 5.13 (s, 2H), 6.18 (t, J=6.8Hz, 1H), 7.26 (dd, J=8.4, 1.2Hz, 1H), 7.49 (s, 1H), 7.91 (d, J=8.4Hz, 1H), 9.33 (br, 3H). LC-MS: m / z=386.2[M+H] + (95.71% purity, 254 nm)

[0663] Step 4:

[0664] C052-1 (180 mg, 0.55 mmol) was dissolved in methanol (5 ml), and 10% Pd / C (108 mg) was added. The mixture was purged with hydrogen three times and heated to 50 °C for 1.0 h. The reaction was monitored by LCMS to ensure the starting material was completely reacted. The reaction solution was cooled to room temperature, filtered through a diatomaceous earth sieve, and the filtrate was concentrated to obtain a white solid C053-1 (172 mg, crude product).

[0665] Step 5:

[0666] C053-1 (170 mg, 0.52 mmol) was dissolved in DCM (5 ml). Under nitrogen protection, the solution was cooled to 0°C in an ice-water bath. PBr3 (140 mg, 0.52 mmol, diluted in 0.5 ml DCM) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 hour. The reaction was monitored by TLC to confirm the completeness of the reaction. The reaction solution was then diluted with DCM, and the pH was adjusted to neutral by adding saturated NaHCO3 solution. The mixture was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a white solid C053-2 (182 mg, crude product).

[0667] Step 6:

[0668] Under nitrogen protection, C053-2 (182 mg, 0.46 mmol) was dissolved in ethanol (5 ml), and thiourea (28 mg, 0.37 mmol) was added at room temperature. The mixture was heated to 80 °C and reacted for 1.0 h. TLC was used to detect the complete reaction of the starting material. The reaction solution was cooled to room temperature, and no solid precipitated. The reaction solution was concentrated, and the residue was dissolved in 1.0 ml of ethanol. 3.0 ml of MTBE was added dropwise, and the mixture was stirred at room temperature for 10 min. A large amount of solid precipitated. The mixture was stirred for another 20 min, filtered, and the filter cake was washed with ethanol / MTBE = 1 / 2 to obtain a white solid SYY-C053 (110 mg, three-step yield 51%). 1 H NMR: (DMSO-d6, 400MHz): 1.37 (t, J=7.2Hz, 3H), 1.46-1.91 (m, 12H), 2.75-2.83 (m, 1H), 3.84 (s, 3H), 4.34 (q, J= 7.2Hz, 2H), 5.11 (s, 2H), 7.14 (dd, J=8.4, 1.2Hz, 1H), 7.42 (s, 1H), 7.89 (d, J=8.4Hz, 1H), 9.22 (br, 3H). LC-MS: m / z=388.2[M+H] + (95.32% purity, 220nm)

[0669] Example 41: Preparation of compound SYY-C054

[0670]

[0671] Step 1:

[0672] Under nitrogen protection, C-IN-010 (200 mg, 0.64 mmol) and Na2CO3 (138 mg, 1.30 mmol) were dissolved in a mixed solvent of DCM and H2O (10 mL / 3 mL). The mixture was cooled to approximately 0°C in an ice-water bath. Cbz-Cl (132 mg, 0.77 mmol) was added and stirred for 0.5 h. TLC showed a small amount of reactant remaining. Cbz-Cl (132 mg, 0.77 mmol) was then added and stirred, and TLC showed complete reaction. The reaction mixture was separated into layers, extracted with dichloromethane in the aqueous phase, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain a white solid C054-1 (270 mg, 94% yield). LC-MS: No reaction observed.

[0673] Step 2:

[0674] Under nitrogen protection, C054-1 (270 mg, 0.91 mmol) was dissolved in 1,4-Dioxane (5 mL). PdCl2(dppf) dichloromethane complex (50 mg, 0.06 mmol), pinacol diboronate (235 mg, 0.93 mmol), and potassium acetate (180 mg, 1.83 mmol) were added at room temperature. The mixture was heated to 100 °C and reacted for 3 h. TLC showed that the starting material reacted almost completely. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give a white solid C054-2 (225 mg, 72% yield).

[0675] Step 3:

[0676] C054-2 (480 mg, 1.40 mmol) was dissolved in AcOH (9 mL), and 30% hydrogen peroxide (0.45 mL, 4.50 mmol) was added. After stirring at room temperature for 0.5 h, a large amount of solid precipitated, and TLC showed that the starting material disappeared. Water (90 mL) was added to the reaction solution, and the mixture was stirred for 15 min. The mixture was filtered, and the filter cake was washed thoroughly with water and dried to obtain a white solid C054-3 (320 mg, 98% yield). 1 H NMR (400MHz, DMSO_d6): δ1.33 (t, J=7.2Hz, 3H), 2.66 (s, 3H), 3.60 (s, 3H), 4.25 (q, J=7.2Hz, 2H), 6.68 (dd, J=8.4, 2.0Hz, 1H), 6.79 (d, J=2.0Hz, 1H), 7.73(d,J=8.4Hz,1H),9.17(s,1H).LCMS:m / z=234.1[M+H] +

[0677] Step 4:

[0678] C054-3 (100 mg, 0.40 mmol) was dissolved in DMF (3 mL), and K2CO3 (166 mg, 1.20 mmol) and bromocyclopentane (0.2 mL, 1.87 mmol) were added at room temperature. The mixture was heated to 50 °C and stirred for 10 h. TLC showed that the starting material was basically completely reacted. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain C054-4 (110 mg, yield 87%).

[0679] Step 5:

[0680] C054-4 (100 mg, 0.22 mmol) was dissolved in methanol (10 ml), and 10% Pd / C (50 mg) was added. The mixture was purged with hydrogen three times and reacted at room temperature for 1.5 h. TLC showed that the starting material had basically reacted completely. The reaction solution was filtered through a diatomaceous earth filter, and the filtrate was concentrated to obtain colorless oil C054-5 (65 mg, crude product).

[0681] Step 6:

[0682] C054-5 (65 mg, crude) was dissolved in acetonitrile (3 ml), and 1H-pyrazole-1-formamidin hydrochloride (45 mg, 0.31 mmol) and DIEA (106 mg, 0.82 mmol) were added at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature for 2 days, and TLC was used to detect the complete reaction of the starting material. The reaction mixture was filtered, and the filter cake was washed and dried to obtain a white solid SYY-C054 (45 mg, two-step yield 56%). 1 HNMR: (DMSO-d6, 400MHz): δ1.37 (t, J=7.2Hz, 3H), 1.53-1.66 (m, 2H), 1.67-1.80 (m, 4H), 1.87-2.04 (m, 2H), 3.80 (s, 3H), 4.34 (q, J=7.2Hz, 2H), 4.87-4.96(m,3H),6.88(dd,J=2.0,8.4Hz,1H),7.12(d,J=1.6Hz,1H),7.38(br,3H), 7.86(d,J=8.8Hz,1H),8.26(br,1H).LCMS:m / z=359.2[M+H] + (98.62% purity, 220 nm)

[0683] Example 42: Preparation of compound SYY-C055

[0684]

[0685] Step 1:

[0686] C-IN-015 (1.0 g, 3.20 mmol) was dissolved in 1,4-Dioxane (25 mL). Pinarasanol diboronate (1.28 g, 5.04 mmol), PdCl2(dppf) dichloromethane complex (140 mg, 0.17 mmol), and potassium acetate (660 mg, 6.72 mmol) were added at room temperature. The mixture was purged with nitrogen three times and heated to 100 °C for 3.0 h. TLC showed complete reaction. The reaction solution was cooled to room temperature, extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to give a white solid C055-1 (1.07 g, 93% yield). LCMS: m / z = 342.2 [M-17] +

[0687] Step 2:

[0688] C055-1 (300 mg, 0.84 mmol) was dissolved in DME (15 mL). 3,4-dihydronaphth-1-yltrifluoromethanesulfonate (462 mg, 1.66 mmol), Pd(PPh3)4 (96 mg, 0.083 mmol), NaHCO3 (211 mg, 2.51 mmol), and water (3 mL) were added at room temperature. The mixture was purged with nitrogen three times and heated to 85 °C for 2.0 h. TLC showed complete reaction. The reaction solution was cooled to room temperature, extracted with water and ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain brown oil C055-2 (300 mg, 99% yield).

[0689] Step 3:

[0690] C055-2 (150 mg, 0.42 mmol) was dissolved in methanol (10 ml), and 10% Pd / C (80 mg) was added at room temperature. The mixture was purged with hydrogen three times, and the mixture was stirred at room temperature for 1.5 h. LC-MS was used to determine the completeness of the reaction. The reaction solution was filtered through a diatomaceous earth filter, and the filtrate was concentrated to obtain a white solid, C055-3 (153 mg, crude product). LC-MS: No reaction observed.

[0691] Step 4:

[0692] C055-3 (153 mg, 0.42 mmol) was dissolved in DCM (5 ml), cooled to 0°C in an ice-water bath, and PBr3 (113 mg, 0.42 mmol, diluted in 0.5 ml DCM) was added dropwise under nitrogen protection. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 h, and the reaction was monitored by TLC to confirm the completeness of the reaction. The reaction solution was diluted with DCM, and the pH was adjusted to neutral by adding saturated NaHCO3 solution. The mixture was separated, washed with saturated brine of the organic phase, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a white solid C055-4 (176 mg, crude product).

[0693] Step 5:

[0694] Under nitrogen protection, C055-4 (176 mg, crude product) was dissolved in ethanol (5 ml), and thiourea (25 mg, 0.33 mmol) was added at room temperature. The mixture was heated to 80 °C and reacted for 1.0 h. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, and no solid precipitated. The solution was concentrated, and the residue was slurried with 2.0 ml of ethanol. A large amount of solid precipitated. The mixture was stirred for another 20 min, filtered, and the filter cake was washed with ethanol to give a white solid (75 mg, 43% yield in three steps).

[0695] 1 H NMR: (DMSO-d6, 400MHz): δ1.37 (t, J=7.2Hz, 3H), 1.68-1.81 (m, 1H), 1.84-1.97(m,2H),2.06-2.19(m,1H),2.77-2.99(m,2H),3.81(s,3H),4.17-4.28(m ,1H),4.33(q,J=7.2Hz,2H),5.11(s,2H),6.69(d,J=7.6Hz,1H),6.93-7.02(m,2H), 7.06-7.17(m,2H),7.40(s,1H),7.91(d,J=8.4Hz,1H),9.20(br,3H).LCMS: m / z = 422.2[M+H] + (95.92% purity, 254nm)

[0696] Example 43: Preparation of compounds SYY-C056 and SYY-C060

[0697]

[0698] Step 1:

[0699] 4,4-Difluorocyclohexanone (3.00 g, 22.37 mmol) was dissolved in dichloromethane (40 mL). Under nitrogen protection, the mixture was cooled to approximately 0 °C, and pyridine compound (5.5 g, 26.78 mmol) was added. The mixture was stirred for ten minutes, and then trifluoromethanesulfonic anhydride (7.57 g, 26.83 mmol) was added. After the addition was complete, the reaction mixture was slowly allowed to return to room temperature and reacted overnight. TLC analysis showed that the reaction was not complete. The reaction mixture was then heated to 30 °C and reacted for 6 hours. TLC analysis showed that the starting material was still not completely consumed. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was slurried with petroleum ether, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain a colorless oil (1.3 g, yield 22%).

[0700] Step 2:

[0701] C055-1 (360 mg, 1.00 mmol) was dissolved in DME (20 mL). C056-4 (400 mg, 1.50 mmol), Pd(PPh3)4 (116 mg, 0.10 mmol), NaHCO3 (250 mg, 3.00 mmol), and water (4 mL) were added at room temperature. The mixture was purged with nitrogen three times, heated to 85 °C, and reacted for 2.0 h. TLC showed the reaction was complete. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 3 / 1) to give a yellow solid C056-1 (320 mg, 91% yield). LCMS: m / z = 332.2 [M-17] +

[0702] Step 3:

[0703] C056-1 (130 mg, 0.37 mmol) was dissolved in methanol (15 ml), and 10% Pd / C (100 mg) was added at room temperature. The mixture was purged with hydrogen three times and heated to 40 °C for 1.0 h. TLC showed that the reaction was complete. The reaction solution was filtered through a diatomaceous earth filter, and the filtrate was concentrated to give a white solid C056-2 (136 mg, crude product). LCMS: m / z = 334.2 [M-17] +

[0704] Step 3:

[0705] C056-2 (136 mg, crude) was dissolved in DCM (5 ml), cooled to 0°C in an ice-water bath, and PBr3 (105 mg, 0.39 mmol, diluted in 0.5 ml DCM) was added dropwise under nitrogen protection. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 h, and the reaction was monitored for completeness by TLC. The reaction solution was diluted with DCM, and the pH was adjusted to neutral by adding saturated NaHCO3 solution. The mixture was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a pale yellow solid C056-3 (150 mg, crude).

[0706] Step 4:

[0707] Under nitrogen protection, C056-3 (150 mg, 0.36 mmol) was dissolved in ethanol (3 ml), and thiourea (22 mg, 0.29 mmol) was added at room temperature. The mixture was heated to 80 °C and reacted for 1.0 h. The reaction was confirmed to be complete by TLC. The reaction solution was cooled to room temperature, and no solid precipitated. The solution was concentrated, and 1.5 ml of ethanol was added. A solid precipitated. The mixture was stirred for 20 min, filtered, and the filter cake was washed with ethanol to obtain a white solid SYY-C056 (60 mg, 39% yield in three steps). 1 H NMR:(DMSO-d6, 400MHz): δ1.38(t,J=7.2Hz,3H),1.70-2.20(m,8H),2.78-2.91(m,1H),3.86(s,3H), 4.34(q,J=6.8Hz,2H),5.11(s,2H),7.18(dd,J=8.4,1.2Hz,1H),7.49(s,1H),7.92(d, J=8.0Hz,1H),9.20(br,3H).LCMS:m / z=410.2[M+H] + (99.78% purity, 220nm)

[0708] Step 6:

[0709] Under nitrogen protection, C056-3 (192 mg, 0.46 mmol) was added to DMF (8 ml), followed by NaN3 (45 mg, 0.69 mmol). The reaction was allowed to proceed overnight at room temperature, and TLC was used to determine the completeness of the reaction. The reaction solution was then extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain colorless oil C060-1 (240 mg, crude product), which was directly added to the next step.

[0710] Step 7:

[0711] Under nitrogen protection, the previous step's CO60-1 (240 mg, crude product) was dissolved in THF (12 ml) and water (4 ml). PPh3 (182 mg, 0.69 mmol) was added at room temperature, and the mixture was heated to 50 °C for 1.5 h. The reaction was confirmed to be complete by TLC. The reaction solution was diluted with ethyl acetate, separated, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by pre-TLC (DCM / MeOH = 10 / 1) to give a white solid CO60-2 (85 mg, two-step yield 52%).

[0712] Step 8:

[0713] Under nitrogen protection, CO60-2 (85 mg, 0.24 mmol) was dissolved in acetonitrile (6 mL), and 1H-pyrazole-1-formamidinium hydrochloride (54 mg, 0.37 mmol) and DIEA (125 mg, 0.97 mmol) were added. The reaction was carried out at room temperature for 24 h, and the reaction was confirmed to be complete by TLC. The reaction solution was filtered to give a white solid SYY-C060 (45 mg, yield 47%). 1 H NMR: (DMSO-d6, 400MHz): δ1.38 (t, J=7.2Hz, 3H), 1.72-2.21 (m, 8H), 2.77-2.90 (m, 1H),3.85(s,3H),4.35(q,J=7.2Hz,2H),4.92(s,2H),7.17(dd,J=8.0,1.2Hz,1H), 7.22-7.71(m,4H),7.93(d,J=8.4Hz,1H),8.32(br,1H).LCMS: m / z=393.2[M+H] + (98.99% purity, 220nm)

[0714] Example 44: Preparation of compound SYY-C057

[0715]

[0716] Step 1:

[0717] 1-Tetrahydronaphthone (4.0 g, 27.36 mmol) was dissolved in THF (40 mL). Under nitrogen protection, the solution was cooled to approximately -70°C, and a NaHMDS THF solution (20 mL, 40.00 mmol, 2.0 M) was added dropwise. After the addition was complete, the mixture was stirred at -70°C for 1 h. Then, a bis(trifluoromethanesulfonylbenzyl) THF solution (11.6 g, 32.47 mmol) was added. After the addition was complete, the reaction was continued at this temperature for another 1 h, then slowly raised to room temperature and allowed to proceed overnight. The reaction was confirmed to be complete by TLC. The reaction solution was quenched with ammonium chloride aqueous solution, extracted with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to obtain a pale yellow oil C057-1 (5.2 g, yield 68%).

[0718] Step 1

[0719] C-IN-010 (1.5 g, 4.82 mmol) was dissolved in 1,4-Dioxane (50 mL). Pinarasanol diboronate (1.84 g, 7.23 mmol), potassium acetate (946 mg, 9.64 mmol), and Pd(dppf)₂Cl₂ (176 mg, 0.24 mmol) were added at room temperature. The mixture was purged with nitrogen three times and heated to 100 °C for 8 h. TLC showed complete reaction. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give solid C057-2 (0.8 g, 46% yield).

[0720] Step 2

[0721] C057-2 (300 mg, 0.84 mmol) was dissolved in a mixed solvent of DME (50 mL) and water (5 mL). C057-1 (468 mg, 1.68 mmol), sodium bicarbonate (212 mg, 2.52 mmol), and Pd(PPh3)4 (93 mg, 0.08 mmol) were added at room temperature. The mixture was purged with nitrogen three times, and the temperature was raised to 80 °C for 4 h. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by pre-TLC to obtain C057-3 (220 mg, crude product). LC-MS: m / z = 344.2 [M-NH2] + .

[0722] Step 3

[0723] C057-3 (220 mg, crude) was dissolved in methanol (10 ml), and 10% Pd / C (22 mg) was added at room temperature. The mixture was purged with hydrogen three times, heated to 50 °C, and reacted for 3 hours. The reaction was monitored by LC-MS to ensure complete reaction. The reaction solution was cooled to room temperature, filtered (using diatomaceous earth as a filter), and the filtrate was concentrated to obtain a white solid, C057-4 (120 mg, crude). LC-MS: m / z = 346.2 [M-NH2]. + .

[0724] Step 4

[0725] Under nitrogen protection, C057-4 (120 mg, crude product) was dissolved in acetonitrile (10 mL), and 1H-pyrazole-1-formamidinium hydrochloride (60 mg, 0.40 mmol) and DIEA (170 mg, 1.32 mmol) were added. The reaction was carried out at room temperature for 24 h, and the reaction was monitored by TLC until complete. The reaction solution was filtered, and the filter cake was washed and dried to give a white solid SYY-C057 (62 mg, 46% yield in three steps). 1 H NMR: (DMSO-d6, 400MHz): δ1.37 (t, J=7.2Hz, 3H), 1.72-1.76 (m, 1H),1.88-1.96(m,2H),2.11-2.20(m,1H),2.84-2.97(m,2H),3.79(s,3H),4.21-4.23(m, 1H),4.34(q,J=7.2Hz,2H),6.68(d,J=8.0Hz,1H),6.96-6.98(m,2H),7.08-7.16( m,2H),7.30(br,4H),7.41(s,1H),7.93(d,J=8.0Hz,1H).LC-MS: m / z=405.2[M+H] +

[0726] Example 45: Preparation of compound SYY-C058

[0727]

[0728] Step 1:

[0729] Under nitrogen protection, C-IN-015 (200 mg, 0.64 mmol) was dissolved in DMF (5 mL). NaH (60%) (51 mg, 1.28 mmol) was added in an ice bath, and the mixture was stirred for 15 min. Then, 132 mg, 0.77 mmol of bromine was added, and stirring continued for 1 h. TLC showed the reaction was complete. The reaction mixture was then extracted with 20 mL of saturated ammonium chloride solution, combined with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give a white solid C058-1 (190 mg, 74% yield).

[0730] Step 2:

[0731] Under nitrogen protection, C058-1 (190 mg, 0.47 mmol) was dissolved in dioxane (5 mL). Pd(dppf)Cl2 dichloromethane complex (41 mg, 0.05 mmol), pinacol diboronate (235 mg, 0.93 mmol), and KOAc (138 mg, 1.41 mmol) were added at room temperature. The mixture was heated to 100 °C and stirred for 3 h. TLC showed that the starting material had essentially disappeared. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain a colorless oily substance C058-2 (180 mg, 85% yield).

[0732] Step 3:

[0733] Under nitrogen protection, CO58-2 (180 mg, 0.40 mmol) was dissolved in AcOH (3 mL), and 30% H2O2 (0.14 mL, 1.40 mmol) was added. The mixture was stirred at room temperature for 16 h, and TLC showed that the starting material had essentially disappeared. The reaction solution was extracted with water and ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a pale yellow oil. This oil was directly dissolved in methanol, and Pd / C (80 mg) was added. The mixture was purged three times with hydrogen balloons and reacted at room temperature for 2 h. TLC confirmed the reaction was complete. The reaction solution was filtered through a diatomaceous earth liner, and the filtrate was concentrated to obtain CO58-3 (100 mg, crude product).

[0734] Step 4:

[0735] Under nitrogen protection, C058-3 (100 mg, 0.40 mmol) was dissolved in DMF (3 mL). K2CO3 (166 mg, 1.20 mmol) and bromocyclopentane (238 mg, 1.60 mmol) were added at room temperature. The mixture was heated to 50 °C and stirred for 10 h. TLC showed that the starting material was basically completely reacted. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give a white solid C058-4 (100 mg, 79% yield in two steps).

[0736] Step 5:

[0737] Under nitrogen protection, CO58-4 (100 mg, 0.32 mmol) was dissolved in THF (3 mL). PBr3 (103 mg, 0.38 mmol) was added in an ice bath, and stirring continued for 0.5 h after the addition was complete. TLC showed that the starting material had essentially reacted completely. The reaction solution was diluted with DCM, adjusted to neutral with 10% NaHCO3 solution, extracted to separate the layers, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain CO58-5 (119 mg, crude product).

[0738] Step 6:

[0739] Under nitrogen protection, CO58-5 (119 mg, 0.31 mmol) and thiourea (22 mg, 0.29 mmol) were dissolved in EtOH (4 mL), and the mixture was heated to 60 °C and stirred for 0.5 h. TLC showed that the starting material disappeared. The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by Pre-TLC to give an off-white solid (50 mg, two-step yield 42%). 1 H NMR(400MHz, DMSO_d6)δ1.37(t,J=7.2Hz,3H),1.55-1.65(m,2H),1.68-1.79(m,4H),1.89-2.02(m, 2H),3.82(s,3H),4.33(q,J=7.2Hz,2H),4.89-4.95(m,1H),5.10(s,2H),6.87(dd,J= 8.8,2.0Hz,1H),7.10(d,J=2.0Hz,1H),7.85(d,J=8.8Hz,1H),9.35(br,3H).LCMS: m / z=300.2[M-SC(NH)2+H] +

[0740] Example 46: Preparation of compound SYY-C059

[0741]

[0742] Step 1:

[0743] Under N2 protection, 3-phenoxyaniline (500 mg, 2.70 mmol), ethyl acetoacetate (351 mg, 2.70 mmol), AcOH (1 drop), and anhydrous magnesium sulfate (1.0 g, 8.31 mmol) were dissolved in DCM (5 mL). The mixture was stirred at room temperature for 36 hours, and TLC showed that 1 / 3 of the starting material remained. The reaction solution was filtered, and the filtrate was concentrated to obtain C059-1 (crude product), which was used directly in the next step.

[0744] Step 2:

[0745] Under N2 protection, C059-1 (crude product, theoretically 2.70 mmol), Pd(OAc)2 (61 mg, 0.27 mmol), Cu(OAc)2 (1.53 g, 8.42 mmol), and K2CO3 (1.16 g, 8.39 mmol) were dispersed in DMF (20 mL). The mixture was heated to 100 °C and stirred for 1 h. TLC showed that the starting material disappeared. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give a pale yellow solid C059-2 (400 mg, 50% yield in two steps). 1 H NMR(400MHz,DMSO_d6) δ1.34(t,J=7.2Hz,3H),2.64(s,3H),4.27(t,J=7.2Hz,2H),6.88(dd,J=8.6,2.2Hz, 1H),6.96-6.98(m,3H),7.09(t,J=7.4Hz,1H),7.30-7.39(m,2H),7.91(d,J=8.6Hz, 1H),11.77(s,1H).LCMS: m / z=296.2[M+H] +

[0746] Step 3:

[0747] Under N2 protection, C059-2 (400 mg, 1.35 mmol) was dissolved in DMF (10 mL). NaH (60%) (81 mg, 2.02 mmol) was added in an ice bath, and stirring was continued for 15 min after the addition was complete. Iodomethane (0.1 mL, 1.61 mmol) was then added, and the reaction was continued for 1 h. TLC showed the disappearance of the starting material. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give a pale yellow solid C059-3 (300 mg, 72% yield). 1H NMR (400MHz, CDCl3) δ1.47 (t,J=7.2Hz,3H),2.79(s,3H),3.64(s,3H),4.42(q,J=7.2Hz,2H),6.97-7.04(m,4H), 7.09(d,J=7.4Hz,1H),7.31-7.35(m,2H),8.10(d,J=9.2Hz,1H)

[0748] Step 4:

[0749] Under N2 protection, CO59-3 (300 mg, 0.97 mmol) was dissolved in CCl4 (5 mL), and BPO (70%) (20 mg, 0.058 mmol) was added at room temperature. The mixture was heated to 80 °C, and NBS (173 mg, 0.97 mmol) was added. The reaction was continued for 1.5 h, and TLC showed that the reaction was complete. The reaction solution was cooled, and the crude product was purified by silica gel column chromatography to obtain 130 mg of a yellow semi-solid crude product. Pre-TLC purification yielded a pale yellow solid CO59-4 (90 mg, yield 24%).

[0750] Step 5:

[0751] Under N2 protection, CO59-4 (90 mg, 0.23 mmol) and thiourea (18 mg, 0.24 mmol) were dissolved in EtOH (4 mL), and the mixture was heated to 60 °C and stirred for 1 h. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by Pre-TLC to give a white solid (60 mg, yield 67%). 1 H NMR (400MHz, dmso) δ1.38 (t, J=7.2Hz, 3H), 3.81 (s, 3H), 4.35 (q, J=7.2Hz, 2H), 5.11 (s, 2H), 6.96-7.02 (m, 3H), 7.08-7.13(m,1H),7.35-7.39(m,3H),8.01(d,J=8.8Hz,1H),9.25(br,3H).LCMS: m / z=308.1[M-SC(NH)2+H] +

[0752] Example 47: Preparation of compound SYY-C061

[0753]

[0754] Step 1:

[0755] C055-1 (300 mg, 0.84 mmol) was dissolved in pyridine (5 mL), and DMAP (10 mg, 0.08 mmol) and acetic anhydride (103 mg, 1.01 mmol) were added sequentially. The reaction was carried out at room temperature for 2 h, and the reaction was confirmed to be complete by TLC. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a brownish-yellow solid C061-1 (310 mg, crude product).

[0756] Step 2:

[0757] C061-1 (310 mg, 0.77 mmol) was dissolved in acetic acid (5 mL), and 30% hydrogen peroxide (0.4 mL, 3.99 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1 h, and the reaction was confirmed to be complete by TLC. The reaction solution was then diluted with water, extracted with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a yellow-brown solid C061-2 (220 mg, 90% yield).

[0758] Step 3:

[0759] C061-2 (180 mg, 0.62 mmol) and cyclohexanol (98 mg, 0.98 mmol) were dissolved in THF (8 mL). Triphenylphosphine (257 mg, 0.98 mmol) was added, and the mixture was cooled to approximately 0 °C under nitrogen protection. DEAD (171 mg, 0.98 mmol) was added dropwise. After the addition was complete, the reaction mixture was slowly heated to room temperature and stirred overnight. The reaction was confirmed to be complete by TLC. The reaction mixture was quenched with water, extracted with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain a colorless oily substance C061-3 (180 mg, 78% yield). 1 H NMR: (CDCl3,400MHz): δ1.32-1.42(m,2H),1.45(t,J=7.2Hz,3H),1.56-1.62(m,4H), 1.79-1.88(m,2H),1.96-2.06(m,2H),2.10(s,3H),3.74(s,3H),4.29-4.35(m,1H),4.39 (q,J=7.2Hz,2H),5.74(s,2H),6.86(d,J=2.4Hz,1H),6.94(dd,J=8.8,2.0Hz,1H), 8.06(d,J=8.4Hz,1H).

[0760] Step 4:

[0761] C061-3 (180 mg, 0.48 mmol) was dissolved in ethanol (10 mL), and saturated sodium carbonate aqueous solution (5 mL) was added. The reaction mixture was heated to 80 °C and reacted for 1 h. The reaction was confirmed to be complete by TLC. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a grayish-white solid C061-4 (110 mg, crude product). LCMS: m / z = 314.1 [M-17] +

[0762] Step 5:

[0763] 061-4 (110 mg, 0.33 mmol) was dissolved in dichloromethane (5 mL), and DMF (1 drop) was added. Under nitrogen protection, the mixture was cooled to approximately 0 °C, and a dichloromethane solution of oxaloyl chloride (0.17 mL, 0.34 mmol, 2.0 mol / L in DCM) was added dropwise. After the addition was complete, the reaction was carried out at 0 °C for 2 h, and the reaction was monitored by TLC to ensure completeness. The reaction solution was concentrated at room temperature, and the residue was carried over three times with dichloromethane to obtain C061-5 (crude product), which was used directly in the next step.

[0764] Step 6:

[0765] C061-5 (crude product, 0.33 mmol, theoretically) and thiourea (13 mg, 0.17 mmol) were dispersed in acetonitrile (3 mL) and heated to 75 °C for 1 h. The reaction was confirmed to be complete by TLC. The reaction solution was cooled to room temperature, and a solid precipitated. The solid was filtered, and the filter cake was washed and dried to give a pale yellow solid SYY-C061 (65 mg, 35% yield in three steps). 1 H NMR: (DMSO-d6, 400MHz): δ1.27-1.34(m,1H),1.37(t,J=7.2Hz,3H),1.35-1.38(m, 1H),1.41-1.48(m,3H),1.52-1.61(m,1H),1.69-1.79(m,2H),1.90-2.02(m,2H),3.82 (s,3H),4.33(q,J=7.2Hz,2H),4.39-4.49(m,1H),5.11(s,2H),6.90(dd,J=8.4,2.0Hz, 1H),7.16(d,J=2.0Hz,1H),7.85(d,J=8.8Hz,1H),9.38(br,3H).LCMS: m / z = 314.2[M-SC(NH2)2+H] + (99.51% purity, 220nm)

[0766] Example 48: Preparation of compound SYY-C062

[0767]

[0768] Step 1:

[0769] Under nitrogen protection, 2-naphthylamine (5.0 g, 34.92 mmol) was dissolved in DMSO (100 mL), and NIS (7.5 g, 33.33 mmol) was added at room temperature. The reaction was allowed to proceed for 2.0 h at room temperature, and TLC showed that the starting material had completely reacted. The reaction solution was then extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give brown oil C062-1 (8.7 g, 93% yield). 1 HNMR(400MHz, DMSO_d6)δ5.73(s,2H),7.13(d,J=8.8Hz, 1H),7.20(t,J=7.4Hz,1H),7.45(t,J=7.6Hz,1H),7.65(t,J=7.5Hz,2H),7.78(d,J =8.5Hz,1H).LCMS: m / z=270.1[M+H] +

[0770] Step 2:

[0771] Under nitrogen protection, CO62-1 (8.7 g, 32.33 mmol) was dissolved in DMSO (170 mL). Ethyl acetoacetate (25.2 g, 193.6-4.0 mmol), tetrazolium acetic acid (828 mg, 6.46 mmol), cuprous iodide (615 mg, 3.23 mmol), and cesium carbonate (21.0 g, 64.45 mmol) were added at room temperature. The mixture was heated to 100 °C and reacted for 4 h. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, and water was added. A large amount of solid precipitated. The mixture was filtered, the filter cake was washed with water, dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give a yellow solid, CO62-1 (3.2 g, 39% yield). LCMS: m / z = 254.1 [M+H] +

[0772] Step 3:

[0773] Under nitrogen protection, CO62-2 (3.2 g, 12.63 mmol) was dissolved in DMF (30 ml), cooled to 0 °C in an ice bath, and NaH (586 mg, 14.65 mmol) was added in portions. After the addition was complete, the mixture was allowed to react at room temperature for 0.5 h, then cooled to 0 °C in an ice bath. CH3I solution (2.1 g, 14.79 mmol, diluted in 1 ml DMF) was added dropwise, and the mixture was allowed to react at 0 °C for 20 min. The reaction was monitored by TLC to ensure completeness. The reaction solution was quenched with water, resulting in the precipitation of a large amount of solid. The solid was filtered, the filter cake was washed with water, dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography (PE / EA = 5 / 1) to give a grayish-white solid CO62-3 (3.0 g, 88% yield). LCMS: m / z = 268.1 [M+H] +

[0774] Step 4:

[0775] Under nitrogen protection, CO62-3 (3.0 g, 11.22 mmol) was dissolved in carbon tetrachloride (60 mL). NBS (2.0 g, 11.24 mmol) and BPO (272 mg, 1.12 mmol) were added at room temperature, and the mixture was heated to 80 °C and reacted for 1.5 h. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, and the crude product was subjected to silica gel column chromatography (DCM / PE = 1 / 2) to give a yellow solid CO62-4 (2.8 g, yield 72%).

[0776] Step 5:

[0777] Under nitrogen protection, CO62-4 (2.6 g, 7.51 mmol) was dissolved in carbon tetrachloride (60 ml), and NBS (1.34 g, 7.53 mmol) and BPO (110 mg, 0.45 mmol) were added at room temperature. The mixture was heated to 80 °C and reacted for 1.5 h. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature and concentrated to obtain CO62-5 (crude product), which was used directly in the next step.

[0778] Step 6:

[0779] Under nitrogen protection, the crude CO62-5 from the previous step was dissolved in DMF (20 ml), and the solution was adjusted to neutral with DIEA. Potassium acetate (1.5 g, 15.28 mmol) was then added, and the mixture was heated to 30 °C and reacted for 1.0 h. TLC showed that the reaction was complete. Water was added to the reaction solution, resulting in the precipitation of a large amount of solid. The mixture was filtered, the filter cake was dissolved in DCM, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain a pale yellow solid CO62-6 (965 mg, 32% yield in two steps).

[0780] Step 7:

[0781] Under nitrogen protection, CO62-6 (250 mg, 62 mmol) was dissolved in methanol (20 mL), and Pd / C (120 mg) was added at room temperature. The mixture was heated to 30 °C and reacted for 1.0 h. TLC was used to determine the completeness of the reaction. The reaction solution was cooled to room temperature, filtered through a diatomaceous earth sieve, and the filtrate, CO62-7 (crude product), was used directly in the next reaction step.

[0782] Step 8:

[0783] Add 5 ml of saturated sodium carbonate solution to the previous reaction solution 062-7 (crude product), heat to 80 degrees Celsius and react for 1 hour. TLC showed that the reaction was complete. Concentrate the reaction solution, extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and separate the crude product by silica gel column chromatography to obtain a white solid C062-8 (110 mg, two-step yield 63%).

[0784] Step 9:

[0785] C062-8 (110 mg, 0.39 mmol) was dissolved in DCM (10 mL), and DMF (1 drop) was added at room temperature. The mixture was cooled in an ice bath, and then a DCM solution of oxalyl chloride (51 mg, 0.40 mmol) (1 mL) was added. After the addition was complete, the mixture was stirred in an ice-water bath for 1 hour. TLC showed that the reaction was complete. The reaction solution was concentrated at low temperature to obtain C062-9 (crude product), which was used directly in the next step.

[0786] Step 10:

[0787] C062-9 (crude product) and thiourea (19 mg, 0.25 mmol) were dissolved in acetonitrile (3 mL), heated to 75°C and reacted for 1 h. The reaction was confirmed to be complete by TLC. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed and dried to obtain a pale yellow substance SYY-C062 (65 mg, two-step yield 49%). 1 H NMR (400MHz, DMSO_d6) δ1.42(t,J=7.2 Hz,3H),3.99(s,3H),4.45(q,J=7.2Hz,2H),5.13(s,2H),7.46-7.50(m,1H),7.54-7.58 (m,1H),7.82(s,2H),7.99(dd,J=8.0,0.8Hz,1H),9.03(d,J=8.4Hz,1H),9.52(br,3H).LCMS: m / z=266.1[M-SC(NH)2+H] +

[0788] Example 49: Preparation of compound SYY-C063

[0789]

[0790] Step 1:

[0791] Under nitrogen protection, a tetrahydrofuran (30 mL) solution of bicyclo[2.2.1]heptanone (3.0 g, 27.23 mmol) was added dropwise to an LDA (14.3 mL, 28.60 mmol, 2 mol / L) solution cooled to approximately -70 °C. The addition was completed over about half an hour. The reaction solution was then kept at -70 °C for 30 minutes, then heated to 0 °C and stirred for 30 minutes. The temperature was then lowered to approximately -70 °C, and N-phenylbis(trifluoromethanesulfonyl)imide (10.70 g, 29.95 mmol) was added dropwise. After the addition was complete, stirring was continued for 1 hour, then the temperature was raised to 0 °C and stirred for 3 hours. The remaining starting material was detected by TLC. The reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with methyl tert-butyl ether, and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was concentrated and purified by silica gel column chromatography to obtain a pale yellow oil C063-1 (5.7 g, yield 86%).

[0792] Step 2:

[0793] Under nitrogen protection, C-IN-015 (2.0 g, 6.41 mmol) was dissolved in 1,4-Dioxane (20 mL). Pinarayl diboronate (2.4 g, 9.45 mmol), Pd(dppf)Cl2 dichloromethane complex (468 mg, 0.57 mmol), and potassium acetate (1.3 g, 13.25 mmol) were added at room temperature. The mixture was purged with nitrogen three times and heated to 100 °C for 4.0 h. TLC showed complete reaction. The reaction solution was cooled to room temperature, extracted with water and ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography (PE / EA = 2 / 1) to give a pale yellow solid C063-2 (2.3 g, 100% yield).

[0794] Step 3:

[0795] Under nitrogen protection, CO63-2 (1.12 g, 3.12 mmol) was dissolved in DMF (20 mL). CO63-1 (1.66 g, 6.85 mmol), Pd(dppf)Cl2 dichloromethane complex (523 mg, 0.64 mmol), and Cs2CO3 (2.0 g, 6.14 mmol) were added at room temperature. The mixture was purged with nitrogen three times and heated to 85 °C for 2.0 h. TLC showed complete reaction. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was concentrated and purified by silica gel column chromatography (PE / EA = 4 / 1) to give yellow oil CO63-3 (560 mg, 55% yield).

[0796] Step 4:

[0797] C063-3 (560 mg, 1.72 mmol) was dissolved in methanol (30 ml), and 10% Pd / C (90 mg) was added. The mixture was purged with hydrogen three times and reacted at room temperature for 1.0 h. TLC showed complete reaction of the starting material. The mixture was filtered through diatomaceous earth, the filtrate was concentrated, and the residue was purified by Pre-TLC to give a pale yellow solid C063-4 (375 mg, yield 67%).

[0798] LCMS: m / z = 310.2 [M-17] +

[0799] Step 5:

[0800] Under nitrogen protection, CO63-4 (65 mg, 0.20 mmol) was dissolved in DCM (3 ml), and DMF (2 drops) was added. The mixture was cooled in an ice-water bath, and oxalyl chloride (26 mg, 0.20 mmol, diluted in 0.5 ml DCM) was added dropwise at 0 °C. After the addition was complete, the reaction was carried out at 0 °C for 0.5 h, and TLC showed that the reaction was complete. The reaction solution was concentrated, and the residue was carried forward three times with DCM to obtain CO63-5 (crude product), which was directly used in the next step.

[0801] Step 6:

[0802] Under nitrogen protection, the crude CO63-5 from the previous step was dissolved in acetonitrile (3 ml), and thiourea (12 mg, 0.16 mmol) was added at room temperature. The mixture was heated to 80 °C and reacted for 1.0 h. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, and a solid precipitated. The solid was filtered, and the filter cake was washed and dried to give a white solid (24 mg, two-step yield 31%). 1 H NMR: (DMSO-d6,400MHz): δ1.12-1.27(m,3H),1.36(t,J=7.2Hz,3H),1.41-1.59(m,4H), 1.90-1.98(m,1H),2.28-2.33(m,1H),2.41-2.46(m,1H),3.29-3.33(m,1H),3.86(s,3 H),4.32(q,J=7.2Hz,2H),5.14(s,2H),7.14(d,J=8.4Hz,1H),7.40(s,1H),7.90(d,J= 8.4Hz,1H),9.44(br,3H).LCMS: m / z=386.2[M+H] + (98.07% purity, 254nm)

[0803] Example 50: Preparation of compound SYY-C065

[0804]

[0805] Step 1:

[0806] C-IN-016 (300 mg, 0.73 mmol) and 2-naphthoboric acid (188 mg, 1.09 mmol) were dissolved in DMF (6 mL). Cesium carbonate (476 mg, 1.46 mmol) and PdCl2(dppf) dichloromethane complex (60 mg, 0.07 mmol) were added. The mixture was purged with nitrogen three times and heated to 80 °C for 2 h. The reaction was confirmed to be complete by TLC. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give a white solid C065-1 (250 mg, yield 67%).

[0807] Step 2:

[0808] C065-1 (240 mg, 0.52 mmol) was dissolved in dioxane hydrochloride solution (10 mL, 40 mmol, 4 mol / L) and stirred at room temperature for 2 h, precipitating a white solid. TLC showed that a small amount of the starting material had not reacted completely. Ethanol (5 mL) was added to the reaction solution to aid dissolution, and the mixture was heated to 40 °C for 2 h. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, concentrated to a minimum, neutralized with saturated sodium carbonate aqueous solution, filtered, and the filter cake was dissolved in dichloromethane and methanol (10 V / 1 V), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Pre-TLC to obtain a white solid C065-2 (160 mg, yield 85%). 1 H NMR(400MHz,DMSO_d6)δ1.43(t,J=7.2Hz,3H),3.42(br,2H),3.96(s, 3H),4.39(q,J=7.2Hz,2H),4.46(s,2H),7.50-7.57(m,2H),7.77(s,2H),7.89(dd,J= 8.5, 1.6Hz, 1H), 7.95 (d, J = 7.6Hz, 1H), 8.03 (d, J = 8.4Hz, 2H), 8.22 (s, 1H), 8.45 (s, 1H). LCMS: m / z=342.1[M-NH2] +

[0809] Step 3:

[0810] C065-2 (160 mg, 0.45 mmol) was dispersed in acetonitrile (3 mL), and DIEA (232 mg, 1.80 mmol) was added. The mixture was stirred for 5 minutes, but not completely dissolved. Pyrazole formamidin hydrochloride (98 mg, 0.67 mmol) was then added. The reaction mixture was stirred at room temperature for 2 days. LC-MS showed that approximately one-third of the starting material remained unreacted. The reaction mixture was filtered, yielding a 130 mg filter cake. The mixture was then re-added and stirred at room temperature for 2 days. The reaction mixture was filtered again, and the filter cake was washed and dried to obtain SYY-C065 (110 mg, 61% yield). 1 H NMR: (DMSO-d6, 400MHz): δ1.42 (t, J=7.2Hz, 3H), 3.92 (s, 3H), 4.41 (q, J=7.2Hz, 2H), 4.98 (s, 2H), 7.31-7.67 (m, 5H), 7.79 (s, 2H), 7.88 (dd, J= 8.4,1.6Hz,1H),7.95(d,J=7.6Hz,1H),7.99-8.08(m,2H),8.22(s,1H),8.27-8.59(m,2H).LCMS: m / z=401.2[M+H] + (99.65% purity, 254nm)

[0811] Example 51: Preparation of compound SYY-C066

[0812]

[0813] Step 1:

[0814] C-IN-017 (500 mg, 1.22 mmol) and 4-quinolineboronic acid (421 mg, 2.43 mmol) were dissolved in DMF (10 mL). Cesium carbonate (795 mg, 2.44 mmol) and PdCl2(dppf) dichloromethane complex (50 mg, 0.06 mmol) were added. The mixture was purged with nitrogen three times and heated to 80°C for 3 h. The reaction was confirmed to be complete by TLC. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give an off-white solid C066-1 (530 mg, 95% yield).

[0815] Step 2:

[0816] C066-1 (530 mg, 1.15 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 1 h, and the reaction was confirmed to be complete by TLC. The reaction solution was neutralized with saturated sodium carbonate aqueous solution, extracted with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give a pale yellow-brown solid C066-2 (330 mg, yield 80%). 1 H NMR (400MHz, DMSO_d6): δ1.40 (t, J=7.2Hz, 3H), 1.99 (br, 2H), 3.90 (s, 3H), 4.24 (s, 2H), 4.35 (q, J=7.2Hz, 2H), 7.38 (dd,J=8.4,1.6Hz,1H),7.53(d,J=4.4Hz,1H),7.59(t,J=7.6Hz,1H),7.83-7.73(m, 2H),7.98(d,J=8.4Hz,1H),8.12(d,J=8.4Hz,1H),8.17(d,J=8.4Hz,1H),8.97(d,J=4.4Hz,1H).LCMS: m / z=360.2[M+H] +

[0817] Step 3:

[0818] C066-2 (150 mg, 0.42 mmol) and DIEA (217 mg, 1.68 mmol) were dissolved in acetonitrile (5 mL), stirred for 5 minutes, and then pyrazole formamidin hydrochloride (92 mg, 0.63 mmol) was added. The mixture was stirred overnight at room temperature. A solid precipitated from the reaction solution, which was filtered, and the filter cake was washed and dried to give a white solid SYY-C066 (140 mg, yield 83%). 1 H NMR: (DMSO-d6, 400MHz): δ1.42 (t, J=7.2Hz, 3H), 3.93 (s, 3H), 4.41 (q, J=7.2Hz, 2H),5.00(s,2H),7.44-7.62(m,7H),7.79-7.83(m,1H),7.88(s,1H),7.95(d,J=8.8Hz, 1H),8.13(d,J=8.4Hz,1H),8.20(d,J=8.4Hz,1H),8.98(d,J=8.4Hz,1H).LCMS: m / z=402.2[M+H] + (98.95% purity, 254nm)

[0819] Example 52: Preparation of compound SYY-C067

[0820]

[0821] Step 1:

[0822] C-IN-017 (300 mg, 0.73 mmol) and 5-quinolineboronic acid (253 mg, 1.46 mmol) were dissolved in dioxane (15 mL) and water (5 mL). Sodium carbonate (155 mg, 1.46 mmol) and a complex of PdCl2(dppf) and dichloromethane (60 mg, 0.073 mmol) were added. The mixture was purged with nitrogen three times and heated to 100°C for 3 h. The reaction was confirmed to be complete by TLC. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give a white solid C067-1 (330 mg, 99% yield).

[0823] Step 2:

[0824] C067-1 (330 mg, 0.72 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 h, and the reaction was confirmed to be complete by TLC. The reaction solution was neutralized with saturated sodium carbonate aqueous solution, extracted with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give a pale yellow solid C067-2 (200 mg, yield 78%). 1 H NMR (400MHz, DMSO_d6) δ1.43(t,J=7.2Hz,3H),3.96(s,3H),4.39(q,J=7.2Hz,2H),4.49(s,2H),7.01(br,2H),7.37(d,J= 8.4Hz,1H),7.50-7.54(m,1H),7.64(d,J=7.2Hz,1H),7.79(s,1H),7.84-7.88(m,1H ),8.09(d,J=8.4Hz,1H),8.18(d,J=8.4Hz,1H),8.24(d,J=8.4Hz,1H),8.97-8.91(m, 1H).LCMS: m / z=360.2[M+H] +

[0825] Step 3:

[0826] C067-2 (190 mg, 0.53 mmol) and DIEA (274 mg, 2.12 mmol) were dissolved in acetonitrile (5 mL), stirred for 5 minutes, and then pyrazole formamidin hydrochloride (116 mg, 0.79 mmol) was added. The mixture was stirred overnight at room temperature. The reaction solution was filtered, the filter cake was washed, and dried to give a white solid SYY-C067 (190 mg, 90% yield). 1 H NMR(400 MHz, DMSO_d6)δ1.42(t,J=7.2Hz,3H),3.92(s,3H),4.41(q,J=7.2Hz,2H),5.00(s,2H ),7.37-7.65(m,6H),7.80(s,1H),7.84-7.88(m,1H),8.08(d,J=8.4Hz,1H),8.17(d,J =8.0Hz,1H),8.25(d,J=8.8Hz,1H),8.44(br,1H),8.95(dd,J1=4.0Hz,J2=1.6).LCMS: m / z=402.2[M+H] + (97.81% purity, 254nm)

[0827] Example 53: Preparation of compound SYY-C068

[0828]

[0829] Step 1:

[0830] C-IN-017 (7.0 g, 17.02 mmol) and pinacol diborate (6.5 g, 25.60 mmol) were dissolved in dioxane (200 mL), followed by the addition of potassium acetate (3.34 g, 34.03 mmol) and PdCl2(dppf) dichloromethane complex (139 mg, 0.17 mmol). The mixture was purged with nitrogen three times and heated to 100 °C for 3 h. The reaction was confirmed to be complete by TLC. The reaction solution was cooled to room temperature, extracted with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give a pale yellow solid (7.5 g, 96% yield).

[0831] Step 2:

[0832] C068-1 (400 mg, 0.87 mmol) and C057-1 (726 mg, 2.59 mmol) were dissolved in DMF (10 mL) and water (0.5 mL). Cesium carbonate (567 mg, 1.74 mmol) and PdCl2(dppf) dichloromethane complex (70 mg, 0.086 mmol) were added. The mixture was purged with nitrogen three times and heated to 100°C for 3 h. The reaction was confirmed to be complete by TLC. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to give an off-white solid C068-2 (320 mg, 80% yield).

[0833] Step 3:

[0834] C068-2 (320 mg, 0.69 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 h, and the reaction was confirmed to be complete by TLC. The reaction solution was neutralized with saturated sodium carbonate aqueous solution, extracted with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a pale yellow-brown solid C068-3 (250 mg, crude product). The TLC purity was good, and it was directly added to the next reaction. LCMS: m / z = 344.1 [M–NH2] +

[0835] Step 4:

[0836] C068-3 (250 mg, crude) and DIEA (358 mg, 2.77 mmol) were dispersed in acetonitrile (5 mL), stirred for 5 minutes, and then pyrazole formamidin hydrochloride (152 mg, 1.04 mmol) was added. The mixture was stirred overnight at room temperature. The reaction solution was filtered, and the filter cake was washed and dried to give a white solid SYY-C068 (192 mg, 69% yield in two steps). 1 H NMR: (DMSO-d6,400MHz): δ1.40(t,J=7.2Hz,3H),2.39-2.41(m,2H),2.83(t,J=7.6Hz, 2H),3.86(s,3H),4.38(q,J=7.2Hz,2H),4.96(s,2H),6.18(t,J=4.4Hz,1H),6.89(d,J=7.2Hz,1H),7.11-7.13(m 1H),7.15-7.23(m,2H),7.25-7.59(m,5H),8.03(d,J=8.4 Hz,1H),8.21-8.48(m,1H).LCMS: m / z=403.2[M+H] +

[0837] Example 54: Preparation of compound SYY-C069

[0838]

[0839] Step 1:

[0840] Under nitrogen protection, CO63-4 (185 mg, 0.57 mmol) was dissolved in DCM (8 ml), cooled in an ice-water bath, and PBr3 (154 mg, 0.57 mmol, diluted in 0.6 ml DCM) was added dropwise at 0 °C. After the addition was complete, the reaction was carried out at 0 °C for 0.5 h, and TLC showed that the reaction was complete. 8 ml of DCM was added to the reaction solution, and the solution was adjusted to neutral by adding saturated NaHCO3 solution. The mixture was extracted and separated, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a pale yellow oil, CO69-1 (212 mg, crude product).

[0841] Step 2:

[0842] Under nitrogen protection, C069-1 (212 mg, crude) was dissolved in DMF (5 ml), and NaN3 (53 mg, 0.82 mmol) was added at room temperature. After the addition was complete, the reaction solution was heated to 50 °C and reacted for 1.0 h. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow oil C069-2 (232 mg, crude).

[0843] Step 3:

[0844] Under nitrogen protection, C069-2 (232 mg, crude product) was dissolved in THF (9 ml) and water (3 ml). Triphenylphosphine (259 mg, 0.99 mmol) was added at room temperature, and the mixture was heated to 50 °C for 2.0 h. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by pre-TLC (DCM / MeOH = 10 / 1) to give a pale yellow solid C069-3 (140 mg, 76% yield in three steps). LCMS: m / z = 310.2 [M-NH2] +

[0845] Step 4:

[0846] Under nitrogen protection, C069-3 (140 mg, 0.43 mmol) was dissolved in acetonitrile (8 mL). DIEA (221 mg, 1.71 mmol) and 1H-pyrazole-1-formamidinium hydrochloride (94 mg, 0.64 mmol) were added at room temperature. The reaction was carried out at room temperature for 24 h, and the reaction was monitored for completeness by LC-MS. The reaction solution was filtered, and the filter cake was washed and dried to give a white solid SYY-C069 (120 mg, yield 76%). 1 H NMR: (DMSO-d6, 400MHz): δ1.09-1.31 (m, 3H), 1.38 (t, J= 7.2Hz,3H),1.43-1.61(m,4H),1.91-2.02(m,1H),2.30-2.35(m,1H),2.43-2.48(m,1H) ,3.36-3.39(m,1H),3.85(s,3H),4.35(q,J=7.2Hz,2H),4.92(s,2H),7.15(d,J=8.4Hz, 1H),7.24-7.70(m,4H),7.93(d,J=8.4Hz,1H),8.36(br,1H).LCMS: m / z=369.2[M+H] + (99.43% purity, 220nm)

[0847] Example 55: Preparation of compound SYY-C070

[0848]

[0849] Step 1:

[0850] Under nitrogen protection, C-IN-016 (300 mg, 0.73 mmol) was dissolved in a mixed solvent of DMF (15 ml) and water (5 ml). At room temperature, 1-naphthoboric acid (251 mg, 1.46 mmol), Pd(dppf)Cl2 dichloromethane complex (60 mg, 0.073 mmol), and Na2CO3 (302 mg, 2.85 mmol) were added. The mixture was purged with nitrogen three times and heated to 100 °C for 2.0 h. TLC showed complete reaction. The reaction solution was cooled to room temperature, extracted with water and ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography (PE / EA = 10 / 1) to give a white solid C070-1 (296 mg, 88% yield).

[0851] Step 2:

[0852] C070-1 (296 mg, 0.65 mmol) was dissolved in DCM (3 ml), cooled to 0°C in an ice-water bath, and trifluoroacetic acid (1.0 ml) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 1.0 h, and TLC showed that the reaction was complete. The reaction solution was concentrated at low temperature, and the crude product was diluted with 1.0 ml of ethyl acetate. The solution was adjusted to weakly alkaline by adding saturated sodium bicarbonate solution, resulting in the precipitation of a large amount of solid. The solution was stirred for 20 min, filtered, and the filter cake was dissolved in dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a pale yellow solid C070-2 (140 mg, crude product). 1 H NMR(400MHz, DMSO_d6)δ1.27(t, J=7.2Hz,3H),2.07(br,1H),3.92(s,3H),4.24(s,2H),4.28(q,J=7.2Hz,2H),7.34(dd, J=8.4,1.6Hz,1H),7.46-7.49(m,2H),7.54(m,1H),7.60(m,1H),7.71(d,J=8.4Hz, 1H),7.87(d,J=8.4Hz,1H),7.95(d,J=8.4Hz,1H),8.01(d,J=8.4Hz,1H),8.11(d,J=1.6Hz,1H).LCMS: m / z=342.1[M-NH2] +

[0853] Step 3:

[0854] C070-2 (140 mg, 0.39 mmol) was dissolved in acetonitrile (5 mL), and DIPEA (202 mg, 1.56 mmol) and 1H-pyrazole-1-formamidinium hydrochloride (86 mg, 0.59 mmol) were added. The reaction was carried out at room temperature for 24 h, and the reaction was monitored by LCMS until complete. The reaction solution was filtered, and the filter cake was washed and dried to give a white solid SYY-C070 (110 mg, two-step yield 43%). 1 H NMR: (DMSO-d6, 400MHz): δ1.27 (t, J=7.2Hz, 3H), 3.95 (s, 3H), 4.32 (q, J=7.2 Hz,2H),5.00(s,2H),7.29-7.71-(m,8H),7.80(d,J=8.4Hz,1H),7.84(d,J=8.4Hz, 1H),7.97(d,J=8.0Hz,1H),8.02(d,J=8.0Hz,1H),8.13-8.78(m,2H).LCMS: m / z=401.1[M+H] + (98.53% purity, 220nm)

[0855] Example 56: Preparation of compound SYY-C071

[0856]

[0857] Step 1:

[0858] Under nitrogen protection, C-IN-016 (500 mg, 1.22 mmol) was dissolved in 1,4-dioxane (15 ml). Pinara diboronic acid ester (464 mg, 1.83 mmol), Pd(dppf)Cl2 dichloromethane complex (50 mg, 0.061 mmol), and potassium acetate (238 mg, 2.43 mmol) were added at room temperature. The mixture was purged with nitrogen three times and heated to 100 °C for 3 hours. TLC showed complete reaction. The reaction solution was cooled to room temperature, extracted with water and ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was concentrated and purified by silica gel column chromatography (PE / EA = 2 / 1) to give a pale yellow oil C071-1 (509 mg, 91% yield).

[0859] Step 2:

[0860] Under nitrogen protection, C071-1 (488 mg, 1.06 mmol) was dissolved in DME (27 mL). C057-1 (1.15 g, 4.14 mmol), Pd(PPh3)4 (123 mg, 0.11 mmol), and saturated NaHCO3 solution (2.7 mL) were added at room temperature. The mixture was purged with nitrogen three times and heated to 85 °C for 2 hours. TLC showed the reaction was complete. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography (PE / EA = 10 / 1) to give brownish-yellow oil C071-2 (490 mg, 100% yield).

[0861] Step 3:

[0862] C071-2 (490 mg, 1.06 mmol) was dissolved in DCM (6 ml), cooled to 0°C in an ice-water bath, and trifluoroacetic acid (2.0 ml) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 1.0 h, and TLC showed that the reaction was complete. The reaction solution was adjusted to weakly alkaline by adding saturated sodium bicarbonate aqueous solution dropwise, stirred for 20 min, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Pre-TLC (DCM / MeOH = 10 / 1) to give a white solid C071-3 (210 mg, yield 55%). 1H NMR (400MHz, DMSO_d6): δ1.32(t,J=7.2Hz,3H),2.39(m,2H), 2.83(t,J=7.8Hz,2H),3.94(s,3H),4.31(q,J=7.2Hz,2H),4.48(s,2H),6.13(t,J= 4.7Hz,1H),6.88(d,J=7.6Hz,1H),7.10(t,J=7.2Hz,1H),7.18(t,J=7.6Hz,1H), 7.28–7.23(m,2H),7.66(d,J=8.4Hz,1H),8.01(s,1H).LCMS: m / z=344.1[M-NH2] +

[0863] Step 4:

[0864] C071-3 (200 mg, 0.56 mmol) was dissolved in acetonitrile (10 mL), and DIPEA (286 mg, 2.21 mmol) and 1H-pyrazole-1-formamidinium hydrochloride (122 mg, 0.83 mmol) were added. The reaction was carried out at room temperature for 24 h, and the reaction was monitored by LCMS until complete. The reaction solution was filtered, and the filter cake was washed and dried to give a white solid SYY-C071 (151 mg, yield 68%). 1 H NMR: (DMSO-d6, 400MHz): δ1.29 (t, J=7.2Hz, 3H), 2.34-2.44 (m, 2H), 2.82 (t, J= 7.6Hz,2H),3.89(s,3H),4.32(q,J=7.2Hz,2H),4.95(s,2H),6.13(t,J=4.0Hz,1H), 6.89(d,J=7.6Hz,1H),7.10(t,J=7.2Hz,1H),7.17(t,J=7.2Hz,1H),7.25(d,J=4.0Hz,2H),7.31-7.90(m,5H),8.00(s,1H).LCMS: m / z=403.2[M+H] + (94.83% purity, 254 nm)

[0865] Example 57: Preparation of compound SYY-C072

[0866]

[0867] Step 1:

[0868] Under nitrogen protection, C068-1 (500 mg, 1.09 mmol) was dissolved in DMF (10 mL). 1-Bromo-4-methylnaphthalene (485 mg, 2.20 mmol), Pd(dppf)Cl2 dichloromethane complex (80 mg, 0.10 mmol), and Cs2CO3 (712 mg, 2.19 mmol) were added at room temperature. The mixture was purged with nitrogen three times and heated to 85 °C for 2.0 h. TLC showed complete reaction. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was concentrated and purified by silica gel column chromatography (PE / EA = 20 / 1) to give a pale yellow oil C072-1 (324 mg, 63% yield).

[0869] Step 2:

[0870] C072-1 (324 mg, 0.69 mmol) was dissolved in DCM (6 ml), cooled in an ice-water bath, and trifluoroacetic acid (2.0 ml) was added dropwise at 0 °C. After the addition was complete, the reaction was allowed to proceed at room temperature for 1.0 h, and TLC showed that the reaction was complete. The reaction solution was concentrated to dryness at low temperature. The crude product was diluted with 1.0 ml of EA, and the solution was adjusted to weakly alkaline by adding saturated sodium bicarbonate aqueous solution. A large amount of solid precipitated out. The solution was stirred for 20 min, filtered, and the filter cake was dissolved in dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was concentrated. 2.0 ml of ethyl acetate was added, and the solution was stirred for 30 min. The mixture was then filtered to obtain a pale yellow solid C072-2 (140 mg, yield 62%). LCMS: m / z = 356.2 [M-NH2] +

[0871] Step 3:

[0872] C072-2 (140 mg, 0.38 mmol) was dissolved in acetonitrile (15 ml), and then DIEA (195 mg, 1.51 mmol) and 1H-pyrazole-1-formamidinium hydrochloride (83 mg, 0.57 mmol) were added. The reaction was carried out at room temperature for 24 h. The reaction solution was filtered to give a solid (95 mg, yield 61%). 1 H NMR: (DMSO-d6, 400MHz): δ1.42 (t, J=7.2Hz, 3H), 2.72(s,3H),3.90(s,3H),4.41(q,J=7.2Hz,2H),5.00(s,2H),7.29-7.66(m,8H ),7.72(s,1H),7.85(d,J=8.8Hz,1H),8.10-8.61(m,3H).LCMS: m / z=415.2[M+H] + (96.38% purity, 254nm)

[0873] Example 58: Preparation of compound SYY-C073

[0874]

[0875] Step 1:

[0876] C-IN-017 (300 mg, 0.73 mmol) and 4-isoquinoline boric acid (260 mg, 1.50 mmol) were dissolved in DMF (10 ml), followed by the addition of water (0.5 ml), then Cs₂CO₃ (714 mg, 2.19 mmol) and PdCl₂(dppf) dichloromethane complex (50 mg, 0.061 mmol). The mixture was substituted three times with N₂ and reacted at 100°C for 2 h under N₂ protection. After the reaction was confirmed to be complete by TLC, the mixture was washed with water, extracted with Ea, washed three times with saturated brine, dried, concentrated, and purified by silica gel column chromatography to obtain product C073-1 (330 mg, 99% yield).

[0877] Step 2:

[0878] C073-1 (330 mg, 0.72 mmol) was dissolved in DCM (6 ml), and then TFA (2 ml) was added. The mixture was reacted at room temperature for 2 h. After the reaction was complete as shown by TLC, the solution was concentrated and neutralized with NaHCO3 solution. A solid precipitated out. The solid was filtered, the filter cake was dissolved in DCM, dried over anhydrous Na2SO4, filtered, evaporated to dryness, and purified by silica gel column chromatography to obtain product C073-2 (250 mg, yield 97%).

[0879] Step 3:

[0880] C073-2 (150 mg, 0.42 mmol) was dissolved in CH3CN (5 mL), and DIPEA (220 mg, 1.70 mmol) was added. The mixture was stirred at room temperature for 20 min, and then pyrazole formamidin hydrochloride (92 mg, 0.63 mmol) was added. The mixture was stirred overnight at room temperature. LC-MS showed that the reaction proceeds were completely reacted. The reaction mixture was filtered, and the filter cake was washed and dried to give a white solid C073-3 (102 mg, yield 61%). 1H NMR: (DMSO-d6, 400MHz): δ1.42(t,J=7.2Hz,3H), 3.93(s,3H),4.41(q,J=7.2Hz,2H),5.02(s,2H),7.40-7.82(m,6H),7.86(s,1H),7.91 (d, J=8.4Hz, 1H), 8.19 (d, J=8.4Hz, 1H), 8.24 (d, J=8.4Hz, 1H), 8.52 (s, 1H), 8.57 (br, 1H), 9.37 (s, 1H). LC-MS: m / z=402.2 (98.02% purity, 254nm)

[0881] Example 59: Preparation of compound SYY-C074

[0882]

[0883] Step 1:

[0884] C-IN-017 (400 mg, 0.97 mmol) and 5-isoquinoline boric acid (340 mg, 1.97 mmol) were dissolved in DMF (10 ml), and water (0.5 ml), Cs₂CO₃ (980 mg, 3.01 mmol), and PdCl₂(dppf) dichloromethane complex (50 mg, 0.061 mmol) were added. The mixture was substituted three times with N₂, heated to 100 °C, and reacted for 2 h. TLC showed that the reaction was complete. The reaction solution was added to water, extracted with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give C074-1 (370 mg, yield 83%).

[0885] Step 2:

[0886] C074-1 (340 mg, 0.74 mmol) was dissolved in DCM (6 ml), and TFA (2 ml) was added. The reaction was carried out at room temperature for 2 h, and TLC showed that the reaction was complete. The reaction solution was concentrated and neutralized with saturated NaHCO3 solution, resulting in the precipitation of a solid. The solid was filtered, the filter cake was dissolved in DCM, dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography to obtain C074-1 (250 mg, 78% yield).

[0887] Step 3:

[0888] C074-1 (150 mg, 0.42 mmol) was dissolved in CH3CN (5 ml), and DIPEA (220 mg, 1.70 mmol) was added. The mixture was stirred at room temperature for 20 min, followed by the addition of pyrazole formamidin hydrochloride (92 mg, 0.63 mmol). The mixture was stirred overnight at room temperature. LC-MS showed that the reaction proceeds were completely reacted. The reaction mixture was filtered, and the filter cake was washed and dried to obtain SYY-C074 (134 mg, 80% yield). 1 H NMR: (DMSO-d6, 400MHz): δ1.42(t,J=7.2Hz,3H),3.92(s,3H),4.41(q,J=7.2Hz,2H),5.00(s,2H),6.96-8.03(m,9H),8.15-8.24(m,2H),8.49(d, J=6.0Hz,1H),9.42(s,1H).LCMS: m / z=402.2[M+H] + (93.05% purity, 220nm)

[0889] Example 60: Preparation of compound SYY-C075

[0890]

[0891] Step 1:

[0892] C068-1 (400 mg, 0.87 mmol) and 8-bromoisoquinoline (340 mg, 1.63 mmol) were dissolved in DMF (10 mL). Water (0.5 mL), Cs₂CO₃ (980 mg, 3.01 mmol), and a PdCl₂(dppf)dichloromethane complex (50 mg, 0.061 mmol) were added at room temperature. The mixture was purged with nitrogen three times and heated to 100 °C for 2 h. TLC showed complete reaction. The reaction solution was washed, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain C075-1 (340 mg, 85% yield).

[0893] Step 2:

[0894] C075-1 (340 mg, 0.74 mmol) was dissolved in DCM (6 ml), and TFA (2 ml) was added. The reaction was carried out at room temperature for 2 h, and TLC showed that the reaction was complete. The reaction solution was concentrated and neutralized with saturated NaHCO3 solution, resulting in the precipitation of a solid. The solid was filtered, the filter cake was dissolved in DCM, dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography to obtain C075-2 (240 mg, 90% yield).

[0895] Step 3:

[0896] C075-2 (150 mg, 0.42 mmol) was dissolved in CH3CN (5 ml), and DIPEA (220 mg, 1.70 mmol) was added. The mixture was stirred at room temperature for 20 min, and then pyrazole formamidin hydrochloride (92 mg, 0.63 mmol) was added. The mixture was stirred overnight at room temperature. The reaction solution was filtered, and the filter cake was washed and dried to give a white solid SYY-C075 (130 mg, 77% yield). 1 H NMR: (DMSO-d6, 400MHz): δ1.41(t,J=7.2Hz,3H),3.89(s,3H),4.39(q,J =7.2Hz,2H),4.99(s,2H),7.31-7.72(m,6H),7.85(dd,J=7.2,1.2Hz,1H),7.88(s,1H), 8.01(dd,J=8.0,1.2Hz,1H),8.08(d,J=8.4Hz,1H),8.36-8.48(m,2H),8.90(dd,J=4.4,2.0Hz,1H).LCMS: m / z=402.2[M+H] + (95.38% purity, 254nm)

[0897] Example 61: Preparation of compound SYY-C076

[0898]

[0899] Step 1:

[0900] C068-1 (460 mg, 1.00 mmol) and 1-bromo-4-fluoronaphthalene (450 mg, 2.01 mmol) were dissolved in DMF (10 ml). Water (0.5 ml), Cs₂CO₃ (660 mg, 2.03 mmol), and a PdCl₂(dppf) dichloromethane complex (90 mg, 0.11 mmol) were added at room temperature. The mixture was substituted three times with N₂, and the temperature was raised to 100 °C for 2 h. TLC showed the reaction was complete. The reaction solution was cooled to room temperature, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give C076-1 (420 mg, 88% yield).

[0901] Step 2:

[0902] C076-1 (420 mg, 0.88 mmol) was dissolved in DCM (6 ml), and TFA (3 ml) was added. The reaction was carried out at room temperature for 2 h, and TLC showed that the reaction was complete. The reaction solution was concentrated, neutralized with saturated NaHCO3 solution, and the solid precipitated. The solid was filtered, the filter cake was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain C076-2 (240 mg, yield 72%).

[0903] Step 3:

[0904] C076-2 (150 mg, 0.40 mmol) was dissolved in CH3CN (5 ml), and DIPEA (220 mg, 1.70 mmol) was added. The mixture was stirred at room temperature for 20 min, followed by the addition of pyrazole formamidin hydrochloride (92 mg, 0.63 mmol). The mixture was stirred overnight at room temperature. LC-MS showed that the reaction proceeds were completely reacted. The reaction mixture was filtered, and the filter cake was washed and dried to obtain SYY-C076 (113 mg, yield 68%). 1 H NMR: (DMSO-d6, 400MHz): δ1.41 (t, J=7.2Hz, 3H), 3.89 (s, 3H), 4.40 (q, J=7.2Hz, 2H), 4.99 (s, 2H), 7.18-7.67 (m, 8H), 7.76 (s, 1H), 7.86(d,J=8.8Hz,1H),8.13-8.16(m,2H),8.39(br,1H).LCMS: m / z=419.2[M+H] + (97.63% purity, 254nm)

[0905] Example 62: Preparation of compound SYY-C077

[0906]

[0907] Step 1:

[0908] C068-1 (400 mg, 0.87 mmol) and 8-bromoisoquinoline (271 mg, 1.29 mmol) were dissolved in DMF (10 mL) and water (1 mL). Cesium carbonate (567 mg, 1.74 mmol) and PdCl2(dppf) dichloromethane complex (70 mg, 0.086 mmol) were added. After purging with nitrogen three times, the mixture was heated to 100°C and reacted for 3 h. The reaction was confirmed to be complete by TLC. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give an off-white solid C077-1 (300 mg, 75% yield).

[0909] Step 2:

[0910] C077-1 (300 mg, 0.65 mmol) was dissolved in dichloromethane (3 mL), cooled to approximately 0°C, and a solution of trifluoroacetic acid (1 mL) in dichloromethane (1 mL) was added dropwise. After the addition was complete, the mixture was stirred at 0°C for 1 h, and TLC was used to confirm the complete reaction of the starting material. The reaction solution was neutralized with saturated sodium carbonate aqueous solution, extracted with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a yellow solid C077-2 (230 mg, 98% yield). 1 H NMR(400 MHz, DMSO_d6): δ1.39(t,J=7.2Hz,3H),3.08(br,2H),3.88(s,3H),4.24(s,2H), 4.5(q,J=7.2Hz,2H),7.36(dd,J=8.2,1.3Hz,1H),7.64(d,J=7.0Hz,1H),7.76(s, 1H),7.82-7.85(m,1H),7.89(d,J=5.6Hz,1H),7.98(d,J=8.2Hz,1H),8.16(d,J=8.2 Hz,1H),8.53(d,J=5.7Hz,1H),9.24(s,1H).LCMS: m / z=360.2[M+H] +

[0911] Step 3:

[0912] C077-2 (220 mg, 0.61 mmol) and DIEA (315 mg, 2.44 mmol) were dispersed in acetonitrile (5 mL), and pyrazole formamidin hydrochloride (135 mg, 0.92 mmol) was added. The mixture was stirred overnight at room temperature, but TLC showed no complete reaction. The reaction solution was filtered to give an off-white solid (145 mg, 0.40 mmol), which, along with DIEA (208 mg, 1.61 mmol), was dispersed in acetonitrile (5 mL) and methanol (1 mL). The mixture was stirred overnight at room temperature, and LCMS showed complete reaction. The reaction solution was filtered, and the filter cake was washed and dried to give a white solid SYY-C077 (100 mg, 41% yield). 1 H NMR: (DMSO-d6,400MHz): δ1.42(t,J=7.2Hz,3H),4.40(q,J=7.2Hz,2H),3.91(s,3H), 4.99(s,2H),7.02-7.91(m,8H),7.93(d,J=6.0Hz,1H),8.03(d,J=8.4Hz,1H),8.18(d, J=8.4Hz,1H),8.55(d,J=5.6Hz,1H),9.21(s,1H).LCMS: m / z=402.2[M+H]+ (99.71% purity, 254nm)

[0913] Example 63: Preparation of compound SYY-C078

[0914]

[0915] Step 1:

[0916] Under nitrogen protection, C071-1 (500 mg, 1.09 mmol) was dissolved in DMF (10 mL). 9-Bromoanthracene (561 mg, 2.19 mmol), Pd(dppf)Cl2 dichloromethane complex (80 mg, 0.10 mmol), and Cs2CO3 (712 mg, 2.19 mmol) were added at room temperature. The mixture was purged with nitrogen three times, and the temperature was raised to 85 °C for 2.0 h. TLC showed that the starting material reacted completely. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography (PE / EA = 20 / 1) to give a pale yellow oil C078-1 (366 mg, yield 66%).

[0917] Step 2:

[0918] Under nitrogen protection, C078-1 (366 mg, 0.72 mmol) was dissolved in DCM (4.5 ml), cooled to 0°C in an ice-water bath, and trifluoroacetic acid (1.5 ml) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 1.0 h, and TLC showed that the reaction was complete. The reaction solution was concentrated at low temperature, and the crude product was diluted with ethyl acetate (1.0 ml). The solution was adjusted to weakly alkaline by adding saturated sodium bicarbonate aqueous solution, resulting in the precipitation of a large amount of solid. The mixture was stirred for 20 min, filtered, and the filter cake was dissolved in dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was added with ethyl acetate (2.0 ml). The mixture was stirred for 30 min, filtered, and the filter cake was washed and dried to obtain a pale yellow solid C078-2 (153 mg, yield 52%).

[0919] LCMS: m / z = 392.1 [M-NH2] +

[0920] Step 3:

[0921] Under nitrogen protection, C078-2 (105 mg, 0.26 mmol) was dissolved in acetonitrile (10 mL), and DIEA (133 mg, 1.03 mmol) and 1H-pyrazole-1-formamidinium hydrochloride (56 mg, 0.38 mmol) were added. The reaction was carried out at room temperature for 48 h, and the reaction was monitored by LCMS to determine the completeness of the reaction. The reaction solution was filtered, and the filter cake was washed and dried to obtain SYY-C078 (70 mg, yield 60%). 1H NMR: (DMSO-d6, 400MHz): δ1.43 (t, J=7.2Hz, 3H), 3.87 (s, 3H), 4.42 (q, J=7.2Hz,2H),5.01(s,2H),7.17-7.99(m,12H),8.16(d,J=8.4Hz,2H),8.25(d,J=8.0Hz,1H),8.69(s,1H).LCMS: m / z=451.2[M+H] + (96.72% purity, 220nm)

[0922] Example 64: Preparation of compound SYY-C079

[0923]

[0924] Step 1:

[0925] Under nitrogen protection, IN-009-3 (2.0 g, 7.12 mmol) was dissolved in DMF (20 ml), cooled to 0°C in an ice-water bath, and 60% NaH (850 mg, 21.25 mmol) was added in portions. After the addition was complete, the reaction was allowed to proceed at room temperature for 30 min. Iodopropane (12 g, 70.60 mmol) was added dropwise at 0°C. After the addition was complete, the reaction was allowed to proceed overnight at 40°C, and the reaction was monitored for completeness by TLC. The reaction solution was quenched with water, resulting in the precipitation of a large amount of solid. The mixture was stirred for 20 min, filtered, and the filter cake was dissolved in ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain a brownish-yellow solid C079-1 (1.0 g, yield 43%). LCMS: m / z = 324.0 [M+H] +

[0926] Step 2:

[0927] Under nitrogen protection, C079-1 (874 mg, 2.71 mmol) was dissolved in CCl4 (20 ml), and BPO (65 mg, 0.27 mmol) and NBS (576 mg, 3.24 mmol) were added at room temperature. The mixture was heated to 80 °C and reacted for 1.5 h. The reaction was monitored by TLC until complete. After cooling to room temperature, the crude product was purified by silica gel column chromatography (PE / EA = 10 / 1 to 5 / 1) to obtain yellow oil C079-2 (1.45 g, crude product).

[0928] Step 3:

[0929] Under nitrogen protection, C079-2 (1.45 g, crude) was dissolved in DMF (20 ml), and NaN3 (352 mg, 5.41 mmol) was added. The reaction was carried out overnight at room temperature, and the reaction was monitored by TLC until complete. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a brownish-yellow solid C079-3 (1.1 g, crude).

[0930] Step 4:

[0931] Under nitrogen protection, C079-3 (1.1 g, crude product) was dissolved in THF (21 ml) and water (7 ml). Triphenylphosphine (1.18 g, 4.50 mmol) was added at room temperature, and the mixture was heated to 50 °C and reacted for 2.0 h. The reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product was concentrated and purified by silica gel column chromatography (DCM / MeOH = 60 / 1) to give a light yellow-brown oil C079-4 (590 mg, 64% yield in three steps). LCMS: m / z = 339.1 / 341.1 [M+H] +

[0932] Step 5:

[0933] Under nitrogen protection, C079-4 (590 mg, 1.75 mmol) was dissolved in DCM (10 mL), and DIPEA (449 mg, 3.47 mmol) was added. The mixture was cooled to 0 °C in an ice-water bath, and di-tert-butyl dicarbonate (417 mg, 1.91 mmol) was added in portions. After the addition was complete, the mixture was reacted at room temperature for 1.0 h, and the reaction was monitored by TLC to ensure complete reaction of the starting material. The reaction solution was extracted with 1N dilute hydrochloric acid (10 mL) and dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow-brown oil C079-5 (843 mg, crude product).

[0934] Step 6:

[0935] Under nitrogen protection, C079-5 (843 mg, 1.92 mmol) was dissolved in 1,4-dioxane (30 ml) and water (10 ml). Boric acid (660 mg, 3.84 mmol), Pd(dppf)Cl2 dichloromethane complex (156 mg, 0.19 mmol), and Na2CO3 (610 mg, 5.76 mmol) were added at room temperature. The mixture was purged with nitrogen three times and heated to 95 °C for 2.0 h. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography (PE / EA = 10 / 1) to give yellow oil C079-6 (800 mg, crude product).

[0936] Step 7:

[0937] Under nitrogen protection, C079-6 (800 mg, 1.65 mmol) was dissolved in DCM (9 ml), cooled to 0°C in an ice-water bath, and trifluoroacetic acid (3.0 ml) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 1.0 h. TLC showed that the starting material reacted completely. The reaction solution was adjusted to weakly alkaline by adding saturated sodium bicarbonate aqueous solution dropwise, stirred for 20 min, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain brownish-yellow oil C079-7 (590 mg, crude product). LCMS: m / z = 370.1 [M-NH2] +

[0938] Step 8:

[0939] Under nitrogen protection, C079-7 (360 mg, 0.93 mmol) was dissolved in acetonitrile (10 mL), and DIEA (481 mg, 3.72 mmol) and 1H-pyrazole-1-formamidinium hydrochloride (205 mg, 1.40 mmol) were added. The reaction was carried out at room temperature for 24 h, and the reaction was monitored for completeness by LCMS. The reaction solution was filtered, and the filter cake was washed and dried to give a pale yellow solid SYY-C079 (270 mg, 59% yield in four steps). 1H NMR: (DMSO-d6, 400MHz): δ1.41 (t, J = 9.2Hz, 3H), 1.62 (d, J = 7.2Hz, 6H), 4.40 (q, J = 7.2Hz, 2H), 4.84-4.96 (m, 1H), 5.02 (s, 2H), 7.27-7.75 (m, 8H),7.80(s,1H),7.86(d,J=8.8Hz,1H),7.97(d,J=8.0Hz,1H),8.02(d,J=8.0Hz, 1H),8.21(d,J=8.4Hz,1H),8.34(m,1H).LCMS: m / z=429.2[M+H] + (97.19% purity, 220nm)

[0940] Example 65: Preparation of compound SYY-C080

[0941]

[0942] Step 1:

[0943] 5-Bromo-2-naphtholic acid (2.0 g, 8.00 mmol) was dispersed in THF (25 mL), cooled to approximately 0°C, and under nitrogen protection, a boranetetrahydrofuran complex (20 mL, 20.00 mmol, 1 mol / L) was added dropwise. After the addition was complete, the reaction was continued at 0°C for half an hour, then allowed to return to room temperature for 1 hour. TLC showed very little reaction. The reaction was then heated to 75°C for 1 hour, and TLC showed complete reaction. The reaction solution was cooled to 0°C, and the reaction was quenched dropwise with methanol. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a white solid C080-1 (1.5 g, crude product).

[0944] Step 2:

[0945] Under nitrogen protection, C080-1 (1.5 g, crude) was dissolved in DCM (60 ml), cooled in an ice-water bath, and phosphorus tribromide (2.28 g, 8.42 mmol, diluted in 5.0 ml DCM) was added dropwise at 0 °C. After the addition was complete, the reaction was carried out at 0 °C for 0.5 h, and TLC showed that the reaction was complete. The reaction solution was adjusted to neutral by adding saturated sodium bicarbonate aqueous solution, separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a white solid C080-2 (1.6 g, crude).

[0946] Step 3:

[0947] Under nitrogen protection, C080-2 (1.6 g, crude) was dissolved in DMSO (20 ml). Sodium borohydride (407 mg, 10.76 mmol) was added in portions at room temperature. After the addition was complete, the reaction was allowed to proceed at room temperature for 0.5 h. TLC showed that the reaction was complete. The reaction solution was quenched with water, stirred at room temperature for 1 h, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow solid C080-3 (1.14 g, crude). 1 H NMR (400MHz, DMSO_d6) δ2.48(s,3H),7.37(t,J=8.0Hz,1H),7.49(dd,J=8.8,1.6Hz,1H),7.73(s,1H),7.77(d, J=6.4Hz,1H),7.85(d,J=8.0Hz,1H),8.00(d,J=8.8Hz,1H)

[0948] Step 4:

[0949] Under nitrogen protection, C068-1 (300 mg, 0.65 mmol) was dissolved in DMF (10 mL). C080-3 (290 mg, 1.32 mmol), Pd(dppf)Cl2 dichloromethane complex (54 mg, 0.066 mmol), and Cs2CO3 (427 mg, 1.31 mmol) were added at room temperature. The mixture was purged with nitrogen three times, and the temperature was raised to 80 °C for 3.0 h. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography (PE / EA = 10 / 1) to give a pale yellow oil C080-4 (203 mg, 43% yield in four steps).

[0950] Step 5:

[0951] Under nitrogen protection, C080-4 (200 mg, 0.42 mmol) was dissolved in DCM (3 ml), cooled in an ice-water bath, and trifluoroacetic acid (1.0 ml) was added dropwise at 0 °C. After the addition was complete, the reaction was allowed to proceed at room temperature for 1.0 h, and TLC showed that the reaction was complete. The reaction solution was adjusted to a weakly alkaline state by adding sodium bicarbonate aqueous solution dropwise, stirred for 20 min, extracted with DCM, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a pale yellow oil C080-5 (147 mg, crude product). 1 H NMR(400MHz, DMSO_d6)δ1.40(t,J=7.2Hz,3H),2.04(br,2H),2.48(s,3H),3.85(s,3H),4.23(s,2H), 4.34(q,J=7.2Hz,2H),7.28-7.32(m,2H),7.42(d,J=7.0Hz,1H),7.57-7.51(m,1H), 7.64(s,1H),7.76-7.78(m,2H),7.85(d,J=8.1Hz,1H),8.11(d,J=8.2Hz,1H). LCMS: m / z=356.1[M-NH2] +

[0952] Step 6:

[0953] Under nitrogen protection, C080-5 (147 mg, 0.39 mmol) was dissolved in acetonitrile (10 mL), and DIEA (204 mg, 1.58 mmol) and 1H-pyrazole-1-formamidinium hydrochloride (87 mg, 0.59 mmol) were added. The reaction was carried out at room temperature for 48 h, and the reaction was monitored for completeness by LCMS. The reaction solution was filtered, and the filter cake was washed and dried to give a pale yellow solid SYY-C080 (120 mg, 68% yield in two steps). 1H NMR: (DMSO-d6, 400MHz): δ1.42 (t, J=7.2Hz, 3H), 2.49 (s, 3H), 3.90 (s,3H),4.40(q,J=7.2Hz,2H),5.00(s,2H),7.31-7.78(m,11H),7.87(d,J=8.4Hz, 1H),8.14(d,J=8.8Hz,1H).LCMS: m / z=415.2[M+H] + (95.40% purity, 220nm)

[0954] Example 66: Preparation of compound SYY-C081

[0955]

[0956] Step 1:

[0957] Under nitrogen protection, 5-bromo-1-naphthoic acid (2.0 g, 7.97 mmol) was dissolved in THF (25 ml), purged three times with nitrogen, cooled in an ice-water bath, and a THF solution of borane (20 ml, 20.00 mmol, 1.0 M) was added dropwise at 0 °C. After the addition was complete, the reaction was allowed to proceed overnight at room temperature, and TLC showed that the reaction was complete. The reaction solution was quenched dropwise with methanol at low temperature, stirred for 20 min, concentrated to dryness, extracted with water and ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a white solid C081-1 (1.9 g, crude product). 1 H NMR (400MHz, CDCl3): δ1.88(s,1H),5.17 (d,J=2.8Hz,2H),7.39-7.43(m,1H),7.56–7.61(m,2H),7.85(dd,J=7.6,0.8Hz,1H), 8.13(d,J=8.4Hz,1H),8.27(dd,J=7.6,1.2Hz,1H)

[0958] Step 2:

[0959] Under nitrogen protection, C081-1 (1.9 g, 8.01 mmol) was dissolved in dichloromethane (60 ml), cooled in an ice-water bath, and phosphorus tribromide (2.16 g, 7.98 mmol, diluted in 5.0 ml DCM) was added dropwise at 0 °C. After the addition was complete, the reaction was allowed to proceed at 0 °C for 0.5 h, and TLC showed that the reaction was complete. The reaction solution was adjusted to neutral by adding saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a white solid C081-2 (1.55 g, crude product).

[0960] Step 3:

[0961] Under nitrogen protection, C081-2 (1.55 g, 5.17 mmol) was dissolved in DMSO (20 ml). Sodium borohydride (394 mg, 10.42 mmol) was added in portions at room temperature. After the addition was complete, the reaction was allowed to proceed at room temperature for 0.5 h. TLC showed that the reaction was complete. The reaction solution was quenched with water, stirred at room temperature for 1 h, extracted with ethyl acetate, and the organic phases were combined, dried over saturated brine and anhydrous sodium sulfate, and concentrated to give a pale yellow solid C081-3 (1.0 g, crude product). 1 H NMR (400MHz, CDCl3) δ2.74(s,3H),7.36-7.42(m,2H),7.49-7.53(m,1H),7.83(dd,J=7.2,0.8Hz,1H),8.01 (d,J=8.4Hz,1H),8.18(d,J=8.4Hz,1H)

[0962] Step 4:

[0963] Under nitrogen protection, C068-1 (400 mg, 0.87 mmol) was dissolved in DMF (10 mL), and C081-3 (386 mg, 1.75 mmol), Pd(dppf)Cl2 dichloromethane complex (72 mg, 0.09 mmol), and Cs2CO3 (569 mg, 1.75 mmol) were added. The mixture was purged with nitrogen three times, and the temperature was raised to 80 °C for 3.0 h. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over saturated brine and anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography (PE / EA = 10 / 1) to give a white solid C081-4 (281 mg, 68% yield in four steps).

[0964] Step 5:

[0965] Under nitrogen protection, C081-4 (281 mg, 0.59 mmol) was dissolved in DCM (3 ml), cooled in an ice-water bath, and trifluoroacetic acid (1.0 ml) was added dropwise at 0 °C. After the addition was complete, the reaction was allowed to proceed at room temperature for 1.0 h, and TLC showed that the reaction was complete. The reaction solution was adjusted to a weakly alkaline state by adding saturated sodium bicarbonate aqueous solution dropwise, stirred for 20 min, extracted with dichloromethane, and the organic phases were combined. The mixture was dried over saturated brine and anhydrous sodium sulfate, and concentrated to obtain a pale yellow oil C081-5 (220 mg, crude product). 1H NMR (400MHz, DMSO_d6)δ1.40(t,J=7.2Hz,3H),1.92(br,2H),2.71(s,3H),3.86(s,3H) ,4.22(s,2H),4.34(q,J=7.2Hz,2H),7.27(dd,J=8.0,12Hz,1H),7.32–7.39(m,2H), 7.50(d,J=6.0Hz,1H),7.61-7.65(m,2H),7.70(d,J=8.4Hz,1H),8.06(d,J=8.4Hz,1H),8.11(d,J=8.0Hz,1H) LCMS: m / z=356.2[M-NH2] +

[0966] Step 6:

[0967] Under nitrogen protection, C081-5 (220 mg, 0.59 mmol) was dissolved in acetonitrile (10 mL), and DIEA (381 mg, 2.95 mmol) and 1H-pyrazole-1-formamidinium hydrochloride (174 mg, 1.19 mmol) were added. The reaction was carried out at room temperature for 24 h, and the reaction was monitored by LCMS to ensure the complete reaction of the starting material. The reaction solution was filtered, and the filter cake was washed and dried to give a pale yellow solid SYY-C081 (170 mg, 69% yield in two steps). 1 H NMR: (DMSO-d6, 400MHz): δ1.42(t,J=7.2Hz,3H), 2.72(s,3H),3.90(s,3H),4.40(q,J=7.2Hz,2H),5.00(s,2H),7.17-7.98(m,11H),8.08 (d,J=8.4Hz,1H),8.14(d,J=8.0Hz,1H).LCMS: m / z=415.2[M+H] + (98.55% purity, 220nm)

[0968] Example 67: Preparation of compound SYY-C082

[0969]

[0970] Step 1:

[0971] IN-009-3 (6.0 g, 21.27 mmol) and phenylboronic acid (3.0 g, 25.52 mmol) were dissolved in dichloromethane (60 mL). Copper acetate (5.5 g, 31.91 mmol), DMAP (3.7 g, 31.91 mmol), and triethylamine (3.1 g, 31.91 mmol) were added sequentially. After purging with nitrogen three times, the reaction was allowed to proceed overnight at room temperature. TLC analysis showed the formation of new spots, indicating that a significant amount of the starting material had not reacted completely. The reaction solution was quenched with 1N hydrochloric acid solution, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain a brownish-yellow oily substance C082-1 ​​(1.5 g, crude product).

[0972] Step 2:

[0973] C082-1 ​​(1.5 g, crude), NBS (754 mg, 4.23 mmol), and BPO (50 mg, 0.21 mmol) were dispersed in carbon tetrachloride (30 mL) and reacted at 80°C for 2 h. The reaction solution was cooled to room temperature and purified by direct silica gel column chromatography to obtain a brownish-yellow oily substance C082-2 (1.6 g, crude).

[0974] Step 3:

[0975] C082-2 (1.6 g, crude) was dissolved in DMF (15 mL), and sodium azide (277 mg, 4.27 mmol) was added at room temperature. The reaction solution was heated to 60°C and reacted for 2 h. The reaction was confirmed to be complete by TLC. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a brownish-yellow oily substance C082-3 (1.4 g, crude).

[0976] Step 4:

[0977] C082-3 (1.4 g, crude) and triphenylphosphine (1.85 g, 7.0 mmol) were dispersed in a mixed solvent of THF (50 mL) and water (5 mL). The mixture was heated to 80°C and reacted for 3 h. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, and 1 N dilute hydrochloric acid / EA was added. The mixture was extracted and separated. The organic layer was discarded, and the aqueous layer was adjusted to alkaline with sodium hydroxide and extracted with EA. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow solid C082-4 (400 mg, 5% yield in four steps).

[0978] Step 5:

[0979] C082-4 (400 mg, 1.07 mmol) was dissolved in DCM (10 ml), and DIPEA (420 mg, 3.21 mmol) was added. The mixture was stirred in an ice bath for 20 min, followed by the slow addition of (Boc)₂O (281 mg, 1.28 mmol). The mixture was stirred at room temperature for 2 h, and TLC showed that the reaction was complete. The reaction solution was extracted with 1 N dilute hydrochloric acid and dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain C082-5 (380 mg, crude product), which was used directly in the next step.

[0980] Step 6:

[0981] C082-5 (380 mg, crude) and boric acid (210 mg, 1.20 mmol) were dissolved in DMF (10 mL), and water (0.5 mL), Cs2CO3 (530 mg, 1.60 mmol), and PdCl2 (dppf) (70 mg, 0.08 mmol) were added. The mixture was substituted with N2 three times, heated to 100 °C and refluxed for 2 h. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain C082-6 (460 mg, 91% in two steps).

[0982] Step 7:

[0983] C082-6 (460 mg, 0.88 mmol) was dissolved in DCM (6 ml), and TFA (3 ml) was added. The reaction was carried out at room temperature for 2 h, and TLC showed that the reaction was complete. The reaction solution was concentrated, neutralized with saturated NaHCO3 solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concen...

Claims

1. Use of a compound, or a pharmaceutically acceptable salt thereof, in the preparation of a composition or formulation, characterized in that, The composition or preparation is used for the prevention and / or treatment of thrombosis. The compounds mentioned above are selected from the following group: 。 2. The use as described in claim 1, characterized in that, The aforementioned prevention and / or treatment of thrombosis achieves antithrombotic effects without affecting or improving bleeding.

3. The use as described in claim 2, characterized in that, The improvement of bleeding includes inhibiting bleeding, not increasing the risk of bleeding, reducing the risk of bleeding, not causing bleeding side effects, and / or not affecting hemostasis.

4. The use as described in claim 1, characterized in that, The thrombus mentioned is a cardiovascular and cerebrovascular disease thrombus, which is selected from the following group: myocardial infarction thrombus, cerebral infarction thrombus, ischemic stroke, atherosclerotic thrombus, or a combination thereof.

5. The use as described in claim 1, characterized in that, The prevention and / or treatment of thrombosis includes one or more methods selected from the group consisting of: (3-1) Inhibits the platelet stretching function on solid-phase fibrinogen; (3-2) Inhibits platelet aggregation, adhesion and / or stretching; (3-3) Inhibits fibrin clot retraction; (3-3) It does not affect the binding function of platelets to free fibrinogen.

6. The use as described in claim 1, characterized in that, The composition or preparation described herein is a pharmaceutical composition or preparation.

7. The use as described in claim 1, characterized in that, The composition or formulation may also include a pharmaceutically acceptable carrier.

8. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compounds are selected from the group consisting of: 。 9. A pharmaceutical composition, characterized in that, The composition comprises: (a) the compound of claim 8, or a pharmaceutically acceptable salt thereof; and (b) Pharmaceutically acceptable carriers.

10. The pharmaceutical composition according to claim 9, characterized in that, The dosage form of the pharmaceutical composition is selected from the group consisting of: injections, capsules, tablets, pills, powders, granules, aerosols, suppositories, films, and drop pills.

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