Complement factor b inhibitor, and pharmaceutical composition thereof, preparation method therefor and use thereof

Abstract

A piperidine-containing heterocyclic compound represented by formula (I) that treats "G disease," a pathology related to the activation of the complement alternative pathway, by inhibiting / regulating complement factor B. I

Description

Technology Field

[0001] Cross-reference of related applications

[0002] The present invention claims priority to a prior application filed with the National Intellectual Property Administration of China on August 7, 2020, with patent application number 202010790872.8 and titled "Complement Factor B Inhibitor and Pharmaceutical Composition, Method of Preparation and Use thereof," and the full text of the said prior application is incorporated by reference into the present invention.

[0003] The present invention belongs to the field of medicine and, specifically, relates to a complement factor B inhibitor and its pharmaceutical composition, method of preparation, and use. Background Technology

[0004] Complement is a soluble pattern recognition molecule of the immune system capable of performing various effector functions. Under natural conditions, complement components exist in the form of inactive zymogens, from which various specific and non-specific immunological mechanisms degrade these inactive zymogens to generate active large and small fragments. Here, the large fragments typically remain on the surface of pathogens or cells to cleave the latter or accelerate their elimination; the small fragments leave the cell surface to mediate various inflammatory responses. Complement activation consists of two closely linked processes, from which the complement activation cascade reaction is formed. Currently known complement activation pathways mainly include three pathways: the classical pathway, the lectin pathway, and the alternative pathway. Although the initiation mechanisms and activation sequences of the three complement activation pathways differ, they share a common terminal pathway. Here, the activation of the alternative pathway does not rely on antigen-antibody complexes; typically, C3b deposited on the cell surface binds to Factor B, becoming easily degraded by Factor D in the serum, during which Factor B is degraded into Ba and Bb; Subsequently, C3b and Bb form a complex to become the C3-convertase C3bBb within the alternative pathway; in this process, complement factor B plays an early and key role in the activation of the alternative pathway of the complement cascade. Here, C3b is not only a product generated after the C3-convertase degrades C3, but also a component of the alternative pathway C3-convertase, thereby forming a feedback amplification mechanism in which the classical pathway and the alternative pathway influence each other. In the current study, it was discovered that various diseases, including hematological, autoimmune, inflammatory, and neurodegenerative conditions, are associated with dysfunction of the complement system.

[0005] Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic disease characterized by persistent hemolysis. It is a non-malignant clonal disease caused by acquired somatic PIG-A gene mutations in one or more hematopoietic stem cells and is classified as a very rare blood disorder (Medicine (Baltimore) 1997, 76(2): 63-93). The course of the disease can manifest as varying degrees of hemolytic exacerbation (paroxysmal), chronic or recurrent acute intravascular hemolysis, or subsequent venous / arterial thrombosis, ultimately leading to progressive end-organ damage and death. Although it is a typical PNH with chronic intravascular hemolysis, hemoglobinuria, and hemosiderinuria as the main symptoms, most patients often have atypical and slow onset, with a delayed course and varying severity of the disease.

[0006] There are more than 10 proteins on the surface of red blood cells that inhibit complement pathway activation, all of which are anchored to the cell membrane via glycosylphosphatidylinositol (GPI) and are collectively referred to as GPI-anchor proteins (AP). Currently, the pathogenesis of PNH is considered to be that hematopoietic stem cells first undergo mutations under certain conditions to produce glycosylphosphatidylinositol (GPI)-deficient PNH clones; then, due to some factors (currently considered mostly immune factors), hematopoietic function is impaired or hematopoietic insufficiency occurs, and PNH clones acquire proliferative dominance and outnumber normal clones. Various antigens linked to GPI also complicate the interpretation of the biological behavior of PNH cells; here, the most important proteins inhibiting complement pathway activation—the C3 convertase degradation accelerator CD55 and the Membrane Attack Complex (MAC) inhibitor CD59—are closely associated with PNH in terms of pathogenesis, clinical symptoms, diagnosis, and treatment (Frontiers in Immunology 2019, 10, 1157). CD59 may act to inhibit the complement terminal attack response by preventing C9 from doping into the C5b-8 complex and inhibiting the formation of the MAC unit. Currently, the typical signs of PNH—intravascular hemolysis and thrombosis—are considered to be due to CD59 deficiency. Reports indicate that patients with congenital CD59 deficiency exhibit many typical symptoms of PNH, such as intravascular hemolysis, hemoglobinuria, and venous thrombosis. In patients with PNH, defects in GPI synthesis prevent CD59 from binding to the cell membranes of red blood cells, causing it to lose its function of inhibiting complement pathway activation; consequently, abnormal activation of the complement pathway occurs, attacking red blood cells and causing various clinical symptoms such as intravascular hemolysis, hemoglobinuria, and smooth muscle dysfunction. Currently, there are no other effective treatment methods for PNH in clinical practice other than the treatment of reconstructing normal hematopoietic function through hematopoietic stem cell transplantation.Since hematopoietic stem cell transplantation carries certain risks and PNH is a benign clonal disease, controlling hemolytic attacks remains a primary strategy for the clinical treatment of this disease. Currently, only eculizumab is approved for the treatment of PNH. However, many patients still experience anemia after eculizumab treatment, and many still require continuous blood transfusions. Furthermore, eculizumab must be administered intravenously. Therefore, it is crucial to develop novel inhibitors of the complement pathway for the treatment of PNH.

[0007] IgAN is the most common primary glomerulonephritis, characterized by IgA deposition in the mesangial region on immunofluorescence; its clinical manifestations are variable and typically present as recurrent microscopic or gross hematuria. Existing data indicate that the development of IgAN is associated with congenital or acquired immune dysregulation. Irritation of the respiratory or digestive tract by viruses, bacteria, and food proteins leads to increased mucosal IgA1 synthesis, or the deposition of IgA1-containing immune complexes in the mesangial region, which activates the complement replacement pathway and causes glomerular damage. Human IgA molecules are divided into two subtypes, IgA1 and IgA2; IgA1 is the dominant form in blood circulation in healthy individuals (accounting for approximately 85%) and is also the major component deposited in the glomerular mesangial region of IgAN patients. IgA molecules can exist in two forms: monomeric and polymeric. The IgA1 molecule possesses a unique heavy chain hinge region between the first and second constant regions as a domain of the O-linked glycan group linkage site. Recent studies have discovered that IgA molecules deposited in the serum and glomerular mesangium of IgAN patients are primarily glycosylated-deficient IgA1 (gd-IgA1). Currently, the initiation link of the IgAN pathogenesis mechanism is considered to be an abnormal increase in gd-IgA1.

[0008] Complement C3 deposition is associated with the glomerular mesangial region in more than 90% of IgAN patients. Co-deposition of properin, IgA, and C3 is present in the renal tissue of 75% to 100% of IgAN patients, and co-deposition of complement factor H, IgA, and C3 is present in the renal tissue of 30% to 90% of IgAN patients. In addition to deposition in renal tissue, some studies have also found that the levels of complement alternative pathway markers in the plasma of IgAN patients are associated with IgAN activity (J Nephrol 2013, 26(4): 708-715). Studies have demonstrated that C3a in renal tissue and urine, as well as C3a receptors in renal tissue, are significantly associated with the activity and severity of renal injury (J clin Immunol 2014, 34(2): 224-232). Other studies have demonstrated that IgA can activate the complement alternative pathway under in vitro conditions. In this process, abnormalities in the IgA hinge region do not play a decisive role, and the formation of IgA multimers is the key link (Eur J Immunol 1987, 17(3): 321-326). Currently, the deposition of complement C3 in the glomerular mesangium has become an auxiliary diagnostic marker for IgAN. A study that performed immunofluorescence detection of C3c and C3d on kidney tissues from 163 IgAN patients showed that IgAN patients with higher C3c deposition intensity than C3d deposition intensity had lower glomerular filtration rates, a higher incidence of glomerular capillary proliferation, and more severe hematuria, indicating that glomerular C3c deposition is associated with active lesions of IgAN (Am J Nephrol. 2000, 20(2):122-128). Currently, there are no specific drugs for the treatment of IgAN in clinical practice, and they mainly consist of general-purpose drugs such as renin-angiotensin inhibitors (ACEI or ARB), glucocorticoids, and various immunosuppressants.In addition, the safety of these drugs is also a concern that cannot be overlooked. For example, while glucocorticoids are effective in reducing proteinuria, the STOP-IgAN and TESTING-I trials clearly demonstrated the potential side effects of glucocorticoids (IgA nephropathy 2019, 95, 4, 750-756).

[0009] Arthritis is a common chronic disease caused by inflammation, infection, degeneration, trauma, or other factors. Clinical symptoms include joint redness, swelling, heat, pain, dysfunction, and joint deformity, often leading to severe pain, limited mobility, and physical deformity. In severe cases, it can cause disability and affect the patient's quality of life. A study found that K / BxN mouse serum could not induce arthritis in complement B factor-deficient mice, while wild-type mice could develop arthritis under the induction of K / BxN mouse serum (Immunity, 2002, 16, 157-168). This indicates that the complement system plays a significant pathogenic role in the K / BxN mouse serum-induced arthritis model and that complement B factor is a potential target for arthritis treatment.

[0010] Other diseases associated with the complement cascade include membranous nephropathy (MN), C3 glomerulonephritis (C3G), age-related macular degeneration (AMD), geographic atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), complications of hemodialysis, hemolytic anemia or hemodialysis, neuromyelitis optica (NMO), hepatitis, inflammatory bowel disease, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), respiratory disease and cardiovascular disease.

[0011] Currently, there are no small molecule complement factor B inhibitor drugs available for clinical treatment, and IONIS Pharmaceuticals Inc. is a known project currently under investigation. Developed oligonucleotide drugs are used as complement factor B (CFB) specific inhibitors to treat, prevent, or alleviate diseases associated with dysregulation of the complement substitution pathway (WO2015038939). Small molecule complement factor B inhibitors developed by Novartis AG are used to treat diseases such as age-related macular degeneration (AMD) (WO2013164802, WO2013192345, WO2014143638, WO2015009616, WO2015066241), and to treat diseases such as C3G and IgAN (WO2019043609A1). Small molecule complement factor B inhibitors developed by Achillion Pharmaceuticals Inc. are used to treat diseases such as age-related macular degeneration (AMD) (WO2018005552).

[0012] Inflammatory and immune-related diseases are characterized by their diversity and difficulty in treatment; while eculizumab is the only commercially available drug for PNH, its high cost places a significant burden on patients; at the same time, many patients still experience anemia after eculizumab treatment, and many require continuous blood transfusions; furthermore, eculizumab must be administered via intravenous injection. There are currently no specific treatments for some diseases, such as IgAN. There is still unmet clinical demand in these fields, necessitating the development of new small molecule drugs for medical treatment.

[0013] To improve upon the above technical problem, the present invention provides a compound represented by formula (I), its racemic mixture, stereoisomer, tautomeric mixture, isotope marker, solvate, polymorph, pharmaceutically acceptable salt, or a prodrug compound thereof.

[0014]

[0015] I

[0016] In Equation (I), R 1 halogen, OH, CN, NO2, unsubstituted, or optionally one, two, or more R a C substituted by 1-40 Alkyl, C 2-40 alkenyl, C 2-40 alkynyl, C 3-40 cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 won Heteroaryl, 3-20 won Heterocyclyl, C 1-40 Alkyloxy, C 2-40 alkenyloxy, C 2-40 alkynyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 Selected from aryloxy, 5-20 won heteroaryloxy, 3-20 won heterocyclyloxy, and NH2;

[0017] R 2 is H, halogen, OH, CN, NO2, unsubstituted, or optionally one, two, or more R b C substituted by 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkinyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkinyl, C 6-20 Aryl, 5-20 won Heteroaryl, 3-20 won Heterocyclil, C1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkinyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkinyloxy, C 6-20 Selected from aryloxy, 5-20 won heteroaryloxy, 3-20 won heterocyclyloxy, and NH2;

[0018] R 3 halogens, OH, CN, NO2, unsubstituted, or optionally one, two, or more R c C substituted by 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkinyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkinyl, C 6-20 Aryl, 5-20 won Heteroaryl, 3-20 won Heterocyclil, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkinyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkinyloxy, C 6-20 Selected from aryloxy, 5-20 won heteroaryloxy, 3-20 won heterocyclyloxy, and NH2;

[0019] R 4 is H, non-substitutable, or optionally one, two, or more of R d C substituted by 1-40 Alkyl, C 3-40 Cycloalkyl, C 1-40 Alkyl-C(O)-, C 3-40 Cycloalkyl-C(O)-, C 1-40 Alkyl-S(O)2-, C 3-40 Selected from cycloalkyl-C(O)2-;

[0020] R 5is H, halogen, OH, CN, NO2, unsubstituted, or optionally one, two, or more R e C substituted by 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkinyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkinyl, C 6-20 Aryl, 5-20 won Heteroaryl, 3-20 won Heterocyclil, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkinyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkinyloxy, C 6-20 Selected from aryloxy, 5-20 won heteroaryloxy, 3-20 won heterocyclyloxy, and NH2;

[0021] R 6 H, halogen, OH, CN, NO2, unsubstituted, or optionally one, two, or more R f C substituted by 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkinyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkinyl, C 6-20 Aryl, 5-20 won Heteroaryl, 3-20 won Heterocyclil, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkinyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkinyloxy, C 6-20 Selected from aryloxy, 5-20 won heteroaryloxy, 3-20 won heterocyclyloxy, and NH2;

[0022] R 7 Silver consists of hydrogen, OH, CN, unsubstituted, or optionally one, two, or more R groups.g C substituted by 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkinyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkinyl, C 6-20 Aryl, 5-20 won Heteroaryl, 3-20 won Heterocyclil, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkinyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkinyloxy, C 6-20 Selected from aryloxy, 5-20 won heteroaryloxy, 3-20 won heterocyclyloxy, NH2;

[0023] Or, R 1 , R 7 together with the atoms connected thereto, one, two, or more unsubstituted or optionally R h A ring structure of 5-20 months substituted by, and said 5-20 month ring structure is, for example, C 5-20 Cycloalkenyl, C 6-20 Can be selected from aryl, 5-20 member heterocyclil, 5-20 member heteroaryl;

[0024] Or, R 6 , R 7 together with the atoms connected thereto, one, two, or more unsubstituted or optionally R i A 5-20 member ring structure substituted by, and said 5-20 member ring structure is, for example, C 5-20 Cycloalkenyl, C 6-20 It can be selected from aryl, 5-20 member heterocyclil, and 5-20 member heteroaryl;

[0025] Cy is R 8 , R 9 , R 10 , R 11C substituted by 1, 2, 3, 4, 5, 6, 7, 8 or more substituents independently selected from 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkinyl, C 6-20 Aryl, 5-20 won Heteroaryl, 3-20 won Heterocyclil, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkinyloxy, C 6-20 Aryloxy, 5-20 won Heteroaryloxy, 3-20 won Heterocyclyloxy, C 3-40 Cycloalkyl-C 1-40 Alkyl-, C 3-40 Cycloalkenyl-C 1-40 Alkyl-, C 3-40 Cycloalkinyl-C 1-40 Alkyl-, C 6-20 Aryl-C 1-40 Alkyl-, 5-20 member heteroaryl-C 1-40 Alkyl-, 3-20 member heterocyclyl-C 1-40 Alkyl-, C 3-40 Cycloalkyl-C 1-40 Alkyl-, C 3-40 Cycloalkenyl-C 1-40 Alkyl-, C 3-40 Cycloalkinyl-C 1-40 Alkyl-, C 6-20 Aryl-C 1-40 Alkyl-, 5-20 member heteroaryl-C 1-40 Alkyl-, 3-20 member heterocyclyl-C 1-40 Selected from alkyl-, wherein the 3-20-membered heterocyclyl in group Cy comprises 1 to 5 heteroatoms selected from N, O, and S, and comprises at most only one N atom;

[0026] R 8 , R 9 is identical or different and independently H, non-substitutable or optionally one, two or more R j C substituted by 1-40 Alkyl, C 2-40 Alkenyl, C2-40 Alkinyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkinyl, C 6-20 Aryl, 5-20 won Heteroaryl, 3-20 won Heterocyclil, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkinyloxy, C 6-20 Aryloxy, 5-20 won Heteroaryloxy, 3-20 won Heterocyclyloxy, C 3-40 Cycloalkyl-C 1-40 Alkyl-, C 3-40 Cycloalkenyl-C 1-40 Alkyl-, C 3-40 Cycloalkinyl-C 1-40 Alkyl-, C 6-20 Aryl-C 1-40 Alkyl-, 5-20 member heteroaryl-C 1-40 Alkyl-, 3-20 member heterocyclyl-C 1-40 Selected from alkyl-;

[0028] *R 10 , R 11 ...is identical or different and independently of each other H, absence, halogen, OH, CN, NO2, unsubstituted, or optionally one, two or more R k C substituted by 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkinyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkinyl, C 6-20 Aryl, 5-20 won Heteroaryl, 3-20 won Heterocyclil, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkinyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkinyloxy, C 6-20 Selected from aryloxy, 5-20 won heteroaryloxy, 3-20 won heterocyclyloxy, NH2;

[0029] Or, R 8 , R 9 together with the atoms connected thereto, one, two, or more unsubstituted or optionally R j A 5-20 member ring structure substituted by, and said 5-20 member ring structure is, for example, C 3-20 Cycloalkyl, C 5-20 Cycloalkenyl, C 6-20 Can be selected from aryl, 5-20 member heterocyclil, 5-20 member heteroaryl;

[0030] Or, R 10 , R 11 together with the atoms connected thereto, one, two, or more unsubstituted or optionally R k A 5-20 member ring structure substituted by, and said 5-20 member ring structure is, for example, C 3-20 Cycloalkyl, C 5-20 Cycloalkenyl, C 6-20 It can be selected from aryl, 5-20 member heterocyclil, and 5-20 member heteroaryl;

[0031] Each R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k is identical or different and independently of each other H, halogen, OH, CN, NO2, oxo (=O), thioxo (=S), unsubstituted or optionally one, two or more R p C substituted by 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkinyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkinyl, C 6-20Aryl, 5-20 won Heteroaryl, 3-20 won Heterocyclil, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkinyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkinyloxy, C 6-20 Aryloxy, 5-20 won Heteroaryloxy, 3-20 won Heterocyclyloxy, C 1-40 alkylthio, C 2-40 alkenylthio, C 2-40 alkynylthio, C 3-40 cycloalkylthio, C 3-40 cycloalkenylthio, C 3-40 cycloalkynylthio, C 6-20 arylthio, 5-20 won heteroarylthio, 3-20 won heterocyclylthio, NH2, -C(O)R 12 , -C(O)OR 13 , -OC(O)R 14 , -S(O)2R 15 , -S(O)2OR 16 , -OS(O)2R 17 , -B(OR 18 )(OR 19 ), -P(O)(OR 20 )(OR 21 ), Selected from;

[0032] Each R p is identical or different and independently of each other H, halogen, OH, CN, NO2, oxo (=O), thioxo (=S), unsubstituted or optionally one, two or more R q C substituted by 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkinyl, C 3-40Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkinyl, C 6-20 Aryl, 5-20 won Heteroaryl, 3-20 won Heterocyclil, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkinyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkinyloxy, C 6-20 Aryloxy, 5-20 won Heteroaryloxy, 3-20 won Heterocyclyloxy, C 1-40 Alkylthio, C 2-40 Alkenylthio, C 2-40 Alkynylthio, C 3-40 Cycloalkylthio, C 3-40 Cycloalkenylthio, C 3-40 Cycloalkynylthio, C 6-20 Arylthio, 5-20 won Heteroaryltio, 3-20 won Heterocyclylthio, NH2, -C(O)R 121 , -C(O)OR 131 , -OC(O)R 141 , -S(O)2R 151 , -S(O)2OR 161 , -OS(O)2R 171 , -B(OR 181 )(OR 191 ), -P(O)(OR 201 )(OR 211 ), Selected from;

[0033] Each R q are identical or different, and independently of each other H, halogen, OH, CN, NO2, iodine (=O), thioxine (=S), C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkinyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkinyl, C 6-20 Aryl, 5-20 won Heteroaryl, 3-20 won Heterocyclil, C 1-40 Alkyloxy, C2-40 Alkenyloxy, C 2-40 Alkinyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkinyloxy, C 6-20 Aryloxy, 5-20 won Heteroaryloxy, 3-20 won Heterocyclyloxy, C 1-40 Alkylthio, C 2-40 Alkenylthio, C 2-40 Alkynylthio, C 3-40 Cycloalkylthio, C 3-40 Cycloalkenylthio, C 3-40 Cycloalkynylthio, C 6-20 Arylthio, 5-20 won Heteroaryltio, 3-20 won Heterocyclylthio, NH2, -C(O)C 1-40 Alkyl, -C(O)NH2, -C(O)NHC 1-40 Alkyl, -C(O)-NH-OH, -COOC 1-40 Alkyl, -COOH, -OC(O)C 1-40 Alkyl, -OC(O)H, -S(O)2C 1-40 Alkyl, S(O)2H, -S(O)2OC 1-40 Alkyl, -OS(O)2C 1-40 Alkyl, -P(O)(OH)2, -B(OH)2, Selected from;

[0034] R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 121 , R 131 , R 141 , R 151 , R 161 , R 171 , R 181 , R 191 , R 201 , R 211 , R 122 , R 132 , R 142, R 152 , R 162 , R 172 , R 182 , R 192 , R 202 , R 212 is identical or different, and independently H, C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkinyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkinyl, C 6-20 Selected from aryl, 5-20g heteroaryl, 3-20g heterocyclil, and NH2.

[0035] According to an embodiment of the present invention, R 1 halogens, OH, CN, NO2, unsubstituted, or optionally one, two, or more R a C substituted by 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkyloxy, C 3-8 It is selected from cycloalkyloxy, NH2.

[0036] According to an embodiment of the present invention, R 2 is H, halogen, OH, CN, NO2, unsubstituted, or optionally one, two, or more R b C substituted by 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkyloxy, C 3-8 It is selected from cycloalkyloxy, NH2.

[0037] According to an embodiment of the present invention, R 3 halogens, OH, CN, NO2, unsubstituted, or optionally one, two, or more R c C substituted by 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkyloxy, C 3-8 It is selected from cycloalkyloxy, NH2.

[0038] According to an embodiment of the present invention, R 4 is H, non-substitutable, or optionally one, two, or more of R d C substituted by 1-6 Selected from alkyls.

[0039] According to an embodiment of the present invention, R 5 is H, halogen, OH, CN, NO2, unsubstituted, or optionally one, two, or more R e C substituted by 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkyloxy, C 3-8 It is selected from cycloalkyloxy, NH2.

[0040] According to an embodiment of the present invention, R 6 H, halogen, OH, CN, NO2, unsubstituted, or optionally one, two, or more R f C substituted by 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkyloxy, C 3-8 It is selected from cycloalkyloxy, NH2.

[0041] R 7 Silver consists of hydrogen, OH, CN, unsubstituted, or optionally one, two, or more R groups. g C substituted by 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkyloxy, C 3-8 It is selected from cycloalkyloxy, NH2.

[0043] According to an embodiment of the present invention, optionally, R 1 , R 7 together with the atoms connected thereto, one, two, or more unsubstituted or optionally R h C substituted by 5-10 Cycloalkenyl, C 6-10 Aryl, 5-10 member heterocyclil, 5-10 member heteroaryl, e.g., C5-6 Cycloalkenyl, C6aryl, 5-6-membered heterocyclyl, and 5-6-membered heteroaryl can be formed. Preferably, the 5-6-membered heterocyclyl and 5-6-membered heteroaryl comprise 1, 2, 3, 4, 5 or more heteroatoms selected, for example, from O, S, and N, wherein N and S may optionally not be oxidized or may be oxidized to various oxidation states. As an embodiment, R 1 , R 7 is condensed with an indole group of formula (I) together with atoms connected thereto, and is unsubstituted or optionally has one, two, or more R h It can form cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrothiopyranyl substituted by (wherein the sulfur atom is not oxidized or is oxidized to a -S(O)2- group).

[0044] According to an embodiment of the present invention, optionally, R 6 , R 7 together with the atoms connected thereto, one, two, or more unsubstituted or optionally R i C substituted by 5-20 Cycloalkenyl, C 6-20 Aryl, 5-20 won heterocyclil, 5-20 won heteroaryl, e.g., C 5-6 Cycloalkenyl, C6aryl, 5-6-membered heterocyclyl, and 5-6-membered heteroaryl can be formed. Preferably, the 5-6-membered heterocyclyl and 5-6-membered heteroaryl comprise 1, 2, 3, 4, 5 or more heteroatoms selected, for example, from O, S, and N, wherein N and S may optionally not be oxidized or may be oxidized to various oxidation states. As an embodiment, R 6 , R 7is condensed with the indole group of formula (I) together with the atoms connected thereto, and is unsubstituted or optionally 1, 2, or more R h It can form cyclopentyl, cyclohexyl, tetrahydrofuranil, tetrahydropyranil, and tetrahydrothiopyranil substituted by (wherein the sulfur atom is not oxidized or is oxidized to a -S(O)2- group).

[0045] According to an embodiment of the present invention, Cy is R 8 , R 9 , R 10 , R 11 C substituted by 1, 2, 3, 4, 5, 6, 7, 8 or more substituents independently selected from 3-40 Cycloalkyl, C 6-20 It may be selected from aryl, 5-20-membered heteroaryl, and 3-20-membered heterocyclil, wherein the 3-20-membered heterocyclil in group Cy comprises 1 to 3 heteroatoms selected from N, O, and S, and comprises at most only one N atom.

[0046] According to a preferred embodiment of the present invention, Cy is R 8 , R 9 , R 10 and R 11 It can be selected from 3-20-membered heterocyclils substituted by 1, 2, 3, 4, 5, 6, 7, or 8 substituents selected from, for example, Cy is R 8 , R 9 , R 10 and R 11 Substituted by and also optionally R 8 , R 9 , R 10 , R 11Selected from 3-20 heterocyclils further substituted by 1, 2, 3, or 4 substituents independently selected from, wherein the 3-20 heterocyclil in group Cy comprises 1 or 2 heteroatoms selected from N, O, and S, and comprises at most only one N atom.

[0047] According to an exemplary embodiment of the present invention, Cy may be selected from saturated or unsaturated non-aromatic carbon rings or heterocyclic ring systems, such as a 4-, 5-, 6-, or 7-membered single ring, a 7-, 8-, 9-, 10-, 11-, or 12-membered double ring (e.g., condensation ring, bridge ring, spiro ring), or a 10-, 11-, 12-, 13-, 14-, or 15-membered triple ring system, and said heterocyclic ring system comprises 1 to 5 heteroatoms selected from O, S, and N, and comprises at most only one N atom, wherein if present, the N atom and the S atom may optionally not be oxidized or may be oxidized to various oxidation states.

[0048] According to an exemplary embodiment of the present invention, Cy comprises one N atom and one or two atoms selected from O or S, which may or may not be present. Preferably, when Cy is selected from a double ring system, the N atom and the O atom or S atom are in different ring structures in the double ring.

[0049] According to an exemplary embodiment of the present invention, Cy comprises up to two heteroatoms, and only one of the heteroatoms is selected from N atoms.

[0050] According to an exemplary embodiment of the present invention, Cy is,

[0051] piperidinyl;

[0052] Piperidinyl condensed with a ring system selected from cyclopropyl, tetrahydrofuranil, tetrahydropyranil, and phenyl;

[0053] Spiro[2.4], [3.4], [4.4], [2.5], [3.5], [4.5] or [5.5] ring groups of aza and / or oxa;

[0054] It may be selected from the aza and / or oxa bicyclo[2.2.1], [2.2.2], [3.2.1], [3.2.2] or [3.3.2] ring groups.

[0055] According to a preferred embodiment of the present invention, the N atom in Cy is the Cy group of formula (I) and R 7 The group can be bonded to a shared C atom.

[0056] As an embodiment, Cy is a single ring, a condensed ring, a bridge ring group, for example

[0057] Piperidinyl;

[0058] , , , , , , , , , , , ;

[0059] , , , , , , , ;

[0060] , It can be selected from.

[0061] According to an embodiment of the present invention, R 8 is optionally 1, 2, or more R jC substituted by 6-10 It can be selected from aryl, 5-10-membered heteroaryl, 3-20-membered heterocyclyl, e.g., phenyl, pyridyl, pyrazinyl, furyl, pyranyl, benzocyclohexyl, benzocyclopentyl, benzofuryl, and phenylpropanetetrahydrofuranyl.

[0062] According to an embodiment of the present invention, R 9 is identical or different and independently H, non-substitutable or optionally one, two or more R j C substituted by 1-6 Selected from alkyls.

[0063] According to an embodiment of the present invention, optionally, R 8 , R 9 together with the atoms connected thereto, one, two, or more unsubstituted or optionally R j C substituted by 5-10 Cycloalkenyl, C 6-10 It can form aryls, 5-10-membered heterocyclils, and 5-10-membered heteroaryls.

[0064] According to an embodiment of the present invention, R 10 , R 11 may be identical or different, and independently of each other, halogen, OH, CN, NO2, unsubstituted, or optionally one, two or more R k C substituted by 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6-membered heteroaryl, 3-6-membered heterocyclil, C 1-6 Alkyloxy, C 3-6 Cycloalkyloxy, C 6-10 Selected from aryloxy, 5-6-membered heteroaryloxy, 3-6-membered heterocyclyloxy, and NH2;

[0065] According to an embodiment of the present invention, optionally, R 10 , R 11 together with the atoms connected thereto, one, two, or more unsubstituted or optionally R k C substituted by 5-10 Cycloalkenyl, C 6-10 It can form aryls, 5-10-membered heterocyclils, and 5-10-membered heteroaryls.

[0066] According to an embodiment of the present invention, each R j are identical or different, and independently of one, two, or more R's are non-substitutable or optional. p C substituted by 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-10 prismatic heteroaryl, 3-10 prismatic heterocyclil, C 1-6 Alkyloxy, C 3-8 Cycloalkyloxy, C 6-10 Aryloxy, 5-10 won Heteroaryloxy, 3-10 won Heterocyclyloxy, NH2, -C(O)R 12 , -C(O)OR 13 , -B(OR 18 )(OR 19 ), -P(O)(OR 20 )(OR 21 ), Selected from.

[0067] According to an embodiment of the present invention, each R k is identical or different and independently of each other halogen, OH, CN, NO2, unsubstituted or optionally one, two or more R p C substituted by 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6-membered heteroaryl, 3-6-membered heterocyclil, C 1-6 Alkyloxy, C 3-6 Cycloalkyloxy, C 6-10It is selected from aryloxy, 5-6-membered heteroaryloxy, 3-6-membered heterocyclyloxy, and NH2.

[0068] According to an embodiment of the present invention, each R p is identical or different and independently of each other H, halogen, OH, unsubstituted or optionally one, two or more R q C substituted by 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6-membered heteroaryl, 3-6-membered heterocyclil, C 1-6 Alkyloxy, C 3-8 Cycloalkyloxy, C 6-10 Aryloxy, 5-6-membered heteroaryloxy, 3-6-membered heterocyclyloxy, NH2, -C(O)R 121 , -C(O)OR 131 , -B(OR 181 )(OR 191 ), -P(O)(OR 201 )(OR 211 ), Selected from.

[0069] According to an embodiment of the present invention, R q is as defined above.

[0070] According to an embodiment of the present invention, R 12 , R 13 , R 18 , R 19 , R 20 , R 21 , R 121 , R 131 , R 181 , R 191 , R 201 , R 211 is identical or different, and independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 It is selected from aryl, 5-6-membered heteroaryl, 3-6-membered heterocyclil, and NH2.

[0071] According to an embodiment of the present invention, a compound represented by formula (I) may have a structure represented by formula (I-1) or formula (I-2), wherein

[0072]

[0073] I-1 I-2

[0074] W is selected from CH, O, or S;

[0075] Y and Z are identical or different and independent of each other CHR 11 Selected from , O or S;

[0076] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 is independently as defined in the above equation (I).

[0077] According to an embodiment of the present invention, where appropriate, W and Z or Z and Y can form a carbon-carbon single bond or a carbon-carbon double bond.

[0078] According to an embodiment of the present invention, when W is selected from O or S, R 10 It does not exist.

[0079] According to an embodiment of the present invention, when W is selected from CH, R 10 H, halogen, OH, CN, NO2, unsubstituted, or optionally one, two, or more R k C substituted by 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkinyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkinyl, C6-20 Aryl, 5-20 won Heteroaryl, 3-20 won Heterocyclil, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkinyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkinyloxy, C 6-20 Selected from aryloxy, 5-20 won heteroaryloxy, 3-20 won heterocyclyloxy, NH2, wherein R k is as defined above.

[0080] According to an embodiment of the present invention, the compound represented by formula (I) may have a structure represented by formula (I-3) or formula (I-4), wherein

[0081]

[0082] I-3 I-4

[0083] W, Y, Z, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 9 , R 10 , R j is independently as defined above;

[0084] n is selected from 1, 2, 3, 4, or 5.

[0085] According to an embodiment of the present invention, n can be selected from 1, 2, or 3.

[0086] According to an embodiment of the present invention, each R j can be a substituent at the phenyl 2,3-,4- or 5- position.

[0087] According to an embodiment of the present invention, each R j is independently non-substitutable or optionally one, two, or more of R pC substituted by 1-6 Alkyl, NH2, -C(O)R 12 , -C(O)OR 13 , -B(OR 18 )(OR 19 ), -P(O)(OR 20 )(OR 21 ), It can be selected from.

[0088] According to an embodiment of the present invention, R 10 halogens, OH, CN, NO2, unsubstituted, or optionally one, two, or more R k C substituted by 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl)), C 3-8 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl)), 3-6-membered heterocyclyls (e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranil, tetrahydropyranil), C 1-6 Alkyloxy, C 3-6 It is selected from cycloalkyloxy, 3-6-membered heterocyclyloxy, and NH2.

[0089] According to an embodiment of the present invention, each R k is identical or different and independently of each other halogen, OH, CN, NO2, unsubstituted or optionally one, two or more R p C substituted by 1-6Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl), C 3-8 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), C 6-10 Aryl (e.g., phenyl), 5-6-membered heteroaryls (e.g., pyrrolyl, pyridyl, pyrazinyl, imidazolyl, triazolyl), 3-6-membered heterocyclyls (e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxetanil, tetrahydrofuranil, tetrahydropyranil), C 1-6 Alkyloxy, C 3-6 Cycloalkyloxy, C 6-10 It is selected from aryloxy, 5-6-membered heteroaryloxy, and 3-6-membered heterocyclyloxy.

[0090] According to an embodiment of the present invention, each R p is identical or different and independently of each other H, halogen (F, Cl, Br, or I), OH, unsubstituted or optionally one, two, or more R q C substituted by 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6-membered heteroaryl, 3-6-membered heterocyclil, C 1-6 Alkyloxy, C 3-8 Cycloalkyloxy, C 6-10 It is selected from aryloxy, 5-6-membered heteroaryloxy, 3-6-membered heterocyclyloxy, and NH2.

[0091] According to an embodiment of the present invention, one, two, three, or more H atoms in the compound and its substituents (e.g., methyl, ethyl) may be optionally replaced with their isotopes (e.g., D) to form groups such as CD3, C2D5.

[0092] According to an embodiment of the present invention, the compound represented by formula (I) may be selected from the following compounds.

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101] The present invention also provides a compound represented by formula (IV).

[0102]

[0103] IV

[0104] In equation (IV), PG is the protector;

[0105] R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , Cy is independently as defined above.

[0106] The present invention also provides the use of the compound represented by formula (IV) in the preparation of the compound represented by formula (I), its racemic mixture, stereoisomer, tautomeric mixture, isotope marker, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound thereof.

[0107] The present invention also provides a method for preparing a compound represented by formula (I), wherein the method involves reacting a compound represented by formula (IV) with a starting material to obtain a compound represented by formula (Ia), and R 4 A step of obtaining a compound represented by formula (I) where H; and

[0108]

[0109] Optionally, the compound represented by formula (Ia) and R 4 -L 1 By reacting, R 4 a. A step of obtaining a compound represented by formula (I), which is a group other than H among the definitions described above;

[0110] PG, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , Cy is independently as defined above;

[0111] L 1 is a leaving group, for example, OH, F, Cl, Br, I, and C halides. 1-40 It is an alkyl.

[0112] According to an embodiment of the present invention, PG can be selected from amino protecting groups. Here, a suitable PG is C 1-40 Alkyl, C 6-20 Aryl C 1-40 Alkyl-, for example, can be selected from tert-butyl, isopropyl, benzyl, tert-butoxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl (Fmoc), and trifluoroacetyl.

[0113] According to an embodiment of the present invention, a compound represented by formula (IV) is reacted under conditions that remove the protecting group PG to obtain a compound represented by formula (I). The conditions for removing the protecting group PG are reaction conditions known to those skilled in the art.

[0114] The present invention also provides a method for preparing a compound represented by formula (IV), wherein the method comprises the step of reacting a compound represented by formula (II) with a compound represented by formula (III) to obtain a compound represented by formula (IV);

[0115]

[0116] PG, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , Cy is independently as defined above.

[0117] According to an embodiment of the present invention, the manufacturing method may be carried out in the presence of a solvent such as an organic solvent. For example, the organic solvent is an alcohol such as methanol, ethanol, isopropanol, or n-butanol; Ethyl propyl ether, n-butyl ether, anisole, phenetole, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethyl glycol, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, Ethers such as dioxane, dichlorodiethyl ether, and polyethers of ethylene oxide and / or propylene oxide;Aliphatic, alicyclic, or aromatic hydrocarbons such as pentane, hexane, heptane, octane, and nonane, and classes substitutable by fluorine and chlorine atoms such as methylene chloride, dichloromethane, trichloromethane, carbon tetrachloride, fluorobenzene, chlorobenzene, or dichlorobenzene; cyclohexane, methylcyclohexane, petroleum ether, octane, benzene, toluene, chlorobenzene, bromobenzene, and xylene; It may be selected from at least one of esters such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, and dimethyl carbonate, dibutyl carbonate, or ethylene carbonate.;

[0118] According to an embodiment of the present invention, the manufacturing method may be carried out in the presence of a reducing agent; said reducing agent is used to reduce a carbon-nitrogen double bond, said reducing agent may be selected from sodium borohydride, potassium borohydride, lithium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and lithium aluminum hydroxide.

[0119] The present invention also provides a pharmaceutical composition comprising at least one of a compound represented by formula (I), a racemic mixture, stereoisomer, tautomeric isomer, isotope marker, solvate, polymorph, pharmaceutically acceptable salt, or a prodrug compound thereof in a therapeutically effective amount.

[0120] According to an embodiment of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable adjuvants.

[0121] According to an embodiment of the present invention, the pharmaceutical composition may further include one or more additional therapeutic agents.

[0122] The present invention also provides a method for treating diseases related to the activation of the complement alternative pathway, wherein the method comprises the step of administering to a patient at least one of a compound represented by formula (I), a racemic mixture, a stereoisomer, a tautomer, an isotope marker, a solvate, a polymorph, a pharmaceutically acceptable salt, or a prodrug compound thereof in a prophylactic or therapeutically effective amount.

[0123] Diseases related to the activation of the aforementioned complement alternative pathway include paroxysmal nocturnal hemoglobinuria (PNH), primary glomerulonephritis (IgAN), membranous nephropathy (MN), C3 glomerulonephritis (C3G), age-related macular degeneration (AMD), geographic atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), diabetic retinopathy (DR), hemodialysis complications, hemolytic anemia or hemodialysis, neuromyelitis optica (NMO), arthritis, rheumatoid arthritis, hepatitis, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), respiratory diseases and cardiovascular diseases.

[0124] In some embodiments, the patient is a human.

[0125] The present invention also provides at least one of a compound represented by formula (I), its racemic mixture, stereoisomer, tautomeric isomer, isotope marker, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound thereof, or a pharmaceutical composition thereof, used for diseases related to complement alternative pathway activation.

[0126] The present invention also provides for the use of at least one of the compound represented by formula (I), its racemic mixture, stereoisomer, tautomeric mixture, isotope marker, solvate, polymorph, pharmaceutically acceptable salt, or its prodrug compound in the manufacture of drugs.

[0127] The above drug can be used for diseases related to the activation of the complement alternative pathway.

[0128] As a drug, the compounds of the present invention may be administered in the form of a pharmaceutical composition. Such compositions may be prepared in a manner well known in the pharmaceutical field and may be administered via various routes, depending on whether local or systemic treatment is required and the area being treated. They may be administered topically (e.g., transdermal, skin, ocular and nasal, including mucous membranes, vaginal and rectal administration), pulmonaryly (e.g., by inhalation or blowing of powder or aerosol, including by spray; intratracheal, nasal), orally, or parenterally. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial administration, including intrathecal or intraventricular administration. They may be administered parenterally in the form of a bolus, or, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Commonly pharmaceutically acceptable vectors, water, powder or oil matrix, thickeners, etc., may be essential or necessary.

[0129] When preparing the composition of the present invention, the active ingredient is typically mixed with an excipient and diluted through the excipient or enclosed within such a vector in the form of, for example, a capsule, sachet, paper, or other container. When the excipient is used as a diluent, it may be a solid, semi-solid, or liquid substance as a vehicle, vector, or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, pastiles, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (dissolved in a solid or liquid vehicle); for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0130] Some embodiments of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulation may also include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl benzoate and hydroxypropyl benzoate; sweeteners and flavoring agents. The composition of the present invention can be prepared by a method known in the art and administered to a patient, thereby providing the action of rapidly releasing, slowly releasing, or delayed releasing the active ingredient.

[0131] The composition may be prepared according to unit formulations, and each dose contains about 5 to 1000 mg, more typically about 100 to 500 mg of the active ingredient. The term “unit formulation” means a physically separated single dose unit suitable for use in human patients and other mammals, and each unit contains a predetermined amount of active substance that, when mixed with a suitable pharmaceutically acceptable excipient, can produce the required therapeutic effect by calculation.

[0132] The effective dose range of the active compound is very wide, and it can typically be administered at a pharmaceutically acceptable effective dose. However, it should be understood that the actual amount of the compound administered is typically determined by a physician based on relevant circumstances, including the condition being treated, the selected route of administration, and the actual compound being administered; the age, weight, and response of the individual patient; and the severity of the patient's symptoms.

[0133] In the preparation of a solid composition such as a tablet, a major active ingredient is mixed with a pharmaceutically acceptable excipient to form a solid pre-formulation composition of a homogeneous mixture containing the compound of the present invention. When such a pre-formulation composition is referred to as homogeneous, it means that the active ingredient is typically uniformly distributed throughout the entire composition so that the composition can be easily distinguished into equally effective unit formulations such as tablets, pills, or capsules. The solid pre-formulation can then be distinguished into unit formulations of the above type containing, for example, about 0.1 to 1000 mg of the active ingredient of the present invention.

[0134] A formulation providing a long-term effect can be obtained by coating or combining the tablets or pills of the present invention. For example, the tablets or pills contain an internal and an external component, the latter being in the form of a coating of the former. The two components can be separated by an enteric layer, which prevents disintegration in the stomach, thereby allowing the internal component to pass completely through the duodenum or be released with delay. Various materials may be used for such enteric layers or coating agents, and these materials include various high molecular weight acids and mixtures of such materials such as shellac, cetanol, and cellulose acetate.

[0135] Herein, compounds and compositions of the present invention may be doped, and liquid forms for oral or injectable administration include aqueous solutions, syrups with appropriate flavors, water or oily suspensions; emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil; and elixirs and similar pharmaceutically acceptable vehicles.

[0136] Compositions for inhalation or blowing include solutions, suspensions, and powders dissolved in pharmaceutically acceptable water or organic solvents or mixtures thereof. Liquid or solid compositions may include suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered via an oral or nasal breathing route to provide local or phlebolic action. The composition may be atomized using an inert gas. The atomized solution may be inhaled directly by a nebulizer, or the nebulizer may be connected to a face mask or an intermittent positive pressure respirator. The solution, suspension, or powder composition may be administered orally or via the nasal cavity by a device that delivers the formulation in an appropriate manner.

[0137] The amount of a compound or composition administered to a patient is not fixed but is determined by the purpose of administration, such as the drug being administered, prevention or treatment; the patient's condition; the method of administration, etc. In therapeutic applications, an amount of the composition capable of sufficiently treating or at least partially suppressing the symptoms of the disease and its complications may be administered to a patient suffering from the disease. The effective amount must be determined based on the disease state being treated and the judgment of the attending physician, and said judgment is determined by factors such as, for example, the severity of the disease, the patient's age, weight, and general condition.

[0138] The composition administered to the patient may be in the form of the above pharmaceutical composition. This composition may be sterilized through general sterilization techniques or filter sterilization. The aqueous solution may be used as packaged or freeze-dried, and the lyophilized agent and the sterile aqueous vector are mixed prior to administration. The pH of the compound formulation is typically 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It is understood that the use of some of the aforementioned excipients, vectors, or stabilizers may result in the formation of pharmaceutically acceptable salts.

[0139] The therapeutic dose of the compound of the present invention may be determined, for example, based on the specific use of the treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound of the present invention in a pharmaceutical composition is not fixed and may be determined by various factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compound of the present invention may be used for parenteral administration by providing it through a physiological buffered aqueous solution containing about 0.1 to 10% w / v of the compound. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg body weight / day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg body weight / day. The dose may be determined by variables such as the type and degree of development of the disease or pathology, the general health condition of the specific patient, the relative biological efficacy of the selected compound, the excipient formulation, and the route of administration thereof. An effective dose may be obtained by extrapolation through dose-response curves derived from in vitro or animal model test systems.

[0140] Beneficial effects

[0141] The compound provided in the present invention has excellent modulating / inhibitory activity of complement factor B and can be used for the treatment of "G disease," a pathology related to the activation of the complement alternative pathway, and for the manufacture of drugs for such pathology and disease. In addition, the compound exhibits excellent characteristics, such as pharmacokinetics and hepatic microsomal safety. Brief explanation of the drawing

[0142] Figure 1 is experimental data (ng / mL) of the blood drug concentration curve of a crab-eating monkey in a biological example. Figure 2 is experimental data (%) of the serum AP activity curve of a crab-eating monkey in a biological example (at 0h). Figure 3 is experimental data of streptococcal-induced rat rheumatoid arthritis in a biological example. Specific details for implementing the invention

[0143] Definition and Explanation of Terms

[0144] Unless otherwise specified, the definitions of groups and terms described in the specification and claims of the present invention include definitions as embodiments, exemplary definitions, preferred definitions, definitions in tables, definitions of specific compounds of examples, etc., and these may be optionally combined and combined with one another. The definitions of groups and structures of compounds combined and combined in this manner should be understood to be within the scope described in the specification and / or claims of the present invention.

[0145] Unless otherwise specified, numeric ranges described in this specification and claims refer to at least specific integer values. For example, the numeric range “1 to 40” refers to each integer value in the numeric range “1 to 10,” i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and each integer value in the numeric range “11 to 40,” i.e., 11, 12, 13, 14, 15, ......, 35, 36, 37, 38, 39, 40. Additionally, where some numeric ranges are defined as “numbers,” it should be understood that they refer to two endpoints of the range, each integer within the range, and each decimal within the range. For example, "numbers from 0 to 10" should be understood as referring not only to each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also to at least the sum of each integer and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9.

[0146] It must be understood that when describing one, two, or more in the text, "more than" must mean an integer greater than 2, for example, an integer greater than or equal to 3, for example, 3, 4, 5, 6, 7, 8, 9, or 10.

[0147] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0148] Term "C 1-40 "Alkyl" should be understood to refer to a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1 to 40 carbon atoms. For example, "C 1-10 "Alkyl" refers to straight-chain and branched-chain alkyls having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, and "C 1-6 "Alkyl" means a straight-chain and branched-chain alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms. The said alkyl is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, etc. or their It is an isomer.

[0149] Term "C 2-40 "Alkenyl" should be understood to mean a straight-chain or branched-chain monovalent hydrocarbon group having 2 to 40 carbon atoms and preferably containing one or more double bonds, and preferably "C 2-10 It is "Alkenyl". "C 2-10 "Alkenyl" should be understood to mean a straight-chain or branched-chain monovalent hydrocarbon group preferably comprising one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, for example, 2, 3, 4, 5, or 6 carbon atoms (i.e., C 2-6 Having alkenyl) and 2 or 3 carbon atoms (i.e., C 2-3It has an alkenyl. It should be understood that if the alkenyl includes one or more double bonds, the double bonds may be separated from or joined to each other. The above alkenyls are, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0150] Term "C 2-40 "Alkynyl" should be understood to mean a straight-chain or branched-chain monovalent hydrocarbon group containing one or more triple bonds and having 2 to 40 carbon atoms, and preferably "C 2-10 It is "alkynyl". The term "C 2-10"Alkynyl" should be understood to mean a straight-chain or branched-chain monovalent hydrocarbon group preferably comprising one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, for example, 2, 3, 4, 5, or 6 carbon atoms (i.e., "C 2-6 Having an alkynyl group, and 2 or 3 carbon atoms ("C 2-3 "Alkynyl" is present. The alkynyl is, for example, ethinyl, prop-1-inyl, prop-2-inyl, but-1-inyl, but-2-inyl, but-3-inyl, pent-1-inyl, pent-2-inyl, pent-3-inyl, pent-4-inyl, hex-1-inyl, hex-2-inyl, hex-3-inyl, hex-4-inyl, hex-5-inyl, 1-methylprop-2-inyl, 2-methylbut-3-inyl, 1-methylbut-3-inyl, 1-methylbut-2-inyl, 3-methylbut-1-inyl, 1-ethylprop-2-inyl, 3-methylpent-4-inyl, 2-methylpent-4-inyl, It is 1-methylpent-4-inyl, 2-methylpent-3-inyl, 1-methylpent-3-inyl, 4-methylpent-2-inyl, 1-methylpent-2-inyl, 4-methylpent-1-inyl, 3-methylpent-1-inyl, 2-ethylbut-3-inyl, 1-ethylbut-3-inyl, 1-ethylbut-2-inyl, 1-propylprop-2-inyl, 1-isopropylprop-2-inyl, 2,2-dimethylbut-3-inyl, 1,1-dimethylbut-3-inyl, 1,1-dimethylbut-2-inyl, or 3,3-dimethylbut-1-inyl. In particular, the alkynyl is ethinyl, prop-1-inyl, or prop-2-inyl.

[0151] Term "C 3-40 "Cycloalkyl" should be understood to mean a saturated monovalent single ring, double ring (e.g., condensation ring, bridge ring, spiro ring), hydrocarbon ring, or tricyclic alkane having 3 to 40 carbon atoms, and preferably "C 3-10 It is "cycloalkyl". The term "C 3-10"Cycloalkyl" should be understood to mean a saturated monovalent single ring, double ring (e.g., condensation ring, bridge ring, spiro ring), hydrocarbon ring, or triple ring alkane having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The above C 3-10 Cycloalkyls are single-ring hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, or bornyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, It may be a double-ring hydrocarbon group such as 2,6-diazaspiro[3,4]octyl, or a triple-ring hydrocarbon group such as adamantyl.

[0152] Unless otherwise defined, the term “3-20-membered heterocyclil” means a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6-, or 7-membered single ring, a 7-, 8-, 9-, 10-, 11-, or 12-membered double ring (e.g., condensed ring, bridge ring, spiro ring), or a 10-, 11-, 12-, 13-, 14-, or 15-membered triple ring system, comprising at least one, for example, 1, 2, 3, 4, 5 or more heteroatoms selected from O, S, and N, wherein N and S may also optionally be oxidized to various oxidation states to form a nitrogen oxide, -S(O)-, or -S(O)2- state. Preferably, the heterocyclil may be selected from “3-10-membered heterocyclils”. The term "3-10-membered heterocyclil" refers to a saturated or unsaturated non-aromatic ring or ring system and comprises at least one heteroatom selected from O, S, and N. The heterocyclil may be connected to the rest of the molecule through any one of the carbon atoms or a nitrogen atom (if present). The heterocyclil may comprise condensed or cross-linked rings and spiro rings. In particular, the heterocyclil comprises a quaternary ring such as azetidinyl and oxetanyl; a quinternary ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, and pyrrolinyl; or a six-membered ring such as tetrahydropyranil, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a seven-membered ring such as diazephanyl, but not limited thereto. Optionally, the heterocyclyl may be benzo-condensed.The heterocyclyl may be a double ring, for example, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5,6-membered double ring such as a hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring. The heterocyclyl may be partially unsaturated, that is, it may contain one or more double bonds, for example, not limited to dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzo-condensed, for example, not limited to dihydroisoquinolinyl. When the above 3-20-membered heterocyclyl is connected to another group to form the compound of the present invention, the carbon atom on the 3-20-membered heterocyclyl may be connected to the other group, or the hetero atom on the 3-20-membered heterocyclyl may be connected to the other group. For example, if the 3-20-membered heterocyclyl is selected from piperazinyl, the nitrogen atom on piperazinyl may be connected to the other group. Or, if the 3-20-membered heterocyclyl is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and the carbon atom at the para position thereof may be connected to the other group.

[0153] Term "C 6-20 "Aryl" should be understood to preferably mean a monovalent aromatic or partially aromatic single ring, double ring (e.g., condensed ring, bridge ring, spiro ring), or triple ring hydrocarbon ring having 6 to 20 carbon atoms, which may be a single aromatic ring or a polyaromatic ring condensed together, and preferably "C 6-14 It is "Aryl". The term "C" 6-14"Aryl" is preferably a monovalent aromatic or partially aromatic single-ring, double-ring, or triple-ring hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms ("C 6-14 It should be understood to mean "aryl," and in particular, a ring having 6 carbon atoms such as phenyl or biphenyl ("C6-aryl"), a ring having 9 carbon atoms such as indanyl or indenyl ("C9-aryl"), or a ring having 10 carbon atoms such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl ("C 10 aryl," or a ring having 13 carbon atoms such as fluorenyl ("C 13 A ring having 14 carbon atoms, such as an aryl, or anthracenyl ("C 14 It is aryl"). The above C 6-20 When an aryl group is substituted, it may be a single substitution or multiple substitution. Additionally, the substitution site is not limited to, for example, an ortho, para, or meta substitution.

[0154] The term "5-20-membered heteroaryl" should be understood to include such monovalent single-ring, double-ring (e.g., condensed ring, bridge ring, spiro ring), or triple-ring aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O, and S, e.g., "5-14-membered heteroaryl". The term "5-14-membered heteroaryl" should be understood to include such monovalent single-ring, double-ring, or triple-ring aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 5 or 6 or 9 or 10 carbon atoms and containing 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O, and S, and which may also be benzo-condensed in each case. "Heteroaryl" also means a group in which a heteroaromatic ring is condensed to one or more aryl, alicyclic, or heterocyclyl rings, wherein said linked radical or site is on the heteroaromatic ring. Non-limiting embodiments of the term heteroaryl include, for example, pyridyl, pyrazinyl, furyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, 1,2,4-thiadiazolyl, pyridazinyl; and 1-, 2-, 3-, 5-, 6-, 7- or 8-indolazinyl, 1-, 3-, 4-, 5-, 6- or 7-isoindolyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 4-, 5-, 6-, 7- or 8-purinyl,1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinazinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzisoquinolinyl, 2-, 3-, 4- or thieno[2,3-b]furyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrazino[2,3-c]carbazolil, 2-, 3-, 5-, 6- or 7-2H-furo[3,2-b]-pyranil, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido[2,3-d]-o-azinil, 1-, 3- or 5-1H-pyrazolo[4,3-d]-thiazolil, 2-, 4- or 5-1H-imidazo[4,5-d]thiazolil, 3-, 5- or 8-pyrazino[2,3-d]pyridazinil, 2-, 3-, 5- or 6-Imidazoo[2,1-b]thiazolil, 1-, 3-, 6-, 7-, 8- or 9-furo[3,4-c]cinnolinil, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 or 11-4H-pyrido[2,3-c]carbazolil, 2-, 3-, 6- or 7-imidazo[1,2-b][1,2,4]triazinil, 7-benzo[b]thienyl, 2-, 4-, 5-, 6- or 7-benzoxazolil, 2-, 4-, 5-, 6- or 7-benzimidazolil, 2-, 4-, 4-, 5-, 6- or 7-benzothiazollil, Includes 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7- or 8-benzoxapinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-1H-pyrrolo[1,2-b][2]benzazapinyl. Typical condensed heteroaryls include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-benzo[b]thienyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl, and 2-, 4-, 5-, 6- or 7-benzothiazolyl. Where another group is connected to the above 5-20-membered heteroaryl to constitute a compound of the present invention,It may be a carbon atom on a 5-20-membered heteroaryl ring connected to another group, or a heteroatom on a 5-20-membered heteroaryl ring connected to another group. When the above 5-20-membered heteroaryl is substituted, it may be a single substitution or a multiple substitution. Furthermore, without being limited to the substitution site, for example, a hydrogen connected to a carbon atom on the heteroaryl ring may be substituted, or a hydrogen connected to a heteroatom on the heteroaryl ring may be substituted.

[0155] The term "spiro ring" refers to a ring system in which two rings share one ring-forming atom.

[0156] The term "condensed ring" refers to a ring system in which two rings share two ring-forming atoms.

[0157] The term "bridge ring" refers to a ring system in which two rings share three or more ring-forming atoms.

[0158] Unless otherwise specified, heterocyclyl, heteroaryl, or heteroarylene comprises all possible isomer forms thereof, such as positional isomers thereof. Accordingly, in some exemplary non-limiting embodiments, forms may comprise forms substituted or bonded to other groups at one, two, or more of the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12- positions, etc. (if present), and comprise pyridin-2-yl, pyridylene-2-yl, pyridin-3-yl, pyridylene-3-yl, pyridin-4-yl, and pyridylene-4-yl; thienyl or thienylene comprises thiophene-2-yl, thienylene-2-yl, thiophene-3-yl, and thienylene-3-yl; It includes pyrazole-1-day, pyrazole-3-day, pyrazole-4-day, and pyrazole-5-day.

[0159] The term "oxo" refers to a substituent in which a carbon, nitrogen, or sulfur atom is replaced (=O) by an oxygen group formed by oxidation.

[0160] Unless otherwise specified, the definitions of terms in the text are applicable to groups including the above terms, for example, C 1-6 The definition of alkyl is C 1-6 Alkyloxy, C 3-8 Cycloalkyl-C 1-6 It is also applicable to alkyl- etc.

[0161] Those skilled in the art will understand that compounds represented by formula (I) may exist in the form of various pharmaceutically acceptable salts. If such compounds have a basic center, they may form acid addition salts; if such compounds have an acidic center, they may form base addition salts; and if such compounds contain not only an acidic center (e.g., carboxyl) but also a basic center (e.g., amino), they may form internal salts.

[0162] The compound of the present invention may exist in the form of a solvate (e.g., a hydrate), wherein the compound of the present invention comprises a polar solvent, particularly water, methanol, or ethanol, as a structural element of the crystal lattice of the compound. The amount of the polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.

[0163] Since the compounds of the present invention may be chiral depending on their molecular structure, various enantiomer forms may exist. Accordingly, these compounds may exist in a racemic form or an optically active form. The compounds of the present invention include isomers in which each chiral carbon is arranged in an R or S configuration, mixtures thereof, and racemics. The compounds of the present invention or intermediates thereof may be separated into enantiomer compounds or used in synthesis in such a form through chemical or physical methods known to those skilled in the art. In the case of racemic amines, diastereomers are prepared from a mixture by reacting with an optically active decomposition reagent. Examples of suitable degradation reagents include optically active acids, e.g., tartaric acid in R and S forms, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoyl proline or N-benzenesulfonyl proline), or various optically active camphor sulfonic acids. With the aid of optically active degradation reagents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, derivatives of cellulose triacetate or other carbohydrate compounds, or chiral derivatized methacrylate polymers), chromatographic degradation of enantiomers can also be advantageously performed. There is. A suitable eluent for this is a mixture of water or alcohol-containing solvents such as hexane / isopropanol / acetonitrile.

[0164] According to the disclosed method, the corresponding stable isomer can be separated, for example, through extraction, filtration, or column chromatography.

[0165] The term "patient" means any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, most preferably humans.

[0166] The term “therapeutic effective dose” means an amount of an active compound or drug that a researcher, veterinarian, physician, or other clinician seeks in a tissue, system, animal, individual, or human to elicit a biological or medical response, and includes at least one of (1) disease prevention: e.g., prevention of disease, disorder, or symptoms in an individual who is susceptible to disease, disorder, or pathology but has not experienced or developed the disease pathology or symptoms; (2) disease suppression: e.g., suppression of disease, disorder, or pathology in an individual who is experiencing or has developed the disease pathology or symptoms (i.e., prevention of further development of the pathology and / or symptoms); (3) disease alleviation: e.g., alleviation of disease, disorder, or pathology in an individual who is experiencing or has developed the disease pathology or symptoms (i.e., reversal of the pathology or symptoms).

[0167] The technical solution of the present invention will be explained in more detail below in conjunction with specific embodiments. It should be understood that the following embodiments are merely illustrative and interpretive of the present invention and should not be interpreted as limiting the scope of protection of the present invention. All technologies implemented based on the above description of the present invention are included within the scope of protection sought by the present invention.

[0168] Unless otherwise specified, the raw materials and reagents used in the following examples may all be commercially available products or manufactured by known methods.

[0169] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectra (MS). The NMR shift (d) is 10 -6It is given in units of (ppm). NMR measurement is Bruker ASCEND TM -400 nuclear magnetic instruments are used, and the measurement solvent is deuterium dimethyl sulfoxide (DMSO- d 6 ), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0170] MS measurements are performed using Agilent 6110, Agilent 1100, Agilent 6120, and Agilent G6125B liquid chromatography mass spectrometers.

[0171] HPLC measurements are performed using a Shimadzu HPLC-2010C high-pressure liquid chromatography (XBRIDGE 2.1×50 mm, 3.5 µm chromatography column).

[0172] Chiral HPLC analysis and measurement are performed using the THARSFC X5.

[0173] Yantai Qingdao GF254 silica gel plates are used for thin-layer chromatography, and the specifications of the silica gel plates used for thin-layer chromatography (TLC) are 0.15 mm to 0.2 mm, and the specifications of the products separated and purified by thin-layer chromatography are 0.4 mm to 0.5 mm.

[0174] Column chromatography generally uses Qingdao Ocean Silica gel 200 to 300 mesh silica gel as a vector.

[0175] High-performance liquid chromatography preparatives use Waters 2767, Waters 2545, and Tong Heng Innovation LC3000 preparative chromatographs.

[0176] The pressurized hydrogenation reaction uses the Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.

[0177] Microwave reactions use a Biotage initiator+ type microwave reactor.

[0178] Unless otherwise noted, all reactions are carried out in an argon or nitrogen atmosphere. An argon or nitrogen atmosphere means that one argon or nitrogen balloon with a volume of about 1 L is connected to the reaction flask. A hydrogen atmosphere means that one hydrogen balloon with a volume of about 1 L is connected to the reaction flask.

[0179] Unless otherwise specified, all reaction temperatures are room temperature, and the temperature range is 20 to 30°C.

[0180] Example 1

[0181] Intermediate 1:

[0182]

[0183] Tetrahydrofuran (150 mL) and 4-bromobenzonitrile (50 g) were sequentially added to a 3 L three-necked flask, and an isopropyl magnesium chloride-lithium chloride complex (1.3 M, 210 mL) was slowly added to the reaction system under nitrogen protection, and the reaction was carried out at room temperature for 2 hours. Then, the reaction system was diluted with anhydrous tetrahydrofuran (500 mL) and the temperature was lowered to -5°C, 4-methoxypyridine (25 mL) was added, and benzyl chloroformate (35 mL) was slowly added dropwise (maintaining the system temperature below 0°C). After the dropwise addition, the reaction mixture was stirred at 0°C for 2 hours, then the temperature was raised to room temperature and the reaction was continued at room temperature for 16 hours. After the reaction was complete, 6 M hydrochloric acid (150 mL) was added and stirred for half an hour, water (1000 mL) was added for dilution, and the mixture was extracted twice with ethyl acetate (500 mL). The combined extract was washed with saturated saline (50 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain a crude product. This crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1-1:1) to obtain intermediate 1 (23 g, yield: 23%). MS m / z (ESI): 333.0 [M+1].

[0184] Intermediate 2:

[0185]

[0186] Intermediate 1 (28 g), zinc powder (55 g), and acetic acid (200 mL) were sequentially added to a 500 mL single-neck flask, the reaction mixture was heated to 100 °C and stirred at the said temperature for 16 hours. After the reaction was complete, the mixture was filtered, the filtrate was diluted with water (500 mL), extracted with ethyl acetate (500 mL), the extractant was washed twice with an aqueous solution of saturated sodium bicarbonate (500 mL), washed once with saturated saline (100 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 2 (26 g, yield: 73%). MS m / z (ESI): 334.8 [M+1].

[0187] Intermediate 3:

[0188]

[0189] Tetrahydrofuran (100 mL), ethanol (100 mL), and intermediate 2 (26 g) were sequentially added to a 500 mL single-neck flask, followed by the addition of sodium borohydride (2 g) in a batch, and the reaction was carried out at room temperature for 2 hours. After the reaction was complete, the system was cooled to 0°C, and a saturated aqueous ammonium chloride solution (30 mL) was added until the temperature did not rise, diluted with water (500 mL), and extracted twice with ethyl acetate (200 mL); the combined extract was washed with saturated saline (500 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain intermediate 3 (25 g, yield: 76%). MS m / z (ESI): 336.9 [M+1].

[0190] Intermediate 4:

[0191]

[0192] Dichloromethane (200 mL) was added to a 500 mL single-neck flask, followed by the sequential addition of intermediate 3 (25 g), imidazole (6.6 g), and tert-butyldiphenylchlorosilane (25 g), and the reaction was carried out at room temperature for 2 hours. After the reaction was complete, the reaction mixture was washed with water (500 mL), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain intermediate 4 (5.7 g, yield: 13%, R f =0.55; Trans isomer R f =0.50) obtained. MS m / z (ESI):597.0[M+23].

[0193] Intermediate 5:

[0194]

[0195] Intermediate 4 (5 g) and tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 30 mL) were sequentially added to a 250 mL single-neck flask and reacted at room temperature for 2 hours. After the reaction is complete, water (100 mL) is added for dilution, and the mixture is extracted three times with ethyl acetate (50 mL). The combined extract is washed with saturated saline (100 mL), dried with anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure, and the residue is purified by column chromatography (petroleum ether:ethyl acetate = 3:1-0:1) to obtain a racemic intermediate. The intermediate is then chirally separated using SFC (Apparatus: SFC Thar prep 80; Column: CHIRALPAK AD-H, 250 mm × 20 mm, 5 μm; Modifier: 35% methanol (0.2% ammonia solution); Column temperature: 40℃; Column pressure: 60 bar; Wavelength: 214 / 254 nm; Flow rate: 40 g / min; Rt=4.78 min) to obtain 5 intermediates (1.2 g, Yield: Obtained 41%). MS m / z (ESI): 358.8[M+23].

[0196] Intermediate 6:

[0197]

[0198] In a 100 mL single-neck flask, solvent N,N-dimethylformamide (15 mL), intermediate 5 (1.2 g), and iodoethane (1.1 g) were added sequentially. The reaction system was then cooled to 0°C, sodium hydride (60%, 243 mg) was added, the system was raised to room temperature, and the reaction was carried out at this temperature for 2 hours. After the reaction was complete, water (30 mL) was added for dilution, and the mixture was extracted with ethyl acetate (50 mL). The extract was washed with saturated saline (10 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain intermediate 6 (1.2 g, yield: 83%). MS m / z (ESI): 386.9 [M+23].

[0199] Intermediate 7:

[0200]

[0201] Methanol (10 mL), water (10 mL), concentrated sulfuric acid (10 mL), and intermediate 6 (1.2 g) were sequentially added to a 100 mL single-neck flask, the reaction mixture was heated to 80 °C and reacted at the said temperature for 48 hours. After the reaction was complete, the reaction mixture was concentrated to remove methanol, the pH of the residue was adjusted to neutral with an aqueous solution of sodium hydroxide (2 M), extracted three times with ethyl acetate (10 mL), the combined extracts were washed with saturated saline (5 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 7 (850 mg, yield: 81%). MS m / z (ESI): 264.1 [M+1]. 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.3 Hz, 2H), 4.13 (dd, J= 11.7, 2.4 Hz, 1H), 3.92 (s, 3H), 3.82 - 3.70 (m, 1H), 3.62 - 3.47 (m, 2H), 3.27 - 3.10 (m, 1H), 3.02 - 2.88 (m, 1H), 2.07 - 1.97 (m, 1H), 1.95 - 1.85 (m, 1H), 1.82 - 1.62 (m, 2H), 1.27 (t, J = 7.0 Hz, 3H).

[0202] Alternatively, intermediate 7 was obtained in the following way.

[0203] Intermediate 8:

[0204]

[0205] Tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 840 mL) and intermediate 4 (140 g) were sequentially added to a 2 L three-necked flask and reacted at room temperature for 2 hours. After the reaction was complete, water (600 mL) was added for dilution, and the mixture was extracted three times with ethyl acetate (700 mL). The extract phase was washed with saturated saline (500 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1-1:1) to obtain intermediate 8 (77 g, yield 95%). MS m / z (ESI): 358.8 [M+23].

[0206] Intermediate 9:

[0207]

[0208] In a 2 L three-necked flask, solvent N,N-dimethylformamide (700 mL), intermediate 8 (77 g), and iodoethane (56 g) were added sequentially; the reaction system was lowered to 0°C, sodium hydride (60%, 14.61 g) was added, the system was raised to room temperature, and the reaction was carried out at the above temperature for 2 hours. After the reaction was complete, the temperature was lowered to 0°C, and an aqueous ammonium chloride solution was added until the reaction temperature did not rise; the mixture was extracted with ethyl acetate (500 mL), the extract phase was washed with saturated saline (300 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 9 (75 g, yield: 89%). MS m / z (ESI): 386.9 [M+23].

[0209] Intermediate 10:

[0210]

[0211] Isopropanol (300 mL), water (800 mL), intermediate 9 (75 g), and Ba(OH)2·8H2O (233 g) were added sequentially to a 2 L three-necked flask, the reaction mixture was heated to 100°C, and the reaction was carried out at this temperature for 20 hours. After the reaction was complete, the reaction solution was concentrated to remove the isopropanol, the residue was adjusted to pH 2–3 with a saturated aqueous sodium hydroxide solution, extracted three times with dichloromethane (300 mL), the extract phase was washed with saturated saline (200 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 10 (67 g, yield: 85%). MS m / z (ESI): 384.1[M+1].

[0212] Intermediate 11:

[0213]

[0214] N,N-dimethylformamide (670 mL), potassium carbonate (96.6 g), iodomethane (37.3 g), and intermediate 10 (67 g) were sequentially added to a 2 L three-necked flask and reacted at room temperature for 2 hours. After the reaction was complete, 300 mL of water was added to quench the reaction mixture, and it was extracted with methyl tert-butyl ether (300 mL × 2). The extractant was washed with saturated saline (5 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1-3:1) to obtain intermediate 11 (54 g, yield: 78%). MS m / z (ESI): 394.1 [M+1].

[0215] Intermediate 7:

[0216]

[0217] Ethyl acetate (500 mL), palladium carbon (5.4 g, 10% loading), and intermediate 11 (54 g) were sequentially added to a 1 L single-neck flask and reacted at room temperature for 16 hours under a single hydrogen pressure. After the reaction was complete, diatomaceous earth was added to filter the reaction mixture, and the filtrate was concentrated under reduced pressure to obtain a racemic intermediate. The intermediate was then subjected to chiral separation (Apparatus: Shimadzu LC-20AD; Column: CHIRALPAK AD-H(ADH0CD-SK003), 0.46 cm ID*25 cm L; Modifier: (methanol / diethylamine 0.1%) / CO2=25 / 75(V / V); flow rate: 2.0 ml / min; Rt=3.58 min) to obtain intermediate 7 (15.7 g, yield: 43%). MS m / z (ESI): 264.0[M+1]. 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 7.89 (d, J = 8.26 Hz, 2H),7.50 (d, J = 8.26 Hz, 2H), 3.92 (dd,J = 11.36, 2.32 Hz, 1H), 3.84 (s, 3H), 3.69-3.64 (m, 1H), 3.51-3.42 (m, 2H), 2.94 (dt, J = 12.15, 2.56 Hz, 1H), 2.76 (ddd, J = 11.62, 4.24, 2.62 Hz, 1H), 1.85 (dd, J = 13.23, 2.16 Hz, 1H), 1.73 (d, J = 13.47 Hz, 1H), 1.59-1.41 (m, 2H), 1.16 (t, J = 6.98 Hz, 3H).

[0218] Example 2

[0219] Intermediate 1:

[0220]

[0221] Dichloromethane (50 mL), 5-methoxy-7-methyl-1H-indole (3 g), Boc acid anhydride (5.68 g), 4-dimethylaminopyridine (227 mg), and triethylamine (2.26 g) were added sequentially to a 250 mL single-neck flask and reacted at room temperature for 16 hours. After the reaction was complete, saturated ammonium chloride solution (5 mL) was added to the reaction mixture and quenched; the mixture was extracted three times with dichloromethane (20 mL); the combined organic phase was washed with water (5 mL); dried with anhydrous sodium sulfate and filtered; the filtrate was concentrated; and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain intermediate 1 (4.6 g, yield: 94%). MS m / z (ESI): 262.0 [M+1].

[0222] Intermediate 2:

[0223]

[0224] Dichloromethane (80 mL), N-methylformanilide (3.8 g), and oxalyl chloride (3.6 g) were sequentially added to a 250 mL single-neck flask, and the reaction mixture was stirred at room temperature for 3 hours. Then, the temperature of the reaction mixture was lowered to -14°C, intermediate 1 (2.5 g) was added, the reaction system was naturally raised to room temperature, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was poured into ice water (100 mL), extracted three times (100 mL) with dichloromethane, the combined extract was washed twice with water (10 mL), dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain intermediate 2 (1.3 g, yield: 47%). MS m / z (ESI): 290.0[M+1]. 1 H NMR (400 MHz, CDCl3) δ 10.65 (s, 1H), 7.65 (d, J = 3.4 Hz, 1H), 7.49 (d, J = 3.4 Hz, 1H), 6.76 (s, 1H), 3.98 (s, 3H), 2.70 (s, 3H), 1.65 (s, 9H).

[0225] Example 3

[0226] Intermediate 1:

[0227]

[0228] 1-(vinyloxy)butane (10 mL), triethylamine (300 mg), o-phenanthroline (54 mg), palladium acetate (67 mg), and benzyl (2S, 4S)-2-(4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate (Example 1, Intermediate 5) (500 mg) were sequentially added to a 100 mL single-neck flask, and then the reaction mixture was heated to 90 °C under nitrogen protection and stirred at said temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated directly under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain Intermediate 1 (360 mg, yield: 63%). MS m / z (ESI): 384.8 [M+23].

[0229] Intermediate 2:

[0230]

[0231] Under the protection of an ice bath and nitrogen, a solution of dichloromethane (2 mL) of trifluoroacetic acid (228 mg) was added to a solution of dichloromethane (4 mL) of diethyl zinc (1 M, 2 mL); after reacting in an ice bath for 1 hour, a solution of dichloromethane (2 mL) of diiodomethane (536 mg) was added to the reaction system and reacted for 1 hour; then, a solution of dichloromethane (2 mL) of intermediate 5 (362 mg) of Example 1 was added, the reaction mixture was naturally heated to room temperature and stirred continuously at said room temperature for 18 hours. After the reaction was complete, the reaction mixture was quenched with dilute hydrochloric acid (0.1 M, 10 mL), diluted with water (20 mL), extracted with ethyl acetate (30 mL), the extract phase washed with saturated saline (20 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain intermediate 2 (300 mg, yield: 64%). MS m / z (ESI): 398.8 [M+23].

[0232] Intermediate 3:

[0233]

[0234] Sodium hydroxide (320 mg) was added to a mixed solution of isopropanol (2 mL) and water (5 mL) containing intermediate 2 (300 mg). The reaction system was heated to 100°C and stirred at this temperature for 48 hours. After the reaction was complete, dilute hydrochloric acid (1 M) was added to the reaction solution in an ice bath to adjust the pH to 5–6, water (10 mL) was added for dilution, the solution was extracted with ethyl acetate (10 mL), the extract phase was washed with saturated saline (10 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 3 (180 mg, yield: 45%). MS m / z (ESI): 395.9 [M+1].

[0235] Intermediate 4:

[0236]

[0237] Potassium carbonate (126 mg) and iodomethane (129 mg) were sequentially added to an acetonitrile (3 mL) solution of intermediate 3 (180 mg), and then the reaction mixture was heated to 50°C and stirred at the said temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 4 (130 mg, yield: 62%). MS m / z (ESI): 431.8 [M+23].

[0238] Intermediate 5:

[0239]

[0240] Palladium / carbon (20 mg) was added to a 2 mL solution of tetrahydrofuran containing intermediate 4 (120 mg), and catalytic hydrogenation was performed on the reaction mixture for 16 hours under a hydrogen atmosphere and room temperature conditions. After the reaction was complete, the reaction mixture was directly filtered and concentrated under reduced pressure to obtain intermediate 5 (70 mg, yield: 79%). MS m / z (ESI): 275.9 [M+1].

[0241] Intermediate 6:

[0242]

[0243] Intermediate 5 (70 mg) was added to a 1,2-dichloroethane (5 mL) solution of Intermediate 2 (88 mg) from Example 2, and the reaction mixture was stirred at room temperature for 8 hours. Then, sodium triacetoxyborohydride (162 mg) was added, and the reaction was continued for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was passed through column chromatography (dichloromethane:methanol = 20:1) to obtain Intermediate 7 (170 mg, yield: 73%). MS m / z (ESI): 548.8 [M+1].

[0244] Target compound:

[0245]

[0246] Sodium hydroxide (127 mg) was added to a mixed solution of intermediate 6 (175 mg) in methanol (2 mL) and water (2 mL), then the reaction mixture was heated to 75°C and reacted at said temperature for 3 hours. After the reaction was complete, hydrochloric acid (1 M) was added to the reaction mixture in an ice bath to neutralize the pH, and the mixture was directly purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-40%) to obtain the target compound (31.5 mg, yield: 22%, containing 0.5 equivalents of formic acid). MS m / z (ESI): 434.9 [M+1]. 1H NMR (400 MHz, CD3OD) δ 8.44 (s, 0.5H), 8.16 (d, J = 7.9 Hz, 2H), 7.65 (d, J = 7.9 Hz, 2H), 7.31 (d, J = 3.1 Hz, 1H), 6.75 (s, 1H), 6.33 (s, 1H), 4.80 - 4.62 (m, 1H), 4.43 - 4.09 (m, 2H), 4.03 - 3.86 (m, 1H), 3.74 (s, 3H), 3.54 - 3.40 (m, 2H), 3.40 - 3.31 (m, 1H), 2.50 (s, 3H), 2.36 - 2.17 (m, 2H), 2.14 - 1.93 (m, 2H), 0.72 - 0.47 (m, 4H).

[0247] Example 4:

[0248] Intermediate 1:

[0249]

[0250] Imidazole (202 mg) and tert-butyldimethylsilyl chloride (270 mg) were added to a 10 mL solution of intermediate 5 (500 mg) from Example 1 in N,N-dimethylformamide, and the reaction mixture was reacted at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (20 mL), the organic phase washed with saturated saline (50 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated directly to obtain intermediate 1 (700 mg, yield: 88%). MS m / z (ESI): 472.8 [M+23].

[0251] Intermediate 2:

[0252]

[0253] Intermediate 1 (750 mg) was added to dichloromethane (10 mL), and the reaction system was lowered to -78°C under nitrogen protection, after which cyclobutanone (117 mg) and trimethylsilyl trifluoromethanesulfonate (37 mg) were added sequentially. The reaction mixture was stirred at -78°C for 1 hour, triethylsilane (193 mg) was added, the reaction mixture was slowly raised to room temperature, and stirred at the above temperature for 16 hours. After the reaction was complete, a saturated sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution and quenched, water (10 mL) was added and diluted, the solution was extracted with dichloromethane (10 mL), the extractant was washed once with water (10 mL), dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 2 (700 mg, yield: 86%). MS m / z (ESI): 391.0 [M+1].

[0254] Intermediate 3:

[0255]

[0256] Sodium hydroxide (720 mg) was added to a mixed solution of isopropanol (5 mL) and water (10 mL) containing intermediate 2 (700 mg), and then the reaction system was heated to 100°C and stirred at the said temperature for 48 hours. After the reaction was complete, dilute hydrochloric acid (1 M) was added to the reaction solution in an ice bath to adjust the pH to 5–6, 20 mL of water was added for dilution, the solution was extracted with ethyl acetate (20 mL), the extract phase was washed once with saturated saline (20 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 3 (700 mg, yield: 76%). MS m / z (ESI): 409.9 [M+1].

[0257] Intermediate 4:

[0258]

[0259] Potassium carbonate (472 mg) and iodomethane (486 mg) were added to a 5 mL solution of acetonitrile containing intermediate 3 (700 mg), the reaction mixture was heated to 50°C and reacted at this temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated directly, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 4 (380 mg, yield: 47%). MS m / z (ESI): 423.9 [M+1].

[0260] Intermediate 5:

[0261]

[0262] Palladium / carbon (35 mg) was added to a tetrahydrofuran (5 mL) solution of intermediate 4 (350 mg), and catalytic hydrogenation was performed on the reaction mixture for 2 hours under a hydrogen atmosphere at room temperature. After the reaction was complete, the reaction mixture was directly filtered and concentrated under reduced pressure to obtain intermediate 5 (200 mg, yield: 75%). MS m / z (ESI): 290.0 [M+1].

[0263] Intermediate 6:

[0264]

[0265] Intermediate 5 (242 mg) was added to a 1,2-dichloroethane (5 mL) solution of Intermediate 2 (242 mg) from Example 2, and the reaction mixture was stirred at room temperature for 8 hours; then sodium triacetoxyborohydride (532 mg) was added, and the reaction mixture was continuously stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated directly, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain Intermediate 6 (350 mg, yield: 63%). MS m / z (ESI): 562.8 [M+1].

[0266] Target compound:

[0267]

[0268] Methanol (3 mL), water (3 mL), intermediate 6 (350 mg), and sodium hydroxide (248 mg) were added sequentially to a 50 mL single-neck flask. The reaction mixture was heated to 75°C and reacted at this temperature for 3 hours. After the reaction was complete, dilute hydrochloric acid (1 M) was added to the reaction mixture in an ice bath to adjust the pH to 7. The mixture was then concentrated directly and purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18, 150 × 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20–40%) to obtain the target compound (85 mg, yield: 30%, containing 0.4 equivalents of formic acid). MS m / z (ESI): 448.8 [M+1]. 1 H NMR (400 MHz, CD3OD) δ 8.45 (s, 0.4H), 8.15 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 2.8 Hz, 1H), 6.73 (s, 1H), 6.32 (s, 1H), 4.80 - 4.67 (m, 1H), 4.38 - 4.24 (m, 1H), 4.23 - 4.13 (m, 1H), 4.14 - 4.03 (m, 1H), 3.87 - 3.77 (m, 1H), 3.73 (s, 3H), 3.59 - 3.45 (m, 1H), 3.40 - 3.31 (m, 1H), 2.49 (s, 3H), 2.35 - 1.86 (m, 8H), 1.79 - 1.67 (m, 1H), 1.64 - 1.46 (m, 1H).

[0269] Example 5

[0270] Intermediate 1:

[0271]

[0272] Imidazole (486 mg) and tert-butyldimethylsilyl chloride (593 mg) were added to a 10 mL solution of intermediate 5 (1200 mg) from Example 1 in N,N-dimethylformamide, and the reaction mixture was reacted at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL), the extract phase was washed once with saturated saline (50 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated to obtain intermediate 1 (600 mg, yield: 90%). MS m / z (ESI): 472.8 [M+23].

[0273] Intermediate 2:

[0274]

[0275] Intermediate 1 (700 mg) was added to dichloromethane (10 mL) at room temperature, cyclopropane carboxaldehyde (110 mg) and trimethylsilyl trifluoromethanesulfonate (35 mg) were added to the reaction mixture under nitrogen protection and -78°C conditions, the reaction system was maintained at -78°C and stirred for 1 hour, then triethylsilane (180 mg) was added, the reaction mixture was naturally raised to room temperature and stirred continuously at the above temperature for 16 hours. After the reaction was complete, a saturated sodium bicarbonate aqueous solution (20 mL) was added to the reaction solution and quenched, water (10 mL) was added and diluted, the solution was extracted with dichloromethane (10 mL), the extractant was washed once with water (10 mL), dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 2 (400 mg, yield: 46%). MS m / z (ESI): 390.9 [M+1].

[0276] Intermediate 3:

[0277]

[0278] Intermediate 2 (400 mg), isopropanol (2 mL), water (3 mL), and sodium hydroxide (400 mg) were sequentially added to a 50 mL single-neck flask, and the reaction mixture was heated to 100°C and stirred at the said temperature for 16 hours. After the reaction was complete, dilute hydrochloric acid (1 M) was added to the reaction solution in an ice bath to adjust the pH to 5–6, water (5 mL) was added for dilution, the mixture was extracted with ethyl acetate (5 mL), the extract phase was washed once with saturated saline (5 mL), the organic phase was dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated at 45°C to obtain Intermediate 3 (200 mg, yield: 33%). MS m / z (ESI): 431.8 [M+23].

[0279] Intermediate 4:

[0280]

[0281] Potassium carbonate (135 mg) and iodomethane (140 mg) were added to an acetonitrile (5 mL) solution of intermediate 3 (200 mg), and the reaction mixture was heated to 50°C and stirred at this temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated directly, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 4 (180 mg, yield: 40%). MS m / z (ESI): 445.8 [M+23].

[0282] Intermediate 5:

[0283]

[0284] Palladium / carbon (50 mg) was added to a 3 mL solution of tetrahydrofuran containing intermediate 4 (180 mg), and catalytic hydrogenation was performed on the reaction mixture for 2 hours under a hydrogen atmosphere at room temperature. After the reaction was complete, the reaction mixture was filtered, and the filtrate was directly concentrated to obtain intermediate 5 (120 mg, yield: 54%). MS m / z (ESI): 290.0 [M+1].

[0285] Intermediate 6:

[0286]

[0287] Intermediate 5 (120 mg) was added to a 1,2-dichloroethane (5 mL) solution of Intermediate 2 (119 mg) from Example 2, and the reaction mixture was stirred at room temperature for 8 hours. Then, sodium triacetoxyborohydride (261 mg) was added and stirring continued at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated directly, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain Intermediate 6 (200 mg, yield: 26%). MS m / z (ESI): 562.8 [M+1].

[0288] Target compound:

[0289]

[0290] Methanol (2 mL), water (2 mL), intermediate 6 (200 mg), and sodium hydroxide (150 mg) were sequentially added to a 50 mL single-neck flask, and the reaction mixture was heated to 75°C and stirred at this temperature for 3 hours. After the reaction was complete, dilute hydrochloric acid (1 M) was added to the reaction mixture in an ice bath to adjust the pH to 7, and then the mixture was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18, 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-40%) to obtain the target compound (30.6 mg, yield: 18%; containing 0.5 equivalents of formic acid). MS m / z (ESI): 448.9 [M+1]. 1 H NMR (400 MHz, CD3OD) δ 8.36 (s, 0.5H), 8.18 (d, J = 7.7 Hz, 2H), 7.69 (d, J= 7.7 Hz, 2H), 7.32 (s, 1H), 6.76 (s, 1H), 6.34 (s, 1H), 4.88 - 4.61 (m, 1H), 4.44 - 4.07 (m, 2H), 3.95 - 3.81 (m, 1H), 3.75 (s, 3H), 3.63 - 3.47 (m, 1H), 3.46 - 3.33 (m, 3H), 2.50 (s, 3H), 2.35 - 2.14 (m, 2H), 2.13 - 1.94 (m, 2H), 1.23 - 1.04 (m, 1H), 0.58 (d, J = 7.2 Hz, 2H), 0.28 (d, J = 3.8 Hz, 2H).

[0291] Example 6

[0292] Intermediate 1:

[0293]

[0294] Under nitrogen protection and at -78°C, intermediate 1 (700 mg) of Example 5 was added to dichloromethane (7 mL), cyclobutanecarboxaldehyde (130 mg) and trimethylsilyl trifluoromethanesulfonate (35 mg) were added, maintained at -78°C and stirred at the above temperature for 1 hour, then triethylsilane (180 mg) was added, the temperature of the reaction mixture was slowly raised to room temperature and stirred at the above temperature for 16 hours. After the reaction was complete, a saturated sodium bicarbonate aqueous solution (20 mL) was added to the reaction solution and quenched, water (10 mL) was added and diluted, the mixture was extracted with dichloromethane (10 mL), the extractant was washed with water (10 mL), dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 1 (240 mg, yield: 34%). MS m / z (ESI): 426.8 [M+23].

[0295] Intermediate 2:

[0296]

[0297] Isopropanol (1 mL), water (3 mL), intermediate 1 (240 mg), and sodium hydroxide (240 mg) were sequentially added to a 50 mL single-neck flask, and the reaction mixture was heated to 100°C and reacted at said temperature for 16 hours. After the reaction was complete, dilute hydrochloric acid (1 M) was added to the reaction solution in an ice bath to adjust the pH to 5–6, water (5 mL) was added for dilution, the mixture was extracted with ethyl acetate (5 mL), the extract phase was washed with saline solution (5 mL), dried with anhydrous sodium sulfate and filtered, and the filtrate was directly concentrated to obtain intermediate 2 (200 mg, yield: 72%). MS m / z (ESI): 446.1 [M+23].

[0298] Intermediate 3:

[0299]

[0300] Potassium carbonate (130 mg) and iodomethane (134 mg) were added to a 5 mL solution of acetonitrile containing intermediate 2 (200 mg), and the reaction mixture was heated to 50°C and reacted at the said temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated directly, and the residue was purified using a silica gel column (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 3 (200 mg, yield: 87%). MS m / z (ESI): 459.8 [M+23].

[0301] Intermediate 4:

[0302]

[0303] Palladium / carbon (50 mg) was added to a 3 mL solution of tetrahydrofuran containing intermediate 3 (200 mg), and catalytic hydrogenation was performed on the reaction mixture for 2 hours under a hydrogen atmosphere at room temperature. After the reaction was complete, the reaction mixture was directly filtered and concentrated under reduced pressure to obtain intermediate 4 (110 mg, yield: 71%). MS m / z (ESI): 303.9 [M+1].

[0304] Intermediate 5:

[0305]

[0306] Intermediate 4 (110 mg) was added to a 1,2-dichloroethane (5 mL) solution of Intermediate 2 (105 mg) from Example 2, and the reaction mixture was stirred at room temperature for 8 hours; then sodium triacetoxyborohydride (229 mg) was added and the mixture was stirred continuously at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated directly, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain Intermediate 5 (250 mg, yield: 72%). MS m / z (ESI): 576.8 [M+1].

[0307] Target compound:

[0308]

[0309] Methanol (2 mL), water (2 mL), intermediate 5 (250 mg), and sodium hydroxide (175 mg) were sequentially added to a 50 mL single-neck flask, and the reaction mixture was heated to 75°C and reacted at this temperature for 3 hours. After the reaction was complete, dilute hydrochloric acid (1 M) was added to the reaction mixture in an ice bath to adjust the pH to 7, and the mixture was concentrated directly and purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18, 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 35-60%) to obtain the target compound (4.4 mg, yield: 2%). MS m / z (ESI): 462.9 [M+1]. 1 H NMR (400 MHz, CD3OD) δ 8.16 (d, J = 7.5 Hz, 2H), 7.64 (d, J = 7.5 Hz, 2H), 7.31 (d, J= 3.0 Hz, 1H), 6.75 (s, 1H), 6.31 (s, 1H), 4.79 - 4.55 (m, 1H), 4.43 - 4.23 (m, 1H), 4.23 - 4.05 (m, 1H), 3.88 - 3.65 (m, 4H), 3.59 - 3.41 (m, 3H), 3.40 - 3.32 (m, 1H), 2.73 - 2.58 (m, 1H), 2.50 (s, 3H), 2.28 - 1.78 (m, 10H).

[0310] Example 7

[0311] Intermediate 1:

[0312]

[0313] Silver trifluoromethanesulfonate (1600 mg), potassium fluoride (483 mg), and 1-chloromethyl-4-fluoro-1,4-diazoniabicycle[2.2.2]octanbis(tetrafluoroborate) (1100 mg) were weighed in a glove box and added to a 50 mL single-neck flask. Under nitrogen protection, a 10 mL ethyl acetate solution of intermediate 5 (700 mg) of Example 1, 2-fluoropyridine (609 mg), and trifluoromethyltrimethylsilyl (889 mg) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was directly purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 1 (300 mg, yield: 32%). MS m / z (ESI): 426.8 [M+23].

[0314] Intermediate 2:

[0315]

[0316] Isopropanol (2 mL), water (3 mL), intermediate 1 (400 mg), and sodium hydroxide (400 mg) were sequentially added to a 50 mL single-neck flask, and the reaction mixture was heated to 100°C and reacted at said temperature for 16 hours. After the reaction was complete, dilute hydrochloric acid (1 M) was added to the reaction solution in an ice bath to adjust the pH to 5–6, water (5 mL) was added for dilution, the mixture was extracted with ethyl acetate (5 mL), the extract phase was washed with saturated saline (5 mL), dried with anhydrous sodium sulfate and filtered, and the filtrate was directly concentrated to obtain intermediate 2 (260 mg, yield: 56%). MS m / z (ESI): 445.7 [M+23].

[0317] Intermediate 3:

[0318]

[0319] Potassium carbonate (170 mg) and iodomethane (175 mg) were added to an acetonitrile (5 mL) solution of intermediate 2 (260 mg), and then the reaction mixture was heated to 50°C and reacted at the said temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated directly, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 3 (200 mg, yield: 67%). MS m / z (ESI):459.8 [M+23].

[0320] Intermediate 4:

[0321]

[0322] Palladium / carbon (50 mg) was added to a 3 mL solution of tetrahydrofuran containing intermediate 3 (200 mg), and catalytic hydrogenation was performed on the reaction mixture for 2 hours under a hydrogen atmosphere at room temperature. After the reaction was complete, the reaction mixture was directly filtered and concentrated under reduced pressure to obtain intermediate 4 (130 mg, yield: 84%). MS m / z (ESI): 303.9 [M+1].

[0323] Intermediate 5:

[0324]

[0325] Intermediate 4 (130 mg) was added to a 1,2-dichloroethane (5 mL) solution of Intermediate 2 (125 mg) from Example 2, and the reaction mixture was stirred at room temperature for 8 hours; then sodium triacetoxyborohydride (273 mg) was added, and the reaction mixture was continuously stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated directly, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain Intermediate 5 (280 mg, yield: 56%). MS m / z (ESI): 576.7 [M+1].

[0326] Target compound:

[0327]

[0328] In a 50 mL single-neck flask, methanol (2 mL), water (2 mL), intermediate 5 (280 mg), and sodium hydroxide (194 mg) were added sequentially, then the reaction mixture was heated to 75°C and reacted at said temperature for 16 hours. After the reaction was complete, dilute hydrochloric acid (1 M) was added to the reaction mixture in an ice bath to adjust the pH to 7, and the mixture was directly purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18 150×21.2 mm, 5 µm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 25-50%) to obtain the target compound (38.5 mg, yield: 16%, containing 0.2 equivalents of formic acid). MS m / z (ESI): 462.8 [M+1]. 1 H NMR (400 MHz, CD3OD) δ 8.45 (s, 0.2H), 8.14 (d, J = 7.8 Hz, 2H), 7.66 (d, J = 7.8 Hz, 2H), 7.29 (d, J = 2.9 Hz, 1H), 6.73 (s, 1H), 6.34 (d, J= 2.9 Hz, 1H), 4.87 - 4.78 (m, 1H), 4.64 - 4.45 (m, 1H), 4.20 (d, J = 12.4 Hz, 1H), 4.00 (d, J = 12.4 Hz, 1H), 3.75 (s, 3H), 3.38 - 3.31 (m, 2H), 2.48 (s, 3H), 2.43 - 2.05 (m, 4H). 19F NMR (376 MHz, CD3OD) δ -59.65.

[0329] Example 8

[0330] Intermediate 1:

[0331]

[0332] At -70°C, n-butyllithium (6.25 mL) was slowly added dropwise to a tetrahydrofuran (100 mL) solution of methyltriphenylphosphonium bromide (5.35 g), the reaction mixture was stirred at -70°C for 0.5 hours, then a tetrahydrofuran (30 mL) solution of intermediate 2 (3.34 g) of Example 1 was slowly added dropwise, the reaction mixture was naturally raised to room temperature and stirred at room temperature for 16 hours. After the reaction was complete, saturated ammonium chloride (20 mL) was added to quench the reaction mixture, diluted with water (100 mL), extracted twice with ethyl acetate (100 mL), the combined extract was washed with saturated saline (20 mL), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain intermediate 1 (850 mg, yield: 24%). MS m / z (ESI): 333.1 [M+1].

[0333] Intermediate 2:

[0334]

[0335] Sodium iodide (75 mg) and trifluoromethyltrimethylsilane (1160 mg) were added to a 10 mL solution of tetrahydrofuran containing intermediate 1 (800 mg), and the reaction mixture was heated to 70°C and reacted under closed conditions at the said temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated directly, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 2 (800 mg, 82%). MS m / z (ESI): 382.9 [M+1].

[0336] Intermediate 3:

[0337]

[0338] Methanol (10 mL), a mixed solution of sulfuric acid and water (1:1, 10 mL), and intermediate 2 (480 mg) were sequentially added to a 100 mL single-neck flask, and the reaction mixture was heated to 80°C and reacted at this temperature for 2 days. After the reaction was complete, the reaction solution was naturally cooled to room temperature, poured into ice water, extracted twice with ethyl acetate (50 mL), the combined organic phase was washed once with saturated saline (10 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 3 (300 mg, yield: 85%). MS m / z (ESI): 282.0 [M+1].

[0339] Intermediate 4:

[0340]

[0341] At room temperature, intermediate 3 (100 mg) was added to a 1,2-dichloroethane (3 mL) solution of intermediate 2 (100 mg) from Example 2. After stirring the reaction mixture at room temperature for 8 hours, sodium triacetoxyborohydride (220 mg) was added, and the reaction mixture was continued to be stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was directly purified by column chromatography (methanol:dichloromethane = 1:20) to obtain intermediate 4 (110 mg, 54%). MS m / z (ESI): 554.9 [M+1].

[0342] Target compound:

[0343]

[0344] Methanol (3 mL), water (3 mL), intermediate 4 (110 mg), and sodium hydroxide (40 mg) were sequentially added to a 25 mL single-neck flask, and the reaction mixture was heated to 75°C and reacted at said temperature for 3 hours. After the reaction was complete, the reaction solution was directly purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18, 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-40%), the resulting solution was concentrated, and the remaining small amount of aqueous solution was freeze-dried to obtain the target compound (50.6 mg, yield: 75%, containing 0.5 equivalents of formic acid). MS m / z (ESI): 440.9 [M+1]. 1 H NMR (400 MHz, CD3OD) δ 8.37 (s, 0.5H), 8.16 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 2.8 Hz, 1H), 6.76 (s, 1H), 6.34 (d, J = 2.8 Hz, 1H), 4.41 - 4.25 (m, 2H), 4.06 (d, J= 12.4 Hz, 1H), 3.77 (s, 3H), 3.56 - 3.47 (m, 1H), 3.20 - 3.07 (m, 1H), 2.60 - 2.45 (m, 4H), 2.35 - 2.18 (m, 1H), 1.90 - 1.66 (m, 2H), 1.42 - 1.28 (m, 2H).

[0345] Example 9

[0346] Intermediate 1:

[0347]

[0348] 1,4-dioxane (8 mL), water (2 mL), methyl 4-(dihydroxyboryl)benzoate (500 mg), 2-bromo4-(trifluoromethyl)pyridine (693 mg), potassium carbonate (413 mg), and tetrakis(triphenylphosphine)palladium (693 mg) were added sequentially to a 100 mL single-neck flask. The reaction mixture was heated to 90°C under nitrogen protection and reacted at the said temperature for 16 hours. After the reaction was complete, the reaction solution was naturally cooled to room temperature, poured into water (50 mL), extracted three times with ethyl acetate (100 mL), the combined organic phase was washed with saturated saline (20 mL), dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain intermediate 1 (600 mg, yield: 76%). MS m / z (ESI): 282.0 [M+1].

[0349] Intermediate 2:

[0350]

[0351] Methanol (6 mL), intermediate 1 (180 mg), platinum dioxide (14 mg), and a catalytic amount of hydrochloric acid were sequentially added to a 50 mL single-neck flask, and the reaction mixture was subjected to catalytic hydrogenation for 16 hours under a hydrogen atmosphere at room temperature. After the reaction was complete, the reaction solution was directly filtered under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain intermediate 2 (30 mg, yield: 16%). MS m / z (ESI): 288.1 [M+1].

[0352] Intermediate 3:

[0353]

[0354] 1,2-dichloroethane (4 mL), intermediate 2 (30 mg), intermediate 2 of Example 2 (44 mg), and sodium triacetoxyborohydride (66 mg) were added sequentially to a 50 mL single-neck flask, and the reaction mixture was stirred for 16 hours under a nitrogen atmosphere at room temperature. After the reaction was complete, methanol was added to the reaction mixture until the solution became clear, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain intermediate 3 (30 mg, yield: 53%). MS m / z (ESI): 560.7 [M+1].

[0355] Target compound:

[0356]

[0357] Methanol (4 mL), water (1 mL), intermediate 3 (65 mg), and sodium hydroxide (92 mg) were added sequentially to a 50 mL single-neck flask, and the reaction mixture was stirred at room temperature for 48 hours. After the reaction was complete, the reaction solution was diluted with water (3 mL), and the pH was adjusted to 7–8 using a dilute hydrochloric acid (1 M) solution. The mixture was then concentrated under reduced pressure and purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18 150×21.2 mm, 5 m; mobile phase: acetonitrile-water (0.1% formic acid) gradient: 15–40%; UV: 214 nm) to obtain the target compound (13.7 mg, yield: 25%, containing 0.9 equivalents of formic acid). MS m / z (ESI): 447.0 [M+1]. 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 12.89 (s, 1H), 10.85 (s, 1H), 8.13 (s, 0.9H), 7.99 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H), 7.26 (t, J = 2.6 Hz, 1H), 6.66 (s, 1H), 6.42 (t, J = 2.6 Hz,, 1H), 3.71 (s, 3H), 3.53 (d, J = 11.6 Hz, 1H), 3.21 (d, J = 11.6 Hz, 1H), 2.84 (d, J = 12.0 Hz, 1H), 2.70 - 2.65 (m, 0.5H), 2.54 (s, 1H), 2.42 (s, 3H), 2.35 - 2.30 (m, 0.5H), 2.12 - 2.02 (m, 1H), 1.86 - 1.70 (m, 2H), 1.59 - 1.48 (m, 1H), 1.38 - 1.29 (m, 1H).

[0358] Example 10

[0359] Intermediate 1:

[0360]

[0361] At -78°C, diethylaminosulfor trifluoride (3.48 g) was slowly added to a solution of 2-bromopyridine-4-carbaldehyde (1 g) in dichloromethane (10 mL), and then the reaction mixture was slowly heated to room temperature and stirred at that temperature for 2 hours. After the reaction was complete, the reaction mixture was quenched with saturated sodium bicarbonate (50 mL), extracted with dichloromethane (50 mL), the extract phase washed with water (10 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain intermediate 1 (1 g, yield: 86%). MS m / z (ESI): 207.9 [M+1].

[0362] Intermediate 2:

[0363]

[0364] 1,4-dioxane (10 mL), water (1 mL), intermediate 1 (1 g), 4-(dihydroxyboryl)methyl benzoate (0.95 g), sodium carbonate (1.02 g), and tetrakis(triphenylphosphine)palladium (0.166 mg) were sequentially added to a 10 mL three-necked flask, the reaction mixture was heated to 95°C under nitrogen protection, and stirred at the said temperature for 18 hours. After the reaction was complete, the reaction mixture was naturally cooled to room temperature, quenched with saturated aqueous ammonium chloride solution (2 mL), and extracted three times with ethyl acetate (50 mL). The combined organic matter was dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 2 (0.4 g, yield: 29.17%). MS m / z(ESI): 264.2[M+1].

[0365] Intermediate 3:

[0366]

[0367] Methanol (4 mL), concentrated hydrochloric acid (0.2 mL), intermediate 2 (340 mg), and platinum oxide (292.9 mg) were sequentially added to a 10 mL single-neck flask, and catalytic hydrogenation was performed on the reactants for 18 hours under a hydrogen atmosphere at room temperature. After the reaction was complete, the reaction mixture was directly filtered and concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (chromatography column: C18 spherical, 100A, 20 g, 20-35 μm; acetonitrile-water = 10-70%; UV: 214 nm) to obtain intermediate 3 (120 mg, yield: 33.51%). MS m / z (ESI): 270.1 [M+1].

[0368] Intermediate 4:

[0369]

[0370] 1,2-dichloroethane (2 mL), intermediate 3 (140 mg), and intermediate 2 of Example 2 (196 mg) were sequentially added to a 10 mL single-neck flask, and the reaction mixture was stirred at room temperature for 8 hours. Then, sodium triacetoxyborohydride (330 mg) was added, and stirring continued at room temperature for 18 hours. After the reaction was complete, dichloromethane (10 mL) was added to dilute the mixture, it was washed with water (10 mL), the organic phase was dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 4 (200 mg, yield: 64.4%). MS m / z (ESI): 542.8 [M+1].

[0371] Target compound:

[0372]

[0373] Methanol (2 mL), tetrahydrofuran (2 mL), water (2 mL), intermediate 4 (180 mg), and sodium hydroxide (132 mg) were added sequentially to a 10 mL three-necked flask, and the reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-25%) to obtain the target compound (19.5 mg, yield: 13.09%, containing 0.4 equivalents of formic acid). MS m / z (ESI): 429.2 [M+1]. 1 H NMR (400 MHz, CD3OD) δ 8.36 (s, 0.4H), 8.18 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 2.8 Hz, 1H), 6.78 - 6.72 (m, 1H), 6.30 (s, 1H), 5.81 (td, J = 16.4 Hz, 3.6Hz, 1H), 4.55 - 4.45 (m, 1H), 4.37 - 4.27 (m, 1H), 4.10 - 4.03 (m, 1H), 3.78 - 3.72 (m, 3H), 3.61 - 3.52 (m, 1H), 3.29 - 3.24 (m, 1H), 2.50 (s, 3H), 2.45 - 2.32 (m, 1H), 2.21 - 2.13 (m, 1H), 2.10 - 1.92 (m, 2H), 1.88 - 1.74 (m, 1H).

[0374] Example 11

[0375] Intermediate 1:

[0376]

[0377] Under room temperature and nitrogen protection, an isopropyl magnesium bromide magnesium chloride complex (85 mL) was added to a tetrahydrofuran (100 mL) solution of 4-bromobenzonitrile (18.2 g), and the reaction mixture was stirred at room temperature for 3 hours to produce a 4-cyanophenyl magnesium bromide solution (reactant 1).

[0378] (1R, 2S, 5R)-2-isopropyl-5-methylcyclohexylchloroformate (20.4 g) was added dropwise to a tetrahydrofuran (200 mL) solution of 4-methoxypyridine (10 g) under -78°C and nitrogen protection, and the reaction mixture was stirred at -78°C for 15 minutes, after which a freshly prepared 4-cyanophenylmagnesium bromide solution (reaction mixture 1) was added. The reaction mixture was continuously stirred at -78°C for 1 hour. After the reaction was complete, the reaction mixture was quenched with dilute hydrochloric acid (1 M, 150 mL), then the temperature was naturally raised to room temperature and stirred continuously for 30 minutes, diluted by adding water (150 mL), and extracted three times (200 mL) with ethyl acetate. After washing the combined organic phase twice (200 mL) with saturated saline solution, drying with anhydrous sodium sulfate and filtering, concentrating the filtrate under reduced pressure, and purifying the residue by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 1 (16.4 g, yield: 50%).

[0379] Intermediate 2:

[0381] *

[0382] Zinc powder (28 g) was added to an acetic acid (200 mL) solution of intermediate 1 (16.4 g), and the reaction mixture was heated to 100°C and stirred at the temperature for 5 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain intermediate 2 (3 g, yield: 30%).

[0383] Intermediate 3:

[0384]

[0385] Dichloromethane (4 mL) and intermediate 2 (210 mg) were added to a 50 mL single-neck flask, diethylaminosulfur trifluoride (177 mg) was added in an ice bath, the reaction mixture was heated to 40°C under nitrogen protection and stirred at the said temperature for 16 hours. After the reaction was completed, the reaction mixture was poured into ice water (10 mL), extracted three times with ethyl acetate (50 mL), the combined organic phase was washed with saturated saline (5 mL), the organic phase was dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain intermediate 3 (144 mg, yield: 54%).

[0386] Intermediate 4:

[0387]

[0388] Trifluoroacetic acid (4 mL) and intermediate 3 (144 mg) were added to a 50 mL single-neck flask, and the reaction mixture was heated to 80°C and stirred at the said temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain intermediate 4 (80 mg, yield: 60%).

[0389] Intermediate 5:

[0390]

[0391] Intermediate 4 (80 mg) was added to an 80% sulfuric acid / methanol (1:1, 4 mL) system in a 50 mL single-neck flask, the reaction mixture was heated to 90°C and stirred at the above temperature for 6 hours. After the reaction was completed, water (10 mL) was added at room temperature to dilute the mixture, and the pH was adjusted to 7-8 with a sodium hydroxide solution (2 M). Then, the mixture was extracted three times (50 mL) with ethyl acetate, the combined organic phase was dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) to obtain intermediate 5 (64 mg, yield: 69%).

[0392] Intermediate 6:

[0393]

[0394] 1,2-dichloroethane (2 mL), intermediate 5 (22 mg), intermediate 2 of Example 2 (34 mg), and sodium triacetoxyborohydride (50 mg) were sequentially added to a 50 mL single-neck flask, and the reaction mixture was stirred for 16 hours at room temperature under nitrogen protection. After the reaction was complete, methanol was added to the reaction mixture until the solution became clear, and the mixture was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 6 (20 mg, yield: 42%).

[0395] Target compound:

[0396]

[0397] Methanol (1.5 mL), water (0.5 mL), intermediate 6 (20 mg), and sodium hydroxide (30 mg) were sequentially added to a 50 mL single-neck flask, and the reaction mixture was stirred at room temperature for 48 hours. After the reaction was complete, the reaction mixture was poured into water (5 mL), the pH was adjusted to 7–8 with dilute hydrochloric acid (1 M), and then concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (chromatography column: AZZOTA C18 100A, 10 μm; mobile phase: acetonitrile-water (0.05% ammonia solution); gradient: 15–28%), and the obtained product was further purified by thin-layer chromatography (dichloromethane:methanol=10:1) to obtain the target compound (6 mg, yield: 20%). MS m / z (ESI): 414.45[M+1]. 1 H NMR (400 MHz, CD3OD) δ 8.14 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 3.2 Hz, 1H), 6.73 (s, 1H), 6.41 (d, J = 3.2 Hz, 1H), 3.92 - 3.83 (m, 2H), 3.79 (s, 3H), 3.53 - 3.46 (m, 1H), 3.20 - 3.12 (m, 1H), 2.68 - 2.58 (m, 1H), 2.49 (s, 3H), 2.30 - 2.20 (m, 2H), 2.10 - 2.00 (m, 2H).

[0398] Example 12

[0399] Intermediate 1:

[0400]

[0401] At room temperature, tetrakis(triphenylphosphine)palladium (1.43 g), 4-bromophenylboronic acid (5 g), 2-bromopyridine (4.72 g), and sodium carbonate (6.87 g) were sequentially added to a solution of 1,4-dioxane (90 mL) and water (15 mL). Then, under nitrogen protection, the reaction mixture was heated to 90°C and reacted at said temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated directly, and the residue was passed through column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain intermediate 1 (5.3 g, yield 90%). MS m / z (ESI): 233.9 [M+1].

[0402] Intermediate 2:

[0403]

[0404] [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (700 mg) was added to a toluene (20 mL) solution of 2-(4-bromophenyl)pyridine (2 g), diethyl phosphite (4.7 g), and DIEA (2.2 g). The reaction mixture was then heated to 110°C under nitrogen protection and reacted at this temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was passed through column chromatography (petroleum ether:ethyl acetate = 5:1-1:1) to obtain intermediate 2 (1.4 g, yield 60%). MS m / z (ESI): 291.9 [M+1].

[0405] Intermediate 3:

[0406]

[0407] Platinum oxide (280 mg, 20% wt / wt) was added to a solution of EtOH (20 mL) and hydrochloric acid (4 mL) containing intermediate 2 (1.4 g), and catalytic hydrogenation was performed on the reaction mixture for 48 hours under 0.4 MPa. After the reaction was complete, the reaction mixture was filtered through diatomite, and the filtrate was concentrated under reduced pressure to obtain intermediate 3 (1.28 g, yield 90%). MS m / z (ESI): 297.9 [M+1].

[0408] Intermediate 4:

[0409]

[0410] Tetraethyl titanate (226 mg) was added to a tetrahydrofuran (20 mL) solution of intermediate 2 (300 mg) and intermediate 3 (367 mg) of Example 2, the reaction mixture was heated to 70°C and stirred at that temperature for 16 hours. The reaction system was cooled to room temperature, sodium triacetylborohydride (655 mg) was added, and the mixture was heated to 70°C and stirred continuously at that temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol=50:1) to obtain intermediate 4 (700 mg, purity: 80%, yield 80%). MS m / z (ESI): 571.1 [M+1].

[0411] Target compound:

[0412]

[0413] At 0°C, bromotrimethylsilane (2 mL) was added to a solution of intermediate 4 (200 mg) in dichloromethane (6 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-40%) to obtain the target compound (60 mg, yield 82%). MS m / z (ESI): 414.9 [M+1]. 1 H NMR (400 MHz, CD3OD) δ 8.07 (s, 2H), 8.06 - 7.95 (m, 2H), 7.66 - 7.61 (m, 2H), 7.32 (d, J = 3.1 Hz, 1H), 6.76 (s, 1H), 6.33 (d, J= 3.1 Hz, 1H), 4.49 - 4.38 (m, 1H), 4.34 (d, J = 12.7 Hz, 1H), 4.12 (d, J = 12.7 Hz, 1H), 3.76 (s, 3H), 3.51 (d, J = 12.8 Hz, 1H), 3.28 - 3.18 (m, 1H), 2.50 (s, 3H), 2.12 - 2.04 (m, 2H), 1.96 - 1.81 (m, 4H).

[0414] Example 13

[0415] Intermediate 1:

[0416]

[0417] Tetraethyl titanate (151 mg) was added to a 15 mL tetrahydrofuran solution of intermediate 2 (200 mg) of Example 2 and 2-(4-bromophenyl)piperidine (195 mg), the reaction system was heated to 70°C and stirred at that temperature for 16 hours. The reaction mixture was allowed to cool naturally to room temperature, sodium triacetylborohydride (438 mg) was added, the system was heated to 70°C and stirred continuously at that temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain solid intermediate 1 (252 mg, yield 71%). MS m / z (ESI): 512.7 [M+1].

[0418] Intermediate 2:

[0419]

[0420] Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)(X-Phos-Pd-G2) (19 mg) was added to an ethanol (15 mL) solution of intermediate 1 (252 mg), diboran 1,1,2,2-tetraol (131 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos) (23 mg), and potassium acetate (144 mg), then the reaction mixture was heated to 90°C under nitrogen protection and stirred at the said temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated directly under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol=5:1) to obtain intermediate 2 (200 mg, yield 85%). MS m / z (ESI): 478.9 [M+1].

[0421] Target compound:

[0422]

[0423] At 0°C, bromotrimethylsilane (3 mL) was added to a solution of intermediate 2 (200 mg) in dichloromethane (9 mL), and the reaction was carried out at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-35%) to obtain the target compound (42 mg, yield 33%, containing 0.8 equivalents of formic acid). MS m / z (ESI): 378.9 [M+1]. 1 H NMR (400 MHz, CD3OD) δ 8.47 (s, 0.8H), 7.83 (s, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.30 (s, 1H), 6.75 (s, 1H), 6.27 (s, 1H), 4.44 - 4.30 (m, 2H), 4.10 (d, J= 12.6 Hz, 1H), 3.75 (s, 3H), 3.55 - 3.46 (m 1H), 3.29 - 3.16 (m, 1H), 2.50 (s, 3H), 2.15 - 2.00 (m, 2H), 2.00 - 1.70 (m, 4H).

[0424] Example 14

[0425] Intermediate 1:

[0426]

[0427] 4-thiomethyl-phenylboronic acid pinacol ester (13.8 g), 2-bromopyridine (10 g), tetrakis(triphenylphosphine)palladium (2.19 g) and sodium carbonate (50.32 g) were sequentially added to a mixed solvent of toluene (140 mL), water (140 mL), and ethanol (40 mL), and then the reaction system was heated to 95°C under nitrogen protection and stirred at the said temperature for 8 hours. After the reaction was completed, the reaction system was naturally cooled to room temperature, quenched by adding a saturated aqueous ammonium chloride solution (50 mL), and extracted three times with ethyl acetate (250 mL). The combined organic phase was dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 1 (300 mg, yield: 74.52%). MS m / z (ESI): 202.2 [M+1].

[0428] Intermediate 2:

[0429]

[0430] Toluene (100 mL), intermediate 1 (1 g), diphenylsilane (4.61 g), diphenylamine (3.3844 g), and tris(pentafluorophenyl)boron (0.26 g) were sequentially added to a 250 mL three-necked flask. Then, under nitrogen protection, the reaction system was heated to 110 °C and stirred at this temperature for 18 h. After the reaction was complete, the reaction system was allowed to cool naturally to room temperature, quenched with saturated aqueous ammonium chloride solution (50 mL), and extracted three times with ethyl acetate (50 mL). The combined organic matter was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 2 (0.9 g, yield: 80%). MS m / z (ESI): 208.2 [M+1].

[0431] Intermediate 3:

[0432]

[0433] 1,2-dichloroethane (10 mL), intermediate 2 (500 mg), and intermediate 2 of Example 2 (909 mg) were sequentially added to a 50 mL three-necked flask. After stirring the reaction system at room temperature for 8 hours, sodium triacetoxyborohydride (1.53 g) was added, and the reaction was continued at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted by adding dichloromethane (10 mL), washed once with water (10 mL), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 3 (300 mg, yield: 25.6%). MS m / z (ESI): 481.4 [M+1].

[0434] Intermediate 4:

[0435]

[0436] Intermediate 3 (100 mg) was added to a methanol (2 mL) solution of ammonium carbamate (24.36 mg) and iododiacetate phenylacetate (140.69 mg), and the reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was directly separated and purified by preparative high-performance liquid chromatography (chromatography column: C18 spherical, 100A, 20 g, 20-35 µm; acetonitrile-water = 10-70%; UV: 214 nm) to obtain intermediate 4 (30 mg, yield: 17.6%). MS m / z (ESI): 512.3 [M+1].

[0437] Target compound:

[0438]

[0439] Dichloromethane (6 mL), intermediate 4 (30 mg), and bromotrimethylsilane (0.6 mL) were added sequentially to a 10 mL single-neck flask. The reaction system was stirred at room temperature for 8 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-20%) to obtain the target compound (11.6 mg, yield: 44.67%, containing 0.6 equivalents of formic acid). MS m / z (ESI): 412.3 [M+1]. 1 H NMR (400 MHz, DMSO) δ 10.83 (s, 1H), 8.21 (s, 0.6H), 7.93 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.25 (t, J = 2.4 Hz, 1H), 6.65 (s, 1H), 6.49 (td, J= 9.6 Hz, 2.4 Hz, 1H), 4.20 (s, 1H), 3.56 (s, 3H), 3.57 - 3.52 (m, 1H), 3.25 - 3.15 (m, 2H), 3.07 (s, 3H), 2.77 (d, J = 10.4 Hz, 1H), 2.41 (s, 3H), 1.75 - 1.64 (m, 2H), 1.57 - 1.43 (m, 2H), 1.41 - 1.28 (m, 2H).

[0440] Example 15

[0441] Intermediate 1:

[0442]

[0443] A mixed solvent of dioxane and water (8:1, 50 mL), 4-methoxyformylphenylboronic acid pinacol ester (5.0 g), 2-bromopyridine (3.3 g), sodium carbonate (3 g), and tetrakis(triphenylphosphine)palladium (662 mg) were sequentially added to a 250 mL single-neck flask, and then the reaction system was heated to 80°C under nitrogen protection and stirred at the said temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, the residue was diluted by adding 100 mL of water, and extracted three times (200 mL) with ethyl acetate. The combined organic phase was washed with saturated saline (50 mL), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 1 (1.1 g, yield: 27%). MS m / z (ESI): 214.1 [M+1].

[0444] Intermediate 2:

[0445]

[0446] Methanol (30 mL), intermediate 1 (1.9 g), platinum dioxide (202 mg), and hydrochloric acid (0.5 mL) were sequentially added to a 50 mL reaction vessel, and the mixture was subjected to catalytic hydrogenation for 20 hours at 0.4 MPa (hydrogen) and room temperature. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 2 (1.55 g, yield: 79%). MS m / z (ESI): 219.9 [M+1].

[0447] Intermediate 3:

[0448]

[0449] Tetrahydrofuran (10 ml), intermediate 2 of Example 2 (150 mg), intermediate 2 (150 mg), and tetraethyl titanate (120 mg) were sequentially added to a 50 mL single-neck flask, and the reaction system was heated to 100°C under nitrogen protection and stirred at the said temperature for 8 hours, then the temperature of the reaction mixture was lowered to room temperature, sodium triacetoxyborohydride (330 mg) was added, and stirring continued for 1 hour. After the reaction was completed, the reaction mixture was poured into water and extracted three times (50 mL) with ethyl acetate, the combined organic phase was dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain intermediate 3 (135 mg, yield: 40%).

[0450] Target compound:

[0451]

[0452] N,N-dimethylformamide (6 mL), intermediate 3 (100 mg), hydroxylamine hydrochloride (55 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (110 mg) and triethylamine (80 mg) were added sequentially to a 50 mL single-neck flask, and the reaction system was stirred at room temperature for 48 h. After the reaction was complete, the reaction solution was poured into water and extracted three times with ethyl acetate (100 mL). The combined organic phase was washed once with saturated saline (20 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was separated and purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-30%) to obtain the target compound (11.7 mg, yield: 11%). MS m / z (ESI): 394.1 [M+1]. 1 H NMR (400 MHz, CD3OD) δ 8.51 (s, 1H), 7.94 (d, J = 7.8 Hz, 2H), 7.71 (d, J = 7.8 Hz, 2H), 7.31 (d, J = 2.8 Hz, 1H), 6.76 (s, 1H), 6.34 (s, 1H), 4.45 - 4.25 (m, 2H), 4.12 - 4.00 (m, 1H), 3.76 (s, 3H), 3.55 - 3.42 (m, 1H), 3.22 - 3.12 (m, 1H), 2.50 (s, 3H), 2.10 - 1.75 (m, 6H).

[0453] Example 16

[0454] Intermediate 1:

[0455]

[0456] Under -78°C and nitrogen protection, 3,3-difluorocyclobutan-1-one (203 mg) and trimethylsilyl trifluoromethanesulfonate (42 mg) were added to the dichloromethane (5 mL) of intermediate 1 (860 mg) of Example 6, and the reaction mixture was stirred at -78°C for 1 hour, then triethylsilane (222 mg) was added, the reaction mixture was naturally heated to room temperature and continued to be stirred at room temperature for 16 hours. After the reaction was complete, an aqueous sodium bicarbonate solution (10 mL) was slowly added to the reaction solution and quenched, water (10 mL) was added to dilute, the mixture was extracted with dichloromethane (10 mL), the extract phase was washed once with saturated saline (10 mL), dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 1 (80 mg, yield: 8.36%). MS m / z (ESI): 448.8 [M+23].

[0457] Intermediate 2:

[0458]

[0459] Intermediate 1 (100 mg) and sodium hydroxide (94 mg) were sequentially added to a mixed solution of isopropanol and water (1 mL / 3 mL), then the reaction mixture was heated to 100°C and stirred at the said temperature for 16 hours. After the reaction was complete, dilute hydrochloric acid (1 M, 2.50 mL) was added to the reaction mixture in an ice bath to adjust the pH to 5–6, water (5 mL) was added for dilution, the mixture was extracted with ethyl acetate (5 mL), the extract phase was washed with saturated saline (5 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 2 (70 mg, yield: 60%). MS m / z (ESI): 445.9 [M+1].

[0460] Intermediate 3:

[0461]

[0462] Potassium carbonate (43 mg) and iodomethane (45 mg) were added to an acetonitrile (2 mL) solution of intermediate 2 (70 mg), and the reaction mixture was heated to 50°C and stirred at the said temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated directly, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 3 (60 mg, yield: 73%). MS m / z (ESI): 481.7 [M+23].

[0463] Intermediate 4:

[0464]

[0465] Palladium / carbon (10 mg) was added to a 1 mL solution of tetrahydrofuran containing intermediate 3 (60 mg), and catalytic hydrogenation was performed on the reactants for 16 hours under a hydrogen atmosphere at room temperature. After the reaction was complete, the reaction mixture was filtered, and the filtrate was directly concentrated to obtain intermediate 4 (35 mg, yield: 74%). MS m / z (ESI): 325.9 [M+1].

[0466] Intermediate 5:

[0467]

[0468] Intermediate 4 (35 mg) was added to a 1,2-dichloroethane (2 mL) solution of Intermediate 2 (32 mg) from Example 2, and the reaction mixture was stirred at room temperature for 8 hours; then, sodium triacetoxyborohydride (70 mg) was added and stirring continued at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated directly, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain Intermediate 5 (80 mg, yield: 37.5%). MS m / z (ESI): 598.8 [M+1].

[0469] Target compound:

[0470]

[0471] At room temperature, intermediate 5 (80 mg, 0.134 mmol) and sodium hydroxide (54 mg, 1.35 mmol) were sequentially added to a mixed solution of methanol and water (1 mL / 1 mL), then the reaction mixture was heated to 75°C and stirred at the above temperature for 3 hours. After the reaction was completed, dilute hydrochloric acid (1 M, 1.35 mL) was added to the reaction solution in an ice bath to adjust the pH to about 7, the solvent was directly freeze-dried, and the residue was separated and purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18, 150×21.2 mm, 5 μm; column temperature: 25℃; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-50%) to obtain the target compound (4.7 mg, yield: 7.23%, containing 0.2 equivalents of formic acid). 1 H NMR (400 MHz, CD3OD) δ 8.44 (s, 0.2H), 8.15 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.49 - 7.25 (m, 5H), 6.75 (s, 1H), 6.32 (s, 1H), 4.84 - 4.71 (m, 1H), 4.64 (q, J = 11.8 Hz, 2H), 4.42 - 4.12 (m, 2H), 4.02 - 3.86 (m, 1H), 3.74 (s, 3H), 3.64 - 3.48 (m, 1H), 3.48 - 3.31 (m, 1H), 2.50 (s, 3H), 2.38 - 1.97 (m, 4H). MS m / z (ESI): 484.8[M+1].

[0472] Example 17

[0473] Intermediate 1:

[0474]

[0475] Under -40°C and nitrogen protection, a tetrahydrofuran solution of methyl magnesium bromide (1 M, 6 mL) (maintaining the temperature of the reaction mixture below -40°C during the addition process) was slowly added dropwise to the tetrahydrofuran (50 mL) solution of intermediate 2 (2 g) of Example 1. After addition, the reaction mixture was continuously stirred and allowed to naturally rise to room temperature, after which it was stirred continuously at room temperature for 2 hours. After the reaction was complete, a saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture to quench it, ethyl acetate (100 mL) and water (100 mL) were added to dilute it, the organic phase was separated and washed with saturated saline (50 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 1 (1.7 g, yield: 40%). MS m / z (ESI): 351.0 [M+1].

[0476] Intermediate 2:

[0477]

[0478] In an ice bath, diethylaminosulfur trifluoride (413 mg) was added dropwise to a dichloromethane (20 mL) solution of intermediate 1 (900 mg), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, a saturated sodium bicarbonate aqueous solution (20 mL) was added to the reaction mixture to quench the reaction mixture, water (100 mL) was added to dilute it, and it was extracted with ethyl acetate (100 mL). The extract was washed once with water (100 mL), dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 2 (280 mg, yield: 27%). MS m / z (ESI): 352.9 [M+1].

[0479] Intermediate 3:

[0480]

[0481] At room temperature, intermediate 2 (250 mg) and an aqueous sodium hydroxide solution (4 M, 3 mL) were sequentially added to isopropanol (3 mL), the reaction mixture was heated to 100°C and stirred at said temperature for 30 hours. After the reaction was complete, dilute hydrochloric acid (1 M, 13 mL) was slowly added to the reaction mixture in an ice bath to adjust the pH to 5–6, water (20 mL) was added for dilution, the mixture was extracted with ethyl acetate (20 mL), the extract phase was washed with saturated saline (20 mL), dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 3 (200 mg, yield: 64%). MS m / z (ESI): 371.9 [M+1].

[0482] Intermediate 4:

[0483]

[0484] At room temperature, potassium carbonate (138 mg) and iodomethane (140 mg) were sequentially added to a 5 mL solution of acetonitrile containing intermediate 3 (200 mg), then the reaction mixture was heated to 50°C and stirred at the said temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated directly, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 4 (200 mg, yield: 86%). MS m / z (ESI): 385.9 [M+1].

[0485] Intermediate 5:

[0487] *

[0488] Palladium / carbon (50 mg) was added to a 5 mL solution of tetrahydrofuran containing intermediate 4 (200 mg), and the reactants were reacted for 16 hours at room temperature under a hydrogen atmosphere at 1 atm. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated directly under reduced pressure to obtain intermediate 5 (95 mg, yield: 27%). MS m / z (ESI): 251.9 [M+1].

[0489] Intermediate 6:

[0490]

[0491] At room temperature, intermediate 5 (50 mg), 2,8,9-trioxo-5-aza-1-silabicyclo[3.3.3]undecane (150 mg), and acetic acid (30 mg) were sequentially added to a tetrahydrofuran (5 mL) solution of intermediate 2 (60 mg) from Example 2, and then the reaction mixture was heated to 70°C and stirred at said temperature for 24 hours. After the reaction was complete, the reaction mixture was concentrated directly, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain intermediate 6 (40 mg, yield: 26%). MS m / z (ESI): 525.2[M+1].

[0492] Target compound:

[0493]

[0494] At room temperature, intermediate 6 (40 mg) and sodium hydroxide (40 mg) were sequentially added to a mixed solution of methanol / water (2 mL / 2 mL), then the reaction mixture was heated to 75°C and stirred at the said temperature for 3 hours. After the reaction was complete, dilute hydrochloric acid (1 M, 1 mL) was added to the reaction mixture in an ice bath to adjust the pH to about 8, the mixture was concentrated under reduced pressure, and the residue was separated and purified by preparative high-performance liquid chromatography (chromatography column: AQ-C18; 30×250 mm, 10 μm; column temperature: 25°C; flow rate: 45 mL / min; wavelength: 214 nm; column pressure: 19 bar; mobile phase: acetonitrile-water (0.05% NH3); gradient: 10-40%) to obtain the target compound (14.0 mg, yield: 17%). MS m / z (ESI): 410.9[M+1]. 1 H NMR (400 MHz, CD3OD) δ 8.16 - 8.08 (m, 2H), 7.63 (d, J= 8.0 Hz, 2H), 7.32 - 7.25 (m, 1H), 6.77 - 6.70 (m, 1H), 6.37 - 6.29 (m, 1H), 4.70 - 4.51 (m, 1H), 4.35 - 3.70 (m, 6H), 3.42 - 3.35 (m, 1H), 2.52 - 2.46 (m, 3H), 2.30 - 1.90 (m, 4H), 1.67 - 1.35 (m, 3H).

[0495] Example 18

[0496] Intermediate 1:

[0497]

[0498] At room temperature, ethylene glycol (558 mg) and p-toluenesulfonic acid (114 mg) were added to a toluene (40 mL) solution of intermediate 2 (2 g) from Example 1, and the reaction mixture was heated to 110°C and reacted for 10 hours while stirring. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 1 (1.6 g, yield: 70%). MS m / z (ESI): 379.2 [M+1].

[0499] Intermediate 2:

[0500]

[0501] At room temperature, sodium hydroxide (1.7 g) was added to a mixed solution of methanol and water (20 mL / 20 mL) containing intermediate 1 (1.6 g), the reaction mixture was heated to 70°C and stirred at the above temperature for 18 hours. After the reaction was completed, the reaction system was naturally cooled to room temperature, the pH was adjusted to about 2 with dilute hydrochloric acid (2 M), the resulting mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by preparative high-performance liquid chromatography (chromatography column: -Gemini-C18 150×21.2 mm, 5 μm, column temperature: 25°C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar, mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-70%) to obtain intermediate 2 (150 mg, yield: 47.6%). MS m / z (ESI): 398.2[M+1].

[0502] Intermediate 3:

[0503]

[0504] In an ice bath, thionyl chloride (1.34 g) was slowly added dropwise to a methanol (10 mL) solution of intermediate 2 (800 mg), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (10 mL) was added to dilute the reaction mixture, and the reaction mixture was quenched by continuing stirring for 2 hours. The reaction mixture was then concentrated under reduced pressure to obtain intermediate 3 (680 mg, yield: 77.8%). MS m / z (ESI): 368.2 [M+1].

[0505] Intermediate 4:

[0506]

[0507] In an ice bath, an ammonia methanol solution (1 M, 5.8 mL) was added to a 1,2-dichloroethane (2 mL) solution of intermediate 3 (600 mg). After stirring the reaction mixture at room temperature for 8 hours, sodium triacetoxyborohydride (1 g) was added and stirring continued at room temperature for 18 hours. The resulting mixture was diluted by adding dichloromethane (10 mL) and water (10 mL), the organic phase was dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 4 (150 mg, yield: 24.98%). MS m / z (ESI): 369.1 [M+1].

[0508] Intermediate 5:

[0509]

[0510] At room temperature, acetic anhydride (38.79 mg) was added to an ethyl acetate (5 mL) solution of intermediate 4 (140 mg), and the reaction mixture was stirred continuously at room temperature for 18 hours. After the reaction was complete, potassium carbonate (105 mg) was added to the reaction mixture and stirred continuously for 30 minutes, filtered, the filtrate concentrated under reduced pressure, and the residue purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 5 (110 mg, yield: 67%). MS m / z (ESI): 411.3 [M+1].

[0511] Intermediate 6:

[0512]

[0513] At room temperature, palladium hydroxide / carbon (10 mg) was added to a methanol (5 mL) solution of intermediate 5 (70 mg), and the reaction mixture was stirred for 18 hours at room temperature under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated directly under reduced pressure to obtain intermediate 6 (50 mg, yield: 89.41%). MS m / z (ESI): 277.0 [M+1].

[0514] Intermediate 7:

[0515]

[0516] At room temperature, intermediate 6 (40 mg) and intermediate 2 (52.8 mg) of Example 2 were added to a solution of 1,2-dichloroethane (2 mL), and the reaction mixture was stirred at room temperature for 8 hours; sodium triacetoxyborohydride (89 mg) was added, and the reaction mixture was stirred continuously at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted by adding dichloromethane (10 mL), washed with water (10 mL), the organic phase was dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 7 (30 mg, yield: 37%). MS m / z (ESI): 550.1 [M+1].

[0517] Target compound:

[0518]

[0519] At room temperature, intermediate 7 (30 mg) and sodium hydroxide (20 mg) were added to a mixed solution of methanol / water / tetrahydrofuran (0.5 mL / 0.5 mL / 0.5 mL), and the reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, dilute hydrochloric acid (2 M, 0.5 mL) was added to the reaction solution in an ice bath to adjust the pH to 7, and the residue was purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18, 150×21.2 mm, 5 μm; column temperature: 25℃; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 0-20%) to obtain the target compound (4 mg, yield: 12.86%; containing 0.3 equivalents of formic acid). MS m / z (ESI): 436[M+1]. 1 H NMR (400 MHz, CD3OD) δ8.40 (s, 0.3H), 8.15 (d,J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 4.0 Hz, 1H), 6.75 (s, 1H), 6.30 (s, 1H), 4.53 - 4.41 (m, 1H), 4.34 - 4.23 (m, 1H), 4.15 - 3.98 (m, 2H), 3.75(s, 3H), 3.50 - 3.43 (m, 1H), 3.27 - 3.23 (m, 1H), 2.49 (s, 3H), 2.31 - 2.22 (m, 1H), 2.11 - 2.03 (m, 2H), 1.91 (s, 3H), 1.83 - 1.70 (m, 1H).

[0520] Example 19

[0521] Intermediate 1:

[0522]

[0523] At room temperature, ethylamine tetrahydrofuran solution (0.41 mL) was added to the 1,2-dichloroethane (2 mL) solution of intermediate 2 (200 mg) from Example 1. The reaction mixture was stirred at room temperature for 8 hours, sodium triacetoxyborohydride (343 mg) was added, and the reaction mixture was continued to be stirred at room temperature for 18 hours. After the reaction was complete, dichloromethane (10 mL) was added to the reaction system to dilute it, washed with water (10 mL), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 1 (100 mg, yield: 44.4%). MS m / z (ESI): 397.3 [M+1].

[0524] Intermediate 2:

[0525]

[0526] At room temperature, di-tert-butyl dicarbonate (131 mg) and triethylamine (76 mg) were added to a dichloromethane (2 mL) solution of intermediate 1 (200 mg), and the reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted by adding dichloromethane (10 mL), washed with water (10 mL), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 2 (200 mg, yield: 76.5%). MS m / z (ESI): 497.3 [M+1].

[0527] Intermediate 3:

[0528]

[0529] At room temperature, palladium hydroxide / carbon (20 mg) was added to a methanol (5 mL) solution of intermediate 2 (180 mg), and the reaction mixture was stirred for 18 hours at room temperature under a hydrogen balloon atmosphere. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 3 (120 mg, yield: 82.8%). MS m / z (ESI): 363.3 [M+1].

[0530] Intermediate 4:

[0531]

[0532] At room temperature, intermediate 3 (150 mg) was added to a 1,2-dichloroethane (2 mL) solution of intermediate 2 (142 mg) from Example 2, and the reaction mixture was stirred at room temperature for 8 hours; sodium triacetoxyborohydride (261 mg) was added, and the reaction mixture was stirred continuously at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted by adding dichloromethane (10 mL), washed with water (10 mL), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated, and the residue purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain intermediate 4 (50 mg, yield: 17.24%). MS m / z (ESI): 636.3 [M+1].

[0533] Intermediate 5:

[0534]

[0535] At room temperature, bromotrimethylsilane (0.2 mL) was added to a dichloromethane (1 mL) solution of intermediate 4 (40 mg), and the reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was concentrated directly under reduced pressure to obtain intermediate 5 (40 mg, yield: 99.67%). MS m / z (ESI): 436.3 [M+1].

[0536] Target compound:

[0537]

[0538] At room temperature, intermediate 5 (40 mg) and sodium hydroxide (36 mg) were sequentially added to a mixed solution of methanol / water / tetrahydrofuran (0.5 mL / 0.5 mL / 0.5 mL), and the reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, dilute hydrochloric acid (2 M, 0.5 mL) was added to the reaction solution in an ice bath to adjust the pH to approximately 7, the resulting mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18, 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); column temperature: 25°C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar, gradient: 0-20%) to obtain the target compound (4 mg, yield: 9.22%; containing 2 equivalents of formic acid). MS m / z (ESI): 422[M+1]. 1 H NMR (400 MHz, CD3OD) δ 8.43 (s, 2H), 8.09 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 2.8 Hz, 1H), 6.69 (s, 1H), 6.37 (d, J = 2.8 Hz, 1H), 3.87 - 3.81 (m, 1H), 3.75 (s, 3H), 3.62 - 3.56 (m, 1H), 3.42 - 3.36 (m, 1H), 3.21 - 3.13 (m, 1H), 3.07 - 2.98 (m, 2H), 2.51 - 2.37 (m, 4H), 2.22 - 2.16 (m, 1H), 2.06 - 2.00 (m, 1H), 1.90 - 1.78 (m, 1H), 1.72 - 1.55 (m, 2H), 0.91 - 0.80 (m, 3H).

[0539] Example 20

[0540] Intermediate 1:

[0541]

[0542] At room temperature, potassium carbonate (4.47 g) was added to a DMF (100 mL) solution of methyl 4-bromo-3-hydroxybenzoate (5 g) and bromoacetaldehyde diethyl acetal (4.68 g), then the reaction mixture was heated to 100°C and stirred at the said temperature for 16 hours. After the reaction was complete, the reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with saturated saline (100 mL × 3), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain intermediate 1 (7.9 g, yield: 80%). MS m / z (ESI): 268.7 [M+23].

[0543] Intermediate 2:

[0544]

[0545] At room temperature, polyphosphoric acid (3 g) was added to a chlorobenzene (15 mL) solution of intermediate 1 (1 g), the reaction mixture was heated to 130°C and stirred at the said temperature for 16 hours. After the reaction was complete, water (50 mL) was added to the reaction mixture to dilute it, and it was extracted with ethyl acetate (30 mL × 3). The combined extract was washed with saturated saline (20 mL × 3), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 2 (300 mg, yield: 40%). GC-MS m / z: 254, 256 [M].

[0546] Intermediate 3:

[0547]

[0548] At room temperature, bistriphenylphosphinopalladium dichloride (54 mg) was added to a dioxane (15 mL) solution of intermediate 2 (200 mg), 2-(tributylstanyl)pyridine (344 mg), and cuprous iodide (15 mg), and the reaction mixture was heated to 100°C and stirred at said temperature for 16 hours. After the reaction was complete, the reaction mixture was naturally cooled to room temperature and concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 3 (140 mg, yield 70%). MS m / z (ESI): 253.9 [M+1].

[0549] Intermediate 4:

[0550]

[0551] At room temperature, platinum dioxide (10 mg) was added to a methanol / concentrated hydrochloric acid (4 mL / 0.5 mL) mixture of intermediate 3 (20 mg), and the reaction mixture was stirred for 16 hours in a hydrogen autoclave at room temperature and 4 atm. After the reaction was complete, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain intermediate 4 (20 mg, yield: 95%). MS m / z (ESI): 261.9 [M+1].

[0552] Intermediate 5:

[0554] *

[0555] At room temperature, tetraethyl titanate (83 mg) was added to a 10 mL tetrahydrofuran solution containing intermediate 4 (99 mg) and intermediate 2 (110 mg) of Example 2, and the reaction mixture was heated to 70°C and stirred at said temperature for 16 hours. The reaction mixture was cooled to room temperature, sodium triacetylborohydride (241 mg, 1.14 mmol) was added, and the reaction mixture was heated to 70°C and stirred for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain intermediate 5 (50 mg, yield: 24%). MS m / z (ESI): 534.8 [M+1].

[0556] Target compound:

[0557]

[0558] At room temperature, sodium hydroxide (36 mg) was added to a methanol / water (4 mL / 1 mL) mixed solution of intermediate 5 (50 mg), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and hydrochloric acid (5 M, 1 mL) was added to the residue in an ice bath to adjust the pH to 5–6, and then concentrated under reduced pressure. The resulting crude product was purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18, 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 15–40%, column temperature: 25℃; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain the target compound (12 mg, yield: 31%, containing 0.9 equivalents of formic acid). 1 H NMR (400 MHz, CD3OD) δ 8.49 (s, 0.9H), 7.54 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.29 (d, J= 2.8 Hz, 1H), 6.76 (s, 1H), 6.29 (d, J = 2.8 Hz, 1H), 4.69 (t, J = 9.0 Hz, 2H), 4.56 (d, J = 10.4 Hz, 1H), 4.44 (d, J = 12.7 Hz, 1H), 4.18 (d, J = 12.7 Hz, 1H), 3.78 (s, 3H), 3.58 (t, J = 8.8 Hz, 2H), 3.51 (d, J = 13.2 Hz, 1H), 3.24 - 3.22 (m, 1H), 2.50 (s, 3H), 2.23 - 2.17 (m, 1H), 2.10 - 1.62 (m, 5H). MS m / z (ESI): 421.0 [M+1].

[0559] Example 21

[0560] Intermediate 1:

[0561]

[0562] At room temperature, a chloroform (70 mL) solution of liquid bromine (10.13 g, 0.0634 mmol) was slowly added dropwise to a chloroform (408 mL) solution of methyl 6-aminopyridine-2-carboxylate (9.64 g, 0.0634 mol) (dropwise addition process 60 min). After dropwise addition, the reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, a saturated sodium thiosulfate solution (150 mL) was added to the reaction mixture to quench the reaction mixture and separate the phases. The aqueous phase was extracted with dichloromethane (150 mL), the combined organic phase was washed with a water solution (10 mL × 3), dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain intermediate 1 (1.1 g, yield: 7.10%). MS m / z (ESI): 230.8 [M+23].

[0563] Intermediate 2:

[0564]

[0565] At room temperature, intermediate 1 (1 g) was added to a 20 mL isopropanol solution of 40% chloroacetaldehyde (1.69 g), the reaction mixture was heated to 80°C and stirred at the said temperature for 18 hours. After the reaction was complete, the reaction system was allowed to cool naturally to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 2 (1 g, yield: 86.05%). MS m / z (ESI): 254.8 [M+23].

[0566] Intermediate 3:

[0567]

[0568] At room temperature, 1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (1.35 g), iridium reagent (Ir[dF(CF3)ppy]2(dtbppy))PF6 (cas: 870987-63-6, 43.98 mg), nickel chloride ethylene glycol dimethyl ether complex (86.25 mg), 4,4'-di-tert-butyl-2,2'-bipyridine (157.84 mg), and cesium carbonate (3832.13 mg) were sequentially added to a DMF (20 mL) solution of intermediate 2 (1 g), and after replacing the reaction system with nitrogen three times, the mixture was placed in an LED blue light reactor (26 W, Compact fluorescent light, 300-400 nM) and reacted for 48 hours. After the reaction was complete, the reaction solution was diluted by adding ethyl acetate (200 mL), washed with water (200 mL × 5), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 3 (300 mg, yield: 20.17%). MS m / z (ESI): 360 [M+23].

[0569] Intermediate 4:

[0570]

[0571] At room temperature, trifluoroacetic acid (0.6 mL) was added to a solution of intermediate 3 (300 mg, 0.832 mmol) in dichloromethane (3 mL), and the reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was concentrated directly under reduced pressure to obtain intermediate 4 (100 mg, yield: 46%). MS m / z (ESI): 260.2 [M+23].

[0572] Intermediate 5:

[0573]

[0574] At room temperature, intermediate 4 (100 mg) was added to a 1,2-dichloroethane (2 mL) solution of intermediate 2 (134 mg) from Example 2, and the reaction mixture was stirred at room temperature for 8 hours. Then, sodium triacetoxyborohydride (245.2 mg, 1.16 mmol) was added, and the reaction mixture was continuously stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted by adding dichloromethane (10 mL), washed with water (10 mL), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 5 (100 mg, yield: 46.16%). MS m / z (ESI): 533.3 [M+23].

[0575] Target compound:

[0576]

[0577] At room temperature, sodium hydroxide (75 mg) was added to the tetrahydrofuran / methanol / water (0.5 mL / 0.5 mL / 0.5 mL) of intermediate 5 (100 mg), and the reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18, 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); column temperature: 25℃; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar, gradient: 0-70%) to obtain the target compound (21 mg, yield: 26.52%). 1H-NMR (400 MHz, MeOD) δ 8.96 (s, 1H), 7.77 (s, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.26 (d, J = 3.2 Hz, 1H), 6.63 (s, 1H), 6.26 (d, J = 3.2 Hz, 1H), 4.95 - 4.92 (m, 1H), 4.42 - 4.27 (m, 2H), 3.77 (s, 3H), 3.60 - 3.52 (m, 1H), 3.27 - 3.20 (m, 1H), 2.65 - 2.47 (m, 1H), 2.45 (s, 3H), 2.20 - 2.10 (m, 1H), 2.05 - 1.88 (m, 3H), 1.86 - 1.72 (m, 1H). MS m / z (ESI): 419.2[M+23].

[0578] Example 22

[0579] Intermediate 1:

[0580]

[0581] Under -40°C and nitrogen protection, a 1.3 M solution of isopropyl magnesium chloride lithium chloride tetrahydrofuran (36 mL) was added to a 100 mL solution of tetrahydrofuran in methyl 4-iodo-benzoate (9.9 g). After stirring the reaction mixture at -40°C for 1 hour, a 50 mL solution of tetrahydrofuran in pyridine N-oxide (3.0 g) was added; after stirring the reaction mixture at -40°C for 1 hour, a 50 mL solution of methanol in sodium borohydride (1438 mg, 37.85 mmol) was added, and the reaction mixture was continued to be stirred at -40°C for 1 hour, the temperature was slowly raised to room temperature, and stirring was continued for 16 hours. After the reaction was complete, saturated ammonium chloride solution (100 mL) was added to the reaction mixture and stirred for half an hour, then diluted with water (400 mL), extracted with ethyl acetate (200 mL), washed the extract phase with saturated saline (400 mL), dried with anhydrous sodium sulfate and filtered, concentrated the filtrate, and purified the residue by column chromatography (dichloromethane:methanol=20:1) to obtain intermediate 1 (2.0 g, yield: 22%). MS m / z (ESI): 234.1[M+1].

[0582] Intermediate 2:

[0583]

[0584] At room temperature, zinc powder (2.8 g) and water (20 mL) were added to an acetic acid (20 mL) solution of intermediate 1 (2 g), then the reaction mixture was heated to 50°C and stirred at the above temperature for 2 hours. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, the residue was diluted with water (50 mL), 2 M sodium hydroxide solution was added to the diluent in an ice bath to adjust the pH to 8–10, the mixture was extracted with ethyl acetate (50 mL), the extract phase was washed with saturated saline (100 mL), dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the crude product was decomposed by supercritical chiral preparative chromatography (chromatography column: chiralpak-AD-H, 250×20 mm, 5 μm; column temperature: 40℃; flow rate: 40 g / min; wavelength: 214 nm; gradient: methanol (0.2% ammonia solution) / carbon dioxide=35 / 65; back pressure: 100 bar) to obtain intermediate 2 (670 mg, yield: 35%). MS m / z (ESI): 218.1[M+1].

[0585] Intermediate 3:

[0587] *

[0588] At room temperature, Boc2O (2.0 g) and triethylamine (865 mg) were added to a 10 mL solution of dichloromethane containing intermediate 2 (930 mg), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated directly, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain intermediate 3 (1.4 g, yield: 92%). MS m / z (ESI): 340.0 [M+23].

[0589] Intermediate 4:

[0590]

[0591] Under the protection of an ice bath and nitrogen, a diethyl ether solution of diazomethane (1 M, 6.3 mL) was slowly added dropwise to a diethyl ether solution (2 mL) of intermediate 3 (200 mg) and palladium acetate (20 mg, 10%), and the reaction mixture was stirred for 2 hours under the protection of an ice bath and nitrogen. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated directly to obtain the crude product. Monitoring revealed that only some of the raw materials were converted into the target product, and after repeating the above reaction operation 4 times, intermediate 3 was basically completely converted. The obtained crude product was purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18, 150×21.2 mm, 5 μm; column temperature: 25℃; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 60-80%) to obtain intermediate 4 (70 mg, yield: 32%). MS m / z (ESI): 354.0 [M+23].

[0592] Intermediate 5:

[0593]

[0594] At room temperature, 0.5 mL of 4 M dioxane hydrochloride solution was added to 1 mL of a dichloromethane solution containing intermediate 4 (70 mg), and the reactants were reacted at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated directly under reduced pressure to obtain intermediate 5 (70 mg, purity: 50%, yield: 72%). MS m / z (ESI): 232.2 [M+1].

[0595] Intermediate 6:

[0596]

[0597] At room temperature, intermediate 5 (70 mg, 0.30 mmol) was added to a 1,2-dichloroethane (2 mL) solution of intermediate 2 (88 mg) from Example 2, and the reaction mixture was stirred at room temperature for 8 hours; then, sodium triacetoxyborohydride (192 mg) was added and stirring continued at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain intermediate 6 (90 mg, yield: 53%). MS m / z (ESI): 505.1 [M+1].

[0598] Target compound:

[0599]

[0600] At room temperature, sodium hydroxide (143 mg) was added to a mixed solution of methanol / water (3 mL / 3 mL) of intermediate 6 (90 mg), then the reaction mixture was heated to 80°C and stirred at the above temperature for 8 hours. After the reaction was completed, dilute hydrochloric acid (2 M) was added to the reaction system in an ice bath to adjust the pH to about 7, the resulting mixture was freeze-dried directly to remove the solvent, and the residue was purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18, 150 × 21.2 mm, 5 μm; column temperature: 25°C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 15-40%) to obtain the target compound (30 mg, yield: 43%, containing 0.3 equivalents of formic acid). 1 H NMR (400 MHz, CD3OD) δ8.47 (s, 0.3H), 8.20 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 3.1 Hz, 1H), 6.74 (s, 1H), 6.15 (d, J = 3.1 Hz, 1H), 4.44 (d,J = 3.0 Hz, 1H), 4.35 (d, J = 12.8 Hz, 1H), 4.07 (d, J = 12.8 Hz, 1H), 3.68 (s, 3H), 3.48 - 3.34 (m, 1H), 3.02 (td, J = 13.2, 4.0 Hz, 1H), 2.51 (s, 3H), 2.44 - 2.30 (m, 1H), 2.11 - 1.98 (m, 1H), 1.41 - 1.29 (m, 2H), 1.13 - 1.02 (m, 1H), 0.87 - 0.78 (m, 1H). MS m / z (ESI): 391.1[M+1].

[0601] Example 23

[0602] Intermediate 1:

[0603]

[0604] At room temperature, sodium borohydride (1.1 g) was added to a methanol (80 mL) solution of intermediate 1 (5.0 g) of Example 1 and cerium trichloride (3.7 g). After stirring the reaction mixture at room temperature for 3 hours, sodium borohydride (1.1 g) was added, and the reaction mixture was continued to be stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was dissolved in water (80 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated saline (50 mL × 2), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain intermediate 1 (4.6 g, yield 87%). MS m / z (ESI): 356.8 [M+23].

[0605] Intermediate 2:

[0606]

[0607] In an ice bath, sodium hydride (660 mg, 60%) was added to a DMF (50 mL) solution of intermediate 1 (4.6 g), and the reaction mixture was stirred for 5 minutes; iodoethane (3.2 g) was then added, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, water (0.5 mL) was added for quenching, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain intermediate 2 (1.5 g, yield 30%). MS m / z (ESI): 384.9 [M+23].

[0608] Intermediate 3:

[0609]

[0610] In an ice bath, a diethylzinc hexane solution (1 mol / L, 3 mL) was added to a dichloromethane (20 mL) solution of intermediate 2 (1.1 g) and diiodomethane (620 mg), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 3 (950 mg, yield 29%). MS m / z (ESI): 376.9 [M+H].

[0611] Intermediate 4:

[0612]

[0613] At room temperature, an aqueous sodium hydroxide solution (1.01 g) was added to an ethanol / water (20 mL / 7 mL) solution of intermediate 3 (950 mg), the reaction mixture was heated to 90°C and stirred at the said temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to remove ethanol, water (15 mL) was added to the residue, the pH was adjusted to 4–5 with a 5 M dilute hydrochloric acid solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated saline solution (20 mL × 2), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain intermediate 4 (810 mg, yield 81%). MS m / z (ESI): 395.9 [M+H].

[0614] Intermediate 5:

[0615]

[0616] At room temperature, thionyl chloride (1.5 mL) was added to a methanol (15 mL) solution of intermediate 4 (810 mg), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain intermediate 5 (810 mg, yield 81%). MS m / z (ESI): 409.9 [M+H].

[0617] Intermediate 6:

[0618]

[0619] At room temperature, palladium acetate (109 mg) was added to a solution of intermediate 5 (400 mg), triethylamine (493 mg), and triethylsilane (1.76 g) in dichloromethane (15 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain intermediate 6 (400 mg, yield 74%). MS m / z (ESI): 276.0 [M+H].

[0620] Intermediate 7:

[0621]

[0622] At room temperature, sodium triacetylborohydride (219 mg) was added to a 1,2-dichloroethane (10 mL) solution of intermediate 6 (94 mg, 0.344 mmol) and intermediate 2 (100 mg) of Example 2, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain intermediate 7 (130 mg, yield 68%). MS m / z (ESI): 548.8 [M+H].

[0623] Target compound:

[0624]

[0625] At room temperature, sodium hydroxide (102 mg) was added to a methanol / water (8 mL / 2 mL) mixed solution of intermediate 7 (130 mg), and the reaction mixture was stirred at room temperature for 48 hours. After the reaction was complete, the solvent was removed by direct vacuum concentration, and the residue was purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18, 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-40%, column temperature: 25°C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain the target compound (30 mg, yield 27%). MS m / z (ESI): 434.9 [M+1]. 1 H NMR (400 MHz, MeOD) δ 8.12 (d, J = 7.6 Hz, 2H), 7.64 (d, J = 7.6 Hz, 2H), 7.29 (d, J = 3.1 Hz, 2H), 6.73 (s, 1H), 6.45 (d, J = 3.1 Hz, 1H), 4.33 (d, J= 12.0 Hz, 1H), 4.27 - 4.17 (m, 2H), 4.16 - 4.08 (m, 1H), 3.83 - 3.67 (m, 4H), 3.52 - 3.42 (m, 1H), 2.77 - 2.67 (m, 1H), 2.49 (s, 3H), 2.34 - 2.21 (m, 1H), 1.84 (d, J = 15.0 Hz, 1H), 1.79 - 1.61 (m, 2H), 1.26 (t, J = 7.0 Hz, 3H), 1.00 - 0.90 (m, 1H).

[0626] Example 24

[0627] Intermediate 1:

[0628]

[0629] At -78°C, lithium bis(trimethylsilyl)amide (4.5 mL, 4.5 mmol) was slowly added dropwise to a THF (4 mL) solution of intermediate 1 (1 g, 3.0 mmol) of Example 1. After reacting at -78°C for 1 hour, methyl bromoacetate (1.4 g, 9.0 mmol) was slowly added to the reaction system at the above temperature, stirred continuously for 1 hour at the above temperature, the temperature of the reaction system was naturally raised to room temperature, and stirred overnight at room temperature. After the reaction was complete, the reaction solution was diluted by adding water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined extract was washed with saturated saline (100 mL), dried with anhydrous sodium sulfate, filtered, concentrated, and the residue purified by column chromatography (dichloromethane:methanol = 5:1) to obtain intermediate 1 (330 mg, yield: 28%). MS m / z (ESI): 405.2 [M+1].

[0630] Intermediate 2:

[0631]

[0632] At 0°C, sodium borohydride (1.2 g, 32 mmol) was slowly added to a methanol (30 mL) solution of intermediate 1 (1.6 g, 4.0 mmol), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (100 mL) was added to the reaction system and quenched, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined extract was washed with saturated saline (200 mL), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated, and the residue purified by column chromatography (dichloromethane:methanol = 2:1) to obtain intermediate 2 (900 mg, yield: 60%). MS m / z (ESI): 381.1 [M+1].

[0633] Intermediate 3:

[0634]

[0635] At room temperature, p-toluenesulfonyl chloride (1.8 g, 9.5 mmol) was slowly added to dichloromethane (40 mL) containing intermediate 2 (1.2 g, 3.2 mmol), 4-dimethylaminopyridine (77 mg, 0.6 mmol), and triethylamine (957 mg, 9.5 mmol), and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was washed with water (10 mL), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated, and the residue purified by column chromatography (dichloromethane:methanol=3:1) to obtain intermediate 3 (500 mg, yield: 44%). MS m / z(ESI): 386.1[M+23].

[0636] Intermediate 4:

[0637]

[0638] At room temperature, intermediate 3 (500 mg, 1.4 mmol) and barium hydroxide (1.6 g, 5.0 mmol) were added to an isopropanol / water (5 mL / 12.5 mL) mixing system, the reaction mixture was heated to 100°C and stirred at said temperature for 16 hours. After the reaction was complete, a dilute aqueous hydrochloric acid solution (2 M) was added to the reaction mixture to adjust the pH to approximately 2, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined extract was washed with saturated saline (50 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain intermediate 4 (300 mg, yield: 57%). MS m / z (ESI): 404.1 [M+23].

[0639] Intermediate 5:

[0640]

[0641] At room temperature, iodomethane (224 mg, 1.6 mmol) was added to a solution of N,N-dimethylformamide (5 mL) containing intermediate 4 (300 mg, 0.8 mmol) and potassium carbonate (217 mg, 1.6 mmol), and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction liquid (20 mL) was diluted and extracted with ethyl acetate (20 mL × 3). The extracted organic phases were combined, washed with saturated saline (30 mL × 4), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain intermediate 5 (300 mg, yield: 96%). MS m / z (ESI): 418.1 [M+23].

[0642]

[0643] Intermediate 6:

[0644] At room temperature, palladium acetate (85 mg, 0.4 mmol) was added to a 10 mL solution of dichloromethane containing intermediate 5 (300 mg, 0.8 mmol), triethylsilane (881 mg, 7.6 mmol), and triethylamine (384 mg, 3.8 mmol), and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by reverse-phase C18 column chromatography (acetonitrile:methanol=10:1) to obtain intermediate 6 (200 mg, yield: 77%). MS m / z(ESI): 262.1 [M+1].

[0645] Intermediate 7:

[0646]

[0647] At room temperature, intermediate 6 (100 mg, 0.383 mmol) was added to a tetrahydrofuran (5 mL) solution of intermediate 2 (110 mg, 1.91 mmol) of Example 2, silatrane (200 mg, 1.53 mmol), and glacial acetic acid (4 drops), then the reaction mixture was heated to 75°C and stirred at the above temperature for 24 hours. After the reaction was completed, the reaction mixture was diluted by adding water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined extract was washed with saturated saline (50 mL), dried with anhydrous sodium sulfate, filtered, concentrated the filtrate, and purified the residue by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 7 (110 mg, yield: 53%). MS m / z(ESI): 534.7[M+1].

[0648] Target compound:

[0649]

[0650] At room temperature, sodium hydroxide (150 mg, 3.73 mmol) was added to a mixed solution of methanol and water (2 mL / 2 mL) of intermediate 7 (100 mg, 0.19 mmol), and the reaction mixture was stirred at room temperature for 48 hours. After the reaction was completed, dilute hydrochloric acid (2 M) was added dropwise to the reaction mixture to adjust the pH to about 5 to 7. The obtained mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative high-performance liquid chromatography (chromatography column: AQ-C18; 150×21.2 mm, 5 μm; column temperature: 25℃; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-30%) to obtain the target compound (29.2 mg, yield: 37%, containing 0.4 equivalents of formic acid). MS m / z (ESI): 420.8 [M+1]. 1 H NMR (400 MHz, CD3OD): δ8.32 (s, 0.4H), 8.17 (d, J = 7.9 Hz, 2H), 7.74 - 7.62 (m, 2H), 7.29 (d, J = 3.1 Hz, 1H), 6.72 (s, 1H), 6.26 (d, J = 2.8 Hz, 1H), 4.55 - 4.04 (m, 3H), 4.01 - 3.85 (m, 2H), 3.74 - 3.69 (m, 3H), 3.62 - 3.53 (m, 1H), 3.49 - 3.32 (m, 1H), 2.48 (s, 3H), 2.27 - 2.10 (m, 2H), 2.09 - 1.81 (m, 1H), 1.79 - 1.42 (m, 2H).

[0651] Example 25

[0652] Intermediate 1:

[0653]

[0654] Under -78°C and nitrogen protection, 2,2-difluorocyclopropane-1-carbaldehyde (320 mg) and trimethylsilyl trifluoromethanesulfonate (168 mg) were sequentially added to a dichloromethane (5 mL) solution of Intermediate 1 (680 mg) of Example 6, the reaction mixture was stirred at -78°C for 1 hour, triethylsilane (351 mg) was added, the temperature of the reaction mixture was naturally raised to room temperature, and the reaction was continued at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain Intermediate 1 (100 mg, yield: 14%). MS m / z (ESI): 426.8 [M+1].

[0655] Intermediate 2:

[0656]

[0657] At room temperature, Intermediate 1 (300 mg, 0.70 mmol) and sodium hydroxide (563 mg, 14.07 mmol) were added to a mixed solution of isopropanol / water (2.5 mL / 2.5 mL), the reaction mixture was heated to 100°C and stirred at this temperature for 24 hours. After the reaction was complete, dilute hydrochloric acid (2 M, 7.5 mL) was slowly added to the reaction mixture in an ice bath to adjust the pH to 5–6, water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (10 mL). The extract was washed with saturated saline (20 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain Intermediate 2 (270 mg, yield: 77%). MS m / z (ESI): 445.8 [M+1].

[0658] Intermediate 3:

[0659]

[0660] At room temperature, potassium carbonate (167 mg) and iodomethane (172 mg) were added to a 3 mL solution of acetonitrile containing intermediate 2 (270 mg), then the reaction mixture was heated to 50°C and stirred at the said temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 3 (190 mg, yield: 61%). MS m / z (ESI): 481.8 [M+23].

[0661] Intermediate 4:

[0662]

[0663] Under room temperature and nitrogen protection, palladium / carbon (50 mg) was added to a 3 mL solution of tetrahydrofuran containing intermediate 3 (190 mg), and catalytic hydrogenation was performed on the reactants for 16 hours under a hydrogen atmosphere and at room temperature. After the reaction was complete, the reaction mixture was filtered, and the filtrate was directly concentrated to obtain intermediate 4 (135 mg, yield: 90%). MS m / z (ESI): 325.9 [M+1].

[0664] Intermediate 5:

[0665]

[0666] At room temperature, intermediate 4 (135 mg) was added to a 1,2-dichloroethane (3 mL) solution of intermediate 2 (132 mg) from Example 2, and the reaction mixture was stirred at room temperature for 8 hours; sodium triacetoxyborohydride (264 mg) was added, and the reaction was continued at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain intermediate 5 (160 mg, yield: 52%). MS m / z (ESI): 598.7 [M+1].

[0667] Target compound:

[0668]

[0669] At room temperature, sodium hydroxide (214 mg) was added to a methanol / water (2 mL / 2 mL) mixed solution of intermediate 5 (160 mg), then the reaction mixture was heated to 80°C and stirred at the above temperature for 24 hours. After the reaction was complete, dilute hydrochloric acid (2 M, 2.7 mL) was added to the reaction solution in an ice bath to adjust the pH to approximately 7, the resulting mixture was freeze-dried directly to remove the solvent, and the residue was purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18, 150×21.2 mm, 5 μm; column temperature: 25℃; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-40%) to obtain the target compound (50.7 mg, yield: 39%, containing 0.2 equivalents of formic acid). MS m / z (ESI): 484.8 [M+1]. 1 H NMR (400 MHz, MeOD) δ8.41 (s, 0.2H), 8.16 (d, J = 8.2 Hz, 2H), 7.72 - 7.60 (m, 2H), 7.31 (d, J = 3.1 Hz, 1H), 6.75 (s, 1H), 6.42 - 6.20 (m, 1H), 4.82 - 4.66 (m, 1H), 4.37 - 4.12 (m, 2H), 3.97 - 3.82 (m, 1H), 3.81 - 3.68 (m, 4H), 3.58 - 3.45 (m, 2H), 3.44 - 3.32 (m, 1H), 2.50 (s, 3H), 2.34 - 2.17 (m, 2H), 2.10 - 1.95 (m, 3H), 1.62 - 1.51 (m, 1H), 1.28 - 1.19 (m, 1H).

[0670] Example 26

[0671] Intermediate 1:

[0672]

[0673] Under nitrogen protection, a solution of intermediate 1 (930 mg) of Example 5 in dichloromethane (20 mL) was cooled to -78°C, cyclopropanecarboxaldehyde (289 mg) and trimethylsilyl trifluoromethanesulfonate (229 mg) were added sequentially, the reaction mixture was stirred at -78°C for 1 hour, triethylsilane (479 mg) was added, the reaction mixture was naturally raised to room temperature, and stirring continued at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 1 (600 mg, yield: 67%). MS m / z (ESI): 390.9 [M+1].

[0674] Intermediate 2:

[0675]

[0676] At room temperature and under nitrogen protection, palladium / carbon (50 mg) was added to a tetrahydrofuran (3 mL) solution of intermediate 1 (340 mg), and the reaction mixture was catalytically hydrogenated for 16 hours at room temperature under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated directly under reduced pressure to obtain intermediate 2 (220 mg, yield: 89%). MS m / z (ESI): 257.0 [M+1].

[0677] Intermediate 3:

[0678]

[0679] At room temperature, intermediate 2 (220 mg) was added to a 1,2-dichloroethane (5 mL) solution of intermediate 2 (248 mg) from Example 2, and the reaction mixture was stirred at room temperature for 8 hours; then sodium triacetoxyborohydride (546 mg) was added, and the reaction mixture was continuously stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain intermediate 3 (400 mg, yield: 61%). MS m / z (ESI): 529.8 [M+1].

[0680] Intermediate 4:

[0681]

[0682] At room temperature, azidotrimethylsilane (174 mg) and dibutyltin diacetate (265 mg) were added to a toluene (5 mL) solution of intermediate 3 (400 mg), then the reaction mixture was heated to 90°C and stirred at the said temperature for 24 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain intermediate 4 (800 mg, purity: 50%, yield: 92%). MS m / z (ESI): 572.8 [M+1].

[0683] Target compound:

[0684]

[0685] At room temperature, sodium hydroxide (1.1 g) was added to a mixed solution of methanol / water (5 mL) / 5 mL of intermediate 4 (780 mg), then the reaction mixture was heated to 80°C and stirred at the above temperature for 16 hours. After the reaction was completed, dilute hydrochloric acid (6 M, 4.6 mL) was added to the reaction mixture in an ice bath to adjust the pH to about 7, the resulting mixture was freeze-dried directly to remove the solvent, and the resulting residue was purified by preparative high-performance liquid chromatography (chromatography column: Xbridge-C18, 150×19 mm, 5 μm; column temperature: 25°C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 93 bar; mobile phase: acetonitrile-water (0.05% ammonia solution); gradient: 25-35%) to obtain the target compound (103.8 mg, yield: 16%). MS m / z (ESI): 472.9[M+1]. 1 H NMR (400 MHz, MeOD) δ 8.25 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 2.4 Hz, 1H), 6.71 (s, 1H), 6.34 (d, J = 2.4 Hz, 1H), 4.79 - 4.65 (m, 1H), 4.41 - 4.28 (m, 1H), 4.25 - 4.12 (m, 1H), 3.84 - 3.77 (m, 1H), 3.72 (s, 3H), 3.59 - 3.50 (m, 1H), 3.42 - 3.34 (m, 3H), 2.48 (s, 3H), 2.28 - 2.18 (m, 2H), 2.07 - 1.94 (m, 2H), 1.18 - 1.07 (m, 1H), 0.63 - 0.53 (m, 2H), 0.31 - 0.23 (m, 2H).

[0686] Example 27

[0687] Intermediate 1:

[0688]

[0689] At room temperature, iridium reagent (Ir[dF(CF3)ppy]2(dtbppy))PF6 (cas: 870987-63-6, 26 mg) was added to a solution of N,N-dimethylformamide (6 mL) containing methyl 5-bromopyridine-2-carboxylate (500 mg), 1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (799 mg), nickel chloride ethylene glycol dimethyl ether complex (57 mg), 4'-di-tert-butyl-2,2'-dipyridine (310 mg), and cesium carbonate (1.5 g, 4.63 mmol). After replacing the reaction system with nitrogen three times, it was placed in an LED blue light reactor (26 W, Compact fluorescent light, 300-400 nM) and reacted for 16 hours. After the reaction was complete, the reaction solution was poured into water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated saline (20 mL × 3), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain intermediate 1 (500 mg, yield: 33%). MS m / z (ESI): 321.0 [M+H].

[0690] Intermediate 2:

[0691]

[0692] At room temperature, m-chloroperoxybenzoic acid (2.7 g) was added to a dichloromethane (20 mL) solution of intermediate 1 (1.0 g), and the reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete, dichloromethane (30 mL) was added to the reaction system to dilute it, and it was washed sequentially with saturated sodium bicarbonate solution (15 mL × 2) and saturated saline (15 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to obtain intermediate 2 (900 mg, yield: 86%). MS m / z (ESI): 336.0 [M+H].

[0693] Intermediate 3:

[0694]

[0695] In an ice bath, trifluoroacetic anhydride (5.6 g) was added to a DMF (20 mL) solution of intermediate 2 (900 mg), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was sequentially washed with a saturated sodium bicarbonate aqueous solution (20 mL) and saturated saline solution (20 mL × 3), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) to obtain intermediate 3 (350 mg, yield 38%). MS m / z (ESI): 336.9 [M+1].

[0696] Intermediate 4:

[0697]

[0698] At room temperature, intermediate 3 (350 mg) was dissolved in a dioxane hydrochloride solution (15 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated directly under reduced pressure to obtain intermediate 4 (300 mg, yield 98%). MS m / z (ESI): 236.9 [M+1].

[0699] Intermediate 5:

[0700]

[0701] At room temperature, silatrain (371 mg) was added to a 1,2-dichloroethane (15 mL) solution of intermediate 2 (245 mg, 0.84 mmol) and intermediate 4 (200 mg, 0.84 mmol) of Example 2 and acetic acid (0.5 mL), then the reaction mixture was heated to 90°C and stirred at said temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain intermediate 5 (130 mg, yield: 52%). MS m / z (ESI): 495.8 [M+1].

[0702] Target compound:

[0703]

[0704] In an ice bath, bromotrimethylsilane (1 mL) was added to a solution of intermediate 5 (130 mg) in dichloromethane (4 mL) and water (1 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated directly under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18, 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-30%, column temperature: 25°C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain the target compound (43 mg, yield: 41%, containing 1 equivalent of formic acid). MS m / z (ESI): 812.5 [M+23]. 1 H NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), 8.31 - 8.26 (m, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.30 (d, J= 3.2 Hz, 1H), 6.68 (s, 1H), 6.44 (s, 1H), 4.22 - 4.05 (m, 2H), 3.97 - 3.89 (m, 1H), 3.88 - 3.76 (m, 3H), 3.46 - 3.38 (m, 1H), 3.03 - 2.87 (m, 1H), 2.46 (s, 3H), 1.98 - 1.60 (m, 6H).

[0705] Example 28

[0706] Intermediate 1:

[0707]

[0708] At room temperature, silver tetrafluoroborate (26 g) was slowly added to a nitromethane (15 mL) solution of diphenyl sulfide (8 g) and 1-chloro-3-iodopropane (8 g), and the reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, dichloromethane (100 mL) was added to dilute the mixture, filtered, the filtrate concentrated under reduced pressure, and the residual phase stirred in methyl tert-butyl ether (100 mL) for 30 minutes until a white solid precipitated, filtered, and the filter cake collected to obtain intermediate 1 (8 g, yield: 50%). MS m / z (ESI): 263.1 [M+1].

[0709] Intermediate 2:

[0710]

[0711] At room temperature, N,N-dimethylformamide (24 mL) of potassium tert-butoxide (4 g) was added to a tetrahydrofuran (120 mL) solution of intermediate 1 (12 g). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, dichloromethane (400 mL) was added to the reaction system to dilute it, and the mixture was washed with water (150 mL). The organic phase was dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and methyl tert-butyl ether (300 mL) was added to the resulting residue and stirred for 1 hour. The methyl tert-butyl ether phase was removed by pouring, and the remaining oil phase was recrystallized with ethanol and methyl tert-butyl ether (1:10) to obtain intermediate 2 (3 g, yield: 26.6%). MS m / z (ESI): 226.8 [M+1].

[0712] Intermediate 3:

[0713]

[0714] At -40°C, potassium hexamethyldisilazide (18 mL, 10 mmol) was slowly added dropwise to a tetrahydrofuran (30 mL) solution of intermediate 2 (3 g). After adding dropwise, the reaction mixture was stirred at -40°C for 10 minutes, and intermediate 2 (3 g) of Example 1 was added dropwise. The reaction mixture was continuously stirred at -40°C for 30 minutes, then the temperature was naturally raised to room temperature and stirred at room temperature for 18 hours. After the reaction was complete, water (20 mL) was added to the reaction system to quench it, and it was extracted with ethyl acetate (100 mL × 2). The combined extract was dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated directly, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 3 (1.5 g, yield: 44.4%). MS m / z (ESI): 407.9[M+H].

[0715] Intermediate 4:

[0716]

[0717] At room temperature, lithium tetrafluoroborate (0.02 g) was added to a toluene (10 mL) solution of intermediate 3 (1.5 g), and the reaction mixture was heated to 70°C and stirred at the said temperature for 3 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the resulting residue was passed through column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 4 (1.2 g, yield: 47.5%). MS m / z (ESI): 408.2 [M+1].

[0718] Intermediate 5:

[0719]

[0720] In an ice bath, a tetrahydrofuran solution of lithium triisobutylhydroborate (1 M, 4.3 mL) was slowly added dropwise to a tetrahydrofuran solution (20 mL) of intermediate 4 (1.6 g, 3.93 mmol), the reaction mixture was naturally heated to room temperature and stirred at room temperature for 18 hours. After the reaction was complete, methanol (5 mL) was added to the reaction mixture and quenched; the resulting mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 5 (0.8 g, yield 80%). MS m / z (ESI): 410.1 [M+H].

[0721] Intermediate 6:

[0722]

[0723] In an ice bath, a 1 M, 1 mL solution of potassium tert-butoxide tetrahydrofuran was added to a 2 mL solution of intermediate 5 (200 mg) and the reaction mixture was stirred at room temperature for 1 hour. Then, 347 mg of iodomethane was added and the reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, 2 mL of methanol was added and the mixture was quenched. The resulting mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 6 (100 mg, yield 45.9%). MS m / z (ESI): 424.2 [M+H].

[0724] Intermediate 7:

[0725]

[0726] At room temperature and under nitrogen protection, palladium hydroxide / carbon (10%, 13 mg) was added to a methanol (5 mL) solution of intermediate 6 (100 mg). The reaction system was switched with hydrogen three times and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 7 (50 mg, yield: 69.5%). MS m / z (ESI): 290.2 [M+1].

[0727] Intermediate 8:

[0728]

[0729] At room temperature, intermediate 7 (50 mg) was added to a 1,2-dichloroethane (2 mL) solution of intermediate 2 (60 mg) from Example 2, and the reaction mixture was stirred at room temperature for 8 hours. Then, sodium triacetoxyborohydride (110 mg) was added, and the reaction mixture was stirred continuously at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted by adding dichloromethane (10 mL), washed with water (10 mL), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol=10:1) to obtain intermediate 8 (50 mg, yield: 48.73%). MS m / z (ESI): 563.3[M+1].

[0730] Target compound:

[0731]

[0732] At room temperature, sodium hydroxide (35.5 mg) was added to a mixed solution of tetrahydrofuran / methanol / water (0.5 mL / 0.5 mL / 0.5 mL) of intermediate 8 (50 mg), then the reaction mixture was heated to 70°C and stirred at the above temperature for 18 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18, 150×21.2 mm, 5 µm; mobile phase: acetonitrile-water (0.1% formic acid); column temperature: 25°C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar, gradient: 0-70%) to obtain Example 28-P1 (13.3 mg, yield: 31.79%), which is component 1. MS m / z (ESI): 448.9[M+1]. 1H NMR (400 MHz, MeOD) δ 8.25 - 8.15 (m, 2H), 7.75 - 7.56 (m 2H), 7.35 - 7.27 (m, 1H), 6.74 (s, 1H), 6.31 (s, 1H), 4.60 - 4.25 (m, 2H), 4.15 - 4.07 (m, 1H), 3.74 (s, 3H), 3.67 - 3.57 (m, 1H), 3.53 - 3.34 (m, 2H), 3.24 (s, 3H), 2.49 (s, 3H), 2.30 - 2.17 (m, 2H), 2.15 - 2.05 (m, 2H), 2.02 - 1.84 (m, 2H), 1.80 - 1.53 (m, 2H) Component 2 Example 28-P2 (5.4 mg, yield: 12.85%): MS m / z (ESI): 448.9[M+1]. 1 H NMR (400 MHz, MeOD) δ 8.13 (d, J = 8.0 Hz, 2H), 7.73 - 7.56 (m, 2H), 7.29 (s, 1H), 6.73 (s, 1H), 6.35 - 6.15 (m, 1H), 4.75 - 4.25 (m, 2H), 4.15 - 4.03 (m, 1H), 3.96 - 3.82 (m, 1H), 3.73 (s, 3H), 3.57 - 3.42 (m, 1H), 3.34 (s, 3H), 2.47 (s, 3H), 2.40 - 2.30 (m, 1H), 2.27 - 2.12 (m, 2H), 2.08 - 1.77 (m, 3H), 1.75 - 1.40 (m, 3H).

[0733] Example 29

[0734] Intermediate 1:

[0735]

[0736] In an ice bath, a solution of potassium tert-butoxide tetrahydrofuran (1 M, 1.5 mL) was added to a solution of tetrahydrofuran (4 mL) of intermediate 5 (200 mg) of Example 28, the reaction mixture was naturally heated and stirred at room temperature for 1 hour, iodoethane (381 mg) was added, and stirring continued at room temperature for 18 hours. After the reaction was complete, methanol (2 mL) was added and quenched, the resulting mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 1 (80 mg, yield 35.6%). MS m / z (ESI): 451.8 [M+1].

[0737] Intermediate 2:

[0738]

[0739] At room temperature and under nitrogen protection, palladium hydroxide / carbon (10%, 10 mg) was added to a methanol (5 mL) solution of intermediate 1 (80 mg). The reaction system was switched with hydrogen three times and stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 2 (50 mg, yield: 84.4%). MS m / z (ESI): 317.9 [M+1].

[0740] Intermediate 3:

[0741]

[0742] At room temperature, intermediate 2 (50 mg) was added to a 1,2-dichloroethane (2 mL) solution of intermediate 2 (55 mg) from Example 2, and the reaction mixture was stirred at room temperature for 8 hours; sodium triacetoxyborohydride (100 mg) was added, and the reaction mixture was continuously stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted by adding dichloromethane (10 mL), washed with water (10 mL), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol=10:1) to obtain intermediate 3 (50 mg, yield: 48.7%). MS m / z (ESI): 563.3[M+1].

[0743] Target compound:

[0744]

[0745] At room temperature, sodium hydroxide (34 mg) was added to a mixed solution of tetrahydrofuran / methanol / water (0.5 mL / 0.5 mL / 0.5 mL) of intermediate 3 (50 mg), then the reaction mixture was heated to 65°C and stirred at the above temperature for 18 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18, 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); column temperature: 25°C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar, gradient: 0-70%) to obtain Example 29-P1 (32.2 mg, yield: 39.1%), which is component 1. MS m / z (ESI): 462.8[M+1]. 1 H NMR (400 MHz, CD3OD) δ 8.20 - 8.10 (m, 2H), 7.72 - 7.58 (m, 2H), 7.30 (t, J= 3.2 Hz, 1H), 6.77 - 6.70 (m, 1H), 6.37 - 6.25 (m, 1H), 4.60 - 4.20 (m, 2H), 4.14 - 4.09 (m, 1H), 3.77 - 3.63 (m, 4H), 3.52 - 3.32 (m, 3H), 3.23 - 3.10 (m, 1H), 2.48 (d, J = 2.8 Hz, 3H), 2.27 - 1.83 (m, 6H), 1.78 - 1.52 (m, 2H), 1.10 (t, J = 6.8 Hz, 3H); and Component 2 Example 29-P2 (7.3 mg, yield: 8.9%): MS m / z (ESI): 462.8[M+1]. 1 H NMR (400 MHz, MeOD) δ 8.14 (d, J = 8.0 Hz, 2H), 7.75 - 7.55 (m, 2H), 7.30 (s, 1H), 6.74 (s, 1H), 6.35 - 6.15 (m, 1H), 4.60 - 4.22 (m, 2H), 4.15 - 3.90 (m, 2H), 3.74 (s, 3H), 3.63 - 3.32 (m, 4H), 2.57 - 2.30 (m, 4H), 2.27 - 1.61 (m, 5H), 1.60 - 1.40 (m, 2H), 1.36 -1.15 (m, 3H).

[0746] Example 30

[0747] Intermediate 1:

[0748]

[0749] At room temperature, tert-butyldiphenylchlorosilane (25 g) was sequentially added to dichloromethane (200 mL) containing intermediate 3 (25 g) of Example 1 and imidazole (6.6 g), and reacted at room temperature for 2 hours. After the reaction was complete, the reaction mixture was washed with water (500 mL), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 1 (11.4 g, yield: 26%). MS m / z (ESI): 597.0 [M+23].

[0750] Intermediate 2:

[0751]

[0752] At room temperature, intermediate 1 (3 g, 6.7 mmol) was added to a mixed solvent of 80% sulfuric acid / methanol = 1 / 1 (16 mL), the reaction mixture was heated to 100°C and stirred at the said temperature for 16 hours. After the reaction was complete, the reaction mixture was allowed to cool naturally to room temperature, diluted with water (50 mL), and the pH was adjusted to 6–7 with a dilute aqueous sodium hydroxide solution (2 M). The resulting mixture was freeze-dried to remove the solvent, and the residue was purified by column chromatography (dichloromethane:methanol = 5:1) to obtain intermediate 2 (1.07 g, yield: 67%). MS m / z (ESI): 235.9 [M+1].

[0753] Intermediate 3:

[0754]

[0755] At room temperature, (4-nitrophenyl)[2-(trimethylsilyl)ethyl]carbonate (1.3 g), triethylamine (552 mg), and 4-dimethylaminopyridine (280 mg) were sequentially added to a 6 mL DMF solution of intermediate 2 (1.1 g), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (50 mL) was added to dilute the mixture, and it was extracted with ethyl acetate (100 mL × 3). The combined extract was washed with saturated saline (50 mL), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated, and the residue purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 3 (1.13 g, yield: 60%). MS m / z (ESI): 401.8 [M+23].

[0756] Intermediate 4:

[0757]

[0758] At room temperature, Des-Martine reagent (2.4 g) was added to a solution of intermediate 3 (1.1 g) in dichloromethane (8 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was filtered directly, the filtrate was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), the combined extract was washed with saturated saline (50 mL), dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain intermediate 4 (560 mg, yield: 48%). MS m / z (ESI): 399.7 [M+23].

[0759] Intermediate 5:

[0760]

[0761] At room temperature, potassium tert-butoxide (613 mg) and tert-butanol (6 mL) were sequentially added to trimethylsulfoxonium iodide (1.63 g), the reaction mixture was heated to 60°C and stirred at said temperature for 1 hour, intermediate 4 (560 mg) was added, and the reaction mixture was continuously stirred at 60°C for 16 hours. After the reaction was complete, water (50 mL) was added to dilute the mixture, and it was extracted with ethyl acetate (100 mL × 3). The combined extract was washed with saturated saline (50 mL), dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain intermediate 5 (427 mg, yield: 73%). MS m / z (ESI): 413.7 [M+23].

[0762] Intermediate 6:

[0763]

[0764] At room temperature, trimethylsilyldiazomethane (0.7 mL, 2 M) was added to a toluene / methanol (4 mL / 1 mL) mixed solution of intermediate 5 (300 mg), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, acetic acid (2 mL) was added to the reaction system for quenching, water (50 mL) was added for dilution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined extract was washed with saturated saline (50 mL), dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 6 (133 mg, yield: 43%). MS m / z (ESI): 427.8 [M+23].

[0765] Intermediate 7:

[0766]

[0767] At room temperature, a tetrahydrofuran solution of tetrabutylammonium fluoride (0.6 mL, 1 M) was added to a tetrahydrofuran solution (4 mL) of intermediate 6 (133 mg), and the reactants were reacted at room temperature for 16 hours while stirring. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (ethyl acetate:tetrahydrofuran = 4:1) to obtain intermediate 7 (75 mg, yield: 94%). MS m / z (ESI): 261.8 [M+1].

[0768] Intermediate 8:

[0769]

[0770] At room temperature, intermediate 2 (111 mg) of Example 2, silatrain (201 mg), and acetic acid (0.04 mL) were added to a 10 mL solution of tetrahydrofuran containing intermediate 7 (100 mg), and the reaction mixture was heated to 70°C and stirred at the said temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain intermediate 8 (40 mg, yield: 20%). MS m / z (ESI): 534.7 [M+1].

[0771] Target compound:

[0772]

[0773] At room temperature, sodium hydroxide (75 mg) was added to a methanol / water (2 mL / 2 mL) mixed solution of intermediate 8 (50 mg), and the reaction mixture was stirred at room temperature for 40 hours. After the reaction was complete, the reaction mixture was directly purified by preparative high-performance liquid chromatography (chromatography column: Xbridge-C18; 150×19 mm, 5 μm; column temperature: 25°C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar; mobile phase: acetonitrile-water (0.05% NH3); gradient: 10-30%) to obtain the target compound (3.2 mg, yield: 8%). MS m / z (ESI): 411.0 [M+1]. 1 H NMR (400 MHz, CD3OD) δ 8.16 (d, J = 7.9 Hz, 2H), 7.66 (d, J = 7.9 Hz, 2H), 7.30 (d, J = 2.8 Hz, 1H), 6.75 (s, 1H), 6.32 - 6.22 (m, 1H), 4.59 (t, J = 7.7 Hz, 2H), 4.44 - 4.20 (m, 2H), 4.00 - 3.90 (m, 1H), 3.78 - 3.71 (m, 3H), 3.50 - 3.33 (m, 2H), 3.20 - 3.05 (m, 1H), 2.85 - 2.65 (m, 2H), 2.53 - 2.47 (m, 3H), 2.45 - 2.15 (m, 3H).

[0774] Example 31

[0775] Intermediate 1:

[0776]

[0777] Under -78°C and nitrogen protection, a solution of n-butyllithium (2.4 M, 25 mL) was slowly added to a solution of tetrahydrofuran (200 mL) of ethyl propiolate (5.89 g) and reacted at the above temperature for 0.5 hours, intermediate 2 of Example 1 (5 g, 14.95 mmol) was slowly added, and the reaction mixture was continued to react at -78°C for 1.5 hours. After the reaction was complete, the reaction mixture was quenched by slowly adding a saturated aqueous ammonium chloride solution (20 mL), diluted by adding water (200 mL), extracted with ethyl acetate (200 mL), washed the extract phase with saturated saline solution (20 mL), dried with anhydrous sodium sulfate and filtered, concentrated the filtrate under reduced pressure, and purified the residue by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 1 (4 g, yield: 59%). MS m / z (ESI): 433.0 [M+1].

[0778] Intermediate 2:

[0779]

[0780] In an ice bath, intermediate 1 (1.9 g) was added to an ethanol (50 mL) solution of nickel chloride hexahydrate (300 mg), the reaction mixture was stirred at the above temperature for 10 minutes, sodium borohydride (800 mg) was added in batches, and the reaction mixture was continuously stirred in an ice bath for 20 minutes. After the reaction was complete, water (100 mL) was added to dilute the mixture, and it was extracted with ethyl acetate (100 mL). The extract was then washed with saturated saline (100 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain intermediate 2 (1.9 g, yield: 90%). MS m / z (ESI): 437.1 [M+1].

[0781] Intermediate 3:

[0782]

[0783] In an ice bath, lithium aluminum hydroxide (200 mg) was slowly added to a solution of ethanol and tetrahydrofuran (20 mL / 20 mL) containing intermediate 2 (1.9 g), and the reaction mixture was stirred at the above temperature for 1 hour. After the reaction was complete, a saturated aqueous Na2SO4 solution (1 mL) was added to quench the reaction mixture, the reaction mixture was filtered, the filtrate was concentrated directly, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain intermediate 3 (1.5 g, yield: 73%). MS m / z (ESI): 395.1 [M+1].

[0784] Intermediate 4:

[0785]

[0786] In an ice bath, diisopropyl azodicarboxylate (0.92 g) was slowly added to a tetrahydrofuran (30 mL) solution of intermediate 3 (1.5 g) and triphenylphosphine (1.99 g), and the reaction mixture was naturally heated to room temperature and stirred at that temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted by adding water (100 mL), extracted with ethyl acetate (50 mL), the extract phase washed with saturated saline (100 mL), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated, and the residue purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 4 (1.5 g, yield: 89%). MS m / z (ESI): 376.9 [M+1].

[0787] Intermediate 5:

[0788]

[0789] At room temperature, water (20 mL) and barium hydroxide octahydrate (6.3 g) were sequentially added to an isopropanol (20 mL) solution of intermediate 4 (1.5 g), then the reaction mixture was heated to 100°C and stirred at said temperature for 16 hours. After the reaction was complete, the reaction solution was diluted by adding water (50 mL), the pH was adjusted to about 3 with dilute hydrochloric acid, extracted with ethyl acetate (100 mL), the extract phase was washed with saturated saline (20 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain intermediate 5 (1.5 g, yield: 85%). MS m / z (ESI): 396.0 [M+1].

[0790] Intermediate 6:

[0791]

[0792] At room temperature, potassium carbonate (500 mg) and iodomethane (500 mg) were sequentially added to an acetonitrile (20 mL) solution of intermediate 5 (500 mg), the reaction mixture was heated to 65°C and stirred at said temperature for 16 hours. After the reaction was complete, water (100 mL) was added to dilute the mixture, and it was extracted with ethyl acetate (100 mL). The extract was washed with saturated saline (200 mL), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain intermediate 6 (400 mg, yield: 77%). MS m / z (ESI): 410.1 [M+1].

[0793] Intermediate 7:

[0794]

[0795] At room temperature and under nitrogen protection, palladium hydroxide / carbon (10%, 50 mg) was slowly added to a 10 mL solution of tetrahydrofuran containing intermediate 6 (200 mg), and the reaction mixture was stirred for 16 hours at room temperature under a hydrogen atmosphere of 2 atm. After the reaction was complete, the reaction mixture was filtered, and the filtrate was directly concentrated to obtain intermediate 7 (150 mg, yield: 84%). MS m / z (ESI): 276.1 [M+1].

[0796] Intermediate 8:

[0797]

[0798] At room temperature, glacial acetic acid (50 mg) and silatrain (200 mg) were added to a tetrahydrofuran (5 mL) solution of intermediate 7 (150 mg) and intermediate 2 (150 mg) of Example 2, and then the reaction mixture was heated to 75°C and stirred at said temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated directly, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain intermediate 8 (150 mg, yield: 71%). MS m / z (ESI): 549.2 [M+1].

[0799] Target compound:

[0800]

[0801] At room temperature, sodium hydroxide (40 mg) was added to a methanol and water (3 mL / 3 mL) mixed solution of intermediate 8 (150 mg), and the reaction mixture was heated to 75°C and stirred at said temperature for 3 hours. After the reaction was complete, the reaction mixture was concentrated, and the residue was purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18, 150×21.2 mm, 5 μm; column temperature: 25°C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar; mobile phase: acetonitrile-water (0.05% NH3); gradient: 10-40%) to obtain the target compound (58.0 mg, yield: 48%). MS m / z (ESI): 435.1 [M+1]. 1 H NMR (400 MHz, CD3OD) δ 8.13 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 3.2 Hz, 1H), 6.74 (s, 1H), 6.30 (s, 1H), 4.45- 3.98 (m, 3H), 3.83 (m, 2H), 3.74(s, 3H), 3.52 - 3.12 (m, 2H), 2.50(s, 3H), 2.32 - 1.72(m,8H).

[0802] Example 32

[0803] Intermediate 1:

[0804]

[0805] At room temperature, toluenesulfonic acid (35 mg) was added to a toluene (10 mL) solution of intermediate 2 (800 mg) of Example 31, heated to 110°C, and reacted at said temperature for 18 hours. After the reaction was complete, it was cooled naturally to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 1 (550 mg, yield: 73.0%). MS m / z (ESI): 391.2 [M+1].

[0806] Intermediate 2:

[0807]

[0808] In an ice bath, a tetrahydrofuran solution of methyl magnesium chloride (3 M, 1.4 mL) was slowly added dropwise to a tetrahydrofuran solution (10 mL) of intermediate 1 (550 mg), the reaction mixture was allowed to rise naturally, and the mixture was stirred at the above temperature for 18 hours. After the reaction was complete, water (10 mL) was added to the reaction system for quenching, and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phase was washed with saturated saline (10 mL), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 2 (150 mg, yield: 25.0%). MS m / z (ESI): 404.8 [M+1].

[0809] Intermediate 3:

[0810]

[0811] At room temperature, barium hydroxide octahydrate (584 mg) was added to a mixed solution of isopropanol and water (3 mL / 6 mL) containing intermediate 2 (150 mg), the reaction mixture was heated to 100°C and stirred at said temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted by adding water (10 mL), the pH was adjusted to about 5 with dilute hydrochloric acid (1 M), the resulting mixture was extracted with ethyl acetate (20 mL × 2), the combined extract was washed with saturated saline (20 mL), dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloroethane:methanol=10:1) to obtain intermediate 3 (50 mg, yield: 30.3%). MS m / z (ESI): 423.8 [M+1].

[0812] Intermediate 4:

[0813]

[0814] At room temperature, iodomethane (54 mg) was added to an acetone (5 mL) solution of intermediate 3 (50 mg) and potassium carbonate (52 mg), and reacted at room temperature for 18 hours. After the reaction was complete, water (5 mL) was added to dilute the mixture, and it was extracted with ethyl acetate (10 mL × 2). The combined extract was washed with saturated saline (10 mL), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain intermediate 4 (50 mg, yield: 91.77%). MS m / z (ESI): 438.2 [M+1].

[0815] Intermediate 5:

[0816]

[0817] Palladium hydroxide / carbon (3 mg) was added to a methanol (5 mL) solution of intermediate 4 (30 mg) at room temperature and under nitrogen protection, and the reaction system was stirred for 18 hours at room temperature and under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated directly under reduced pressure to obtain intermediate 5 (20 mg, purity: 85%, yield: 81.6%).

[0818] Intermediate 6:

[0819]

[0820] At room temperature, intermediate 5 (20 mg) was added to a 1,2-dichloroethane (2 mL) solution of intermediate 2 (23 mg) from Example 2, and the reaction mixture was stirred at room temperature for 8 hours; sodium triacetoxyborohydride (42 mg) was added, and the reaction mixture was continuously stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted by adding dichloromethane (10 mL), washed with water (10 mL), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 10:1) to obtain intermediate 6 (20 mg, yield: 49.9%). MS m / z (ESI): 577.1 [M+1].

[0821] Target compound:

[0822]

[0823] At room temperature, sodium hydroxide (33.8 mg) was added to a mixed solution of tetrahydrofuran / methanol / water (0.5 mL / 0.5 mL / 0.5 mL) of intermediate 6 (20 mg, 0.08 mmol), then the reaction mixture was heated to 65°C and stirred at the above temperature for 18 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash preparative chromatography (chromatography column: Gemini-C18, 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); column temperature: 25°C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar, gradient: 15-40%) to obtain the target compound (10.1 mg, yield: 59.8%). MS m / z (ESI): 463.1[M+1]. 1 H NMR (400 MHz, MeOD) δ 8.14 (d, J = 8.0 Hz, 2H), 7.64 (d, J= 8.0 Hz, 2H), 7.32 - 7.26 (m, 1H), 6.76 - 6.67 (m, 1H), 6.32 - 6.25 (m, 1H), 4.50 (d, J = 12.0 Hz, 1H), 4.27 (d, J = 12.0 Hz, 1H), 4.13 - 4.03 (m, 1H), 3.72 (s, 3H), 3.52 - 3.42 (m, 1H), 3.35 - 3.30 (m, 1H), 2.47 (s, 3H), 2.35 - 2.15 (m, 3H), 2.10 - 1.96 (m, 2H), 1.95 - 1.88 (m, 2H), 1.86 - 1.77 (m, 1H), 1.21 (s, 3H), 1.19 (s,3H).

[0824] Example 33

[0825] Intermediate 1:

[0826]

[0827] At room temperature, compounds S-(-)-1,1'-vinafthyl-2,2'-bisdiphenylphosphine (cas: 76189-56-5) (404 mg) and rhodium bis(dicyclopentadiene)tetrafluoroborate (cas: 36620-11-8) (202 mg) were added to a 1,4-dioxane (7 mL) solution of 3-fluoro-4-methoxycarbonylphenylboronic acid (2568 mg), the reaction mixture was stirred for 8 hours under nitrogen protection and room temperature conditions, 4-oxo-3,4-dihydropyridine-1(2H)-benzyl carboxylate (cas: 185847-84-1) (2500 mg), triethylamine (1094 mg), and water (0.7 mL) were added sequentially, then the temperature of the reaction mixture was raised to 40°C under nitrogen protection and at said temperature Stirring was continued for 16 hours. After the reaction was complete, the reaction solution was concentrated directly, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain Intermediate 1 (3000 mg, purity: 30%, yield: 22%). MS m / z (ESI): 385.8 [M+1].

[0828] Intermediate 2:

[0829]

[0830] At room temperature, sodium borohydride (196 mg) was added in batches to a mixed solution of tetrahydrofuran and ethanol (15 mL / 15 mL) of intermediate 1 (3000 mg), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the temperature of the reaction mixture was lowered to below 0°C, and the reaction mixture was quenched by slowly adding a saturated aqueous ammonium chloride solution (5 mL). The mixture was diluted by adding water (50 mL) and extracted with ethyl acetate (20 mL). The extract was then washed with saturated saline solution (10 mL), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain intermediate 2 (1100 mg, purity: 40%, yield: 14%). MS m / z (ESI): 401.8 [M+1].

[0831] Intermediate 3:

[0832]

[0833] At room temperature, imidazole (242 mg) and tert-butyldiphenylchlorosilane (904 mg) were added to a dichloromethane (20 mL) solution of intermediate 2 (1100 mg), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted by adding water (20 mL), extracted with dichloromethane (50 mL), the extractant was dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain intermediate 3 (390 mg, yield: 20%). MS m / z (ESI): 661.6 [M+23].

[0834] Intermediate 4:

[0835]

[0836] At room temperature, intermediate 3 (390 mg) was added to a tetrabutylammonium fluoride solution (1.0 M, 3 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (20 mL) was added to dilute the mixture, and it was extracted with ethyl acetate (10 mL). The extract was washed once with saturated saline (20 mL), dried with anhydrous sodium sulfate, filtered, the filtrate concentrated, and the residue purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain intermediate 4 (180 mg, yield: 66%). MS m / z (ESI): 423.8 [M+23].

[0837] Intermediate 5:

[0838]

[0839] At room temperature, imidazole (61 mg) and tert-butyldimethylsilyl chloride (74 mg) were added to a DMF (3 mL) solution of intermediate 4 (180 mg), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted by adding water (20 mL), extracted with ethyl acetate (10 mL), the extract phase was washed with saturated saline (20 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain intermediate 5 (200 mg, yield: 78%). MS m / z (ESI): 537.8 [M+23].

[0840] Intermediate 6:

[0841]

[0842] Under -78°C and nitrogen protection, cyclopropane-carboxaldehyde (147 mg) and trimethylsilyl trifluoromethanesulfonate (168 mg) were sequentially added to a 13 mL solution of dichloromethane containing intermediate 5 (685 mg), the reaction mixture was stirred at -78°C for 1 hour, triethylsilane (308 mg) was added, the reaction mixture was naturally heated to room temperature, and stirring continued at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain intermediate 6 (500 mg, yield: 74%). MS m / z (ESI): 477.7 [M+23].

[0843] Intermediate 7:

[0844]

[0845] At room temperature and under nitrogen protection, palladium / carbon (50 mg) was added to a 5 mL solution of tetrahydrofuran containing intermediate 6 (500 mg, 1.10 mmol), and the reaction mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was filtered, and the filtrate was directly concentrated to obtain intermediate 7 (330 mg, yield: 84%). MS m / z (ESI): 322.0 [M+1].

[0846] Intermediate 8:

[0847]

[0848] At room temperature, intermediate 7 (180 mg) was added to a 1,2-dichloroethane (5 mL) solution of intermediate 2 (178 mg) from Example 2, and the reaction mixture was stirred at room temperature for 8 hours; then sodium triacetoxyborohydride (356 mg) was added, and the reaction mixture was continuously stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated directly, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain intermediate 8 (350 mg, yield: 84%). MS m / z (ESI): 594.8 [M+1].

[0849] Target compound:

[0850]

[0851] At room temperature, sodium hydroxide (470 mg) was added to a methanol / water (5 mL / 5 mL) mixed solution of compound 9 (350 mg), the reaction mixture was heated to 80°C and stirred at the above temperature for 16 hours. After the reaction was completed, dilute hydrochloric acid (2 M) was added to the reaction mixture in an ice bath to adjust the pH to about 7, the solvent was freeze-dried directly, and the residue was purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18, 150×21.2 mm, 5 μm; column temperature: 25°C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-40%) to obtain the target compound (91.7 mg, yield: 32%, containing 0.6 equivalents of formic acid). 1 H NMR (400 MHz, CD3OD) δ8.29 (s, 0.6H), 7.89 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 10.1 Hz, 2H), 7.33 (d, J= 3.0 Hz, 1H), 6.75 (s, 1H), 6.38 (s, 1H), 4.82 - 4.68 (m, 1H), 4.43 - 4.28 (m, 1H), 4.27 - 4.11 (m, 1H), 3.91 - 3.81 (m, 1H), 3.78 (s, 3H), 3.60 - 3.45 (m, 1H), 3.38 (d, J = 6.9 Hz, 3H), 2.50 (s, 3H), 2.31 - 2.14 (m, 2H), 2.10 - 1.89 (m, 2H), 1.20 - 1.05 (m, 1H), 0.65 - 0.51 (m, 2H), 0.32 - 0.21 (m, 2H). MS m / z (ESI): 467.1[M+1].

[0852] The following compounds were prepared according to the methods of Examples 3 to 33 above.

[0853]

[0854] MS m / z (ESI): 449.2 [M+1] MS m / z (ESI): 455.2 [M+1]

[0855]

[0856] MS m / z (ESI): 435.2 [M+1] MS m / z (ESI): 455.2 [M+1]

[0857]

[0858] MS m / z (ESI): 463.3 [M+1] MS m / z (ESI): 421.2 [M+1]

[0859]

[0860] MS m / z (ESI): 449.2 [M+1] MS m / z (ESI): 452.3 [M+1]

[0861]

[0862] MS m / z (ESI): 425.2 [M+1] MS m / z (ESI): 439.2 [M+1]

[0863]

[0864] MS m / z (ESI): 449.2 [M+1] MS m / z (ESI): 449.2 [M+1]

[0865]

[0866] MS m / z (ESI): 449.2 [M+1] MS m / z (ESI): 449.2 [M+1]

[0867]

[0868] MS m / z (ESI): 463.3 [M+1] MS m / z (ESI): 465.2 [M+1]

[0869]

[0870] MS m / z (ESI): 477.3 [M+1] MS m / z (ESI): 491.3 [M+1]

[0871]

[0872] MS m / z (ESI): 479.3 [M+1] MS m / z (ESI): 479.3 [M+1]

[0873]

[0874] MS m / z (ESI): 465.2 [M+1] MS m / z (ESI): 493.3 [M+1]

[0875]

[0876] MS m / z (ESI): 493.3 [M+1] MS m / z (ESI): 493.3 [M+1]

[0877]

[0878] MS m / z (ESI): 481.2 [M+1] MS m / z (ESI): 391.2 [M+1]

[0879]

[0880] MS m / z (ESI): 445.2 [M+1] MS m / z (ESI): 435.2 [M+1]

[0881]

[0882] MS m / z (ESI): 471.2 [M+1] MS m / z (ESI): 435.2 [M+1]

[0883]

[0884] MS m / z (ESI): 463.3 [M+1] MS m / z (ESI): 435.2 [M+1]

[0885]

[0886] MS m / z (ESI): 467.2 [M+1] MS m / z (ESI): 477.3 [M+1]

[0887]

[0888] MS m / z (ESI): 449.2 [M+1] MS m / z (ESI): 463.3 [M+1]

[0889]

[0890] MS m / z (ESI): 421.2 [M+1] MS m / z (ESI): 435.2 [M+1]

[0891]

[0892] MS m / z (ESI): 467.2 [M+1] MS m / z (ESI): 427.2 [M+1]

[0893]

[0894] MS m / z (ESI): 405.2 [M+1] MS m / z (ESI): 435.2 [M+1]

[0895]

[0896] MS m / z (ESI): 433.2 [M+1] MS m / z (ESI): 421.2 [M+1]

[0897]

[0898] MS m / z (ESI): 435.2 [M+1] MS m / z (ESI): 451.2 [M+1]

[0899]

[0900] MS m / z (ESI): 483.2 [M+1] MS m / z (ESI): 419.2 [M+1]

[0901]

[0902] MS m / z (ESI): 451.2 [M+1] MS m / z (ESI): 461.2 [M+1]

[0903]

[0904] MS m / z (ESI): 449.2 [M+1] MS m / z (ESI): 447.2 [M+1]

[0905]

[0906] MS m / z (ESI): 445.2 [M+1] MS m / z (ESI): 459.3 [M+1]

[0907]

[0908] MS m / z (ESI): 509.2 [M+1] MS m / z (ESI): 475.3 [M+1]

[0909]

[0910] MS m / z (ESI): 477.2 [M+1] MS m / z (ESI): 499.3 [M+1]

[0911]

[0912] MS m / z (ESI): 500.3 [M+1] MS m / z (ESI): 477.2 [M+1]

[0913]

[0914] MS m / z (ESI): 489.2 [M+1] MS m / z (ESI): 466.2 [M+1]

[0915]

[0916] MS m / z (ESI): 500.3 [M+1] MS m / z (ESI): 503.3 [M+1]

[0917]

[0918] MS m / z (ESI): 489.3 [M+1] MS m / z (ESI): 466.2 [M+1]

[0919]

[0920] MS m / z (ESI): 449.2 [M+1] MS m / z (ESI): 451.2 [M+1]

[0921]

[0922] MS m / z (ESI): 491.3 [M+1] MS m / z (ESI): 424.2 [M+1]

[0923]

[0924] MS m / z (ESI): 438.2 [M+1] MS m / z (ESI): 452.3 [M+1]

[0925]

[0926] MS m / z (ESI): 426.2 [M+1] MS m / z (ESI): 421.2 [M+1]

[0927]

[0928] MS m / z (ESI): 449.2 [M+1]

[0929] Preparation of the control compound (Example-26c, WO2015009616A1):

[0930] கார்க்கு முக்குசை 1:

[0931]

[0932] Tetrahydrofuran (3 mL), intermediate 7 of Example 1 (127 mg), intermediate 2 of Example 2 (130 mg), and tetraethyl titanate (56 mg) were added to a 50 mL sealed tube. Under nitrogen protection, the reaction mixture was heated to 70°C and reacted with stirring for 16 hours. After cooling the reaction mixture to room temperature, sodium triacetoxyborohydride (52 mg) was added, and the temperature was raised to 70°C and reacted for 1 hour. The reaction mixture was cooled to room temperature, and 4 mL of methanol was added to quench the reaction. The reaction mixture was concentrated, and the residue was separated and purified by column chromatography (methanol:dichloromethane = 1:10) to obtain control intermediate 1 (170 mg, yield: 52%).

[0933] Control compound:

[0934]

[0935] Methanol (3 mL), water (1 mL), intermediate 1 (160 mg), and sodium hydroxide (230 mg) were added to a 50 mL single-neck flask. The reaction was carried out at room temperature for 16 hours. After the reaction was complete, water (10 mL) was added for dilution, the pH was adjusted to 7–8 with a dilute hydrochloric acid solution (1 M), the solvent (water bath: 45 °C) was removed under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (chromatography column: Gemini-C18, 150 x 21.2 mm, 5 µm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 15–30%) to obtain the target compound (29 mg, yield: 24%). MS m / z (ESI): 423.1 [M+1]. 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 8.17 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.33 (t, J= 2.8 Hz, 1H), 6.78 (s, 1H), 6.35 (s, 1H), 4.82 - 4.67 (m, 1H), 4.40 - 4.17 (m, 2H), 3.90 - 3.81 (m, 1H), 3.77 (s, 3H), 3.62 (q, J = 6.8 Hz, 2H), 3.57 - 3.50 (m, 1H), 3.45 - 3.35 (m, 1H), 2.52 (s, 3H), 2.32 - 2.22 (m, 2H), 2.14 - 1.96 (m, 2H), 1.32 (t, J = 6.8 Hz, 3H).

[0936] Biological Examples

[0937] 1. Detection of Optical Surface Plasmon Resonance (SPR) Coupling Forces

[0938] SPR experiments were performed at 25°C using PBS buffer supplemented with 0.05% (v / v) P20 and 5% DMSO as the run buffer, and the analyzer used was a GE Healthcare Biacore 8K. The CM7 chip (GE Healthcare) was activated with 400 mM EDC and 100 mM NHS at a flow rate of 30 μL / min for 420 s. Complement B factor was diluted to 50 μg / mL with 10 mM sodium acetate (pH 4.0) and then coupled at a flow rate of 10 μL / min for 1200 s to co-immobilize the complement B factor on the detection chip (protein immobilization level 25000 RU); then, the detection chip was blocked with 1 M ethanolamine hydrochloride at a flow rate of 10 μL / min for 300 s. The concentration of the compound to be tested is 500 μM, the binding time is 120 s, and the dissociation time is 300 s. Data analysis was performed using a 1:1 binding model (Biacore Insight Evaluation Software, Version 2.0.15.12933).

[0939] Experimental Results:

[0940] The experimental results of the compounds of some examples are shown in Table 1. At a concentration of 500 μM, Examples 5 and 6 show more pronounced binding ability to the target protein and are significantly superior to the control compound, which indicates that the compounds of the present invention have excellent binding ability to the target protein.

[0941] Example number Rmax(RU) Example 4 29.1 Example 5 274.2 Example 6 106.5 Example 7 21.6 Example 8 47.7 Example 9 23.3 Example 10 30.7 Example 11 ND control compound 33.7

[0942] Note: ND means that SPR bonding force data was not detected.

[0943] 2. Detection of TR-FRET binding force

[0944] The inhibitory activity of the compounds against human complement factor B was screened by competitive binding experiments using Cy5 fluorescently labeled small molecule inhibitors as probes. Complement factor B and EZ-Link TM Sulfo-NHS-LC-LC-Biotin was incubated on ice at a 1:2 ratio for 1 hour, and then the reaction was terminated by adding 1 M Tris (pH 7.5). Then, 2 mL of Zeba TM Biotin-labeled complement factor B was obtained by purification twice using a desalt spin column (EZ-Link TM (Sulfo-NHS-LC-Biotin guidelines). For the experiment, biotin-labeled complement factor B at a final concentration of 10 nM and compounds of different concentrations were pre-incubated in buffer at room temperature for 1 hour. The reaction was initiated by adding Cy5 fluorescently labeled probe and europium chelate-labeled streptavidin (petroleum ether, RKin Elmer, #AD0060) at final concentrations of 75 nM and 5 nM, respectively. Kinetic readings were performed using a microplate reader (337 nm excitation, 665 nm emission, 70 μs time-gated), and time-dependent fluorescence energy transfer (TR-FRET) data were read to determine IC₀. 50 Decided.

[0945] 3. Detection of C3 activity in complement system hydrolysis

[0946] The test concentration of the test compound starts at 10 μM, with a 3-fold dilution, 7 concentration points, and single-well detection. In a 96-well plate, the test compound was diluted with DMSO to a final concentration solution 1000-fold, and then the Diluent (WIESLAB ® The solution was diluted to a final concentration of 5 times using COMPLEMENT SYSTEM ALTERNATIVE PATHWAY AP330. 30 μL was transferred to a 96-well plate, 120 μL of reserve serum was added, and the mixture was incubated at room temperature for 15 minutes. 30 μL of 5‰ DMSO and 120 μL of reserve serum were added to the positive control wells, and 30 μL of 5‰ DMSO and 120 μL of diluent were added to the negative control wells. (3) 100 μL was taken and added to the reaction plate, and the mixture was incubated at 37°C for 60 minutes. The liquid in the wells was discarded, and each well was washed three times with 300 μL of wash solution. 100 μL of Conjugate (WIESLAB) was added to each well. ® COMPLEMENT SYSTEM ALTERNATIVE PATHWAY AP330 was added, and the plates were incubated at room temperature for 30 minutes. The liquid in the wells was discarded, and each well was washed three times with 300 μL of wash solution. Then, 100 μL of substrate was added to each well, and the plates were incubated at room temperature for 30 minutes. The plates were detected using a microplate reader (Perkin Elmer, EnSight), and the OD405 values ​​were read.

[0947] 4. Detection of complement hemolytic activity

[0948] For the hemolysis experiment, refer to the description in Xuan Yuan et al., Haematologica. (2017) 102:466-475, and prior to the experiment, the optimal concentration of normal human serum (NHS) required to achieve 100% lysis of rabbit red blood cells (RE) was obtained through titration testing. In the above experiment, NHS was diluted in GVB0 buffer containing 10 mM Mg-EGTA (0.1% gelatin, 5 mM Veronal, 145 mM NaCl, 0.025% NaN3, pH 7.3, Complement Technology) and incubated with test compounds of various concentration gradients at 37°C for 15 minutes. Freshly suspended RE (taken from healthy Japanese white rabbits) was added to GVB0 buffer containing 10 mM Mg-EGTA to 1 × 10⁶ 8 The final concentration of cells / ml was achieved, and the samples were incubated at 37°C for 30 minutes. The positive control (100% lysis) consisted of GVB0 buffer containing 10 mM Mg-EGTA with NHS and RE but without the test compound; the negative control (0% lysis) consisted of GVB0 buffer containing 10 mM Mg-EGTA with inactivated NHS (heated at 56°C for 30 minutes or at 65°C for 5 minutes) and RE but without the test compound. The samples were centrifuged at 2000 g for 5 minutes, and the supernatant was collected. Absorbance at 415 nm (A415) was detected using a microplate reader (Molecular Devices, SpectraMax i3X). IC 50 The value was calculated from the percentage of hemolysis as a function of the test compound concentration through nonlinear regression.

[0949] Experimental Results:

[0950] The experimental results of the compounds of some examples are shown in Table 2, where the inhibitory activity of Example 5 against complement B factor in human serum is significantly superior to that of the control compound, which indicates that the compounds of the present invention inhibit the activity of complement B factor in human serum better and can prevent hemolysis caused by attack on rabbit red blood cells.

[0951] Example number Hemolytic IC 50 (nM) Example 3 216.3 Example 4 280.0 Example 5 87.9 Example 6 217.3 Example 7 228.4 Example 8 358.2 Example 9 725.0 Example 10 610.6 Example 16 187.9 Example 17 391.0 Example 22 184.2 Example 23 852.5 Example 25 234.0 Example 26 319.2 Example 28 673.5 control compound 379.4

[0952] 5. Liver Microsome Stability Experiment (1) Preparation of Buffer Solution

[0953] A 0.1 M aqueous distilled solution of dipotassium hydrogen phosphate (containing 1 mM ethylenediaminetetraacetic acid) was taken, and then the pH was adjusted to 7.4 with a 0.1 M aqueous distilled solution of dipotassium hydrogen phosphate (containing 1 mM ethylenediaminetetraacetic acid).

[0954] (2) Preparation of microsome-derived and working solutions

[0955] Microsome origin:

[0956] Rat: SD Rat Liver Microsomes, Cat.No.:LM-DS-02 M, RILD Red Liver Disease Research (Shanghai) Co., Ltd.

[0957] Monkey: Cynomolgus Monkey Liver Microsomes, Cat.No.: LM-SXH-02 M, RILD Red Liver Disease R e search (Shanghai) Co., Ltd.

[0958] Human: Pooled Human Liver Microsomes (Mongolian), Cat.No.: LM-R-02 M, RILD Red Liver Disease R e search (Shanghai) Co., Ltd.

[0959] Preparation of working solution

[0960] The control compound and the test compound were each prepared as 10 mM solutions in DMSO, and 10 µL was taken and added to 190 µL of acetonitrile to prepare a 0.5 mM mother liquor. 1.5 µL of the 0.5 mM compound mother liquor was taken, and 18.75 µM of 20 mg / mL liver microsomes and 479.75 µL of buffer were added. (The actual preparation amount may be adjusted depending on the usage situation).

[0961] (3) Experimental process

[0962] 10 mg / mL of reduced coenzyme II (NADPH) was prepared as a buffer. A 96-well plate was placed on ice, and corresponding wells at different time points (0, 10, 30, 60, 90 min, Non-NADPH) were set for each compound, and 30 μL of working solution was added to each well. In the 0 min well, 155 μL of ice acetonitrile solution (internal standard concentration 1 μM) was first added and mixed thoroughly with a pipette gun, followed by the addition of 15 μL of NADPH (10 mg / mL). Before starting the reaction, the 96-well plate was pre-incubated in a constant temperature microplate shaker (37°C) for 5 minutes, and the metabolic reaction was initiated by adding 15 μL of NADPH (10 mg / mL) to each well. After performing the reaction for 10, 30, 60, and 90 minutes, 155 μL of ice acetonitrile solution (internal standard concentration 1 μM) was added to each corresponding well to terminate the reaction. After 90 minutes, 155 μL of ice acetonitrile solution (internal standard concentration 1 μM) was added to the Non-NADPH system to terminate the reaction. After the reaction was completed, the 96-well plate was shaken with a microplate shaker (600 rpm) for 10 minutes, centrifuged at 4°C and 4000 g for 15 minutes, 50 μL of the supernatant was taken and added to a new 2 mL 96-well plate, 300 μL of deionized water was added, and the sample was analyzed using an AB SCIEX ExionLC-Triple Quad 5500 high-performance liquid chromatography-mass spectrometer with Analyst 1.6.3 software. The test results are as shown in Table 3.

[0963] Example Compound Number MMS (Rat) MMS (Monkey) MMS (human) T 1 / 2 (min) Remaining(T=90min) T 1 / 2 (min) Remaining(T=90min) T 1 / 2 (min) Remaining(T=90min) Example 4 221.058 72.23% 364.082 80.68% 416.398 84.79% Example 5 547.65 89.14% 770.376 93.32% 672.513 91.04% Example 6 59.176 33.55% 130.27 60.37% 237.48 74.57%

[0964] Experimental results: According to the data, the compounds of Examples 4, 5, and 6 all have more pronounced liver microsome stability.

[0965] 6. PK experiment of single-tube administration in rats

[0966] Experimental Method:

[0967] 6–9 week old male Wistar Han rats (Shanghai Sippe-Bk Lab Animal Co., Ltd.) were used. They were fasted overnight, with 3 rats per group, and administered via gastric tube. Each rat was administered 3 mg / kg of the control compound, the compounds of Example 5, and Example 6, with an administration volume of 10 mL / kg. 0.2 mL of blood was collected via jugular vein at each time point, anticoagulated with EDTA-K2, and immediately centrifuged at 4000 rpm × 5 min at 4°C. The supernatant was collected, and the samples were frozen in a refrigerator at -80°C until detection. Blood collection times: before administration, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, and 24 h. The condition of the animals was monitored frequently after administration, and the animals were euthanized after blood collection was completed at all time points. Plasma samples are measured by LC-MS / MS, and kinetic parameters (Tmax, Cmax, T) are calculated using WinNonlin software. 1 / 2 , AUC) was performed.

[0968] Experimental Results:

[0969] The test results are as shown in Table 4.

[0970] group Tmax(hr) Cmax(ng / mL) T1 / 2(hr) AUC0-t(hr*ng / mL) AUCinf(hr*ng / mL) Example 5 Mean 0.25 1923.36 1.58 3120.14 3282.35 SD 0.00 602.66 0.21 721.79 692.86 Example 6 Mean 0.25 1184.20 2.28 2194.70 2257.24 SD 0.00 219.30 1.33 227.42 186.67 control compound Mean 0.33 783.97 2.42 2533.81 2726.42 SD 0.14 166.87 0.69 260.00 104.81

[0971] 7. PK / PD Experiment of Single-Tube Administration in Crab-eating Monkeys Experimental Methods:

[0972] Crab-eating monkeys were used, and three monkeys per group were administered a control compound and compounds 3 & 30 mpk of Example 5 via gastric tube. Blood samples were collected at different times for drug concentration analysis and complement activity detection. Plasma compound concentrations were measured by LC-MS / MS, and serum complement activity was detected using a wieslab assay kit (Svar Life Science AB, COMPL AP330 RUO), where Normal Human Serum (Complement Technology, NHS) was used.

[0973] Experimental Results:

[0974] Within the detected concentration and time range, the average blood drug concentration of the compound of Example 5 under the same dose was significantly higher than that of the control compound. The blood drug concentration curve of crab-eating monkeys is as shown in Fig. 1, and the inhibition of serum AP activity in crab-eating monkeys is as shown in Fig. 2. Fig. 2 indicates that the compound of the present invention can effectively inhibit serum AP activity in crab-eating monkeys.

[0975] 8. Streptococcus-induced rat rheumatoid arthritis (RA) model

[0976] Experimental Method:

[0977] The experiment was conducted on 6 to 9-week-old female Lewis rats (Beijing Vital R i (ver) was used, with 6 rats per group; D1 was intraperitoneally injected with a peptidoglycan complex of the cell wall of Streptococcus and various other bacteria (2–3 mg per rat), and the control compound (15 mpk) and Example 5 (15 mpk) were administered daily via gastric tube for 25 days, and arthritis scoring was performed on the rats at different intervals. The scoring criteria are as follows: Scoring was performed on a scale of 0 to 4 based on the varying degrees of lesions (redness and edema), with a maximum score of 4 points for each limb and a maximum total score of 16 points for the limbs of each animal. The scoring criteria are as follows: 0 points, no redness and edema; 1 point, redness and edema of 1–2 interphalangeal joints; 2 points, redness and edema of 3–4 interphalangeal joints; 3 points, redness and edema of 4 or more interphalangeal joints; 4 points, severe redness and swelling of the toes or fingers, ankle joint, or wrist joint.

[0978] Experimental Results:

[0979] The experimental results are as shown in Figure 3, and the data indicate that both the dezo compound and Example 5 can improve the arthritis score of the compound, and that the effect of the compound of Example 5 is significantly superior to that of the control compound, which demonstrates that the compounds of the present invention, particularly the compounds of the examples, can more effectively improve streptococcal-induced rat rheumatoid arthritis.

[0980] The exemplary embodiments of the present invention have been described above. It should be understood that the scope of protection of the present invention is not limited to the exemplary embodiments described above. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.

Claims

Claim 1 Compounds of the following formula (I) or their racemic mixtures, stereoisomers, tautomers, solvates, or pharmaceutically acceptable salts: In the above equation, R 1 C 1-6 Alkyl, C 3-8 Cycloalkyl and C 1-6 Selected from alkyloxy; R 2 is selected from H, halogen; R 3 is C 1-6 Alkyl and C 3-8 Selected from cycloalkyl; R 4 is H and C 1-6 Selected from alkyl; R 5 is selected from H and halogens; R 6 is selected from H and halogens; R 7 is hydrogen; Cy is R 8 , R 9 , R 10 and R 11 Selected from the following groups replaced with: and ; Here, the N atom of Cy is the Cy group and R 7 Bonded to the C atom shared by;R 8 It is non-substitutable or optionally one, two, or more of R j Selected from phenyl substituted with pyridinyl, pyrazinyl, furanyl, pyranyl, benzocyclohexyl, benzocyclopentyl, benzofuranyl, and benzotetrahydrofuranyl; R 9 H and C 1-6 Selected from alkyl; R 10 H, halogens, OH, CN, and unsubstituted or optionally one, two, or more R k C substituted by 1-6 Alkyl, C 3-8 Cycloalkyl and C 1-6 Selected from alkyloxy; R 11 H, halogens, and C 1-6 Selected from alkyls; each R j is different or identical and independently halogen, 5-membered heteroaryl and -C(O)OR 13 Selected from; each R k is different or identical and independently halogen, OH, CN, and unsubstituted or optionally one, two, or more R p C substituted with 1-6 Alkyl, C 3-8 Cycloalkyl, 3-6-membered heterocyclyl, C 1-6 Alkyloxy, C 3-6 Selected from cycloalkyloxy, 3-6-membered heterocyclyloxy, and NH2; each R p is different or identical, and independently halogen and C 1-6 Selected from alkyl; R 13 H, C 1-6 It is selected from alkyl and NH2. Claim 2 In paragraph 1, Cy is R 8 , R 9 , R 10 and R 11 Selected from the following groups replaced with: and ;R 8 , R 9 , R 10 and R 11 A compound or its racemic, stereoisomer, tautomeric, solvate, or pharmaceutically acceptable salt as defined in claim 1, independently. Claim 3 In paragraph 1, R 10 H, halogens, and unsubstituted or optionally one, two, or more R k C substituted by 1-6 Selected from alkyloxy; R 11 is H; each R k is different or identical, and independently halogen, C 3-8 A compound selected from cycloalkyl, 3-6-membered heterocyclyl, or its racemic, stereoisomer, tautomeric, solvate, or pharmaceutically acceptable salt. Claim 4 In paragraph 1, R 10 H and C 1-6 Selected from alkyloxy; R 11 A compound or its racemic, stereoisomer, tautomeric, solvate, or pharmaceutically acceptable salt that is H. Claim 5 In paragraph 1, R 1 C 1-6 Selected from alkyloxy; R 2 is H and R 3 is C 1-6 Selected from alkyl; R 4 is H and;R 5 is H and;R 6 is a compound or its racemic mixture, stereoisomer, tautomeric, solvate, or pharmaceutically acceptable salt that is H. Claim 6 In paragraph 1, R 8 is optionally 1, 2, or more R j It is a phenyl substituted with , and each R j A compound that is -C(O)OH, or its racemic mixture, stereoisomer, tautomeric, solvate, or pharmaceutically acceptable salt. Claim 7 In paragraph 1, R 1 C 1-6 It is an alkyloxy and;R 2 is H and R 3 is C 1-6 It is alkyl and;R 4 is H and;R 5 is H and;R 6 is H, and Cy is independently R 8 and R 10 Replaced by Igo;R 8 is R j It is a phenyl substituted with;R j is -C(O)OH and;R 10 C 1-6 Alkyloxyphosphates, compounds, or their racemic mixtures, stereoisomers, tautomeric mixtures, solvates, or pharmaceutically acceptable salts. Claim 8 In claim 1, the compound or its racemic mixture, stereoisomer, tautomeric mixture, solvate, or pharmaceutically acceptable salt is characterized in that the compound is selected from the following compounds: . Claim 9 In paragraph 8, the compound is a compound or its racemic mixture, stereoisomer, tautomeric, solvate, or pharmaceutically acceptable salt, wherein the compound is the following compound: . Claim 10 Compound of the following chemical formula (IV): IV In the above formula, PG is tert -Butyl, isopropyl, benzyl, tert -Selected from butoxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl (Fmoc), and trifluoroacetyl; R 1 , R 2 , R 3 , R 5 , R 6 , R 7 and Cy are independently as defined in Paragraph 1. Claim 11 A method for preparing a compound of any one of claims 1 to 9 or a racemic mixture, stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, wherein a compound of the following formula (IV) is reacted as a starting material with R 4 A step of producing a compound of chemical formula (I) in which is H; and optionally R 4 A compound of chemical formula (I) in which is H and R 4 -L 1 By reacting additionally, R 4 The method comprises the step of producing a compound of formula (I) according to any one of claims 1 to 9 other than H; wherein PG is tert -Butyl, isopropyl, benzyl, tert -Selected from butoxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl (Fmoc), and trifluoroacetyl; L 1 OH, F, Cl, Br, I, or halogenated C 1-6 A leaving group selected from alkyl and R 1 , R 2 , R 3 , R 5 , R 6 , R 7 and Cy are independently a manufacturing method as defined in claim 1. Claim 12 In claim 11, the above manufacturing method comprises the step of reacting a compound of the following formula (II) with a compound of the following formula (III) to produce a compound of the formula (IV); Here, PG, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 and Cy are independently a method of manufacturing as defined in Paragraph 11. Claim 13 In claim 12, the above manufacturing method is carried out in the presence of a reducing agent; wherein the reducing agent is used to reduce a carbon-nitrogen double bond and is selected from sodium borohydride, potassium borohydride, lithium borohydride, sodium borohydride acetate, sodium cyanoborohydride and lithium aluminum hydride. Claim 14 A pharmaceutical composition for preventing or treating a disease or disorder mediated by complement alternative pathway activation, comprising at least one of a compound according to any one of claims 1 to 9, a racemic mixture, stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof in a therapeutically effective amount; The disease or disorder mediated by the activation of the above complement alternative pathway is a pharmaceutical composition selected from paroxysmal nocturnal hemoglobinemia (PNH), primary glomerulonephritis (IgAN), membranous nephropathy (MN), C3 glomerulonephritis (C3G), age-related macular degeneration (AMD), geographic atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), diabetic retinopathy (DR), hemodialysis complications, hemolytic anemia, neuromyelitis optica (NMO), arthritis, rheumatoid arthritis, hepatitis, dermatomyositis, and amyotrophic lateral sclerosis, myasthenia gravis (MG), respiratory diseases, and cardiovascular diseases. Claim 15 A compound according to any one of claims 1 to 9, its racemic mixture, stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt, used to prevent or treat a disease or disorder selected from nocturnal hemoglobinemia (PNH), primary glomerulonephritis (IgA N), membranous nephropathy (MN), C3 glomerulonephritis (C3G), age-related macular degeneration (AMD), geographic atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), diabetic retinopathy (DR), hemodialysis complications, hemolytic anemia, neuromyelitis optica (NMO), arthritis, rheumatoid arthritis, hepatitis, dermatomyositis, and amyotrophic lateral sclerosis, myasthenia gravis (MG), respiratory disease, and cardiovascular disease; a compound, its racemic mixture, stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt.

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