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

Abstract

To provide a complement factor B inhibitor, and a pharmaceutical composition thereof, a preparation method therefor and use thereof.SOLUTION: Provided is a piperidine-containing heterocyclic compound represented by formula (I), a racemate thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

Detailed Description of the Invention

[0001] This application claims priority from a prior application filed by the applicant with the State Intellectual Property Office of China on August 7, 2020, bearing patent application number 202010790872.8 and entitled "Complement factor B inhibitors and pharmaceutical compositions, preparation methods and uses thereof," the entire text of which is incorporated herein by reference.

[0002] [Technical Field] The present invention relates to the pharmaceutical field, specifically to a complement factor B inhibitor and its pharmaceutical composition, preparation method and use.

[0003] [Background technology] Complement is a soluble pattern recognition molecule in the immune system that can perform multiple effector functions. Under natural conditions, complement components exist in the form of inactive zymogens, which are cleaved by multiple specific and nonspecific immunological mechanisms to form active large and small fragments. The large fragments typically remain on the surface of pathogens or cells, lysing or accelerating their clearance, while the small fragments detach from the cell surface and mediate multiple inflammatory responses. Complement activation consists of two closely linked processes, forming a cascade of complement activation reactions. Currently known complement activation pathways include the classical pathway, the lectin pathway, and the alternative pathway. Although the three complement activation pathways differ in their initiation mechanisms and activation sequences, they share a common terminal pathway. Activation of the alternative pathway is independent of antigen-antibody complexes. Normally, C3b deposited on cell surfaces binds to factor B, making it susceptible to degradation by factor D in serum. During this process, factor B is cleaved to Ba and Bb, after which C3b and Bb form a complex to form the C3 invertase C3bBb in the alternative pathway. In this process, complement factor B plays an early and central role in alternative pathway activation of the complement cascade. C3b is not only the product of C3 invertase's degradation of C3, but also a component of alternative pathway C3 invertase, forming a feedback loop that mutually influences the classical and alternative pathways. Current research has shown that multiple diseases, including hematological, autoimmune, inflammatory, and neurodegenerative, can lead to dysfunction of the complement system.

[0004] Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, persistently hemolytic disease. It is a non-malignant clonal disorder caused by acquired somatic PIG-A gene mutations in one or more hematopoietic stem cells. It is an ultra-rare blood disorder (Medicine (Baltimore) 1997, 76(2): 63-93). The disease course manifests as various degrees of worsening hemolysis (paroxysmal), chronic or recurrent acute intravascular hemolysis, or subsequent venous or arterial thrombosis, ultimately leading to progressive end-organ damage and death. While typical PNH manifests as chronic intravascular hemolysis, hemoglobinuria, and hemosiderinuria, most patients present with atypical disease, with insidious onset, a prolonged disease course, and variable disease severity.

[0005] There are over 10 types of proteins on the surface of red blood cells that inhibit the activation of the complement pathway. All of these proteins are anchored to the cell membrane by glycosylphosphatidylinositol (GPI) and are collectively known as GPI-anchored proteins (APs). The current mechanism of PNH pathogenesis is thought to be as follows: First, hematopoietic stem cells undergo mutation under certain conditions, producing PNH clones that are deficient in glycosylphosphatidylinositol (GPI); second, some factor (currently thought to be an immune factor) damages or weakens hematopoietic function, and the PNH clones gain a growth advantage over normal clones. The multiple GPI-linked antigens also complicate the understanding of the biological behavior of PNH cells. Among these, the C3 invertase decay-accelerating factor CD55, which inhibits complement pathway activation, and the membrane attack complex (MAC) inhibitor CD59 are closely related to PNH in terms of pathogenesis, clinical findings, diagnosis, and treatment (Frontiers in Immunology 2019, 10, 1157). CD59 prevents C9 from entering the C5b-8 complex, thereby preventing the formation of membrane attack units and inhibiting the complement terminal attack response. Currently, intravascular hemolysis and thrombosis, typical manifestations of PNH, are thought to be caused by CD59 deficiency. Patients with congenital CD59 deficiency have been reported to exhibit many of the typical symptoms of PNH, such as intravascular hemolysis, hemoglobinuria, and venous thrombosis. In patients with PNH, a defect in GPI synthesis prevents CD59 from binding to the red blood cell membrane, resulting in the loss of its ability to inhibit complement pathway activation. This leads to abnormal activation of the complement pathway and attacks on red blood cells, resulting in multiple clinical manifestations, including intravascular hemolysis, hemoglobinuria, and smooth muscle dysfunction. Currently, there is no effective treatment for PNH other than hematopoietic stem cell transplantation, which restores normal hematopoietic function. Because hematopoietic stem cell transplantation carries certain risks and PNH is a benign clonal disease, controlling hemolysis remains the primary clinical treatment strategy for this disease. Currently, only eculizumab is approved for the treatment of PNH.However, many patients still develop anemia despite treatment with eculizumab, and many still require continuous blood transfusions. Furthermore, eculizumab must be administered intravenously. Therefore, the development of novel complement pathway inhibitors for PNH is of great importance.

[0006] IgAN is the most common primary glomerular nephritis. It is characterized by IgA deposition in the mesangial region as demonstrated by immunofluorescence. Clinical findings vary, with recurrent episodes of microscopic or macroscopic hematuria being the most common. Existing evidence suggests that the development of IgAN is associated with congenital or acquired immune dysregulation. Airway or gastrointestinal irritation by viruses, bacteria, and food proteins can increase mucosal IgA1 synthesis or deposit IgA1-containing immune complexes in the mesangial region, leading to activation of the alternative complement pathway and glomerular damage. Human IgA molecules are divided into two isoforms, IgA1 and IgA2. IgA1 is the predominant form circulating in healthy individuals (accounting for approximately 85%) and is also the major component deposited in the mesangial region of glomeruli in IgAN patients. IgA molecules can exist in two forms: monomeric and polymeric. IgA1 molecules contain a special heavy chain hinge region between the first and second constant domains, which can serve as a binding domain for O-linked glycan groups. Recent studies have shown that the IgA molecules in the serum and mesangial regions of IgAN patients are primarily glycosylated IgA1 (gd-IgA1). It is currently believed that the onset of IgAN pathogenesis is the increase in abnormalities in gd-IgA1.

[0007] Over 90% of IgAN patients have complement C3 deposition in the mesangial region of the kidney. 75%-100% of IgAN patients have co-deposition of properdin, IgA, and C3 in renal tissue, and 30%-90% have co-deposition of complement factor H, IgA, and C3 in renal tissue. In addition to renal tissue deposition, several studies have also found that the levels of alternative pathway markers in the plasma of IgAN patients are associated with IgAN activity (J Nephrol 2013, 26(4): 708-715). Studies have also confirmed that renal and urinary C3a and C3a receptors in renal tissue are significantly associated with the activity and severity of renal injury (J Clin Immunol 2014, 34(2): 224-232). Another study confirmed that IgA can activate the alternative complement pathway under in vitro conditions. In this process, abnormalities in the IgA hinge region do not play a critical role, and the formation of IgA polymers is a crucial part (Eur J Immunol 1987, 17(3): 321-326). Currently, the deposition of complement C3 in the glomerular mesangial region has become one of the auxiliary diagnostic markers for IgAN. A study using C3c and C3d immunofluorescence detection in renal tissues of 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 endocapillary proliferation, and more severe hematuria, suggesting that glomerular C3c deposition is associated with active IgAN lesions (Am J Nephrol. 2000, 20(2): 122-128). Currently, there is no specific cure for IgAN, and the only treatments available are generic drugs such as renin-angiotensin inhibitors (ACEIs or ARBs), glucocorticoids, and various immunosuppressants. The safety of these drugs is also a significant issue. For example, while glucocorticoids have the effect of reducing proteinuria, the STOP-IgAN and TESTING-I trials have clearly identified potential side effects of glucocorticoids (IgA nephropathy 2019, 95, 4, 750-756).

[0008] Arthritis is a common chronic disease caused by inflammation, infection, degeneration, wounds, or other factors. Clinical manifestations include joint redness, swelling, heat, pain, functional impairment, and joint deformity, often resulting in severe pain, limited mobility, and disfigurement. In severe cases, it can cause permanent disability and affect patients' quality of life. Research has shown that K / BxN mouse serum cannot induce arthritis in mice lacking complement factor B, whereas wild-type mice can develop arthritis when challenged with K / BxN mouse serum (Immunity, 2002, 16, 157-168). This suggests that the complement system plays an important pathogenic role in the K / BxN mouse serum-induced arthritis model and that complement factor B is a potential target for treating arthritis.

[0009] Other diseases associated with the complement cascade further include membranous nephropathy (MN), C3-glomerulonephritis (C3G), age-related macular degeneration (AMD), geographic atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), hemodialysis complications, hemolytic anemia or hemodialysis, neuromyelitis (NMO), liver inflammation, inflammatory bowel disease, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), respiratory and cardiovascular diseases.

[0010] Currently, there are no small molecule complement factor B inhibitors available for clinical use. Among the currently known and researched projects, an oligonucleotide drug developed by IONIS Pharmaceuticals Inc. is a specific inhibitor of complement factor B (CFB) that treats, prevents, or alleviates diseases associated with disorders of the alternative complement 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 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).

[0011] Inflammation and immune-related diseases are characterized by their diversity and intractability. The only commercially available drug for PNH is eculizumab, but its high cost places a significant burden on patients. Many patients still experience anemia even after treatment with eculizumab, and many patients still require continuous blood transfusions. Furthermore, eculizumab must be administered intravenously. Meanwhile, for some diseases, such as IgAN, there is currently no specific therapeutic agent. These areas present unmet clinical needs, necessitating the development of new small molecule drugs for medical treatment.

[0012] Summary of the Invention In order to solve the above technical problems, the present invention provides a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, crystalline polymorph, pharmaceutically acceptable salt or prodrug compound thereof:

[0013] [ka]

[0014] Among them, R 1 is halogen, OH, CN, NO, unsubstituted or optionally one, two or more R a C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 selected from an aryloxy group, a 5- to 20-membered heteroaryloxy group, a 3- to 20-membered heterocyclyloxy group, and NH; R 2 is H, halogen, OH, CN, NO, unsubstituted or optionally one, two or more R b C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 selected from an aryloxy group, a 5- to 20-membered heteroaryloxy group, a 3- to 20-membered heterocyclyloxy group, and NH; R3 is halogen, OH, CN, NO, unsubstituted or optionally one, two or more R c C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 selected from an aryloxy group, a 5- to 20-membered heteroaryloxy group, a 3- to 20-membered heterocyclyloxy group, and NH; R 4 is H, unsubstituted or optionally one, two or more R d C replaced by 1-40 Alkyl group, C 3-40 Cycloalkyl groups, C 1-40 Alkyl-C(O)-, C 3-40 Cycloalkyl-C(O)-, C 1-40 Alkyl-S(O)2-, C 3-40 cycloalkyl-C(O)2-; R 5 is H, halogen, OH, CN, NO, unsubstituted or optionally one, two or more R e C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 Alkyloxy group, C2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 selected from an aryloxy group, a 5- to 20-membered heteroaryloxy group, a 3- to 20-membered heterocyclyloxy group, and NH; R 6 is H, halogen, OH, CN, NO, unsubstituted or optionally one, two or more R f C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 selected from an aryloxy group, a 5- to 20-membered heteroaryloxy group, a 3- to 20-membered heterocyclyloxy group, and NH; R 7 is hydrogen, OH, CN, unsubstituted or optionally one, two or more R g C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 selected from an aryloxy group, a 5- to 20-membered heteroaryloxy group, a 3- to 20-membered heterocyclyloxy group, and NH; Or, R 1 , R 7 are unsubstituted or optionally one, two or more R h The 5- to 20-membered ring structure is, for example, 5-20 Cycloalkenyl group, C 6-20 may be selected from an aryl group, a 5- to 20-membered heterocyclyl group, and a 5- to 20-membered heteroaryl group; Or, R 6 , R 7 are unsubstituted or optionally one, two or more R i The 5- to 20-membered ring structure is, for example, 5-20 Cycloalkenyl group, C 6-20 may be selected from an aryl group, a 5- to 20-membered heterocyclyl group, and a 5- to 20-membered heteroaryl group; Cy is independently R 8 , R 9 , R 10 , R 11 C substituted by 1, 2, 3, 4, 5, 6, 7, 8 or more substituents selected from 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 Aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, C 3-40 Cycloalkyl-C1-40 Alkyl-, C 3-40 Cycloalkenyl-C 1-40 Alkyl-, C 3-40 Cycloalkynyl-C 1-40 Alkyl-, C 6-20 Aryl-C 1-40 Alkyl-, 5-20 membered heteroaryl-C 1-40 Alkyl-, 3- to 20-membered heterocyclyl-C 1-40 Alkyl-, C 3-40 Cycloalkyl-C 1-40 Alkyl-, C 3-40 Cycloalkenyl-C 1-40 Alkyl-, C 3-40 Cycloalkynyl-C 1-40 Alkyl-, C 6-20 Aryl-C 1-40 Alkyl-, 5-20 membered heteroaryl-C 1-40 Alkyl-, 3- to 20-membered heterocyclyl-C 1-40 alkyl-, wherein the 3- to 20-membered heterocyclyl group in group Cy contains 1 to 5 heteroatoms selected from N, O and S, and at most one N atom; R 8 , R 9 are identical or different and independently represent H, unsubstituted or optionally one, two or more R j C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 Aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, C 3-40 Cycloalkyl-C 1-40 Alkyl-, C 3-40Cycloalkenyl-C 1-40 Alkyl-, C 3-40 Cycloalkynyl-C 1-40 Alkyl-, C 6-20 Aryl-C 1-40 Alkyl-, 5-20 membered heteroaryl-C 1-40 Alkyl-, 3- to 20-membered heterocyclyl-C 1-40 alkyl-, R 10 , R 11 are identical or different and independently represent H, absent, halogen, OH, CN, NO, unsubstituted or optionally one, two or more R k C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 selected from an aryloxy group, a 5- to 20-membered heteroaryloxy group, a 3- to 20-membered heterocyclyloxy group, and NH; Or, R 8 , R 9 are unsubstituted or optionally one, two or more R j The 5- to 20-membered ring structure is, for example, 3-20 Cycloalkyl groups, C 5-20 Cycloalkenyl group, C 6-20 may be selected from an aryl group, a 5- to 20-membered heterocyclyl group, and a 5- to 20-membered heteroaryl group; Or, R 10 , R 11are unsubstituted or optionally one, two or more R k The 5- to 20-membered ring structure is, for example, 3-20 Cycloalkyl groups, C 5-20 Cycloalkenyl group, C 6-20 may be selected from an aryl group, a 5- to 20-membered heterocyclyl group, and a 5- to 20-membered heteroaryl group; Each R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k are the same or different and independently represent H, halogen, OH, CN, NO, oxo (=O), thio (=S), unsubstituted or optionally one, two or more R p C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 Aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, C 1-40 Alkylthio group, C 2-40 Alkenylthio group, C 2-40 Alkynylthio group, C 3-40 Cycloalkylthio group, C 3-40 Cycloalkenylthio group, C 3-40Cycloalkynylthio group, C 6-20 Arylthio group, 5- to 20-membered heteroarylthio group, 3- to 20-membered heterocyclylthio group, 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 ),

[0015] [ka]

[0016] Selected from Each R p are the same or different and independently represent H, halogen, OH, CN, NO, oxo (=O), thio (=S), unsubstituted or optionally one, two or more R q C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 Aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, C 1-40 Alkylthio group, C 2-40 Alkenylthio group, C 2-40 Alkynylthio group, C3-40 Cycloalkylthio group, C 3-40 Cycloalkenylthio group, C 3-40 Cycloalkynylthio group, C 6-20 Arylthio group, 5- to 20-membered heteroarylthio group, 3- to 20-membered heterocyclylthio group, 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 ),

[0017] [ka]

[0018] Selected from Each R q are the same or different and independently represent H, halogen, OH, CN, NO2, oxo (=O), thio (=S), C 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 Aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, C 1-40 Alkylthio group, C 2-40 Alkenylthio group, C2-40 Alkynylthio group, C 3-40 Cycloalkylthio group, C 3-40 Cycloalkenylthio group, C 3-40 Cycloalkynylthio group, C 6-20 Arylthio group, 5- to 20-membered heteroarylthio group, 3- to 20-membered heterocyclylthio group, NH2, -C(O)C 1-40 Alkyl group, -C(O)NH2, -C(O)NHC 1-40 Alkyl group, -C(O)-NH-OH, -COOC 1-40 Alkyl groups, -COOH, -OC(O)C 1-40 Alkyl groups, -OC(O)H, -S(O)2C 1-40 Alkyl groups, S(O)2H, -S(O)2OC 1-40 Alkyl group, -OS(O)2C 1-40 Alkyl groups, -P(O)(OH)2, -B(OH)2,

[0019] [ka]

[0020] Selected from 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 212are homologous or different, and independently represent H, C 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 It is selected from an aryl group, a 5- to 20-membered heteroaryl group, a 3- to 20-membered heterocyclyl group, and NH2.

[0021] According to an embodiment of the present invention, R 1 is halogen, OH, CN, NO, unsubstituted or optionally one, two or more R a C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 1-6 Alkyloxy group, C 3-8 cycloalkyloxy group, NH2.

[0022] According to an embodiment of the present invention, R 2 is H, halogen, OH, CN, NO, unsubstituted or optionally one, two or more R b C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 1-6 Alkyloxy group, C 3-8 cycloalkyloxy group, NH2.

[0023] According to an embodiment of the present invention, R 3 is halogen, OH, CN, NO, unsubstituted or optionally one, two or more R c C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 1-6 Alkyloxy group, C 3-8 cycloalkyloxy group, NH2.

[0024] According to an embodiment of the present invention, R 4 is H, unsubstituted or optionally one, two or more Rd C replaced by 1-6 It is selected from alkyl groups.

[0025] According to an embodiment of the present invention, R 5 is H, halogen, OH, CN, NO, unsubstituted or optionally one, two or more R e C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 1-6 Alkyloxy group, C 3-8 cycloalkyloxy group, NH2.

[0026] According to an embodiment of the present invention, R 6 is H, halogen, OH, CN, NO, unsubstituted or optionally one, two or more R f C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 1-6 Alkyloxy group, C 3-8 cycloalkyloxy group, NH2.

[0027] R 7 is hydrogen, OH, CN, unsubstituted or optionally one, two or more R g C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 1-6 Alkyloxy group, C 3-8 cycloalkyloxy group, NH2.

[0028] According to an embodiment of the present invention, optionally, R 1 , R 7 are unsubstituted or optionally one, two or more R h C replaced by 5-10 Cycloalkenyl group, C 6-10 Aryl groups, 5- to 10-membered heterocyclyl groups, 5- to 10-membered heteroaryl groups, for example, C 5-6It may form a cycloalkenyl group, a C6 aryl group, a 5- to 6-membered heterocyclyl group, or a 5- to 6-membered heteroaryl group. Preferably, the 5- to 6-membered heterocyclyl group and the 5- to 6-membered heteroaryl group contain 1, 2, 3, 4, 5, or more heteroatoms selected from, for example, O, S, and N, of which N and S may optionally be unoxidized or oxidized to various oxidation states. Illustratively, R 1 , R 7 are unsubstituted or optionally one, two or more R fused together with the atom to which they are connected to the indole group in formula (I). h and the sulfur atom may be unoxidized or oxidized to -S(O)2-yl.

[0029] According to an embodiment of the present invention, optionally, R 6 , R 7 are unsubstituted or optionally one, two or more R i C replaced by 5-20 Cycloalkenyl group, C 6-20 Aryl groups, 5- to 20-membered heterocyclyl groups, 5- to 20-membered heteroaryl groups, for example, C 5-6 It may form a cycloalkenyl group, a C6 aryl group, a 5- to 6-membered heterocyclyl group, or a 5- to 6-membered heteroaryl group. Preferably, the 5- to 6-membered heterocyclyl group and the 5- to 6-membered heteroaryl group contain 1, 2, 3, 4, 5, or more heteroatoms selected from, for example, O, S, and N, of which N and S may optionally be unoxidized or oxidized to various oxidation states. Illustratively, R 6 , R 7 are unsubstituted or optionally one, two or more R fused together with the atom to which they are connected to the indole group in formula (I). hand the sulfur atom may be unoxidized or oxidized to -S(O)2-yl.

[0030] According to an embodiment of the present invention, Cy independently represents R 8 , R 9 , R 10 , R 11 C substituted by 1, 2, 3, 4, 5, 6, 7, 8 or more substituents selected from 3-40 Cycloalkyl groups, C 6-20 It may be selected from an aryl group, a 5- to 20-membered heteroaryl group, and a 3- to 20-membered heterocyclyl group, wherein the 3- to 20-membered heterocyclyl group in the group Cy contains 1 to 3 heteroatoms selected from N, O, and S, and at most contains only one N atom.

[0031] According to a preferred embodiment of the present invention, Cy is R 8 , R 9 , R 10 and R 11 For example, Cy may be selected from 3 to 20-membered heterocyclyl groups substituted by 1, 2, 3, 4, 5, 6, 7, or 8 substituents selected from R 8 , R 9 , R 10 and R 11 and optionally further independently substituted by R 8 , R 9 , R 10 , R 11 wherein the 3- to 20-membered heterocyclyl group in group Cy contains 1 or 2 heteroatoms selected from N, O and S, and contains at most one N atom.

[0032] According to exemplary embodiments of the present invention, Cy may be selected from the following saturated or unsaturated non-aromatic carbocyclic or heterocyclic ring systems: a 4-, 5-, 6-, or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring (e.g., fused, bridged, spirocyclic ring), or a 10-, 11-, 12-, 13-, 14-, or 15-membered tricyclic ring system, wherein the heterocyclic ring system contains 1 to 5 heteroatoms selected from O, S, and N, and contains at most one N atom, of which the N and S atoms, if present, are optionally unoxidized or oxidized to various oxidation states.

[0033] According to an exemplary embodiment of the present invention, Cy comprises one N atom and optionally one or two atoms selected from O or S, which may or may not be present. Preferably, when Cy is selected from a bicyclic ring system, the N atom and the O or S atom are in different ring structures in the bicycle.

[0034] According to an exemplary embodiment of the present invention, Cy comprises at most two heteroatoms, of which only one is selected from N atoms.

[0035] According to an exemplary embodiment of the present invention, Cy is a cyclyl group as follows: piperidinyl group, a piperidinyl group fused with a ring system selected from a cyclopropyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, and a phenyl group; aza and / or oxa spiro[2.4], [3.4], [4.4], [2.5], [3.5], [4.5] or [5.5]cyclyl groups; Aza and / or oxa bicyclic [2.2.1], [2.2.2], [3.2.1], [3.2.2] or [3.3.2]cyclyl groups may be selected from

[0036] According to a preferred embodiment of the present invention, the N atom in Cy is in a position corresponding to the Cy group of formula (I) and R 7 The groups may be bonded to a common C atom.

[0037] Illustratively, Cy may be a monocyclic, fused ring, or bridged ring group, such as piperidinyl group,

[0038] [ka]

[0039] It may be selected from the group:

[0040] According to an embodiment of the present invention, R 8 optionally one, two or more R j C replaced by 6-10 It may be selected from an aryl group, a 5- to 10-membered heteroaryl group, and a 3- to 20-membered heterocyclyl group, for example, a phenyl group, a pyridyl group, a pyrazinyl group, a furanyl group, a pyranyl group, a benzocyclohexane group, a benzocyclopentane group, a benzofuranyl group, and a benzotetrahydrofuranyl group.

[0041] According to an embodiment of the present invention, R 9 are identical or different and independently represent H, unsubstituted or optionally one, two or more R j C replaced by 1-6 It is selected from alkyl groups.

[0042] According to an embodiment of the present invention, optionally, R 8 , R 9 are unsubstituted or optionally one, two or more R j C replaced by 5-10 Cycloalkenyl group, C 6-10 An aryl group, a 5- to 10-membered heterocyclyl group, or a 5- to 10-membered heteroaryl group may be formed.

[0043] According to an embodiment of the present invention, R 10 , R 11 are the same or different and independently represent halogen, OH, CN, NO, unsubstituted or optionally one, two or more R k C replaced by1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 6-10 Aryl group, 5- to 6-membered heteroaryl group, 3- to 6-membered heterocyclyl group, C 1-6 Alkyloxy group, C 3-6 Cycloalkyloxy group, C 6-10 It may be selected from an aryloxy group, a 5- to 6-membered heteroaryloxy group, a 3- to 6-membered heterocyclyloxy group, and NH2.

[0044] According to an embodiment of the present invention, optionally, R 10 , R 11 are unsubstituted or optionally one, two or more R k C replaced by 5-10 Cycloalkenyl group, C 6-10 An aryl group, a 5- to 10-membered heterocyclyl group, or a 5- to 10-membered heteroaryl group may be formed.

[0045] According to an embodiment of the present invention, each R j are identical or different and are independently unsubstituted or optionally substituted with one, two or more R p C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, 3- to 10-membered heterocyclyl group, C 1-6 Alkyloxy group, C 3-8 Cycloalkyloxy group, C 6-10 Aryloxy group, 5- to 10-membered heteroaryloxy group, 3- to 10-membered heterocyclyloxy group, NH2, -C(O)R 12 , -C(O)OR 13 , -B(OR 18 )(OR 19 ), -P(O)(OR 20 )(OR 21 ),

[0046] [ka]

[0047] Selected from.

[0048] According to an embodiment of the present invention, each R k are the same or different and independently represent halogen, OH, CN, NO, unsubstituted or optionally one, two or more R p C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 6-10 Aryl group, 5- to 6-membered heteroaryl group, 3- to 6-membered heterocyclyl group, C 1-6 Alkyloxy group, C 3-6 Cycloalkyloxy group, C 6-10 It is selected from an aryloxy group, a 5- to 6-membered heteroaryloxy group, a 3- to 6-membered heterocyclyloxy group, and NH2.

[0049] According to an embodiment of the present invention, each R p are identical or different and independently represent H, halogen, OH, unsubstituted or optionally one, two or more R q C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 6-10 Aryl group, 5- to 6-membered heteroaryl group, 3- to 6-membered heterocyclyl group, C 1-6 Alkyloxy group, C 3-8 Cycloalkyloxy group, C 6-10 Aryloxy group, 5- to 6-membered heteroaryloxy group, 3- to 6-membered heterocyclyloxy group, NH2, -C(O)R 121 , -C(O)OR 131 , -B(OR 181 )(OR 191 ), -P(O)(OR 201 )(OR 211 ),

[0050] [ka]

[0051] Selected from.

[0052] According to an embodiment of the present invention, R q has the definition given above.

[0053] 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 are homologous or different, and independently represent H, C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 6-10 It is selected from an aryl group, a 5- to 6-membered heteroaryl group, a 3- to 6-membered heterocyclyl group, and NH2.

[0054] According to an embodiment of the present invention, the compound of formula (I) may have a structure of formula (I-1) or formula (I-2):

[0055] [ka]

[0056] wherein W is selected from CH, O or S; Y and Z are homologous or different and independently form CHR 11 , O or S; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and independently have the definitions in formula (I) above.

[0057] According to an embodiment of the present invention, where appropriate, a carbon-carbon single bond or a carbon-carbon double bond may be formed between W and Z or between Z and Y.

[0058] According to an embodiment of the present invention, when W is selected from O or S, R 10 does not exist.

[0059] According to an embodiment of the present invention, when W is selected from CH, R 10 is H, halogen, OH, CN, NO, unsubstituted or optionally one, two or more R k C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, and NH2, among which R k has the definition given above.

[0060] According to an embodiment of the present invention, the compound of formula (I) may have a structure of formula (I-3) or formula (I-4):

[0061] [ka]

[0062] Among them, W, Y, Z, and R 1 , R 2 , R 3, R 5 , R 6 , R 7 , R 9 , R 10 , R j are independently defined above, n is selected from 1, 2, 3, 4, and 5.

[0063] According to an embodiment of the present invention, n may be selected from 1, 2 or 3.

[0064] According to an embodiment of the present invention, each R j may be a substituent at the 2-, 3-, 4- or 5-position of the phenyl group.

[0065] According to an embodiment of the present invention, each R j are independently unsubstituted or optionally substituted with one, two or more R p C replaced by 1-6 Alkyl group, NH2, -C(O)R 12 , -C(O)OR 13 , -B(OR 18 )(OR 19 ), -P(O)(OR 20 )(OR 21 ),

[0066] [ka]

[0067] may be selected from

[0068] According to an embodiment of the present invention, R 10 is halogen, OH, CN, NO, unsubstituted or optionally one, two or more R k C replaced by 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl), C 3-8Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), 3- to 6-membered heterocyclyl groups (e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl), C 1-6 Alkyloxy group, C 3-6 It is selected from a cycloalkyloxy group, a 3- to 6-membered heterocyclyloxy group, and NH2.

[0069] According to an embodiment of the present invention, each R k are the same or different and independently represent halogen, OH, CN, NO, unsubstituted or optionally one, two or more R p C replaced by 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl), C 3-8 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), C 6-10 Aryl groups (e.g., phenyl groups), 5- to 6-membered heteroaryl groups (e.g., pyrrolyl groups, pyridyl groups, pyrazinyl groups, imidazolyl groups, triazolyl groups), 3- to 6-membered heterocyclyl groups (e.g., pyrrolidinyl groups, imidazolidinyl groups, piperidinyl groups, piperazinyl groups, oxetanyl groups, tetrahydrofuranyl groups, tetrahydropyranyl groups), C 1-6 Alkyloxy group, C 3-6 Cycloalkyloxy group, C 6-10 It is selected from an aryloxy group, a 5- to 6-membered heteroaryloxy group, and a 3- to 6-membered heterocyclyloxy group.

[0070] According to an embodiment of the present invention, each R p are identical or different and independently represent H, halogen (F, Cl, Br, or I), OH, unsubstituted or optionally one, two, or more R q C replaced by 1-6 Alkyl group, C3-8 Cycloalkyl groups, C 6-10 Aryl group, 5- to 6-membered heteroaryl group, 3- to 6-membered heterocyclyl group, C 1-6 Alkyloxy group, C 3-8 Cycloalkyloxy group, C 6-10 It is selected from an aryloxy group, a 5- to 6-membered heteroaryloxy group, a 3- to 6-membered heterocyclyloxy group, and NH2.

[0071] According to embodiments of the present invention, one, two, three or more H atoms in the above compounds and their substituents (e.g., methyl group, ethyl group) may be optionally replaced with their isotopes (e.g., D) to form groups such as CD3, C2D5.

[0072] According to an embodiment of the present invention, the compound of formula (I) may be selected from the following compounds:

[0073] [ka] TIFF2025186330000012.tif202169 TIFF2025186330000013.tif230169 TIFF2025186330000014.tif202169 TIFF2025186330000015.tif202169 TIFF2025186330000016.tif240169 TIFF2025186330000017.tif240169 TIFF2025186330000018.tif202169 TIFF2025186330000019.tif154169

[0074] The present invention further provides a compound of formula (IV):

[0075] [ka]

[0076] Among them, PG is a protecting group, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , Cy independently have the definitions given above.

[0077] The present invention further provides use of a compound represented by formula (IV) in the manufacture of a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotopically labeled form, solvate, crystalline polymorph, pharmaceutically acceptable salt or prodrug compound thereof.

[0078] The present invention relates to a method for preparing a compound of formula (I), which comprises reacting a compound of formula (IV) as a starting material to obtain a compound of formula (Ia), and then reacting R 4 to obtain a compound of formula (I) wherein is H:

[0079] [ka]

[0080] and, optionally, reacting the compound of formula (Ia) with R 4 -L 1 React with R 4 is a group other than H as defined above, Among them, PG, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , Cy independently have the definitions set forth above; L 1 OH, F, Cl, Br, I, Halo C 1-40 The method further provides a leaving group such as an alkyl group.

[0081] According to an embodiment of the present invention, PG may be selected from amino protecting groups, among which preferred PG is C 1-40 Alkyl group, C 6-20 Aryl C 1-40 Alkyl- may be selected from, for example, a tert-butyl group, an isopropyl group, a benzyl group, a tert-butoxycarbonyl group (Boc), a 2-biphenyl-2-propoxycarbonyl group, a benzyloxycarbonyl group, a fluorenylmethoxycarbonyl group (Fmoc), and a trifluoroacetyl group.

[0082] According to an embodiment of the present invention, the compound of formula (IV) is reacted under conditions for removing the protecting group PG to obtain the compound of formula (I). The conditions for removing the protecting group PG are reaction conditions known to those skilled in the art.

[0083] The present invention relates to a method for preparing a compound of formula (IV), which comprises reacting a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (IV),

[0084] [ka]

[0085] Among them, PG, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , Cy independently have the definitions set forth above.

[0086] According to an embodiment of the present invention, the production method may be carried out in the presence of a solvent such as an organic solvent. For example, the organic solvent may be 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, diisoamyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxane, or dichlorodiethyl ether, or ethylene oxide and / or propyl ether. The hydrocarbon may be at least one selected from ethers such as polyethers of olefin oxides; pentane, hexane, heptane, octane, nonane; and types that can be substituted with fluorine and chlorine atoms, for example, aliphatic, alicyclic, or aromatic hydrocarbons such as methylene chloride, dichloromethane, trichloromethane, carbon tetrachloride, fluorobenzene, chlorobenzene, or dichlorobenzene, cyclohexane, methylcyclohexane, petroleum ether, octane, benzene, toluene, chlorobenzene, bromobenzene, and xylene; and esters such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, and dimethyl carbonate, dibutyl carbonate, or vinyl carbonate.

[0087] According to an embodiment of the present invention, the preparation method may be carried out in the presence of a reducing agent for reducing the carbon-nitrogen double bond, and the reducing agent may be selected from sodium borohydride, potassium borohydride, lithium borohydride, sodium borohydride acetate, sodium cyanoborohydride, and lithium aluminum hydride.

[0088] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of a compound of formula (I), its racemate, stereoisomer, tautomer, isotopically labeled form, solvate, crystalline polymorph, pharmaceutically acceptable salt, or prodrug compound thereof.

[0089] According to an embodiment of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0090] According to embodiments of the present invention, the pharmaceutical composition may further comprise one or more additional therapeutic agents.

[0091] The present invention further provides a method for treating a disease associated with activation of the alternative complement pathway, comprising administering to a patient a prophylactically or therapeutically effective amount of at least one of a compound of formula (I), its racemate, stereoisomer, tautomer, isotopically labeled form, solvate, crystalline polymorph, pharmaceutically acceptable salt, or prodrug compound thereof.

[0092] Diseases associated with activation of the alternative complement 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 (NMO), arthritis, rheumatoid arthritis, liver inflammation, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), respiratory and cardiovascular diseases, etc.

[0093] In some embodiments, the patient is a human.

[0094] The present invention further provides at least one of a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, crystalline polymorph, pharmaceutically acceptable salt or prodrug compound thereof, or a pharmaceutical composition thereof, for use in a disease associated with activation of the alternative complement pathway.

[0095] The present invention further provides use of at least one of the compounds of formula (I), their racemates, stereoisomers, tautomers, isotopically labeled forms, solvates, crystalline polymorphs, pharmaceutically acceptable salts or prodrug compounds thereof in the manufacture of a medicament.

[0096] The drug may be used for diseases associated with activation of the alternative complement pathway.

[0097] When used as a drug, the compounds of the present invention may be administered in the form of pharmaceutical compositions. These compositions can be prepared according to methods well known in the pharmaceutical art and can be administered by various routes, depending on whether local or systemic treatment is required and the area to be treated. They may be administered topically (e.g., transdermally, via mucous membranes, including ophthalmic and nasal administration, vaginally and rectally), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer, intratracheally, intranasally), orally, or parenterally. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion, or intracranial, such as intrathecal or intraventricular, administration. Parenteral administration may be in the form of a single bolus or may be administered, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations administered topically may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional drug carriers, water, powder or oily bases, thickeners and the like may be necessary or required.

[0098] In preparing the compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted by the excipient, or placed within a carrier, such as a capsule, sachet, paper, or other container form. When used as a diluent, the excipient may be a solid, semi-solid, or liquid substance, and is used as a solvent, carrier, or vehicle for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, topical tablets, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (dissolved in a solid or liquid vehicle), ointments containing up to 10% by weight of the active compound, soft or hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, xanthan gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations may also include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl benzoate and hydroxypropyl benzoate, sweeteners, and flavoring agents. The compositions of the present invention may be formulated by methods known in the art so as to provide immediate, sustained, or delayed release of the active ingredient after administration to the patient.

[0099] The compositions may be prepared in unit dosage form, each dose containing about 5 to 1000 mg, more usually about 100 to 500 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as single doses for human patients and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, mixed with a suitable pharmaceutical excipient.

[0100] The effective dosage range of the active compound may be very large and is usually administered in a pharmaceutically effective amount, but it will be understood that the amount of the compound actually administered will usually be determined by a physician according to the relevant circumstances, including the disease being treated, the selected route of administration, the actual compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0101] Solid compositions such as tablets are prepared by mixing the primary active ingredient with pharmaceutical excipients to form a solid preformulation, which is a homogeneous mixture containing a compound of the present invention. These preformulations are referred to as homogeneous, meaning that the active ingredient is generally evenly distributed throughout the composition, allowing the composition to be readily divided into equally effective unit dosage forms, such as tablets, pills, and capsules. The solid preformulations are then divided into unit dosage forms containing about 0.1 to 1000 mg of the active ingredient of the present invention of the type described above.

[0102] The tablets or pills of the present invention can be coated or compounded to provide a dosage form that offers the advantage of prolonged action. For example, the tablet or pill may contain an inner dosage component and an outer dosage component, the latter being a coating of the former. The two components can be separated by an enteric layer, which serves to prevent disintegration in the stomach so that the inner component passes completely through the duodenum or is delayed in release. Several materials can be used for such enteric layers or coatings, including several polymeric acids and mixtures of polymeric acids with such materials, such as shellac, cetyl alcohol, and cellulose acetate.

[0103] Liquid forms for oral or injectable administration into which the compounds and compositions of the present invention may be incorporated include aqueous solutions, suitably flavored syrups, water or oil suspensions, emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, and pharmaceutical vehicles similar to elixirs.

[0104] Compositions for inhalation or blowing include solutions in pharmaceutically acceptable water or organic solvents or mixtures thereof, as well as suspensions and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered via the oral or nasal respiratory route to achieve local or systemic effects. The compositions can be atomized using an inert gas. The atomized solution can be inhaled directly from an atomizer, or the atomizer can be connected to a mask curtain or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally via a device that delivers the formulation in a suitable manner.

[0105] The amount of compound or composition administered to a patient will vary and will depend on factors such as the drug being administered, the purpose of administration (e.g., prophylaxis or treatment), the condition of the patient, the mode of administration, etc. In therapeutic applications, a patient suffering from a disease will be administered an amount of the composition sufficient to cure or at least partially suppress the symptoms of the disease and its complications. The effective dose should be determined by the condition of the disease being treated and the judgment of the attending clinician, which will depend on factors such as the severity of the disease, the age, weight, and general condition of the patient, etc.

[0106] The compositions administered to patients may be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques or by sterile filtration. Aqueous solution packages may be used as is, or may be lyophilized and the lyophilized formulation mixed with a sterile aqueous carrier 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 certain of the above-mentioned excipients, carriers, or stabilizers can result in the formation of drug salts.

[0107] The therapeutic dosage of a compound of the present invention can be determined, for example, by the specific application being treated, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present invention in a pharmaceutical composition may vary and will depend on a variety of factors, including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For parenteral administration, a compound of the present invention may be provided, for example, in an aqueous physiological buffer solution containing about 0.1 to 10% w / v of the compound. A typical dosage range is about 1 μg / kg to about 1 g / kg body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg body weight per day. Dosage will likely depend on variables such as the type and progression of the disease or condition, the general health of the particular patient, the relative biological potency of the selected compound, the excipient formulation, and its route of administration. Effective dosages can be obtained by extrapolation of dose-response curves derived from in vitro or animal model test systems.

[0108] [Beneficial Effects] The compounds provided by the present invention have good complement factor B regulating / inhibitory effects and can be used to treat diseases and disorders associated with activation of the alternative complement pathway, and to manufacture drugs for such diseases and disorders. Moreover, the compounds have good pharmacokinetics, liver microsome stability, etc.

[0109] BRIEF DESCRIPTION OF THE DRAWINGS <Figure 1> Experimental data (ng / mL) of the blood drug concentration curve in cynomolgus monkeys in a biological example.

[0110] <Figure 2> Experimental data (% relative to 0 h) of serum AP activity curves in cynomolgus monkeys in biological examples.

[0111] <Fig. 3> Experimental data on streptococcal-induced rheumatoid arthritis in rats in a biological example.

[0112] [Definition and explanation of terms] Unless otherwise specified, the definitions of groups and terms described in the specification and claims of this application include exemplary definitions, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, etc., and can be arbitrarily combined or combined with each other. It should be understood that the group definitions and compound structures after such combinations and combinations are within the scope described in the specification and / or claims of this application.

[0113] Unless otherwise specified, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, a numerical range of "1 to 40" is equivalent to describing the integer values ​​1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 in the numerical range "1 to 10," and the integer values ​​11, 12, 13, 14, 15, ..., 35, 36, 37, 38, 39, and 40 in the numerical range "11 to 40." Furthermore, when a numerical range is defined as a "number," it should be understood that the two endpoints of the range, each integer in the range, and each decimal point in the range are described. For example, "a number from 0 to 10" should be understood to include not only the integers 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also the sum of each of the integers and at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9.

[0114] As used herein, when referring to 1, 2 or more, it should be understood that "more" refers to an integer greater than 2, such as 3 or greater, for example, 3, 4, 5, 6, 7, 8, 9 or 10.

[0115] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0116] "C 1-40 The term "alkyl group" should be understood to denote a linear or branched saturated monovalent hydrocarbon group having from 1 to 40 carbon atoms. For example, "C 1-10 "Alkyl group" refers to straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms; 1-6The term "alkyl group" refers to straight-chain and branched-chain alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of the alkyl group include 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, and 1,2-dimethylbutyl, and isomers thereof.

[0117] "C 2-40 The term "alkenyl group" should be understood to denote a linear or branched monovalent hydrocarbon group, preferably containing one or more double bonds and having 2 to 40 carbon atoms, and "C 2-10 "Alkenyl group" is preferred. 2-10 An "alkenyl group" preferably contains one or more double bonds and has 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 alkenyl groups) and have 2 or 3 carbon atoms (i.e., C 2-3 It should be understood that the term "alkenyl group" refers to a linear or branched monovalent hydrocarbon group having an alkyl group (e.g., an alkenyl group). When the alkenyl group contains more than one double bond, it should be understood that the double bonds may be separate or conjugated. The alkenyl group may be, for example, a vinyl group, an allyl group, an (E)-2-methylvinyl group, a (Z)-2-methylvinyl group, an (E)-but-2-enyl group, a (Z)-but-2-enyl group, an (E)-but-1-enyl group, a (Z)-but-1-enyl group, a pent-4-enyl group, an ( E)-Pent-3-enyl group, (Z)-pent-3-enyl group, (E)-pent-2-enyl group, (Z)-pent-2-enyl group, (E)-pent-1-enyl group, (Z)-pent-1-enyl group, hex-5-enyl group, (E)-hex-4-enyl group, (Z)-hex-4-enyl group, (E)-hex-3-enyl group, (Z)-hex-3-enyl group, (E)-hex-2-enyl group, (Z)-hex-2-enyl group, (E)-hex-1-enyl group, (Z)-hex-1-enyl group, isopropenyl group, 2-methylprop-2-enyl group, 1-methylprop- 2-enyl group, 2-methylprop-1-enyl group, (E)-1-methylprop-1-enyl group, (Z)-1-methylprop-1-enyl group, 3-methylbut-3-enyl group, 2-methylbut-3-enyl group, 1-methylbut-3-enyl group, 3-methylbut-2-enyl group, (E)-2-methylbut-2-enyl group, (Z)-2-methylbut-2-enyl group, (E)-1-methylbut-2-enyl group, (Z)-1-methylbut-2-enyl group 1-ethylbut-2-enyl group, (E)-3-methylbut-1-enyl group, (Z)-3-methylbut-1-enyl group, (E)-2-methylbut-1-enyl group, (Z)-2-methylbut-1-enyl group, (E)-1-methylbut-1-enyl group, (Z)-1-methylbut-1-enyl group, 1,1-dimethylprop-2-enyl group, 1-ethylprop-1-enyl group, 1-propylvinyl group, and 1-isopropylvinyl group.

[0118] "C 2-40 The term "alkynyl group" should be understood to denote a linear or branched monovalent hydrocarbon group containing one or more triple bonds and having 2 to 40 carbon atoms, and "C 2-10 "Alkynyl group" is preferred. 2-10 The term "alkynyl group" preferably includes one or more triple bonds and has 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 alkynyl groups) and have 2 or 3 carbon atoms (i.e., C 2-3It should be understood that the term "alkynyl group" refers to a linear or branched monovalent hydrocarbon group having a substituted or unsubstituted alkyl group. Examples of the alkynyl group include an ethynyl group, a prop-1-ynyl group, a prop-2-ynyl group, a but-1-ynyl group, a but-2-ynyl group, a but-3-ynyl group, a pent-1-ynyl group, a pent-2-ynyl group, a pent-3-ynyl group, a pent-4-ynyl group, a hex-1-ynyl group, a hex-2-ynyl group, a hex-3-ynyl group, a hex-4-ynyl group, a hex-5-ynyl group, a 1-methylprop-2-ynyl group, a 2-methylbut-3-ynyl group, a 1-methylbut-3-ynyl group, a 1-methylbut-2-ynyl group, a 3-methylbut-1-ynyl group, a 1-ethylprop-2-ynyl group, a 3-methylpent-4-ynyl group, a 2-methylprop-2-ynyl group, a 2 ...3-ynyl group, a 1-methylbut-2-ynyl group, a 3-methylbut-4-ynyl group, a 2-methylbut-5-ynyl group, a 2-methylbut-5-ynyl group, a 2-methylbut-5-ynyl group, a 2-methylbut-5-ynyl group, a 2-methylbut-5-ynyl group, a 2-methylbut-5-ynyl group, a 2-methylbut-5-ynyl group, a 2-methylbut-5-ynyl group, a 2-methylbut-5-ynyl group, a 2-methylbut-5- and 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, 3,3-dimethylbut-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is an ethynyl group, a prop-1-ynyl group or a prop-2-ynyl group.

[0119] "C 3-40 The term "cycloalkyl group" should be understood to represent a saturated monovalent monocyclic, bicyclic (e.g., fused, bridged, spiro) hydrocarbon ring or tricyclic alkane having 3 to 40 carbon atoms, and "C 3-10 "Cycloalkyl group" is preferred. 3-10 The term "cycloalkyl group" should be understood to represent a saturated monovalent monocyclic, bicyclic (e.g., bridged, spirocyclic) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 3-10The cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl; a bicyclic hydrocarbon group such as borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, dicyclo[2.1.1]hexyl, dicyclo[2.2.1]heptyl, dicyclo[2.2.1]heptene, 6,6-dimethyldicyclo[3.1.1]heptyl, 2,6,6-trimethyldicyclo[3.1.1]heptyl, dicyclo[2.2.2]octyl, 2,7-diazaspiro[3.5]nonane, or 2,6-diazaspiro[3.4]octane; or a tricyclic hydrocarbon group such as adamantyl.

[0120] Unless otherwise defined, the term "3- to 20-membered heterocyclyl group" refers to a saturated or unsaturated non-aromatic ring or ring system, such as a 4-, 5-, 6-, or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring (e.g., fused, bridged, or spirocyclic ring), or a 10-, 11-, 12-, 13-, 14-, or 15-membered tricyclic ring system, containing at least one, e.g., 1, 2, 3, 4, 5, or more, heteroatoms selected from O, S, and N, wherein N and S may be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)-, or -S(O)2-. Preferably, the heterocyclyl group may be selected from "3- to 10-membered heterocyclyl groups." The term "3- to 10-membered heterocyclyl group" refers to a saturated or unsaturated non-aromatic ring or ring system containing at least one heteroatom selected from O, S, and N. The heterocyclyl group may be linked to the remainder of the molecule through any one of the carbon atoms or the nitrogen atom, if present. The heterocyclyl group may include fused or bridged rings and spirocyclic rings. In particular, the heterocyclyl group may include, but is not limited to, a 4-membered ring such as azetidinyl or oxetanyl, a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, or pyrrolinyl, a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, or a 7-membered ring such as diazepanyl. Optionally, the heterocyclyl group may be benzo-fused. The heterocyclyl group may be bicyclic, for example, but not limited to, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring.The heterocyclyl group may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, a dihydrofuranyl group, a dihydropyranyl group, a 2,5-dihydro-1H-pyrrolyl group, a 4H-[1,3,4]thiadiazinyl group, a 4,5-dihydrooxazolyl group, or a 4H-[1,4]thiazinyl group, or it may be benzo-fused, such as, but not limited to, a dihydroisoquinolyl group. When the above-mentioned 3- to 20-membered heterocyclyl group is bonded to another group to form a compound of the present invention, a carbon atom in the 3- to 20-membered heterocyclyl group may be bonded to the other group, or a heterocyclic atom in the ring of the 3- to 20-membered heterocyclyl group may be bonded to the other group. For example, when the 3- to 20-membered heterocyclyl group is selected from a piperazinyl group, a nitrogen atom in the piperazinyl group may be bonded to the other group. Alternatively, when the 3- to 20-membered heterocyclyl group is selected from a piperidinyl group, the nitrogen atom in the piperidinyl ring and the carbon atom at the para-position thereto may be bonded to another group.

[0121] "C 6-20 It should be understood that the term "aryl group" refers to a monovalent aromatic or partially aromatic monocyclic, bicyclic (e.g., fused, bridged, spiro) or tricyclic hydrocarbon ring, preferably having from 6 to 20 carbon atoms, and may be a monoaromatic ring or a fused polyaromatic ring; 6-14 The term "C aryl group" is preferred. 6-14 An "aryl group" is preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms ("C 6-14 aryl groups), in particular rings having 6 carbon atoms ("C6 aryl groups"), such as phenyl or biphenyl groups, or rings having 9 carbon atoms ("C9 aryl groups"), such as indanyl or indenyl groups, or rings having 10 carbon atoms ("C 10 aryl group), such as a tetrahydronaphthyl group, a dihydronaphthyl group, or a naphthyl group, or a ring having 13 carbon atoms ("C 13 aryl group), such as a fluorenyl group, or a ring having 14 carbon atoms ("C14 It should be understood that the above C represents an aryl group, for example, an anthryl group. 6-20 When an aryl group is substituted, it may be substituted singly or multiply, and the substitution site is not limited, and may be, for example, ortho-, para-, or meta-substituted.

[0122] The term "5- to 20-membered heteroaryl group" should be understood to include such monovalent monocyclic, bicyclic (e.g., fused, bridged, spiro) or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, such as a "5- to 14-membered heteroaryl group." The term "5- to 14-membered heteroaryl group" should be understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, in particular 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 furthermore, which in each case may be benzo-fused. The term "heteroaryl" also refers to a group in which a heteroaryl ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, wherein the connecting point or site is on the heteroaryl ring. Non-limiting examples of the term heteroaryl include, for example, pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furanyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, 1,2,4-thiadiazolyl group, pyridazinyl group, and 1-, 2-, 3-, 5-, 6-, 7- or 8-indazinyl group, 1-, 3-, 4-, 5-, 6- or 7-isoindolyl group, 2-, 3-, 4-, 5-, 6- or 7-indolyl group, 2-, 3-, 4-, 5-, 6- or 7-indazolyl group, 2-, 4-, 5-, 6-, 7- or 8-purine group, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinoazinyl group, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl group, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl group, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3-, 4-, 5-, or 6-naphthalidinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-carbazolylcarbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-, 2-, 3-, or 4- , 6-, 7-, 8-, 9- or 10-phenanthridinyl group, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl group, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-dinyl group, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthrolinyl group, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenazinyl group, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazinyl group, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl group, 2-, 3-, 4-, 5- , 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-benzoisoquinolyl, 2-, 3-, 4- or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6- or 7-2H-furo[3,2-b]pyranyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido[2,3-d]-o-azinyl, 1-, 3- or 5-1H-pyrazolo[4,3-d]thiazolyl, 2-, 4- or 5-1H-imidazo[4,5-d]thiazolyl group, 3-, 5- or 8-pyrazino[2,3-d]pyridazinyl group, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl group, 1-, 3-, 6-, 7-, 8- or 9-furo[3,4-c]cinnolinyl group, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10- or 11-4H-pyrido[2,3-c]carbazolyl group, 2-, 3-, 6- or 7-imidazo[1,2-b][1,2,4]triazinyl group, 7-benzo[b]thienyl group, 2-, 4-, 5-, 6- 1-, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-1H-pyrrolo[1,2-b][2]benzoazapinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl groups, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl groups, 2-, 3-, 4-, 5-, 6-, or 7-indolyl groups, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl groups, 2-, 4-, 5-, 6-, or 7-benzoxazolyl groups, 2-, 4-, 5-, 6-, or 7-benzimidazolyl groups, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl groups. When the above 5- to 20-membered heteroaryl groups are bonded to other groups to form the compounds of the present invention, a carbon atom in the ring of the 5- to 20-membered heteroaryl group may be bonded to the other group, or a heteroatom in the ring of the 5- to 20-membered heteroaryl group may be bonded to the other group. When the 5- to 20-membered heteroaryl group is substituted, it may be substituted singly or plurally. Moreover, the substitution site is not limited, and for example, a hydrogen atom bonded to a carbon atom in the ring of the heteroaryl group may be substituted, or a hydrogen atom bonded to a heteroatom in the ring of the heteroaryl group may be substituted.

[0123] The term "spirocycle" refers to a ring system in which two rings share one ring-forming atom.

[0124] The term "fused ring" refers to a ring system in which two rings share two ring-forming atoms.

[0125] The term "bridged ring" refers to a ring system in which two rings share three or more ring-forming atoms.

[0126] Unless otherwise specified, a heterocyclyl group, heteroaryl group, or heteroarylene group includes all possible isomeric forms thereof, for example, positional isomers thereof. Thus, some illustrative, non-limiting examples include those 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), including pyridin-2-yl, pyridylidene-2-yl, pyridin-3-yl, pyridylidene-3-yl, pyridin-4-yl and pyridylidene-4-yl, thienyl or thienylidenyl groups, including thien-2-yl, thien-3-yl, thienylidene-3-yl, and pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, and pyrazol-5-yl.

[0127] The term "oxo" refers to an oxy substituent (=O) formed by oxidation of a carbon, nitrogen, or sulfur atom in a substituent.

[0128] Unless otherwise stated, the definitions of terms herein apply equally to groups that contain the term, e.g., C 1-6 The definition of an alkyl group is C 1-6 Alkyloxy group, C 3-8 Cycloalkyl-C 1-6 This also applies to alkyl-, etc.

[0129] Those skilled in the art will recognize that the compounds of formula (I) can exist in a variety of pharmaceutically acceptable salt forms: if they contain a basic center, they can form acid addition salts; if they contain an acidic center, they can form base addition salts; and if they contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form inner salts.

[0130] The compounds of the present invention may exist in the form of solvates (e.g., hydrates), in which the compounds of the present invention contain polar solvents, in particular, for example, water, methanol, or ethanol, which are constituents of the crystalline lattice of said compounds. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0131] Depending on their molecular structure, the compounds of the present invention may be chiral and therefore may exist in various enantiomeric forms. Therefore, these compounds can exist in racemic or optically active forms. The compounds of the present invention encompass isomers in which each chiral carbon is in the R or S configuration, or mixtures thereof, i.e., racemates. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds or used in synthesis in this form by chemical or physical methods well known to those skilled in the art. In the case of racemic amines, non-enantiomers can be prepared from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline and N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic resolution of enantiomers can also be achieved well with optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized methacrylate polymers). Suitable eluents for this purpose are water or alcohol-containing solvent mixtures, e.g., hexane / isopropanol / acetonitrile.

[0132] The corresponding stable isomers can be separated by known methods, such as, for example, extraction, filtration or column chromatography.

[0133] The term "patient" refers to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse or primate, and most preferably a human.

[0134] The term "therapeutically effective amount" refers to an amount of an active compound or drug that elicits the biological or medical response sought by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, individual, or human, and includes one or more of the following: (1) disease prevention: e.g., preventing a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who is not experiencing or exhibiting the pathology or symptoms of the disease; (2) disease inhibition: e.g., inhibiting a disease, disorder, or condition (i.e., preventing further progression of the pathology and / or symptoms) in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, disorder, or condition; and (3) disease mitigation: e.g., alleviating a disease, disorder, or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, disorder, or condition.

[0135] [Mode for Carrying Out the Invention] The technical solutions of the present invention will be described in more detail below with reference to specific examples. The following examples are merely for illustrative purposes and should not be construed as limiting the scope of the claims of the present invention. Any technology realized based on the above content of the present invention is included within the scope of the claims of the present invention.

[0136] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0137] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts (δ) are 10 -6 The NMR data are expressed in ppm (ppm). A Bruker ASCEND (trademark)-400 nuclear magnetometer was used for the NMR measurements, and the solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0138] For MS measurements, Agilent 6110, Agilent 1100, Agilent 6120, and Agilent G6125B liquid chromatograph mass spectrometers were used.

[0139] For HPLC measurements, a Shimadzu HPLC-2010C high-performance liquid chromatograph (XBRIDGE 2.1*50 mm, 3.5 μm column) was used.

[0140] A THARSFC X5 was used for the chiral HPLC analysis.

[0141] The thin-layer chromatography silica gel plate used was Yantai Qingdao GF254 silica gel plate. The silica gel plate specifications for thin-layer chromatography (TLC) were 0.15 mm to 0.2 mm, and those for product separation and purification by thin-layer chromatography were 0.4 mm to 0.5 mm.

[0142] For column chromatography, Qingdao Marine Silica Gel 200-300 mesh silica gel was generally used as the carrier.

[0143] For high-speed liquid preparative separation, Waters 2767, Waters 2545, and Shinshin Hengtong LC3000 preparative chromatographs were used.

[0144] The pressurized hydrogenation reaction was carried out using a Beijing Jiawei Technology GCD-500G hydrogen generator.

[0145] For the microwave reaction, a Biotage initiator+ type microwave reactor was used.

[0146] Unless otherwise noted, all reactions were carried out under an argon or nitrogen atmosphere. By argon or nitrogen, we mean that the reaction flask was connected to a balloon of argon or nitrogen gas with a volume of about 1 liter. By hydrogen, we mean that the reaction flask was connected to a balloon of hydrogen gas with a volume of about 1 liter.

[0147] Unless otherwise specified, all reaction temperatures are room temperature, and the temperature range is 20 to 30°C.

[0148] [Example 1] Intermediate 1:

[0149] [ka]

[0150] In a 3 L three-neck flask, tetrahydrofuran (150 mL) and 4-bromobenzonitrile (50 g) were added sequentially. Under nitrogen gas protection, isopropyl magnesium chloride-lithium chloride complex (1.3 M, 210 mL) was slowly added to the reaction mixture, and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was then diluted with anhydrous tetrahydrofuran (500 mL), cooled to -5°C, and 4-methoxypyridine (25 mL) was added. Benzyl chloroformate (35 mL) was slowly added dropwise (maintaining the system temperature below 0°C). After the addition was complete, the mixture was allowed to react with stirring at 0°C for 2 hours, and then warmed to room temperature and allowed to react at room temperature for 16 hours. After the reaction was complete, 6 M hydrochloric acid (150 mL) was added and stirred for 0.5 hours. The mixture was diluted with water (1000 mL) and extracted twice with ethyl acetate (500 mL). The combined extracts were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to give Intermediate 1 (23 g, yield: 23%). MS m / z (ESI): 333.0 [M+1].

[0151] Intermediate 2:

[0152] [ka]

[0153] Intermediate 1 (28 g), zinc powder (55 g), and acetic acid (200 mL) were added sequentially to a 500 mL single-neck flask, and the reaction mixture was heated to 100°C and stirred at that temperature for 16 hours. After completion of the reaction, the mixture was filtered. The filtrate was diluted with water (500 mL) and extracted with ethyl acetate (500 mL). The extract was washed twice with saturated aqueous sodium bicarbonate (500 mL) and once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Intermediate 2 (26 g, 73% yield). MS m / z (ESI): 334.8 [M+1].

[0154] Intermediate 3:

[0155] [ka]

[0156] In a 500 mL single-neck flask, tetrahydrofuran (100 mL), ethanol (100 mL), and intermediate 2 (26 g) were added in that order, followed by the addition of sodium borohydride (2 g) in several portions. The reaction was allowed to proceed at room temperature for 2 hours. After completion of the reaction, the system was cooled to 0 °C, saturated aqueous ammonium chloride (30 mL) was added until the temperature no longer rose, and the mixture was diluted with water (500 mL). The mixture was extracted twice with ethyl acetate (200 mL). The combined extracts were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 3 (25 g, 76% yield). MS m / z (ESI): 336.9 [M+1].

[0157] Intermediate 4:

[0158] [ka]

[0159] Dichloromethane (200 mL) was added to a 500 mL single-neck flask, followed by the addition of Intermediate 3 (25 g), imidazole (6.6 g), and tert-butyldiphenylchlorosilane (25 g) in that order, and the reaction was allowed to proceed at room temperature for 2 hours. After completion of the reaction, the reaction mixture was washed with water (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was 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). MS m / z (ESI):597.0[M+23].

[0160] Intermediate 5:

[0161] [ka]

[0162] In a 250 mL single-neck flask, Intermediate 4 (5 g) and a tetrabutylammonium fluorotetrahydrofuran solution (1 M, 30 mL) were added in this order, and the mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with water (100 mL) and extracted three times with ethyl acetate (50 mL). The combined extracts were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1 to 0:1) to obtain the racemic intermediate. This intermediate was then chiral separated by SFC (Apparatus: SFC Thar prep 80, Column: CHIRALPAK AD-H, 250 mm x 20 mm, 5 μm, Modifier: 35% methanol (0.2% aqueous ammonia), Column temperature: 40 °C, Column pressure: 60 bar, Wavelength: 214 / 254 nm, Flow rate: 40 g / min, Rt = 4.78 min) to obtain Intermediate 5 (1.2 g, Yield: 41%). MS m / z (ESI): 358.8 [M+23].

[0163] Intermediate 6:

[0164] [ka]

[0165] In a 100 mL single-neck flask, N,N-dimethylformamide (15 mL), intermediate 5 (1.2 g), and iodoethane (1.1 g) were added in that order. The reaction mixture was cooled to 0 °C, and then sodium hydride (60%, 243 mg) was added. The reaction mixture was then warmed to room temperature and incubated at that temperature for 2 hours. After completion of the reaction, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL). The extract was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 6 (1.2 g, 83% yield). MS m / z (ESI): 386.9 [M+23].

[0166] Intermediate 7:

[0167] [ka]

[0168] In a 100 mL single-neck flask, methanol (10 mL), water (10 mL), concentrated sulfuric acid (10 mL), and intermediate 6 (1.2 g) were added in that order, and the reaction mixture was heated to 80°C and reacted at that temperature for 48 hours. After completion of the reaction, the reaction mixture was concentrated to remove methanol, and the residue was adjusted to neutral pH with aqueous sodium hydroxide (2 M). The mixture was extracted three times with ethyl acetate (10 mL). The combined extracts were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 7 (850 mg, 81% yield). 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).

[0169] Alternatively, intermediate 7 can be obtained by the following method: Intermediate 8:

[0170] [ka]

[0171] In a 2 L three-neck flask, tetrabutylammonium fluorotetrahydrofuran solution (1 M, 840 mL) and intermediate 4 (140 g) were added in sequence and reacted at room temperature for 2 hours. After completion of the reaction, the mixture was diluted with water (600 mL) and extracted three times with ethyl acetate (700 mL). The extract was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to give intermediate 8 (77 g, 95% yield). MS m / z (ESI): 358.8 [M+23].

[0172] Intermediate 9:

[0173] [ka]

[0174] In a 2 L three-neck flask, the solvent N,N-dimethylformamide (700 mL), intermediate 8 (77 After the reaction mixture was cooled to 0°C, sodium hydride (60%, 14.61 g) was added, and the mixture was then warmed to room temperature and allowed to react for 2 hours. After the reaction was completed, the mixture was cooled to 0°C, and aqueous ammonium chloride solution was added until the reaction temperature stopped rising. The mixture was then extracted with ethyl acetate (500 mL). The extracted phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give intermediate 9 (75 g, yield: 89%). MS m / z (ESI): 386.9[M+23].

[0175] Intermediate 10:

[0176] [ka]

[0177] In a 2 L three-neck flask, isopropanol (300 mL), water (800 mL), intermediate 9 (75 g), and Ba(OH)₂·8H₂O (233 g) were added in that order, and the reaction was heated to 100 °C and continued at that temperature for 20 h. After completion of the reaction, the reaction mixture was concentrated to remove isopropanol, and the residue was adjusted to pH 2-3 with saturated aqueous sodium hydroxide. The mixture was extracted three times with dichloromethane (300 mL). The extract was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give intermediate 10 (67 g, 85% yield). MS m / z (ESI): 384.1 [M+1].

[0178] Intermediate 11:

[0179] [ka]

[0180] In a 2 L three-neck flask, N,N-dimethylformamide (670 mL), potassium carbonate (96.6 g), iodomethane (37.3 g), and intermediate 10 (67 g) were added in that order and reacted at room temperature for 2 hours. After completion of the reaction, the reaction was quenched by adding 300 mL of water, extracted with methyl tert-butyl ether (300 mL * 2), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 3:1) to give intermediate 11 (54 g, yield: 78%). MS m / z (ESI): 394.1 [M+1].

[0181] Intermediate 7:

[0182] [ka]

[0183] Ethyl acetate (500 mL), palladium on carbon (5.4 g, 10% loading), and intermediate 11 (54 g) were added to a 1 L single-neck flask in this order and reacted under hydrogen gas pressure at room temperature for 16 hours. After completion of the reaction, diatomaceous earth was added to the reaction mixture and filtered. The filtrate was concentrated under reduced pressure to obtain the racemic intermediate. This intermediate was then subjected to chiral separation (Apparatus: Shimadzu LC-20AD, Column: CHIRALPAK AD-H (ADH0CD-SK003), 0.46 cm ID x 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 H NMR (400 MHz, DMSO-d6) 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).

[0184] [Example 2] Intermediate 1:

[0185] [ka]

[0186] Dichloromethane (50 mL), 5-methoxy-7-methyl-1H-indole (3 g), Boc anhydride (5.68 g), 4-dimethylaminopyridine (227 mg), and triethylamine (2.26 g) were added to a 250 mL single-neck flask in this order and reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (5 mL) and extracted three times with dichloromethane (20 mL). The combined organic phase was washed with water (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give Intermediate 1 (4.6 g, 94% yield). MS m / z (ESI): 262.0 [M+1].

[0187] Intermediate 2:

[0188] [ka]

[0189] In a 250 mL single-neck flask, dichloromethane (80 mL), N-methylformanilide (3.8 g), and oxalyl chloride (3.6 g) were added in that order and allowed to react at room temperature with stirring for 3 hours. The reaction mixture was then cooled to -14°C, and Intermediate 1 (2.5 g) was added. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into ice water (100 mL) and extracted three times with dichloromethane (100 mL). The combined extracts were washed twice with water (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to give 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).

[0190] [Example 3] Intermediate 1:

[0191] [ka]

[0192] In a 100 mL single-neck flask, 1-(vinyloxy)butane (10 mL), triethylamine (300 mg), phenanthroline (54 mg), palladium acetate (67 mg), and benzyl (2S,4S)-2-(4-cyanophenyl)-4-hydroxypiperidinyl-1-carboxylate (Example 1, Intermediate 5) (500 mg) were added in this order, and the reaction mixture was heated to 90°C under nitrogen gas protection and stirred at that temperature for 16 hours. After completion of the reaction, the reaction mixture was directly concentrated 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].

[0193] Intermediate 2:

[0194] [ka]

[0195] Under ice bath and nitrogen gas protection, a solution of trifluoroacetic acid (228 mg) in dichloromethane (2 mL) was added to a solution of diethylzinc (1 M, 2 mL) in dichloromethane (4 mL). The reaction mixture was then incubated in an ice bath for 1 hour. After this, a solution of diiodomethane (536 mg) in dichloromethane (2 mL) was added and the reaction mixture was incubated for 1 hour. A solution of intermediate 5 (362 mg) from Example 1 in dichloromethane (2 mL) was then added. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 18 hours. After completion of the reaction, 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), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give intermediate 2 (300 mg, yield: 64%). MS m / z (ESI): 398.8[M+23].

[0196] Intermediate 3:

[0197] [ka]

[0198] Sodium hydroxide (320 mg) was dissolved in a solution of intermediate 2 (300 mg) in isopropanol (2 mL) and water (5 mL). The reaction mixture was heated to 100°C and stirred at that temperature for 48 hours. After completion of the reaction, the reaction mixture was adjusted to pH 5-6 with dilute hydrochloric acid (1 M) in an ice bath, diluted with water (10 mL), extracted with ethyl acetate (10 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 3 (180 mg, yield: 45%). MS m / z (ESI): 395.9 [M+1].

[0199] Intermediate 4:

[0200] [ka]

[0201] To a solution of intermediate 3 (180 mg) in acetonitrile (3 mL), potassium carbonate (126 mg) and iodomethane (129 mg) were added in that order, and the reaction mixture was heated to 50°C and stirred at that temperature for 16 hours. After completion of the reaction, 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].

[0202] Intermediate 5:

[0203] [ka]

[0204] Palladium on carbon (20 mg) was added to a solution of intermediate 4 (120 mg) in tetrahydrofuran (2 mL), and the reaction mixture was subjected to catalytic hydrogenation under a hydrogen gas atmosphere at room temperature for 16 hours. After completion of the reaction, the reaction mixture was directly filtered and concentrated under reduced pressure to give intermediate 5 (70 mg, yield: 79%). MS m / z (ESI): 275.9 [M+1].

[0205] Intermediate 6:

[0206] [ka]

[0207] Intermediate 5 (70 mg) was added to a solution of Intermediate 2 (88 mg) from Example 2 in 1,2-dichloroethane (5 mL), and the mixture was stirred at room temperature for 8 hours. Sodium borohydride acetate (162 mg) was then added, and the mixture was allowed to react for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain Intermediate 7 (170 mg, yield: 73%). MS m / z (ESI): 548.8 [M+1].

[0208] Target compound:

[0209] [ka]

[0210] Sodium hydroxide (127 mg) was added to a mixture of intermediate 6 (175 mg) in methanol (2 mL) and water (2 mL), and the reaction mixture was heated to 75 °C and reacted at that temperature for 3 hours. After the reaction was completed, the reaction mixture was adjusted to neutral pH with 1 M hydrochloric acid in an ice bath. The mixture was then directly purified by high-performance liquid preparative chromatography (column: Gemini-C18, 150 × 21.2 mm, 5 μm, mobile phase: acetonitrile-water (0.1% formic acid), gradient: 20–40%) to give the target compound (31.5 mg, yield: 22%, containing 0.5 equivalents of formic acid). MS m / z (ESI): 434.9 [M+1]. 1 H 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).

[0211] [Example 4] Intermediate 1:

[0212] [ka]

[0213] Imidazole (202 mg) and tert-butyldimethylchlorosilane (270 mg) were added to a solution of intermediate 5 (500 mg) from Example 1 in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was directly concentrated to give intermediate 1 (700 mg, yield: 88%). MS m / z (ESI): 472.8 [M+23].

[0214] Intermediate 2:

[0215] [ka]

[0216] Intermediate 1 (750 mg) was added to dichloromethane (10 mL). The reaction mixture was cooled to -78 °C under nitrogen gas protection, and cyclobutanone (117 mg) and trimethylsilyl trifluoromethanesulfonate (37 mg) were added sequentially. After stirring at -78 °C for 1 hour, triethylsilane (193 mg) was added. The mixture was then gradually warmed to room temperature and stirred at that temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL), diluted with water (10 mL), extracted with dichloromethane (10 mL), washed once with water (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give Intermediate 2 (700 mg, yield: 86%). MS m / z (ESI): 391.0 [M+1].

[0217] Intermediate 3:

[0218] [ka]

[0219] Sodium hydroxide (720 mg) was added to a solution of intermediate 2 (700 mg) in a mixture of isopropanol (5 mL) and water (10 mL). The reaction mixture was heated to 100 °C and stirred at that temperature for 48 hours. After completion of the reaction, the reaction mixture was adjusted to pH 5-6 with dilute hydrochloric acid (1 M) in an ice bath, diluted with 20 mL of water, and extracted with ethyl acetate (20 mL). The extract was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 3 (700 mg, 76% yield). MS m / z (ESI): 409.9 [M+1].

[0220] Intermediate 4:

[0221] [ka]

[0222] Potassium carbonate (472 mg) and iodomethane (486 mg) were added to a solution of intermediate 3 (700 mg) in acetonitrile (5 mL), and the reaction mixture was heated to 50°C and reacted at that temperature for 16 hours. After completion of the reaction, the reaction mixture was directly concentrated, 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].

[0223] Intermediate 5:

[0224] [ka]

[0225] Palladium on carbon (35 mg) was added to a solution of intermediate 4 (350 mg) in tetrahydrofuran (5 mL), and the reaction mixture was subjected to catalytic hydrogenation under a hydrogen gas atmosphere at room temperature for 2 hours. After completion of the reaction, the reaction mixture was directly filtered and concentrated under reduced pressure to give intermediate 5 (200 mg, yield: 75%). MS m / z (ESI): 290.0 [M+1].

[0226] Intermediate 6:

[0227] [ka]

[0228] Intermediate 5 (242 mg) was added to a solution of Intermediate 2 (242 mg) from Example 2 in 1,2-dichloroethane (5 mL) and the mixture was stirred at room temperature for 8 hours. Sodium borohydride acetate (532 mg) was then added and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was directly concentrated, 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].

[0229] Target compound:

[0230] [ka]

[0231] In a 50 mL single-neck flask, methanol (3 mL), water (3 mL), Intermediate 6 (350 mg), and sodium hydroxide (248 mg) were added in this order. The reaction mixture was heated to 75 °C and reacted at this temperature for 3 hours. After the reaction was completed, the reaction mixture was adjusted to pH 7 by adding dilute hydrochloric acid (1 M) in an ice bath. The mixture was then directly concentrated and purified by high-performance liquid preparative 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).

[0232] [Example 5] Intermediate 1:

[0233] [ka]

[0234] To a solution of Intermediate 5 (1200 mg) from Example 1 in N,N-dimethylformamide (10 mL), imidazole (486 mg) and tert-butyldimethylchlorosilane (593 mg) were added and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL). The extracted phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was directly concentrated to give Intermediate 1 (600 mg, yield: 90%). MS m / z (ESI): 472.8[M+23].

[0235] Intermediate 2:

[0236] [ka]

[0237] Intermediate 1 (700 mg) was added to dichloromethane (10 mL) at room temperature. Under nitrogen gas protection and at -78 °C, cyclopropanecarboxaldehyde (110 mg) and trimethylsilyl trifluoromethanesulfonate (35 mg) were added to the reaction mixture. The reaction mixture was stirred at -78 °C for 1 hour. Triethylsilane (180 mg) was then added, and the mixture was allowed to warm to room temperature and stirred at that temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (20 mL), diluted with water (10 mL), extracted with dichloromethane (10 mL), washed once with water (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give Intermediate 2 (400 mg, yield: 46%). MS m / z (ESI): 390.9[M+1].

[0238] Intermediate 3:

[0239] [ka]

[0240] Intermediate 2 (400 mg), isopropanol (2 mL), water (3 mL), and sodium hydroxide (400 mg) were added sequentially to a 50 mL single-neck flask. The reaction mixture was heated to 100 °C and stirred at that temperature for 16 hours. After completion of the reaction, the reaction mixture was adjusted to pH 5-6 with dilute hydrochloric acid (1 M) in an ice bath, diluted with water (5 mL), extracted with ethyl acetate (5 mL), washed once with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated at 45 °C to give Intermediate 3 (200 mg, 33% yield). MS m / z (ESI): 431.8 [M+23].

[0241] Intermediate 4:

[0242] [ka]

[0243] Potassium carbonate (135 mg) and iodomethane (140 mg) were added to a solution of intermediate 3 (200 mg) in acetonitrile (5 mL), and the reaction mixture was heated to 50°C and stirred at that temperature for 16 hours. After completion of the reaction, the reaction mixture was directly concentrated, 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].

[0244] Intermediate 5:

[0245] [ka]

[0246] Palladium on carbon (50 mg) was added to a solution of intermediate 4 (180 mg) in tetrahydrofuran (3 mL), and the reaction mixture was subjected to catalytic hydrogenation under a hydrogen gas atmosphere at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was directly concentrated to give intermediate 5 (120 mg, yield: 54%). MS m / z (ESI): 290.0 [M+1].

[0247] Intermediate 6:

[0248] [ka]

[0249] Intermediate 5 (120 mg) was added to a solution of Intermediate 2 (119 mg) from Example 2 in 1,2-dichloroethane (5 mL), and the mixture was stirred at room temperature for 8 hours. Sodium borohydride acetate (261 mg) was then added, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was directly concentrated, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to give Intermediate 6 (200 mg, yield: 26%). MS m / z (ESI): 562.8 [M+1].

[0250] Target compound:

[0251] [ka]

[0252] To a 50 mL single-neck flask, methanol (2 mL), water (2 mL), intermediate 6 (200 mg), and sodium hydroxide (150 mg) were added in that order, and the reaction mixture was heated to 75 °C and stirred at that temperature for 3 h. After completion of the reaction, the reaction mixture was adjusted to pH 7 by adding dilute hydrochloric acid (1 M) in an ice bath, then directly concentrated and purified by high-performance liquid preparative 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).

[0253] [Example 6] Intermediate 1:

[0254] [ka]

[0255] Under nitrogen gas protection at -78°C, intermediate 1 (700 mg) from Example 5 was added to dichloromethane (7 mL), cyclobutanecarboxaldehyde (130 mg) and trimethylsilyl trifluoromethanesulfonate (35 mg) were added, and the mixture was stirred at -78°C for 1 hour. Triethylsilane (180 mg) was then added, and the reaction mixture was gradually warmed to room temperature and stirred at that temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (20 mL), diluted with water (10 mL), extracted with dichloromethane (10 mL), washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. 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].

[0256] Intermediate 2:

[0257] [ka]

[0258] In a 50 mL single-neck flask, isopropanol (1 mL), water (3 mL), intermediate 1 (240 mg), and sodium hydroxide (240 mg) were added in that order, and the reaction mixture was heated to 100 °C and reacted at that temperature for 16 hours. After the reaction was completed, the reaction mixture was adjusted to pH 5-6 with dilute hydrochloric acid (1 M) in an ice bath, diluted with water (5 mL), and extracted with ethyl acetate (5 mL). The extract was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated to give intermediate 2 (200 mg, yield: 72%). MS m / z (ESI): 446.1 [M+23].

[0259] Intermediate 3:

[0260] [ka]

[0261] To a solution of intermediate 2 (200 mg) in acetonitrile (5 mL), potassium carbonate (130 mg) and iodomethane (134 mg) were added, and the reaction mixture was heated to 50°C and reacted at that temperature for 16 hours. After completion of the reaction, the reaction mixture was directly concentrated, 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].

[0262] Intermediate 4:

[0263] [ka]

[0264] Palladium on carbon (50 mg) was added to a solution of intermediate 3 (200 mg) in tetrahydrofuran (3 mL), and the reaction mixture was subjected to catalytic hydrogenation under a hydrogen gas atmosphere at room temperature for 2 hours. After completion of the reaction, the reaction mixture was directly filtered and concentrated under reduced pressure to give intermediate 4 (110 mg, yield: 71%). MS m / z (ESI): 303.9 [M+1].

[0265] Intermediate 5:

[0266] [ka]

[0267] Intermediate 4 (110 mg) was added to a solution of Intermediate 2 (105 mg) from Example 2 in 1,2-dichloroethane (5 mL) and the mixture was stirred at room temperature for 8 hours. Sodium borohydride acetate (229 mg) was then added and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was directly concentrated, 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].

[0268] Target compound:

[0269] [ka]

[0270] Methanol (2 mL), water (2 mL), intermediate 5 (250 mg), and sodium hydroxide (175 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 completed, the reaction mixture was adjusted to pH 7 by adding dilute hydrochloric acid (1 M) in an ice bath. The mixture was directly concentrated and purified by high-performance liquid preparative 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).

[0271] [Example 7] Intermediate 1:

[0272] [ka]

[0273] In a glovebox, silver trifluoromethanesulfonate (1600 mg), potassium fluoride (483 mg), and 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis(tetrafluoroborate) (1100 mg) were weighed and added to a 50 mL single-neck flask. Then, under nitrogen gas protection, a solution of intermediate 5 (700 mg) from Example 1 in ethyl acetate (10 mL), 2-fluoropyridine (609 mg), and trifluoromethyltrimethylsilane (889 mg) were added by injection. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was directly purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give intermediate 1 (300 mg, yield: 32%). MS m / z (ESI): 426.8 [M+23].

[0274] Intermediate 2:

[0275] [ka]

[0276] In a 50 mL single-neck flask, isopropanol (2 mL), water (3 mL), intermediate 1 (400 mg), and sodium hydroxide (400 mg) were added in that order, and the reaction mixture was heated to 100 °C and reacted at that temperature for 16 hours. After the reaction was completed, the reaction mixture was adjusted to pH 5-6 with dilute hydrochloric acid (1 M) in an ice bath, diluted with water (5 mL), and extracted with ethyl acetate (5 mL). The extract was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was directly concentrated to give intermediate 2 (260 mg, 56% yield). MS m / z (ESI): 445.7 [M+23].

[0277] Intermediate 3:

[0278] [ka]

[0279] To a solution of intermediate 2 (260 mg) in acetonitrile (5 mL), potassium carbonate (170 mg) and iodomethane (175 mg) were added, and the reaction mixture was heated to 50°C and reacted at that temperature for 16 hours. After completion of the reaction, the reaction mixture was directly concentrated, 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].

[0280] Intermediate 4:

[0281] [ka]

[0282] Palladium on carbon (50 mg) was added to a solution of intermediate 3 (200 mg) in tetrahydrofuran (3 mL), and the reaction mixture was subjected to catalytic hydrogenation under a hydrogen gas atmosphere at room temperature for 2 hours. After completion of the reaction, the reaction mixture was directly filtered and concentrated under reduced pressure to give intermediate 4 (130 mg, yield: 84%). MS m / z (ESI): 303.9 [M+1].

[0283] Intermediate 5:

[0284] [ka]

[0285] Intermediate 4 (130 mg) was added to a solution of Intermediate 2 (125 mg) from Example 2 in 1,2-dichloroethane (5 mL) and the mixture was stirred at room temperature for 8 hours. Sodium borohydride acetate (273 mg) was then added and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was directly concentrated, 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].

[0286] Target compound:

[0287] [ka]

[0288] In a 50 mL single-neck flask, methanol (2 mL), water (2 mL), intermediate 5 (280 mg), and sodium hydroxide (194 mg) were added in that order, and the reaction mixture was heated to 75 °C and allowed to react at that temperature for 16 h. After completion of the reaction, the reaction mixture was adjusted to pH 7 by adding dilute hydrochloric acid (1 M) in an ice bath, and then directly purified by high-performance liquid preparative chromatography (column: Gemini-C18, 150 × 21.2 mm, 5 μm, mobile phase: acetonitrile-water (0.1% formic acid), gradient: 25–50%) to give 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). 19 F NMR (376 MHz, CD3OD) δ -59.65.

[0289] [Example 8] Intermediate 1:

[0290] [ka]

[0291] At -70°C, n-butyllithium (6.25 mL) was slowly added dropwise to a solution of methyltriphenylphosphonium bromide (5.35 g) in tetrahydrofuran (100 mL). The mixture was stirred at -70°C for 0.5 hours, followed by the addition of a solution of Intermediate 2 (3.34 g) from Example 1 in tetrahydrofuran (30 mL). The mixture was then allowed to warm to room temperature and stirred at room temperature for 16 hours. After completion of the reaction, the reaction was quenched by the addition of saturated ammonium chloride (20 mL), diluted with water (100 mL), and extracted twice with ethyl acetate (100 mL). The combined extracts were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give Intermediate 1 (850 mg, yield: 24%). MS m / z (ESI): 333.1 [M+1].

[0292] Intermediate 2:

[0293] [ka]

[0294] To a solution of intermediate 1 (800 mg) in tetrahydrofuran (10 mL), sodium iodide (75 mg) and trifluoromethyltrimethylsilane (1160 mg) were added, and the reaction mixture was heated to 70°C and reacted at that temperature for 16 hours in a sealed container. After completion of the reaction, the reaction mixture was directly concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain intermediate 2 (800 mg, yield: 82%). MS m / z (ESI): 382.9 [M+1].

[0295] Intermediate 3:

[0296] [ka]

[0297] In a 100 mL single-neck flask, methanol (10 mL), a mixed solution of sulfuric acid and water (1:1, 10 mL), and intermediate 2 (480 mg) were added in this order, and the reaction mixture was heated to 80°C and reacted at that temperature for 2 days. After completion of the reaction, the reaction mixture was naturally cooled to room temperature, poured into ice water, and ethyl acetate (50 The combined organic phase was washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give intermediate 3 (300 mg, yield: 85%). MS m / z (ESI): 282.0 [M+1].

[0298] Intermediate 4:

[0299] [ka]

[0300] Intermediate 3 (100 mg) was added to a solution of Intermediate 2 (100 mg) from Example 2 in 1,2-dichloroethane (3 mL) at room temperature. After stirring at room temperature for 8 hours, sodium triacetoxyborohydride (220 mg) was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was directly purified by column chromatography (methanol:dichloromethane = 1:20) to obtain Intermediate 4 (110 mg, yield: 54%). MS m / z (ESI): 554.9 [M+1].

[0301] Target compound:

[0302] [ka]

[0303] Methanol (3 mL), water (3 mL), intermediate 4 (110 mg), and sodium hydroxide (40 mg) were added to a 25 mL single-neck flask in this order. The reaction mixture was heated to 75 °C and reacted at this temperature for 3 hours. After completion of the reaction, the reaction mixture was directly purified by high-performance liquid preparative 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 lyophilized 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).

[0304] [Example 9] Intermediate 1:

[0305] [ka]

[0306] In a 100 mL single-neck flask, 1,4-dioxane (8 mL), water (2 mL), methyl 4-(dihydroxyboranyl)benzoate (500 mg), 2-bromo-4-(trifluoromethyl)pyridine (693 mg), potassium carbonate (413 mg), and tetrakis(triphenylphosphino)palladium (693 mg) were added in this order. The reaction mixture was heated to 90 °C under nitrogen gas protection and reacted at that temperature for 16 h. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, poured into water (50 mL), and extracted three times with ethyl acetate (100 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to give Intermediate 1 (600 mg, yield: 76%). MS m / z (ESI): 282.0 [M+1].

[0307] Intermediate 2:

[0308] [ka]

[0309] Methanol (6 mL), intermediate 1 (180 mg), platinum dioxide (14 mg), and a catalytic amount of hydrochloric acid were added to a 50 mL single-neck flask in this order, and the reaction mixture was subjected to catalytic hydrogenation under a hydrogen gas atmosphere at room temperature for 16 hours. After completion of the reaction, the reaction mixture was directly filtered and the pressure was reduced. The residue was purified by column chromatography (dichloromethane:methanol = 10:1) to give intermediate 2 (30 mg, yield: 16%). MS m / z (ESI): 288.1 [M+1].

[0310] Intermediate 3:

[0311] [ka]

[0312] To a 50 mL single-neck flask, 1,2-dichloroethane (4 mL), Intermediate 2 (30 mg), Intermediate 2 from Example 2 (44 mg), and sodium triacetoxyborohydride (66 mg) were added in that order, and the reaction mixture was stirred under a nitrogen atmosphere at room temperature for 16 hours. After the reaction was completed, methanol was added to the reaction mixture until the solution became clear, and then the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to give Intermediate 3 (30 mg, yield: 53%). MS m / z (ESI): 560.7 [M+1].

[0313] Target compound:

[0314] [ka]

[0315] 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 completion of the reaction, the reaction mixture was diluted with water (3 mL) and the pH was adjusted to 7-8 with dilute hydrochloric acid (1 M). The mixture was then directly concentrated under reduced pressure and purified by high-performance liquid preparative chromatography (column: Gemini-C18, 150 x 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]v 1 H NMR (400 MHz, DMSO-d6) 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).

[0316] [Example 10] Intermediate 1:

[0317] [ka]

[0318] Diethylaminosulfur trifluoride (3.48 g) was slowly added to a solution of 2-bromopyridine-4-formaldehyde (1 g) in dichloromethane (10 mL) at -78 °C, and the reaction mixture was gradually warmed to room temperature and stirred at that temperature for 2 hours. After completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate (50 mL), extracted with dichloromethane (50 mL), washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Intermediate 1 (1 g, yield: 86%). MS m / z (ESI): 207.9 [M+1].

[0319] Intermediate 2:

[0320] [ka]

[0321] To a 10 mL three-neck flask, 1,4-dioxane (10 mL), water (1 mL), intermediate 1 (1 g), methyl 4-(dihydroxyboranyl)benzoate (0.95 g), sodium carbonate (1.02 g), and tetrakis(triphenylphosphino)palladium (0.166 mg) were added in that order. The reaction mixture was heated to 95 °C under nitrogen gas protection and stirred at that temperature for 18 h. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, quenched by the addition of saturated aqueous ammonium chloride (2 mL), and extracted three times with ethyl acetate (50 mL). The combined organic layer was dried over 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 give intermediate 2 (0.4 g, yield: 29.17%). MS m / z (ESI): 264.2 [M+1].

[0322] Intermediate 3:

[0323] [ka]

[0324] In a 10 mL single-neck flask, methanol (4 mL), concentrated hydrochloric acid (0.2 mL), intermediate 2 (340 mg), and platinum oxide (292.9 mg) were added in this order, and the reaction was catalytically hydrogenated under a hydrogen gas atmosphere at room temperature for 18 hours. After completion of the reaction, the reaction mixture was directly filtered and concentrated under reduced pressure. The residue was purified by high-performance liquid preparative chromatography (column: C18 spherical, 100 A, 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].

[0325] Intermediate 4:

[0326] [ka]

[0327] In a 10 mL single-neck flask, 1,2-dichloroethane (2 mL), Intermediate 3 (140 mg), and Intermediate 2 (196 mg) from Example 2 were added in that order. The reaction mixture was stirred at room temperature for 8 hours, followed by the addition of sodium triacetoxyborohydride (330 mg) and further stirring at room temperature for 18 hours. After completion of the reaction, the mixture was diluted with dichloromethane (10 mL) and washed with water (10 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give Intermediate 4 (200 mg, yield: 64.4%). MS m / z (ESI): 542.8 [M+1].

[0328] Target compound:

[0329] [ka]

[0330] To a 10 mL three-neck flask, methanol (2 mL), tetrahydrofuran (2 mL), water (2 mL), intermediate 4 (180 mg), and sodium hydroxide (132 mg) were added in that order, and the reaction mixture was stirred at room temperature for 18 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by high-performance liquid preparative chromatography (column: Gemini-C18, 150 x 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).

[0331] [Example 11] Intermediate 1:

[0332] [ka]

[0333] At room temperature and under nitrogen gas protection, isopropylmagnesium bromide magnesium chloride complex (85 mL) was added to a solution of 4-bromobenzonitrile (18.2 g) in tetrahydrofuran (100 mL) and the mixture was stirred at room temperature for 3 hours to produce a 4-cyanophenylmagnesium bromide solution (Reactant 1).

[0334] Under nitrogen gas protection at -78°C, (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl chloroformate (20.4 g) was added dropwise to a solution of 4-methoxypyridine (10 g) in tetrahydrofuran (200 mL). The mixture was stirred at -78°C for 15 minutes, followed by the addition of freshly prepared 4-cyanophenylmagnesium bromide solution (Reactant 1). The mixture was stirred at -78°C for 1 hour. After completion of the reaction, the reaction mixture was quenched with dilute hydrochloric acid (1 M, 150 mL), allowed to warm to room temperature, and stirred for 30 minutes. The mixture was then diluted with water (150 mL) and extracted three times with ethyl acetate (200 mL). The combined organic phase was washed twice with saturated brine (200 mL), dried over 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 1 (16.4 g, yield: 50%).

[0335] Intermediate 2:

[0336] [ka]

[0337] Zinc powder (28 g) was added to a solution of intermediate 1 (16.4 g) in acetic acid (200 mL), and the reaction was heated to 100° C. and stirred at that 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 give intermediate 2 (3 g, yield: 30%).

[0338] Intermediate 3:

[0339] [ka]

[0340] Dichloromethane (4 mL) and Intermediate 2 (210 mg) were added to a 50 mL single-neck flask, followed by the addition of diethylaminosulfur trifluoride (177 mg) in an ice bath. The reaction mixture was heated to 40°C under nitrogen gas protection and stirred at that temperature for 16 hours. After completion of the reaction, ice water (10 mL) was poured into the reaction mixture, extracted three times with ethyl acetate (50 mL), and the combined organic phase was washed with saturated brine (5 mL). The organic phase was dried over 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 give Intermediate 3 (144 mg, yield: 54%).

[0341] Intermediate 4:

[0342] [ka]

[0343] 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 that temperature for 16 hours. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure to give intermediate 4 (80 mg, yield: 60%).

[0344] Intermediate 5:

[0345] [ka]

[0346] In a 50 mL single-neck flask, intermediate 4 (80 mg) was dissolved in 80% sulfuric acid / methanol (1:1, 4 The reaction mixture was heated to 90°C and stirred at this temperature for 6 hours. After completion of the reaction, the mixture was diluted with water (10 mL) at room temperature and the pH was adjusted to 7-8 with sodium hydroxide solution (2 M), followed by extraction with ethyl acetate (50 mL) three times. The combined organic phase was dried over 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 give intermediate 5 (64 mg, yield: 69%).

[0347] Intermediate 6:

[0348] [ka]

[0349] In a 50 mL single-neck flask, 1,2-dichloroethane (2 mL), Intermediate 5 (22 mg), Intermediate 2 (34 mg) from Example 2, and sodium triacetoxyborohydride (50 mg) were added in that order, and the mixture was allowed to react at room temperature under nitrogen gas protection for 16 hours with stirring. After the reaction was completed, methanol was added to the reaction mixture until the solution became clear, and then the mixture was directly concentrated under reduced pressure. The residue was purified by thin-layer chromatography (petroleum ether:ethyl acetate=5:1) to give Intermediate 6 (20 mg, yield: 42%).

[0350] Target compound:

[0351] [ka]

[0352] To a 50 mL single-neck flask, methanol (1.5 mL), water (0.5 mL), intermediate 6 (20 mg), and sodium hydroxide (30 mg) were added in that order, and the reaction mixture was stirred at room temperature for 48 h. After completion of the reaction, the reaction mixture was poured into water (5 mL), the pH was adjusted to 7-8 with dilute hydrochloric acid (1 M), and the mixture was directly concentrated under reduced pressure. The residue was purified by high-performance liquid preparative chromatography (column: AZZOTA C18 100 A, 10 μm, mobile phase: acetonitrile-water (0.05% aqueous ammonia), gradient: 15-28%). The resulting 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).

[0353] [Example 12] Intermediate 1:

[0354] [ka]

[0355] Tetrakis(triphenylphosphonium)palladium (1.43 g), 4-bromophenylboronic acid (5 g), 2-bromopyridine (4.72 g), and sodium carbonate (6.87 g) were added sequentially to a solution of 1,4-dioxane (90 mL) and water (15 mL) at room temperature. The reaction was heated to 90°C under nitrogen gas protection and continued at that temperature for 16 hours. After completion of the reaction, the reaction mixture was directly concentrated, and the residue was purified by 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].

[0356] Intermediate 2:

[0357] [ka]

[0358] [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (700 mg) was added to a solution of 2-(4-bromophenyl)pyridine (2 g), diethyl phosphite (4.7 g), and DIEA (2.2 g) in toluene (20 mL). The reaction was heated to 110 °C under nitrogen gas protection and continued at that temperature for 16 hours. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) to obtain intermediate 2 (1.4 g, 60% yield). MS m / z (ESI): 291.9 [M+1].

[0359] Intermediate 3:

[0360] [ka]

[0361] Platinum oxide (280 mg, 20% wt / wt) was added to a solution of intermediate 2 (1.4 g) in EtOH (20 mL) and hydrochloric acid (4 mL), and the reaction mixture was subjected to catalytic hydrogenation under 0.4 MPa for 48 hours. After completion of the reaction, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give intermediate 3 (1.28 g, 90% yield). MS m / z (ESI): 297.9 [M+1].

[0362] Intermediate 4:

[0363] [ka]

[0364] Tetraethyl titanate (226 mg) was added to a solution of Intermediate 2 (300 mg) and Intermediate 3 (367 mg) from Example 2 in tetrahydrofuran (20 mL), and the reaction mixture was heated to 70°C and stirred at that temperature for 16 hours. The reaction mixture was cooled to room temperature, and sodium triacetylborohydride (655 mg) was added. The mixture was then heated to 70°C and stirred at that temperature for 1 hour. After completion of the reaction, 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].

[0365] Target compound:

[0366] [ka]

[0367] Trimethylbromosilane (2 mL) was added to a solution of intermediate 4 (200 mg) in dichloromethane (6 mL) at 0 °C, and the reaction was allowed to proceed with stirring at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by high-performance liquid preparative chromatography (column: Gemini-C18, 150 x 21.2 mm, 5 μm, mobile phase: acetonitrile-water (0.1% formic acid), gradient: 10-40%) to obtain the target compound (60 mg, 82% yield). 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).

[0368] [Example 13] Intermediate 1:

[0369] [ka]

[0370] Tetraethyl titanate (151 mg) was added to a solution of Intermediate 2 (200 mg) from Example 2 and 2-(4-bromophenyl)piperidine (195 mg) in tetrahydrofuran (15 mL), and the reaction system was heated to 70°C and stirred at that temperature for 16 hours. The reaction was allowed to cool to room temperature, and sodium triacetylborohydride (438 mg) was added. The mixture was heated to 70°C and stirred at that temperature for 1 hour. After completion of the reaction, the reaction solution was directly 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, 71% yield). MS m / z (ESI): 512.7 [M+1].

[0371] Intermediate 2:

[0372] [ka]

[0373] 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 a solution of intermediate 1 (252 mg), diborane 1,1,2,2-tetraol (131 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos) (23 mg), and potassium acetate (144 mg) in ethanol (15 mL). The reaction mixture was heated to 90 °C under nitrogen gas protection and stirred at that temperature for 16 h. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 5:1) to give intermediate 2 (200 mg, 85% yield). MS m / z (ESI): 478.9 [M+1].

[0374] Target compound:

[0375] [ka]

[0376] Trimethylbromosilane (3 mL) was added to a solution of intermediate 2 (200 mg) in dichloromethane (9 mL) at 0 °C, and the reaction was allowed to proceed for 16 hours at room temperature. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure, and the residue was purified by high-performance liquid preparative chromatography (column: Gemini-C18, 150 x 21.2 mm, 5 μm, mobile phase: acetonitrile-water (0.1% formic acid), gradient: 10-35%) to obtain the target compound (42 mg, 33% yield, 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).

[0377] [Example 14] Intermediate 1:

[0378] [ka]

[0379] 4-Thiomethyl-phenylboronic acid pinacol ester (13.8 g), 2-bromopyridine (10 g), tetrakis(triphenylphosphino)palladium (2.19 g), and sodium carbonate (50.32 g) were added sequentially to a mixture of toluene (140 mL), water (140 mL), and ethanol (40 mL). The reaction mixture was heated to 95 °C under nitrogen gas protection and stirred at that temperature for 8 h. After completion of the reaction, the reaction mixture was allowed to cool to room temperature and quenched by the addition of saturated aqueous ammonium chloride (50 mL). The mixture was then extracted three times with ethyl acetate (250 mL). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give intermediate 1 (300 mg, yield: 74.52%). MS m / z (ESI): 202.2 [M+1].

[0380] Intermediate 2:

[0381] [ka]

[0382] To a 250 mL three-neck flask, toluene (100 mL), intermediate 1 (1 g), diphenylsilane (4.61 g), diphenylamine (3.3844 g), and tris(pentafluorophenyl)borane (0.26 g) were added in this order. The reaction mixture was heated to 110 °C under nitrogen gas protection and stirred at that temperature for 18 h. After completion of the reaction, the reaction mixture was allowed to cool to room temperature and quenched by the addition of saturated aqueous ammonium chloride (50 mL). The mixture was extracted three times with ethyl acetate (50 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give intermediate 2 (0.9 g, 80% yield). MS m / z (ESI): 208.2 [M+1].

[0383] Intermediate 3:

[0384] [ka]

[0385] In a 50 mL three-neck flask, 1,2-dichloroethane (10 mL), Intermediate 2 (500 mg), and Intermediate 2 (909 mg) from Example 2 were added in this order. The reaction mixture was stirred at room temperature for 8 hours, then sodium triacetoxyborohydride (1.53 g) was added, and the reaction continued at room temperature for 18 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane (10 mL), washed once with water (10 mL), dried over 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 3 (300 mg, yield: 25.6%). MS m / z (ESI): 481.4 [M+1].

[0386] Intermediate 4:

[0387] [ka]

[0388] Intermediate 3 (100 mg) was added to a solution of ammonium carbamate (24.36 mg) and phenylacetic acid iododiacetic acid (140.69 mg) in methanol (2 mL) and allowed to react for 30 minutes at room temperature with stirring. After completion of the reaction, the reaction mixture was directly purified by high-performance liquid preparative chromatography (column: C18 spherical, 100 A, 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].

[0389] Target compound:

[0390] [ka]

[0391] Dichloromethane (6 mL), intermediate 4 (30 mg), and trimethylbromosilane (0.6 mL) were added sequentially to a 10 mL single-neck flask. The reaction mixture was stirred at room temperature for 8 hours. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure, and the residue was purified by high-performance liquid preparative 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).

[0392] [Example 15] Intermediate 1:

[0393] [ka]

[0394] In a 250 mL single-neck flask, a mixture of dioxane and water (8:1, 50 mL), 4-methoxybenzoylboronic acid pinacol ester (5.0 g), 2-bromopyridine (3.3 g), sodium carbonate (3 g), and tetrakis(triphenylphosphino)palladium (662 mg) were added in that order. The reaction mixture was heated to 80 °C under nitrogen gas protection and stirred at that temperature for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 100 mL of water and extracted three times with ethyl acetate (200 mL). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give intermediate 1 (1.1 g, yield: 27%). MS m / z (ESI): 214.1 [M+1].

[0395] Intermediate 2:

[0396] [ka]

[0397] Methanol (30 mL), intermediate 1 (1.9 g), platinum dioxide (202 mg), and hydrochloric acid (0.5 mL) were added sequentially to a 50 mL reaction vessel, and the mixture was subjected to catalytic hydrogenation at 0.4 MPa (hydrogen gas) and room temperature for 20 hours. After completion of the reaction, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give intermediate 2 (1.55 g, yield: 79%). MS m / z (ESI): 219.9 [M+1].

[0398] Intermediate 3:

[0399] [ka]

[0400] To a 50 mL single-neck flask, tetrahydrofuran (10 mL), Intermediate 2 (150 mg) from Example 2, Intermediate 2 (150 mg), and tetraethyl titanate (120 mg) were added in that order. The reaction system was heated to 100°C under nitrogen gas protection and stirred at that temperature for 8 hours. The reaction was then cooled to room temperature, and sodium triacetoxyborohydride (330 mg) was added and stirred for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted three times with ethyl acetate (50 mL). The combined organic phase was dried over 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%).

[0401] Target compound:

[0402] [ka]

[0403] N,N-Dimethylformamide (6 mL), Intermediate 3 (100 mg), hydroxylamine hydrochloride (55 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (110 mg), and triethylamine (80 mg) were added to a 50 mL single-neck flask in this order, and the reaction mixture was stirred at room temperature for 48 h. After completion of the reaction, the reaction mixture was poured into water and extracted three times with ethyl acetate (100 mL). The combined organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid preparative chromatography (column: Gemini-C18, 150 x 21.2 mm, 5 μm, mobile phase: acetonitrile-water (0.1% formic acid), gradient: 10-30%) to give the target compound (11.7 mg, yield: 11%). MS m / z (ESI): 394.1 [M+1]. 1H 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).

[0404] [Example 16] Intermediate 1:

[0405] [ka]

[0406] At -78°C under nitrogen gas protection, 3,3-difluorocyclobutan-1-one (203 mg) and trimethylsilyl trifluoromethanesulfonate (42 mg) were added to dichloromethane (5 mL) containing Intermediate 1 (860 mg) from Example 6. The mixture was stirred at -78°C for 1 hour. Triethylsilane (222 mg) was added, and the reaction mixture was allowed to warm to room temperature and continued stirring at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched by slowly adding aqueous sodium bicarbonate (10 mL), diluted with water (10 mL), extracted with dichloromethane (10 mL), washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give Intermediate 1 (80 mg, yield: 8.36%). MS m / z (ESI): 448.8 [M+23].

[0407] Intermediate 2:

[0408] [ka]

[0409] Intermediate 1 (100 mg) and sodium hydroxide (94 mg) were added sequentially to a mixture of isopropanol and water (1 mL / 3 mL), and the reaction mixture was heated to 100°C and stirred at that temperature for 16 hours. After completion of the reaction, the reaction mixture was adjusted to pH 5-6 by adding dilute hydrochloric acid (1 M, 2.50 mL) in an ice bath, diluted with water (5 mL), and extracted with ethyl acetate (5 mL). The extract was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Intermediate 2 (70 mg, yield: 60%). MS m / z (ESI): 445.9 [M+1].

[0410] Intermediate 3:

[0411] [ka]

[0412] Potassium carbonate (43 mg) and iodomethane (45 mg) were added to a solution of intermediate 2 (70 mg) in acetonitrile (2 mL), and the reaction mixture was heated to 50°C and stirred at that temperature for 2 hours. After completion of the reaction, the reaction mixture was directly concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate=3:1) to give intermediate 3 (60 mg, yield: 73%). MS m / z (ESI): 481.7 [M+23]. Intermediate 4:

[0413] [ka]

[0414] Palladium on carbon (10 mg) was added to a solution of intermediate 3 (60 mg) in tetrahydrofuran (1 mL), and the reaction was carried out by catalytic hydrogenation under a hydrogen gas atmosphere at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was directly concentrated to give intermediate 4 (35 mg, yield: 74%). MS m / z (ESI): 325.9 [M+1].

[0415] Intermediate 5:

[0416] [ka]

[0417] Intermediate 4 (35 mg) was added to a solution of Intermediate 2 (32 mg) from Example 2 in 1,2-dichloroethane (2 mL), and the mixture was stirred at room temperature for 8 hours. Sodium triacetoxyborohydride (70 mg) was then added, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was directly concentrated, 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].

[0418] Target compound:

[0419] [ka]

[0420] Intermediate 5 (80 mg, 0.134 mmol) and sodium hydroxide (54 mg, 1.35 mmol) were added sequentially to a mixture of methanol and water (1 mL / 1 mL) at room temperature, and the reaction mixture was heated to 75 °C and stirred at that temperature for 3 h. After completion of the reaction, dilute hydrochloric acid (1 M, 1.35 mL) was added to the reaction mixture in an ice bath to adjust the pH to approximately 7. The solvent was then directly lyophilized, and the residue was purified by high-performance liquid preparative 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: 30–50%) to obtain the target compound (4.7 mg, yield: 7.23%, containing 0.2 equivalents of formic acid). 1H 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].

[0421] [Example 17] Intermediate 1:

[0422] [ka]

[0423] A solution of methylmagnesium bromide (1 M, 6 mL) in tetrahydrofuran (maintaining the reaction temperature below -40°C during the addition) was slowly added dropwise to a solution of Intermediate 2 (2 g) from Example 1 in tetrahydrofuran (50 mL) at -40°C under nitrogen gas protection. After the addition was complete, the reaction was continued with stirring and allowed to warm to room temperature. The mixture was then stirred for 2 hours. After the reaction was complete, the reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL) and diluted with ethyl acetate (100 mL) and water (100 mL). The organic phase was separated, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give Intermediate 1 (1.7 g, 40% yield). MS m / z (ESI): 351.0 [M+1].

[0424] Intermediate 2:

[0425] [ka]

[0426] Diethylaminosulfur trifluoride (413 mg) was added dropwise to a solution of intermediate 1 (900 mg) in dichloromethane (20 mL) in an ice bath, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (20 mL), diluted with water (100 mL), extracted with ethyl acetate (100 mL), washed once with water (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give intermediate 2 (280 mg, yield: 27%). MS m / z (ESI): 352.9 [M+1].

[0427] Intermediate 3:

[0428] [ka]

[0429] Intermediate 2 (250 mg) and aqueous sodium hydroxide (4 M, 3 mL) were added sequentially to isopropanol (3 mL) at room temperature, and the reaction mixture was heated to 100 °C and stirred at that temperature for 30 hours. After completion of the reaction, the reaction mixture was adjusted to pH 5-6 by slowly adding dilute hydrochloric acid (1 M, 13 mL) in an ice bath, diluted with water (20 mL), and extracted with ethyl acetate (20 mL). The extract was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Intermediate 3 (200 mg, 64% yield). MS m / z (ESI): 371.9 [M+1].

[0430] Intermediate 4:

[0431] [ka]

[0432] Potassium carbonate (138 mg) and iodomethane (140 mg) were added sequentially to a solution of intermediate 3 (200 mg) in acetonitrile (5 mL) at room temperature, and the reaction mixture was heated to 50°C and stirred at that temperature for 16 hours. After completion of the reaction, the reaction mixture was directly concentrated, 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].

[0433] Intermediate 5:

[0434] [ka]

[0435] Palladium on carbon (50 mg) was added to a solution of intermediate 4 (200 mg) in tetrahydrofuran (5 mL), and the mixture was reacted under a hydrogen gas atmosphere at 1 atmosphere pressure at room temperature for 16 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was directly concentrated under reduced pressure to give intermediate 5 (95 mg, yield: 27%). MS m / z (ESI): 251.9 [M+1].

[0436] Intermediate 6:

[0437] [ka]

[0438] Intermediate 5 (50 mg), 2,8,9-trioxo-5-aza-1-silabicyclo[3.3.3]undecane (150 mg), and acetic acid (30 mg) were added sequentially to a solution of Intermediate 2 (60 mg) from Example 2 in tetrahydrofuran (5 mL) at room temperature, and the reaction mixture was heated to 70°C and stirred at that temperature for 24 hours. After completion of the reaction, the reaction mixture was directly concentrated, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to give Intermediate 6 (40 mg, yield: 26%). MS m / z (ESI): 525.2 [M+1].

[0439] Target compound:

[0440] [ka]

[0441] Intermediate 6 (40 mg) and sodium hydroxide (40 mg) were dissolved in methanol / water (2 mL / 2 The reaction mixture was heated to 75°C and stirred at this temperature for 3 hours. After completion of the reaction, dilute hydrochloric acid (1 M, 1 mL) was added to the reaction mixture in an ice bath to adjust the pH to approximately 8. The mixture was concentrated under reduced pressure, and the residue was purified by high-performance liquid preparative 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).

[0442] [Example 18] Intermediate 1:

[0443] [ka]

[0444] Ethylene glycol (558 mg) and p-toluenesulfonic acid (114 mg) were added to a solution of Intermediate 2 (2 g) from Example 1 in toluene (40 mL) at room temperature, and the reaction was heated to 110°C and stirred for 18 hours. After completion of the reaction, the reaction solution 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].

[0445] Intermediate 2:

[0446] [ka]

[0447] Sodium hydroxide (1.7 g) was added to a solution of intermediate 1 (1.6 g) in a 20 mL / 20 mL mixture of methanol and water at room temperature, and the mixture was heated to 70 °C and stirred at this temperature for 18 h. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, and the pH was adjusted to approximately 2 with dilute hydrochloric acid (2 M). The resulting mixture was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid preparative 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 give intermediate 2 (150 mg, yield: 47.6%). MS m / z (ESI): 398.2 [M+1].

[0448] Intermediate 3:

[0449] [ka]

[0450] Thionyl chloride (1.34 g) was slowly added dropwise to a solution of intermediate 2 (800 mg) in methanol (10 mL) in an ice bath, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and stirred for 2 hours to quench the reaction. The reaction mixture was then directly concentrated under reduced pressure to give intermediate 3 (680 mg, yield: 77.8%). MS m / z (ESI): 368.2 [M+1].

[0451] Intermediate 4:

[0452] [ka]

[0453] Ammonia methanol solution (1 M, 5.8 mL) was added to a solution of intermediate 3 (600 mg) in 1,2-dichloroethane (2 mL) in an ice bath. The reaction mixture was stirred at room temperature for 8 hours, and then sodium borohydride acetate (1 g) was added and stirred at room temperature for 18 hours. The resulting mixture was diluted with dichloromethane (10 mL) and water (10 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give intermediate 4 (150 mg, yield: 24.98%). MS m / z (ESI): 369.1[M+1].

[0454] Intermediate 5:

[0455] [ka]

[0456] Acetic anhydride (38.79 mg) was added to a solution of intermediate 4 (140 mg) in ethyl acetate (5 mL) at room temperature, and the mixture was stirred for 18 hours. After completion of the reaction, potassium carbonate (105 mg) was added to the reaction mixture, which was stirred for 30 minutes and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give intermediate 5 (110 mg, yield: 67%). MS m / z (ESI): 411.3 [M+1].

[0457] Intermediate 6:

[0458] [ka]

[0459] Palladium hydroxide on carbon (10 mg) was added to a solution of intermediate 5 (70 mg) in methanol (5 mL) at room temperature, and the reaction mixture was stirred at room temperature under a hydrogen gas atmosphere for 18 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was directly concentrated under reduced pressure to give intermediate 6 (50 mg, yield: 89.41%). MS m / z (ESI): 277.0 [M+1].

[0460] Intermediate 7:

[0461] [ka]

[0462] Intermediate 6 (40 mg) and Intermediate 2 (52.8 mg) from Example 2 were added to a solution of 1,2-dichloroethane (2 mL) at room temperature and stirred for 8 hours. Sodium borohydride acetate (89 mg) was then added and the mixture was stirred for 18 hours at room temperature. After completion of the reaction, the reaction mixture was diluted with dichloromethane (10 mL) and washed with water (10 mL). The organic phase was dried over 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].

[0463] Target compound:

[0464] [ka]

[0465] 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) at room temperature, and the mixture was stirred for 18 hours at room temperature. After the reaction was completed, 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 high-performance liquid preparative 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: 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), 7.3 1 (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).

[0466] [Example 19] Intermediate 1:

[0467] [ka]

[0468] At room temperature, an ethylamine tetrahydrofuran solution (0.41 mL) was added to the intermediate 2 (200 A solution of 1,2-dichloroethane (2 mL) of 1,2-dichloroethane (2 mg) was added. After stirring at room temperature for 8 hours, sodium triacetoxyborohydride (343 mg) was added and the reaction was continued at room temperature for 18 hours with stirring. After the reaction was completed, the reaction mixture was diluted with dichloromethane (10 mL), washed with water (10 mL), dried over 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 1 (100 mg, yield: 44.4%). MS m / z (ESI): 397.3 [M+1].

[0469] Intermediate 2:

[0470] [ka]

[0471] To a solution of intermediate 1 (200 mg) in dichloromethane (2 mL) was added di-tert-butyl dicarbonate (131 mg) and triethylamine (76 mg) at room temperature, and the reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane (10 mL), washed with water (10 mL), dried over 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 give intermediate 2 (200 mg, yield: 76.5%). MS m / z (ESI): 497.3 [M+1].

[0472] Intermediate 3:

[0473] [ka]

[0474] Palladium hydroxide on carbon (20 mg) was added to a solution of intermediate 2 (180 mg) in methanol (5 mL) at room temperature, and the mixture was stirred at room temperature under a hydrogen gas atmosphere for 18 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give intermediate 3 (120 mg, yield: 82.8%). MS m / z (ESI): 363.3 [M+1].

[0475] Intermediate 4:

[0476] [ka]

[0477] Intermediate 3 (150 mg) was dissolved in 1,2-dichloroethane (2 The resulting mixture was added to a 2 mL (2.5 mL) solution and stirred at room temperature for 8 hours. Sodium borohydride acetate (261 mg) was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane (10 mL), washed with water (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was 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].

[0478] Intermediate 5:

[0479] [ka]

[0480] Trimethylbromosilane (0.2 mL) was added to a solution of intermediate 4 (40 mg) in dichloromethane (1 mL) at room temperature, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure to give intermediate 5 (40 mg, yield: 99.67%). MS m / z (ESI): 436.3 [M+1].

[0481] Target compound:

[0482] [ka]

[0483] Intermediate 5 (40 mg) and sodium hydroxide (36 mg) were added sequentially to a mixture of methanol / water / tetrahydrofuran (0.5 mL / 0.5 mL / 0.5 mL) at room temperature and allowed to react for 18 hours with stirring. After completion of the reaction, the reaction mixture was adjusted to approximately pH 7 by adding dilute hydrochloric acid (2 M, 0.5 mL) in an ice bath. The resulting mixture was concentrated under reduced pressure, and the residue was purified by high-performance liquid preparative 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).

[0484] [Example 20] Intermediate 1:

[0485] [ka]

[0486] Potassium carbonate (4.47 g) was added to a solution of methyl 4-bromo-3-hydroxybenzoate (5 g) and bromoacetaldehyde diethyl acetal (4.68 g) in DMF (100 mL) at room temperature, and the reaction mixture was heated to 100 °C and stirred at that temperature for 16 hours. After completion of the reaction, the reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Intermediate 1 (7.9 g, 80% yield). MS m / z (ESI): 268.7 [M+23].

[0487] Intermediate 2:

[0488] [ka]

[0489] Polyphosphoric acid (3 g) was added to a solution of intermediate 1 (1 g) in chlorobenzene (15 mL) at room temperature, and the reaction mixture was heated to 130 °C and stirred at that temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined extracts were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give intermediate 2 (300 mg, yield: 40%). GC-MS m / z: 254,256 [M].

[0490] Intermediate 3:

[0491] [ka]

[0492] At room temperature, bistriphenylphosphinopalladium dichloride (54 mg) was added to a solution of intermediate 2 (200 mg), 2-(tributylstannyl)pyridine (344 mg), and cuprous iodide (15 mg) in dioxane (15 mL), and the reaction mixture was heated to 100 °C and stirred at that temperature for 16 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give intermediate 3 (140 mg, yield: 70%). MS m / z (ESI): 253.9 [M+1].

[0493] Intermediate 4:

[0494] [ka]

[0495] At room temperature, platinum dioxide (10 mg) was added to a solution of intermediate 3 (20 mg) in a methanol / concentrated hydrochloric acid (4 mL / 0.5 mL) mixture, and the reaction mixture was stirred at room temperature and in a pressure cooker under 4 atmospheres of hydrogen gas for 16 hours. After the reaction was completed, 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].

[0496] Intermediate 5:

[0497] [ka]

[0498] Tetraethyl titanate (83 mg) was added to a solution of Intermediate 4 (99 mg) and Intermediate 2 (110 mg) from Example 2 in tetrahydrofuran (10 mL) at room temperature, and the reaction mixture was heated to 70°C and stirred at that temperature for 16 hours. After cooling to room temperature, sodium triacetylborohydride (241 mg, 1.14 mmol) was added, and the reaction mixture was further heated to 70°C and stirred for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to give Intermediate 5 (50 mg, yield: 24%). MS m / z (ESI): 534.8 [M+1].

[0499] Target compound:

[0500] [ka]

[0501] Sodium hydroxide (36 mg) was added to a solution of intermediate 5 (50 mg) in a methanol / water (4 mL / 1 mL) mixture at room temperature, and the mixture was stirred for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The pH of the residue was adjusted to 5-6 with 5 M hydrochloric acid (1 mL) in an ice bath, and the mixture was concentrated under reduced pressure. The resulting crude product was purified by preparative high-performance liquid chromatography (Gemini-C18 column, 150 x 21.2 mm, 5 μm column, mobile phase: acetonitrile-water (0.1% formic acid), gradient: 15-40%, column temperature: 25 °C, 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). 1H 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].

[0502] [Example 21] Intermediate 1:

[0503]

change

[0504] A solution of liquid bromine (10.13 g, 0.0634 mmol) in chloroform (70 mL) was slowly added dropwise to a solution of methyl 6-aminopyridine-2-carboxylate (9.64 g, 0.0634 mol) in chloroform (408 mL) at room temperature (60 min). After the addition was complete, the reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, saturated sodium thiosulfate solution (150 mL) was added to quench the reaction. The phases were separated, the aqueous phase was extracted with dichloromethane (150 mL), and the combined organic phase was washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give Intermediate 1 (1.1 g, yield: 7.10%). MS m / z (ESI): 230.8 [M+23].

[0505] Intermediate 2:

[0506] [ka]

[0507] Intermediate 1 (1 g) was added to a 40% solution of chloroacetaldehyde (1.69 g) in isopropanol (20 mL) at room temperature, and the reaction mixture was heated to 80°C and stirred at that temperature for 18 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give Intermediate 2 (1 g, yield: 86.05%). MS m / z (ESI): 254.8 [M+23].

[0508] Intermediate 3:

[0509] [ka]

[0510] 1-(tert-Butoxycarbonyl)piperidine-2-carboxylic acid (1.35 g), iridium reagent (Ir[dF(CF3)ppy]2(dtbppy))PF6 (cassette: 870987-63-6, 43.98 mg), nickel chloride ethylene glycol dimethyl ether complex (86.25 mg), 4,4'-ditert-butyl-2,2'-bipyridine (157.84 mg), and cesium carbonate (3832.13 mg) were added sequentially to a solution of intermediate 2 (1 g) in DMF (20 mL) at room temperature. The reaction system was purged with nitrogen gas three times, and then placed in an LED blue light reactor (26 W, compact fluorescent light, 300-400 nM) for 48 h. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (200 mL), washed with water (200 mL x 5), dried over 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 give intermediate 3 (300 mg, yield: 20.17%). MS m / z (ESI): 360 [M+23].

[0511] Intermediate 4:

[0512] [ka]

[0513] Trifluoroacetic acid (0.6 mL) was added to a solution of intermediate 3 (300 mg, 0.832 mmol) in dichloromethane (3 mL) at room temperature, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure to give intermediate 4 (100 mg, yield: 46%). MS m / z (ESI): 260.2 [M+23].

[0514] Intermediate 5:

[0515] [ka]

[0516] Intermediate 4 (100 mg) was dissolved in 1,2-dichloroethane (2 The resulting mixture was added to a 100 mL (1.4 mL) solution and stirred at room temperature for 8 hours. Sodium triacetoxyborohydride (245.2 mg, 1.16 mmol) was then added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane (10 mL), washed with water (10 mL), dried over 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 give intermediate 5 (100 mg, yield: 46.16%). MS m / z (ESI): 533.3 [M+23].

[0517] Target compound:

[0518] [ka]

[0519] Sodium hydroxide (75 mg) was added to intermediate 5 (100 mg) in tetrahydrofuran / methanol / water (0.5 mL / 0.5 mL / 0.5 mL) at room temperature, and the mixture was stirred for 18 hours at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by high-performance liquid preparative chromatography (column: Gemini-C18, 150 x 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 the target compound (21 mg, yield: 26.52%). 1 H-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), 4.9 5 - 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].

[0520] [Example 22] Intermediate 1:

[0521] [ka]

[0522] At -40°C under nitrogen gas protection, a 1.3 M solution of isopropyl magnesium chloride and lithium chloride in tetrahydrofuran (36 mL) was added to a solution of methyl 4-iodobenzoate (9.9 g) in tetrahydrofuran (100 mL). The reaction mixture was stirred at -40°C for 1 hour, and then a solution of pyridine nitroxide (3.0 g) in tetrahydrofuran (50 mL) was added. The mixture was stirred at -40°C for 1 hour. A solution of sodium borohydride (1438 mg, 37.85 mmol) in methanol (50 mL) was added, and the mixture was stirred at -40°C for 1 hour. The mixture was then gradually warmed to room temperature and stirred for 16 hours. After the reaction was completed, saturated ammonium chloride solution (100 mL) was added to the reaction mixture, stirred for 0.5 hours, diluted with water (400 mL), extracted with ethyl acetate (200 mL), washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, concentrated the filtrate, and purified the residue by column chromatography (dichloromethane:methanol = 20:1) to give Intermediate 1 (2.0 g, yield: 22%). MS m / z (ESI): 234.1 [M+1].

[0523] Intermediate 2:

[0524] [ka]

[0525] Zinc powder (2.8 g) and water (20 mL) were added to a solution of intermediate 1 (2 g) in acetic acid (20 mL) at room temperature, and the reaction mixture was heated to 50 °C and stirred at that temperature for 2 hours. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was diluted with water (50 mL). 2 M sodium hydroxide solution was added to the diluted mixture in an ice bath to adjust the pH to 8-10. The mixture was extracted with ethyl acetate (50 mL). The extract was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by supercritical chiral preparative chromatography (column: chiralpak-AD-H, 250 × 20 mm, 5 μm, column temperature: 40 °C, flow rate: 40 g / min, wavelength: 214 nm, gradient: methanol (0.2% aqueous ammonia) / carbon dioxide = 35 / 65, back pressure: 100 bar) to give intermediate 2 (670 mg, yield: 35%). MS m / z (ESI): 218.1 [M+1].

[0526] Intermediate 3:

[0527] [ka]

[0528] BocO (2.0 g) and triethylamine (865 mg) were added to a solution of intermediate 2 (930 mg) in dichloromethane (10 mL) at room temperature, and the mixture was stirred for 16 hours at room temperature. After completion of the reaction, the reaction mixture was directly concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give intermediate 3 (1.4 g, yield: 92%). MS m / z (ESI): 340.0 [M+23].

[0529] Intermediate 4:

[0530] [ka]

[0531] Under the protection of an ice bath and nitrogen gas, an ether solution of diazomethane (1 M, 6.3 mL) was slowly added dropwise to a solution of intermediate 3 (200 mg) and palladium acetate (20 mg, 10%) in ether (2 mL). The mixture was stirred under the protection of an ice bath and nitrogen gas for 2 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was directly concentrated to obtain the crude product. Monitoring revealed that only a portion of the starting material was converted to the target product. After repeating the above reaction procedure four times, it was confirmed that intermediate 3 was essentially completely converted. The crude product was purified by high-performance liquid preparative 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: 60–80%) to obtain intermediate 4 (70 mg, yield: 32%). MS m / z (ESI): 354.0 [M+23].

[0532] Intermediate 5:

[0533] [ka]

[0534] A 4 M solution of hydrochloric acid in dioxane (0.5 mL) was added to a solution of intermediate 4 (70 mg) in dichloromethane (1 mL) at room temperature, and the mixture was stirred for 2 hours. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure to give intermediate 5 (70 mg, purity: 50%, yield: 72%). MS m / z (ESI): 232.2 [M+1].

[0535] Intermediate 6:

[0536] [ka]

[0537] Intermediate 5 (70 mg, 0.30 mmol) was added to a solution of Intermediate 2 (88 mg) from Example 2 in 1,2-dichloroethane (2 mL) at room temperature, and the mixture was stirred for 8 hours at room temperature. Sodium triacetoxyborohydride (192 mg) was then added, and the mixture was stirred for 16 hours at room temperature. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to give Intermediate 6 (90 mg, yield: 53%). MS m / z (ESI): 505.1 [M+1].

[0538] Target compound:

[0539] [ka]

[0540] Sodium hydroxide (143 mg) was added to a solution of intermediate 6 (90 mg) in a methanol / water (3 mL / 3 mL) mixture at room temperature, and the reaction mixture was heated to 80 °C and stirred at that temperature for 8 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 approximately 7. The resulting mixture was directly lyophilized to remove the solvent, and the residue was purified by high-performance liquid preparative 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].

[0541] [Example 23] Intermediate 1:

[0542] [ka]

[0543] Sodium borohydride (1.1 g) was added to a solution of Intermediate 1 (5.0 g) from Example 1 and cerium trichloride (3.7 g) in methanol (80 mL) at room temperature. The reaction was allowed to proceed with stirring at room temperature for 3 hours, and then sodium borohydride (1.1 g) was added. The reaction was allowed to proceed with stirring at room temperature for another 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (80 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Intermediate 1 (4.6 g, 87% yield). MS m / z (ESI): 356.8 [M+23].

[0544] Intermediate 2:

[0545] [ka]

[0546] Sodium hydride (660 mg, 60%) was added to a solution of intermediate 1 (4.6 g) in DMF (50 mL) in an ice bath and stirred for 5 minutes. After that, iodoethane (3.2 g) was added and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was quenched with water (0.5 mL). The reaction mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give intermediate 2 (1.5 g, 30% yield). MS m / z (ESI): 384.9 [M+23].

[0547] Intermediate 3:

[0548] [ka]

[0549] A diethylzinc hexane solution (1 mol / L, 3 mL) was added to a solution of intermediate 2 (1.1 g) and diiodomethane (620 mg) in dichloromethane (20 mL) in an ice bath, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give intermediate 3 (950 mg, 29% yield). MS m / z (ESI): 376.9 [M+H].

[0550] Intermediate 4:

[0551] [ka]

[0552] Aqueous sodium hydroxide (1.01 g) was added to a solution of intermediate 3 (950 mg) in ethanol / water (20 mL / 7 mL) at room temperature, and the reaction mixture was heated to 90°C and stirred at that temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove ethanol. Water (15 mL) was added to the residue, and the pH was adjusted to 4-5 with 5 M dilute hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 4 (810 mg, 81% yield). MS m / z (ESI): 395.9 [M+H].

[0553] Intermediate 5:

[0554] [ka]

[0555] Thionyl chloride (1.5 mL) was added to a solution of intermediate 4 (810 mg) in methanol (15 mL) at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was directly concentrated under reduced pressure to give intermediate 5 (810 mg, 81% yield). MS m / z (ESI): 409.9 [M+H].

[0556] Intermediate 6:

[0557] [ka]

[0558] 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) at room temperature, and the mixture was stirred for 16 hours at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give intermediate 6 (400 mg, 74% yield). MS m / z (ESI): 276.0 [M+H].

[0559] Intermediate 7:

[0560] [ka]

[0561] Sodium triacetylborohydride (219 mg) was added to a solution of intermediate 6 (94 mg, 0.344 mmol) and intermediate 2 (100 mg) from Example 2 in 1,2-dichloroethane (10 mL) at room temperature, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate=2:1) ​​to give intermediate 7 (130 mg, 68% yield). MS m / z (ESI): 548.8 [M+H].

[0562] Target compound:

[0563] [ka]

[0564] Sodium hydroxide (102 mg) was added to a solution of Intermediate 7 (130 mg) in methanol / water (8 mL / 2 The reaction mixture was added to a mixture of 1 mL of acetonitrile and 1 mL of acetonitrile, and the mixture was stirred at room temperature for 48 hours. After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure to remove the solvent, and the residue was purified by high-performance liquid preparative chromatography (column: Gemini-C18, 150 × 21.2 mm, 5 μm, mobile phase: acetonitrile-water (0.1% formic acid), gradient: The target compound was obtained by elution with a 20-40% column temperature at 25°C, a flow rate of 14 mL / min, a wavelength of 214 nm, and a column pressure of 80 bar (30 mg, 27% yield). MS m / z (ESI): 434.9 [M+1]. 1H 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).

[0565] [Example 24] Intermediate 1:

[0566] [ka]

[0567] Lithium bis(trimethylsilyl)amide (4.5 mL, 4.5 mmol) was added dropwise to a solution of Intermediate 1 (1 g, 3.0 mmol) from Example 1 in THF (4 mL) at -78°C. After reacting at -78°C for 1 hour, methyl bromoacetate (1.4 g, 9.0 mmol) was added dropwise to the reaction mixture at the same temperature. The mixture was stirred at the same temperature for 1 hour, then allowed to warm to room temperature and stirred overnight at room temperature. After the reaction was complete, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined extracts were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (dichloromethane:methanol = 5:1) to give Intermediate 1 (330 mg, yield: 28%). MS m / z (ESI): 405.2 [M+1].

[0568] Intermediate 2:

[0569] [ka]

[0570] Sodium borohydride (1.2 g, 32 mmol) was slowly added to a solution of intermediate 1 (1.6 g, 4.0 mmol) in methanol (30 mL) at 0 °C and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined extracts were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (dichloromethane:methanol = 2:1) to give intermediate 2 (900 mg, yield: 60%). MS m / z (ESI): 381.1 [M+1].

[0571] Intermediate 3:

[0572] [ka]

[0573] p-Toluenesulfonyl chloride (1.8 g, 9.5 mmol) was added to intermediate 2 (1.2 g, 3.2 mmol) at room temperature. A solution of (40 mL) dichloromethane (77 mg, 0.6 mmol), 4-dimethylaminopyridine (77 mg, 0.6 mmol), and triethylamine (957 mg, 9.5 mmol) was slowly added, and the reaction mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was washed with water (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (dichloromethane:methanol = 3:1) to give intermediate 3 (500 mg, yield: 44%). MS m / z (ESI): 386.1 [M+23].

[0574] Intermediate 4:

[0575] [ka]

[0576] Intermediate 3 (500 mg, 1.4 mmol) and barium hydroxide (1.6 g, 5.0 mmol) were added to a mixture of isopropanol and water (5 mL / 12.5 mL) at room temperature, and the reaction mixture was heated to 100 °C and stirred at that temperature for 16 hours. After the reaction was completed, the reaction mixture was adjusted to approximately pH 2 with dilute aqueous hydrochloric acid (2 M) and extracted with ethyl acetate (30 mL x 3). The combined extracts were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give Intermediate 4 (300 mg, 57% yield). MS m / z (ESI): 404.1 [M+23].

[0577] Intermediate 5:

[0578] [ka]

[0579] Iodomethane (224 mg, 1.6 mmol) was added to a solution of intermediate 4 (300 mg, 0.8 mmol) and potassium carbonate (217 mg, 1.6 mmol) in N,N-dimethylformamide (5 mL) at room temperature, and the reaction mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The extracted organic phases were combined, washed with saturated brine (30 mL × 4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give intermediate 5 (300 mg, yield: 96%). MS m / z (ESI):418.1[M+23].

[0580] [ka]

[0581] Intermediate 6: Palladium acetate (85 mg, 0.4 mmol) was added to a solution of intermediate 5 (300 mg, 0.8 mmol), triethylsilane (881 mg, 7.6 mmol), and triethylamine (384 mg, 3.8 mmol) in dichloromethane (10 mL) at room temperature, and the mixture was stirred for 3 hours. After completion of the reaction, 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 give intermediate 6 (200 mg, yield: 77%). MS m / z (ESI): 262.1 [M+1].

[0582] Intermediate 7:

[0583] [ka]

[0584] Intermediate 6 (100 mg, 0.383 mmol) was added to a solution of Intermediate 2 (110 mg, 1.91 mmol) from Example 2, silatrane (200 mg, 1.53 mmol), and glacial acetic acid (4 drops) in tetrahydrofuran (5 mL) at room temperature. The reaction mixture was heated to 75 °C and stirred at this temperature for 24 hours. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined extracts were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give Intermediate 7 (110 mg, yield: 53%). MS m / z (ESI): 534.7 [M+1].

[0585] Target compound:

[0586] [ka]

[0587] Sodium hydroxide (150 mg, 3.73 mmol) was added to a solution of intermediate 7 (100 mg, 0.19 mmol) in a mixture of methanol and water (2 mL / 2 mL) at room temperature, and the mixture was stirred for 48 hours at room temperature. After the reaction was completed, dilute hydrochloric acid (2 M) was added dropwise to the reaction mixture to adjust the pH to approximately 5-7. The resulting mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative high-performance liquid chromatography (column: AQ-C18, 150 × 21.2 mm, 5 μm, column temperature: 25 °C, flow rate: 20 mL / min, wavelength: 214 nm ... Purification was performed under ram pressure of 80 bar, with a mobile phase of acetonitrile-water (0.1% formic acid), gradient of 10-30%, to give the target compound (29.2 mg, yield: 37%, containing 0.4 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).

[0588] [Example 25] Intermediate 1:

[0589] [ka]

[0590] At -78°C under nitrogen gas protection, 2,2-difluorocyclopropane-1-formaldehyde (320 mg) and trimethylsilyl trifluoromethanesulfonate (168 mg) were added in sequence to a solution of Intermediate 1 (680 mg) from Example 6 in dichloromethane (5 mL). The reaction was allowed to proceed with stirring at -78°C for 1 hour. Triethylsilane (351 mg) was then added, and the reaction was allowed to warm to room temperature and continued at room temperature for 16 hours. After completion of the reaction, 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].

[0591] Intermediate 2:

[0592] [ka]

[0593] Intermediate 1 (300 mg, 0.70 mmol) and sodium hydroxide (563 mg, 14.07 mmol) were added to a mixture of isopropanol and water (2.5 mL / 2.5 mL) at room temperature, and the reaction mixture was heated to 100 °C and stirred at that temperature for 24 h. After completion of the reaction, the reaction mixture was adjusted to pH 5-6 by slowly adding dilute hydrochloric acid (2 M, 7.5 mL) in an ice bath, diluted with water (20 mL), and extracted with ethyl acetate (10 mL). The extract was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give Intermediate 2 (270 mg, 77% yield). MS m / z (ESI): 445.8 [M+1].

[0594] Intermediate 3:

[0595] [ka]

[0596] Potassium carbonate (167 mg) and iodomethane (172 mg) were added to a solution of intermediate 2 (270 mg) in acetonitrile (3 mL) at room temperature, and the reaction mixture was heated to 50°C and stirred at that temperature for 2 hours. After completion of the reaction, the reaction mixture was directly 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].

[0597] Intermediate 4:

[0598] [ka]

[0599] Palladium on carbon (50 mg) was added to a solution of intermediate 3 (190 mg) in tetrahydrofuran (3 mL) at room temperature under nitrogen gas protection, and the reaction was catalytically hydrogenated under a hydrogen gas atmosphere at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was directly concentrated to give intermediate 4 (135 mg, yield: 90%). MS m / z (ESI): 325.9 [M+1].

[0600] Intermediate 5:

[0601] [ka]

[0602] Intermediate 4 (135 mg) was dissolved in 1,2-dichloroethane (3 mg) of Intermediate 2 (132 mg) of Example 2 at room temperature. The resulting mixture was added to a 2 mL (2.5 mL) solution and stirred at room temperature for 8 hours. Sodium triacetoxyborohydride (264 mg) was then added, and the mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction mixture was directly 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].

[0603] Target compound:

[0604] [ka]

[0605] Sodium hydroxide (214 mg) was added to a solution of Intermediate 5 (160 mg) in methanol / water (2 mL / 2 The reaction mixture was heated to 80 °C and stirred at that temperature for 24 h. After completion of the reaction, dilute hydrochloric acid (2 M, 2.7 mL) was added to the reaction mixture in an ice bath to adjust the pH to approximately 7. The resulting mixture was directly lyophilized to remove the solvent. The residue was purified by high-performance liquid preparative 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 (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).

[0606] [Example 26] Intermediate 1:

[0607] [ka]

[0608] Under nitrogen gas protection, a solution of intermediate 1 (930 mg) from Example 5 in dichloromethane (20 mL) was cooled to -78 °C. Cyclopropanecarboxaldehyde (289 mg) and trimethylsilyl trifluoromethanesulfonate (229 mg) were added in sequence. The reaction was stirred at -78 °C for 1 hour, followed by the addition of triethylsilane (479 mg). The reaction mixture was then allowed to warm to room temperature and stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give intermediate 1 (600 mg, yield: 67%). MS m / z (ESI): 390.9 [M+1].

[0609] Intermediate 2:

[0610] [ka]

[0611] Palladium on carbon (50 mg) was added to a solution of intermediate 1 (340 mg) in tetrahydrofuran (3 mL) at room temperature under nitrogen gas protection, and the reaction mixture was subjected to catalytic hydrogenation at room temperature under a hydrogen gas atmosphere for 16 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was directly concentrated under reduced pressure to give intermediate 2 (220 mg, yield: 89%). MS m / z (ESI): 257.0 [M+1].

[0612] Intermediate 3:

[0613] [ka]

[0614] Intermediate 2 (220 mg) was dissolved in 1,2-dichloroethane (5 mg) of Intermediate 2 (248 mg) of Example 2 at room temperature. The reaction mixture was stirred at room temperature for 8 hours, and then sodium triacetoxyborohydride (546 mg) was added, followed by stirring at room temperature for 16 hours. After completion of the reaction, the reaction mixture was directly 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].

[0615] Intermediate 4:

[0616] [ka]

[0617] Azidotrimethylsilane (174 mg) and dibutyltin diacetate (265 mg) were added to a solution of intermediate 3 (400 mg) in toluene (5 mL) at room temperature, and the reaction mixture was heated to 90°C and stirred at that temperature for 24 hours. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to give intermediate 4 (800 mg, purity: 50%, yield: 92%). MS m / z (ESI): 572.8 [M+1].

[0618] Target compound:

[0619] [ka]

[0620] Sodium hydroxide (1.1 g) was added to a solution of intermediate 4 (780 mg) in methanol / water (5 mL / 5 mL) at room temperature, and the reaction mixture was heated to 80°C and stirred at that 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 directly freeze-dried to remove the solvent, and the resulting residue was purified by high-performance liquid preparative chromatography (column: Xbridge-C18, 150 × 19 mm, 5 μm, column temperature: 25°C, flow rate: 20 mL / min, wavelength: 214 nm, pressure: 93 bar, mobile phase: アセトニトリル-water (0.05% のアンモニアwater), blending: 25~35%) target compound をた (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).

[0621] [Example 27] Intermediate 1:

[0622]

change

[0623] The iridium reagent (Ir[dF(CF3)ppy]2(dtbppy))PF6 (cassette: 870987-63-6, 26 mg) was added to a solution of 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'-ditert-butyl-2,2'-dipyridine (310 mg), and cesium carbonate (1.5 g, 4.63 mmol) in N,N-dimethylformamide (6 mL) at room temperature. The reaction mixture was purged with nitrogen gas three times and then placed in an LED blue light reactor (26 W, compact fluorescent light, 300-400 nM) for 16 hours. After completion of the reaction, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give Intermediate 1 (500 mg, yield: 33%). MS m / z (ESI): 321.0 [M+H].

[0624] Intermediate 2:

[0625] [ka]

[0626] Metachloroperbenzoic acid (2.7 g) was added to a solution of intermediate 1 (1.0 g) in dichloromethane (20 mL) at room temperature, and the reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane (30 mL), washed sequentially with saturated sodium bicarbonate solution (15 mL × 2) and saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 2 (900 mg, 86% yield). MS m / z (ESI): 336.0 [M+H].

[0627] Intermediate 3:

[0628] [ka]

[0629] Trifluoroacetic anhydride (5.6 g) was added to a solution of intermediate 2 (900 mg) in DMF (20 mL) in an ice bath, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed successively with saturated aqueous sodium bicarbonate (20 mL) and saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) to give intermediate 3 (350 mg, 38% yield). MS m / z (ESI): 336.9 [M+1].

[0630] Intermediate 4:

[0631] [ka]

[0632] Intermediate 3 (350 mg) was dissolved in a solution of hydrogen chloride in dioxane (15 mL) at room temperature and allowed to react with stirring for 16 hours. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure to give Intermediate 4 (300 mg, 98% yield). MS m / z (ESI): 236.9 [M+1].

[0633] Intermediate 5:

[0634] [ka]

[0635] Silatrane (371 mg) was added to a solution of Intermediate 2 (245 mg, 0.84 mmol) from Example 2, Intermediate 4 (200 mg, 0.84 mmol), and acetic acid (0.5 mL) in 1,2-dichloroethane (15 mL) at room temperature, and the reaction mixture was heated to 90°C and stirred at that temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane:methanol = 10:1) to give Intermediate 5 (130 mg, yield: 52%). MS m / z (ESI): 495.8 [M+1].

[0636] Target compound:

[0637] [ka]

[0638] In an ice bath, trimethylbromosilane (1 mL) was added to a solution of Intermediate 5 (130 mg) in dichloromethane (4 The resulting mixture was added to a solution of 1 mL of acetonitrile and water (1 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure, and the residue was purified by high-performance liquid preparative chromatography (column: Gemini-C18, 150 x 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).

[0639] [Example 28] Intermediate 1:

[0640] [ka]

[0641] Silver tetrafluoroborate (26 g) was slowly added to a solution of diphenyl sulfide (8 g) and 1-chloro-3-iodopropane (8 g) in nitromethane (15 mL) at room temperature, and the mixture was stirred for 18 hours at room temperature. After the reaction was complete, the mixture was diluted with dichloromethane (100 mL), filtered, and the filtrate was concentrated under reduced pressure. The remaining phase was stirred in methyl tert-butyl ether (100 mL) for 30 minutes to precipitate a white solid. The solid was filtered, and the filter cake was collected to obtain Intermediate 1 (8 g, 50% yield). MS m / z (ESI): 263.1 [M+1].

[0642] Intermediate 2:

[0643] [ka]

[0644] Potassium tert-butoxide (4 g) in N,N-dimethylformamide (24 mL) was added to a solution of intermediate 1 (12 g) in tetrahydrofuran (120 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was diluted with dichloromethane (400 mL) and washed with water (150 mL). The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. Methyl tert-butyl ether (300 mL) was added to the resulting residue and stirred for 1 hour. The methyl tert-butyl ether phase was poured off, and the remaining oil was recrystallized from 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].

[0645] Intermediate 3:

[0646] [ka]

[0647] At -40°C, potassium hexamethyldisilazide (18 mL, 10 mmol) was slowly added dropwise to a solution of intermediate 2 (3 g) in tetrahydrofuran (30 mL). After the addition was complete, the reaction was stirred at -40°C for 10 minutes, and then intermediate 2 (3 g) from Example 1 was added dropwise. The reaction was continued with stirring at -40°C for 30 minutes, then allowed to warm to room temperature and stirred at room temperature for 18 hours. After the reaction was complete, the reaction was quenched by adding water (20 mL) and extracted with ethyl acetate (100 mL x 2). The combined extracts were dried over anhydrous sodium sulfate and filtered. The filtrate was directly concentrated, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give intermediate 3 (1.5 g, yield: 44.4%). MS m / z (ESI): 407.9 [M+H].

[0648] Intermediate 4:

[0649] [ka]

[0650] At room temperature, lithium tetrafluoroborate (0.02 g) was added to a solution of intermediate 3 (1.5 g) in toluene (10 mL), and the reaction mixture was heated to 70°C and stirred at that temperature for 3 hours. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate=3:1) to give intermediate 4 (1.2 g, yield: 47.5%). MS m / z (ESI): 408.2 [M+1].

[0651] Intermediate 5:

[0652] [ka]

[0653] In an ice bath, a solution of lithium tri-sec-butylborohydride in tetrahydrofuran (1 M, 4.3 The resulting mixture was quenched by adding methanol (5 mL). The resulting mixture was directly concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give intermediate 5 (0.8 g, 80% yield). MS m / z (ESI): 410.1 [M+H].

[0654] Intermediate 6:

[0655] [ka]

[0656] A solution of potassium tert-butoxide in tetrahydrofuran (1 M, 1 mL) was added to a solution of intermediate 5 (200 mg) in tetrahydrofuran (2 mL) in an ice bath and stirred at room temperature for 1 hour. After this, iodomethane (347 mg) was added and the reaction was continued at room temperature for 18 hours with stirring. After completion of the reaction, the mixture was quenched with 2 mL of methanol. The resulting mixture was directly concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give intermediate 6 (100 mg, 45.9% yield). MS m / z (ESI): 424.2 [M+H].

[0657] Intermediate 7:

[0658] [ka]

[0659] Palladium hydroxide on carbon (10%, 13 mg) was added to a solution of intermediate 6 (100 mg) in methanol (5 mL) at room temperature under nitrogen gas protection. The reaction mixture was purged with hydrogen gas three times and then stirred at room temperature for 18 hours. After completion of the reaction, 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 give intermediate 7 (50 mg, yield: 69.5%). MS m / z (ESI): 290.2 [M+1].

[0660] Intermediate 8:

[0661] [ka]

[0662] Intermediate 7 (50 mg) was added to a solution of Intermediate 2 (60 mg) from Example 2 in 1,2-dichloroethane (2 mL) at room temperature, and the mixture was stirred for 8 hours at room temperature. Sodium triacetoxyborohydride (110 mg) was then added, and the mixture was stirred for 18 hours at room temperature. After the reaction was complete, the reaction mixture was diluted with dichloromethane (10 mL), washed with water (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 10:1) to give Intermediate 8 (50 mg, yield: 48.73%). MS m / z (ESI): 563.3 [M+1].

[0663] Target compound:

[0664] [ka]

[0665] Sodium hydroxide (35.5 mg) was added to a solution of Intermediate 8 (50 mg) in tetrahydrofuran / methanol / water (0.5 mL / 0.5 mL / 0.5 mL) at room temperature, and the reaction mixture was heated to 70 °C and stirred at that temperature for 18 hours. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid preparative 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 the following component: Component 1, Example 28-P1 (13.3 mg, yield: 31.79%): MS m / z (ESI): 448.9 [M+1]. 1 H 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, Actual Treatment 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).

[0666] [Example 29] Intermediate 1:

[0667]

change

[0668] In an ice bath, a solution of potassium tert-butoxide in tetrahydrofuran (1 M, 1.5 mL) was added to a solution of Intermediate 5 (Example 28) (200 mg) in tetrahydrofuran (4 mL). The reaction was allowed to warm and stirred at room temperature for 1 hour. Iodoethane (381 mg) was added and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the mixture was quenched with methanol (2 mL). The resulting mixture was directly concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give Intermediate 1 (80 mg, 35.6% yield). MS m / z (ESI): 451.8 [M+1].

[0669] Intermediate 2:

[0670] [ka]

[0671] Palladium hydroxide on carbon (10%, 10 mg) was added to a solution of intermediate 1 (80 mg) in methanol (5 mL) at room temperature under nitrogen gas protection. The reaction mixture was purged with hydrogen gas three times and then stirred at room temperature for 18 hours. After completion of the reaction, 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 give intermediate 2 (50 mg, yield: 84.4%). MS m / z (ESI): 317.9 [M+1].

[0672] Intermediate 3:

[0673] [ka]

[0674] Intermediate 2 (50 mg) was added to a solution of Intermediate 2 (55 mg) from Example 2 in 1,2-dichloroethane (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 8 hours, followed by the addition of sodium triacetoxyborohydride (100 mg), and the reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane (10 mL), washed with water (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 10:1) to give Intermediate 3 (50 mg, yield: 48.7%). MS m / z (ESI): 563.3 [M+1].

[0675] Target compound:

[0676] [ka]

[0677] Sodium hydroxide (34 mg) was added to a solution of intermediate 3 (50 mg) in tetrahydrofuran / methanol / water (0.5 mL / 0.5 mL / 0.5 mL) at room temperature, and the reaction mixture was heated to 65 °C and stirred at that temperature for 18 hours. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid preparative 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 the following component: Component 1, Example 29-P1 (32.2 mg, yield: 39.1%): MS m / z (ESI): 462.8 [M+1]. 1H 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 the actual treatment of component 2 (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).

[0678] [Example 30] Intermediate 1:

[0679]

change

[0680] At room temperature, tert-butyldiphenylchlorosilane (25 g) was added sequentially to a solution of Intermediate 3 (25 g) from Example 1 and imidazole (6.6 g) in dichloromethane (200 mL), and the mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction mixture was washed with water (500 mL), dried over 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 1 (11.4 g, yield: 26%). MS m / z (ESI): 597.0 [M+23].

[0681] Intermediate 2:

[0682] [ka]

[0683] Intermediate 1 (3 g, 6.7 mmol) was added to a 1:1 mixture of 80% sulfuric acid and methanol (16 mL) at room temperature, and the reaction mixture was heated to 100 °C and stirred at that temperature for 16 h. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, diluted with water (50 mL), and the pH was adjusted to 6-7 with dilute aqueous sodium hydroxide (2 M). The resulting mixture was lyophilized to remove the solvent, and the residue was purified by column chromatography (dichloromethane:methanol = 5:1) to give Intermediate 2 (1.07 g, 67% yield). MS m / z (ESI): 235.9 [M+1].

[0684] Intermediate 3:

[0685] [ka]

[0686] At room temperature, (4-nitrophenyl)[2-(trimethylsilyl)ethyl]carbonate (1.3 g), triethylamine (552 mg), and 4-dimethylaminopyridine (280 mg) were added to prepare Intermediate 2. The resulting mixture was added to a DMF (6 mL) solution of 1.1 g of HCl and stirred at room temperature for 16 hours. After completion of the reaction, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined extracts were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give intermediate 3 (1.13 g, yield: 60%). MS m / z (ESI): 401.8 [M+23].

[0687] Intermediate 4:

[0688] [ka]

[0689] Des-Martin reagent (2.4 g) was added to a solution of intermediate 3 (1.1 g) in dichloromethane (8 mL) at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was directly filtered. The filtrate was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined extracts were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give intermediate 4 (560 mg, yield: 48%). MS m / z (ESI): 399.7 [M+23].

[0690] Intermediate 5:

[0691] [ka]

[0692] Potassium tert-butoxide (613 mg) and tert-butanol (6 mL) were added sequentially to trimethylsulfoxonium iodide (1.63 g) at room temperature, and the reaction mixture was heated to 60 °C and stirred at that temperature for 1 hour. Intermediate 4 (560 mg) was then added, and the reaction mixture was stirred at 60 °C for 16 hours. After the reaction was complete, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined extracts were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give Intermediate 5 (427 mg, yield: 73%). MS m / z (ESI): 413.7 [M+23].

[0693] Intermediate 6:

[0694] [ka]

[0695] Trimethylsilyldiazomethane (0.7 mL, 2 M) was added to a solution of intermediate 5 (300 mg) in toluene / methanol (4 mL / 1 mL) at room temperature and stirred for 1 hour. After completion of the reaction, the reaction mixture was quenched with acetic acid (2 mL), diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined extracts were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give intermediate 6 (133 mg, yield: 43%). MS m / z (ESI): 427.8 [M+23].

[0696] Intermediate 7:

[0697] [ka]

[0698] A solution of tetrabutylammonium fluoride in tetrahydrofuran (0.6 mL, 1 M) was added to a solution of intermediate 6 (133 mg) in tetrahydrofuran (4 mL) at room temperature, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (ethyl acetate:tetrahydrofuran = 4:1) to give intermediate 7 (75 mg, yield: 94%). MS m / z (ESI): 261.8 [M+1].

[0699] Intermediate 8:

[0700] [ka]

[0701] At room temperature, Intermediate 2 (111 mg) from Example 2, silatrane (201 mg), and acetic acid (0.04 mL) were added to a solution of Intermediate 7 (100 mg) in tetrahydrofuran (10 mL), and the reaction mixture was heated to 70°C and stirred at that temperature for 16 hours. After completion of the reaction, 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].

[0702] Target compound:

[0703] [ka]

[0704] Sodium hydroxide (75 mg) was added to a solution of intermediate 8 (50 mg) in a methanol / water (2 mL / 2 mL) mixture at room temperature, and the mixture was stirred for 40 hours at room temperature. After completion of the reaction, the reaction mixture was directly purified by high-performance liquid preparative chromatography (Xbridge-C18 column, 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), 6.3 2 - 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).

[0705] [Example 31] Intermediate 1:

[0706] [ka]

[0707] At -78°C under nitrogen gas protection, n-butyllithium (2.4 M, 25 mL) solution was slowly added to a solution of ethyl propiolate (5.89 g) in tetrahydrofuran (200 mL). After reacting at this temperature for 0.5 hours, intermediate 2 (5 g, 14.95 mmol) from Example 1 was slowly added, and the reaction mixture was stirred at -78°C for 1.5 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (20 mL) was slowly added to quench the reaction, followed by dilution with water (200 mL) and extraction with ethyl acetate (200 mL). The extract was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified 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].

[0708] Intermediate 2:

[0709] [ka]

[0710] Intermediate 1 (1.9 g) was added to a solution of nickel chloride hexahydrate (300 mg) in ethanol (50 mL) in an ice bath and stirred for 10 minutes at that temperature. Sodium borohydride (800 mg) was then added in portions, and the reaction mixture was stirred for 20 minutes in an ice bath. After completion of the reaction, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The extract was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give Intermediate 2 (1.9 g, 90% yield). MS m / z (ESI): 437.1 [M+1].

[0711] Intermediate 3:

[0712] [ka]

[0713] Lithium aluminum hydride (200 mg) was slowly added to a solution of intermediate 2 (1.9 g) in ethanol and tetrahydrofuran (20 mL / 20 mL) in an ice bath, and the reaction mixture was stirred at the same temperature for 1 hour. After completion of the reaction, saturated aqueous NaSO (1 mL) was added to quench the reaction. The reaction mixture was filtered, the filtrate was directly concentrated, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to give intermediate 3 (1.5 g, yield: 73%). MS m / z (ESI): 395.1 [M+1].

[0714] Intermediate 4:

[0715] [ka]

[0716] Diisopropyl azodicarboxylate (0.92 g) was slowly added to a solution of intermediate 3 (1.5 g) and triphenylphosphine (1.99 g) in tetrahydrofuran (30 mL) in an ice bath. The reaction mixture was allowed to warm to room temperature and stirred at that temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL). The extract was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give intermediate 4 (1.5 g, 89% yield). MS m / z (ESI): 376.9 [M+1].

[0717] Intermediate 5:

[0718] [ka]

[0719] Water (20 mL) and barium hydroxide octahydrate (6.3 g) were added sequentially to a solution of intermediate 4 (1.5 g) in isopropanol (20 mL) at room temperature, and the reaction mixture was heated to 100°C and stirred at that temperature for 16 hours. After the reaction was completed, the reaction mixture was diluted with water (50 mL), adjusted to a pH of approximately 3 with dilute hydrochloric acid, and extracted with ethyl acetate (100 mL). The extracted phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give intermediate 5 (1.5 g, 85% yield). MS m / z (ESI): 396.0 [M+1].

[0720] Intermediate 6:

[0721] [ka]

[0722] Potassium carbonate (500 mg) and iodomethane (500 mg) were added sequentially to a solution of intermediate 5 (500 mg) in acetonitrile (20 mL) at room temperature, and the reaction mixture was heated to 65°C and stirred at that temperature for 16 hours. After the reaction was completed, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The extract was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give intermediate 6 (400 mg, yield: 77%). MS m / z (ESI): 410.1 [M+1].

[0723] Intermediate 7:

[0724] [ka]

[0725] Palladium hydroxide on carbon (10%, 50 mg) was slowly added to a solution of intermediate 6 (200 mg) in tetrahydrofuran (10 mL) at room temperature under nitrogen gas protection, and the mixture was stirred at room temperature under a hydrogen gas atmosphere at 2 atm for 16 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was directly concentrated to give intermediate 7 (150 mg, yield: 84%). MS m / z (ESI): 276.1 [M+1].

[0726] Intermediate 8:

[0727] [ka]

[0728] Glacial acetic acid (50 mg) and silatrane (200 mg) were added to a solution of Intermediate 7 (150 mg) and Intermediate 2 (150 mg) from Example 2 in tetrahydrofuran (5 mL) at room temperature, and the reaction mixture was heated to 75°C and stirred at this temperature for 16 hours. After completion of the reaction, the reaction mixture was directly concentrated, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to give Intermediate 8 (150 mg, yield: 71%). MS m / z (ESI): 549.2 [M+1].

[0729] Target compound:

[0730] [ka]

[0731] Sodium hydroxide (40 mg) was added to a solution of Intermediate 8 (150 mg) in methanol and water (3 mL / 3 The reaction mixture was heated to 75°C and stirred at this temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated and the residue was purified by high-performance liquid preparative chromatography (column: Gemini-C18, 150 x 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).

[0732] [Example 32] Intermediate 1:

[0733] [ka]

[0734] Toluenesulfonic acid (35 mg) was added to a solution of Intermediate 2 (800 mg) from Example 31 in toluene (10 mL) at room temperature, heated to 110°C, and reacted at that temperature for 18 hours. After the reaction was completed and allowed to cool to room temperature, the reaction mixture was directly concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give Intermediate 1 (550 mg, yield: 73.0%). MS m / z (ESI): 391.2 [M+1].

[0735] Intermediate 2:

[0736] [ka]

[0737] A 3 M solution of methylmagnesium chloride in tetrahydrofuran (1.4 mL) was slowly added dropwise to a solution of intermediate 1 (550 mg) in tetrahydrofuran (10 mL) in an ice bath. The reaction mixture was allowed to warm naturally and stirred at that temperature for 18 hours. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give intermediate 2 (150 mg, yield: 25.0%). MS m / z (ESI): 404.8 [M+1].

[0738] Intermediate 3:

[0739] [ka]

[0740] Barium hydroxide octahydrate (584 mg) was added to a solution of intermediate 2 (150 mg) in a mixture of isopropanol and water (3 mL / 6 mL) at room temperature, and the reaction mixture was heated to 100 °C and stirred at that temperature for 18 hours. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and the pH was adjusted to approximately 5 with dilute hydrochloric acid (1 M). The resulting mixture was extracted with ethyl acetate (20 mL x 2). The combined extracts were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloroethane:methanol = 10:1) to give intermediate 3 (50 mg, yield: 30.3%). MS m / z (ESI): 423.8 [M+1].

[0741] Intermediate 4:

[0742] [ka]

[0743] Iodomethane (54 mg) was added to a solution of intermediate 3 (50 mg) and potassium carbonate (52 mg) in acetone (5 mL) at room temperature, and the mixture was allowed to react at room temperature for 18 hours. After the reaction was completed, the mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL × 2). The combined extracts were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was 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].

[0744] Intermediate 5:

[0745] [ka]

[0746] Palladium hydroxide on carbon (3 mg) was added to a solution of intermediate 4 (30 mg) in methanol (5 mL) under nitrogen gas protection at room temperature, and the reaction mixture was stirred at room temperature under a hydrogen gas atmosphere for 18 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was directly concentrated under reduced pressure to give intermediate 5 (20 mg, purity: 85%, yield: 81.6%).

[0747] Intermediate 6:

[0748] [ka]

[0749] Intermediate 5 (20 mg) was added to a solution of Intermediate 2 (23 mg) from Example 2 in 1,2-dichloroethane (2 mL) at room temperature, and the reaction mixture was stirred at room temperature for 8 hours. Sodium triacetoxyborohydride (42 mg) was then added, and the reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane (10 mL), washed with water (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 10:1) to give Intermediate 6 (20 mg, yield: 49.9%). MS m / z (ESI): 577.1 [M+1].

[0750] Target compound:

[0751] [ka]

[0752] Sodium hydroxide (33.8 mg) was added to a solution of intermediate 6 (20 mg, 0.08 mmol) in tetrahydrofuran / methanol / water (0.5 mL / 0.5 mL / 0.5 mL) at room temperature, and the reaction mixture was heated to 65 °C and stirred at that temperature for 18 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by high-performance preparative 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]. 1H 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).

[0753] [Example 33] Intermediate 1:

[0754] [ka]

[0755] At room temperature, compound S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (cas: 76189-56-5) (404 mg) and rhodium bis(dicyclopentadienyl) tetrafluoroborate (cas: 36620-11-8) (202 mg) were added to a solution of 3-fluoro-4-methylbenzeneboronic acid (2568 mg) in 1,4-dioxane (7 mL), and the reaction was carried out under nitrogen gas protection and room temperature with stirring for 8 hours. Then, 4-oxo-3,4-dihydropyridine-1(2H)-carboxylic acid benzyl ester (cas: 185847-84-1) (2500 mg), triethylamine (1094 mg), and water (0.7 mL) were added in this order, and the reaction was heated to 40 ° C under nitrogen gas protection and continued at that temperature for 16 hours. After the reaction was completed, the reaction mixture was directly concentrated, 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].

[0756] Intermediate 2:

[0757] [ka]

[0758] Sodium borohydride (196 mg) was added in portions to a solution of intermediate 1 (3000 mg) in tetrahydrofuran and ethanol (15 mL / 15 mL) at room temperature, and the mixture was stirred for 16 hours at room temperature. After completion of the reaction, the reaction mixture was cooled to below 0°C and quenched by slowly adding saturated aqueous ammonium chloride (5 mL). The mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL). The extract was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give intermediate 2 (1100 mg, purity: 40%, yield: 14%). MS m / z (ESI): 401.8 [M+1].

[0759] Intermediate 3:

[0760] [ka]

[0761] Imidazole (242 mg) and tert-butyldiphenylchlorosilane (904 mg) were added to a solution of intermediate 2 (1100 mg) in dichloromethane (20 mL) at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (50 mL). The extract was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 15:1) to give intermediate 3 (390 mg, yield: 20%). MS m / z (ESI): 661.6 [M+23].

[0762] Intermediate 4:

[0763] [ka]

[0764] Intermediate 3 (390 mg) was added to a tetrabutylammonium fluoride solution (1.0 M, 3 mL) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL). The extract was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give Intermediate 4 (180 mg, yield: 66%). MS m / z (ESI): 423.8 [M+23].

[0765] Intermediate 5:

[0766] [ka]

[0767] Imidazole (61 mg) and tert-butyldimethylchlorosilane (74 mg) were added to a solution of intermediate 4 (180 mg) in DMF (3 mL) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL). The extract was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give intermediate 5 (200 mg, 78% yield). MS m / z (ESI): 537.8 [M+23].

[0768] Intermediate 6:

[0769] [ka]

[0770] Cyclopropanecarboxaldehyde (147 mg) and trimethylsilyl trifluoromethanesulfonate (168 mg) were added sequentially to a solution of intermediate 5 (685 mg) in dichloromethane (13 mL) at -78 °C under nitrogen gas protection. The reaction was allowed to proceed with stirring at -78 °C for 1 hour. Triethylsilane (308 mg) was then added, and the reaction mixture was allowed to warm to room temperature and continued stirring at room temperature for 16 hours. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give intermediate 6 (500 mg, yield: 74%). MS m / z (ESI): 477.7 [M+23].

[0771] Intermediate 7:

[0772] [ka]

[0773] Palladium / carbon (50 mg) was added to a solution of intermediate 6 (500 mg, 1.10 mmol) in tetrahydrofuran (5 mL) at room temperature under nitrogen gas protection, and the mixture was stirred at room temperature under a hydrogen gas atmosphere for 2 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was directly concentrated to give intermediate 7 (330 mg, yield: 84%). MS m / z (ESI): 322.0[M+1].

[0774] Intermediate 8:

[0775] [ka]

[0776] Intermediate 7 (180 mg) was dissolved in 1,2-dichloroethane (5 mg) of Intermediate 2 (178 mg) of Example 2 at room temperature. The reaction mixture was stirred at room temperature for 8 hours, and then sodium triacetoxyborohydride (356 mg) was added, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was directly concentrated, and the residue was purified by column chromatography (dichloromethane:methanol=20:1) to give intermediate 8 (350 mg, yield: 84%). MS m / z (ESI): 594.8 [M+1].

[0777] Target compound:

[0778] [ka]

[0779] Sodium hydroxide (470 mg) was dissolved in compound 9 (350 mg) in methanol / water (5 mL / 5 mL) at room temperature. The reaction mixture was heated to 80°C and stirred at that 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 then directly freeze-dried, and the residue was purified by high-performance liquid preparative 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].

[0780] The following compounds were produced by the methods of Examples 3 to 33 above.

[0781] [ka] TIFF2025186330000235.tif150166 TIFF2025186330000236.tif207167 TIFF2025186330000237.tif203166 TIFF2025186330000238.tif202166 TIFF2025186330000239.tif202167 TIFF2025186330000240.tif112166

[0782] Preparation of control compound (Example-26c, WO2015009616A1): Control Intermediate 1:

[0783] [ka]

[0784] Tetrahydrofuran (3 mL), Intermediate 7 from Example 1 (127 mg), Intermediate 2 from Example 2 (130 mg), and tetraethyl titanate (56 mg) were added to a 50 mL sealed tube. The reaction mixture was heated to 70°C under nitrogen gas protection and reacted with stirring for 16 hours. The reaction mixture was cooled to room temperature, and sodium triacetoxyborohydride (52 mg) was added. The mixture was heated to 70°C and reacted for 1 hour. After cooling to room temperature, 4 mL of methanol was added to quench the reaction. The reaction mixture was concentrated, and the residue was purified by column chromatography (methanol:dichloromethane = 1:10) to obtain reference intermediate 1 (170 mg, yield: 52%).

[0785] Control Compound:

[0786] [ka]

[0787] 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 allowed to proceed at room temperature for 16 hours. After completion of the reaction, the mixture was diluted with water (10 mL) and adjusted to pH 7-8 with dilute hydrochloric acid (1 M). The solvent was removed under reduced pressure (water bath: 45 °C). The residue was purified by high-performance liquid preparative chromatography (column: Gemini-C18, 150 × 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 H NMR (400 MHz, DMSO-d6) 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).

[0788] [Biological Examples] 1. Optical Surface Plasmon Resonance (SPR) Binding Force Detection The SPR experiment was carried out at 25°C using PBS buffer supplemented with 0.05% (v / v) P20 and 5% DMSO as the running buffer, and the analytical instrument used was a GE Healthcare Biacore 8K. A CM7 chip (GE Healthcare) was activated with 1 mM EDC and 100 mM NHS at a flow rate of 30 μL / min for 420 s. Complement factor B was covalently immobilized to the detection chip by diluting it to 50 μg / mL in 10 mM sodium acetate (pH 4.0) and coupling it at a flow rate of 10 μL / min for 1,200 s (protein immobilization level: 25,000 RU). The detection chip was then sealed with 1 M ethanolamine hydrochloride at a flow rate of 10 μL / min for 300 s. The target compound concentration was 500 μM, the binding time was 120 s, and the separation time was 300 s. Data analysis was performed using a 1:1 binding model (Biacore Insight Evaluation Software, Version 2.0.15.12933).

[0789] Test Results: The experimental results of the compounds according to some examples are shown in Table 1. At a concentration of 500 μM, Examples 5 and 6 have more significant binding ability with the target protein, which is significantly superior to the control compound, indicating that the compounds of the present invention have relatively good binding ability with the target protein.

[0790] [Table 1]

[0791] Legend: ND means no SPR binding force data detected.

[0792] 2. Detection of TR-FRET binding strength The inhibitory activity of compounds against human complement factor B was screened by competitive binding experiments using a Cy5 fluorescently labeled small molecule inhibitor as a probe. Complement factor B and EZ-Link™ Sulfo-NHS-LC-LC-Biotin were incubated at a 1:2 ratio on ice for 1 hour, and then 1 M Tris (pH 7.5) was added to terminate the reaction. Biotin-labeled complement factor B was then purified twice using a 2 mL Zeba™ Desalt spin column (EZ-Link™ Sulfo-NHS-LC-Biotin instructions). For the experiment, biotin-labeled complement factor B (final concentration: 10 nM) and various concentrations of compounds were preincubated 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-based Elmer, #AD0060) (final concentrations: 75 nM and 5 nM, respectively). Kinetic readings were performed on a microplate reader (excitation at 337 nm, emission at 665 nm, time-gated for 70 μs) to obtain time-dependent fluorescence energy transfer (TR-FRET) data and calculate the IC 50 It was decided that:

[0793] 3. Detection of C3 hydrolysis activity by the complement system The test compound was tested at a concentration of 10 μM, diluted 3-fold, for seven concentration points, and detected per well. In a 96-well plate, the test compound was diluted with DMSO to a final concentration of 1000x, and then further diluted with Diluent (WIESLAB® COMPLEMENT SYSTEM ALTERNATIVE PATHWAY AP330) to a final concentration of 5x. 30 μL was transferred to a 96-well plate, 120 μL of pre-sera was added, and the mixture was incubated at room temperature for 15 minutes. 30 μL of 5% DMSO and 120 μL of pre-sera were added to positive control wells, while 30 μL of 5% DMSO and 120 μL of diluent were added to negative control wells. (3) 100 μL was added to the reaction plate and 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 washing solution. 100 μL of conjugate (WIESLAB® COMPLEMENT SYSTEM ALTERNATIVE PATHWAY AP330) was added to each well and 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 washing solution. Next, 100 μL of substrate was added to each well and incubated at room temperature for 30 minutes. Detection was performed using a microplate reader (Perkin Elmer, EnSight), and the OD405 value was read.

[0794] 4. Detection of complement hemolytic activity The hemolysis experiment was performed as described in Xuan Yuan et al., Hematologica (2017) 102:466-475. Prior to the experiment, the optimal concentration of normal human serum (NHS) required to achieve 100% lysis of rabbit red blood cells (RE) was determined by titration. In this experiment, NHS was diluted with GVB0 buffer (0.1% gelatin, 5 mM Veronal, 145 mM NaCl, 0.025% NaN3, pH 7.3, Complement Technology) containing 10 mM Mg-EGTA and incubated with various concentrations of test compounds at 37°C for 15 minutes. Freshly suspended RE (obtained from healthy Japanese white rabbits) in GVB0 buffer containing 10 mM Mg-EGTA was added to a final concentration of 1 x 108 cells / mL and 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 no test compound. The negative control (0% lysis) consisted of GVB0 buffer containing inactivated NHS (heated at 56°C for 30 min or at 65°C for 5 min) and RE but no test compound, containing 10 mM Mg-EGTA. The samples were centrifuged at 2000g for 5 min, and the supernatants were collected. The absorbance at 415 nm (A415) was detected using a microplate reader (Molecular Devices, SpectraMax i3X). IC 50 Values ​​were calculated from the percentage hemolysis as a function of test compound concentration by nonlinear regression.

[0795] Test Results: The experimental results of the compounds according to some of the examples are shown in Table 2, among which, Example 5 has significantly better inhibitory activity against complement factor B in human serum than the control compound, indicating that the compounds of the present invention can relatively effectively inhibit the activity of complement factor B in human serum and prevent hemolysis caused by attack on rabbit red blood cells.

[0796] [Table 2]

[0797] 5. Liver microsome stability experiments (1) Preparation of buffer solution A 0.1 M dipotassium hydrogen phosphate distilled aqueous solution (containing 1 mM ethylenediaminetetraacetic acid) was taken, and then the pH was adjusted to 7.4 with 0.1 M dipotassium hydrogen phosphate distilled aqueous solution (containing 1 mM ethylenediaminetetraacetic acid).

[0798] (2) Preparation of microsome source and working solution Microsome Source: Rat: SD Rat Liver Microsomes, Cat. No.: LM-DS-02M, RILD Research Institute for Liver Diseases (Shanghai) Co., Ltd.

[0799] Monkey: Cynomolgus Monkey Liver Microsomes, Cat. No.: LM-SXH-02M, RILD Ruide Liver Disease Research (Shanghai) Co., Ltd.

[0800] Human: Pooled Human Liver Microsomes (Mongolian), Cat. No.: LM-R-02M, RILD Research Institute for Liver Diseases (Shanghai) Co., Ltd.

[0801] Preparation of working fluid The control compound and test compound were each prepared in DMSO to a 10 mM solution, and then 10 μL of the solution was added to 190 μL of acetonitrile to prepare a 0.5 mM solution. 1.5 μL of the 0.5 mM compound solution was added to 18.75 μM of 20 mg / mL liver microsomes and 479.75 μL of buffer solution. (The actual amount can be adjusted depending on the usage situation.)

[0802] (3) Experimental process A 10 mg / mL solution of reduced coenzyme II (NADPH) was prepared in buffer. A 96-well plate was placed on ice, and each compound was placed in a corresponding well at different time points (0, 10, 30, 60, 90 min, non-NADPH). 30 μL of working solution was added to each well. 155 μL of ice-cold acetonitrile solution (1 μM internal standard concentration) was added to the 0 min well, mixed evenly with a pipette, and then 15 μL of NADPH (10 mg / mL) was added. Before the reaction, the 96-well plate was preincubated for 5 min on a thermostatic microwell plate shaker (37°C). Then, 15 μL of NADPH (10 mg / mL) was added to each well to initiate the metabolic reaction. After 10, 30, 60, and 90 min of reaction, the reaction was stopped by adding 155 μL of ice-cold acetonitrile solution (1 μM internal standard concentration) to the corresponding well. After 90 minutes in the non-NADPH system, the reaction was stopped by adding 155 μL of ice-cold acetonitrile solution (internal standard concentration 1 μM). After the reaction was completed, the 96-well plate was shaken for 10 minutes on a microwell plate shaker (600 rpm), then centrifuged for 15 minutes at 4°C and 4000 g. 50 μL of the supernatant was added to a new 2 mL 96-well plate, and 300 μL of deionized water was added. The mixture was analyzed on an AB SCIEX ExionLC-Triple Quad 5500 high-performance liquid chromatography mass spectrometer using Analyst 1.6.3 software. The test results are shown in Table 3.

[0803] [Table 3]

[0804] Experimental Results: The data show that the compounds of Examples 4, 5 and 6 all have greater liver microsomal stability.

[0805] 6. PK study of single intragastric administration in rats Experimental Method: Male Wistar Han rats (Shanghai Xipuer-Bikai Experimental Animal Co., Ltd.) aged 6 to 9 weeks were used. They were fasted overnight, and divided into groups of 3 rats. The control compound, the compounds of Example 5 and Example 6 were administered intragastrically at 3 mg / kg, respectively. The administration volume was 10 mL / kg. Blood was collected from the jugular vein at 0.2 mg / kg at each time point. The samples were anticoagulated with EDTA-K2 and immediately centrifuged at 4000 rpm for 5 min at 4°C. The supernatant was collected and stored in a -80°C refrigerator until further analysis. Blood was collected at the following time points: pre-administration, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, and 24 h. After administration, the animals were monitored regularly and euthanized after blood collection at all time points. Plasma samples were analyzed by LC-MS / MS, and kinetic parameters (Tmax, Cmax, T1 / 2, AUC) were calculated using WinNonlin software.

[0806] Test Results: The test results are shown in Table 4.

[0807] [Table 4]

[0808] 7. PK / PD study of single intragastric administration in cynomolgus monkeys Experimental Method: Cynomolgus monkeys were used, with three monkeys per group, and the control compound, Compounds 3 & 30 mpk of Example 5, were administered intragastrically. Blood samples were taken at different time points 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), among which Normal Human Serum (Complement Technology, NHS).

[0809] Test Results: Within the detected concentration and time range, under the same dose, the average blood drug concentration of the compound of Example 5 is significantly higher than that of the control compound. The blood drug concentration curve of cynomolgus monkeys is shown in Figure 1, and the inhibition of serum AP activity of cynomolgus monkeys is shown in Figure 2. Figure 2 shows that the compounds of the present invention can effectively inhibit serum AP activity of cynomolgus monkeys.

[0810] 8. Streptococcus-induced rat rheumatoid arthritis (RA) model Experimental Method: In the experiment, 6-9 week-old female Lewis rats (Beijing Weitong Lihua) were used, with six rats per group. On Day 1, streptococcus and several other bacterial cell wall peptidoglycan complexes (2-3 mg per rat) were administered intraperitoneally. The control compound (15 mpk) and Example 5 (15 mpk) were administered intragastrically daily for 25 consecutive days. The rats were scored for arthritis at different times. The scoring criteria were as follows: The severity of the lesions (redness and swelling) was scored on a scale of 0 to 4 points, with a maximum score of 4 for each limb and a maximum score of 16 for all four limbs of each animal. The scoring criteria were as follows: A score of 0 is no redness or swelling, 1 is redness and swelling of 1-2 interphalangeal joints, 2 is redness and swelling of 3-4 interphalangeal joints, 3 is redness and swelling of 4 or more interphalangeal joints, and 4 is severe redness and swelling from the toes or fingers to the ankle or wrist.

[0811] Test Results: The experimental results are shown in Figure 3. The data show that both the control compound and Example 5 can improve the compound scores for arthritis, and the effect of the compound of Example 5 is significantly better than that of the control compound, proving that the compounds of the present invention, especially the compounds of the Examples, can more effectively improve streptococcal-induced rat rheumatoid arthritis.

[0812] The exemplary embodiments of the present invention have been described above. It should be understood that the scope of the claims of the present application is not limited to the above exemplary embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art without departing from the spirit and principles of the present invention are also included in the scope of the claims of the present application. [Brief explanation of the drawings]

[0813] [Figure 1] 1 shows experimental data (ng / mL) of blood drug concentration curves in cynomolgus monkeys in a biological example. [Figure 2] 1 shows experimental data (% relative to 0 h) of serum AP activity curves in cynomolgus monkeys in a biological example. [Figure 3] 1 shows experimental data on streptococcal-induced rheumatoid arthritis in rats in a biological example.

Claims

1. A compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, crystalline polymorph, pharmaceutically acceptable salt or prodrug compound thereof, 【Chemistry 1】 Among them, R 1 are halogens, OH, CN, NO 2 , unsubstituted or optionally one, two or more R a C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl groups, 5- to 20-membered heteroaryl groups, 3- to 20-membered heterocyclyl groups, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 Aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, NH 2 Selected from R 2 H, halogen, OH, CN, NO 2 , unsubstituted or optionally one, two or more R b C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl groups, 5- to 20-membered heteroaryl groups, 3- to 20-membered heterocyclyl groups, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 Aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, NH 2 Selected from R 3 are halogens, OH, CN, NO 2 , unsubstituted or optionally one, two or more R c C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl groups, 5- to 20-membered heteroaryl groups, 3- to 20-membered heterocyclyl groups, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 Aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, NH 2 Selected from R 4 is H, unsubstituted or optionally one, two or more R d C replaced by 1-40 Alkyl group, C 3-40 Cycloalkyl groups, C 1-40 Alkyl-C(O)-, C 3-40 Cycloalkyl-C(O)-, C 1-40 Alkyl-S(O) 2 -, C 3-40 Cycloalkyl-C(O) 2 -Selected from R 5 H, halogen, OH, CN, NO 2 , unsubstituted or optionally one, two or more R e C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl groups, 5- to 20-membered heteroaryl groups, 3- to 20-membered heterocyclyl groups, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 Aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, NH 2 Selected from R 6 H, halogen, OH, CN, NO 2 , unsubstituted or optionally one, two or more R f C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl groups, 5- to 20-membered heteroaryl groups, 3- to 20-membered heterocyclyl groups, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 Aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, NH 2 Selected from R 7 is hydrogen, OH, CN, unsubstituted or optionally one, two or more R g C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl groups, 5- to 20-membered heteroaryl groups, 3- to 20-membered heterocyclyl groups, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 Aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, NH 2 Selected from Or, R 1 , R 7 are unsubstituted or optionally one, two or more R h and the 5- to 20-membered ring structure is, for example, C 5-20 Cycloalkenyl group, C 6-20 may be selected from an aryl group, a 5- to 20-membered heterocyclyl group, and a 5- to 20-membered heteroaryl group; Or, R 6 , R 7 are unsubstituted or optionally one, two or more R i and the 5- to 20-membered ring structure is, for example, C 5-20 Cycloalkenyl group, C 6-20 may be selected from an aryl group, a 5- to 20-membered heterocyclyl group, and a 5- to 20-membered heteroaryl group; Cy is independently R 8 , R 9 , R 10 , R 11 C substituted by 1, 2, 3, 4, 5, 6, 7, 8 or more substituents selected from 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl groups, 5- to 20-membered heteroaryl groups, 3- to 20-membered heterocyclyl groups, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 Aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, C 3-40 Cycloalkyl-C 1-40 Alkyl-, C 3-40 Cycloalkenyl-C 1-40 Alkyl-, C 3-40 Cycloalkynyl-C 1-40 Alkyl-, C 6-20 Aryl-C 1-40 Alkyl-, 5- to 20-membered heteroaryl-C 1-40 Alkyl-, 3- to 20-membered heterocyclyl-C 1-40 Alkyl-, C 3-40 Cycloalkyl-C 1-40 Alkyl-, C 3-40 Cycloalkenyl-C 1-40 Alkyl-, C 3-40 Cycloalkynyl-C 1-40 Alkyl-, C 6-20 Aryl-C 1-40 Alkyl-, 5- to 20-membered heteroaryl-C 1-40 Alkyl-, 3- to 20-membered heterocyclyl-C 1-40 alkyl-, wherein the 3- to 20-membered heterocyclyl group in the group Cy contains 1 to 5 heteroatoms selected from N, O and S, and at most one N atom; R 8 , R 9 are identical or different and independently represent H, unsubstituted or optionally one, two or more R j C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl groups, 5- to 20-membered heteroaryl groups, 3- to 20-membered heterocyclyl groups, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 Aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, C 3-40 Cycloalkyl-C 1-40 Alkyl-, C 3-40 Cycloalkenyl-C 1-40 Alkyl-, C 3-40 Cycloalkynyl-C 1-40 Alkyl-, C 6-20 Aryl-C 1-40 Alkyl-, 5- to 20-membered heteroaryl-C 1-40 Alkyl-, 3- to 20-membered heterocyclyl-C 1-40 alkyl-, R 10 , R 11 are the same or different and independently represent H, absent, halogen, OH, CN, NO 2 , unsubstituted or optionally one, two or more R k C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl groups, 5- to 20-membered heteroaryl groups, 3- to 20-membered heterocyclyl groups, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 Aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, NH 2 Selected from Or, R 8 , R 9 are unsubstituted or optionally one, two or more R j and the 5- to 20-membered ring structure is, for example, C 3-20 Cycloalkyl groups, C 5-20 Cycloalkenyl group, C 6-20 may be selected from an aryl group, a 5- to 20-membered heterocyclyl group, and a 5- to 20-membered heteroaryl group; Or, R 10 , R 11 are unsubstituted or optionally one, two or more R k and the 5- to 20-membered ring structure is, for example, C 3-20 Cycloalkyl groups, C 5-20 Cycloalkenyl group, C 6-20 may be selected from an aryl group, a 5- to 20-membered heterocyclyl group, and a 5- to 20-membered heteroaryl group; Each R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k are the same or different and independently represent H, halogen, OH, CN, NO 2 , oxo (=O), thio (=S), unsubstituted or optionally one, two or more R p C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl groups, 5- to 20-membered heteroaryl groups, 3- to 20-membered heterocyclyl groups, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 Aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, C 1-40 Alkylthio group, C 2-40 Alkenylthio group, C 2-40 Alkynylthio group, C 3-40 Cycloalkylthio group, C 3-40 Cycloalkenylthio group, C 3-40 Cycloalkynylthio group, C 6-20 Arylthio group, 5- to 20-membered heteroarylthio group, 3- to 20-membered heterocyclylthio group, NH 2 , -C(O)R 12 , -C(O)OR 13 , -OC(O)R 14 , -S(O) 2 R 15 , -S(O) 2 OR 16 、-OS(O) 2 R 17 、-B(OR 18 )(OR 19 )、-P(O)(OR 20 )(OR 21 )、 【Chemistry 2】 Selected from Each R p are the same or different and independently represent H, halogen, OH, CN, NO 2 , oxo (=O), thio (=S), unsubstituted or optionally one, two or more R q C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl groups, 5- to 20-membered heteroaryl groups, 3- to 20-membered heterocyclyl groups, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 Aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, C 1-40 Alkylthio group, C 2-40 Alkenylthio group, C 2-40 Alkynylthio group, C 3-40 Cycloalkylthio group, C 3-40 Cycloalkenylthio group, C 3-40 Cycloalkynylthio group, C 6-20 Arylthio group, 5- to 20-membered heteroarylthio group, 3- to 20-membered heterocyclylthio group, NH 2 , -C(O)R 121 , -C(O)OR 131 , -OC(O)R 141 , -S(O) 2 R 151 , -S(O) 2 OR 161 , -OS(O) 2 R 171 , -B (OR 181 ) (OR 191 ), -P(O)(OR 201 ) (OR 211 ), 【Transformation 3】 Selected from Each R q are the same or different and independently represent H, halogen, OH, CN, NO 2 , oxo (=O), thio (=S), C 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl groups, 5- to 20-membered heteroaryl groups, 3- to 20-membered heterocyclyl groups, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 Aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, C 1-40 Alkylthio group, C 2-40 Alkenylthio group, C 2-40 Alkynylthio group, C 3-40 Cycloalkylthio group, C 3-40 Cycloalkenylthio group, C 3-40 Cycloalkynylthio group, C 6-20 Arylthio group, 5- to 20-membered heteroarylthio group, 3- to 20-membered heterocyclylthio group, NH 2 , -C(O)C 1-40 Alkyl group, -C(O)NH 2 , -C(O)NHC 1-40 Alkyl group, -C(O)-NH-OH, -COOC 1-40 Alkyl groups, -COOH, -OC(O)C 1-40 Alkyl groups, -OC(O)H, -S(O) 2 C 1-40 Alkyl group, S(O) 2 H, -S(O) 2 OC 1-40 Alkyl group, -OS(O) 2 C 1-40 Alkyl group, -P(O)(OH) 2 , -B(OH) 2 、 【Chemistry 4】 Selected from 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 are homologous or different, and independently represent H, C 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl group, 5- to 20-membered heteroaryl group, 3- to 20-membered heterocyclyl group, NH 2 Selected from A compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope label, solvate, crystalline polymorph, pharmaceutically acceptable salt or prodrug compound thereof.

2. R 1 are halogens, OH, CN, NO 2 , unsubstituted or optionally one, two or more R a C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 1-6 Alkyloxy group, C 3-8 Cycloalkyloxy group, NH 2 Selected from Preferably, R 2 H, halogen, OH, CN, NO 2 , unsubstituted or optionally one, two or more R b C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 1-6 Alkyloxy group, C 3-8 Cycloalkyloxy group, NH 2 Selected from Preferably, R 3 are halogens, OH, CN, NO 2 , unsubstituted or optionally one, two or more R c C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 1-6 Alkyloxy group, C 3-8 Cycloalkyloxy group, NH 2 Selected from Preferably, R 4 is H, unsubstituted or optionally one, two or more R d C replaced by 1-6 selected from alkyl groups, Preferably, R 5 H, halogen, OH, CN, NO 2 , unsubstituted or optionally one, two or more R e C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 1-6 Alkyloxy group, C 3-8 Cycloalkyloxy group, NH 2 Selected from Preferably, R 6 H, halogen, OH, CN, NO 2 , unsubstituted or optionally one, two or more R f C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 1-6 Alkyloxy group, C 3-8 Cycloalkyloxy group, NH 2 Selected from R 7 is hydrogen, OH, CN, unsubstituted or optionally one, two or more R g C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 1-6 Alkyloxy group, C 3-8 Cycloalkyloxy group, NH 2 Selected from Preferably, R 1 , R 7 are unsubstituted or optionally one, two or more R h C replaced by 5-10 Cycloalkenyl group, C 6-10 Aryl groups, 5- to 10-membered heterocyclyl groups, 5- to 10-membered heteroaryl groups, such as C 5-6 Cycloalkenyl group, C 6 and R 1 , R 7 are unsubstituted or optionally one, two or more R fused together with the atom connected thereto to the indole group in formula (I). h Cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl groups, in which the sulfur atom is not oxidized or is substituted by -S(O) 2 -yl), Preferably, R 6 , R 7 are unsubstituted or optionally one, two or more R i C replaced by 5-20 Cycloalkenyl group, C 6-20 Aryl groups, 5- to 20-membered heterocyclyl groups, 5- to 20-membered heteroaryl groups, such as C 5-6 Cycloalkenyl group, C 6 and R 6 , R 7 are unsubstituted or optionally one, two or more R fused together with the atom connected thereto to the indole group in formula (I). h Cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl groups, in which the sulfur atom is not oxidized or is substituted by -S(O) 2 -yl), Preferably, Cy is independently R 8 , R 9 , R 10 , R 11 C substituted by 1, 2, 3, 4, 5, 6, 7, 8 or more substituents selected from 3-40 Cycloalkyl groups, C 6-20 aryl group, a 5- to 20-membered heteroaryl group, and a 3- to 20-membered heterocyclyl group, wherein the 3- to 20-membered heterocyclyl group in the group Cy contains 1 to 5 heteroatoms selected from N, O, and S, and contains at most one N atom; Preferably, Cy is R 8 , R 9 , R 10 and R 11 For example, Cy may be selected from 3 to 20 membered heterocyclyl groups substituted by 1, 2, 3, 4, 5, 6, 7, or 8 substituents selected from R 8 , R 9 , R 10 and R 11 and optionally further independently substituted by R 8 , R 9 , R 10 , R 11 wherein the 3- to 20-membered heterocyclyl group in group Cy contains 1 to 3 heteroatoms selected from N, O and S, and at most one N atom; Preferably, Cy may be selected from the following saturated or unsaturated non-aromatic carbocyclic or heterocyclic ring systems: a 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic (e.g., fused, bridged, spiro) ring, or a 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system, which ring system contains 1 to 5 heteroatoms selected from O, S and N, and contains at most one N atom, of which the N and S atoms, if present, are optionally unoxidized or oxidized to various oxidation states; Preferably, Cy comprises one N atom and optionally present or absent 1 or 2 atoms selected from O or S, and preferably, when Cy is selected from a bicyclic ring system, the N atom and the O or S atom are in different ring structures in the bicycle; Preferably, Cy contains at most two heteroatoms, of which only one is selected from N atoms; Preferably, Cy is a cyclyl group, i.e., a piperidinyl group, a piperidinyl group fused with a ring system selected from a cyclopropyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, and a phenyl group; aza and / or oxa spiro[2.4], [3.4], [4.4], [2.5], [3.5], [4.5] or [5.5]cyclyl groups; Aza and / or oxa bicyclic [2.2.1], [2.2.2], [3.2.1], [3.2.2] or [3.3.2] cyclyl groups may be selected from Preferably, the N atom in Cy is in a position corresponding to the Cy group of formula (I) and R 7 The group bonds to the shared C atom, Preferably, Cy is a monocyclic, fused ring, or bridged ring group, such as piperidinyl group, 【Transformation 5】 may be selected from the group Preferably, R 8 optionally one, two or more R j C replaced by 6-10 may be selected from an aryl group, a 5- to 10-membered heteroaryl group, or a 3- to 20-membered heterocyclyl group, such as a phenyl group, a pyridyl group, a pyrazinyl group, a furanyl group, a pyranyl group, a benzocyclohexane group, a benzocyclopentane group, a benzofuranyl group, or a benzotetrahydrofuranyl group; Preferably, R 9 are identical or different and independently represent H, unsubstituted or optionally one, two or more R j C replaced by 1-6 selected from alkyl groups, Preferably, R 8 , R 9 are unsubstituted or optionally one, two or more R j C replaced by 5-10 Cycloalkenyl group, C 6-10 may form an aryl group, a 5- to 10-membered heterocyclyl group, or a 5- to 10-membered heteroaryl group; Preferably, R 10 , R 11 are the same or different and independently represent halogen, OH, CN, NO 2 , unsubstituted or optionally one, two or more R k C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 6-10 Aryl group, 5- to 6-membered heteroaryl group, 3- to 6-membered heterocyclyl group, C 1-6 Alkyloxy group, C 3-6 Cycloalkyloxy group, C 6-10 Aryloxy group, 5- to 6-membered heteroaryloxy group, 3- to 6-membered heterocyclyloxy group, NH 2 may be selected from Preferably, R 10 , R 11 are unsubstituted or optionally one, two or more R k C replaced by 5-10 Cycloalkenyl group, C 6-10 may form an aryl group, a 5- to 10-membered heterocyclyl group, or a 5- to 10-membered heteroaryl group; Preferably, each R j are identical or different and are independently unsubstituted or optionally substituted with one, two or more R p C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 6-10 Aryl group, 5- to 10-membered heteroaryl group, 3- to 10-membered heterocyclyl group, C 1-6 Alkyloxy group, C 3-8 Cycloalkyloxy group, C 6-10 Aryloxy group, 5- to 10-membered heteroaryloxy group, 3- to 10-membered heterocyclyloxy group, NH 2 , -C(O)R 12 , -C(O)OR 13 , -B (OR 18 ) (OR 19 ), -P(O)(OR 20 ) (OR 21 ), 【Transformation 6】 Selected from Preferably, each R k are the same or different and independently represent halogen, OH, CN, NO 2 , unsubstituted or optionally one, two or more R p C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 6-10 Aryl group, 5- to 6-membered heteroaryl group, 3- to 6-membered heterocyclyl group, C 1-6 Alkyloxy group, C 3-6 Cycloalkyloxy group, C 6-10 Aryloxy group, 5- to 6-membered heteroaryloxy group, 3- to 6-membered heterocyclyloxy group, NH 2 may be selected from Preferably, each R p are identical or different and independently represent H, halogen, OH, unsubstituted or optionally one, two or more R q C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 6-10 Aryl group, 5- to 6-membered heteroaryl group, 3- to 6-membered heterocyclyl group, C 1-6 Alkyloxy group, C 3-8 Cycloalkyloxy group, C 6-10 Aryloxy group, 5- to 6-membered heteroaryloxy group, 3- to 6-membered heterocyclyloxy group, NH 2 , -C(O)R 121 , -C(O)OR 131 , -B (OR 181 ) (OR 191 ), -P(O)(OR 201 ) (OR 211 ), 【Transformation 7】 Selected from Preferably, R q has the definition set forth in claim 1, Preferably, R 12 , R 13 , R 18 , R 19 , R 20 , R 21 , R 121 , R 131 , R 181 , R 191 , R 201 , R 211 are homologous or different, and independently represent H, C 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 6-10 Aryl group, 5- to 6-membered heteroaryl group, 3- to 6-membered heterocyclyl group, NH 2 The compound according to claim 1, its racemate, stereoisomer, tautomer, isotope label, solvate, crystalline polymorph, pharmaceutically acceptable salt or prodrug compound thereof, is selected from the group consisting of:

3. The compound has a structure represented by formula (I-1) or formula (I-2), 【Transformation 8】 wherein W is selected from CH, O or S; Y and Z are homologous or different and independently form CHR 11 , O or S; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 have independently the definitions set forth in claim 1 or 2, Preferably, a carbon-carbon single bond or a carbon-carbon double bond may be formed between W and Z or between Z and Y; Preferably, when W is selected from O or S, R 10 does not exist, Preferably, when W is selected from CH, R 10 H, halogen, OH, CN, NO 2 , unsubstituted or optionally one, two or more R k C replaced by 1-40 Alkyl group, C 2-40 Alkenyl group, C 2-40 Alkynyl group, C 3-40 Cycloalkyl groups, C 3-40 Cycloalkenyl group, C 3-40 Cycloalkynyl group, C 6-20 Aryl groups, 5- to 20-membered heteroaryl groups, 3- to 20-membered heterocyclyl groups, C 1-40 Alkyloxy group, C 2-40 Alkenyloxy group, C 2-40 Alkynyloxy group, C 3-40 Cycloalkyloxy group, C 3-40 Cycloalkenyloxy group, C 3-40 Cycloalkynyloxy group, C 6-20 Aryloxy group, 5- to 20-membered heteroaryloxy group, 3- to 20-membered heterocyclyloxy group, NH 2 Among them, R k The compound according to claim 1 or 2, characterized in that: has the definition set forth in claim 1 or 2, its racemate, stereoisomer, tautomer, isotopically labeled, solvate, crystalline polymorph, pharmaceutically acceptable salt or prodrug compound thereof.

4. The compound has a structure represented by formula (I-3) or formula (I-4), 【Chemistry 9】 Among them, W, Y, Z, and R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 9 , R 10 , R j has independently the definition set forth in claim 3, n is selected from 1, 2, 3, 4 or 5; Preferably, n may be selected from 1, 2 or 3; Preferably, each R j may be a substituent at the 2-, 3-, 4- or 5-position of the phenyl group, Preferably, each R j are independently unsubstituted or optionally substituted with one, two or more R p C replaced by 1-6 Alkyl group, NH 2 , -C(O)R 12 , -C(O)OR 13 , -B (OR 18 ) (OR 19 ), -P(O)(OR 20 ) (OR 21 ), 【Chemistry 10】 may be selected from Preferably, R 10 are halogens, OH, CN, NO 2 , unsubstituted or optionally one, two or more R k C replaced by 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl), C 3-8 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), 3- to 6-membered heterocyclyl groups (e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl), C 1-6 Alkyloxy group, C 3-6 Cycloalkyloxy group, 3- to 6-membered heterocyclyloxy group, NH 2 Selected from Preferably, each R k are the same or different and independently represent halogen, OH, CN, NO 2 , unsubstituted or optionally one, two or more R p C replaced by 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl), C 3-8 Cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), C 6-10 Aryl groups (e.g., phenyl groups), 5- to 6-membered heteroaryl groups (e.g., pyrrolyl groups, pyridyl groups, pyrazinyl groups, imidazolyl groups, triazolyl groups), 3- to 6-membered heterocyclyl groups (e.g., pyrrolidinyl groups, imidazolidinyl groups, piperidinyl groups, piperazinyl groups, oxetanyl groups, tetrahydrofuranyl groups, tetrahydropyranyl groups), C 1-6 Alkyloxy group, C 3-6 Cycloalkyloxy group, C 6-10 selected from an aryloxy group, a 5- to 6-membered heteroaryloxy group, and a 3- to 6-membered heterocyclyloxy group; Preferably, each R p are identical or different and independently represent H, halogen (F, Cl, Br, or I), OH, unsubstituted or optionally one, two, or more R q C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 6-10 Aryl group, 5- to 6-membered heteroaryl group, 3- to 6-membered heterocyclyl group, C 1-6 Alkyloxy group, C 3-8 Cycloalkyloxy group, C 6-10 Aryloxy group, 5- to 6-membered heteroaryloxy group, 3- to 6-membered heterocyclyloxy group, NH 2 Selected from Preferably, one, two, three or more H atoms in the compound and its substituents (e.g., methyl, ethyl) are optionally replaced with their isotopes (e.g., D) to form CD 3 , C 2 D 5 may form a group such as The compound according to claim 3, its racemate, stereoisomer, tautomer, isotope label, solvate, crystalline polymorph, pharmaceutically acceptable salt or prodrug compound thereof.

5. The compound is the following compound: 【Chemistry 11】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 The compound according to any one of claims 1 to 4, or a racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, crystalline polymorph, pharmaceutically acceptable salt, or prodrug compound thereof, may be selected from the group consisting of:

6. A compound of formula (IV), 【Chemistry 12】 Wherein, PG is a protecting group, and PG may be selected from amino protecting groups, among which, preferred PG is C 1-40 Alkyl group, C 6-20 Aryl C 1-40 alkyl-, for example, may be selected from tert-butyl, isopropyl, benzyl, tert-butoxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl; R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , Cy independently have the definition set forth in any one of claims 1 to 5; A compound represented by formula (IV):

7. A method for producing the compound according to any one of claims 1 to 5, or a racemate, stereoisomer, tautomer, isotope-labeled product, solvate, crystalline polymorph, pharmaceutically acceptable salt, or prodrug thereof, comprising reacting a compound of formula (IV) as a starting material to obtain a compound of formula (Ia), and then reacting R 4 obtaining a compound of formula (I) wherein is H, 【Chemistry 13】 and, optionally, reacting the compound of formula (Ia) with R 4 -L 1 React with R 4 is a group other than H in any one of claims 1 to 5, and 1 OH, F, Cl, Br, I, Halo C 1-40 a leaving group such as an alkyl group; Among them, PG, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , Cy independently have the definition set forth in any one of claims 1 to 6; According to an embodiment of the present invention, a compound of formula (IV) is reacted under conditions that remove the protecting group PG to give a compound of formula (I): Preferably, the process for preparing the compound of formula (IV) comprises reacting a compound of formula (II) with a compound of formula (III) to obtain the compound of formula (IV), 【Chemistry 14】 Among them, PG, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , Cy independently have the definition set forth in any one of claims 1 to 6; Preferably, the production method may be carried out in the presence of a solvent such as an organic solvent. For example, the organic solvent may be 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, diisoamyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, or dichlorodiethyl ether. ethers such as polyethers of ethylene oxide and / or propylene oxide; pentane, hexane, heptane, octane, nonane; and aliphatic, alicyclic or aromatic hydrocarbons such as pentane, hexane, heptane, octane, nonane, and those which can be substituted with fluorine and chlorine atoms, for example, methylene chloride, dichloromethane, trichloromethane, carbon tetrachloride, fluorobenzene, chlorobenzene or dichlorobenzene, cyclohexane, methylcyclohexane, petroleum ether, octane, benzene, toluene, chlorobenzene, bromobenzene, and xylene; and esters such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, and dimethyl carbonate, dibutyl carbonate or vinyl carbonate. Preferably, the preparation method may be carried out in the presence of a reducing agent, the reducing agent being for reducing the carbon-nitrogen double bond, and the reducing agent may be selected from sodium borohydride, potassium borohydride, lithium borohydride, sodium borohydride acetate, sodium cyanoborohydride, and lithium aluminum hydride; A method for producing the compound according to any one of claims 1 to 5, its racemate, stereoisomer, tautomer, isotope label, solvate, crystalline polymorph, pharmaceutically acceptable salt, or prodrug compound thereof.

8. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound according to any one of claims 1 to 5, its racemate, stereoisomer, tautomer, isotopically labeled form, solvate, crystalline polymorph, pharmaceutically acceptable salt, or prodrug compound thereof.

9. A method for treating a disease associated with activation of the alternative complement pathway, comprising administering to a patient a prophylactically or therapeutically effective amount of at least one of the compounds according to any one of claims 1 to 5, or a racemate, stereoisomer, tautomer, isotopically labeled form, solvate, crystalline polymorph, pharmaceutically acceptable salt, or prodrug thereof; Preferably, the diseases associated with activation of the 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 (NMO), arthritis, rheumatoid arthritis, liver inflammation, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), respiratory and cardiovascular diseases, etc. A method for treating a disease associated with activation of the alternative complement pathway.

10. Use of the compound represented by formula (IV) according to claim 6 in the production of the compound according to any one of claims 1 to 5, or a racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, crystalline polymorph, pharmaceutically acceptable salt, or prodrug compound thereof.

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