Complement factor B inhibitor as well as pharmaceutical composition, preparation method and application thereof

Abstract

The invention provides a heterocyclic compound containing piperidine as shown in a formula (I). The compounds are used for treating diseases and diseases related to complement bypass pathway activation by inhibiting / regulating a complement factor B, such as paroxysmal sleep hemoglobinuria (PNH), IgA nephropathy (IgAN), various glomerular diseases including C3 glomerulopathy (C3G) and membranous nephropathy (MN), atypical hemolytic uremic syndrome (aHUS), age-related macular degeneration (AMD), and the like. Diabetic retinopathy (DR) and other diseases associated with abnormal activation of the alternative complement pathway. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese invention patent application with patent application number 202110898008.4 and name “Complement factor B inhibitors and their pharmaceutical compositions, preparation methods and uses”.

[0002] This application claims the priority of the prior application filed by the applicant with the State Intellectual Property Office of China on August 7, 2020, with patent application number 202010790872.8 and invention name “Complement factor B inhibitor and its pharmaceutical composition, preparation method and use”. The full text of the prior application is incorporated into this application by reference. Technical Field

[0003] The present invention belongs to the field of medicine, and in particular relates to a complement factor B inhibitor and a pharmaceutical composition, a preparation method and use thereof. Background Art

[0004] Complement is a class of soluble pattern recognition molecules in the immune system that can perform a variety of effector functions. Under natural conditions, complement components exist in the form of inactive zymogens. A variety of specific and nonspecific immunological mechanisms decompose these inactive zymogens to produce active large and small fragments. Among them, large fragments usually stay on the surface of pathogens or cells, causing the latter to lyse or accelerate their clearance; small fragments leave the cell surface and mediate a variety of inflammatory responses. The activation of complement consists of two closely related processes, which form a cascade reaction of complement activation. Currently known complement activation pathways mainly include three: the classical pathway, the lectin pathway, and the alternative pathway. Although the initiation mechanisms and activation orders of the three complement activation pathways are different, they have a common terminal pathway. Among them, the activation of the alternative pathway does not rely on antigen-antibody complexes. Usually, C3b deposited on the cell surface combines with factor B and becomes a state that is easily decomposed by factor D in the serum. In this process, factor B is decomposed into Ba and Bb; then C3b and Bb form a complex to become the C3 convertase C3bBb in the alternative pathway; in this process, complement factor B plays an early and core role in the activation of the alternative pathway of the complement cascade. Here, C3b is both a product that appears after the C3 convertase decomposes C3, and a component of the C3 convertase of the alternative pathway, thus forming a feedback amplification mechanism in which the classical pathway and the alternative pathway influence each other. Current studies have found that a variety of diseases such as hematologic, autoimmune, inflammatory, and neurodegenerative diseases are related to abnormal complement system function.

[0005] Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic disease with persistent hemolysis. It is caused by a non-malignant clonal disease caused by acquired somatic PIG-A gene mutation in one or several hematopoietic stem cells. It is an ultra-rare blood disease (Medicine (Baltimore) 1997, 76 (2): 63-93). The course of the disease can be manifested as varying degrees of hemolysis (paroxysmal), chronic or repeated acute intravascular hemolysis or subsequent venous / arterial thrombosis, ultimately leading to progressive end-organ damage and death. It is a typical PNH with chronic intravascular hemolysis, hemoglobinuria and hemosiderinuria as the main manifestations, but most patients are often atypical, with insidious onset, prolonged course, and varying severity.

[0006] There are more than ten proteins on the surface of red blood cells that inhibit the activation of the complement pathway. They are all anchored on their cell membranes through glycosylated phosphatidylinositol (GPI), collectively referred to as GPI-anchored proteins (AP). It is currently believed that the pathogenesis of PNH is first that hematopoietic stem cells mutate under certain conditions and produce PNH clones with glycosylphosphatidylinositol (GPI) defects; then, due to certain factors (now mostly considered to be immune factors), hematopoietic function damage or hematopoietic function failure occurs, and PNH clones gain proliferation advantages and exceed normal clones. The multiple antigens connected by GPI also cause the complexity of explaining the biological behavior of PNH cells. Among them, the most important protein C3 convertase decay accelerating factor CD55 and membrane attack complex (MAC) inhibitor CD59 that inhibit complement pathway activation are closely related to PNH in pathogenesis, clinical manifestations, diagnosis and treatment (Frontiers in Immunology 2019, 10, 1157). CD59 can prevent C9 from being incorporated into the C5b-8 complex and prevent the formation of membrane attack units, thereby inhibiting the terminal attack reaction of complement. It is currently believed that the typical manifestations of PNH - intravascular hemolysis and thrombosis are caused by CD59 deficiency. It has been reported that patients with congenital CD59 deficiency show many typical symptoms of PNH, such as intravascular hemolysis, hemoglobinuria and venous thrombosis. In PNH patients, due to the defect in GPI synthesis, CD59 cannot bind to the cell membrane of red blood cells, resulting in the loss of its function of inhibiting the activation of the complement pathway; therefore, the abnormal activation of the complement pathway occurs and attacks red blood cells, leading to multiple clinical manifestations such as intravascular hemolysis, hemoglobinuria, and smooth muscle dysfunction. At present, there is no other effective cure for PNH except for the treatment of hematopoietic stem cell transplantation to restore normal hematopoietic function. Since hematopoietic stem cell transplantation has certain risks and PNH is a benign clonal disease, controlling hemolytic episodes remains the main strategy for clinical treatment of the disease. At present, only Eculizumab is approved for the treatment of PNH. However, many patients still experience anemia after treatment with Eculizumab, and many patients still require continuous blood transfusions. In addition, eculizumab requires intravenous injection. Therefore, the development of new inhibitors of the complement pathway for the treatment of PNH is of great significance.

[0007] IgAN is the most common primary glomerulonephritis. The disease is characterized by IgA deposition in the mesangial area by immunofluorescence. Its clinical manifestations are diverse, usually manifested as recurrent microscopic or macroscopic hematuria. Existing data show that the occurrence of IgAN is related to innate or acquired immune regulation abnormalities. Due to the stimulation of the respiratory or digestive tract by viruses, bacteria, and food proteins, the synthesis of mucosal IgA1 increases, or immune complexes containing IgA1 are deposited in the mesangial area, activating the complement bypass pathway, causing glomerular damage. Human IgA molecules are divided into two subtypes, IgA1 and IgA2. Among them, IgA1 is the main form of blood circulation in healthy individuals (accounting for about 85%), and is also the main component of glomerular mesangial deposition in IgAN patients. IgA molecules can exist in two forms: monomers and polymers. IgA1 molecules have a unique heavy chain hinge region between the first and second constant regions, which can serve as a domain for the attachment site of O-linked glycan groups. Recent studies have found that the IgA molecules deposited in the serum and glomerular mesangial area of ​​IgAN patients are mainly glycosylation-deficient IgA1 (gd-IgA1). It is currently believed that the initiation link of the pathogenesis of IgAN is the abnormal increase in the production of gd-IgA1.

[0008] More than 90% of IgAN patients have complement C3 deposits in the glomerular mesangial area. 75%-100% of IgAN patients have co-deposition of properdin, IgA and C3 in the renal tissue, and 30%-90% of IgAN patients have co-deposition of complement factor H, IgA and C3 in the renal tissue. In addition to deposition in renal tissue, some studies have also found that the levels of complement alternative pathway markers in the plasma of IgAN patients are also related to the activity of IgAN (J Nephrol 2013, 26(4): 708-715). Studies have confirmed that C3a in renal tissue and urine and C3a receptors in renal tissue are significantly correlated with the activity and severity of renal damage (J clinImmunol 2014, 34(2): 224-232). Other studies have confirmed that IgA can activate the complement alternative pathway under in vitro conditions. In this process, abnormalities in the hinge region of IgA do not play a decisive role, but the formation of IgA polymers is the key link (Eur J Immunol 1987, 17 (3): 321-326). Currently, the deposition of complement C3 in the glomerular mesangial region has become an auxiliary diagnostic marker for IgAN. A study conducted C3c and C3d immunofluorescence detection on the renal tissues of 163 IgAN patients. The results showed that IgAN patients with higher C3c deposition intensity than C3d deposition intensity showed lower glomerular filtration rate, higher incidence of glomerular capillary hyperplasia, and more severe hematuria, indicating that glomerular C3c deposition is related to active lesions of IgAN (Am J Nephrol. 2000, 20 (2): 122-128). Currently, there is no specific drug for the treatment of IgAN in clinical practice. The main drugs are general-purpose drugs such as angiotensin-converting enzyme inhibitors (ACEI or ARB), glucocorticoids, and various immunosuppressants. In addition, the safety of this type of drug is also an issue that cannot be ignored. For example, although glucocorticoids have the effect of reducing proteinuria, the STOP-IgAN trial and TESTING-I trial clearly confirmed the potential side effects of glucocorticoids (IgA nephropathy 2019, 95, 4, 750-756).

[0009] Arthritis is a common chronic disease, an inflammatory disease caused by inflammation, infection, degeneration, trauma or other factors. Clinical manifestations include redness, swelling, heat, pain, dysfunction and joint deformity of the joints, which often cause severe pain, limited movement and body deformation. In severe cases, it can cause disability and affect the quality of life of patients. Studies have found that K / BxN mouse serum cannot induce arthritis in mice with complement factor B deficiency, while wild-type mice develop arthritis under the induction of K / BxN mouse serum (Immunity, 2002, 16, 157–168). This shows that the complement system plays an important pathogenic role in the K / BxN mouse serum-induced arthritis model, and complement factor B is a potential target for the treatment of arthritis.

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

[0011] At present, there are no small molecule drugs for complement factor B inhibitors for clinical treatment. The currently known and under-developed projects include: Oligonucleotide drugs developed by IONIS Pharmaceuticals Inc. as specific inhibitors of complement factor B (CFB) to treat, prevent or alleviate diseases related to complement alternative pathway disorders (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 are used to treat diseases such as C3G and IgAN (WO2019043609A1). Small molecule complement factor B inhibitors developed by Achillion Pharmaceuticals Inc. are used to treat diseases such as age-related macular degeneration (AMD) (WO2018005552).

[0012] Diseases related to inflammation and immunity are diverse and difficult to cure. The only drug on the market for PNH is eculizumab, but due to its price, it has placed a heavy burden on patients. At the same time, many patients still experience anemia after treatment with eculizumab, and many patients still need continuous blood transfusions. In addition, eculizumab requires intravenous injection. Some diseases, such as IgAN, do not have specific therapeutic drugs to date. There are unmet clinical needs in these areas, and new small molecule drugs need to be developed for medical treatment. Summary of the invention

[0013] In order to improve the above technical problems, the present invention provides a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound:

[0014]

[0015] Among them, R 1 is selected from halogen, OH, CN, NO2, unsubstituted or optionally substituted with 1, 2 or more R a Substituted with the following groups: C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic group, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH2;

[0016] R 2 is selected from H, halogen, OH, CN, NO2, unsubstituted or optionally substituted with 1, 2 or more R b Substituted with the following groups: C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic group, C 1-40 Alkyloxy, C2-40 Alkenyloxy, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH2;

[0017] R 3 is selected from halogen, OH, CN, NO2, unsubstituted or optionally substituted with 1, 2 or more R c Substituted with the following groups: C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic group, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH2;

[0018] R 4 is selected from H, unsubstituted or optionally substituted with 1, 2 or more R d Substituted with the following groups: C 1-40 Alkyl, C 3-40 Cycloalkyl, C 1-40 Alkyl-C(O)-, C 3-40 Cycloalkyl-C(O)-, C 1-40 Alkyl-S(O)2-, C 3-40 Cycloalkyl-C(O)2-;

[0019] R 5 is selected from H, halogen, OH, CN, NO2, unsubstituted or optionally substituted with 1, 2 or more R e Substituted with the following groups: C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic group, C 1-40 Alkyloxy, C2-40 Alkenyloxy, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH2;

[0020] R 6 is selected from H, halogen, OH, CN, NO2, unsubstituted or optionally substituted with 1, 2 or more R f Substituted with the following groups: C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic group, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH2;

[0021] R 7 is selected from hydrogen, OH, CN, unsubstituted or optionally substituted with 1, 2 or more R g Substituted with the following groups: C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic group, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH2;

[0022] Or, R 1 , R 7Together with the atoms to which it is attached, it forms an unsubstituted or optionally substituted group consisting of 1, 2 or more R h The 5-20 membered ring structure can be selected from the following groups: 5-20 Cycloalkenyl, C 6-20 Aryl, 5-20 membered heterocyclyl, 5-20 membered heteroaryl;

[0023] Or, R 6 , R 7 Together with the atoms to which it is attached, it forms an unsubstituted or optionally substituted group consisting of 1, 2 or more R i The 5-20 membered ring structure can be selected from the following groups: 5-20 Cycloalkenyl, C 6-20 Aryl, 5-20 membered heterocyclyl, 5-20 membered heteroaryl;

[0024] Cy is selected from 1, 2, 3, 4, 5, 6, 7, 8 or more independently selected from R 8 , R 9 , R 10 , R 11 The following groups are substituted by substituents: C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic group, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, 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-, 3-20 membered heterocyclic-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 1-40Alkyl-, 3-20 membered heterocyclic-C 1-40 Alkyl-, wherein the 3-20 membered heterocyclic group in the group Cy contains 1-5 heteroatoms selected from N, O, S, and contains at most one N atom;

[0025] R 8 , R 9 are the same or different and are independently selected from H, unsubstituted or optionally substituted with 1, 2 or more R j Substituted with the following groups: C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic group, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, 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-, 3-20 membered heterocyclic-C 1-40 alkyl-;

[0026] R 10 , R 11 are the same or different and are independently selected from H, absent, halogen, OH, CN, NO2, unsubstituted or optionally substituted by 1, 2 or more R k Substituted with the following groups: C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic group, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH2;

[0027] Or, R 8 , R 9 Together with the atoms to which it is attached, it forms an unsubstituted or optionally substituted group consisting of 1, 2 or more R j The 5-20 membered ring structure can be selected from the following groups: 3-20 Cycloalkyl, C 5-20 Cycloalkenyl, C 6-20 Aryl, 5-20 membered heterocyclyl, 5-20 membered heteroaryl;

[0028] Or, R 10 , R 11 Together with the atoms to which it is attached, it forms an unsubstituted or optionally substituted group consisting of 1, 2 or more R k The 5-20 membered ring structure can be selected from the following groups: 3-20 Cycloalkyl, C 5-20 Cycloalkenyl, C 6-20 Aryl, 5-20 membered heterocyclyl, 5-20 membered heteroaryl;

[0029] Every 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 are independently selected from H, halogen, OH, CN, NO2, oxo (=O), thio (=S), unsubstituted or optionally substituted with 1, 2 or more R p Substituted with the following groups: C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic group, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, C 1-40 Alkylthio, C 2-40 Alkenylthio, C 2-40 Alkynylthio, C 3-40 Cycloalkylthio, C 3-40 Cycloalkenylthio, C 3-40 Cycloalkynylthio, C 6-20 Arylthio, 5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, NH2, -C(O)R 12 、-C(O)OR 13 、-OC(O)R 14 、-S(O)2R 15 、-S(O)2OR 16 、-OS(O)2R 17 、-B(OR 18 )(OR 19 )、-P(O)(OR 20 )(OR 21 ),

[0030] Every R p are the same or different and are independently selected from H, halogen, OH, CN, NO2, oxo (=O), thio (=S), unsubstituted or optionally substituted with 1, 2 or more R q Substituted with the following groups: C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic group, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, C 1-40 Alkylthio, C 2-40 Alkenylthio, C 2-40 Alkynylthio, C 3-40 Cycloalkylthio, C 3-40 Cycloalkenylthio, C 3-40 Cycloalkynylthio, C 6-20 Arylthio, 5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, NH2, -C(O)R121 、-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 ),

[0031]

[0032] Every R q are the same or different and are independently selected from H, halogen, OH, CN, NO2, oxo (=O), thio (=S), C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic group, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, C 1-40 Alkylthio, C 2-40 Alkenylthio, C 2-40 Alkynylthio, C 3-40 Cycloalkylthio, C 3-40 Cycloalkenylthio, C 3-40 Cycloalkynylthio, C 6-20 arylthio, 5-20 membered heteroarylthio, 3-20 membered heterocyclylthio, NH2, -C(O)C 1-40 Alkyl, -C(O)NH2, -C(O)NHC 1-40 Alkyl, -C(O)-NH-OH, -COOC 1-40 Alkyl, -COOH, -OC(O)C 1-40 Alkyl, -OC(O)H, -S(O)2C 1-40 Alkyl, S(O)2H, -S(O)2OC 1-40 Alkyl, -OS(O)2C 1-40Alkyl, -P(O)(OH)2, -B(OH)2,

[0033] 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 The same or different, independently selected from H, C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclyl, NH2.

[0034] According to an embodiment of the present invention, R 1 is selected from halogen, OH, CN, NO2, unsubstituted or optionally substituted with 1, 2 or more R a Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkyloxy, C 3-8 Cycloalkyloxy, NH2.

[0035] According to an embodiment of the present invention, R 2 is selected from H, halogen, OH, CN, NO2, unsubstituted or optionally substituted with 1, 2 or more R b Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, C1-6 Alkyloxy, C 3-8 Cycloalkyloxy, NH2.

[0036] According to an embodiment of the present invention, R 3 is selected from halogen, OH, CN, NO2, unsubstituted or optionally substituted with 1, 2 or more R c Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkyloxy, C 3-8 Cycloalkyloxy, NH2.

[0037] According to an embodiment of the present invention, R 4 is selected from H, unsubstituted or optionally substituted with 1, 2 or more R d Substituted C 1-6 alkyl.

[0038] According to an embodiment of the present invention, R 5 is selected from H, halogen, OH, CN, NO2, unsubstituted or optionally substituted with 1, 2 or more R e Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkyloxy, C 3-8 Cycloalkyloxy, NH2.

[0039] According to an embodiment of the present invention, R 6 is selected from H, halogen, OH, CN, NO2, unsubstituted or optionally substituted with 1, 2 or more R f Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkyloxy, C 3-8 Cycloalkyloxy, NH2.

[0040] R 7 is selected from hydrogen, OH, CN, unsubstituted or optionally substituted with 1, 2 or more R g Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkyloxy, C 3-8 Cycloalkyloxy, NH2.

[0041] According to an embodiment of the present invention, as an option, R 1 , R 7 It may be taken together with the atoms to which it is attached to form an unsubstituted or optionally substituted group consisting of 1, 2 or more R h Substituted with the following groups: C 5-10 Cycloalkenyl, C6-10 Aryl, 5-10 membered heterocyclic group, 5-10 membered heteroaryl, such as C 5-6 Cycloalkenyl, C6 aryl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl. Preferably, the 5-6 membered heterocyclyl and 5-6 membered heteroaryl contain, for example, 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S may be optionally not oxidized or oxidized to various oxidation states. As an example, R 1 , R 7 The atoms to which it is attached may form a fused indole group in formula (I), unsubstituted or optionally substituted with 1, 2 or more R h Substituted cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl (wherein the sulfur atom is not oxidized or is oxidized to a -S(O)2- group).

[0042] According to an embodiment of the present invention, as an option, R 6 , R 7 It may be taken together with the atoms to which it is attached to form an unsubstituted or optionally substituted group consisting of 1, 2 or more R i Substituted with the following groups: C 5-20 Cycloalkenyl, C 6-20 Aryl, 5-20 membered heterocyclyl, 5-20 membered heteroaryl, such as C 5-6 Cycloalkenyl, C6 aryl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl. Preferably, the 5-6 membered heterocyclyl and 5-6 membered heteroaryl contain, for example, 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S may be optionally not oxidized or oxidized to various oxidation states. As an example, R 6 , R 7 The atoms to which it is attached may form a fused indole group in formula (I), unsubstituted or optionally substituted with 1, 2 or more R h Substituted cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl (wherein the sulfur atom is not oxidized or is oxidized to a -S(O)2- group).

[0043] According to an embodiment of the present invention, Cy can be selected from 1, 2, 3, 4, 5, 6, 7, 8 or more independently selected from R 8 , R 9 , R 10 , R 11 The following groups are substituted by substituents: C 3-40 Cycloalkyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic group, wherein the 3-20 membered heterocyclic group in the Cy group contains 1-3 heteroatoms selected from N, O, S, and contains at most one N atom.

[0044] According to a preferred embodiment of the present invention, Cy can be selected from 1, 2, 3, 4, 5, 6, 7, 8 selected from R 8 , R 9 , R 10 and R 11 A 3-20 membered heterocyclic group substituted with a substituent, for example, Cy is selected from R 8 , R 9 , R 10 and R 11 and optionally further substituted by 1, 2, 3 or 4 independently selected from R 8 , R 9 , R 10 , R 11 The 3-20 membered heterocyclic group is substituted with a substituent, wherein the 3-20 membered heterocyclic group in the Cy group contains 1 or 2 heteroatoms selected from N, O, and S, and contains at most one N atom.

[0045] According to an exemplary embodiment of the present invention, Cy can 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 (such as a fused ring, a bridged ring, a spirocyclic ring) or a 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system, and the heterocyclic ring system contains 1-5 heteroatoms selected from O, S and N, and contains at most one N atom, wherein if present, the N atom and the S atom can be optionally not oxidized or oxidized to various oxidation states.

[0046] According to an exemplary embodiment of the present invention, Cy comprises 1 N atom and optionally 1 or 2 atoms selected from O or S. Preferably, when Cy is selected from a bicyclic ring system, the N atom and the O atom or S atom are in different ring structures in the bicyclic ring.

[0047] According to an exemplary embodiment of the present invention, Cy contains at most 2 heteroatoms, and one and only one heteroatom is selected from N atoms.

[0048] According to an exemplary embodiment of the present invention, Cy may be selected from the following cyclic groups:

[0049] piperidinyl;

[0050] piperidinyl fused to a ring system selected from cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl;

[0051] an aza and / or oxa spiro[2.4], [3.4], [4.4], [2.5], [3.5], [4.5] or [5.5] ring group;

[0052] Aza and / or oxa bicyclic [2.2.1], [2.2.2], [3.2.1], [3.2.2] or [3.3.2] ring groups.

[0053] According to a preferred embodiment of the present invention, the N atom in Cy can be connected with the Cy group of formula (I) and R 7 The groups are bonded to the common C atoms.

[0054] As an example, Cy can be selected from monocyclic, fused, bridged ring groups, such as the following groups:

[0055] piperidinyl;

[0056]

[0057] According to an embodiment of the present invention, R 8 can be selected from optionally 1, 2 or more R j Substituted with the following groups: C 6-10 Aryl, 5-10 membered heteroaryl, 3-20 membered heterocyclic group, for example phenyl, pyridyl, pyrazinyl, furyl, pyranyl, benzocyclohexyl, benzocyclopentyl, benzofuranyl, phenyltetrahydrofuranyl.

[0058] According to an embodiment of the present invention, R 9 are the same or different and are independently selected from H, unsubstituted or optionally substituted with 1, 2 or more R j Substituted C 1-6 alkyl.

[0059] According to an embodiment of the present invention, as an option, R 8 , R 9 It may be taken together with the atoms to which it is attached to form an unsubstituted or optionally substituted group consisting of 1, 2 or more R j Substituted with the following groups: C 5-10 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl.

[0060] According to an embodiment of the present invention, R 10 , R 11 may be the same or different and independently selected from halogen, OH, CN, NO2, unsubstituted or optionally substituted with 1, 2 or more R k Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclic group, C 1-6 Alkyloxy, C 3-6 Cycloalkyloxy, C 6-10Aryloxy, 5-6 membered heteroaryloxy, 3-6 membered heterocyclyloxy, NH2;

[0061] According to an embodiment of the present invention, as an option, R 10 , R 11 It may be taken together with the atoms to which it is attached to form an unsubstituted or optionally substituted group consisting of 1, 2 or more R k Substituted with the following groups: C 5-10 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl.

[0062] According to an embodiment of the present invention, each R j The same or different, independently selected from unsubstituted or optionally substituted with 1, 2 or more R p Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic group, C 1-6 Alkyloxy, C 3-8 Cycloalkyloxy, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, 3-10 membered heterocyclyloxy, NH2, -C(O)R 12 、-C(O)OR 13 、-B(OR 18 )(OR 19 )、-P(O)(OR 20 )(OR 21 ),

[0063] According to an embodiment of the present invention, each R k are the same or different and are independently selected from halogen, OH, CN, NO2, unsubstituted or optionally substituted by 1, 2 or more R p Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclic group, C 1-6 Alkyloxy, C 3-6 Cycloalkyloxy, C 6-10 Aryloxy, 5-6 membered heteroaryloxy, 3-6 membered heterocyclyloxy, NH2.

[0064] According to an embodiment of the present invention, each R p are the same or different and are independently selected from H, halogen, OH, unsubstituted or optionally substituted by 1, 2 or more R q Substituted with the following groups: C 1-6 Alkyl, C 3-8Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclic group, C 1-6 Alkyloxy, C 3-8 Cycloalkyloxy, C 6-10 Aryloxy, 5-6 membered heteroaryloxy, 3-6 membered heterocyclyloxy, NH2, -C(O)R 121 、-C(O)OR 131 、-B(OR 181 )(OR 191 )、-P(O)(OR 201 )(OR 211 ),

[0065] According to an embodiment of the present invention, R q Has the definition given above.

[0066] 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 The same or different, independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, NH2.

[0067] According to an embodiment of the present invention, the compound represented by formula (I) may have a structure represented by formula (I-1) or formula (I-2):

[0068]

[0069] wherein W is selected from CH, O or S;

[0070] Y and Z are the same or different and are independently selected from CHR 11 , O or S;

[0071] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10, R 11 are independently as defined above in formula (I).

[0072] According to an embodiment of the present invention, a carbon-carbon single bond or a carbon-carbon double bond may be formed between W and Z or between Z and Y, if appropriate.

[0073] According to an embodiment of the present invention, when W is selected from O or S, R 10 Does not exist.

[0074] According to an embodiment of the present invention, when W is selected from CH, R 10 is selected from H, halogen, OH, CN, NO2, unsubstituted or optionally substituted with 1, 2 or more R k Substituted with the following groups: C 1-40 Alkyl, C 2-40 Alkenyl, C 2-40 Alkynyl, C 3-40 Cycloalkyl, C 3-40 Cycloalkenyl, C 3-40 Cycloalkynyl, C 6-20 Aryl, 5-20 membered heteroaryl, 3-20 membered heterocyclic group, C 1-40 Alkyloxy, C 2-40 Alkenyloxy, C 2-40 Alkynyloxy, C 3-40 Cycloalkyloxy, C 3-40 Cycloalkenyloxy, C 3-40 Cycloalkynyloxy, C 6-20 Aryloxy, 5-20 membered heteroaryloxy, 3-20 membered heterocyclyloxy, NH2, wherein R k Has the definition given above.

[0075] According to an embodiment of the present invention, the compound represented by formula (I) may have a structure represented by formula (I-3) or formula (I-4):

[0076]

[0077] Among them, W, Y, Z, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 9 , R 10 , R j independently having the definitions set out above;

[0078] n is selected from 1, 2, 3, 4 or 5.

[0079] According to an embodiment of the present invention, n may be selected from 1, 2 or 3.

[0080] According to an embodiment of the present invention, each R j It may be a substituent at the 2-, 3-, 4- or 5-position of the phenyl group.

[0081] According to an embodiment of the present invention, each R j may be independently selected from unsubstituted or optionally substituted with 1, 2 or more R p Substituted with the following groups: C 1-6 Alkyl, NH2, -C(O)R 12 、-C(O)OR 13 、-B(OR 18 )(OR 19 )、-P(O)(OR 20 )(OR 21 ),

[0082] According to an embodiment of the present invention, R 10 is selected from halogen, OH, CN, NO2, unsubstituted or optionally substituted with 1, 2 or more R k Substituted with the following groups: C 1-6 Alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl), C 3-8 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), 3-6 membered heterocyclic group (e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl), C 1-6 Alkyloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, NH2.

[0083] According to an embodiment of the present invention, each R k are the same or different and are independently selected from halogen, OH, CN, NO2, unsubstituted or optionally substituted by 1, 2 or more R p Substituted with the following groups: C 1-6 Alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl), C 3-8 Cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), C 6-10 Aryl (such as phenyl), 5-6 membered heteroaryl (such as pyrrolyl, pyridyl, pyrazinyl, imidazolyl, triazolyl), 3-6 membered heterocyclic group (such as pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl), C 1-6 Alkyloxy, C 3-6 Cycloalkyloxy, C 6-10 Aryloxy, 5-6 membered heteroaryloxy, 3-6 membered heterocyclyloxy.

[0084] According to an embodiment of the present invention, each R p are the same or different and are independently selected from H, halogen (F, Cl, Br or I), OH, unsubstituted or optionally substituted with 1, 2 or more R q Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclic group, C 1-6 Alkyloxy, C 3-8 Cycloalkyloxy, C 6-10 Aryloxy, 5-6 membered heteroaryloxy, 3-6 membered heterocyclyloxy, NH2.

[0085] According to an embodiment of the present invention, 1, 2, 3 or more H atoms in the compound and its substituents (such as methyl, ethyl) can be optionally replaced with their isotopes (such as D) to form groups such as CD3, C2D5.

[0086] According to an embodiment of the present invention, the compound represented by formula (I) can be selected from the following compounds:

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095] The present invention also provides a compound represented by formula (IV):

[0096]

[0097] Wherein, PG is a protecting group;

[0098] R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , Cy independently have the definitions described above.

[0099] The present invention also provides the use of the compound represented by formula (IV) in the preparation of the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof.

[0100] The present invention also provides a method for preparing a compound represented by formula (I), comprising reacting a compound represented by formula (IV) as a starting material to obtain a compound represented by formula (Ia), and obtaining R 4 The compound represented by formula (I) is H:

[0101]

[0102] and optionally, the compound of formula (Ia) and R 4 -L 1 Reaction to obtain R 4 A compound represented by formula (I) having a group other than H in the above definition;

[0103] Among them, PG, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , Cy independently have the definitions as described above;

[0104] L 1 is a leaving group, such as OH, F, Cl, Br, I, halogenated C 1-40 alkyl.

[0105] According to an embodiment of the present invention, PG can be selected from amino protecting groups. Among them, suitable PG can be selected from C 1-40 Alkyl, C 6-20 Aryl C 1-40 Alkyl-, for example tert-butyl, isopropyl, benzyl, tert-butoxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl.

[0106] According to an embodiment of the present invention, the compound of formula (IV) is reacted under the conditions of removing the protecting group PG to obtain the compound of formula (I). The conditions of removing the protecting group PG are those reaction conditions known to those skilled in the art.

[0107] The present invention also provides a method for preparing a compound of formula (IV), comprising reacting a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (IV);

[0108]

[0109] Among them, PG, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , Cy independently have the definitions described above.

[0110] According to an embodiment of the present invention, the preparation method can be carried out in the presence of a solvent such as an organic solvent. For example, the organic solvent can be selected from at least one of the following: alcohols, such as methanol, ethanol, isopropanol, and n-butanol; ethers, such as ethyl propyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethyl ethylene glycol, biphenyl 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, dichlorodiethyl ether, and Polyethers of ethylene oxide and / or propylene oxide; aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, heptane, octane, nonane, and those possibly substituted by fluorine and chlorine atoms, such as methylene chloride, dichloromethane, chloroform, carbon tetrachloride, fluorobenzene, chlorobenzene or dichlorobenzene; cyclohexane, methylcyclohexane, petroleum ether, octane, benzene, toluene, chlorobenzene, bromobenzene, xylene; esters such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate and dimethyl carbonate, dibutyl carbonate or ethylene carbonate.

[0111] According to an embodiment of the present invention, the preparation method can be carried out in the presence of a reducing agent; the reducing agent is used to reduce the carbon-nitrogen double bond, and the reducing agent can be selected from sodium borohydride, potassium borohydride, lithium borohydride, sodium acetate borohydride, sodium cyanoborohydride, and lithium aluminum hydride.

[0112] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof.

[0113] According to an embodiment of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0114] According to an embodiment of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0115] The present invention also provides a method for treating diseases associated with activation of the complement alternative pathway, comprising administering to a patient a preventive or therapeutically effective amount of a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or at least one of its prodrug compounds.

[0116] The diseases associated with activation of the complement alternative pathway include paroxysmal nocturnal hemoglobinuria (PNH), primary glomerulonephritis (IgAN), membranous nephropathy (MN), C3 glomerulonephritis (C3G), age-related macular degeneration (AMD), geographic atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), diabetic retinopathy (DR), hemodialysis complications, hemolytic anemia or hemodialysis, neuromyelitis (NMO), arthritis, rheumatoid arthritis, hepatitis, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), respiratory diseases and cardiovascular diseases

[0117] In some embodiments, the patient is a human.

[0118] The present invention also provides a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or at least one of its prodrug compounds, or a pharmaceutical composition thereof for use in diseases associated with activation of the complement alternative pathway.

[0119] The present invention also provides the use of at least one of the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof in the preparation of a drug.

[0120] The medicament can be used for diseases associated with activation of the alternative complement pathway.

[0121] As a drug, the compounds of the present invention can be administered in the form of a pharmaceutical composition. These compositions can be prepared in a manner well known in the pharmaceutical field, and they can be administered by a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. It can be administered topically (e.g., transdermal, skin, eye and mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizers; intratracheal, intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. It can be administered parenterally in a single large dose form, or it can be administered by, for example, a continuous infusion pump. Topically administered pharmaceutical compositions and preparations can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, water, powders or oily bases, thickeners, etc. may be necessary or required.

[0122] In preparing the compositions of the present invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed in such a carrier in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semisolid or liquid substance, which acts as a solvent, carrier or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or dissolved in a liquid medium); ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

[0123] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose. The formulation may also contain: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl benzoate and hydroxypropyl benzoate; sweeteners and flavoring agents. The composition of the present invention may be formulated using methods known in the art to provide an immediate release, sustained release or delayed release of the active ingredient after administration to the patient.

[0124] The composition can be formulated in unit dosage form, each dose containing about 5 to 1000 mg, more usually about 100 to 500 mg of active ingredient. The term "unit dosage form" refers to physically discrete single dosage units suitable for use by human patients and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect in admixture with a suitable pharmaceutical excipient.

[0125] The effective dosage range of the active compound can be very large, and is generally administered in a pharmaceutically effective amount. However, it is understood that the actual amount of compound administered is usually determined by the physician based on relevant circumstances, including the condition being treated, the route of administration selected, the actual compound being administered; the age, weight and response of the individual patient; the severity of the patient's symptoms, etc.

[0126] For preparing solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compound of the invention. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is generally evenly distributed throughout the composition, so that the composition can be easily divided into equally effective unit dosage forms such as tablets, pills and capsules. The solid preformulation is then divided into unit dosage forms of the above type containing, for example, about 0.1 to 1000 mg of the active ingredient of the invention.

[0127] The tablets or pills of the present invention may be coated or compounded to obtain dosage forms that provide the advantage of prolonged action. For example, the tablet or pill contains an inner dose and an outer dose component, the latter being a film-coated form of the former. The two components may be isolated by an enteric layer that is used to prevent disintegration in the stomach so that the inner component passes intact through the duodenum or is delayed in release. A variety of materials may be used for such enteric layers or coatings, including a variety of polymeric acids and mixtures of polymeric acids and such materials as shellac, cetyl alcohol, and cellulose acetate.

[0128] Liquid forms in which the compounds and compositions of the present invention may be incorporated for oral or injectable administration include aqueous solutions, appropriately flavored syrups, aqueous or oil suspensions; and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil; as well as elixirs and similar pharmaceutically acceptable vehicles.

[0129] Compositions for inhalation or insufflation include solutions and suspensions, powders dissolved in pharmaceutically acceptable water or organic solvents or mixtures thereof. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In certain embodiments, the composition is administered by oral or nasal respiratory route to achieve local or systemic effect. The composition may be atomized by using an inert gas. The atomized solution may be inhaled directly from an atomizing device, or the atomizing device may be connected to a mask curtain or an intermittent positive pressure breathing machine. Solutions, suspensions or powder compositions may be administered orally or by a device that delivers the formulation in an appropriate manner through the nose.

[0130] The amount of compound or composition administered to a patient is not fixed and depends on the drug being administered, the purpose of administration, such as prevention or treatment; the patient's condition, the mode of administration, etc. In therapeutic applications, a patient already suffering from a disease may be administered a composition in an amount sufficient to cure or at least partially suppress the symptoms of the disease and its complications. The effective dose will depend on the disease state being treated and the judgment of the attending clinician, which depends on factors such as the severity of the disease, the patient's age, weight and general condition.

[0131] The composition administered to the patient may be in the form of a pharmaceutical composition as described above. These compositions may be sterilized by conventional sterilization techniques or by filtration sterilization. The aqueous solution may be packaged for use as is, or lyophilized, and the lyophilized preparation may be mixed with a sterile aqueous carrier before administration. The pH of the compound preparation is generally 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It will be appreciated that the use of some of the aforementioned excipients, carriers or stabilizers may result in the formation of a pharmaceutical salt.

[0132] The therapeutic dose of the compounds of the present invention may be determined, for example, based on the specific use of the treatment, the mode of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compounds of the present invention in the pharmaceutical composition may not be fixed, depending on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds of the present invention may be provided in a physiologically buffered aqueous solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg body weight / day. In certain embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg body weight / day. The dosage is likely to depend on such variables as the type and extent of the disease or condition, the general health status of the specific patient, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration. The effective dose can be obtained by extrapolation of a dose-response curve derived from an in vitro or animal model test system.

[0133] Beneficial Effects

[0134] The compound provided by the present invention has good complement factor B regulation / inhibition effect, and can be used to treat symptoms and diseases related to complement alternative pathway activation, as well as to prepare drugs for such symptoms and diseases. In addition, the compound has good pharmacokinetics, liver microsome stability and other properties. BRIEF DESCRIPTION OF THE DRAWINGS

[0135] Figure 1 The experimental data of the blood drug concentration curve of cynomolgus monkeys in the biological examples (ng / mL);

[0136] Figure 2 The experimental data of AP activity curve of cynomolgus monkey serum in the biological examples (% relative to 0h);

[0137] Figure 3 The experimental data of streptococcal-induced rheumatoid arthritis in rats in the biological examples are shown.

[0138] Definition and explanation of terms

[0139] Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The definitions of groups and compound structures after such combinations and combinations should be understood to be within the scope of the specification and / or claims of this application.

[0140] Unless otherwise specified, the numerical ranges recorded in this specification and claims are equivalent to recording at least each specific integer value therein. For example, the numerical range "1-40" is equivalent to recording each integer value in the numerical range "1-10", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and each integer value in the numerical range "11-40", namely 11, 12, 13, 14, 15, ..., 35, 36, 37, 38, 39, 40. In addition, when certain numerical ranges are defined as "numbers", it should be understood that the two endpoints of the range, each integer in the range, and each decimal in the range are recorded. For example, "a number from 0 to 10" should be understood as not only recording each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording the sum of each integer therein and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.

[0141] It should be understood that herein, in the description of 1, 2 or more, "more" should refer to an integer greater than 2, for example, greater than or equal to 3, for example 3, 4, 5, 6, 7, 8, 9 or 10.

[0142] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0143] The term "C 1-40 "Alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 40 carbon atoms. For example, "C 1-10 "Alkyl" means straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 1-6The term "alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.

[0144] The term "C 2-40 "Alkenyl" is understood to mean preferably a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2 to 40 carbon atoms, preferably "C 2-10 "C 2-10 The term "alkenyl" is understood to mean preferably a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example having 2, 3, 4, 5 or 6 carbon atoms (i.e., C 2-6 alkenyl), having 2 or 3 carbon atoms (i.e., C 2-3It is understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from one another or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl , 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl but-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0145] The term "C 2-40 "Alkynyl" is understood to mean a linear or branched monovalent hydrocarbon radical containing one or more triple bonds and having 2 to 40 carbon atoms, preferably "C 2-10 The term "C 2-10 "Alkynyl" is understood to mean preferably a straight or branched monovalent hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example having 2, 3, 4, 5 or 6 carbon atoms (i.e., "C 2-6 Alkynyl”), having 2 or 3 carbon atoms (“C 2-3The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4 In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0146] The term "C 3-40 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (such as condensed, bridged, spiro) hydrocarbon ring or tricyclic alkane having 3 to 40 carbon atoms, preferably "C 3-10 The term "Cycloalkyl" 3-10 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (eg bridged, spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 3-10 The cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonanyl, 2,6-diazaspiro[3,4]octanyl, or a tricyclic hydrocarbon group such as adamantyl.

[0147] Unless otherwise defined, the term "3-20 membered heterocyclyl" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, it is a 4-, 5-, 6- or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic ring (such as a fused ring, a bridged ring, a spirocyclic ring) or a 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system, and contains at least one, for example 1, 2, 3, 4, 5 or more heteroatoms selected from O, S and N, wherein N and S may also be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)- or -S(O)2- states. Preferably, the heterocyclyl may be selected from "3-10 membered heterocyclyl". The term "3-10 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N. The heterocyclic group can be connected to the rest of the molecule by any one of the carbon atoms or the nitrogen atom (if present). The heterocyclic group can include fused or bridged rings and spirocyclic rings. In particular, the heterocyclic group can include but is not limited to: 4-membered rings, such as azetidinyl, oxetanyl; 5-membered rings, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or 7-membered rings, such as diazepanyl. Optionally, the heterocyclic group can be benzo-fused. The heterocyclic 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]pyrazine-2(1H)-yl ring. The heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, such as but not limited to dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl. When the 3-20-membered heterocyclic group is connected to other groups to form the compounds of the present invention, the carbon atoms on the 3-20-membered heterocyclic group may be connected to other groups, or the heterocyclic atoms on the 3-20-membered heterocyclic group may be connected to other groups. For example, when the 3-20 membered heterocyclic group is selected from piperazinyl, the nitrogen atom on the piperazinyl group may be connected to other groups. Or when the 3-20 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring and the carbon atom at the para position may be connected to other groups.

[0148] The term "C 6-20 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic (such as fused, bridged, spiro) or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, which may be a single aromatic ring or a polyaromatic ring fused together, preferably "C 6-14The term "C 6-14 The term "aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl”), such as anthracenyl. When the C 6-20 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Also, there is no limitation on the substitution position, for example, it may be substituted at the ortho position, para position or meta position.

[0149] The term "5-20 membered heteroaryl" is understood to include 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, for example "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, in each case, furthermore, may be benzo-fused. "Heteroaryl" also refers to a radical in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples of the term heteroaryl include, for example, pyridyl, pyrazinyl, furanyl, thiophenyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, 1,2,4-, 5-, 6-, 7- or 8-thiadiazolyl, pyridazinyl; and 1-, 2-, 3-, 5-, 6-, 7- or 8-indolizinyl, 1-, 3-, 4-, 5-, 6- or 7-isoindolyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 4-, 5-, 6-, 7- or 8-purinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6- naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aHcarbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-carbazolylcarbazolyl, 1 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-pyridinyl, 2-, 3-, 4-, 5- , 6-, 8-, 9- or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-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-oxazinyl, 1-, 3- or 5-1H-pyrazolo[4,3-d]-thiazolyl, 2-, 4- or 5-1H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3- , 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10 or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6- or 7-imidazo[1,2-b][1,2,4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-1H-pyrrolo[1,2-b][2]benzazepinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6- or 7-benzo[b]thienyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl and 2-, 4-, 5-, 6- or 7-benzothiazolyl. When the 5-20 membered heteroaryl group is connected to other groups to form the compound of the present invention, it can be a carbon atom on the 5-20 membered heteroaryl ring connected to other groups, or it can be a heteroatom on the 5-20 membered heteroaryl ring connected to other groups. When the 5-20 membered heteroaryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there is no limitation on the substitution site, for example, the hydrogen bonded to the carbon atom on the heteroaryl ring may be substituted, or the hydrogen bonded to the heteroatom on the heteroaryl ring may be substituted.

[0150] The term "spirocyclic" refers to a ring system in which two rings share one ring-forming atom.

[0151] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0152] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0153] Unless otherwise specified, heterocyclic groups, heteroaryls or heteroarylene groups include all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative non-limiting examples, forms substituted or bonded to other groups at 1, 2 or more positions in the 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) may include pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene and pyridin-4-ylene; thienyl or thienylene groups include thien-2-yl, thien-2-ylene, thien-3-ylene and thien-3-ylene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.

[0154] The term "oxo" refers to a substituent in which a carbon atom, a nitrogen atom or a sulfur atom is oxidized to form an oxy group (=O).

[0155] Unless otherwise stated, the definitions of terms herein also apply to groups containing the term, e.g. 1-6 The definition of alkyl also applies to C 1-6 Alkyloxy, C 3-8 Cycloalkyl-C 1-6 Alkyl- etc.

[0156] Those skilled in the art will appreciate that the compounds of formula (I) may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form a base addition salt; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form an inner salt.

[0157] The compounds of the present invention may exist in the form of solvates (e.g. hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol. The amount of polar solvents, in particular water, may exist in a stoichiometric or non-stoichiometric ratio.

[0158] According to its molecular structure, the compounds of the present invention may be chiral, and therefore various enantiomeric forms may exist. Thus, these compounds may exist in racemic form or optically active form. The compounds of the present invention encompass isomers or mixtures, racemates in which each chiral carbon is in R or S configuration. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolution agent. Examples of suitable resolution agents are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids in R and S forms. Chromatographic enantiomer resolution can also be advantageously carried out with the aid of optically active resolving agents such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane / isopropanol / acetonitrile.

[0159] The corresponding stable isomers can be separated according to known methods, for example by extraction, filtration or column chromatography.

[0160] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0161] The term "therapeutically effective amount" refers to the amount of an active compound or drug that elicits the biological or medical response that a researcher, veterinarian, physician or other clinician is seeking in a tissue, system, animal, individual or human, and includes one or more of the following: (1) Preventing disease: e.g., preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but does not yet experience or develop the pathology or symptoms of the disease. (2) Inhibiting disease: e.g., inhibiting a disease, disorder or condition (i.e., preventing further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. (3) Alleviating disease: e.g., alleviating a disease, disorder or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. DETAILED DESCRIPTION

[0162] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0163] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0164] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker ASCEND TM -400 NMR spectrometer, the determination solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0165] MS was determined using Agilent 6110, Agilent 1100, Agilent 6120, and Agilent G6125B liquid chromatography-mass spectrometers.

[0166] HPLC determination was performed using Shimadzu HPLC-2010C high pressure liquid chromatograph (XBRIDGE 2.1*50 mm, 3.5 um column).

[0167] Chiral HPLC analysis was performed using THARSFC X5.

[0168] The thin layer chromatography silica gel plate used was Yantai Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) had a specification of 0.15 mm to 0.2 mm, and the specification used for thin layer chromatography separation and purification products was 0.4 mm to 0.5 mm.

[0169] Column chromatography generally uses Qingdao Marine Silica Gel 200-300 mesh silica gel as the carrier.

[0170] High performance liquid phase preparation used Waters 2767, Waters 2545, and Chuangxin Hengtong LC3000 preparative chromatographs.

[0171] The pressurized hydrogenation reaction uses a Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.

[0172] The microwave reaction was carried out using a Biotage initiator+ type microwave reactor.

[0173] Unless otherwise specified, the reactions were carried out under an argon atmosphere or a nitrogen atmosphere. Argon atmosphere or a nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 liter. Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1 liter.

[0174] Unless otherwise specified, the reaction temperature is room temperature, ranging from 20-30°C.

[0175] Example 1

[0176] Intermediate 1:

[0177]

[0178] In a 3L three-necked flask, tetrahydrofuran (150mL) and 4-bromobenzonitrile (50g) were added in sequence, and isopropylmagnesium chloride lithium chloride complex (1.3M, 210mL) was slowly added to the reaction system under nitrogen protection, and the reaction was carried out at room temperature for 2 hours. Then anhydrous tetrahydrofuran (500mL) was added to the reaction system for dilution and the temperature was lowered to -5°C, 4-methoxypyridine (25mL) was added, and benzyl chloroformate (35mL) was slowly added dropwise (maintaining the system temperature below 0°C), and the reaction was stirred at 0°C for 2 hours after the addition was completed, and then the temperature was raised to room temperature and the reaction was continued at room temperature for 16 hours. After the reaction, 6M hydrochloric acid (150 mL) was added, stirred for half an hour, and diluted with water (1000 mL), extracted twice with ethyl acetate (500 mL), and the combined extracts were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The crude product obtained after the filtrate was concentrated was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1-1: 1) to obtain intermediate 1 (23 g, yield: 23%). MS m / z (ESI): 333.0 [M+1].

[0179] Intermediate 2:

[0180]

[0181] Intermediate 1 (28 g), zinc powder (55 g) and acetic acid (200 mL) were added to a 500 mL single-mouth bottle in sequence, and the reaction was heated to 100 ° C and stirred at this temperature for 16 hours. After the reaction was completed, the filtrate was filtered, diluted with water (500 mL), extracted with ethyl acetate (500 mL), and the extract was washed twice with saturated sodium bicarbonate aqueous solution (500 mL), washed once with saturated brine (100 mL), dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 2 (26 g, yield: 73%). MS m / z (ESI): 334.8 [M+1].

[0182] Intermediate 3:

[0183]

[0184] In a 500mL single-mouth bottle, tetrahydrofuran (100mL), ethanol (100mL) and intermediate 2 (26g) were added in sequence, and then sodium borohydride (2g) was added in batches. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the system was cooled to 0°C, saturated ammonium chloride aqueous solution (30mL) was added until the temperature no longer increased, water (500mL) was added for dilution, and ethyl acetate (200mL) was used for extraction twice; the combined extract phase was washed with saturated brine (500mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 3 (25g, yield: 76%). MS m / z (ESI): 336.9 [M+1].

[0185] Intermediate 4:

[0186]

[0187] Dichloromethane (200 mL) was added to a 500 mL single-mouth bottle, and then intermediate 3 (25 g), imidazole (6.6 g) and tert-butyldiphenylsilyl chloride (25 g) were added in sequence, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was washed with water (500 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. 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].

[0188] Intermediate 5:

[0189]

[0190] In a 250 mL single-necked bottle, intermediate 4 (5 g) and tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 30 mL) were added in sequence, and the reaction was carried out at room temperature for 2 hours. After the reaction, water (100 mL) was added for dilution, and ethyl acetate (50 mL) was used for extraction three times. The combined extracts were washed with saturated brine (100 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 = 3:1-0:1) to obtain a racemic intermediate. The intermediate was subjected to chiral separation by SFC (Apparatus: SFC Thar prep 80; Column: CHIRALPAK AD-H, 250 mm × 20 mm, 5 μm; Modifier: 35% methanol (0.2% ammonia water); 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].

[0191] Intermediate 6:

[0192]

[0193] In a 100mL single-mouth bottle, solvent N,N-dimethylformamide (15mL), intermediate 5 (1.2g) and iodoethane (1.1g) were added in sequence. After the reaction system was cooled to 0°C, sodium hydride (60%, 243mg) was added, and then the system was heated to room temperature and carried out at this temperature for 2 hours. After the reaction was completed, water (30mL) was added for dilution, ethyl acetate (50mL) was extracted, the extract was washed with saturated brine (10mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 6 (1.2g, yield: 83%). MS m / z (ESI): 386.9 [M+23].

[0194] Intermediate 7:

[0195]

[0196] In a 100 mL single-mouth bottle, methanol (10 mL), water (10 mL), concentrated sulfuric acid (10 mL) and intermediate 6 (1.2 g) were added in sequence, and the reaction was heated to 80 ° C and reacted at this temperature for 48 hours. After the reaction was completed, the reaction solution was concentrated to remove methanol, and the residue was adjusted to a neutral pH with a sodium hydroxide (2M) aqueous solution, extracted three times with ethyl acetate (10 mL), and the combined extracts were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 7 (850 mg, yield: 81%). MS m / z (ESI): 264.1 [M+1]. 1 H NMR (400MHz, CDCl3) δ8.01(d,J=8.3Hz,2H),7.49(d,J=8.3Hz,2H),4.13(dd,J=11.7,2.4Hz,1H),3.92(s,3H),3.82–3.70(m,1H),3.6 2–3.47(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=7.0Hz,3H).

[0197] Alternatively, intermediate 7 is obtained by the following method:

[0198] Intermediate 8:

[0199]

[0200] In a 2L three-necked flask, tetrabutylammonium fluoride tetrahydrofuran solution (1M, 840mL) and intermediate 4 (140g) were added in sequence, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, water (600mL) was added for dilution, and ethyl acetate (700mL) was used for extraction three times. The extract was washed with saturated brine (500mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 3:1-1:1) to obtain intermediate 8 (77g, yield 95%), MS m / z (ESI): 358.8 [M+23].

[0201] Intermediate 9:

[0202]

[0203] In a 2L three-necked flask, solvent N,N-dimethylformamide (700mL), intermediate 8 (77g) and iodoethane (56g) were added in sequence; after the reaction system was cooled to 0°C, sodium hydride (60%, 14.61g) was added, and then the system was heated to room temperature and carried out at this temperature for 2 hours. After the reaction was completed, the temperature was lowered to 0°C, and an aqueous solution of ammonium chloride was added until the reaction did not heat up, and ethyl acetate (500mL) was used for extraction. The extract was washed with saturated brine (300mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 9 (75g, yield: 89%). MS m / z (ESI): 386.9 [M+23].

[0204] Intermediate 10:

[0205]

[0206] In a 2L three-necked flask, isopropanol (300mL), water (800mL), intermediate 9 (75g), and Ba(OH)2·8H2O (233g) were added in sequence, and the reaction was heated to 100°C and carried out at this temperature for 20 hours. After the reaction was completed, the reaction solution was concentrated to remove isopropanol, and the residue was adjusted to pH 2-3 with saturated sodium hydroxide aqueous solution, extracted three times with dichloromethane (300mL), and the extract was washed with saturated brine (200mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 10 (67g, yield: 85%). MS m / z (ESI): 384.1 [M+1].

[0207] Intermediate 11:

[0208]

[0209] In a 2L three-necked flask, N,N-dimethylformamide (670mL), potassium carbonate (96.6g), iodomethane (37.3g) and intermediate 10 (67g) were added in sequence and reacted at room temperature for 2 hours. After the reaction was completed, 300mL of water was added to quench the reaction, and methyl tert-butyl ether was used for extraction (300mL*2 times). The extract was washed with saturated brine (5mL), 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 = 10:1-3:1) to obtain intermediate 11 (54g, yield: 78%). MS m / z (ESI): 394.1 [M+1].

[0210] Intermediate 7:

[0211]

[0212] In a 1L single-mouth bottle, ethyl acetate (500mL), palladium carbon (5.4g, 10% loading), and intermediate 11 (54g) were added in sequence. The reaction was carried out at room temperature for 16 hours under a hydrogen pressure. After the reaction was completed, the reaction solution was filtered by adding diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a racemic intermediate, which was subjected to chiral separation (Apparatus: Shimadzu LC-20AD; Column: CHIRALPAK AD-H (ADHOCD-SK003), 0.46cm ID*25cm L; Modifier: (methanol / diethylamine 0.1%) / CO2=25 / 75 (V / V); Flow rate: 2.0ml / min; Rt=3.58min) to obtain intermediate 7 (15.7g, yield: 43%). MS m / z (ESI): 264.0 [M+1]. 1 H NMR(400MHz,DMSO-d6)δ7.89(d,J=8.26Hz,2H),7.50(d,J=8.26Hz,2H),3.92(dd, J=11.36,2.32Hz,1H),3.84(s,3H),3.69-3.64(m,1H),3.51-3.42(m,2H),2.94(dt ,J=12.15,2.56Hz,1H),2.76(ddd,J=11.62,4.24,2.62Hz,1H),1.85(dd,J=13.23 ,2.16Hz,1H),1.73(d,J=13.47Hz,1H),1.59-1.41(m,2H),1.16(t,J=6.98Hz,3H).

[0213] Example 2

[0214] Intermediate 1:

[0215]

[0216] In a 250mL single-mouth bottle, dichloromethane (50mL), 5-methoxy-7-methyl-1H-indole (3g), Boc anhydride (5.68g), 4-dimethylaminopyridine (227mg) and triethylamine (2.26g) were added in sequence, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the reaction solution was quenched by adding saturated ammonium chloride solution (5mL), extracted with dichloromethane (20mL) three times, and the combined organic phase was washed with water (5mL), 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 obtain intermediate 1 (4.6g, yield: 94%). MS m / z (ESI): 262.0 [M+1].

[0217] Intermediate 2:

[0218]

[0219] In a 250mL single-mouth bottle, dichloromethane (80mL), N-methylformanilide (3.8g) and oxalyl chloride (3.6g) were added in sequence, and the reaction was stirred at room temperature for 3 hours. Then the reaction temperature was lowered to -14°C, and intermediate 1 (2.5g) was added. The reaction system was naturally heated to room temperature and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into ice water (100mL), extracted with dichloromethane (100mL) three times, and the combined extract was washed twice with water (10mL), 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 obtain intermediate 2 (1.3g, yield: 47%). MS m / z (ESI): 290.0 [M+1]. 1 H NMR (400MHz, CDCl3) δ10.65(s,1H),7.65(d,J=3.4Hz,1H),7.49(d,J=3.4Hz,1H),6.76(s,1H),3.98(s,3H),2.70(s,3H),1.65(s,9H).

[0220] Example 3

[0221] Intermediate 1:

[0222]

[0223] In a 100 mL single-mouth bottle, 1-(vinyloxy)butane (10 mL), triethylamine (300 mg), o-phenanthroline (54 mg), palladium acetate (67 mg) and benzyl (2S, 4S)-2-(4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate (Example 1, intermediate 5) (500 mg) were added in sequence. The reaction mixture was heated to 90°C under nitrogen protection and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution 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].

[0224] Intermediate 2:

[0225]

[0226] Under the protection of nitrogen and ice bath, 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); after the reaction was carried out under ice bath for one hour, a solution of diiodomethane (536 mg) in dichloromethane (2 mL) was added to the reaction system and reacted for 1 hour; then a solution of intermediate 5 (362 mg) in dichloromethane (2 mL) of Example 1 was added, and the reaction was naturally warmed to room temperature and continued to stir at room temperature for 18 hours. After the reaction was completed, the reaction was quenched with dilute hydrochloric acid (0.1 M, 10 mL), diluted with water (20 mL), extracted with ethyl acetate (30 mL), the extract was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain intermediate 2 (300 mg, yield: 64%). MS m / z(ESI):398.8[M+23].

[0227] Intermediate 3:

[0228]

[0229] Sodium hydroxide (320 mg) was added to a mixed solution of isopropanol (2 mL) and water (5 mL) of intermediate 2 (300 mg). The reaction system was heated to 100°C and stirred at this temperature for 48 hours. After the reaction was completed, the reaction solution was added with dilute hydrochloric acid (1 M) under an ice bath to adjust the pH to 5-6, and water (10 mL) was added to dilute it, and it was extracted with ethyl acetate (10 mL). The extract was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 3 (180 mg, yield: 45%). MSm / z(ESI):395.9[M+1].

[0230] Intermediate 4:

[0231]

[0232] To a solution of intermediate 3 (180 mg) in acetonitrile (3 mL), potassium carbonate (126 mg) and iodomethane (129 mg) were added in sequence, and the reaction solution was heated to 50°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution 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].

[0233] Intermediate 5:

[0234]

[0235] Palladium / carbon (20 mg) was added to a tetrahydrofuran (2 mL) solution of intermediate 4 (120 mg), and the reaction solution was subjected to catalytic hydrogenation under a hydrogen atmosphere at room temperature for 16 hours. After the reaction, the reaction solution was directly filtered and concentrated under reduced pressure to obtain intermediate 5 (70 mg, yield: 79%). MS m / z (ESI): 275.9 [M+1].

[0236] Intermediate 6:

[0237]

[0238] Intermediate 5 (70 mg) was added to a solution of intermediate 2 (88 mg) in 1,2-dichloroethane (5 mL) of Example 2, and the reaction was stirred at room temperature for 8 hours, and then sodium acetate borohydride (162 mg) was added and the reaction was continued for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography (dichloromethane: methanol = 20: 1) to obtain intermediate 7 (170 mg, yield: 73%). MS m / z (ESI): 548.8 [M+1].

[0239] Target compound:

[0240]

[0241] Sodium hydroxide (127 mg) was added to a mixed solution of methanol (2 mL) and water (2 mL) of intermediate 6 (175 mg), and the reaction solution was heated to 75°C and reacted at this temperature for 3 hours. After the reaction was completed, hydrochloric acid (1 M) was added to the reaction solution in an ice bath to adjust the pH to neutral, and then the mixture was directly purified by high pressure liquid preparative chromatography (chromatographic column: Gemini-C18 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-40%) to obtain the target compound (31.5 mg, yield: 22%, containing 0.5 equivalents of formic acid). MS m / z (ESI): 434.9 [M+1]. 1 H NMR (400MHz, CD3OD) δ8.44 (s, 0.5H), 8.16 (d, J = 7.9Hz, 2H), 7.65 (d, J = 7.9Hz, 2H),7.31(d,J=3.1Hz,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).

[0242] Embodiment 4:

[0243] Intermediate 1:

[0244]

[0245] Imidazole (202 mg) and tert-butyldimethylsilyl chloride (270 mg) were added to a solution of intermediate 5 (500 mg) of Example 1 in N,N-dimethylformamide (10 mL), and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (20 mL), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was directly concentrated to obtain intermediate 1 (700 mg, yield: 88%). MS m / z (ESI): 472.8 [M+23].

[0246] Intermediate 2:

[0247]

[0248] Intermediate 1 (750 mg) was added to dichloromethane (10 mL), and the reaction system was cooled to -78 ° C under nitrogen protection, and cyclobutanone (117 mg) and trimethylsilyl trifluoromethanesulfonate (37 mg) were added in sequence. After the reaction was stirred at -78 ° C for one hour, triethylsilane (193 mg) was added, and then the reaction was slowly warmed to room temperature and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was quenched by adding saturated sodium bicarbonate aqueous solution (10 mL), diluted with water (10 mL), extracted with dichloromethane (10 mL), and the extract was washed once 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 = 3: 1) to obtain intermediate 2 (700 mg, yield: 86%). MS m / z (ESI): 391.0 [M+1].

[0249] Intermediate 3:

[0250]

[0251] Sodium hydroxide (720 mg) was added to a mixed solution of isopropanol (5 mL) and water (10 mL) of intermediate 2 (700 mg), and the reaction system was heated to 100°C and stirred at this temperature for 48 hours. After the reaction was completed, dilute hydrochloric acid (1 M) was added to the reaction solution under an ice bath to adjust the pH to 5-6, 20 mL of water was added to dilute, and extracted with ethyl acetate (20 mL). The extract was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 3 (700 mg, yield: 76%). MS m / z (ESI): 409.9 [M+1].

[0252] Intermediate 4:

[0253]

[0254] Potassium carbonate (472 mg) and iodomethane (486 mg) were added to an acetonitrile (5 mL) solution of intermediate 3 (700 mg), and the reaction solution was heated to 50°C and reacted at this temperature for 16 hours. After the reaction was completed, the reaction solution 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].

[0255] Intermediate 5:

[0256]

[0257] Palladium / carbon (35 mg) was added to a solution of intermediate 4 (350 mg) in tetrahydrofuran (5 mL), and the reaction solution was subjected to catalytic hydrogenation reaction under hydrogen atmosphere at room temperature for 2 hours. After the reaction, the reaction solution was directly filtered and concentrated under reduced pressure to obtain intermediate 5 (200 mg, yield: 75%). MS m / z (ESI): 290.0 [M+1].

[0258] Intermediate 6:

[0259]

[0260] Intermediate 5 (242 mg) was added to a solution of intermediate 2 (242 mg) in 1,2-dichloroethane (5 mL) of Example 2. The reaction was stirred at room temperature for 8 hours, and sodium acetate borohydride (532 mg) was added. The reaction was continued to stir at room temperature for 16 hours. After the reaction was completed, the reaction solution 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].

[0261] Target compound:

[0262]

[0263] In a 50 mL single-mouth bottle, methanol (3 mL), water (3 mL), intermediate 6 (350 mg) and sodium hydroxide (248 mg) were added in sequence. The reaction was heated to 75 ° C and reacted at this temperature for 3 hours. After the reaction was completed, the reaction solution was added with dilute hydrochloric acid (1 M) in an ice bath to adjust the pH to 7, and then the mixture was directly concentrated and purified by high pressure liquid preparative chromatography (chromatographic 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 (400MHz, CD3OD) δ8.45(s,0.4H),8.15(d,J=8.0Hz,2H),7.65(d,J=8.0Hz,2H),7.31 (d,J=2.8Hz,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).

[0264] Example 5

[0265] Intermediate 1:

[0266]

[0267] To a solution of the intermediate 5 (1200 mg) of Example 1 in N,N-dimethylformamide (10 mL), imidazole (486 mg) and tert-butyldimethylsilyl chloride (593 mg) were added, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL), and the extract was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was directly concentrated to obtain the intermediate 1 (600 mg, yield: 90%). MS m / z (ESI): 472.8 [M+23].

[0268] Intermediate 2:

[0269]

[0270] At room temperature, intermediate 1 (700 mg) was added to dichloromethane (10 mL). Under nitrogen protection and -78 ° C, cyclopropylcarboxaldehyde (110 mg) and trimethylsilyl trifluoromethanesulfonate (35 mg) were added to the reaction solution. The reaction system was maintained at -78 ° C and stirred for one hour, and then triethylsilane (180 mg) was added. The reaction was naturally warmed to room temperature and continued to stir at this temperature for 16 hours. After the reaction was completed, the reaction solution was quenched by adding saturated sodium bicarbonate aqueous solution (20 mL), diluted with water (10 mL), extracted with dichloromethane (10 mL), and the extract was washed once 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 = 3: 1) to obtain intermediate 2 (400 mg, yield: 46%). MS m / z (ESI): 390.9 [M+1].

[0271] Intermediate 3:

[0272]

[0273] To a 50 mL single-mouth bottle, intermediate 2 (400 mg), isopropanol (2 mL), water (3 mL), and sodium hydroxide (400 mg) were added in sequence, and the reaction mixture was heated to 100 ° C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was added with dilute hydrochloric acid (1 M) under an ice bath to adjust the pH to 5-6, diluted with water (5 mL), extracted with ethyl acetate (5 mL), and the extract was washed once with saturated brine (5 mL). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated at 45 ° C to obtain intermediate 3 (200 mg, yield: 33%). MS m / z (ESI): 431.8 [M+23].

[0274] Intermediate 4:

[0275]

[0276] Potassium carbonate (135 mg) and iodomethane (140 mg) were added to an acetonitrile (5 mL) solution of intermediate 3 (200 mg), and the reaction solution was heated to 50°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution 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].

[0277] Intermediate 5:

[0278]

[0279] Palladium / carbon (50 mg) was added to a tetrahydrofuran (3 mL) solution of intermediate 4 (180 mg), and the reaction solution was subjected to catalytic hydrogenation reaction at room temperature under a hydrogen atmosphere for 2 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was directly concentrated to obtain intermediate 5 (120 mg, yield: 54%). MS m / z (ESI): 290.0 [M+1].

[0280] Intermediate 6:

[0281]

[0282] Intermediate 5 (120 mg) was added to a solution of intermediate 2 (119 mg) of Example 2 in 1,2-dichloroethane (5 mL), and the reaction was stirred at room temperature for 8 hours, and then sodium acetate borohydride (261 mg) was added and continued to stir at room temperature for 16 hours. After the reaction was completed, the reaction solution was directly concentrated, and the residue was purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain intermediate 6 (200 mg, yield: 26%). MS m / z (ESI): 562.8 [M+1].

[0283] Target compound:

[0284]

[0285] Methanol (2 mL), water (2 mL), intermediate 6 (200 mg) and sodium hydroxide (150 mg) were added to a 50 mL single-mouth bottle in sequence, and the reaction mixture was heated to 75 ° C and stirred at this temperature for 3 hours. After the reaction was completed, the reaction solution was added with dilute hydrochloric acid (1 M) in an ice bath to adjust the pH to 7, and then directly concentrated under reduced pressure and purified by high pressure liquid chromatography (chromatographic 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]. 1H NMR (400MHz, CD3OD) δ8.36 (s, 0.5H), 8.18 (d, J = 7.7Hz, 2H), 7.69 (d, J = 7.7Hz, 2H), 7.3 2(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,2 H),2.13–1.94(m,2H),1.23–1.04(m,1H),0.58(d,J=7.2Hz,2H),0.28(d,J=3.8Hz,2H).

[0286] Example 6

[0287] Intermediate 1:

[0288]

[0289] Under nitrogen protection and -78°C, the intermediate 1 (700 mg) of Example 5 was added to dichloromethane (7 mL), cyclobutylcarboxaldehyde (130 mg) and trimethylsilyl trifluoromethanesulfonate (35 mg), maintained at -78°C and stirred at this temperature for 1 hour, then triethylsilane (180 mg) was added, and the reaction solution was slowly warmed to room temperature and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was quenched by adding saturated sodium bicarbonate aqueous solution (20 mL), diluted with water (10 mL), extracted with dichloromethane (10 mL), the extract 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 (petroleum ether: ethyl acetate = 3: 1) to obtain intermediate 1 (240 mg, yield: 34%). MS m / z (ESI): 426.8 [M+23].

[0290] Intermediate 2:

[0291]

[0292] Isopropanol (1 mL), water (3 mL), intermediate 1 (240 mg) and sodium hydroxide (240 mg) were added to a 50 mL single-mouth bottle in sequence. The reaction mixture was heated to 100 ° C and reacted at this temperature for 16 hours. After the reaction was completed, the reaction solution was added with dilute hydrochloric acid (1 M) to adjust the pH to 5-6 under an ice bath, and water (5 mL) was added to dilute it, and it was extracted with ethyl acetate (5 mL). The extract was washed with brine (5 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was directly concentrated to obtain intermediate 2 (200 mg, yield: 72%). MSm / z (ESI): 446.1 [M+23].

[0293] Intermediate 3:

[0294]

[0295] Potassium carbonate (130 mg) and iodomethane (134 mg) were added to a solution of intermediate 2 (200 mg) in acetonitrile (5 mL), and the reaction mixture was heated to 50°C and reacted at this temperature for 16 hours. After the reaction was completed, the reaction solution was directly concentrated, and the residue was purified by 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].

[0296] Intermediate 4:

[0297]

[0298] Palladium / carbon (50 mg) was added to a tetrahydrofuran (3 mL) solution of intermediate 3 (200 mg), and the reaction solution was subjected to catalytic hydrogenation reaction at room temperature under a hydrogen atmosphere for 2 hours. After the reaction, the reaction solution was directly filtered and concentrated under reduced pressure to obtain intermediate 4 (110 mg, yield: 71%). MS m / z (ESI): 303.9 [M+1].

[0299] Intermediate 5:

[0300]

[0301] Intermediate 4 (110 mg) was added to a solution of intermediate 2 (105 mg) of Example 2 in 1,2-dichloroethane (5 mL), and the reaction was stirred at room temperature for 8 hours, and then sodium acetate borohydride (229 mg) was added and stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution 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].

[0302] Target compound:

[0303]

[0304] Methanol (2 mL), water (2 mL), intermediate 5 (250 mg) and sodium hydroxide (175 mg) were added to a 50 mL single-mouth bottle in sequence, and the reaction mixture was heated to 75°C and reacted at this temperature for 3 hours. After the reaction was completed, dilute hydrochloric acid (1 M) was added to the reaction solution under ice bath to adjust the pH to 7, and the mixture was directly concentrated and purified by high pressure liquid preparative chromatography (chromatographic 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 (400MHz, CD3OD) δ8.16(d,J=7.5Hz,2H),7.64(d,J=7.5Hz,2H),7.31(d,J=3.0Hz,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).

[0305] Example 7

[0306] Intermediate 1:

[0307]

[0308] Silver trifluoromethanesulfonate (1600 mg), potassium fluoride (483 mg), 1-chloromethyl-4-fluoro-1,4-diazotized bicyclo[2.2.2]octane di(tetrafluoroborate) (1100 mg) were weighed in a glove box and added to a 50 mL single-mouth bottle, and then an ethyl acetate (10 mL) solution of the intermediate 5 (700 mg) of Example 1, 2-fluoropyridine (609 mg) and trifluoromethyltrimethylsilane (889 mg) were added by injection under nitrogen protection. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was directly purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain intermediate 1 (300 mg, yield: 32%). MS m / z (ESI): 426.8 [M+23].

[0309] Intermediate 2:

[0310]

[0311] In a 50mL single-mouth bottle, isopropanol (2mL), water (3mL), intermediate 1 (400mg) and sodium hydroxide (400mg) were added in sequence, and the reaction mixture was heated to 100°C and reacted at this temperature for 16 hours. After the reaction, the reaction solution was added with dilute hydrochloric acid (1M) under an ice bath to adjust the pH to 5-6, diluted with water (5mL), extracted with ethyl acetate (5mL), and the extract was washed with saturated brine (5mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was directly concentrated to obtain intermediate 2 (260mg, yield: 56%). MS m / z (ESI): 445.7 [M+23].

[0312] Intermediate 3:

[0313]

[0314] Potassium carbonate (170 mg) and iodomethane (175 mg) were added to a solution of intermediate 2 (260 mg) in acetonitrile (5 mL), and the reaction solution was heated to 50°C and reacted at this temperature for 16 hours. After the reaction was completed, the reaction solution 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].

[0315] Intermediate 4:

[0316]

[0317] Palladium / carbon (50 mg) was added to a tetrahydrofuran (3 mL) solution of intermediate 3 (200 mg), and the reaction solution was subjected to catalytic hydrogenation reaction at room temperature under a hydrogen atmosphere for 2 hours. After the reaction, the reaction solution was directly filtered and concentrated under reduced pressure to obtain intermediate 4 (130 mg, yield: 84%). MS m / z (ESI): 303.9 [M+1].

[0318] Intermediate 5:

[0319]

[0320] Intermediate 4 (130 mg) was added to a solution of intermediate 2 (125 mg) of Example 2 in 1,2-dichloroethane (5 mL). The reaction was stirred at room temperature for 8 hours, and sodium acetate borohydride (273 mg) was added. The reaction was continued to stir at room temperature for 16 hours. After the reaction was completed, the reaction solution 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].

[0321] Target compound:

[0322]

[0323] In a 50 mL single-mouth bottle, methanol (2 mL), water (2 mL), intermediate 5 (280 mg) and sodium hydroxide (194 mg) were added in sequence, and the reaction was heated to 75 ° C and reacted at this temperature for 16 hours. After the reaction was completed, the reaction solution was added with dilute hydrochloric acid (1 M) in an ice bath to adjust the pH to 7, and then directly purified by high pressure liquid preparative chromatography (chromatographic column: Gemini-C18150 x21.2mm, 5um; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 25-50%) to obtain the target compound (38.5 mg, yield: 16%, containing 0.2 equivalents of formic acid). MS m / z (ESI): 462.8 [M+1]. 1 H NMR (400MHz, CD3OD) δ8.45(s,0.2H),8.14(d,J=7.8Hz,2H),7.66(d,J=7.8Hz,2H),7.29(d,J=2.9Hz,1H),6.73(s,1H),6.34(d,J=2.9Hz,1H),4.87 –4.78(m,1H),4.64–4.45(m,1H),4.20(d,J=12.4Hz,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.

[0324] Example 8

[0325] Intermediate 1:

[0326]

[0327] At -70 ° C, n-butyl lithium (6.25 mL) was slowly added dropwise to a solution of methyl triphenylphosphonium bromide (5.35 g) in tetrahydrofuran (100 mL). After the reaction was stirred at -70 ° C for 0.5 hours, a solution of intermediate 2 (3.34 g) in tetrahydrofuran (30 mL) of Example 1 was slowly added dropwise, and then the reaction naturally warmed to room temperature and stirred at room temperature for 16 hours. After the reaction was completed, saturated ammonium chloride (20 mL) was added to quench the reaction, diluted with water (100 mL), extracted twice with ethyl acetate (100 mL), and 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 obtain intermediate 1 (850 mg, yield: 24%). MS m / z (ESI): 333.1 [M+1].

[0328] Intermediate 2:

[0329]

[0330] Sodium iodide (75 mg) and trifluoromethyltrimethylsilane (1160 mg) were added to a solution of intermediate 1 (800 mg) in tetrahydrofuran (10 mL), and the reaction mixture was heated to 70°C and sealed at this temperature for 16 hours. After the reaction, the reaction solution was directly concentrated and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain intermediate 2 (800 mg, 82%). MSm / z (ESI): 382.9 [M+1].

[0331] Intermediate 3:

[0332]

[0333] In a 100mL single-mouth bottle, methanol (10mL), a mixed solution of sulfuric acid and water (1:1, 10mL) and intermediate 2 (480mg) were added in sequence. The reaction mixture was heated to 80°C and reacted at this temperature for two days. After the reaction was completed, the reaction solution was naturally cooled to room temperature, poured into ice water, extracted twice with ethyl acetate (50mL), and the combined organic phase was washed once with saturated brine (10mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to obtain intermediate 3 (300mg, yield: 85%). MS m / z (ESI): 282.0 [M+1].

[0334] Intermediate 4:

[0335]

[0336] At room temperature, intermediate 3 (100 mg) was added to a solution of intermediate 2 (100 mg) of Example 2 in 1,2-dichloroethane (3 mL). After the reaction was stirred at room temperature for 8 hours, sodium triacetoxyborohydride (220 mg) was added, and then the reaction was continued to stir at room temperature for 16 hours. After the reaction was completed, the reaction solution was directly purified by column chromatography (methanol: dichloromethane = 1:20) to obtain intermediate 4 (110 mg, 54%). MS m / z (ESI): 554.9 [M+1].

[0337] Target compound:

[0338]

[0339] In a 25 mL single-mouth bottle, methanol (3 mL), water (3 mL), intermediate 4 (110 mg) and sodium hydroxide (40 mg) were added in sequence, and the reaction mixture was heated to 75 ° C and reacted at this temperature for 3 hours. After the reaction was completed, the reaction solution was directly purified by high pressure liquid preparative chromatography (chromatographic column: Gemini-C18, 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-40%), the obtained solution was concentrated, and the remaining small amount of aqueous solution was freeze-dried to obtain the target compound (50.6 mg, yield: 75%, containing 0.5 equivalents of formic acid). MS m / z (ESI): 440.9 [M+1]. 1 H NMR (400MHz, CD3OD) δ8.37 (s, 0.5H), 8.16 (d, J = 8.1Hz, 2H), 7.68 (d, J = 8.1Hz, 2H),7.31(d,J=2.8Hz,1H),6.76(s,1H),6.34(d,J=2.8Hz,1H),4.41–4.25(m, 2H),4.06(d,J=12.4Hz,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).

[0340] Example 9

[0341] Intermediate 1:

[0342]

[0343] In a 100mL single-mouth bottle, 1,4-dioxane (8mL), water (2mL), methyl 4-(dihydroxyboryl)benzoate (500mg), 2-bromo-4-(trifluoromethyl)pyridine (693mg), potassium carbonate (413mg) and tetrakis(triphenylphosphine)palladium (693mg) were added in sequence. The reaction mixture was heated to 90°C under nitrogen protection and reacted at this temperature for 16 hours. After the reaction, the reaction solution was naturally cooled to room temperature, poured into water (50mL), extracted with ethyl acetate (100ml) three times, and the combined organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain intermediate 1 (600mg, yield: 76%). MS m / z (ESI): 282.0 [M+1].

[0344] Intermediate 2:

[0345]

[0346] In a 50mL single-mouth bottle, methanol (6mL), intermediate 1 (180mg), platinum dioxide (14mg) and catalytic amount of hydrochloric acid were added in sequence, and the reaction mixture was catalytically hydrogenated under hydrogen atmosphere and room temperature for 16 hours. After the reaction was completed, the reaction solution was directly filtered and decompressed, and the residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to obtain intermediate 2 (30mg, yield: 16%). MS m / z (ESI): 288.1 [M+1].

[0347] Intermediate 3:

[0348]

[0349] In a 50 mL single-mouth bottle, 1,2-dichloroethane (4 mL), intermediate 2 (30 mg), intermediate 2 of Example 2 (44 mg) and sodium triacetoxyborohydride (66 mg) were added in sequence, and the reaction mixture was stirred for 16 hours under a nitrogen atmosphere at room temperature. After the reaction was completed, methanol was added to the reaction solution until the solution was clarified, and then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain intermediate 3 (30 mg, yield: 53%). MS m / z (ESI): 560.7 [M+1].

[0350] Target compound:

[0351]

[0352] In a 50 mL single-mouth bottle, methanol (4 mL), water (1 mL), intermediate 3 (65 mg) and sodium hydroxide (92 mg) were added in sequence, and the reaction mixture was stirred at room temperature for 48 hours. After the reaction was completed, the reaction solution was diluted with water (3 mL) and the pH was adjusted to 7-8 with dilute hydrochloric acid (1 M) solution. The mixture was then directly concentrated under reduced pressure and purified by high pressure liquid preparative chromatography (chromatographic column: Gemini-C18 150×21.2 mm, 5 m; mobile phase: acetonitrile-water (0.1% formic acid) gradient: 15-40%; UV: 214 nm) to obtain the target compound (13.7 mg, yield: 25%, containing 0.9 equivalents of formic acid). MS m / z (ESI): 447.0 [M+1]. 1 H NMR (400MHz, DMSO-d6) δ12.89(s,1H),10.85(s,1H),8.13(s,0.9H),7.99(d,J=8.0Hz,2H),7.69(d,J =8.0Hz,2H),7.26(t,J=2.6Hz,1H),6.66(s,1H),6.42(t,J=2.6Hz,1H),3.71(s,3H),3.53(d,J=11.6 Hz,1H),3.21(d,J=11.6Hz,1H),2.84(d,J=12.0Hz,1H),2.70-2.65(m,0.5H),2.54(s,1H),2.42(s,3 H),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).

[0353] Example 10

[0354] Intermediate 1:

[0355]

[0356] At -78 ° C, diethylaminosulfur trifluoride (3.48 g) was slowly added to a dichloromethane (10 mL) solution of 2-bromopyridine-4-carboxaldehyde (1 g), and the reaction mixture was slowly heated to room temperature and stirred at this temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate (50 mL), extracted with dichloromethane (50 mL), the extract was washed with water (10 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 1 (1 g, yield: 86%). MS m / z (ESI): 207.9 [M+1].

[0357] Intermediate 2:

[0358]

[0359] In a 10mL three-necked flask, 1,4-dioxane (10mL), water (1mL), intermediate 1 (1g), methyl 4-(dihydroxyboryl)benzoate (0.95g), sodium carbonate (1.02g) and tetrakis(triphenylphosphine)palladium (0.166mg) were added in sequence, and the reaction was heated to 95°C under nitrogen protection and stirred at this temperature for 18 hours. After the reaction was completed, the reaction mixture was naturally cooled to room temperature, quenched by adding saturated aqueous ammonium chloride solution (2mL), and extracted three times with ethyl acetate (50mL). The combined organic matter was dried over anhydrous sodium sulfate and 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 2 (0.4g, yield: 29.17%). MS m / z (ESI): 264.2 [M+1].

[0360] Intermediate 3:

[0361]

[0362] In a 10mL single-mouth bottle, methanol (4mL), concentrated hydrochloric acid (0.2mL), intermediate 2 (340mg) and platinum oxide (292.9mg) were added in sequence, and the reaction was catalytically hydrogenated for 18 hours under a hydrogen atmosphere and room temperature. After the reaction was completed, the reaction solution was directly filtered and concentrated under reduced pressure, and the residue was purified by high pressure liquid preparative chromatography (chromatographic column: C18 spherical, 100A, 20g, 20-35μm; acetonitrile-water = 10-70%,; UV: 214nm) to obtain intermediate 3 (120mg, yield: 33.51%). MS m / z (ESI): 270.1 [M+1].

[0363] Intermediate 4:

[0364]

[0365] In a 10mL single-mouth bottle, 1,2-dichloroethane (2mL), intermediate 3 (140mg) and intermediate 2 of Example 2 (196mg) were added in sequence. After the reaction mixture was stirred at room temperature for 8 hours, sodium triacetoxyborohydride (330mg) was added and continued to stir at room temperature for 18 hours. After the reaction was completed, dichloromethane (10mL) was added to dilute, washed with water (10mL), 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 4 (200mg, yield: 64.4%). MS m / z (ESI): 542.8 [M+1].

[0366] Target compound:

[0367]

[0368] In a 10 mL three-necked flask, methanol (2 mL), tetrahydrofuran (2 mL), water (2 mL), intermediate 4 (180 mg) and sodium hydroxide (132 mg) were added in sequence, and the reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by high pressure liquid preparative chromatography (chromatographic column: Gemini-C18 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-25%) to obtain the target compound (19.5 mg, yield: 13.09%, containing 0.4 equivalents of formic acid). MS m / z (ESI): 429.2 [M+1]. 1 H NMR (400MHz, CD3OD) δ8.36 (s, 0.4H), 8.18 (d, J=8.0Hz, 2H), 7.68 (d, J=8.0Hz, 2H), 7.31 (d, J= 2.8Hz,1H),6.78-6.72(m,1H),6.30(s,1H),5.81(td,J=16.4Hz,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).

[0369] Embodiment 11

[0370] Intermediate 1:

[0371]

[0372] Isopropylmagnesium bromide / magnesium chloride complex (85 mL) was added to a solution of 4-bromobenzonitrile (18.2 g) in tetrahydrofuran (100 mL) at room temperature under nitrogen protection, and the reaction was stirred at room temperature for 3 hours to generate a 4-cyanophenylmagnesium bromide solution (reactant 1).

[0373] At -78°C and under nitrogen protection, (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). After the reaction was stirred at -78°C for 15 minutes, a freshly prepared solution of 4-cyanophenylmagnesium bromide (reactant 1) was added. The reaction was continued to stir at -78°C for 1 hour. After the reaction was completed, the reaction solution was quenched with dilute hydrochloric acid (1M, 150 mL), naturally warmed to room temperature and continued to stir for 30 minutes, then water (150 mL) was added for dilution, and extracted with ethyl acetate (200 mL) three times. 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%).

[0374] Intermediate 2:

[0375]

[0376] 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 this temperature for 5 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain intermediate 2 (3 g, yield: 30%).

[0377] Intermediate 3:

[0378]

[0379] Dichloromethane (4 mL) and intermediate 2 (210 mg) were added to a 50 mL single-mouth bottle, and then diethylaminosulfur trifluoride (177 mg) was added under ice bath, and the reaction was heated to 40 ° C under nitrogen protection and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was poured into ice water (10 mL), extracted with ethyl acetate (50 mL) three times, and the combined organic phase was washed with saturated brine (5 mL), the organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain intermediate 3 (144 mg, yield: 54%).

[0380] Intermediate 4:

[0381]

[0382] Trifluoroacetic acid (4 mL) and intermediate 3 (144 mg) were added to a 50 mL single-necked bottle, and the reaction was heated to 80°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain intermediate 4 (80 mg, yield: 60%).

[0383] Intermediate 5:

[0384]

[0385] In a 50mL single-mouth bottle, intermediate 4 (80mg) was added to 80% sulfuric acid / methanol = (1:1, 4mL) system, and the reaction was heated to 90°C and stirred at this temperature for 6 hours. After the reaction was completed, water (10mL) was added to dilute at room temperature and the pH was adjusted to 7-8 with sodium hydroxide solution (2M), and then extracted with ethyl acetate (50mL) three times, the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (petroleum ether: ethyl acetate = 2:1) to obtain intermediate 5 (64mg, yield: 69%).

[0386] Intermediate 6:

[0387]

[0388] In a 50 mL single-mouth bottle, 1,2-dichloroethane (2 mL), intermediate 5 (22 mg), intermediate 2 of Example 2 (34 mg) and sodium triacetoxyborohydride (50 mg) were added in sequence, and the reaction was stirred for 16 hours at room temperature under nitrogen protection. After the reaction was completed, methanol was added to the reaction solution until the solution was clear, and then it was directly concentrated under reduced pressure. The residue was purified by thin layer chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain intermediate 6 (20 mg, yield: 42%).

[0389] Target compound:

[0390]

[0391] In a 50mL single-mouth bottle, methanol (1.5mL), water (0.5mL), intermediate 6 (20mg) and sodium hydroxide (30mg) were added in sequence, and the reaction was stirred at room temperature for 48 hours. After the reaction was completed, the reaction solution was poured into water (5mL), and the pH value was adjusted to 7-8 with dilute hydrochloric acid (1M), and it was directly concentrated under reduced pressure. The residue was purified by high pressure liquid phase preparative chromatography (chromatographic column: AZZOTAC18100A, 10μm; mobile phase: acetonitrile-water (0.05% ammonia water); gradient: 15-28%), and the obtained product was purified again by thin layer chromatography (dichloromethane: methanol = 10:1) to obtain the target compound (6mg, yield: 20%). MS m / z (ESI): 414.45 [M+1]. 1H NMR (400MHz, CD3OD) δ8.14(d,J=8.0Hz,2H),7.71(d,J=8.0Hz,2H),7.25(d,J=3.2Hz,1H),6.73(s,1H),6.41(d,J=3.2Hz,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).

[0392] Example 12

[0393] Intermediate 1:

[0394]

[0395] At room temperature, tetrakis(triphenylphosphine)palladium (1.43 g), 4-bromophenylboronic acid (5 g), 2-bromopyridine (4.72 g) and sodium carbonate (6.87 g) were added to a solution of 1,4-dioxane (90 mL) and water (15 mL) in sequence, and the reaction was heated to 90°C under nitrogen protection and carried out at this temperature for 16 hours. After the reaction was completed, the reaction solution was directly concentrated, and the residue was subjected to 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].

[0396] Intermediate 2:

[0397]

[0398] [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (700 mg) was added to a toluene (20 mL) solution of 2-(4-bromophenyl)pyridine (2 g), diethyl phosphite (4.7 g) and DIEA (2.2 g), and the reaction was heated to 110°C under nitrogen protection and carried out at this temperature for 16 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate = 5:1-1:1) to obtain intermediate 2 (1.4 g, yield 60%). MS m / z (ESI): 291.9 [M+1].

[0399] Intermediate 3:

[0400]

[0401] 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 solution was subjected to hydrogenation catalytic reaction at 0.4 MPa for 48 hours. After the reaction, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain intermediate 3 (1.28 g, yield 90%). MS m / z (ESI): 297.9 [M+1].

[0402] Intermediate 4:

[0403]

[0404] Tetraethyl titanate (226 mg) was added to the tetrahydrofuran (20 mL) solution of intermediate 2 (300 mg) and intermediate 3 (367 mg) of Example 2, and the reaction was heated to 70°C and stirred at this temperature for 16 hours. The reaction system was cooled to room temperature, sodium triacetyl borohydride (655 mg) was added, and then heated to 70°C and stirred at this temperature for 1 hour. After the reaction was completed, the reaction solution 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].

[0405] Target compound:

[0406]

[0407] Trimethylsilyl bromide (2 mL) was added to a dichloromethane (6 mL) solution of intermediate 4 (200 mg) at 0°C, and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by high pressure liquid preparative chromatography (chromatographic column: Gemini-C18 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-40%) to obtain the target compound (60 mg, yield 82%). MS m / z (ESI): 414.9 [M+1]. 1H NMR(400MHz,CD3OD)δ8.07(s,2H),8.06–7.95(m,2H),7.66–7.61(m,2H),7.3 2(d,J=3.1Hz,1H),6.76(s,1H),6.33(d,J=3.1Hz,1H),4.49–4.38(m,1H),4. 34(d,J=12.7Hz,1H),4.12(d,J=12.7Hz,1H),3.76(s,3H),3.51(d,J=12.8Hz ,1H),3.28–3.18(m,1H),2.50(s,3H),2.12–2.04(m,2H),1.96–1.81(m,4H).

[0408] Example 13

[0409] Intermediate 1:

[0410]

[0411] Tetraethyl titanate (151 mg) was added to a tetrahydrofuran (15 mL) solution of intermediate 2 (200 mg) of Example 2 and 2-(4-bromophenyl)piperidine (195 mg), and the reaction system was heated to 70°C and stirred at this temperature for 16 hours. The reaction was cooled to room temperature naturally, sodium triacetylborohydride (438 mg) was added, heated to 70°C and stirred at this temperature for 1 hour. After the reaction was completed, 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, yield 71%). MS m / z (ESI): 512.7 [M+1].

[0412] Intermediate 2:

[0413]

[0414] Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (X-Phos-Pd-G2) (19 mg) was added to an ethanol (15 mL) solution of intermediate 1 (252 mg), diborane 1,1,2,2-tetraol (131 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos) (23 mg) and potassium acetate (144 mg). The reaction solution was heated to 90°C under nitrogen protection and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol = 5:1) to obtain intermediate 2 (200 mg, yield 85%). MS m / z (ESI): 478.9 [M+1].

[0415] Target compound:

[0416]

[0417] Add trimethylsilyl bromide (3 mL) to a dichloromethane (9 mL) solution of intermediate 2 (200 mg) at 0°C and react at room temperature for 16 hours. After the reaction, the reaction solution was directly concentrated under reduced pressure, and the residue was separated and purified by high pressure liquid preparative chromatography (chromatographic column: Gemini-C18 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-35%) to obtain the target compound (42 mg, yield 33%, containing 0.8 equivalents of formic acid). MS m / z (ESI): 378.9 [M+1]. 1 HNMR(400MHz,CD3OD)δ8.47(s,0.8H),7.83(s,2H),7.55(d,J=8.0Hz,2H),7.30(s,1H),6.75(s,1H),6.27(s,1H),4.44–4.30(m,2 H),4.10(d,J=12.6Hz,1H),3.75(s,3H),3.55–3.46(m1H),3.29–3.16(m,1H),2.50(s,3H),2.15-2.00(m,2H),2.00–1.70(m,4H).

[0418] Embodiment 14

[0419] Intermediate 1:

[0420]

[0421] 4-Methylthiophenylboronic acid pinacol ester (13.8 g), 2-bromopyridine (10 g), tetrakis(triphenylphosphine)palladium (2.19 g) and sodium carbonate (50.32 g) were added to a mixed solvent of toluene (140 mL), water (140 mL) and ethanol (40 mL) in sequence. The reaction system was heated to 95°C under nitrogen protection and stirred at this temperature for 8 hours. After the reaction was completed, the reaction system was naturally cooled to room temperature, quenched by adding saturated aqueous ammonium chloride solution (50 mL), and 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 obtain intermediate 1 (300 mg, yield: 74.52%). MS m / z (ESI): 202.2 [M+1].

[0422] Intermediate 2:

[0423]

[0424] In a 250mL three-necked flask, toluene (100mL), intermediate 1 (1g), diphenylsilane (4.61g), diphenylamine (3.3844g) and tris(pentafluorophenyl)boron (0.26g) were added in sequence. The reaction system was heated to 110°C under nitrogen protection and stirred at this temperature for 18h. After the reaction was completed, the reaction system was naturally cooled to room temperature, quenched by adding saturated aqueous ammonium chloride solution (50mL), and extracted three times with ethyl acetate (50mL). The combined organic matter was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain intermediate 2 (0.9g, yield: 80%). MS m / z (ESI): 208.2 [M+1].

[0425] Intermediate 3:

[0426]

[0427] In a 50mL three-necked flask, 1,2-dichloroethane (10mL), intermediate 2 (500mg) and intermediate 2 of Example 2 (909mg) were added in sequence. The reaction system was stirred at room temperature for 8 hours, sodium triacetoxyborohydride (1.53g) was added, and the reaction was continued at room temperature for 18 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane (10mL), washed once with water (10mL), 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 (300mg, yield: 25.6%). MS m / z (ESI): 481.4 [M+1].

[0428] Intermediate 4:

[0429]

[0430] Intermediate 3 (100 mg) was added to a methanol (2 mL) solution of ammonium carbamate (24.36 mg) and iodophenylacetic acid diacetate (140.69 mg), and the reaction was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was directly separated and purified by high pressure liquid preparative chromatography (chromatographic column: C18 spherical, 100A, 20 g, 20-35 um; acetonitrile-water = 10-70%; UV: 214 nm) to obtain intermediate 4 (30 mg, yield: 17.6%). MS m / z (ESI): 512.3 [M+1].

[0431] Target compound:

[0432]

[0433] In a 10mL single-mouth bottle, dichloromethane (6mL), intermediate 4 (30mg) and trimethylsilyl bromide (0.6mL) were added in sequence. The reaction system was stirred at room temperature for 8 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the residue was separated and purified by high pressure liquid phase preparative chromatography (chromatographic column: Gemini-C18150×21.2mm, 5μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-20%) to obtain the target compound (11.6mg, yield: 44.67%, containing 0.6 equivalents of formic acid). MS m / z(ESI):412.3[M+1]. 1 H NMR (400MHz, DMSO) δ10.83 (s, 1H), 8.21 (s, 0.6H), 7.93 (d, J=8.0Hz, 2H), 7.74 (d, J= 8.0Hz,2H),7.25(t,J=2.4Hz,1H),6.65(s,1H),6.49(td,J=9.6Hz,2.4Hz,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= 10.4Hz,1H),2.41(s,3H),1.75-1.64(m,2H),1.57-1.43(m,2H),1.41-1.28(m,2H).

[0434] Embodiment 15

[0435] Intermediate 1:

[0436]

[0437] In a 250mL single-mouth bottle, a mixed solvent of dioxane and water (8:1, 50mL), 4-methoxyformylphenylboronic acid pinacol ester (5.0g), 2-bromopyridine (3.3g), sodium carbonate (3g) and tetrakis(triphenylphosphine)palladium (662mg) were added in sequence. The reaction system was heated to 80°C under nitrogen protection and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was diluted with 100mL of water and extracted with ethyl acetate (200mL) three times. The combined organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate and 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 (1.1g, yield: 27%). MS m / z (ESI): 214.1 [M+1].

[0438] Intermediate 2:

[0439]

[0440] Methanol (30 mL), intermediate 1 (1.9 g), platinum dioxide (202 mg) and hydrochloric acid (0.5 mL) were added to a 50 mL reactor in sequence, and the mixture was subjected to catalytic hydrogenation reaction at 0.4 MPa (hydrogen) and room temperature for 20 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain intermediate 2 (1.55 g, yield: 79%). MS m / z (ESI): 219.9 [M+1].

[0441] Intermediate 3:

[0442]

[0443] In a 50 mL single-mouth bottle, tetrahydrofuran (10 ml), intermediate 2 (150 mg) of Example 2, intermediate 2 (150 mg) and tetraethyl titanate (120 mg) were added in sequence. The reaction system was heated to 100 ° C under nitrogen protection and stirred at this temperature for 8 hours, then the reaction was cooled to room temperature, sodium triacetoxyborohydride (330 mg) was added, and stirring was continued for 1 hour. After the reaction was completed, the reaction solution was poured into water, extracted 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 column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain intermediate 3 (135 mg, yield: 40%).

[0444] Target compound:

[0445]

[0446] In a 50 mL single-mouth bottle, N, N-dimethylformamide (6 mL), intermediate 3 (100 mg), acid hydroxylamine (55 mg), 2-(7-azabenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU) (110 mg) and triethylamine (80 mg) were added in sequence, and the reaction system was stirred at room temperature for 48 h. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (100 mL) three times. 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, and the residue was separated and purified by high pressure liquid preparative chromatography (chromatographic column: Gemini-C18 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-30%) to obtain the target compound (11.7 mg, yield: 11%). MS m / z (ESI): 394.1 [M+1]. 1H NMR (400MHz, CD3OD) δ8.51(s,1H),7.94(d,J=7.8Hz,2H),7.71(d,J=7.8Hz,2H),7.31(d,J=2.8Hz,1H),6.76(s,1H),6.34(s,1 H),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).

[0447] Example 16

[0448] Intermediate 1:

[0449]

[0450] At -78°C and under nitrogen protection, 3,3-difluorocyclobutane-1-one (203 mg) and trimethylsilyl trifluoromethanesulfonate (42 mg) were added to dichloromethane (5 mL) of the intermediate 1 (860 mg) of Example 6, and the reaction was stirred at -78°C for one hour, and triethylsilane (222 mg) was added. The reaction was naturally warmed to room temperature and continued to stir at room temperature for 16 hours. After the reaction was completed, the reaction solution was slowly quenched by adding sodium bicarbonate aqueous solution (10 mL), diluted with water (10 mL), extracted with dichloromethane (10 mL), and the extract was washed once with saturated brine (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 = 3: 1) to obtain intermediate 1 (80 mg, yield: 8.36%). MS m / z (ESI): 448.8 [M+23].

[0451] Intermediate 2:

[0452]

[0453] Intermediate 1 (100 mg) and sodium hydroxide (94 mg) were added to a mixed solution of isopropanol and water (1 mL / 3 mL) in sequence, and the reaction was heated to 100°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was added with dilute hydrochloric acid (1M, 2.50 mL) under an ice bath to adjust the pH to 5-6, diluted with water (5 mL), extracted with ethyl acetate (5 mL), and the extract was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 2 (70 mg, yield: 60%). MSm / z (ESI): 445.9 [M+1].

[0454] Intermediate 3:

[0455]

[0456] Potassium carbonate (43 mg) and iodomethane (45 mg) were added to an acetonitrile (2 mL) solution of intermediate 2 (70 mg), and the reaction mixture was heated to 50°C and stirred at this temperature for 2 hours. After the reaction was completed, the reaction solution was directly concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain intermediate 3 (60 mg, yield: 73%). MS m / z (ESI): 481.7 [M+23].

[0457] Intermediate 4:

[0458]

[0459] Palladium / carbon (10 mg) was added to a tetrahydrofuran (1 mL) solution of intermediate 3 (60 mg), and the reaction was catalytically hydrogenated under a hydrogen atmosphere at room temperature for 16 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was directly concentrated to obtain intermediate 4 (35 mg, yield: 74%). MS m / z (ESI): 325.9 [M+1]. .

[0460] Intermediate 5:

[0461]

[0462] Intermediate 4 (35 mg) was added to a solution of intermediate 2 (32 mg) of Example 2 in 1,2-dichloroethane (2 mL), and the reaction was stirred at room temperature for 8 hours, then sodium triacetoxyborohydride (70 mg) was added and stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution 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]. .

[0463] Target compound:

[0464]

[0465] At room temperature, intermediate 5 (80 mg, 0.134 mmol) and sodium hydroxide (54 mg, 1.35 mmol) were added to a mixed solution of methanol and water (1 mL / 1 mL) in sequence, and the reaction was heated to 75°C and stirred at this temperature for 3 hours. After the reaction was completed, dilute hydrochloric acid (1 M, 1.35 mL) was added to the reaction solution under ice bath to adjust the pH to about 7, and then the solvent was directly lyophilized, and the residue was separated and purified by high pressure liquid preparative chromatography (chromatographic 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). 1 H NMR (400MHz, CD3OD) δ8.44(s,0.2H),8.15(d,J=8.0Hz,2H),7.63(d,J=8.0Hz,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=11.8Hz,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]. .

[0466] Embodiment 17

[0467] Intermediate 1:

[0468]

[0469] At -40°C and under nitrogen protection, a tetrahydrofuran solution of methylmagnesium bromide (1M, 6mL) was slowly added dropwise (the temperature of the reaction solution was kept below -40°C during the addition) to a tetrahydrofuran (50mL) solution of the intermediate 2 (2g) of Example 1. After the addition was complete, the reaction was stirred and naturally warmed to room temperature, and then stirred at room temperature for 2 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (20mL) was added to the reaction solution to quench, and then ethyl acetate (100mL) and water (100mL) were added to dilute, the organic phase was separated and washed with saturated brine (50mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the intermediate 1 (1.7g, yield: 40%). MS m / z (ESI): 351.0 [M+1].

[0470] Intermediate 2:

[0471]

[0472] Under ice bath, diethylaminosulfur trifluoride (413 mg) was added dropwise to a solution of intermediate 1 (900 mg) in dichloromethane (20 mL), and the reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution (20 mL) was added to the reaction mixture to quench the reaction, and then water (100 mL) was added to dilute it, and it was extracted with ethyl acetate (100 mL). The extract was washed once with water (100 mL), dried over anhydrous sodium sulfate and 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 2 (280 mg, yield: 27%). MS m / z (ESI): 352.9 [M+1].

[0473] Intermediate 3:

[0474]

[0475] At room temperature, intermediate 2 (250 mg) and aqueous sodium hydroxide solution (4 M, 3 mL) were added to isopropanol (3 mL) in sequence, and the reaction was heated to 100 ° C and stirred at this temperature for 30 hours. After the reaction was completed, the reaction solution was slowly added with dilute hydrochloric acid (1 M, 13 mL) in an ice bath to adjust the pH to 5-6, diluted with water (20 mL), extracted with ethyl acetate (20 mL), and the extract was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 3 (200 mg, yield: 64%). MS m / z (ESI): 371.9 [M+1].

[0476] Intermediate 4:

[0477]

[0478] At room temperature, potassium carbonate (138 mg) and iodomethane (140 mg) were added to an acetonitrile (5 mL) solution of intermediate 3 (200 mg) in sequence, and the reaction solution was heated to 50°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution 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].

[0479] Intermediate 5:

[0480]

[0481] Palladium / carbon (50 mg) was added to a solution of intermediate 4 (200 mg) in tetrahydrofuran (5 mL), and the reaction was allowed to proceed at room temperature under 1 atmosphere of hydrogen for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly concentrated under reduced pressure to obtain intermediate 5 (95 mg, yield: 27%). MS m / z (ESI): 251.9 [M+1].

[0482] Intermediate 6:

[0483]

[0484] At room temperature, intermediate 5 (50 mg), 2,8,9-trioxo-5-aza-1-silabicyclo[3.3.3]undecane (150 mg) and acetic acid (30 mg) were added to a tetrahydrofuran (5 mL) solution of intermediate 2 (60 mg) of Example 2 in sequence, and the reaction was heated to 70°C and stirred at this temperature for 24 hours. After the reaction was completed, the reaction solution was directly concentrated, and the residue was purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain intermediate 6 (40 mg, yield: 26%). MS m / z (ESI): 525.2 [M+1].

[0485] Target compound:

[0486]

[0487] At room temperature, intermediate 6 (40 mg) and sodium hydroxide (40 mg) were added to a mixed solution of methanol / water (2 mL / 2 mL) in sequence, and the reaction was heated to 75°C and stirred at this temperature for 3 hours. After the reaction was completed, dilute hydrochloric acid (1 M, 1 mL) was added to the reaction solution under ice bath to adjust the pH to about 8, the mixture was concentrated under reduced pressure, and the residue was separated and purified by high pressure liquid chromatography (chromatographic 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 (400MHz, CD3OD) δ8.16–8.08(m,2H),7.63(d,J=8.0Hz,2H),7.32–7.25(m,1H),6.77–6.70(m,1H),6.37–6.29(m,1 H), 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).

[0488] Embodiment 18

[0489] Intermediate 1:

[0490]

[0491] At room temperature, ethylene glycol (558 mg) and p-toluenesulfonic acid (114 mg) were added to a toluene (40 mL) solution of the intermediate 2 (2 g) of Example 1, and the reaction was heated to 110°C and stirred for 18 hours. After the reaction was completed, 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].

[0492] Intermediate 2:

[0493]

[0494] At room temperature, sodium hydroxide (1.7 g) was added to a mixed solution of methanol and water (20 mL / 20 mL) of intermediate 1 (1.6 g), and the reaction was heated to 70°C and stirred at this temperature for 18 hours. After the reaction was completed, the reaction system was naturally cooled to room temperature, and the pH was adjusted to about 2 with dilute hydrochloric acid (2 M). The obtained mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by high pressure liquid preparative chromatography (chromatographic column: -Gemini-C18 150×21.2 mm, 5 μm, column temperature: 25°C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar, mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-70%) to obtain intermediate 2 (150 mg, yield: 47.6%). MS m / z (ESI): 398.2 [M+1].

[0495] Intermediate 3:

[0496]

[0497] Under ice bath, thionyl chloride (1.34 g) was slowly added dropwise to a methanol (10 mL) solution of intermediate 2 (800 mg), and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, water (10 mL) was added to the reaction solution to dilute it and continue stirring for 2 hours to quench the reaction, and then the reaction solution was directly concentrated under reduced pressure to obtain intermediate 3 (680 mg, yield: 77.8%). MS m / z (ESI): 368.2 [M+1].

[0498] Intermediate 4:

[0499]

[0500] Under ice bath, ammonia methanol solution (1M, 5.8mL) was added to a solution of intermediate 3 (600mg) in 1,2-dichloroethane (2mL). After the reaction solution was stirred at room temperature for 8 hours, sodium acetate borohydride (1g) was added and stirred at room temperature for 18 hours. Dichloromethane (10mL) and water (10mL) were added to the obtained mixture for dilution, 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 4 (150mg, yield: 24.98%). MS m / z (ESI): 369.1 [M+1].

[0501] Intermediate 5:

[0502]

[0503] At room temperature, acetic anhydride (38.79 mg) was added to a solution of intermediate 4 (140 mg) in ethyl acetate (5 mL), and the reaction was stirred at room temperature for 18 hours. After the reaction was completed, potassium carbonate (105 mg) was added to the reaction mixture, and the mixture was stirred for 30 minutes 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 5 (110 mg, yield: 67%). MS m / z (ESI): 411.3 [M+1].

[0504] Intermediate 6:

[0505]

[0506] At room temperature, palladium hydroxide / carbon (10 mg) was added to a methanol (5 mL) solution of intermediate 5 (70 mg), and the reaction solution was stirred for 18 hours at room temperature under a hydrogen atmosphere. After the reaction was completed, the reaction mixture was filtered, and the filtrate was directly concentrated under reduced pressure to obtain intermediate 6 (50 mg, yield: 89.41%). MS m / z (ESI): 277.0 [M+1].

[0507] Intermediate 7:

[0508]

[0509] At room temperature, intermediate 6 (40 mg) and intermediate 2 of Example 2 (52.8 mg) were added to a solution of 1,2-dichloroethane (2 mL), and the reaction was stirred at room temperature for 8 hours, and then sodium acetate borohydride (89 mg) was added, and the reaction was continued to stir at room temperature for 18 hours. After the reaction was completed, dichloromethane (10 mL) was added to the reaction solution for dilution, 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].

[0510] Target compound:

[0511]

[0512] At room temperature, intermediate 7 (30 mg) and sodium hydroxide (20 mg) were added to a mixed solution of methanol / water / tetrahydrofuran (0.5 mL / 0.5 mL / 0.5 mL), and the reaction was stirred at room temperature for 18 hours. After the reaction was completed, dilute hydrochloric acid (2 M, 0.5 mL) was added to the reaction solution under ice bath to adjust the pH to 7, and the residue was purified by high pressure liquid preparative chromatography (chromatographic 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(400MHz,CD3OD)δ8.40(s,0.3H),8.15(d,J=8.0Hz,2H),7.64(d,J=8.0Hz,2H ),7.31(d,J=4.0Hz,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).

[0513] Embodiment 19

[0514] Intermediate 1:

[0515]

[0516] At room temperature, ethylamine tetrahydrofuran solution (0.41 mL) was added to a solution of intermediate 2 (200 mg) of Example 1 in 1,2-dichloroethane (2 mL). The reaction was stirred at room temperature for 8 hours, sodium triacetoxyborohydride (343 mg) was added, and the reaction was stirred at room temperature for 18 hours. After the reaction was completed, dichloromethane (10 mL) was added to the reaction system for dilution, 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].

[0517] Intermediate 2:

[0518]

[0519] At room temperature, di-tert-butyl dicarbonate (131 mg) and triethylamine (76 mg) were added to a solution of intermediate 1 (200 mg) in dichloromethane (2 mL), and the reaction solution was stirred at room temperature for 18 hours. After the reaction was completed, dichloromethane (10 mL) was added to the reaction solution for dilution, 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 2 (200 mg, yield: 76.5%). MS m / z (ESI): 497.3 [M+1].

[0520] Intermediate 3:

[0521]

[0522] At room temperature, palladium hydroxide / carbon (20 mg) was added to a methanol (5 mL) solution of intermediate 2 (180 mg), and the reaction was stirred at room temperature under a hydrogen balloon atmosphere for 18 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 3 (120 mg, yield: 82.8%). MS m / z (ESI): 363.3 [M+1].

[0523] Intermediate 4:

[0524]

[0525] At room temperature, intermediate 3 (150 mg) was added to a solution of intermediate 2 (142 mg) of Example 2 in 1,2-dichloroethane (2 mL), and the reaction was stirred at room temperature for 8 hours. Sodium acetate borohydride (261 mg) was added, and the reaction was continued to stir at room temperature for 18 hours. After the reaction was completed, dichloromethane (10 mL) was added to the reaction solution for dilution, 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].

[0526] Intermediate 5:

[0527]

[0528] At room temperature, trimethylsilyl bromide (0.2 mL) was added to a solution of intermediate 4 (40 mg) in dichloromethane (1 mL), and the reaction was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain intermediate 5 (40 mg, yield: 99.67%). MS m / z (ESI): 436.3 [M+1].

[0529] Target compound:

[0530]

[0531] At room temperature, intermediate 5 (40 mg) and sodium hydroxide (36 mg) were added to a mixed solution of methanol / water / tetrahydrofuran (0.5 mL / 0.5 mL / 0.5 mL) in sequence, and the reaction was stirred at room temperature for 18 hours. After the reaction was completed, dilute hydrochloric acid (2 M, 0.5 mL) was added to the reaction solution under ice bath to adjust the pH to about 7, and the obtained mixture was concentrated under reduced pressure. The residue was purified by high pressure liquid chromatography (chromatographic 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]. 1H NMR (400MHz, CD3OD) δ8.43(s,2H),8.09(d,J=8.0Hz,2H),7.66(d,J=8.0Hz,2H),7.21(d,J =2.8Hz,1H),6.69(s,1H),6.37(d,J=2.8Hz,1H),3.87-3.81(m,1H),3.75(s,3H),3.62-3.5 6(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).

[0532] Embodiment 20

[0533] Intermediate 1:

[0534]

[0535] At room temperature, potassium carbonate (4.47 g) was added to a DMF (100 mL) solution of methyl 4-bromo-3-hydroxybenzoate (5 g) and bromoacetaldehyde diethyl acetal (4.68 g), and the reaction solution was heated to 100°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 1 (7.9 g, yield: 80%). MS m / z (ESI): 268.7

[0536] [M+23].

[0537] Intermediate 2:

[0538]

[0539] At room temperature, polyphosphoric acid (3 g) was added to a chlorobenzene (15 mL) solution of intermediate 1 (1 g), and the reaction solution was heated to 130°C and stirred at this temperature for 16 hours. After the reaction was completed, water (50 mL) was added to the reaction solution for dilution, and extracted with ethyl acetate (30 mL×3). The combined extract was washed with saturated brine (20 mL×3), 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 2 (300 mg, yield: 40%). GC-MS m / z: 254, 256 [M].

[0540] Intermediate 3:

[0541]

[0542] At room temperature, bistriphenylphosphine palladium dichloride (54 mg) was added to a dioxane (15 mL) solution of intermediate 2 (200 mg), 2-(tributyltinyl)pyridine (344 mg) and cuprous iodide (15 mg), and the reaction was heated to 100°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was naturally cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain intermediate 3 (140 mg, yield 70%). MS m / z (ESI): 253.9 [M+1].

[0543] Intermediate 4:

[0544]

[0545] At room temperature, platinum dioxide (10 mg) was added to a mixed solution of intermediate 3 (20 mg) in methanol / concentrated hydrochloric acid (4 mL / 0.5 mL), and the reaction solution was stirred in a pressure autoclave at room temperature and 4 atmospheres of hydrogen for 16 hours. After the reaction was completed, the reaction solution 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].

[0546] Intermediate 5:

[0547]

[0548] At room temperature, tetraethyl titanate (83 mg) was added to a tetrahydrofuran (10 mL) solution of intermediate 4 (99 mg) and intermediate 2 of Example 2 (110 mg), and the reaction was heated to 70°C and stirred at this temperature for 16 hours. After the reaction solution was cooled to room temperature, sodium triacetyl borohydride (241 mg, 1.14 mmol) was added, and the reaction mixture was heated to 70°C and stirred for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain intermediate 5 (50 mg, yield: 24%). MS m / z (ESI): 534.8 [M+1].

[0549] Target compound:

[0550]

[0551] At room temperature, sodium hydroxide (36 mg) was added to a methanol / water (4 mL / 1 mL) mixed solution of intermediate 5 (50 mg), and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was added with hydrochloric acid (5 M, 1 mL) in an ice bath to adjust the pH to 5-6, and then concentrated under reduced pressure. The crude product was purified by preparative high pressure liquid chromatography (chromatographic column: Gemini-C18, 150×21.2 mm, 5 μm; 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). 1 HNMR(400MHz,CD3OD)δ8.49(s,0.9H),7.54(d,J=8.0Hz,1H),7.34(d,J=8.0Hz,1H),7.29(d, J=2.8Hz,1H),6.76(s,1H),6.29(d,J=2.8Hz,1H),4.69(t,J=9.0Hz,2H),4.56(d,J=10.4Hz, 1H),4.44(d,J=12.7Hz,1H),4.18(d,J=12.7Hz,1H),3.78(s,3H),3.58(t,J=8.8Hz,2H),3.5 1(d,J=13.2Hz,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].

[0552] Embodiment 21

[0553] Intermediate 1:

[0554]

[0555] At room temperature, a solution of bromine (10.13 g, 0.0634 mmol) in chloroform (70 mL) was slowly added dropwise to a solution of 6-aminopyridine-2-carboxylic acid methyl ester (9.64 g, 0.0634 mol) in chloroform (408 mL) (addition process lasted 60 minutes). After the addition was completed, the reaction was stirred at room temperature for 18 hours. After the reaction was completed, a saturated sodium thiosulfate solution (150 mL) was added to the reaction solution to quench the reaction, and the phases were separated. The aqueous phase was extracted with dichloromethane (150 mL), and the combined organic phase was washed with water (10 mL × 3) solution, 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 1 (1.1 g, yield: 7.10%). MS m / z (ESI): 230.8 [M+23].

[0556] Intermediate 2:

[0557]

[0558] At room temperature, the intermediate 1 (1 g) and 40% chloroacetaldehyde (1.69 g) in isopropanol (20 mL) were heated to 80°C and stirred at this temperature for 18 hours. After the reaction, the reaction system was naturally cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain intermediate 2 (1 g, yield: 86.05%). MS m / z (ESI): 254.8 [M+23].

[0559] Intermediate 3:

[0560]

[0561] At room temperature, 1-(tert-butyloxycarbonyl)piperidine-2-carboxylic acid (1.35 g), iridium reagent (Ir[dF(CF3)ppy]2(dtbppy))PF6 (cas: 870987-63-6, 43.98 mg), nickel chloride glycol dimethyl ether complex (86.25 mg), 4,4'-di-tert-butyl-2,2'-bipyridine (157.84 mg) and cesium carbonate (3832.13 mg) were added in sequence to a DMF (20 mL) solution of intermediate 2 (1 g). The reaction system was replaced with nitrogen three times and then placed in a LED blue light reactor (26 W, Compact fluorescent light, 300-400 nM) for 48 hours. After the reaction, the reaction solution was diluted with ethyl acetate (200 mL), washed with water (200 mL × 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 obtain intermediate 3 (300 mg, yield: 20.17%). MS m / z (ESI): 360 [M+23].

[0562] Intermediate 4:

[0563]

[0564] At room temperature, trifluoroacetic acid (0.6 mL) was added to a solution of intermediate 3 (300 mg, 0.832 mmol) in dichloromethane (3 mL), and the reaction was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain intermediate 4 (100 mg, yield: 46%). MS m / z (ESI): 260.2 [M+23].

[0565] Intermediate 5:

[0566]

[0567] At room temperature, intermediate 4 (100 mg) was added to a solution of intermediate 2 (134 mg) of Example 2 in 1,2-dichloroethane (2 mL). The reaction was stirred at room temperature for 8 hours, and sodium triacetoxyborohydride (245.2 mg, 1.16 mmol) was added. The reaction was stirred at room temperature for 18 hours. After the reaction was completed, dichloromethane (10 mL) was added to the reaction solution for dilution, 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 5 (100 mg, yield: 46.16%). MS m / z (ESI): 533.3 [M+23].

[0568] Target compound:

[0569]

[0570] At room temperature, sodium hydroxide (75 mg) was added to tetrahydrofuran / methanol / water (0.5 mL / 0.5 mL / 0.5 mL) of intermediate 5 (100 mg) and the reaction was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by high pressure liquid preparative chromatography (chromatographic 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 target compound (21 mg, yield: 26.52%). 1 H-NMR(400MHz,MeOD)δ8.96(s,1H),7.77(s,1H),7.59(d,J=8.2Hz,1H),7.46(d,J=8 .2Hz,1H),7.26(d,J=3.2Hz,1H),6.63(s,1H),6.26(d,J=3.2Hz,1H),4.95–4.92(m, 1H),4.42–4.27(m,2H),3.77(s,3H),3.60–3.52(m,1H),3.27–3.20(m,1H),2.65–2. 47(m,1H),2.45(s,3H),2.20-2.10(m,1H),2.05–1.88(m,3H),1.86–1.72(m,1H).MS m / z(ESI):419.2[M+23].

[0571] Embodiment 22

[0572] Intermediate 1:

[0573]

[0574] At -40°C and under nitrogen protection, add 1.3M isopropylmagnesium chloride lithium chloride tetrahydrofuran (36mL) solution to a tetrahydrofuran (100mL) solution of 4-iodo-benzoic acid methyl ester (9.9g). Stir the reaction solution at -40°C for 1 hour, add a tetrahydrofuran (50mL) solution of pyridine nitrogen oxide (3.0g); stir the reaction at -40°C for 1 hour, add a methanol (50mL) solution of sodium borohydride (1438mg, 37.85mmol), continue stirring the reaction at -40°C for 1 hour, slowly warm to room temperature and continue stirring for 16 hours. After the reaction, saturated ammonium chloride solution (100 mL) was added to the reaction solution, stirred for half an hour, diluted with water (400 mL), extracted with ethyl acetate (200 mL), washed with saturated brine (400 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated, and the residue was purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain intermediate 1 (2.0 g, yield: 22%). MS m / z (ESI): 234.1 [M+1].

[0575] Intermediate 2:

[0576]

[0577] At room temperature, zinc powder (2.8 g) and water (20 mL) were added to an acetic acid (20 mL) solution of intermediate 1 (2 g), and the reaction was heated to 50° C. and stirred at this temperature for 2 hours. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, the residue was diluted with water (50 mL), 2M sodium hydroxide solution was added to the dilution under ice bath to adjust the pH to 8-10, and the mixture was 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 under reduced pressure, and the crude product was separated by supercritical chiral preparative chromatography (chromatographic 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% ammonia water) / carbon dioxide = 35 / 65; back pressure: 100 bar) to give intermediate 2 (670 mg, yield: 35%). MS m / z(ESI):218.1[M+1].

[0578] Intermediate 3:

[0579]

[0580] At room temperature, Boc2O (2.0 g) and triethylamine (865 mg) were added to a dichloromethane (10 mL) solution of intermediate 2 (930 mg) and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was directly concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain intermediate 3 (1.4 g, yield: 92%). MS m / z (ESI): 340.0 [M+23].

[0581] Intermediate 4:

[0582]

[0583] Under ice bath and nitrogen protection, diazomethane ether solution (1M, 6.3mL) was slowly added dropwise to the ether (2mL) solution of intermediate 3 (200mg) and palladium acetate (20mg, 10%), and the reaction was stirred for 2 hours under ice bath and nitrogen protection. After the reaction was completed, the reaction solution was filtered and the filtrate was directly concentrated to obtain a crude product. Monitoring found that only part of the raw material was converted into the target product. After the above reaction operation was repeated four times, intermediate 3 was basically completely converted. The obtained crude product was purified by high pressure liquid preparative chromatography (chromatographic column: Gemini-C18, 150×21.2mm, 5μm; column temperature: 25℃; flow rate: 14mL / min; wavelength: 214nm; column pressure: 80bar; mobile term: acetonitrile-water (0.1% formic acid); gradient: 60-80%) to obtain intermediate 4 (70mg, yield: 32%). MS m / z(ESI):354.0[M+23].

[0584] Intermediate 5:

[0585]

[0586] At room temperature, a 4M solution of dioxane hydrochloride (0.5 mL) was added to a dichloromethane solution (1 mL) of intermediate 4 (70 mg), and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain intermediate 5 (70 mg, purity: 50%, yield: 72%). MS m / z (ESI): 232.2 [M+1].

[0587] Intermediate 6:

[0588]

[0589] At room temperature, intermediate 5 (70 mg, 0.30 mmol) was added to a solution of intermediate 2 (88 mg) of Example 2 in 1,2-dichloroethane (2 mL), and the reaction was stirred at room temperature for 8 hours, and then sodium triacetoxyborohydride (192 mg) was added and continued to stir at room temperature for 16 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain intermediate 6 (90 mg, yield: 53%). MS m / z (ESI): 505.1 [M+1].

[0590] Target compound:

[0591]

[0592] At room temperature, sodium hydroxide (143 mg) was added to a mixed solution of intermediate 6 (90 mg) in methanol / water (3 mL / 3 mL), and the reaction was heated to 80° C. and stirred at this temperature for 8 hours. After the reaction was completed, dilute hydrochloric acid (2 M) was added to the reaction system under ice bath to adjust the pH to about 7, and the obtained mixture was directly freeze-dried to remove the solvent, and the residue was purified by high pressure liquid preparative chromatography (chromatographic 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 (400MHz, CD3OD) δ8.47 (s, 0.3H), 8.20 (d, J = 8.4Hz, 2H), 7.74 (d, J = 8.4Hz, 2H), 7.30 (d, J = 3. 1Hz,1H),6.74(s,1H),6.15(d,J=3.1Hz,1H),4.44(d,J=3.0Hz,1H),4.35(d,J=12.8Hz,1H),4.07 (d,J=12.8Hz,1H),3.68(s,3H),3.48–3.34(m,1H),3.02(td,J=13.2,4.0Hz,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].

[0593] Embodiment 23

[0594] Intermediate 1:

[0595]

[0596] At room temperature, sodium borohydride (1.1 g) was added to a methanol (80 mL) solution of intermediate 1 (5.0 g) of Example 1 and cerium trichloride (3.7 g). The reaction was stirred at room temperature for 3 hours, sodium borohydride (1.1 g) was added, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (80 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 1 (4.6 g, yield 87%). MS m / z (ESI): 356.8 [M+23].

[0597] Intermediate 2:

[0598]

[0599] Under ice bath, sodium hydride (660mg, 60%) was added to the DMF (50mL) solution of intermediate 1 (4.6g). After stirring for 5 minutes, iodoethane (3.2g) was added and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, water (0.5mL) was added to quench, and then the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain intermediate 2 (1.5g, yield 30%). MS m / z (ESI): 384.9 [M+23].

[0600] Intermediate 3:

[0601]

[0602] Under ice bath, diethylzinc hexane solution (1mol / L, 3mL) was added to a dichloromethane (20mL) solution of intermediate 2 (1.1g) and diiodomethane (620mg), and the reaction was stirred at room temperature for 16 hours. After the reaction, the reaction solution was directly concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain intermediate 3 (950mg, yield 29%). MSm / z(ESI):376.9[M+H].

[0603] Intermediate 4:

[0604]

[0605] At room temperature, sodium hydroxide aqueous solution (1.01 g) was added to an ethanol / water (20 mL / 7 mL) solution of intermediate 3 (950 mg), and the reaction solution was heated to 90°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution 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 5M dilute hydrochloric acid solution, extracted with ethyl acetate (20 mL×3), and the combined organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 4 (810 mg, yield 81%). MS m / z (ESI): 395.9 [M+H].

[0606] Intermediate 5:

[0607]

[0608] At room temperature, thionyl chloride (1.5 mL) was added to a solution of intermediate 4 (810 mg) in methanol (15 mL), and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was directly concentrated under reduced pressure to obtain intermediate 5 (810 mg, yield 81%). MS m / z (ESI): 409.9 [M+H].

[0609] Intermediate 6:

[0610]

[0611] At room temperature, palladium acetate (109 mg) was added to a solution of intermediate 5 (400 mg), triethylamine (493 mg) and triethylsilane (1.76 g) in dichloromethane (15 mL), and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain intermediate 6 (400 mg, yield 74%). MS m / z (ESI): 276.0 [M+H].

[0612] Intermediate 7:

[0613]

[0614] At room temperature, sodium triacetyl borohydride (219 mg) was added to a solution of intermediate 6 (94 mg, 0.344 mmol) and intermediate 2 of Example 2 (100 mg) in 1,2-dichloroethane (10 mL), and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain intermediate 7 (130 mg, yield 68%). MS m / z (ESI): 548.8 [M+H].

[0615] Target compound:

[0616]

[0617] At room temperature, sodium hydroxide (102 mg) was added to a mixed solution of intermediate 7 (130 mg) in methanol / water (8 mL / 2 mL), and the reaction was stirred at room temperature for 48 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to remove the solvent, and the residue was purified by high pressure liquid chromatography (chromatographic column: Gemini-C18, 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-40%, column temperature: 25°C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain the target compound (30 mg, yield 27%). MS m / z (ESI): 434.9 [M+1]. 1 H NMR (400MHz, MeOD) δ8.12(d,J=7.6Hz,2H),7.64(d,J=7.6Hz,2H),7.29(d,J=3.1Hz,2H),6 .73(s,1H),6.45(d,J=3.1Hz,1H),4.33(d,J=12.0Hz,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=15.0Hz,1H),1.79–1.61(m,2H),1.26(t,J=7.0Hz,3H),1.00–0.90(m,1H).

[0618] Embodiment 24

[0619] Intermediate 1:

[0620]

[0621] At -78°C, lithium bis(trimethylsilyl)amide (4.5 mL, 4.5 mmol) was slowly added dropwise to a THF (4 mL) solution of the intermediate 1 (1 g, 3.0 mmol) of Example 1. After the reaction was carried out at -78°C for 1 hour, methyl bromoacetate (1.4 g, 9.0 mmol) was slowly added to the reaction system at this temperature. After stirring for 1 hour at this temperature, the reaction system was naturally warmed to room temperature and stirred overnight at room temperature. After the reaction was completed, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL×3), and the combined 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 (dichloromethane: methanol = 5:1) to obtain intermediate 1 (330 mg, yield: 28%). MS m / z (ESI): 405.2 [M+1].

[0622] Intermediate 2:

[0623]

[0624] At 0°C, sodium borohydride (1.2 g, 32 mmol) was slowly added to a methanol (30 mL) solution of intermediate 1 (1.6 g, 4.0 mmol), and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, water (100 mL) was added to the reaction system for quenching, and extracted with ethyl acetate (100 mL×3). The combined extract was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The residue was purified by column chromatography (dichloromethane: methanol = 2: 1) to obtain intermediate 2 (900 mg, yield: 60%). MS m / z (ESI): 381.1 [M+1].

[0625] Intermediate 3:

[0626]

[0627] At room temperature, p-toluenesulfonyl chloride (1.8 g, 9.5 mmol) was slowly added to the dichloromethane (40 mL) of intermediate 2 (1.2 g, 3.2 mmol), 4-dimethylaminopyridine (77 mg, 0.6 mmol) and triethylamine (957 mg, 9.5 mmol), and the reaction mixture was stirred overnight at room temperature. After the reaction was completed, the reaction solution 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 obtain intermediate 3 (500 mg, yield: 44%). MS m / z (ESI): 386.1 [M+23].

[0628] Intermediate 4:

[0629]

[0630] At room temperature, intermediate 3 (500 mg, 1.4 mmol) and barium hydroxide (1.6 g, 5.0 mmol) were added to a mixture of isopropanol / water (5 mL / 12.5 mL), and the reaction was heated to 100°C and stirred at this temperature for 16 hours. After the reaction was completed, dilute hydrochloric acid aqueous solution (2 M) was added to the reaction solution to adjust the pH value to about 2, and extracted with ethyl acetate (30 mL×3), and the combined extract was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to obtain intermediate 4 (300 mg, yield: 57%). MS m / z (ESI): 404.1 [M+23].

[0631] Intermediate 5:

[0632]

[0633] At room temperature, 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), and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), the extracted organic phases were combined and washed with saturated brine (30 mL × 4), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to obtain intermediate 5 (300 mg, yield: 96%). MS m / z (ESI): 418.1 [M+23].

[0634]

[0635] Intermediate 6:

[0636] At room temperature, 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), and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and the residue was purified by reverse phase C18 column chromatography (acetonitrile: methanol = 10: 1) to obtain intermediate 6 (200 mg, yield: 77%). MS m / z (ESI): 262.1 [M+1].

[0637] Intermediate 7:

[0638]

[0639] At room temperature, intermediate 6 (100 mg, 0.383 mmol) was added to a tetrahydrofuran (5 mL) solution of intermediate 2 (110 mg, 1.91 mmol) of Example 2, chlorosilane (200 mg, 1.53 mmol) and glacial acetic acid (4 drops), and the reaction was heated to 75 ° C and stirred at this temperature for 24 hours. After the reaction was completed, water (50 mL) was added to the reaction solution for dilution, and ethyl acetate (50 mL×3) was used for extraction. The combined extract was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain intermediate 7 (110 mg, yield: 53%). MS m / z (ESI): 534.7 [M+1].

[0640] Target compound:

[0641]

[0642] At room temperature, sodium hydroxide (150 mg, 3.73 mmol) was added to a mixed solution of intermediate 7 (100 mg, 0.19 mmol) in methanol and water (2 mL / 2 mL), and the reaction was stirred at room temperature for 48 hours. After the reaction was completed, dilute hydrochloric acid (2 M) was added dropwise to the reaction solution to adjust the pH to about 5-7. The resulting mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative high pressure liquid chromatography (chromatographic column: AQ-C18; 150×21.2 mm, 5 μm; column temperature: 25°C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-30%) to obtain the target compound (29.2 mg, yield: 37%, containing 0.4 formic acid). MS m / z (ESI): 420.8 [M+1]. 1 H NMR (400MHz, CD3OD): δ8.32 (s, 0.4H), 8.17 (d, J = 7.9Hz, 2H), 7.74–7.62 (m, 2H),7.29(d,J=3.1Hz,1H),6.72(s,1H),6.26(d,J=2.8Hz,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).

[0643] Embodiment 25

[0644] Intermediate 1:

[0645]

[0646] At -78°C and under nitrogen protection, 2,2-difluorocyclopropane-1-carboxaldehyde (320 mg) and trimethylsilyl trifluoromethanesulfonate (168 mg) were added to a dichloromethane (5 mL) solution of the intermediate 1 (680 mg) of Example 6 in sequence. After stirring at -78°C for one hour, triethylsilane (351 mg) was added, and the reaction was naturally warmed to room temperature and continued at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained 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].

[0647] Intermediate 2:

[0648]

[0649] At room temperature, intermediate 1 (300 mg, 0.70 mmol) and sodium hydroxide (563 mg, 14.07 mmol) were added to a mixed solution of isopropanol / water (2.5 mL / 2.5 mL), and the reaction was heated to 100 ° C and stirred at this temperature for 24 hours. After the reaction was completed, the reaction solution was slowly added with dilute hydrochloric acid (2M, 7.5 mL) under an ice bath to adjust the pH to 5-6, 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 and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 2 (270 mg, yield: 77%). MS m / z (ESI): 445.8 [M+1].

[0650] Intermediate 3:

[0651]

[0652] At room temperature, potassium carbonate (167 mg) and iodomethane (172 mg) were added to an acetonitrile (3 mL) solution of intermediate 2 (270 mg), and the reaction solution was heated to 50°C and stirred at this temperature for 2 hours. After the reaction was completed, the reaction solution 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].

[0653] Intermediate 4:

[0654]

[0655] Under nitrogen protection at room temperature, palladium / carbon (50 mg) was added to a solution of intermediate 3 (190 mg) in tetrahydrofuran (3 mL), and the reaction was catalytically hydrogenated under a hydrogen atmosphere at room temperature for 16 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was directly concentrated to obtain intermediate 4 (135 mg, yield: 90%). MS m / z (ESI): 325.9 [M+1].

[0656] Intermediate 5:

[0657]

[0658] At room temperature, intermediate 4 (135 mg) was added to a solution of intermediate 2 (132 mg) of Example 2 in 1,2-dichloroethane (3 mL), and the reaction was stirred at room temperature for 8 hours, and then sodium triacetoxyborohydride (264 mg) was added, and the reaction was continued at room temperature for 16 hours. After the reaction was completed, the reaction solution 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].

[0659] Target compound:

[0660]

[0661] At room temperature, sodium hydroxide (214 mg) was added to a methanol / water (2 mL / 2 mL) mixed solution of intermediate 5 (160 mg), and the reaction was heated to 80°C and stirred at this temperature for 24 hours. After the reaction was completed, dilute hydrochloric acid (2 M, 2.7 mL) was added to the reaction solution under ice bath to adjust the pH to about 7, and the obtained mixture was directly freeze-dried to remove the solvent, and the residue was purified by high pressure liquid preparative chromatography (chromatographic 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]. 1H NMR(400MHz,MeOD)δ8.41(s,0.2H),8.16(d,J=8.2Hz,2H),7.72–7.60(m,2H),7.31( d,J=3.1Hz,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).

[0662] Embodiment 26

[0663] Intermediate 1:

[0664]

[0665] Under nitrogen protection, a solution of the intermediate 1 (930 mg) of Example 5 in dichloromethane (20 mL) was cooled to -78°C, and then cyclopropylcarboxaldehyde (289 mg) and trimethylsilyl trifluoromethanesulfonate (229 mg) were added in sequence. After stirring at -78°C for one hour, triethylsilane (479 mg) was added, and then the reaction mixture was naturally warmed to room temperature and continued to stir at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain intermediate 1 (600 mg, yield: 67%). MS m / z (ESI): 390.9 [M+1].

[0666] Intermediate 2:

[0667]

[0668] Under nitrogen protection at room temperature, palladium / carbon (50 mg) was added to a solution of intermediate 1 (340 mg) in tetrahydrofuran (3 mL), and the reaction mixture was subjected to catalytic hydrogenation reaction for 16 hours at room temperature and in a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly concentrated under reduced pressure to obtain intermediate 2 (220 mg, yield: 89%). MS m / z (ESI): 257.0 [M+1].

[0669] Intermediate 3:

[0670]

[0671] At room temperature, intermediate 2 (220 mg) was added to a solution of intermediate 2 (248 mg) of Example 2 in 1,2-dichloroethane (5 mL), and the reaction solution was stirred at room temperature for 8 hours, and then sodium triacetoxyborohydride (546 mg) was added, and the reaction was continued to stir at room temperature for 16 hours. After the reaction was completed, the reaction solution 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].

[0672] Intermediate 4:

[0673]

[0674] At room temperature, trimethylsilane (174 mg) and dibutyltin diacetate (265 mg) were added to a toluene (5 mL) solution of intermediate 3 (400 mg), and the reaction solution was heated to 90°C and stirred at this temperature for 24 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain intermediate 4 (800 mg, purity: 50%, yield: 92%). MS m / z (ESI): 572.8 [M+1].

[0675] Target compound:

[0676]

[0677] At room temperature, sodium hydroxide (1.1 g) was added to a mixed solution of intermediate 4 (780 mg) in methanol / water (5 mL) / 5 mL), and the reaction was heated to 80°C and stirred at this temperature for 16 hours. After the reaction was completed, dilute hydrochloric acid (6 M, 4.6 mL) was added to the reaction solution under ice bath to adjust the pH to about 7, and the obtained mixture was directly freeze-dried to remove the solvent. The obtained residue was purified by high pressure liquid preparative chromatography (chromatographic column: Xbridge-C18, 150×19 mm, 5 μm; column temperature: 25°C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 93 bar; mobile phase: acetonitrile-water (0.05% ammonia water); gradient: 25-35%) to obtain the target compound (103.8 mg, yield: 16%). MS m / z (ESI): 472.9 [M+1]. 1H NMR (400MHz, MeOD) δ8.25(d,J=8.0Hz,2H),7.72(d,J=8.0Hz,2H),7.31(d,J=2.4Hz,1H),6 .71(s,1H),6.34(d,J=2.4Hz,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).

[0678] Embodiment 27

[0679] Intermediate 1:

[0680]

[0681] At room temperature, iridium reagent (Ir[dF(CF3)ppy]2(dtbppy))PF6 (cas: 870987-63-6, 26 mg) was added to a solution of 5-bromopyridine-2-carboxylic acid methyl ester (500 mg), 1-(tert-butyloxycarbonyl)piperidine-2-carboxylic acid (799 mg), nickel chloride glycol dimethyl ether complex (57 mg), 4'-di-tert-butyl-2,2'-bipyridine (310 mg) and cesium carbonate (1.5 g, 4.63 mmol) in N,N-dimethylformamide (6 mL). The reaction system was replaced with nitrogen three times and then placed in a LED blue light reactor (26 W, Compact fluorescent light, 300-400 nM) for 16 hours. After the reaction was completed, the reaction solution was poured into water (30 mL) and extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain intermediate 1 (500 mg, yield: 33%). MS m / z (ESI): 321.0 [M+H].

[0682] Intermediate 2:

[0683]

[0684] At room temperature, m-chloroperbenzoic acid (2.7 g) was added to a solution of intermediate 1 (1.0 g) in dichloromethane (20 mL), and the reaction solution was stirred at room temperature for 5 hours. After the reaction was completed, dichloromethane (30 mL) was added to the reaction system for dilution, and the mixture was washed with saturated sodium bicarbonate solution (15 mL × 2) and saturated brine (15 mL) in sequence, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 2 (900 mg, yield: 86%). MS m / z (ESI): 336.0 [M+H].

[0685] Intermediate 3:

[0686]

[0687] Under ice bath, trifluoroacetic anhydride (5.6 g) was added to a DMF (20 mL) solution of intermediate 2 (900 mg), and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was poured into water (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated sodium bicarbonate aqueous solution (20 mL) and saturated brine (20 mL × 3), 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 obtain intermediate 3 (350 mg, yield 38%). MS m / z (ESI): 336.9 [M+1].

[0688] Intermediate 4:

[0689]

[0690] At room temperature, intermediate 3 (350 mg) was dissolved in a hydrogen chloride dioxane solution (15 mL), and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain intermediate 4 (300 mg, yield 98%). MS m / z (ESI): 236.9 [M+1].

[0691] Intermediate 5:

[0692]

[0693] At room temperature, chlorosilane (371 mg) was added to a solution of intermediate 2 (245 mg, 0.84 mmol), intermediate 4 (200 mg, 0.84 mmol) and acetic acid (0.5 mL) in 1,2-dichloroethane (15 mL), and the reaction was heated to 90°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to obtain intermediate 5 (130 mg, yield: 52%). MS m / z (ESI): 495.8 [M+1].

[0694] Target compound:

[0695]

[0696] Under ice bath, trimethylsilyl bromide (1 mL) was added to a solution of intermediate 5 (130 mg) in dichloromethane (4 mL) and water (1 mL), and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the residue was purified by high pressure liquid preparative chromatography (chromatographic column: Gemini-C18, 150×21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10-30%, column temperature: 25°C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain the target compound (43 mg, yield: 41%, containing 1 equivalent of formic acid). MS m / z (ESI): 812.5 [M+23]. 1 H NMR (400MHz, CD3OD) δ8.55(s,1H),8.31–8.26(m,1H),7.86(d,J=7.9Hz,1H),7.72(d,J=7.9Hz,1H),7.30(d,J=3.2Hz,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).

[0697] Embodiment 28

[0698] Intermediate 1:

[0699]

[0700] At room temperature, 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), and the reaction was stirred at room temperature for 18 hours. After the reaction was completed, dichloromethane (100 mL) was added for dilution, filtered, and the filtrate was concentrated under reduced pressure. The residual phase was stirred in methyl tert-butyl ether (100 mL) for 30 minutes, and a white solid was precipitated. The filter cake was collected to obtain intermediate 1 (8 g, yield: 50%). MS m / z (ESI): 263.1 [M+1].

[0701] Intermediate 2:

[0702]

[0703] At room temperature, 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). The reaction was stirred at room temperature for 1 hour. After the reaction was completed, dichloromethane (400 mL) was added to the reaction system for dilution and washed with water (150 mL). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was added with methyl tert-butyl ether (300 mL) and stirred for one hour. The methyl tert-butyl ether phase was removed by decanting, and the remaining oil was recrystallized with ethanol and methyl tert-butyl ether (1:10) to obtain intermediate 2 (3 g, yield: 26.6%). MS m / z (ESI): 226.8 [M+1].

[0704] Intermediate 3:

[0705]

[0706] At -40 ° C, potassium hexamethyldisilazide (18 mL, 10 mmol) was slowly added dropwise to a tetrahydrofuran (30 mL) solution of intermediate 2 (3 g). After the addition was completed, the reaction was stirred at -40 ° C for 10 minutes, and then intermediate 2 (3 g) of Example 1 was added dropwise. The reaction was continued to stir at -40 ° C for 30 minutes, then naturally warmed to room temperature and stirred at room temperature for 18 hours. After the reaction was completed, water (20 mL) was added to the reaction system for quenching, and ethyl acetate (100 mL × 2) was used for extraction. The combined extract phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was directly concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain intermediate 3 (1.5 g, yield: 44.4%). MS m / z (ESI): 407.9 [M+H].

[0707] Intermediate 4:

[0708]

[0709] At room temperature, lithium tetrafluoroborate (0.02 g) was added to a toluene (10 mL) solution of intermediate 3 (1.5 g), and the reaction was heated to 70°C and stirred at this temperature for 3 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the resulting residue was subjected to column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain intermediate 4 (1.2 g, yield: 47.5%). MS m / z (ESI): 408.2 [M+1].

[0710] Intermediate 5:

[0711]

[0712] Under ice bath, a tetrahydrofuran solution of lithium tri-sec-butylborohydride (1M, 4.3mL) was slowly added dropwise to a tetrahydrofuran solution (20mL) of intermediate 4 (1.6g, 3.93mmol), and the reaction mixture was naturally warmed to room temperature and stirred at room temperature for 18 hours. After the reaction was completed, methanol (5mL) was added to the reaction solution to quench, and the obtained mixture was directly concentrated under reduced pressure. The obtained residue was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain intermediate 5 (0.8g, yield 80%). MS m / z (ESI): 410.1 [M+H].

[0713] Intermediate 6:

[0714]

[0715] Under ice bath, potassium tert-butoxide tetrahydrofuran (1M, 1mL) solution was added to tetrahydrofuran (2mL) solution of intermediate 5 (200mg), and the reaction was stirred at room temperature for 1 hour, and iodomethane (347mg) was added, and the reaction was stirred at room temperature for 18 hours. After the reaction was completed, 2mL of methanol was added to quench, and the obtained mixture was directly concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain intermediate 6 (100mg, yield 45.9%). MS m / z (ESI): 424.2 [M+H].

[0716] Intermediate 7:

[0717]

[0718] At room temperature and under nitrogen protection, palladium hydroxide / carbon (10%, 13 mg) was added to a methanol (5 mL) solution of intermediate 6 (100 mg). The reaction system was replaced with hydrogen three times and stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain intermediate 7 (50 mg, yield: 69.5%). MS m / z (ESI): 290.2 [M+1].

[0719] Intermediate 8:

[0720]

[0721] At room temperature, intermediate 7 (50 mg) was added to a solution of intermediate 2 (60 mg) of Example 2 in 1,2-dichloroethane (2 mL). The reaction was stirred at room temperature for 8 hours, and then sodium triacetoxyborohydride (110 mg) was added. The reaction was stirred at room temperature for 18 hours. After the reaction was completed, dichloromethane (10 mL) was added to the reaction solution for dilution, 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 obtain intermediate 8 (50 mg, yield: 48.73%). MS m / z (ESI): 563.3 [M+1].

[0722] Target compound:

[0723]

[0724] At room temperature, sodium hydroxide (35.5 mg) was added to a mixed solution of tetrahydrofuran / methanol / water (0.5 mL / 0.5 mL / 0.5 mL) of intermediate 8 (50 mg), and the reaction was heated to 70°C and stirred at this temperature for 18 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the residue was purified by high pressure liquid preparative chromatography (chromatographic column: Gemini-C18, 150×21.2 mm, 5 um; 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 component 1 Example 28-P1 (13.3 mg, yield: 31.79%). MS m / z (ESI): 448.9 [M+1]. 1 H NMR(400MHz,MeOD)δ8.25-8.15(m,2H),7.75-7.56(m 2H), 7.35–7.27 (m, 1H), 6.74 (s, 1H), 6.31 (s, 1H), 4.60-4.25 (m, 2H), 4.15-4.07 (m, 1H), 3.74 (s, 3H), 3.67–3.57 (m, 1H), 3.53-3.34 (m, 2H), 3.24 (s, 3H), 2.49 (s, 3H), 2.30-2.17 (m, 2H), 2.15-2.05 (m, 2H), 2.02-1.84 (m, 2H), 1.80-1.53 ​​(m, 2H) Component 2 Example 28-P2 (5.4 mg, yield: 12.85%): MS m / z (ESI): 448.9 [M+1]. 1H NMR(400MHz,MeOD)δ8.13(d,J=8.0Hz,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),3.9 6-3.82(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).

[0725] Embodiment 29

[0726] Intermediate 1:

[0727]

[0728] Under ice bath, potassium tert-butoxide tetrahydrofuran (1M, 1.5mL) solution was added to tetrahydrofuran (4mL) solution of intermediate 5 (200mg) of Example 28, the reaction was naturally heated and stirred at room temperature for 1 hour, iodoethane (381mg) was added, and stirring was continued at room temperature for 18 hours. After the reaction was completed, methanol (2mL) was added to quench, and the obtained mixture was directly concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain intermediate 1 (80mg, yield 35.6%). MS m / z (ESI): 451.8 [M+1].

[0729] Intermediate 2:

[0730]

[0731] At room temperature and under nitrogen protection, palladium hydroxide / carbon (10%, 10 mg) was added to a methanol (5 mL) solution of intermediate 1 (80 mg). The reaction system was replaced with hydrogen three times and stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain intermediate 2 (50 mg, yield: 84.4%). MS m / z (ESI): 317.9 [M+1].

[0732] Intermediate 3:

[0733]

[0734] At room temperature, intermediate 2 (50 mg) was added to a solution of intermediate 2 (55 mg) of Example 2 in 1,2-dichloroethane (2 mL). After the reaction mixture was stirred at room temperature for 8 hours, sodium triacetoxyborohydride (100 mg) was added, and the reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed, dichloromethane (10 mL) was added to the reaction solution for dilution, 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 obtain intermediate 3 (50 mg, yield: 48.7%). MS m / z (ESI): 563.3 [M+1].

[0735] Target compound:

[0736]

[0737] At room temperature, sodium hydroxide (34 mg) was added to a mixed solution of tetrahydrofuran / methanol / water (0.5 mL / 0.5 mL / 0.5 mL) of intermediate 3 (50 mg), and the reaction was heated to 65° C. and stirred at this temperature for 18 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the resulting residue was purified by high pressure liquid preparative chromatography (chromatographic 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 component 1 Example 29-P1 (32.2 mg, yield: 39.1%): MS m / z (ESI): 462.8 [M+1]. 1 HNMR(400MHz,CD3OD)δ8.20-8.10(m,2H),7.72–7.58(m,2H),7.30(t,J=3.2Hz,1H), 6.77–6.70(m,1H),6.37–6.25(m,1H),4.60-4.20(m,2H),4.14-4.09(m,1H),3.77-3. 63 (m, 4H), 3.52-3.32 (m, 3H), 3.23-3.10 (m, 1H), 2.48 (d, J = 2.8 Hz, 3H), 2.27–1.83 (m, 6H), 1.78-1.52 (m, 2H), 1.10 (t, J = 6.8 Hz, 3H); and component 2 Example 29-P2 (7.3 mg, yield: 8.9%): MS m / z (ESI): 462.8 [M+1]. 1H NMR(400MHz,MeOD)δ8.14(d,J=8.0Hz,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).

[0738] Embodiment 30

[0739] Intermediate 1:

[0740]

[0741] At room temperature, tert-butyldiphenylsilyl chloride (25 g) was added to the intermediate 3 (25 g) of Example 1 and imidazole (6.6 g) in dichloromethane (200 mL) in turn, and the mixture was reacted at room temperature for 2 hours. After the reaction, the reaction solution 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].

[0742] Intermediate 2:

[0743]

[0744] At room temperature, intermediate 1 (3 g, 6.7 mmol) was added to a mixed solvent of 80% sulfuric acid / methanol = 1 / 1 (16 mL), and the reaction was heated to 100 ° C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction was naturally cooled to room temperature, diluted with water (50 mL), and the pH was adjusted to 6-7 with a dilute sodium hydroxide aqueous solution (2 M). The obtained mixture was freeze-dried to remove the solvent, and the residue was purified by column chromatography (dichloromethane: methanol = 5: 1) to obtain intermediate 2 (1.07 g, yield: 67%). MS m / z (ESI): 235.9 [M+1].

[0745] Intermediate 3:

[0746]

[0747] At room temperature, (4-nitrophenyl) [2- (trimethylsilyl) ethyl] carbonate (1.3g), triethylamine (552mg) and 4-dimethylaminopyridine (280mg) were added to a DMF (6mL) solution of intermediate 2 (1.1g) in sequence, and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, water (50mL) was added for dilution, and ethyl acetate (100mL×3) was used for extraction. The combined extracts were washed with saturated brine (50mL), 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 obtain intermediate 3 (1.13g, yield: 60%). MS m / z (ESI): 401.8 [M+23].

[0748] Intermediate 4:

[0749]

[0750] At room temperature, Dess-Martin reagent (2.4 g) was added to a dichloromethane (8 mL) solution of intermediate 3 (1.1 g), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was directly filtered, the filtrate was diluted with water (50 mL), extracted with ethyl acetate (50 mL×3), the combined extract was washed with saturated brine (50 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 (560 mg, yield: 48%). MS m / z (ESI): 399.7 [M+23].

[0751] Intermediate 5:

[0752]

[0753] At room temperature, potassium tert-butoxide (613 mg) and tert-butanol (6 mL) were added to trimethyl sulfoxide iodide (1.63 g) in sequence, the reaction was heated to 60°C and stirred at this temperature for 1 hour, then intermediate 4 (560 mg) was added, and the reaction was stirred at 60°C for 16 hours. After the reaction was completed, water (50 mL) was added to dilute, and ethyl acetate (100 mL×3) was used for extraction. The combined extract was washed with saturated brine (50 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 5 (427 mg, yield: 73%). MS m / z (ESI): 413.7 [M+23].

[0754] Intermediate 6:

[0755]

[0756] At room temperature, trimethylsilyldiazomethane (0.7 mL, 2M) was added to a mixed solution of intermediate 5 (300 mg) in toluene / methanol (4 mL / 1 mL), and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, acetic acid (2 mL) was added to the reaction system to quench, water (50 mL) was added to dilute, and ethyl acetate (50 mL×3) was used for extraction. The combined extracts were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain intermediate 6 (133 mg, yield: 43%). MS m / z (ESI): 427.8 [M+23].

[0757] Intermediate 7:

[0758]

[0759] At room temperature, tetrabutylammonium fluoride in tetrahydrofuran (0.6 mL, 1 M) was added to a solution of intermediate 6 (133 mg) in tetrahydrofuran (4 mL), and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (ethyl acetate: tetrahydrofuran = 4:1) to obtain intermediate 7 (75 mg, yield: 94%). MS m / z (ESI): 261.8 [M+1].

[0760] Intermediate 8:

[0761]

[0762] At room temperature, the intermediate 2 (111 mg) of Example 2, chlorosilane (201 mg) and acetic acid (0.04 mL) were added to a tetrahydrofuran (10 mL) solution of the intermediate 7 (100 mg), and the reaction was heated to 70°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain the intermediate 8 (40 mg, yield: 20%). MS m / z (ESI): 534.7 [M+1].

[0763] Target compound:

[0764]

[0765] At room temperature, sodium hydroxide (75 mg) was added to a mixed solution of intermediate 8 (50 mg) in methanol / water (2 mL / 2 mL), and the reaction was stirred at room temperature for 40 hours. After the reaction was completed, the reaction solution was directly purified by high pressure liquid preparative chromatography (chromatographic column: Xbridge-C18; 150×19 mm, 5 μm; column temperature: 25°C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar; mobile phase: acetonitrile-water (0.05% NH3); gradient: 10-30%) to obtain the target compound (3.2 mg, yield: 8%). MS m / z (ESI): 411.0 [M+1]. 1 H NMR (400MHz, CD3OD) δ8.16(d,J=7.9Hz,2H),7.66(d,J=7.9Hz,2H),7.30(d,J=2.8Hz,1H),6.75(s,1H),6.32–6.22(m,1H),4.59(t,J=7.7Hz,2H),4.4 4–4.20(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).

[0766] Embodiment 31

[0767] Intermediate 1:

[0768]

[0769] At -78°C and under nitrogen protection, n-butyl lithium (2.4M, 25mL) solution was slowly added to a tetrahydrofuran (200mL) solution of ethyl propiolate (5.89g), and the reaction was carried out at this temperature for 0.5 hours, and then the intermediate 2 (5g, 14.95mmol) of Example 1 was slowly added, and the reaction solution was continued at -78°C for 1.5 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (20mL) was slowly added to quench the reaction, and then water (200mL) was added to dilute it, and it was extracted with ethyl acetate (200mL), and the extract was washed with saturated brine (20mL), dried over anhydrous sodium sulfate and 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 (4g, yield: 59%). MS m / z (ESI): 433.0 [M+1].

[0770] Intermediate 2:

[0771]

[0772] Under ice bath, intermediate 1 (1.9 g) was added to an ethanol (50 mL) solution of nickel chloride hexahydrate (300 mg), and the reaction was stirred at this temperature for 10 minutes, and sodium borohydride (800 mg) was added in batches, and the reaction solution was stirred for 20 minutes under ice bath. After the reaction was completed, water (100 mL) was added to dilute, and ethyl acetate (100 mL) was used for extraction. The extract was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to obtain intermediate 2 (1.9 g, yield: 90%). MS m / z (ESI): 437.1 [M+1].

[0773] Intermediate 3:

[0774]

[0775] Under ice bath, lithium aluminum hydride (200 mg) was slowly added to the ethanol and tetrahydrofuran (20 mL / 20 mL) solution of intermediate 2 (1.9 g), and the reaction solution was stirred at this temperature for 1 hour. After the reaction was completed, saturated Na2SO4 aqueous solution (1 mL) was added to quench the reaction, the reaction solution was filtered, the filtrate was directly concentrated, and the residue was purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain intermediate 3 (1.5 g, yield: 73%). MS m / z (ESI): 395.1 [M+1].

[0776] Intermediate 4:

[0777]

[0778] Under ice bath, diisopropyl azodicarboxylate (0.92 g) was slowly added to a tetrahydrofuran (30 mL) solution of intermediate 3 (1.5 g) and triphenylphosphine (1.99 g), and the reaction mixture was naturally heated to room temperature and stirred at this temperature for 16 hours. After the reaction was completed, water (100 mL) was added to the reaction solution for dilution, and ethyl acetate (50 mL) was used for extraction. The extract was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain intermediate 4 (1.5 g, yield: 89%). MS m / z (ESI): 376.9 [M+1].

[0779] Intermediate 5:

[0780]

[0781] At room temperature, water (20 mL) and barium hydroxide octahydrate (6.3 g) were added to an isopropanol (20 mL) solution of intermediate 4 (1.5 g), and the reaction mixture was heated to 100°C and stirred at this temperature for 16 hours. After the reaction was completed, water (50 mL) was added to the reaction solution for dilution, the pH value was adjusted to about 3 with dilute hydrochloric acid, and extracted with ethyl acetate (100 mL). The extract was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to obtain intermediate 5 (1.5 g, yield: 85%). MS m / z (ESI): 396.0 [M+1].

[0782] Intermediate 6:

[0783]

[0784] At room temperature, potassium carbonate (500 mg) and iodomethane (500 mg) were added to an acetonitrile (20 mL) solution of intermediate 5 (500 mg) in sequence, and the reaction mixture was heated to 65°C and stirred at this temperature for 16 hours. After the reaction was completed, water (100 mL) was added for dilution, and ethyl acetate (100 mL) was used for extraction. The extract was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1) to obtain intermediate 6 (400 mg, yield: 77%). MS m / z (ESI): 410.1 [M+1].

[0785] Intermediate 7:

[0786]

[0787] At room temperature and under nitrogen protection, palladium hydroxide / carbon (10%, 50 mg) was slowly added to a tetrahydrofuran (10 mL) solution of intermediate 6 (200 mg), and the reaction was stirred at room temperature and 2 atmospheres of hydrogen for 16 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was directly concentrated to obtain intermediate 7 (150 mg, yield: 84%). MS m / z (ESI): 276.1 [M+1].

[0788] Intermediate 8:

[0789]

[0790] At room temperature, glacial acetic acid (50 mg) and chlorosilane (200 mg) were added to a tetrahydrofuran (5 mL) solution of intermediate 7 (150 mg) and intermediate 2 of Example 2 (150 mg), and the reaction was heated to 75°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was directly concentrated, and the residue was purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain intermediate 8 (150 mg, yield: 71%). MS m / z (ESI): 549.2 [M+1].

[0791] Target compound:

[0792]

[0793] At room temperature, sodium hydroxide (40 mg) was added to a mixed solution of methanol and water (3 mL / 3 mL) of intermediate 8 (150 mg), and the reaction was heated to 75°C and stirred at this temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated and the residue was purified by high pressure liquid preparative chromatography (chromatographic column: Gemini-C18, 150×21.2 mm, 5 μm; column temperature: 25°C; flow rate: 14 mL / min; wavelength: 214 nm; column pressure: 80 bar; mobile phase: acetonitrile-water (0.05% NH3); gradient: 10-40%) to obtain the target compound (58.0 mg, yield: 48%). MS m / z (ESI): 435.1 [M+1]. 1 H NMR (400MHz, CD3OD) δ8.13 (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), 6.3 0(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).

[0794] Embodiment 32

[0795] Intermediate 1:

[0796]

[0797] At room temperature, toluenesulfonic acid (35 mg) was added to a toluene (10 mL) solution of the intermediate 2 (800 mg) of Example 31, and the reaction was heated to 110°C and kept at this temperature for 18 hours. After the reaction was completed and naturally cooled to room temperature, the reaction solution was directly concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain intermediate 1 (550 mg, yield: 73.0%). MS m / z (ESI): 391.2 [M+1].

[0798] Intermediate 2:

[0799]

[0800] Under ice bath, methylmagnesium chloride tetrahydrofuran solution (3M, 1.4mL) was slowly added dropwise to the tetrahydrofuran (10mL) solution of intermediate 1 (550mg), and the reaction solution was naturally heated and stirred at this temperature for 18 hours. After the reaction was completed, water (10mL) was added to the reaction system for quenching, and ethyl acetate (10mL×2) was used for extraction. The combined organic phase was washed with saturated brine (10mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain intermediate 2 (150mg, yield: 25.0%). MS m / z (ESI): 404.8 [M+1].

[0801] Intermediate 3:

[0802]

[0803] At room temperature, barium hydroxide octahydrate (584 mg) was added to a mixed solution of intermediate 2 (150 mg) in isopropanol and water (3 mL / 6 mL), and the reaction solution was heated to 100°C and stirred at this temperature for 18 hours. After the reaction was completed, water (10 mL) was added to the reaction solution for dilution, and the pH was adjusted to about 5 with dilute hydrochloric acid (1 M). The resulting mixture was extracted with ethyl acetate (20 mL×2), and the combined extracts were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloroethane: methanol = 10: 1) to obtain intermediate 3 (50 mg, yield: 30.3%). MS m / z (ESI): 423.8 [M+1].

[0804] Intermediate 4:

[0805]

[0806] At room temperature, iodomethane (54 mg) was added to an acetone (5 mL) solution of intermediate 3 (50 mg) and potassium carbonate (52 mg), and the reaction was carried out at room temperature for 18 hours. After the reaction was completed, water (5 mL) was added for dilution, and ethyl acetate (10 mL×2) was used for extraction. 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].

[0807] Intermediate 5:

[0808]

[0809] At room temperature and under nitrogen protection, palladium hydroxide / carbon (3 mg) was added to a methanol (5 mL) solution of intermediate 4 (30 mg), and the reaction system was stirred for 18 hours at room temperature and under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly concentrated under reduced pressure to obtain intermediate 5 (20 mg, purity: 85%, yield: 81.6%).

[0810] Intermediate 6:

[0811]

[0812] At room temperature, intermediate 5 (20 mg) was added to a solution of intermediate 2 (23 mg) of Example 2 in 1,2-dichloroethane (2 mL). The reaction mixture was stirred at room temperature for 8 hours, and sodium triacetoxyborohydride (42 mg) was added. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed, dichloromethane (10 mL) was added to the reaction solution for dilution, 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 obtain intermediate 6 (20 mg, yield: 49.9%). MS m / z (ESI): 577.1 [M+1].

[0813] Target compound:

[0814]

[0815] At room temperature, sodium hydroxide (33.8 mg) was added to a mixed solution of intermediate 6 (20 mg, 0.08 mmol) in tetrahydrofuran / methanol / water (0.5 mL / 0.5 mL / 0.5 mL), and the reaction solution was heated to 65°C and stirred at this temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by flash preparative chromatography (chromatographic 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(400MHz,MeOD)δ8.14(d,J=8.0Hz,2H),7.64(d,J=8.0Hz,2H),7.32–7.26(m,1H),6.7 6–6.67(m,1H),6.32–6.25(m,1H),4.50(d,J=12.0Hz,1H),4.27(d,J=12.0Hz,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).

[0816] Embodiment 33

[0817] Intermediate 1:

[0818]

[0819] At room temperature, the compound S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (cas: 76189-56-5) (404 mg) and bis(dicyclopentadiene) rhodium tetrafluoroborate (cas: 36620-11-8) (202 mg) were added to a solution of 3-fluoro-4-carboxylic acid methyl ester phenylboronic acid (2568 mg) in 1,4-dioxane (7 mL). After the reaction was stirred at room temperature under nitrogen protection for 8 hours, 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 sequence. The reaction temperature was raised to 40° C. under nitrogen protection and stirring was continued at this temperature for 16 hours. After the reaction was completed, the reaction solution 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].

[0820] Intermediate 2:

[0821]

[0822] At room temperature, sodium borohydride (196 mg) was added in batches to a mixed solution of tetrahydrofuran and ethanol (15 mL / 15 mL) of intermediate 1 (3000 mg), and the reaction was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was cooled to below 0°C, and a saturated aqueous ammonium chloride solution (5 mL) was slowly added to quench the reaction, 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, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain intermediate 2 (1100 mg, purity: 40%, yield: 14%). MSm / z (ESI): 401.8 [M+1].

[0823] Intermediate 3:

[0824]

[0825] At room temperature, imidazole (242 mg) and tert-butyldiphenylsilyl chloride (904 mg) were added to a solution of intermediate 2 (1100 mg) in dichloromethane (20 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (20 mL) was added to the reaction solution for dilution, and the mixture was extracted with dichloromethane (50 mL). The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 15: 1) to obtain intermediate 3 (390 mg, yield: 20%). MS m / z (ESI): 661.6 [M+23].

[0826] Intermediate 4:

[0827]

[0828] At room temperature, intermediate 3 (390 mg) was added to tetrabutylammonium fluoride solution (1.0 M, 3 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (20 mL) was added for dilution, and ethyl acetate (10 mL) was used for extraction. The extract was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain intermediate 4 (180 mg, yield: 66%). MS m / z (ESI): 423.8 [M+23].

[0829] Intermediate 5:

[0830]

[0831] At room temperature, imidazole (61 mg) and tert-butyldimethylsilyl chloride (74 mg) were added to a DMF (3 mL) solution of intermediate 4 (180 mg), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (20 mL) was added to the reaction solution for dilution, and it was extracted with ethyl acetate (10 mL). The extract was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to obtain intermediate 5 (200 mg, yield: 78%). MS m / z (ESI): 537.8 [M+23].

[0832] Intermediate 6:

[0833]

[0834] At -78 ° C and nitrogen protection, cyclopropylcarboxaldehyde (147 mg) and trimethylsilyl trifluoromethanesulfonate (168 mg) were added to a dichloromethane (13 mL) solution of intermediate 5 (685 mg) in sequence. After stirring at -78 ° C for 1 hour, triethylsilane (308 mg) was added, and then the reaction mixture was naturally warmed to room temperature and continued to stir at room temperature for 16 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain intermediate 6 (500 mg, yield: 74%). MS m / z (ESI): 477.7 [M+23].

[0835] Intermediate 7:

[0836]

[0837] At room temperature and under nitrogen protection, palladium / carbon (50 mg) was added to a tetrahydrofuran (5 mL) solution of intermediate 6 (500 mg, 1.10 mmol), and the reaction was stirred for 2 hours at room temperature and under a hydrogen atmosphere. After the reaction was completed, the reaction solution was filtered and the filtrate was directly concentrated to obtain intermediate 7 (330 mg, yield: 84%). MS m / z (ESI): 322.0 [M+1].

[0838] Intermediate 8:

[0839]

[0840] At room temperature, intermediate 7 (180 mg) was added to a solution of intermediate 2 (178 mg) of Example 2 in 1,2-dichloroethane (5 mL). The reaction mixture was stirred at room temperature for 8 hours, and sodium triacetoxyborohydride (356 mg) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was directly concentrated, and the residue was purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain intermediate 8 (350 mg, yield: 84%). MS m / z (ESI): 594.8 [M+1].

[0841] Target compound:

[0842]

[0843] At room temperature, sodium hydroxide (470 mg) was added to a methanol / water (5 mL / 5 mL) mixed solution of compound 9 (350 mg), and the reaction was heated to 80° C. and stirred at this temperature for 16 hours. After the reaction was completed, dilute hydrochloric acid (2 M) was added to the reaction solution under an ice bath to adjust the pH to about 7, and then the solvent was directly lyophilized, and the residue was purified by high pressure liquid preparative chromatography (chromatographic 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 (400MHz, CD3OD) δ8.29(s,0.6H),7.89(t,J=7.6Hz,1H),7.44(t,J=10.1Hz,2H),7.33(d,J =3.0Hz,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=6.9Hz,3H),2.50(s,3H),2.3 1–2.14(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].

[0844] According to the method of the above-mentioned embodiment 3-33, the following compound was prepared:

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851] Preparation of reference compound (Example-26c, WO2015009616A1): Reference intermediate 1:

[0852]

[0853] Tetrahydrofuran (3 mL), intermediate 7 of Example 1 (127 mg), intermediate 2 of Example 2 (130 mg) and tetraethyl titanate (56 mg) were added to a 50 mL sealed tube. The reaction mixture was heated to 70 ° C under nitrogen protection and stirred for 16 hours. The reaction solution was cooled to room temperature, sodium triacetoxyborohydride (52 mg) was added, and the temperature was raised to 70 ° C for 1 hour. After the reaction solution was cooled to room temperature, 4 mL of methanol was added to quench the reaction. The reaction solution was concentrated, and the residue was separated and purified by column chromatography (methanol: dichloromethane = 1:10) to obtain the control intermediate 1 (170 mg, yield: 52%).

[0854] Control compound:

[0855]

[0856] Methanol (3 mL), water (1 mL), intermediate 1 (160 mg) and sodium hydroxide (230 mg) were added to a 50 mL single-mouth bottle. The reaction was carried out at room temperature for 16 hours. After the reaction was completed, water (10 mL) was added for dilution, and the pH was adjusted to 7-8 with dilute hydrochloric acid solution (1 M). The solvent was removed under reduced pressure (water bath: 45 ° C), and the residue was purified by high pressure liquid preparative chromatography (chromatographic column: Gemini-C18, 150x21.2 mm, 5 um; 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]. 1H NMR (400MHz, DMSO-d6) δ8.17(d,J=8.4Hz,2H),7.67(d,J=8.4Hz,2H),7.33(t,J= 2.8Hz,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=6.8Hz,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=6.8Hz,3H).

[0857] Biological Examples

[0858] 1. Optical surface plasmon resonance (SPR) binding force detection

[0859] The SPR experiment was conducted at 25°C with PBS buffer supplemented with 0.05% (v / v) P20 and 5% DMSO as the running buffer, and the analytical instrument used was GE Healthcare's Biacore 8K. 400mM EDC and 100mM NHS activated the CM7 chip (GE Healthcare) at a flow rate of 30μL / min for 420s. Complement factor B was diluted to 50μg / mL with 10mM sodium acetate (pH 4.0), and then coupled at a flow rate of 10μL / min for 1200s to covalently fix complement factor B to the detection chip (protein immobilization level was 25000RU); then the detection chip was blocked with 1M ethanolamine hydrochloride at a flow rate of 10μL / min for 300s. The concentration of the test compound was 500μM, the binding time was 120s, and the dissociation time was 300s. The data were analyzed using a 1:1 binding model (Biacore Insight Evalution Software, Version 2.0.15.12933).

[0860] Experimental results:

[0861] The experimental results of some of the compounds of the examples are shown in Table 1. At a concentration of 500 μM, Examples 5 and 6 have more significant binding abilities with the target protein, which are significantly better than the control compound, indicating that the compounds of the present invention have better binding abilities with the target protein.

[0862] Table 1:

[0863]

[0864]

[0865] Note: ND means no SPR binding data were detected.

[0866] 2.TR-FRET binding assay

[0867] Competitive binding experiments using Cy5 fluorescently labeled small molecule inhibitors as probes were used to screen compounds for their inhibitory activity against human complement factor B. Complement factor B and EZ-Link TM After incubation of Sulfo-NHS-LC-LC-Biotin at a ratio of 1:2 on ice for 1 hour, 1M Tris (pH 7.5) was added to terminate the reaction. TM Desalt spin column purification was performed twice to obtain biotin-labeled complement factor B (EZ-LinkTM Sulfo-NHS-LC-Biotin instruction manual). During the experiment, biotin-labeled complement factor B with a final concentration of 10 nM was taken and pre-incubated with different concentrations of compounds in buffer at room temperature for 1 hour. Cy5 fluorescently labeled probes and europium chelate-labeled streptavidin (petroleum ether rkin Elmer, #AD0060) were added at final concentrations of 75 nM and 5 nM respectively to start the reaction. Kinetic readings were performed on an enzyme reader (337 nm excitation light, 665 nm emission light, 70 μs time-gated), and the time-dependent fluorescence energy transfer (TR-FRET) data were read to determine the IC 50 .

[0868] 3. Detection of complement system hydrolysis C3 activity

[0869] The test compound was tested at a starting concentration of 10 μM, 3-fold dilution, 7 concentration points, and single-well detection. The test compound was diluted to a solution of 1000 times the final concentration with DMSO in a 96-well plate, and then diluted with Diluent ( COMPLEMENTSYSTEM ALTERNATIVE PATHWAY AP330) was diluted to a solution 5 times the final concentration. Transfer 30 μL to a 96-well plate, add 120 μL of spare serum, and incubate at room temperature for 15 minutes. Add 30 μL of 5‰ DMSO and 120 μL of spare serum to the positive control wells, and add 30 μL of 5‰ DMSO and 120 μL of Diluent to the negative control wells. (3) Take 100 μL and add it to the reaction plate, incubate at 37°C for 60 minutes. Discard the liquid in the wells and wash each well 3 times with 300 μL of washing solution. Add 100 μL of Conjugate ( COMPLEMENT SYSTEM ALTERNATIVE PATHWAY AP330), incubate at room temperature for 30 minutes. Remove the liquid in the wells and wash each well three times with 300 μL of washing solution. Then add 100 μL of substrate to each well and incubate at room temperature for 30 minutes. Use an ELISA reader (PerkinElmer, EnSight) to detect and read the OD405 value.

[0870] 4. Complement hemolytic activity detection

[0871] Hemolysis experiment refers to Xuan Yuan et al., Haematologica. (2017) 102: 466-475 description. Before the experiment, the optimal concentration of normal human serum (NHS) required to achieve 100% lysis of rabbit erythrocytes (RE) was obtained by titration test. In this experiment, NHS was diluted in GVB0 buffer (0.1% gelatin, 5mM Veronal, 145mMNaCl, 0.025% NaN3, pH 7.3, Complement technology) containing 10mM Mg-EGTA and incubated with various concentration gradients of test compounds at 37°C for 15 minutes. RE (taken from healthy Japanese white rabbits) newly suspended in GVB0 buffer containing 10mM Mg-EGTA was added to a final concentration of 1×108 cells / ml and incubated at 37°C for 30 minutes. The positive control group (100% lysis) consisted of GVB0 buffer containing 10 mM Mg-EGTA with NHS and RE but without the test compound; the negative control group (0% lysis) consisted of GVB0 buffer containing 10 mM Mg-EGTA with inactivated NHS (heated at 56°C for 30 minutes or 65°C for 5 minutes) and RE but without the test compound. The supernatant was collected after the sample was centrifuged at 2000g for 5 minutes. The absorbance at 415nm (A415) was detected using a microplate reader (Molecular Devices, SpectraMax i3X). IC 50 Values ​​were calculated by nonlinear regression from the percentage of hemolysis as a function of test compound concentration.

[0872] Experimental results:

[0873] The experimental results of some of the example compounds are shown in Table 2, among which Example 5 has significantly better inhibitory activity on complement factor B in human serum than the control compound, indicating that the compounds of the present invention can effectively inhibit the activity of complement factor B in human serum and prevent it from attacking rabbit red blood cells and causing hemolysis.

[0874] Table 2:

[0875]

[0876]

[0877] 5. Liver microsome stability test

[0878] (1) Preparation of buffer

[0879] Take a 0.1 M dipotassium hydrogen phosphate distilled water solution (containing 1 mM ethylenediaminetetraacetic acid), and then use a 0.1 M dipotassium dihydrogen phosphate distilled water solution (containing 1 mM ethylenediaminetetraacetic acid) to adjust the pH to 7.4.

[0880] (2) Microsome source and preparation of working solution

[0881] Microsome Source:

[0882] Rat: SD Rat Liver Microsomes, Cat. No.: LM-DS-02M, RILD Reid Liver Disease Research (Shanghai) Co., Ltd.

[0883] Monkey: Cynomolgus Monkey Liver Microsomes, Cat. No.: LM-SXH-02M, RILD (Shanghai) Liver Disease Research Co., Ltd.

[0884] Human: Pooled Human Liver Microsomes (Mongolian), Cat. No.: LM-R-02M, RILD Reid Liver Disease Research (Shanghai) Co., Ltd.

[0885] Preparation of working fluid

[0886] Prepare 10mM solution of control compound and test compound with DMSO, then take 10uL and add it to 190uL acetonitrile to prepare 0.5mM stock solution. Take 1.5uL of 0.5mM stock solution of compound, add 18.75uM 20mg / mL liver microsomes and 479.75uL buffer. (The actual preparation amount can be adjusted according to the usage).

[0887] (3) Experimental process

[0888] Prepare 10 mg / mL reduced coenzyme II (NADPH) with buffer. Place a 96-well plate on ice, set corresponding wells for each compound at different time points (0, 10, 30, 60, 90 minutes, Non-NADPH), and add 30 μL of working solution to each well. For the 0min well, first add 155 μL of glacial acetonitrile solution (internal standard concentration is 1 μM), mix with a pipette, and then add 15 μL of NADPH (10 mg / mL). Before starting the reaction, pre-incubate the 96-well plate on a thermostatic microplate shaker (37°C) for 5 minutes, and then add 15 μL of NADPH (10 mg / mL) to each well to start the metabolic reaction. After the reaction is carried out for 10, 30, 60, and 90 minutes, add 155 μL of glacial acetonitrile solution (internal standard concentration is 1 μM) to the corresponding wells to terminate the reaction. After 90 minutes, the non-NADPH system was terminated by adding 155 μL of glacial acetonitrile solution (internal standard concentration was 1 μM). After the reaction, the 96-well plate was shaken for 10 minutes using a microplate shaker (600 rpm), then centrifuged at 4°C and 4000 g for 15 minutes, 50 μL of the supernatant was added to a new 2 mL 96-well plate, and then 300 μL of deionized water was added, and the analysis was performed using an AB SCIEX ExionLC-Triple Quad 5500 high performance liquid chromatography-mass spectrometry instrument, and the software used was Analyst 1.6.3. The test results are shown in Table 3.

[0889] Table 3

[0890]

[0891] Experimental results: The data showed that the compounds of Example 4, Example 5 and Example 6 all had more significant liver microsome stability.

[0892] 6. PK experiment of single oral administration in rats

[0893] Experimental methods:

[0894] Wistar han male rats aged 6-9 weeks (Shanghai Xipuer-Bikai Experimental Animal Co., Ltd.) were used, fasted overnight, 3 rats in each group, and administered by gavage. The control compound, Example 5, and Example 6 compounds were given 3 mg / kg each, and the administration volume was 10 mL / kg. Blood was collected through the jugular vein, 0.2 mL at each time point, anticoagulated with EDTA-K2, and immediately centrifuged at 4000rpm*5min, 4°C, and the supernatant was taken. The sample was frozen in a -80°C refrigerator until detection. Blood collection time points: before administration, 5min, 15min, 30min, 1h, 2h, 4h, 7h, 24h. The state of the animal was observed at any time after administration. After completing blood collection at all time points, the animal was euthanized. Plasma samples were measured by LC-MS / MS, and the data were calculated using WinNonlin software for kinetic parameter calculation (Tmax, Cmax, T1 / 2, AUC).

[0895] Experimental results:

[0896] The test results are shown in Table 4.

[0897] Table 4:

[0898]

[0899] 7. PK / PD study of single oral administration in cynomolgus monkeys

[0900] Experimental methods:

[0901] Cynomolgus monkeys were used, 3 in each group were given a compound control compound and Example 5 compound 3&30 mpk by gavage, and blood was collected at different time points for drug concentration analysis and complement activity detection. The plasma compound concentration was determined by LC-MS / MS, and the serum complement activity was detected by wieslab assay (Svar Life Science AB, COMPL AP330 RUO) kit, among which Normal Human Serum (Complement Technology, NHS).

[0902] Experimental results:

[0903] Within the concentration and time range tested, at the same dose, the average blood drug concentration of the compound in Example 5 was significantly higher than that of the control compound. Figure 1 , Cynomolgus monkey serum AP activity inhibition Figure 2 . Figure 2 This indicates that the compounds of the present invention can effectively inhibit the AP activity in the serum of cynomolgus monkeys.

[0904] 8. Streptococcus-induced Rheumatoid Arthritis (RA) Model in Rats

[0905] Experimental methods:

[0906] The experiment used Lewis female rats aged 6-9 weeks (Beijing Weitong Lihua), 6 rats in each group, intraperitoneal injection of streptococcus and other bacterial cell wall peptidoglycan complexes (2-3 mg per rat) on D1, oral administration of control compound (15 mpk) and Example 5 (15 mpk) every day for 25 days, and arthritis scores were performed on rats at different times. The scoring criteria are as follows: according to the different degrees of lesions (redness and swelling), the scores are scored according to the standard of 0-4 points, the highest score for each limb is 4 points, and the highest score for the total of four limbs of each animal is 16 points. The scoring criteria are as follows: 0 points, no redness and swelling; 1 point, redness and swelling of 1 to 2 interphalangeal joints; 2 points, redness and swelling of 3 to 4 interphalangeal joints; 3 points, redness and swelling of more than 4 interphalangeal joints; 4 points, severe redness and swelling of toes or fingers to ankles or wrists.

[0907] Experimental results:

[0908] The experimental results are shown in Figure 3 The data showed that both the control compound and Example 5 could improve the arthritis scores of the compounds, and the effect of the Example 5 compound was significantly better than that of the control compound, proving that the compounds of the present invention, especially the Example compounds, could more effectively improve streptococcal-induced rheumatoid arthritis in rats.

[0909] The exemplary embodiments of the present invention are described above. It should be understood that the protection scope 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 within the spirit and principles of the present invention should be included in the protection scope of the present application.

Claims

1. A compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof: in, R 1 is selected from halogen, OH, CN, NO2, unsubstituted or optionally substituted with 1, 2 or more R a Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkyloxy, C 3-8 Cycloalkyloxy, NH2; R 2 is selected from H, halogen, OH, CN, NO2, unsubstituted or optionally substituted with 1, 2 or more R b Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkyloxy, C 3-8 Cycloalkyloxy, NH2; R 3 is selected from halogen, OH, CN, NO2, unsubstituted or optionally substituted with 1, 2 or more R c Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkyloxy, C 3-8 Cycloalkyloxy, NH2; R 4 is selected from H, unsubstituted or optionally substituted with 1, 2 or more R d Substituted C 1-6 alkyl; R 5 is selected from H, halogen, OH, CN, NO2, unsubstituted or optionally substituted with 1, 2 or more R e Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkyloxy, C 3-8 Cycloalkyloxy, NH2; R 6 is selected from H, halogen, OH, CN, NO2, unsubstituted or optionally substituted with 1, 2 or more R f Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkyloxy, C 3-8 Cycloalkyloxy, NH2; R 7 is selected from H, OH, CN, unsubstituted or optionally substituted with 1, 2 or more R g Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkyloxy, C 3-8 Cycloalkyloxy, NH2; Or, R 1 , R 7 Together with the atoms to which it is attached, it forms an unsubstituted or optionally substituted group consisting of 1, 2 or more R h The substituted 5-10 membered ring structure can be selected from the following groups: 5-10 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl; Or, R 6 , R 7 Together with the atoms to which it is attached, it forms an unsubstituted or optionally substituted group consisting of 1, 2 or more R i The substituted 5-10 membered ring structure can be selected from the following groups: 5-10 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl; Cy is selected from 1, 2, 3, 4, 5, 6, 7, 8 or more independently selected from R 8 , R 9 , R 10 , R 11 The following groups are substituted with substituents: Piperidinyl, Wherein, the N atom in Cy is in the same group as the Cy group in formula (I) and R 7 The groups are bonded by the C atoms they share; R 8 Selected from optionally 1, 2 or more R j Substituted with the following groups: C 6-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl; R 9 are the same or different and are independently selected from H, unsubstituted or optionally substituted with 1, 2 or more R j Substituted C 1-6 alkyl; R 10 , R 11 are the same or different and are independently selected from H, absent, halogen, OH, CN, NO2, unsubstituted or optionally substituted by 1, 2 or more R k Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 3-10 Cycloalkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic group, C 1-6 Alkyloxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkenyloxy, C 3-10 Cycloalkynyloxy, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, 3-10 membered heterocyclyloxy, NH2; Every R a , R b , R c , R d , R e , R f , R g , R h and R i are the same or different and are independently selected from H, halogen, OH, CN, NO2, oxo (=O), thio (=S), unsubstituted or optionally substituted with 1, 2 or more R p Substituted with the following groups: C 1-6 alkyl; Every R j are the same or different and are independently selected from halogen, OH, oxo (=O), unsubstituted or optionally substituted with 1, 2 or more R p Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic group, C 1-6 Alkyloxy, C 3-8 Cycloalkyloxy, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, 3-10 membered heterocyclyloxy, NH2, -C(O)R 12 、-C(O)OR 13 、-B(OR 18 )(OR 19 )、-P(O)(OR 20 )(OR 21 )and Every R k are the same or different and are independently selected from halogen, OH, CN, NO2, unsubstituted or optionally substituted by 1, 2 or more R p Substituted with the following groups: C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclic group, C 1-6 Alkyloxy, C 3-6 Cycloalkyloxy, C 6-10 Aryloxy, 5-6 membered heteroaryloxy, 3-6 membered heterocyclyloxy, NH2; Every R p are the same or different and are independently selected from H, halogen, OH, CN, NO2, oxo (=O), thio (=S) and C 1-6 alkyl; R 12 , R 13 , R 18 , R 19 , R 20 , R 21 , R 22 The same or different, independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, NH2; Provided that, when Cy is piperidinyl, R 9 and R 11 H; R 10 Selected from OH, CN, NO2, 1, 2 or more R k Substituted C 1-6 Alkyloxy, unsubstituted or optionally substituted with 1, 2 or more R k Substituted with the following groups: C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 3-10 Cycloalkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclic group, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkenyloxy, C 3-10 Cycloalkynyloxy, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, 3-10 membered heterocyclyloxy and NH2.

2. The compound according to claim 1, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound, characterized in that: Cy is selected from 1, 2, 3, 4, 5, 6, 7, 8 or more independently selected from R 8 , R 9 , R 10 , R 11 The following groups are substituted with substituents:

3. The compound according to claim 1 or 2, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, characterized in that: R 8 Selected from optionally 1, 2 or more R j Substituted: phenyl, pyridyl, pyrazinyl, furanyl, pyranyl, benzocyclohexyl, benzocyclopentyl, benzofuranyl, phenyltetrahydrofuranyl.

4. The compound according to claim 3, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound, characterized in that: R 8 Selected from optionally 1, 2 or more R j Substituted phenyl or pyridyl.

5. The compound according to any one of claims 1 to 4, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, characterized in that: R 10 , R 11 are the same or different and are independently selected from H, halogen, OH, CN, NO2, unsubstituted or optionally substituted with 1, 2 or more R k Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 1-6 Alkyloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, NH2.

6. The compound according to claim 1, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound, characterized in that: Cy is selected from 1, 2, 3, 4, 5, 6, 7, 8 or more independently selected from R 8 , R 9 , R 10 , R 11 The following groups are substituted with substituents: R 8 Selected from optionally 1, 2 or more R j Substituted: phenyl, pyridyl, pyrazinyl, furyl, pyranyl, benzocyclohexyl, benzocyclopentyl, benzofuranyl, phenyltetrahydrofuranyl; R 10 , R 11 are the same or different and are independently selected from H, halogen, OH, CN, NO2, unsubstituted or optionally substituted with 1, 2 or more R k Substituted with the following groups: C 1-6 Alkyl, C 2-6 Alkenyl, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group, C 1-6 Alkyloxy, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, NH2; R 9 Having the definition as claimed in claim 1.

7. The compound according to claim 1, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, characterized in that: The compound has a structure shown in formula (I-1) or formula (I-2): wherein W is selected from CH, O or S; Y and Z are the same or different and are independently selected from 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 Independently having the definition as described in claim 1; Preferably, a carbon-carbon single bond or a carbon-carbon double bond is 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 Selected from OH, CN, NO2, 1, 2 or more R k Substituted C 1-6 Alkyloxy, unsubstituted or optionally substituted with 1, 2 or more R k Substituted with the following groups: C 2-6 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 3-10 Cycloalkynyl, 3-10 membered heterocyclic group, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkenyloxy, C 3-10 Cycloalkynyloxy, 3-10 membered heterocyclyloxy and NH2, wherein R k Having the definition as claimed in claim 1.

8. The compound according to claim 7, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound, characterized in that: The compound has a structure shown in formula (I-3) or formula (I-4): Among them, W, Y, Z, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 9 , R 10 , R j Independently having the definition as described in claim 7; n is selected from 1, 2, 3, 4 or 5; Preferably, n is selected from 1, 2 or 3; Preferably, each R j is a substituent at the 2-, 3-, 4- or 5-position of the phenyl group; Preferably, each R j are independently selected from unsubstituted or optionally substituted with 1, 2 or more R p Substituted with the following groups: C 1-6 Alkyl, NH2, -C(O)R 12 、-C(O)OR 13 、-B(OR 18 )(OR 19 )、-P(O)(OR 20 )(OR 21 ), Preferably, R 10 Selected from OH, CN, NO2, 1, 2 or more R k Substituted C 1-6 Alkyloxy, unsubstituted or optionally substituted with 1, 2 or more R k Substituted with the following groups: C 3-8 Cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), 3-6 membered heterocyclic group (e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl), C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyloxy, NH2; Preferably, each R k are the same or different and are independently selected from halogen, OH, CN, NO2, unsubstituted or optionally substituted by 1, 2 or more R p Substituted with the following groups: C 1-6 Alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl), C 3-8 Cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), C 6-10 Aryl (such as phenyl), 5-6 membered heteroaryl (such as pyrrolyl, pyridyl, pyrazinyl, imidazolyl, triazolyl), 3-6 membered heterocyclic group (such as pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl), C 1-6 Alkyloxy, C 3-6 Cycloalkyloxy, C 6-10 Aryloxy, 5-6 membered heteroaryloxy, 3-6 membered heterocyclyloxy; Preferably, each R p are the same or different and are independently selected from H, halogen (F, Cl, Br or I), OH, C 1-6 alkyl; Preferably, 1, 2, 3 or more H atoms in the compound and its substituents (such as methyl, ethyl) are optionally replaced with their isotopes (such as D) to form groups such as CD3, C2D5.

9. The compound according to any one of claims 1 to 8, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, characterized in that: The compound may be selected from the following compounds:

10. The compound represented by formula (IV): in, PG is a protecting group; PG can be selected from amino protecting groups; wherein, suitable PG is selected from C 1-40 Alkyl, C 6-20 Aryl C 1-40 Alkyl-, for example 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 has the definition as described in any one of claims 1-9.

11. A method for preparing the compound according to any one of claims 1 to 9, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof, comprising reacting a compound of formula (IV) as a starting material to obtain a compound of formula (Ia), i.e., R 4 The compound represented by formula (I) is H: and optionally, the compound of formula (Ia) and R 4 -L 1 Reaction to obtain R 4 is a compound represented by formula (I) in any one of claims 1 to 9, wherein L 1 is a leaving group, such as OH, F, Cl, Br, I, halogenated C 1-40 alkyl; in, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , Cy independently has the definition as described in any one of claims 1 to 9; PG is defined as in claim 10; Preferably, the compound of formula (IV) is reacted under the conditions of removing the protecting group PG to obtain the compound of formula (I); Preferably, the method for preparing the compound of formula (IV) comprises reacting the compound of formula (II) with the compound of formula (III) to obtain the compound of formula (IV); Among them, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , Cy independently has the definition as described in any one of claims 1 to 9; PG is defined as in claim 10; Preferably, the preparation method is carried out in the presence of a solvent such as an organic solvent; for example, the organic solvent is selected from at least one of the following: alcohols, such as methanol, ethanol, isopropanol, and n-butanol; ethers, such as ethyl propyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethyl ethylene glycol, biphenyl 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, dihydrogen Hexacyclic, dichlorodiethyl ether, and polyethers of ethylene oxide and / or propylene oxide; aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, heptane, octane, nonane, and those possibly substituted with fluorine and chlorine atoms, such as methylene chloride, dichloromethane, chloroform, carbon tetrachloride, fluorobenzene, chlorobenzene or dichlorobenzene; cyclohexane, methylcyclohexane, petroleum ether, octane, benzene, toluene, chlorobenzene, bromobenzene, xylene; esters, such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate and dimethyl carbonate, dibutyl carbonate or ethylene carbonate; Preferably, the preparation method is carried out in the presence of a reducing agent; the reducing agent is used to reduce the carbon-nitrogen double bond, and the reducing agent can be selected from sodium borohydride, potassium borohydride, lithium borohydride, sodium acetate borohydride, sodium cyanoborohydride, and lithium aluminum hydride.

12. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound according to any one of claims 1 to 9, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof.

13. Use of at least one of the compound according to any one of claims 1 to 9, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof in the preparation of a medicament for treating a disease associated with activation of the complement alternative pathway. Preferably, the compound is selected from the following compounds: Preferably, the compound is: Preferably, the disease associated with activation of the alternative complement pathway is selected from paroxysmal nocturnal hemoglobinuria (PNH), idiopathic 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, hepatitis, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), respiratory diseases and cardiovascular diseases.

14. Use of the compound of formula (IV) according to claim 10 in the preparation of the compound according to any one of claims 1 to 9, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof.

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