Spirocyclicalkenyl or azaalkenyl compound, and pharmaceutical composition thereof, preparation method therefor and use thereof

Abstract

A spirocyclicalkenyl or azaalkenyl compound, and a pharmaceutical composition thereof, a preparation method therefor and the use thereof. Specifically, provided are a spirocyclicalkenyl or azaalkenyl compound as shown in formula (I), which can be used for preparing a drug, particularly for preparing a drug for preventing and / or treating a disease or condition by means of the alternative complement pathway. Each group in formula (I) is as defined in the description.

Description

Spirocyclic alkenyl or azaalkenyl compounds and pharmaceutical compositions, preparation methods and uses thereof

[0001] The present invention claims:

[0002] Priority to the prior application, patent application number 202310925729.9, filed with the State Intellectual Property Office of China on July 26, 2023, entitled “Spirocycloalkenyl or azaalkenyl compounds, pharmaceutical compositions, preparation methods and uses thereof”;

[0003] Priority to the prior application, patent application number 202311463438.9, filed with the State Intellectual Property Office of China on November 6, 2023, entitled “Spirocycloalkenyl or azaalkenyl compounds, pharmaceutical compositions, preparation methods and uses thereof”;

[0004] Priority to the prior application, patent application number 202410847520.X, filed with the State Intellectual Property Office of China on June 27, 2024, entitled “Spirocycloalkenyl or azaalkenyl compounds, pharmaceutical compositions, preparation methods and uses thereof”;

[0005] Priority to the prior application, patent application number 202410971035.3, filed with the State Intellectual Property Office of China on July 18, 2024, entitled “Spirocycloalkenyl or azaalkenyl compounds, pharmaceutical compositions, preparation methods and uses thereof”;

[0006] The entire contents of said prior application are incorporated herein by reference. Technical Field

[0007] The present application belongs to the field of medicine, and specifically relates to a spirocyclic alkene or azaalkene compound and its pharmaceutical composition, preparation method and use, which can be used as a complement factor B inhibitor. Background Art

[0008] 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 as inactive zymogens. Various specific and nonspecific immunological mechanisms break down these inactive zymogens, producing active large and small fragments. Large fragments typically remain on the surface of pathogens or cells, causing their lysis or accelerating their clearance; small fragments leave the cell surface and mediate various inflammatory responses. Complement activation consists of two closely related processes, forming a cascade of complement activation reactions. Currently, there are three main known complement activation pathways: the classical pathway, the lectin pathway, and the alternative pathway. Although the three complement activation pathways differ in their initiation mechanisms and activation sequence, they share a common terminal pathway. Activation of the alternative pathway is independent of antigen-antibody complexes. Typically, C3b deposited on the cell surface binds to factor B, becoming susceptible to breakdown by factor D in the serum. During this process, factor B is broken down into Ba and Bb. C3b and Bb then form a complex to form the C3 convertase C3bBb in the alternative pathway. In this process, complement factor B plays an early and central role in activation of the alternative pathway of the complement cascade. C3b is both a product of C3 convertase's breakdown of C3 and a component of the alternative pathway's C3 convertase, forming a feedback amplification mechanism in which the classical and alternative pathways interact. Current research has linked a variety of diseases, including hematologic, autoimmune, inflammatory, and neurodegenerative, to dysfunctional complement systems.

[0009] 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 mutations in one or more 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 by varying degrees of hemolysis (paroxysmal), chronic or recurrent 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. However, most patients are often atypical, with insidious onset, prolonged course, and varying severity.

[0010] There are over ten proteins on the surface of red blood cells that inhibit complement pathway activation. These proteins are all anchored to the cell membrane via glycosylated phosphatidylinositol (GPI) and are collectively referred to as GPI-anchored proteins (APs). It is currently believed that the pathogenesis of PNH begins with the mutation of hematopoietic stem cells under certain conditions, resulting in the generation of GPI-deficient PNH clones. Subsequently, due to factors (mostly believed to be immune), hematopoietic impairment or failure occurs, allowing PNH clones to gain a proliferative advantage over normal clones. The presence of multiple GPI-linked antigens complicates the interpretation of PNH cell biological behavior. Among these, the most important inhibitors of complement pathway activation, CD55 (a decay-accelerating factor for protein C3 convertase) and CD59 (a membrane attack complex (MAC) inhibitor), are closely linked to the pathogenesis, clinical manifestations, diagnosis, and treatment of PNH (Frontiers in Immunology 2019, 10, 1157). CD59 prevents the incorporation of C9 into the C5b-8 complex, thereby preventing the formation of the membrane attack unit and inhibiting the terminal complement attack response. The hallmark manifestations of PNH—intravascular hemolysis and thrombosis—are currently believed to be due to CD59 deficiency. Patients with congenital CD59 deficiency have been reported to exhibit many of the hallmark symptoms of PNH, such as intravascular hemolysis, hemoglobinuria, and venous thrombosis. In PNH patients, defective GPI synthesis prevents CD59 from binding to the red blood cell membrane, resulting in its inability to inhibit complement pathway activation. Consequently, aberrant complement activation occurs, attacking red blood cells and leading to multiple clinical manifestations, including intravascular hemolysis, hemoglobinuria, and smooth muscle dysfunction. Currently, there is no effective cure for PNH other than hematopoietic stem cell transplantation to restore normal hematopoiesis. Due to the risks associated with hematopoietic stem cell transplantation and the fact that PNH is a benign clonal disorder, controlling hemolytic episodes remains the mainstay of clinical treatment. Currently, only eculizumab is approved for the treatment of PNH. However, many patients continue to experience anemia despite eculizumab treatment, and many require ongoing blood transfusions. In addition, eculizumab requires intravenous administration. Therefore, the development of new inhibitors of the complement pathway for the treatment of PNH is of great significance.

[0011] IgAN is the most common primary glomerulonephritis, characterized by immunofluorescence-detected IgA deposits in the mesangium. Clinical manifestations vary, typically presenting with recurrent microscopic or gross hematuria. Existing data suggest that the development of IgAN is associated with innate or acquired immune dysregulation. IgA1 production is increased in the mucosa due to irritation of the respiratory or digestive tract by viruses, bacteria, and food proteins, or immune complexes containing IgA1 are deposited in the mesangium, activating the alternative complement pathway and causing glomerular damage. Human IgA molecules are divided into two subtypes: IgA1 and IgA2. IgA1 is the predominant form circulating in healthy individuals (comprising approximately 85%) and is the primary component of mesangial deposits in patients with IgAN. IgA molecules can exist as both monomers and multimers. IgA1 molecules possess a unique heavy chain hinge region between the first and second constant regions, which serves as the site for the attachment of O-linked glycan groups. Recent studies have found that the IgA molecules deposited in the serum and glomerular mesangium of IgAN patients are primarily glycosylation-deficient IgA1 (gd-IgA1). It is currently believed that the initiation of IgAN pathogenesis is the abnormal increase in gd-IgA1 production.

[0012] More than 90% of IgAN patients have deposits of complement C3 in the glomerular mesangium. 75%-100% of IgAN patients have co-depositions of properdin, IgA, and C3 in the renal tissue, and 30%-90% of IgAN patients have co-depositions of complement factor H, IgA, and C3 in the renal tissue. In addition to deposits in renal tissue, some studies have 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, as well as C3a receptors in renal tissue, are significantly correlated with the activity and severity of renal damage (J clin Immunol 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 multimers is the key link (Eur J Immunol 1987, 17(3): 321-326). Currently, the deposition of complement C3 in the glomerular mesangium has become an auxiliary diagnostic marker for IgAN. A study performed 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 the active lesions of IgAN (Am J Nephrol. 2000, 20(2): 122-128). Currently, there is no specific drug to treat IgAN in clinical practice. The main drugs used are general-purpose renin-angiotensin 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 the TESTING-I trial clearly confirmed the potential side effects of glucocorticoids (IgA nephropathy 2019, 95, 4, 750-756).

[0013] Arthritis is a common chronic inflammatory disease caused by inflammation, infection, degeneration, trauma, or other factors. Clinical manifestations include joint redness, swelling, heat, pain, dysfunction, and deformity. These symptoms often result in severe pain, limited mobility, and physical deformity. In severe cases, they can lead to disability, significantly impacting patients' quality of life. Studies have shown that K / BxN mouse serum does not induce arthritis in mice deficient in complement factor B, whereas wild-type mice develop arthritis in response to K / BxN mouse serum (Immunity, 2002, 16, 157–168). This suggests that the complement system plays a crucial role in the pathogenesis of K / BxN mouse serum-induced arthritis and that complement factor B is a potential therapeutic target for arthritis.

[0014] The small molecule complement factor B inhibitors developed by Novartis AG are used to treat diseases such as age-related macular degeneration (AMD). Related patents include: WO2013164802A1, WO2013192345A1, WO2014143638A1, WO2015009616A1, WO2015066241A1 and WO2019043609A1.

[0015] Inflammatory and immune-related diseases are diverse and difficult to cure. There are unmet clinical needs in these areas, and new small molecule drugs need to be developed for medical treatment.

[0016] Summary of the Invention

[0017] The present application provides a compound represented by formula (IE) or a pharmaceutically acceptable salt thereof,

[0018] in:

[0019] Ring A is selected from phenyl, 5-10 membered heteroaryl and

[0020] Ring B is selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl;

[0021] R 0 Selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, deuterated C 1-6 Alkyl, C 1-6 Hydroxyalkyl and 3-8 membered cycloalkyl;

[0022] G' is CR 7 or N;

[0023] Each R 1 The same or different, each independently selected from H, D, halogen, CN, NH2, OH, C1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and 3-8 membered cycloalkyl;

[0024] R 2 Selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 Alkynyl and 3-8 membered cycloalkyl;

[0025] Each R 3 The same or different, each independently selected from H, D, halogen, CN, NH2, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and 3-8 membered cycloalkyl;

[0026] Each R 4 The same or different, each independently selected from H, halogen, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkynyl and 3-8 membered cycloalkyl;

[0027] R 7 and R 8 The same or different, each independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy;

[0028] or R 7 and R 8 Together with the carbon to which it is attached, it forms a 3-8 membered cycloalkyl or a 3-8 membered heterocycloalkyl, wherein the 3-8 membered cycloalkyl or the 3-8 membered heterocycloalkyl is optionally substituted with one or more halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 substituted by a haloalkoxy substituent;

[0029] m is 0, 1, or 2;

[0030] n is 0, 1, 2, or 3;

[0031] r is 0, 1, 2, 3 and 4.

[0032] In some embodiments, the compound represented by formula (IE) or a pharmaceutically acceptable salt thereof, wherein R 0 Selected from H, halogen and C 1-6 alkyl.

[0033] In some embodiments, the compound represented by formula (IE) or a pharmaceutically acceptable salt thereof, wherein R 0 It is Cl or methyl.

[0034] In some embodiments, the compound of formula (IE) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (IE) has the structure of formula (IG),

[0035] Among them, ring A, G', R 1 、R 2 、R 3 、R 4 、R 8 , r, m and n are as defined in formula (IE).

[0036] In some embodiments, the compound represented by formula (IE) or formula (IG) or a pharmaceutically acceptable salt thereof, Selected from: Ring B, R 4 and r are as defined above in Formula (IE) or Formula (IG).

[0037] In some embodiments, the compound represented by formula (IE) or formula (IG) or a pharmaceutically acceptable salt thereof, Selected from:

[0038] In some embodiments, in the compound represented by formula (IE) or formula (IG) or a pharmaceutically acceptable salt thereof, ring B is selected from 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl and 6 membered heteroaryl;

[0039] In some embodiments, in the compound represented by formula (IE) or formula (IG) or a pharmaceutically acceptable salt thereof, ring B is selected from phenyl, pyridyl, cyclopentenyl, and dihydrofuranyl.

[0040] In some embodiments, in the compound represented by Formula (IE) or Formula (IG) or a pharmaceutically acceptable salt thereof, r is 0, 1 or 2.

[0041] In some embodiments, the compound represented by formula (IE) or formula (IG) has the structure represented by formula (IIG),

[0042] in,

[0043] X and Y are the same or different and are each independently selected from CH or N;

[0044] G'、R 1 、R 2 、R 3 、R 4 、R 8 , m and n are as defined in Formula (IE) or Formula (IG).

[0045] In some embodiments, the compound represented by formula (IIG) or a pharmaceutically acceptable salt thereof, wherein:

[0046] G' is CR 7 or N;

[0047] R 7 and R 8 The same or different, each independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy;

[0048] X and Y are the same or different and are each independently selected from CH or N;

[0049] Each R 1 The same or different, each independently selected from H, D, CN, NH2, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and 3-8 membered cycloalkyl;

[0050] R 2 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy and 3-8 membered cycloalkyl;

[0051] Each R 3 The same or different, each independently selected from H, D, CN, NH2, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and 3-8 membered cycloalkyl;

[0052] Each R 4 the same or different, each independently selected from H, halogen, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy;

[0053] m is 0, 1, or 2;

[0054] n is 0, 1, 2 or 3.

[0055] In some embodiments, the compound represented by formula (IE), formula (IG) or formula (IIG) of the present application or a pharmaceutically acceptable salt thereof, wherein G' is CR 7 ; R 7 As defined above.

[0056] In some embodiments, the compound of formula (IE), formula (IG) or formula (IIG) satisfies one or more of the following conditions:

[0057] (1) C 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

[0058] (2) The halogen is fluorine, chlorine, bromine or iodine, for example fluorine;

[0059] (3) The 3- to 8-membered cycloalkyl group is a 3- to 6-membered cycloalkyl group, such as cyclopropyl, cyclobutyl or cyclopentyl, and further such as cyclopentyl or cyclopropyl;

[0060] (4) The heteroatom in the 3- to 8-membered heterocycloalkyl group is N, O or S, such as N or O; the number of the heteroatoms may be 1, 2 or 3, such as 1;

[0061] (5) The heteroatom in the 5- to 6-membered heteroaryl group is N, O or S, such as N; the number of the heteroatoms may be 1, 2 or 3, such as 1;

[0062] (6) C 1-6 Alkoxy is C 1-4 Alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; for example methoxy;

[0063] (7) C 2-6 Alkynyl is C 2-4 Alkynyl, for example ethynyl, propynyl, butynyl.

[0064] The present application also provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0065] in,

[0066] X and Y are the same or different and are each independently selected from CH or N;

[0067] G is CR 5 or N;

[0068] R 5 and R 6 The same or different, each independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy;

[0069] Each R 3 The same or different, each independently selected from H, D, CN, NH2, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and 3-8 membered cycloalkyl;

[0070] Or, 2 R 3 The carbon atom to which it is connected forms a C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, the C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 substituted with a haloalkoxy group;

[0071] R 1 、R 2 、R 4 , m and n are as defined in any of the above schemes.

[0072] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein: X and Y are the same or different and are independently selected from CH or N; G is CR 5 or N; each R 1 The same or different, each independently selected from H, D, CN, NH2, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and 3-8 membered cycloalkyl; R 2 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy and 3-8 membered cycloalkyl; R 3Selected from H, D, CN, NH2, OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl and 3-8 membered cycloalkyl; or, 2 R 3 The carbon atom to which it is connected forms a C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, the C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 Substituted with haloalkoxy; R 4 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; R 5 and R 6 The same or different, each independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; m is 0, 1 or 2; n is 0, 1, 2 or 3.

[0073] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein G is CR 5 .

[0074] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein G is N.

[0075] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X and Y are both CH.

[0076] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein X is N and Y is CH.

[0077] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0078] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0079] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein two R 3 The carbon atom to which it is connected forms a C3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, the C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 substituted with a haloalkoxy group.

[0080] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein two R 3 The carbon atom to which it is connected forms a C 3-8 Cycloalkyl.

[0081] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein two R 3 It forms a 3-8 membered heterocyclic group with the carbon atom to which it is connected.

[0082] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has the structure represented by formula (III):

[0083] Among them, X, Y, G, R 1 、R 2 、R 3 、R 4 、R 6 , m and n are as defined in formula (I).

[0084] In some embodiments, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof has the structure represented by formula (III-1) and formula (III-2):

[0085] Among them, X, Y, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , m and n are as defined in formula (I).

[0086] In some embodiments, the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 The same or different, each independently selected from H, halogen, CN, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0087] In some embodiments, the compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6are the same or different, and are each independently selected from H, F, CN and methyl.

[0088] In some embodiments, the compound represented by formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R 6 C 1-6 Alkoxy.

[0089] In some embodiments, the compound represented by formula (III-2) or a pharmaceutically acceptable salt thereof, wherein R 6 is methoxy or ethoxy.

[0090] The present application also provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,

[0091] in:

[0092] G' is CR 7 or N;

[0093] R 7 and R 8 The same or different, each independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 haloalkoxy;

[0094] X, Y, R 1 、R 2 、R 3 、R 4 , m and n are as defined in formula (I),

[0095] Not included

[0096] In some embodiments, the compound represented by formula (II) or a pharmaceutically acceptable salt thereof has the structure represented by formula (IV):

[0097] Among them, X, Y, G', R 1 、R 2 、R 3 、R 4 、R 8 , m and n are as defined in formula (II).

[0098] In some embodiments, the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof has the structure represented by formula (IV-1) and formula (IV-2):

[0099] Among them, X, Y, R 1 、R 2 、R3 、R 4 、R 7 、R 8 , m and n are as defined in formula (IV).

[0100] In some embodiments, the compound of formula (IIG) or a pharmaceutically acceptable salt thereof has the structure shown in formula (IVG):

[0101] Among them, X, Y, G', R 1 、R 2 、R 3 、R 4 、R 8 , m and n are as defined above in formula (IIG).

[0102] In some embodiments, the compound of formula (IVG) or a pharmaceutically acceptable salt thereof, the compound of formula (IVG) has the structures shown in formula (IVG-1) and formula (IVG-2):

[0103] Among them, X, Y, R 1 、R 2 、R 3 、R 4 、R 7 、R 8 , m and n are as defined in formula (IVG).

[0104] In some embodiments, the compound represented by formula (IIG) or a pharmaceutically acceptable salt thereof, the compound represented by formula (IIG) has the structure represented by formula (IVG-3):

[0105] Among them, X, Y, R 1 、R 2 、R 3 、R 4 、R 7 、R 8 , m and n are as defined above in formula (IIG).

[0106] In some embodiments, the compound represented by Formula (IE), Formula (IG), Formula (IIG), Formula (IVG), Formula (II), Formula (IV-1), Formula (IVG-1) or Formula (IVG-3) or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 The same or different, each independently selected from H, halogen, CN, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0107] In some embodiments, the compound represented by Formula (IE), Formula (IG), Formula (IIG), Formula (IVG), Formula (II), Formula (IV-1), Formula (IVG-1) or Formula (IVG-3) or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 are the same or different, and are each independently selected from H, F, CN, methyl and -CHF2.

[0108] In some embodiments, the compound represented by Formula (IE), Formula (IG), Formula (IIG), Formula (IVG), Formula (IVG-1) or Formula (IVG-3) or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 H or F; or R 7 and R 8 Together with the carbon to which it is attached it forms a cyclopropyl group.

[0109] In some embodiments, the compound represented by Formula (IE), Formula (IG), Formula (IIG), Formula (IVG), Formula (IVG-1) or Formula (IVG-3) or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 All are F.

[0110] In some embodiments, the compound represented by Formula (IE), Formula (IG), Formula (IIG), Formula (IVG), Formula (II), Formula (IVG-1) or Formula (IVG-3) or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 Together with the carbon to which it is attached, it forms a 3-6 membered cycloalkyl group.

[0111] In some embodiments, the compound represented by Formula (IE), Formula (IG), Formula (IIG), Formula (IVG), Formula (II), Formula (IVG-1) or Formula (IVG-3) or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 Together with the carbon to which it is attached it forms a cyclopropyl group.

[0112] In some embodiments, the compound represented by formula (IV-2) and formula (IVG-2) or a pharmaceutically acceptable salt thereof, wherein R 8 C 1-6 Alkoxy.

[0113] In some embodiments, the compound represented by formula (IV-2) and formula (IVG-2) or a pharmaceutically acceptable salt thereof, wherein R 8 Selected from methoxy and ethoxy.

[0114] In some embodiments, the compound represented by Formula (I), Formula (II), Formula (III), Formula (III-1) or Formula (III-2) or a pharmaceutically acceptable salt thereof, wherein X and Y are both CH.

[0115] In some embodiments, the compound represented by Formula (I), Formula (II), Formula (III), Formula (III-1) or Formula (III-2) or a pharmaceutically acceptable salt thereof, wherein X is N and Y is CH.

[0116] In some embodiments, the compound represented by Formula (I), Formula (II), Formula (III), Formula (III-1) or Formula (III-2) or a pharmaceutically acceptable salt thereof, wherein X is CH and Y is N.

[0117] In some embodiments, the compound represented by formula (I), formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein for

[0118] In some embodiments, the compound represented by Formula (IIG), Formula (IVG), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3) or a pharmaceutically acceptable salt thereof, wherein X and Y are both CH.

[0119] In some embodiments, the compound represented by Formula (IIG), Formula (IVG), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3) or a pharmaceutically acceptable salt thereof, wherein X is CH; Y is N.

[0120] In some embodiments, the compound represented by Formula (IIG), Formula (IVG), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3) or a pharmaceutically acceptable salt thereof, wherein X is N; and Y is CH.

[0121] In some embodiments, the compound represented by Formula (IE), Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1) or Formula (IVG-2) or Formula (IVG-3) or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0122] In some embodiments, the compound represented by Formula (IE), Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3) or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0123] In some embodiments, the compound represented by Formula (IE), Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3), or a pharmaceutically acceptable salt thereof, wherein R 1 For H.

[0124] In some embodiments, the compound represented by Formula (IE), Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3), or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from Cl, methyl, methoxy, deuterated methoxy, ethynyl and cyclopropyl.

[0125] In some embodiments, the compound represented by Formula (IE), Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3), or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from methyl, methoxy, deuterated methoxy and cyclopropyl.

[0126] In some embodiments, the compound represented by Formula (IE), Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3), or a pharmaceutically acceptable salt thereof, wherein R 2 It is a methyl group.

[0127] In some embodiments, the compound represented by Formula (IE), Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3), or a pharmaceutically acceptable salt thereof, wherein R2 It is a methoxy group or a deuterated methoxy group.

[0128] In some embodiments, the compound represented by Formula (IE), Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3), or a pharmaceutically acceptable salt thereof, wherein R 2 It is cyclopropyl.

[0129] In some embodiments, the compound represented by Formula (IE), Formula (IG), Formula (IIG), Formula (IVG), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3) or a pharmaceutically acceptable salt thereof, wherein R 3 is H, halogen or C 1-6 alkyl.

[0130] In some embodiments, the compound represented by Formula (IE), Formula (IG), Formula (IIG), Formula (IVG), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3) or a pharmaceutically acceptable salt thereof, wherein R 3 is H or methyl.

[0131] In some embodiments, the compound represented by Formula (IE), Formula (I), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3), or a pharmaceutically acceptable salt thereof, wherein R 4 For H, OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkynyl, C 3-6 Cycloalkyl or C 1-6 Halogenated alkyl.

[0132] In some embodiments, the compound represented by Formula (IE), Formula (I), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3), or a pharmaceutically acceptable salt thereof, wherein R 4 H, halogen, C 1-6 Alkyl or C 1-6 Alkoxy.

[0133] In some embodiments, the compound represented by Formula (IE), Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3), or a pharmaceutically acceptable salt thereof, wherein R 4 is H, F, Cl, OH, methyl, methoxy, cyclopropyl, difluoromethyl, ethynyl or propynyl.

[0134] In some embodiments, the compound represented by Formula (IE), Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3), or a pharmaceutically acceptable salt thereof, wherein R 4 is H, F, Cl, methyl or methoxy.

[0135] In some embodiments, the compound represented by Formula (IE), Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3) or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

[0136] In some embodiments, the compound represented by formula (IE) or a pharmaceutically acceptable salt thereof, wherein

[0137] for

[0138] G' is CR 7 ;

[0139] R 7 and R 8 H or F;

[0140] or R 7 and R 8 Together with the carbon to which it is attached, it forms a cyclopropyl group;

[0141] R 0 Halogen or C 1-6 alkyl;

[0142] R 1 is H;

[0143] R 2 is selected from Cl, methyl, methoxy, deuterated methoxy, ethynyl and cyclopropyl;

[0144] R3 Selected from H, halogen and C 1-6 alkyl;

[0145] R 4 Selected from H, OH, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkynyl, C 3-6 Cycloalkyl or halogenated C 1-6 alkyl;

[0146] r is 0, 1, or 2;

[0147] m is 0 or 1;

[0148] n is 0, 1 or 2.

[0149] In some embodiments, the compound represented by formula (IIG) or a pharmaceutically acceptable salt thereof, wherein

[0150] X and Y are both CH;

[0151] G' is CR 7 ;

[0152] R 7 and R 8 All F;

[0153] R 1 is H;

[0154] R 2 is selected from methyl, methoxy, deuterated methoxy and cyclopropyl;

[0155] R 3 is H or methyl;

[0156] R 4 Selected from H, halogen, C 1-6 Alkyl or C 1-6 alkoxy;

[0157] m is 0 or 1;

[0158] n is 0, 1 or 2.

[0159] Exemplary specific compounds of the compounds described herein include, but are not limited to, the structures in Table A below:

[0160] Table A

[0161] Exemplary specific compounds of the compounds shown in this application also include, but are not limited to, the structures in Table B below:

[0162] Table B

[0163] The present application also provides a compound represented by formula (IA) or a salt thereof,

[0164] in:

[0165] R w C 1-6 alkyl;

[0166] R p is an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl (Fmoc) or trifluoroacetyl;

[0167] X, Y, G, R 1 、R 2 、R 3 、R 4 、R 6 , m and n are as defined in formula (I).

[0168] The present application also provides a compound represented by formula (IEA) or a salt thereof,

[0169] in:

[0170] R w C 1-6 alkyl;

[0171] R p is an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl (Fmoc) or trifluoroacetyl;

[0172] Ring A, G', R 0 、R 1 、R 2 、R 3 、R 4 、R 8 , r, m and n are as defined in formula (IE).

[0173] The present application also provides a compound represented by formula (IGA) or a salt thereof,

[0174] in:

[0175] R w C 1-6 alkyl;

[0176] R pis an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl (Fmoc) or trifluoroacetyl;

[0177] Ring A, G', R 1 、R 2 、R 3 、R 4 、R 8 , r, m and n are as defined in formula (IG).

[0178] The present application also provides compounds represented by formula (IIA) and formula (IIGA) or their salts,

[0179] in:

[0180] R w C 1-6 alkyl;

[0181] R p is an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl (Fmoc) or trifluoroacetyl;

[0182] X, Y, G', R 1 、R 2 、R 3 、R 4 、R 8 , m and n are as defined in formula (II).

[0183] The present application also provides a compound represented by formula (IIIA), (IIIA-1) or (IIIA-2) or a salt thereof,

[0184] Among them, R w C 1-6 alkyl;

[0185] R p is an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl (Fmoc) or trifluoroacetyl;

[0186] X, Y, G, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , m and n are as defined in formula (III).

[0187] The present application also provides a compound represented by formula (IVA), (IVA-1), (IVA-2), (IVGA), (IVGA-1) or (IVGA-2) or a salt thereof,

[0188] Among them, R w C 1-6 alkyl;

[0189] R p is an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl (Fmoc) or trifluoroacetyl;

[0190] X, Y, G', R 1 、R 2 、R 3 、R 4 、R 7 、R 8 , m and n are as defined in formula (IV).

[0191] Exemplary specific compounds of the intermediate compounds shown in this application include, but are not limited to, the structures in Table C below:

[0192] Table C

[0193] The present application provides a method for preparing a compound represented by formula (I), comprising reacting a compound represented by formula (IA) to obtain a compound represented by formula (I),

[0194] Among them, R w C 1-6 alkyl;

[0195] R p is an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl (Fmoc) or trifluoroacetyl;

[0196] X, Y, G, R 1 、R 2 、R 3 、R 4 、R 6 , m and n are as defined in formula (I).

[0197] Referring to the above-mentioned method for preparing the compound represented by formula (I), the compound represented by formula (IIIA), (IIIA-1) or (IIIA-2) is reacted to obtain the corresponding compound represented by formula (III), (III-1) or (III-2), wherein R wC 1-6 Alkyl; R p is an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl (Fmoc) or trifluoroacetyl.

[0198] The present application provides a method for preparing a compound represented by formula (II), comprising reacting a compound represented by formula (IIA) to obtain a compound represented by formula (II).

[0199] Among them, R w C 1-6 alkyl;

[0200] R p is an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl (Fmoc) or trifluoroacetyl;

[0201] X, Y, G', R 1 、R 2 、R 3 、R 4 、R 8 , m and n are as defined in formula (II).

[0202] Referring to the above method for preparing the compound represented by formula (II), the compound represented by (IVA), (IVA-1) or (IVA-2) is subjected to hydrolysis reaction to obtain the corresponding compound represented by (IV), (IV-1) or (IV-2), wherein R w C 1-6 Alkyl; R p is an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl (Fmoc) or trifluoroacetyl.

[0203] The present application provides a method for preparing a compound represented by formula (IE), comprising hydrolyzing and deprotecting a compound represented by formula (IEA) to obtain a compound represented by formula (IE).

[0204] Among them, R w C 1-6 alkyl;

[0205] R p is an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl (Fmoc) or trifluoroacetyl;

[0206] Ring A, G', R0 、R 1 、R 2 、R 3 、R 4 、R 8 , r, m and n are as defined in formula (IE).

[0207] The present application provides a method for preparing a compound represented by formula (IG), comprising hydrolyzing and deprotecting a compound represented by formula (IGA) to obtain a compound represented by formula (IG).

[0208] Among them, R w C 1-6 alkyl;

[0209] R p is an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl (Fmoc) or trifluoroacetyl;

[0210] Ring A, G', R 1 、R 2 、R 3 、R 4 、R 8 , r, m and n are as defined in formula (IG).

[0211] The present application provides a method for preparing a compound represented by formula (IIG), comprising reacting a compound represented by formula (IIGA) to obtain a compound represented by formula (IIG).

[0212] Among them, R w C 1-6 alkyl;

[0213] R p is an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl (Fmoc) or trifluoroacetyl;

[0214] X, Y, G', R 1 、R 2 、R 3 、R 4 、R 8 , m and n are as defined in formula (II).

[0215] Referring to the above method for preparing the compound represented by formula (II), the compound represented by (IVGA), (IVGA-1) or (IVGA-2) is subjected to hydrolysis reaction to obtain the corresponding compound represented by (IVG), (IVG-1) or (IVG-2), wherein Rw C 1-6 Alkyl; R p is an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl (Fmoc) or trifluoroacetyl.

[0216] The present application also provides a compound represented by formula (IB) or a salt thereof,

[0217] where R w C 1-6 Alkyl; X, Y, G, R 3 、R 4 、R 6 and n are as defined in formula (I).

[0218] The present application also provides a compound represented by formula (IIIB) or a salt thereof,

[0219] where R w C 1-6 Alkyl; X, Y, G, R 3 、R 4 、R 6 and n are as defined in formula (I).

[0220] The present application also provides a compound represented by formula (IGB) or a salt thereof,

[0221] where R w C 1-6 Alkyl; Ring A, G', R 3 、R 4 、R 8 , r and n are as defined in formula (IG).

[0222] The present application also provides compounds represented by formula (IIB) and formula (IIGB) or salts thereof,

[0223] where R w C 1-6 Alkyl; X, Y, G', R 3 、R 4 、R 8 and n are as defined in formula (II).

[0224] The present application also provides compounds represented by formula (IVB) and formula (IVGB) or salts thereof,

[0225] where R w C 1-6 Alkyl; X, Y, G', R 3、R 4 、R 8 and n are as defined in formula (II).

[0226] The present application also provides a method for preparing a compound represented by formula (IA), comprising reacting a compound represented by formula (IB) with a compound represented by formula (IC) to obtain a compound represented by formula (IA).

[0227] where R w 、R p , X, Y, G, R 1 、R 2 、R 3 、R 4 、R 6 , m and n are as defined in formula (IA).

[0228] Referring to the above method for preparing the compound represented by formula (IA), the compound represented by formula (IIIB) is reacted with the compound represented by formula (IC) to obtain the compound represented by formula (IIIA).

[0229] The present application also provides a method for preparing a compound represented by formula (IIA), comprising reacting a compound represented by formula (IIB) with a compound represented by formula (IC) to obtain a compound represented by formula (IIA).

[0230] where R w 、R p , X, Y, G', R 1 、R 2 、R 3 、R 4 、R 8 , m and n are as defined in formula (IIA).

[0231] Referring to the above-mentioned method for preparing the compound represented by formula (IIA), the compound represented by formula (IVB) is reacted with the compound represented by formula (IC) to obtain the compound represented by formula (IVA).

[0232] The present application also provides a method for preparing a compound represented by formula (IGA), comprising reacting a compound represented by formula (IGB) with a compound represented by formula (IC) to obtain a compound represented by formula (IGA).

[0233] where R w 、R p , Ring A, G', R 1 、R 2 、R 3 、R 4 、R 8, m, n and r are as defined in formula (IG).

[0234] The present application also provides a method for preparing a compound represented by formula (IIGA), comprising reacting a compound represented by formula (IIGB) with a compound represented by formula (IC) to obtain a compound represented by formula (IIGA).

[0235] where R w 、R p , X, Y, G', R 1 、R 2 、R 3 、R 4 、R 8 , m and n are as defined in formula (IIA).

[0236] Referring to the above-mentioned method for preparing the compound represented by formula (IIGA), the compound represented by formula (IVGB) is reacted with the compound represented by formula (IC) to obtain the compound represented by (IVGA).

[0237] On the other hand, the present application provides isotope-labeled compounds of formula (I), formula (IG), formula (II), formula (IIG), formula (III), formula (IV), formula (IVG), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (IVG-1), formula (IVG-2) or formula (IVG-3), or compounds shown in Table A or Table B, wherein the isotope label is preferably deuterium (D or 2 H) replaces hydrogen ( 1 H).

[0238] In another aspect, the present application provides a pharmaceutical composition comprising at least one therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0239] On the other hand, the present application also provides a compound shown in Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, and its use in the preparation of a medicament for regulating the activity of the complement alternative pathway in a subject.

[0240] On the other hand, the present application also provides a compound shown in Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, and its use in the preparation of a medicament for preventing and / or treating diseases or conditions affected by the regulation of the complement alternative pathway.

[0241] The present application also provides compounds shown in Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3), or compounds shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, and their use in the preparation of drugs for inhibiting complement factor B.

[0242] The present application also provides compounds shown in Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3), or shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, and their use in the preparation of drugs for preventing and / or treating diseases or conditions mediated by complement factor B inhibitors.

[0243] The present application also provides a compound shown in Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, and its use in the preparation of a medicament for preventing and / or treating autoimmune diseases, inflammatory diseases, hematological and neurodegenerative diseases; preferably, its use in the preparation of a medicament for preventing and / or treating: paroxysmal nocturnal hemoglobinuria (PNH), primary glomerulonephritis (IgAN), membranous nephropathy (MN), diabetic nephropathy (DKD), C3 glomerulonephritis (C3G), lupus nephritis (LN), proliferative nephritis, systemic lupus erythematosus (SLE), age-related macular degeneration (AMD), and the like. D), geographic atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), complications of hemodialysis, hemolytic anemia or hemodialysis, neuromyelitis ocularis (NMO), arthritis, rheumatoid arthritis, psoriatic arthritis, hepatitis, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), Guillain-Barré syndrome (GBS), neuromyelitis optica spectrum disorder (NMOSD), uveitis, retinitis pigmentosa, macular edema, Behçet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular pemphigoid, pemphigus vulgaris, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia Uses of leventinese, Sorsby fundus dystrophy, late-onset macular dystrophy, North Carolina macular dystrophy, Stargardt disease, corneal inflammatory diseases, antineutrophil cytoplasmic antibody-associated vasculitis (ANCA-AAV), Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemia-reperfusion condition, myocardial infarction, balloon angioplasty, post-cardiopulmonary bypass or renal bypass pump syndrome, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, and mesenteric artery reperfusion after aortic reconstruction.

[0244] The present application also provides a method for inhibiting complement factor B, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound shown in Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotope-labeled substance, or the aforementioned pharmaceutical composition comprising the same.

[0245] The present application also provides a method for preventing and / or treating diseases or conditions mediated by complement factor B, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound shown in Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotope-labeled substance, or the aforementioned pharmaceutical composition comprising the same.

[0246] The present application also provides a method for preventing and / or treating autoimmune diseases, inflammatory diseases, hematological diseases and neurodegenerative system diseases, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound shown in Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing.

[0247] The present application also provides a method for preventing and / or treating paroxysmal nocturnal hemoglobinuria (PNH), primary glomerulonephritis (IgAN), membranous nephropathy (MN), diabetic nephropathy (DKD), C3 glomerulonephritis (C3G), lupus nephritis (LN), proliferative nephritis, systemic lupus erythematosus (SLE), age-related macular degeneration (AMD), geographic atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), hemodialysis complications, hemolytic anemia or hemodialysis, neuromyelitis (NMO), arthritis, rheumatoid arthritis, psoriasis Arthritis, hepatitis, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), Guillain-Barré syndrome (GBS), neuromyelitis optica spectrum disorder (NMOSD), uveitis, retinitis pigmentosa, macular edema, Behçet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular pemphigoid, pemphigus vulgaris, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia A method for treating leventinese, Sorsby fundus dystrophy, late-onset macular dystrophy, North Carolina macular dystrophy, Stargardt disease, corneal inflammatory diseases, antineutrophil cytoplasmic antibody-associated vasculitis (ANCA-AAV), Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemia-reperfusion symptoms, myocardial infarction, balloon angioplasty, cardiopulmonary bypass or renal bypass post-pump syndrome, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, etc., which comprises administering to a patient in need thereof a therapeutically effective amount of a compound represented by Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3), or a compound represented by Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0248] The present application also provides a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, which is used as a drug.

[0249] The present application also provides a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, which is used as a complement factor B inhibitor.

[0250] The present application also provides a compound shown in Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3), Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, which is used as a drug for preventing and / or treating diseases or conditions mediated by complement factor B.

[0251] The present application also provides a compound shown in Formula (I), Formula (IG), Formula (II), Formula (IIG), Formula (III), Formula (IV), Formula (IVG), Formula (III-1), Formula (III-2), Formula (IV-1), Formula (IV-2), Formula (IVG-1), Formula (IVG-2) or Formula (IVG-3), Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing, which is used as a drug for preventing and / or treating autoimmune diseases, inflammatory diseases, blood diseases, and neurodegenerative diseases.

[0252] The present application also provides a compound of formula (I), formula (IG), formula (II), formula (IIG), formula (III), formula (IV), formula (IVG), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (IVG-1), formula (IVG-2) or formula (IVG-3), Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for preventing and / or treating paroxysmal nocturnal hemoglobinuria (PNH), primary glomerulonephritis (IgAN), membranous nephropathy (MN), diabetic nephropathy (DKD), C3 glomerulonephritis (C3G), lupus nephritis (LN), proliferative nephritis, systemic lupus erythematosus (SLE), 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 ocularis (NMO), arthritis, rheumatoid arthritis, psoriatic arthritis, hepatitis, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), Guillain-Barré syndrome (GBS), neuromyelitis optica spectrum disorder (NMOSD), uveitis, retinitis pigmentosa, macular edema, Behçet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular pemphigoid, pemphigus ocularis, nonarteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, late-onset macular dystrophy, North Carolina macular dystrophy, Stargardt disease, corneal inflammatory diseases, antineutrophil cytoplasmic antibody-associated vasculitis (ANCA-AAV), Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-cardiopulmonary bypass or renal bypass pump syndrome, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, and mesenteric artery reperfusion after aortic reconstruction.

[0253] The complement factor B-mediated disease described in the present application is selected from autoimmune diseases, inflammatory diseases, blood diseases and neurodegenerative diseases.

[0254] The complement factor B-mediated disease described in the present application is selected from paroxysmal nocturnal hemoglobinuria (PNH), diabetic nephropathy (DKD), primary glomerulonephritis (IgAN), membranous nephropathy (MN), C3 glomerulonephritis (C3G), lupus nephritis (LN), proliferative nephritis, systemic lupus erythematosus (SLE), age-related macular degeneration (AMD), geographic atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), hemodialysis complications, hemolytic anemia or hemodialysis, neuromyelitis (NMO), arthritis, rheumatoid arthritis, silver Psoriatic arthritis, hepatitis, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), Guillain-Barré syndrome (GBS), neuromyelitis optica spectrum disorder (NMOSD), uveitis, retinitis pigmentosa, macular edema, Behçet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular pemphigoid, pemphigus vulgaris, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, late-onset macular dystrophy, North Carolina macular dystrophy, Stargardt disease, corneal inflammatory diseases, antineutrophil cytoplasmic antibody-associated vasculitis (ANCA-AAV), Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, cardiopulmonary bypass or renal bypass post-pump syndrome, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, etc.

[0255] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0256] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope-labeled substance, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope-labeled substance. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope-labeled substance.

[0257] In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned formula (I), formula (IG), formula (II), formula (IIG), formula (III), formula (IV), formula (IVG), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), formula (IVG-1), formula (IVG-2) or formula (IVG-3), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt or an isotope-labeled substance thereof.

[0258] In some embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of one or more pharmaceutically acceptable excipients, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of one or more pharmaceutically acceptable excipients.

[0259] When used as a drug, the compounds of the present application 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 can be administered by a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. Administration can be topical (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 nebulizer; 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. Parenteral administration can be in the form of a single bolus, or can be administered, for example, by a continuous infusion pump.

[0260] In preparing the compositions of the present application, the active ingredient is typically mixed with excipients and the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or dissolved in a liquid vehicle), 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.

[0261] The "excipient" mentioned in this application refers to ingredients other than the active ingredient, including, for example, diluents, fillers, absorbents, wetting agents, binders, disintegrants and lubricants.

[0262] On the other hand, the pharmaceutically acceptable salts of the compounds described in the present application may be inorganic salts or organic salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (such as a carboxyl group) and a basic center (such as an amino group), they can also form internal salts.

[0263] On the other hand, the compounds of the present invention may exist in specific geometric or stereoisomeric forms. For example, cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures and other mixtures, as well as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present application.

[0264] In the chemical structure of the compounds described in this application, the bond Indicates that the configuration is not specified. or Indicates the absolute configuration, that is, if there are chiral isomers in the chemical structure, the bond Can be or or include both and Two configurations, Indicates the presence of axial chirality.

[0265] key indicates unspecified configuration, including cis (E) or trans (Z) configuration.

[0266] In addition, the compounds and intermediates of the present application can also exist in different tautomeric forms, and all such forms are included in the scope of the application. "Tautomers" refer to structural isomers of different energies that can be interconverted via low energy barriers. For example, proton tautomers (also referred to as prototransfer tautomers) include interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactim isomerization. All tautomeric forms of all compounds in the present application are within the scope of the present application. The name of the compound named in a single manner does not exclude any tautomer.

[0267] The present application also includes isotopically labeled compounds of the present application having the same structure as described herein, but with one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0268] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to be deuterium with an abundance of at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). In the example, the compound has an abundance of at least 1000 times greater than the natural abundance of deuterium, at least 2000 times greater than the natural abundance of deuterium, at least 3000 times greater than the natural abundance of deuterium, at least 4000 times greater than the natural abundance of deuterium, at least 5000 times greater than the natural abundance of deuterium, at least 6000 times greater than the natural abundance of deuterium or more. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated compounds with reference to the relevant literature. In preparing deuterated forms of the compounds, commercially available deuterated starting materials may be used, or they may be synthesized using conventional techniques with deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0269] As used herein, a "therapeutically effective amount" refers to the amount of an active compound or drug that is sought by researchers, veterinarians, physicians, or other clinicians to elicit a biological or medical response in a tissue, system, animal, individual, or human, including one or more of the following: (1) preventing disease: for example, preventing a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but has not yet experienced or developed the pathology or symptoms of the disease. (2) inhibiting disease: for example, 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: for example, 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. For drugs or pharmacologically active agents, a "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. The determination of an effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in an individual case can be determined by a person skilled in the art based on routine experiments.

[0270] The term "pharmaceutically acceptable" in this application means that these compounds, materials, compositions and / or dosage forms are, within the scope of reasonable medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, have a reasonable benefit / risk ratio, and are effective for the intended use.

[0271] The term "patient" as used herein refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans. Beneficial effects

[0272] The present application provides a small molecule compound that can be used as a complement factor B inhibitor. This type of compound or pharmaceutical composition can be used to effectively treat or prevent diseases mediated by complement factor B. Compounds of this type of structure have good biological activity.

[0273] Definitions and Explanations of Terms

[0274] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0275] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms (C 1-6 Alkyl). Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched chain isomers thereof. Alkyl groups can be substituted or unsubstituted.

[0276] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20) carbon atoms (i.e., C 1-20 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably an alkylene containing 1 to 6 carbon atoms (i.e., C 1-6Alkylene). Non-limiting examples of alkylene include, but are not limited to, methylene (—CH—), 1,1-ethylene (—CH(CH)—), 1,2-ethylene (—CHCH)—, 1,1-propylene (—CH(CHCH)—), 1,2-propylene (—CHCH(CH)—), 1,3-propylene (—CHCHCHCH—), and 1,4-butylene (—CHCHCHCHCH—). Alkylene may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0277] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined herein. Preferred alkoxy groups (C 1-12 Alkoxy), more preferably an alkoxy containing 1 to 6 carbon atoms (C 1-6 Alkoxy). Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, and butoxy. Alkoxy can be substituted or unsubstituted.

[0278] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring may contain 3 to 20 carbon atoms (i.e., a 3-20 membered cycloalkyl or C 3-20 cycloalkyl), preferably containing 3 to 12 carbon atoms (i.e. 3-12 membered cycloalkyl or C 3-12 cycloalkyl) or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms (i.e., 3-8 membered cycloalkyl or C 3-8 cycloalkyl), more preferably containing 3 to 6 carbon atoms (i.e. 3-6 membered cycloalkyl or C 3-6 Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.

[0279] The term " spiroalkyl " refers to 5 to 20 yuan, a polycyclic group sharing a carbon atom (claiming spiral atom) between each monocycle in the system, which can contain one or more double bonds. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of shared spiral atoms between ring and ring, spiroalkyl is divided into single spiroalkyl, double spiroalkyl or multiple spiroalkyl, preferably single spiroalkyl and double spiroalkyl. More preferably, it is 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiroalkyl. Non-limiting examples of spiroalkyl include:

[0280] Term " fused cycloalkyl " refers to 5 to 20 yuan, and each ring in the system shares the full carbon polycyclic group of a pair of carbon atoms adjacent to other rings in the system, and wherein one or more rings can contain one or more double bonds.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (such as 7,8,9 or 10 yuan).Can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl according to the number of composition ring, preferably bicyclic or tricyclic, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan bicyclic alkyl.Non-limiting examples of fused cycloalkyl include:

[0281] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic, or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0282] The cycloalkyl ring includes a cycloalkyl group as described herein (including monocyclic, spirocyclic, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples of which include etc.; preferred The cycloalkyl group may be substituted or unsubstituted.

[0283] The term "heterocyclyl" or "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, wherein the sulfur may be optionally oxoed (i.e., forming a sulfoxide or sulfone), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3 and 4) are heteroatoms; more preferably, it contains 3 to 8 (e.g., 3, 4, 5, 6, 7 and 8) ring atoms, of which 1 to 3 (e.g., 1, 2 and 3) are heteroatoms; more preferably, it contains 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; and most preferably, it contains 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spiro, fused, and bridged heterocyclyls.

[0284] The term "spiro heterocyclic radical" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of shared spiral atoms between rings, spiro heterocyclic radicals are divided into monospiro heterocyclic radicals, dispiro heterocyclic radicals or polyspiro heterocyclic radicals, preferably monospiro heterocyclic radicals and dispiro heterocyclic radicals. It is more preferably 3 / 5 members, 3 / 6 members, 4 / 4 members, 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members monospiro heterocyclic radicals. Non-limiting examples of spiro heterocyclic radicals include:

[0285] The term "fused heterocyclic radical" refers to 5 to 20 yuan, and each ring in the system shares a polycyclic heterocyclic group of a pair of atoms adjacent to other rings in the system, and one or more rings can contain one or more double bonds, wherein one or more annular atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulphur can be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining annular atoms are carbon. Preferably, it is 6 to 14 yuan, and more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of the composition ring, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic radicals, preferably bicyclic or tricyclic, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan bicyclic fused heterocyclic radicals. The limiting examples of fused heterocyclic radicals include:

[0286] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, wherein any two rings share two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, wherein the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0287] The heterocyclyl ring includes a heterocyclyl as described herein (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic rings) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0288] The heterocyclic group may be substituted or unsubstituted.

[0289] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described herein fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

[0290] Aryl groups can be substituted or unsubstituted.

[0291] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5-membered or 6-membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes a heteroaryl as described herein fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0292] Heteroaryl groups can be substituted or unsubstituted.

[0293] The terms "alkyl", "alkoxy", "cycloalkyl", "heterocyclyl", "aryl" and "heteroaryl" and the like herein may be substituted or unsubstituted; when substituted, they may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more identical or different substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0294] The above-mentioned cycloalkyl, heterocyclic, aryl and heteroaryl groups include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same or two different ring atoms of the parent by removing two hydrogen atoms, i.e., "divalent cycloalkyl", "divalent heterocyclic", "arylene" and "heteroarylene".

[0295] The term "amino-protecting group" refers to an easily removable group introduced onto an amino group to maintain the amino group intact while reacting other sites of a compound. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), acetyl, p-toluenesulfonyl (Ts), benzyl, allyl, and p-methoxybenzyl. These groups may optionally be substituted with one to three substituents selected from halogen, alkoxy, and nitro.

[0296] The term "cycloalkyloxy" refers to a cycloalkyl-O- group wherein cycloalkyl is as defined herein.

[0297] The term "heterocyclyloxy" refers to a heterocyclyl-O- group wherein heterocyclyl is as defined herein.

[0298] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined herein.

[0299] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined herein.

[0300] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined herein.

[0301] The term "halogen" refers to F, Cl, Br or I.

[0302] The term "hydroxy" refers to -OH.

[0303] The term "amino" refers to -NH2.

[0304] The term "cyano" refers to -CN.

[0305] The term "nitro" refers to -NO2.

[0306] The term "oxo" or "oxo" refers to "=0".

[0307] The term "carbonyl" refers to C=O.

[0308] The term "carboxy" refers to -C(O)OH.

[0309] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined herein.

[0310] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not. For example, "a heterocycloalkyl group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocycloalkyl group is substituted with an alkyl group and instances where the heterocycloalkyl group is not substituted with an alkyl group.

[0311] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently replaced by a corresponding number of substituents. When there is a variable group on the ring, when the variable group is optionally CH, it should be understood that C here can also be substituted, for example, in formula (IIG), when X or Y is CH, R 4 It is understood that substitutions are only possible at their chemical positions, and a person skilled in the art will be able to determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond. DETAILED DESCRIPTION

[0312] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative 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 encompassed within the scope of protection that the present invention is intended to protect.

[0313] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0314] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker ASCEND TMThe spectra were analyzed using a 400 nm NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard. MS measurements were performed using Agilent 6110, Agilent 1100, Agilent 6120, and Agilent G6125B liquid chromatography-mass spectrometers.

[0315] HPLC determination was performed using a Shimadzu HPLC-2010C high pressure liquid chromatograph (XBRIDGE 2.1*50 mm, 3.5 μm column).

[0316] Chiral HPLC analysis was performed using THARSFC X5.

[0317] The thin layer chromatography silica gel plate used was Yantai Qingdao GF254 silica gel plate. The specifications of the silica gel plate used in thin layer chromatography (TLC) were 0.15 mm to 0.2 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0318] Column chromatography generally uses Qingdao Marine Silica Gel 200-300 mesh silica gel as the carrier.

[0319] High performance liquid phase preparation was performed using Waters 2767, Waters 2545, and Chuangxin Hengtong LC3000 preparative chromatographs.

[0320] Chiral preparative column chromatography was performed using Shimadzu LC-20AP and THARSFC PREP 80.

[0321] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0322] The pressurized hydrogenation reaction used a Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.

[0323] A Biotage initiator+ microwave reactor was used for the microwave reaction.

[0324] Unless otherwise specified in the experimental examples, all reactions were carried out under an argon or nitrogen atmosphere.

[0325] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 liter.

[0326] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1 liter.

[0327] Unless otherwise specified in the experimental examples, the reaction temperature was room temperature, which ranged from 20°C to 30°C.

[0328] Those skilled in the art will understand that the chiral compounds that have been separated can be distinguished by the order of their retention times in the chiral chromatographic column. Therefore, the chiral compounds separated according to the order of their retention times are distinguished by corresponding numbering suffixes such as P1 and P2. That is, for example, suffix P1 corresponds to a chiral compound with a certain chiral structure that is eluted from the chiral chromatographic column earlier, and suffix P2 corresponds to a chiral compound with a certain chiral structure that is eluted from the chiral chromatographic column later. If the absolute configuration of a compound is listed in the structural formula, it does not mean that it directly corresponds to the compounds with the numbering suffixes P1 and P2, but is only an illustration of two forms of existence of the absolute configuration. The absolute configuration of the compounds with the numbering suffixes P1 and P2 shall be based on the objectively corresponding absolute configuration marked by the specific retention time.

[0329] The reagent names corresponding to the English abbreviations of the reagents are:

[0330] Example

[0331] Synthesis of intermediate compound A1

[0332] Step 1: Synthesis of Compound A1-2

[0333] To a 250 mL single-necked flask, dichloromethane (50 mL), compound A1-1 (3 g), Boc anhydride (5.68 g), 4-dimethylaminopyridine (227 mg), and triethylamine (2.26 g) were added sequentially, and the reaction was carried out at room temperature for 16 hours. After completion of the reaction, the reaction solution was quenched with saturated ammonium chloride solution (5 mL), extracted three times with dichloromethane (20 mL), and the combined organic phases were washed with water (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound A1-2 (4.6 g, yield: 94%). MS m / z (ESI): 262.0 [M+1] + .

[0334] Step 2: Synthesis of Compound A1

[0335] To a 250 mL single-necked flask, dichloromethane (80 mL), N-methylformanilide (3.8 g) and oxalyl chloride (3.6 g) were added in sequence, and the reaction was stirred at room temperature for 3 hours. The reaction temperature was then lowered to -14°C, compound A1-2 (2.5 g) was added, and the reaction system was naturally warmed to room temperature and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into ice water (100 mL), extracted three times with dichloromethane (100 mL), and the combined extracts were washed twice with water (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound A1 (1.3 g, yield: 47%). MS m / z (ESI): 290.0 [M+1] + . 1 H NMR (400MHz, CDCl3) δ 10.65 (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).

[0336] Synthesis of intermediate compound A2

[0337] Step 1: Synthesis of compound A2-1

[0338] Sodium borohydride (392 mg, 10.4 mmol) was added to a solution of compound A1 (1.5 g, 5.18 mmol) in methanol (15 mL) at 0°C, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding water (10 mL) and extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 10-1 / 2) to obtain compound A2-1 (1.1 g, yield 72.8%). MS m / z (ESI): 274.05 [M-17] + .

[0339] Step 2: Synthesis of Compound A2

[0340] (Chloromethylene)dimethylammonium chloride (879 mg, 6.87 mmol) was added to a solution of compound A2-1 (1.1 g, 3.78 mmol) in dichloromethane (25 mL). The reaction mixture was stirred at room temperature for 1 hour under nitrogen. After completion, saturated sodium bicarbonate (10 mL) was added to the reaction solution, which was then extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated sodium chloride (10 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield compound A2 (1.23 g, crude product). The crude product was used directly in the next reaction.

[0341] Example 1 (Compound 1)

[0342] Step 1: Synthesis of compound 1a

[0343] Potassium tert-butoxide (16.3 mL, 16.3 mmol) was added to a solution of methyltriphenylphosphonium bromide (5.84 g, 16.3 mmol) in THF (100 mL) at 0°C. The mixture was stirred at 30°C for 30 minutes, then cooled to 0°C. A solution of compound B1 (2 g, 5.4 mmol, CAS: 2408761-20-4) in THF (20 mL) was added, and the reaction mixture was stirred at 0°C for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, the residue was diluted with water (100 mL), extracted with ethyl acetate (100 mL x 3), and the combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1 to 5 / 1) to afford compound 1a (1.17 g, 58.8% yield). MS m / z (ESI): 366.3 [M+1] + .

[0344] Step 2: Synthesis of compound 1b

[0345] At room temperature, a solution of trichloroacetyl chloride (24.5 g, 0.13 mmol) in DME (30 mL) was slowly added dropwise to a solution of compound 1a (3.26 g, 8.93 mmol) and zinc copper reagent (17.3 g, 0.13 mmol) in DME (90 mL). The reaction mixture was stirred at 30°C for 3 hours. After completion of the reaction, the reaction solution was quenched with saturated sodium bicarbonate solution, the mixture was filtered, and the filtrate was extracted with ethyl acetate (100 mL x 3). The combined organic phases were concentrated under reduced pressure to give compound 1b (4.3 g, crude product). MS m / z (ESI): 475.9 [M+1] + .

[0346] Step 3: Synthesis of compound 1c

[0347] Zinc powder (8.70 g, 0.13 mol) was added to a solution of compound 1b (4.3 g, crude product) in acetic acid (100 mL) at room temperature, and the reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was diluted with water (50 mL). The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 5 / 1 to 3 / 1) to provide compound 1c (3.61 g, 99.2% yield over two steps).

[0348] Step 4: Synthesis of compound 1d

[0349] Dibromodifluoromethane (4.44 g, 21.13 mmol) was added to a THF solution (60 mL) at 0°C. The mixture was stirred at 0°C for 10 minutes, followed by the addition of tri(dimethylamino)phosphine (3.40 g, 20.64 mmol). The mixture was stirred at 0°C for another hour, followed by the addition of compound 1c (2.00 g, 4.91 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 40 minutes. Zinc powder (1.30 g, 19.66 mmol) and tri(dimethylamino)phosphine (280 mg, 2.06 mmol) were then added, and the reaction mixture was stirred at 85°C for 7 hours. After completion of the reaction, the reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford compound 1d (1.26 g, 58.1% yield). MS m / z(ESI):442.3[M+1] + .

[0350] Step 5: Synthesis of compound 1e

[0351] TMSI (1.36 g, 6.80 mmol) was added to a solution of compound 1d (600 mg, 1.36 mmol) in DCM (12 mL) at 0°C. The reaction mixture was stirred at room temperature for 4 hours. After completion, the reaction solution was adjusted to pH > 7 with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1 to 20 / 1) to obtain compound 1e (220 mg, yield 52.6%). MS m / z (ESI): 308.2 [M+1] + .

[0352] Step 6: Synthesis of Compound 1f

[0353] Sodium acetate borohydride (580 mg, 2.74 mmol) was added to a solution of compound 1e (210 mg, 0.68 mmol) and compound A1 (297 mg, 1.03 mmol) in THF (3 mL) at room temperature, and the reaction mixture was stirred at 40°C for 16 hours. After completion, the reaction solution was quenched with saturated sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 50 / 1 to 10 / 1) to provide compound 1f (150 mg, yield 37.8%). MS m / z (ESI): 581.5 [M+1] + .

[0354] Step 7: Synthesis of compound 1

[0355] NaOH (48 mg, 1.20 mmol) was added to a mixture of compound 1f (70 mg, 0.12 mmol) in methanol, tetrahydrofuran, and water (1 mL / 1 mL / 1 mL). The reaction mixture was stirred at 40°C for 16 hours. After completion of the reaction, the reaction mixture was adjusted to pH 5 with glacial acetic acid and concentrated under reduced pressure to remove methanol and tetrahydrofuran. The mixture was filtered, and the filter cake was purified by preparative HPLC (column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-70%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to afford compound 1 (19.6 mg, yield: 35.1%). MS m / z (ESI): 467.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ10.82(s,1H),7.96(d,J=8.0Hz,2H),7.67(d,J=7.6Hz,2H),7.25(s,1H),6.65(s,1H),6.46(s,1H),3.7 0(s,3H),3.52(d,J=11.6Hz,1H),3.23-3.12(m,2H),2.66-2.60(m,2H),2.43-2.31(m,6H),2.01-1.93(m,1H),1.78-1.41(m,4H).

[0356] Example 2 (Compound 19)

[0357] Step 1: Synthesis of compound 19a

[0358] At 0°C, dibromodifluoromethane (3.7 g, 17.57 mmol) was added to a THF (50 mL) solution, and the mixture was stirred at 0°C for 10 minutes. Tris(dimethylamino)phosphine (2.8 g, 17.57 mmol) was added, and the mixture was stirred at 0°C for 1 hour. Compound B1 (1.50 g, 4.09 mmol, CAS: 2408761-20-4) was added, and the reaction mixture was slowly warmed to room temperature and stirred at room temperature for 40 minutes. Zinc powder (1.06 g, 16.35 mmol) and tris(dimethylamino)phosphine (168 mg, 1.03 mmol) were then added, and the reaction mixture was stirred at 85°C for 3 hours. After the reaction was complete, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 20 / 1 to 5 / 1) to obtain compound 19a (1.1 g, yield 68.8%). MS m / z (ESI): 402.0 [M+1] + .

[0359] Step 2: Synthesis of compound 19b

[0360] TMSI (2.60 g, 13.06 mmol) was added to a solution of compound 19a (1.05 g, 2.61 mmol) in DCM (30 mL) at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was adjusted to pH > 7 with saturated sodium bicarbonate solution and extracted with ethyl acetate (100 mL x 3). The combined organic phases were purified by silica gel column chromatography (DCM / MeOH = 50 / 1 to 20 / 1) to obtain compound 19b (500 mg, yield 71.2%). MS m / z (ESI): 268.1 [M+1] + .

[0361] Step 3: Synthesis of compound 19c

[0362] Sodium acetate borohydride (635 mg, 3.00 mmol) was added to a solution of compound 19b (200 mg, 0.75 mmol) and compound A1 (325 mg, 1.12 mmol) in THF (3 mL) at room temperature, and the reaction mixture was stirred at 40°C for 16 hours. After completion, the reaction solution was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (30 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 50 / 1 to 10 / 1) to provide compound 19c (110 mg, yield 27.2%). MS m / z (ESI): 541.3 [M+1] + .

[0363] Step 4: Synthesis of compound 19

[0364] NaOH (74 mg, 1.85 mmol) was added to a mixture of compound 19c (100 mg, 0.19 mmol) in methanol, tetrahydrofuran, and water (1 mL / 1 mL / 1 mL). The reaction mixture was stirred at 40°C for 16 hours. After completion, the reaction solution was adjusted to pH 5 with glacial acetic acid and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-50%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to afford compound 19 (54.8 mg, yield: 69.4%). MS m / z (ESI): 427.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ10.84(s,1H),7.98(d,J=8.0Hz,2H),7.69(d,J=8.4Hz,2H),7.26(t,J=3.0Hz,1H),6.66(s,1H),6.45(t,J=2.2 Hz,1H),3.71(s,3H),3.57-3.31(m,1H),3.30-3.17(m,2H),2.87-2.82(m,1H),2.43-2.35(m,4H),2.27-2.14(m,2H),2.01-1.96(m,2H).

[0365] Example 3 (Compound 22 and Compound 23)

[0366] Step 1: Synthesis of compound 22a

[0367] Diethylzinc (4.1 mL, 8.17 mmol) was added to a solution of compound B1 (1 g, 2.72 mmol, CAS: 2408761-20-4), tribromofluoromethane (2.20 g, 8.17 mmol), and triphenylphosphine (2.10 g, 8.17 mmol) in THF (60 mL) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, MeOH (20 mL) was added and stirred for 30 minutes. The mixture was then diluted with water (60 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 40 / 1 to 10 / 1) to afford compound 22a (1.25 g, 96.2% yield, mixture of E and Z forms). MS m / z (ESI): 462.1 [M+1] + .

[0368] Step 2: Synthesis of compound 22b

[0369] At room temperature, xantphos-Pd-G2 (213 mg, 0.24 mmol, CAS: 1375325-77-1) and Pd2(dba)3 (220 mg, 0.24 mmol) were added to a mixture of compound 22a (1.10 g, 2.38 mmol, a mixture of E and Z forms), methylboronic acid (429 mg, 7.14 mmol), and sodium carbonate (505 mg, 4.76 mmol) in DMF and water (40 mL / 10 mL). The reaction mixture was stirred at 80°C for 6 hours. After completion of the reaction, the reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 40 / 1-10) to afford compound 22b (200 mg, 21.1% yield, a mixture of E and Z forms). MS m / z (ESI): 398.3 [M+1] + .

[0370] Step 3: Synthesis of compound 22c

[0371] TMSI (272 mg, 1.86 mmol) was added to a solution of compound 22b (470 mg, 1.18 mmol, a mixture of E and Z forms) in DCM (10 mL) at 0°C. The reaction mixture was stirred at 0°C for 2 hours. After completion of the reaction, the pH of the reaction solution was adjusted to >7 with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL x 3). The combined organic phases were purified by silica gel column chromatography (DCM / MeOH = 50 / 1 to 20 / 1) to give compound 22c (130 mg, yield 41.8%, a mixture of E and Z forms). MS m / z (ESI): 264.2 [M+1] + .

[0372] Step 4: Synthesis of compound 22d

[0373] Sodium acetate borohydride (388 mg, 1.83 mmol) was added to a solution of compound 22c (120 mg, 0.46 mmol, a mixture of E and Z forms) and compound A1 (199 mg, 0.69 mmol) in THF (2 mL) at room temperature. The reaction mixture was stirred at 40°C for 16 hours. After completion, the reaction solution was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (30 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 20 / 1 to 5 / 1) to afford compound 22d (110 mg, 44.9% yield, a mixture of E and Z forms) as a white solid. MS m / z (ESI): 537.4 [M+1] +Chiral HPLC: retention time 4.814 min, 5.510 min.

[0374] Step 5: Synthesis of Compound 22 and Compound 23

[0375] NaOH (74 mg, 1.86 mmol) was added to a mixture of compound 22d (100 mg, 0.19 mmol, a mixture of E and Z forms) in methanol, tetrahydrofuran, and water (1 mL / 1 mL / 1 mL). The reaction mixture was stirred at 40°C for 16 hours. After completion of the reaction, the pH of the reaction solution was adjusted to 5 with glacial acetic acid. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-70%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compounds 22 and 23 (36.5 mg, yield 46.2%, a mixture of E and Z forms). MS m / z (ESI): 423.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ10.83(s,1H),7.98(d,J=8.0Hz,2H),7.72-7.66(m,2H),7.26(s,1H),6.65(s,1H),6.44(s,1H),3.7 0(s,3H),3.58-3.52(m,1H),3.20-3.15(m,2H),2.87-2.65(m,2H),2.43-2.30(m,4H),2.21-2.15(m,1H),2.01-1.72(m,5H).

[0376] Example 4 (Compound 26 and Compound 27)

[0377] Step 1: Synthesis of compound 26a

[0378] At room temperature, triphenylphosphine (372 mg, 1.42 mmol) was added to a solution of compound 1a (2.59 g, 7.09 mmol), (difluoromethyl)triphenylphosphine bromide (5.0 g, 12.76 mmol), and tris(2-phenylpyridine)iridium (232 mg, 0.35 mmol) in DMA (70 mL). The reaction mixture was stirred for 24 hours under blue light (AC220V, 450-460 nm, Xuzhou Aijia Electronic Technology Co., Ltd.). After completion of the reaction, the reaction solution was diluted with water (400 mL) and extracted with ethyl acetate (400 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 40 / 1 to 10 / 1) to afford compound 26a (2.50 g, 84.5% yield, mixed E and Z forms). MS m / z (ESI): 416.2 [M+1] + .

[0379] Step 2: Synthesis of compound 26b

[0380] TMSI (6 g, 30.05 mmol) was added to a solution of compound 26a (2.50 g, 6.01 mmol, a mixture of E and Z forms) in DCM (50 mL) at 0°C, and the reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction solution was adjusted to pH > 7 with saturated sodium bicarbonate solution and extracted with ethyl acetate (200 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1 to 20 / 1) to obtain compound 26b (1.10 g, yield 65.1%, a mixture of E and Z forms). MS m / z (ESI): 282.1 [M+1] + .

[0381] Step 3: Synthesis of compound 26c

[0382] At room temperature, sodium borohydride acetate (3.30 g, 15.66 mmol) was added to a solution of compound 26b (1.10 g, 3.91 mmol, a mixture of E and Z forms) and compound A1 (1.70 g, 5.87 mmol) in THF (20 mL). The reaction mixture was stirred at 40°C for 16 hours. After completion of the reaction, the reaction solution was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (40 mL × 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 50 / 1 to 10 / 1) to obtain compound 26c (75 mg, yield 3.5%, a mixture of E and Z forms). MS m / z (ESI): 555.4 [M+1] + Chiral HPLC: retention time 4.822 min, 4.963 min.

[0383] Step 4: Synthesis of Compound 26 and Compound 27

[0384] NaOH (54 mg, 1.35 mmol) was added to a mixture of compound 26c (75 mg, 0.14 mmol, a mixture of E and Z forms) in methanol, tetrahydrofuran, and water (1 mL / 1 mL / 1 mL). The reaction mixture was stirred at 40°C for 16 hours. After completion of the reaction, the pH of the reaction solution was adjusted to approximately 5 with glacial acetic acid. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 25-70%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compounds 26 and 27 (24.2 mg, yield 40.3%, a mixture of E and Z forms). MS m / z (ESI): 441.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ10.84(s,1H),8.01-7.97(m,2H),7.73-7.68(m,2H),7.26(s,1H),6.92-6.53(m,2H),6.42(s,1H),5. 52-5.40(m,1H),3.71(s,3H),3.58-3.51(m,1H),3.40-3.17(m,2H),2.92-2.57(m,2H),2.43-2.30(m,4H),2.29-1.93(m,3H).

[0385] Example 5 (Compound 28 and Compound 29)

[0386] Step 1: Synthesis of compound 28a

[0387] Palladium on carbon (150 mg, 10%) was added to a mixture of compound B1 (1.5 g, 4.08 mmol) in tetrahydrofuran and ethyl acetate (8.0 mL / 8.0 mL). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. After completion of the reaction, the reaction mixture was filtered, the filter cake was washed with glacial ethyl acetate (20 mL), and the filtrate was concentrated under reduced pressure to obtain compound 28a (0.9 g, yield 94.5%). MS m / z (ESI): 252.10 [M+19] + .

[0388] Step 2: Synthesis of compound 28b

[0389] Compound A2 (1.08 g, 3.49 mmol), potassium iodide (1.16 g, 6.97 mmol), and cesium carbonate (4.54 g, 13.9 mmol) were added sequentially to a solution of compound 28a (900 mg, 3.83 mmol) in N,N-dimethylformamide (35.0 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with water (40 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 10-1 / 2) to obtain compound 28b (1.38 g, yield 78.2%). MS m / z (ESI): 525.10 [M+19] + .

[0390] Step 3: Synthesis of compound 28c

[0391] Methylhydroxylamine hydrochloride (217 mg, 2.61 mmol) was added to a solution of compound 28b (660 mg, 1.3 mmol) and triethylamine (264 mg, 2.61 mmol) in methanol (8.0 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was diluted with water (5 mL) and extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 28c (660 mg, crude product, mixed E and Z forms). MS m / z (ESI): 536.10 [M+1] +

[0392] Step 4: Synthesis of Compound 28 and Compound 29

[0393] Lithium hydroxide monohydrate (94.0 mg, 2.24 mmol) was added to a mixture of compound 28c (400 mg, 0.747 mmol, a mixture of E and Z forms) in methanol and water (6.0 mL / 1.5 mL). The reaction mixture was stirred at 60°C for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (preparative column: YMC Triart C18, 30*250 mm; flow rate: 40 mL / min, column temperature: room temperature; mobile phase: A: water (0.1% ammonia-water) B: preparative acetonitrile) to obtain compound 28 (or compound 29) (37.5 mg, yield 11.9%) and compound 29 (or compound 28) (50.1 mg, yield 15.9%).

[0394] Compound 28 (or Compound 29):

[0395] MS m / z(ESI):422.10[M+1] + HPLC: retention time 14.857 min, UV=223 nm. 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),7.97(d,J=8.0Hz,2H),7.67(d,J=8.0Hz,2H),7.26(s,1H),6.66(s,1H),6.46(s,1H),3.71(s,6 H),3.58(d,J=12Hz,1H),3.39-3.35(m,1H),3.28-3.24(m,1H),3.09–3.05(m,1H),2.90-2.86(m,1H),2.42(s,3H),2.22–2.10(m,4H).

[0396] Compound 29 (or Compound 28):

[0397] MS m / z(ESI):422.10[M+1] + HPLC: retention time 14.953 min, UV=223 nm. 1 H NMR(400MHz, DMSO-d6)10.86(s,1H),8.00(d,J=8.0Hz,2H),7.70(d,J=8.0Hz ,2H),7.32–7.26(m,1H),6.68(s,1H),6.48–6.44(m,1H),3.73(d,J=1.2Hz,6 H),3.59(d,J=12Hz,1H),3.47–3.44(m,1H),3.30-3.25(m,1H),2.92-2.85(m ,2H),2.44(s,3H),2.39–2.29(m,2H),2.12-2.07(m,1H),1.96–1.88(m,1H).

[0398] Example 6 (Compound 30 and Compound 31)

[0399] Step 1: Synthesis of compound 30a

[0400] Ethylhydroxylamine hydrochloride (223 mg, 2.29 mmol) was added to a solution of compound 28b (580 mg, 1.14 mmol) and triethylamine (232 mg, 2.29 mmol) in methanol (6.0 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was diluted with water (5 mL) and extracted with dichloromethane (10 mL×3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 10-1 / 2) to give compound 30a (568 mg, yield 90.26%, mixture of E and Z forms). Compound 30a (568 mg, mixed E and Z forms) was separated by chiral preparative chromatography (preparative column: CHIRAL ART Amylose-C NEO, 30*250 mm; flow rate: 30 mL / min, column temperature: room temperature; mobile phase: A: n-hexane B: 17% ethanol) to give compound 30a-P1 (230 mg, yield 34.3%), MS m / z (ESI): 550.15 [M+1] + Chiral HPLC: retention time 7.362 min, UV = 220 nm and compound 30a-P2 (240 mg, yield 35.8%), MS m / z (ESI): 550.15 [M+1] + , Chiral HPLC: retention time 10.590 min, UV=220 nm.

[0401] Step 2: Synthesis of Compounds 30 and 31

[0402] Lithium hydroxide monohydrate (52.6 mg, 1.26 mmol) was added to a mixture of methanol and water (3.0 mL / 1.0 mL) of compound 30a-P1 (230 mg, 0.418 mmol). The reaction mixture was stirred at 60°C for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (preparative column: YMC Triart C18, 30*250 mm; flow rate: 40 mL / min, column temperature: room temperature; mobile phase: A: water (0.1% ammonia-water) B: preparative acetonitrile) to obtain compound 30 (or compound 31) (128.7 mg, yield 70.6%). MS m / z (ESI): 436.10 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ10.84 (s, 1H), 7.99–7.94 (m, 2H), 7.65 (d, J = 8.0Hz, 2H),7.26(t,J=2.8Hz,1H),6.66(s,1H),6.48–6.42(m,1H),4.00-3.93(m,2H ),3.71(s,3H),3.59(d,J=12.0Hz,1H),3.39–3.34(m,2H),3.10–3.04(m,1H ), 2.90-2.85 (m, 1H), 2.42 (s, 3H), 2.23-2.12 (m, 4H), 1.15 (t, J = 7.2Hz, 3H).

[0403] Lithium hydroxide monohydrate (55.0 mg, 1.31 mmol) was added to a mixed solution of compound 30a-P2 (240 mg, 0.436 mmol) in methanol and water (3.0 mL / 1.0 mL). The reaction mixture was stirred at 60°C for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC (preparative column: YMC Triart C18, 30*250 mm; flow rate: 40 mL / min, column temperature: room temperature; mobile phase: A: water (0.1% ammonia water-water) B: preparative acetonitrile) to give compound 31 (or compound 30) (129.1 mg, yield 67.9%), MS m / z (ESI): 436.10 [M+1]. + . 1 H NMR(400MHz,DMSO-d6)δ10.86(d,J=8.8Hz,1H),7.94(t,J=7.6Hz,2H),7.58-7.55 (m,2H),7.25(s,1H),6.65(s,1H),6.43(s,1H),3.97(q,J=7.2Hz,2H),3.71(s,3H ),3.58(d,J=11.2Hz,1H),3.22(d,J=12.0Hz,2H),2.91-2.84(m,2H),2.42(s,3H) ,2.40–2.29(m,2H),2.10–2.02(m,1H),1.93-1.85(m,1H),1.15(t,J=7.2Hz,3H).

[0404] Example 7 (Compound 2 and Compound 3)

[0405] Step 1: Synthesis of compound 2a

[0406] Potassium tert-butoxide (4.5 mL, 4.5 mmol) was added to a solution of (fluoromethyl)triphenylphosphonium tetrafluoroborate (1.70 g, 4.42 mmol) in THF (15 mL) at 0°C. The reaction mixture was stirred at 30°C for 0.5 hours. The mixture was then cooled to 0°C and a solution of compound 1c (600 mg, 1.47 mmol) in THF (3 mL) was added. The reaction mixture was stirred at 0°C for 40 minutes. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 10 / 1 to 5 / 1) to afford compound 2a (369 mg, 59.1% yield, a mixture of E and Z forms). MS m / z (ESI): 424.4 [M+1] + .

[0407] Step 2: Synthesis of compound 2b

[0408] TMSI (946 mg, 4.73 mmol) was added to a DCM solution (10 mL) of compound 2a (400 mg, 0.95 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was adjusted to pH > 7 with saturated sodium bicarbonate solution and extracted with DCM (30 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1 to 10 / 1) to obtain compound 2b (260 mg, 95.2% yield, mixed E and Z forms). MS m / z (ESI): 290.2 [M+1] + .

[0409] Step 3: Synthesis of Compounds 2c-P1 and 2c-P2

[0410] Sodium acetate borohydride (646 mg, 3.04 mmol) was added to a THF solution (4 mL) of compound 2b (220 mg, 0.76 mmol) and compound A1 (330 mg, 1.14 mmol) at room temperature, and the reaction mixture was stirred at 40°C for 16 hours. After completion, the reaction solution was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 20 / 1 to 5 / 1) to provide compound 2c (195 mg, 45.5% yield, a mixture of E and Z forms). Compound 2c (230 mg, combined small test batches) was separated by chiral preparative chromatography [equipment: Gilson GX-281, column: chiralpark IE 250 mm*30 mm 10 μm; mobile phase: Hex / EtOH=95-5; flow rate: 25 mL / min] to give compound 2c-P1 (90 mg, yield 39.1%) and compound 2c-P2 (80 mg, yield 34.8%).

[0411] Compound 2c-P1:

[0412] MS m / z(ESI):563.6[M+1] + Chiral HPLC: retention time 9.95 min, UV = 254 nm.

[0413] Compound 2c-P2:

[0414] MS m / z(ESI):563.6[M+1] + Chiral HPLC: retention time 11.36 min, UV = 254 nm.

[0415] Step 4: Synthesis of Compound 2 and Compound 3

[0416] NaOH (50 mg, 1.25 mmol) was added to a mixture of compound 2c-P1 (70 mg, 0.12 mmol) in methanol, tetrahydrofuran, and water (1 mL / 1 mL / 1 mL). The reaction mixture was stirred at 40°C for 16 hours. After completion of the reaction, the reaction solution was adjusted to pH 5 with glacial acetic acid and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-70%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 2 (or compound 3) (23.1 mg, yield 41.8%). MS m / z (ESI): 449.2 [M+1] + . 1H NMR (400MHz, DMSO-d6): δ10.81(s,1H),7.96(d,J=8.0Hz,2H),7.67(d,J=7.2Hz,2H),7.26-7.23(m,1H),6.75-6.51(m,2H),6.47(s, 1H),3.70(s,3H),3.56-3.50(m,1H),3.24-3.12(m,2H),2.67-2.56(m,2H),2.43-2.27(m,6H),2.02-1.93(m,1H),1.75-1.41(m,4H).

[0417] NaOH (57 mg, 1.42 mmol) was added to a mixture of methanol, tetrahydrofuran, and water (1 mL / 1 mL / 1 mL) of compound 2c-P2 (80 mg, 0.14 mmol). The reaction mixture was stirred at 40°C for 16 hours. After completion of the reaction, the reaction solution was adjusted to pH 5 with glacial acetic acid and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-70%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 3 (or compound 2) (40.8 mg, yield 64.7%). MS m / z (ESI): 449.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ10.81(s,1H),7.96(d,J=8.4Hz,2H),7.67(d,J=7.2Hz,2H),7.26-7.23(m,1H),6.79-6.53(m,2H),6.48-6.44( m,1H),3.70(s,3H),3.56-3.50(m,1H),3.24-3.12(m,2H),2.68-2.51(m,2H),2.49-2.32(m,6H),2.02-1.93(m,1H),1.75-1.39(m,4H).

[0418] Example 8 (Compound 8 and Compound 9)

[0419] Step 1: Synthesis of compound 8a

[0420] Sodium acetate (406 mg, 4.95 mmol) was added to a MeOH solution (15 mL) of compound 1c (650 mg, 1.65 mmol) and methylhydroxylamine hydrochloride (276 mg, 3.30 mmol) at room temperature. The reaction mixture was stirred at 60°C for 16 hours. After completion of the reaction, the reaction solution was cooled to room temperature and diluted with water (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 10 / 1 to 3 / 1) to afford compound 8a (470 mg, 65.3% yield, mixed E and Z forms). MS m / z (ESI): 437.4 [M+1] + .

[0421] Step 2: Synthesis of compound 8b

[0422] Under ice-cooling, TMSI (986 mg, 4.93 mmol) was slowly added dropwise to a DCM solution (10 mL) of compound 8a (430 mg, 0.98 mmol, a mixture of E and Z forms). The reaction mixture was stirred at 30°C for 3 hours. After completion, the reaction mixture was adjusted to pH >7 with sodium bicarbonate solution and extracted with ethyl acetate (20 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Xbridge-C18; 19 x 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 25-75%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to afford compound 8b (70 mg, yield 23.7%, a mixture of E and Z forms). MS m / z (ESI): 274.2 [M+1] + and compound 8c (140 mg, yield 52.4%), MS m / z (ESI): 303.3 [M+1] + .

[0423] Step 3: Synthesis of compound 8d

[0424] Sodium acetate borohydride (168 mg, 0.79 mmol) was added to a THF solution (2 mL) of compound 8b (60 mg, 0.20 mmol, a mixture of E and Z forms) and compound A1 (80 mg, 0.27 mmol) at room temperature. The reaction mixture was stirred at 40°C for 16 hours. After completion of the reaction, ethyl acetate (30 mL) was added to the reaction solution and washed with saturated sodium bicarbonate solution (30 mL × 3). The organic phase was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 25-60%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to afford compound 8d (47 mg, yield: 41.2%), a mixture of E and Z forms. MS m / z (ESI): 576.6 [M+1] + .

[0425] Step 4: Synthesis of Compounds 8 and 9

[0426] NaOH (17.4 mg, 0.43 mmol) was added to a mixture of compound 8d (25 mg, 0.043 mmol, a mixture of E and Z forms) in methanol, tetrahydrofuran, and water (0.3 mL / 0.3 mL / 0.3 mL). The reaction mixture was stirred at 40°C for 24 hours. After completion, the reaction solution was adjusted to pH 6 with acetic acid and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 5-60%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to afford a mixture of compound 8 and compound 9 (16.1 mg, yield 80.0%). MS m / z (ESI): 462.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ10.81 (s, 1H), 7.96 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 7. 2Hz,2H),7.24(t,J=2.8Hz,1H),6.65(s,1H),6.47(s,1H),3.70-3.64(m,6H) ,3.53(d,J=12.0Hz,1H),3.31-3.14(m,3H),2.82-2.75(m,1H),2.68-2.57(m ,3H),2.44(s,3H),1.97-1.95(m,1H),1.68-1.67(m,2H),1.51-1.49(m,2H).

[0427] Example 9 (Compound 10 and Compound 11)

[0428] Step 1: Synthesis of compound 10a

[0429] At room temperature, cesium carbonate (572 mg, 1.76 mmol) and potassium iodide (146 mg, 0.88 mmol) were added sequentially to a solution of compound 8c (120 mg, 0.44 mmol) and compound A2 (176 mg, 0.57 mmol) in DMF (5 mL). The reaction mixture was stirred at 30°C for 3 hours. After completion of the reaction, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 25-70%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to afford compound 10a (80 mg, yield: 33.3%). MS m / z (ESI): 547.5 [M+1] + .

[0430] Step 2: Synthesis of compound 10b

[0431] Sodium acetate (26.8 mg, 0.33 mmol) was added to a MeOH solution (8 mL) of compound 10a (60 mg, 0.11 mmol) and ethylhydroxylamine hydrochloride (21.4 mg, 0.22 mmol) at room temperature. The reaction mixture was stirred at 60°C for 16 hours. After completion of the reaction, the reaction solution was cooled to room temperature and diluted with water (10 mL). Extraction was performed with ethyl acetate (10 mL × 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-70%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to afford compound 10b (40.0 mg, yield 62.5%, mixture of E and Z forms). MS m / z (ESI): 590.6 [M+1] + .

[0432] Step 3: Synthesis of Compounds 10 and 11

[0433] NaOH (17 mg, 0.42 mmol) was added to a mixture of compound 10b (25 mg, 0.042 mmol) in methanol, tetrahydrofuran, and water (0.3 mL / 0.3 mL / 0.3 mL). The reaction mixture was stirred at 40°C for 24 hours. After completion of the reaction, the reaction solution was adjusted to pH 6 with acetic acid and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 5-60%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to afford a mixture of compound 10 and compound 11 (13.0 mg, yield 68.4%). MS m / z (ESI): 476.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ10.81(s,1H),7.96(d,J=8.0Hz,2H),7.68(d,J=7.2Hz,2 H),7.25(t,J=2.8Hz,1H),6.65(s,1H),6.47(t,J=2.4Hz,1H),3.98-3.91(m,2H),3 .73(s,3H),3.53(d,J=12.0Hz,1H),3.22-3.12(m,4H),2.81-2.60(m,3H),2.38(s ,3H),2.00-1.98(m,1H),1.69-1.67(m,2H),1.51-1.49(m,2H),1.18-1.11(m,3H).

[0434] Example 10 (Compound 32-P1)

[0435] Step 1: Synthesis of compound 32a

[0436] Under nitrogen, potassium tert-butoxide solution (6.54 mL, 6.54 mmol) was slowly added to a mixture of trimethylsulfoxide iodide (1.44 g, 6.54 mmol) in THF and DMSO (10 mL / 10 mL). The mixture was stirred at room temperature for 0.5 hours, followed by the addition of a solution of compound B1 (2 g, 5.45 mmol) in DMSO (10 mL). The reaction mixture was stirred at 30°C for 16 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 5 / 1 to 2 / 1) to afford compound 32a (1.81 g, 87.0% yield). MS m / z (ESI): 382.4 [M+1] + .

[0437] Step 2: Synthesis of compound 32b

[0438] Tris(pentafluorophenyl)borane (1.34 g, 2.62 mmol) was added to a solution of compound 32a (1 g, 2.62 mmol) in toluene (20 mL) at room temperature, and the reaction mixture was stirred at 30°C for 16 hours. After completion of the reaction, the reaction solution was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 5 / 1 to 2 / 1) to afford compound 32b (0.81 g, 81.0% yield). MS m / z (ESI): 382.2 [M+1] + .

[0439] Step 3: Synthesis of compound 32c

[0440] At room temperature, (triphenylphosphonium)difluoroacetic acid inner salt (1.50 g, 4.20 mmol) was added to a solution of compound 32b (800 mg, 2.10 mmol) in NMP (15 mL). The reaction mixture was stirred at 40°C for 4 hours. After completion of the reaction, the reaction solution was diluted with aqueous solution (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (50 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 40 / 1 to 5 / 1) to obtain compound 32c (570 mg, yield 65.4%). MS m / z (ESI): 416.4 [M+1] + .

[0441] Step 4: Synthesis of compound 32d

[0442] TMSI (1.30 g, 6.51 mmol) was added to a solution of compound 32c (540 mg, 1.30 mmol) in DCM (10 mL) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was adjusted to pH > 7 with saturated sodium bicarbonate solution and extracted with DCM (30 mL × 3). The crude product was purified by silica gel column chromatography (DCM / MeOH = 50 / 1 to 10 / 1) to obtain compound 32d (340 mg, yield 93.2%). MS m / z (ESI): 282.2 [M+1] + .

[0443] Step 5: Synthesis of compound 32e

[0444] Sodium acetate borohydride (905 mg, 4.27 mmol) was added to a solution of compound 32d (300 mg, 1.07 mmol) and compound A1 (463 mg, 1.60 mmol) in THF (5 mL) at room temperature, and the reaction mixture was stirred at 40°C for 16 hours. After completion of the reaction, the reaction solution was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (30 mL × 3). The crude product was purified by silica gel column chromatography (PE / EA = 20 / 1 to 5 / 1) to obtain compound 32e (440 mg, yield 74.5%). MS m / z (ESI): 555.5 [M+1] + .

[0445] Step 6: Synthesis of compound 32-P1

[0446] NaOH (289 mg, 7.22 mmol) was added to a solution of compound 32e (400 mg, 0.72 mmol) in methanol / tetrahydrofuran / water (4 mL / 4 mL / 4 mL). The reaction mixture was stirred at 40°C for 16 hours. After completion, the reaction mixture was adjusted to pH 5 with glacial acetic acid and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-70%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to afford compound 32-P1 (211.3 mg, yield: 66.4%). MS m / z (ESI): 441.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6): δ10.81(s,1H),7.95(d,J=8.4Hz,2H),7.65(d,J=8 .0Hz,2H),7.27-7.23(m,1H),6.65(s,1H),6.51-6.47(m,1H),5.03-4.90( m,1H),3.71(s,3H),3.61-3.48(m,3H),2.69-2.53(m,2H),2.42(s,3H),2. 35-2.20(m,1H),1.89-1.81(m,1H),1.70-1.58(m,2H),1.46-1.41(m,1H).

[0447] Example 11 (Compounds 33-P1 and 33-P2)

[0448] Step 1: Synthesis of compound 33b

[0449] At 0°C, i-PrMgCl.LiCl (104 mL, 135 mmol) was slowly added to a solution of compound 33a (25 g, 90.5 mmol) in THF (250 mL). The mixture was stirred at room temperature for 2 hours, followed by the addition of 250 mL of THF. The mixture was cooled to -30°C, and 4-methoxypyridine (14.8 g, 135 mmol) and Cbz-Cl (22.9 g, 135 mmol) were added sequentially. The reaction mixture was stirred at -30°C for 1 hour. After completion of the reaction, the reaction solution was quenched with water (100 mL), adjusted to pH 5 with 6N hydrochloric acid, and extracted with ethyl acetate (200 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 3 / 1) to afford compound 33b (21.5 g, 62.7% yield). MS m / z (ESI): 380.2 [M+1] + .

[0450] Step 2: Synthesis of compound 33c

[0451] Zinc powder (36 g, 0.55 mol) was added to a solution of compound 33b (21 g, 0.055 mol) in acetic acid (200 mL) at room temperature, and the reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was added with ethyl acetate (200 mL) and washed with saturated sodium bicarbonate solution (100 mL × 3). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 3 / 1) to obtain compound 33c (16 g, yield 76.2%). MS m / z (ESI): 382.3 [M+1] + .

[0452] Step 3: Synthesis of compound 33d

[0453] Under nitrogen, potassium tert-butoxide solution (7.87 mL, 7.87 mmol) was slowly added to a mixture of trimethylsulfoxide iodide (1.73 g, 7.87 mmol) in THF and DMSO (20 mL / 20 mL). The mixture was stirred at room temperature for 1 hour, followed by the addition of a solution of compound 33c (2 g, 5.25 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to afford compound 33d (1.1 g, 53.1% yield). MS m / z (ESI): 396.4 [M+1] + .

[0454] Step 4: Synthesis of compound 33e

[0455] Tris(pentafluorophenyl)borane (3.44 g, 6.72 mmol) was added to a solution of compound 33d (2.41 g, 6.11 mmol) in toluene (50 mL) at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After completion, the reaction solution was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to afford compound 33e (1.37 g, 56.8% yield). MS m / z (ESI): 396.3 [M+1] + .

[0456] Step 5: Synthesis of compound 33f

[0457] Compound 33e (3.35 g, 8.48 mmol) was added to a solution of (triphenylphosphonium) difluoroacetic acid inner salt (6.04 g, 16.96 mmol) in NMP (35 mL). The reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, the reaction solution was diluted with water (500 mL) and extracted with EA (100 mL x 3). The combined organic phases were concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to obtain compound 33f (1.23 g, 33.8% yield, trans). MS m / z (ESI): 430.4 [M+1] + .

[0458] Step 6: Synthesis of compound 33g

[0459] TMSI (1.17 g, 5.82 mmol) was added to a solution of compound 33f (500 mg, 1.17 mmol, trans) in dichloromethane (20 mL) at 0°C, and the reaction mixture was stirred at 0°C for 2 hours. After completion of the reaction, the pH of the reaction solution was adjusted to acidic with dilute hydrochloric acid and extracted with petroleum ether. The aqueous phase was made alkaline with saturated sodium bicarbonate solution and extracted with DCM (30 mL x 3). The combined organic phases were concentrated under reduced pressure to yield compound 33f (0.34 g, 99% yield, trans configuration). MS m / z (ESI): 296.3 [M+1] + .

[0460] Step 7: Synthesis of compounds 33h, 33h-P1 and 33h-P2

[0461] Sodium acetate borohydride (1.02 g, 4.83 mmol) was added to a solution of compound 33g (356 mg, 1.21 mmol, trans) and compound A1 (523 mg, 1.81 mmol) in tetrahydrofuran (10 mL) at room temperature, and the reaction mixture was stirred at 40°C for 16 hours. After completion of the reaction, ethyl acetate (30 mL) was added, and the mixture was washed with saturated sodium bicarbonate solution (10 mL x 3). The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 10 / 1) to provide compound 33h (0.42 g, 61.6% yield, trans configuration). Compound 33h (150 mg, trans configuration) was chirally prepared [equipment: Gilson GX-281, column: chiralpark IG 250 mm*30 mm 10 um; mobile phase: Hex / EtOH=90-10; flow rate: 25 mL / min] and separated to give compound 33h-P1 (70 mg, yield 46.7%) and compound 33h-P2 (65 mg, yield 43.3%).

[0462] 33h-P1:MS m / z(ESI):569.5[M+1] + Chiral HPLC: retention time 4.56 min, UV = 254 nm.

[0463] 33h-P2:MS m / z(ESI):569.5[M+1] + Chiral HPLC: retention time 5.74 min, UV = 254 nm.

[0464] Step 8: Synthesis of compound 33-P1

[0465] NaOH (42 mg, 1.05 mmol) was added to a solution of compound 33h-P1 (60 mg, 0.105 mmol) in methanol / tetrahydrofuran / water (0.6 mL / 0.6 mL / 0.6 mL). The reaction mixture was stirred at 40°C for 16 hours. After completion, the reaction mixture was adjusted to pH 5 with AcOH and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-55%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to afford compound 33h-P1 (39.4 mg, yield: 82.1%). MS m / z (ESI): 455.2 [M+1] + . 1H NMR (400MHz, DMSO-d6): δ10.81(s,1H),7.84(q,J=18.8Hz,2H),7.76(s,1H),7.26(t,J=2.8Hz,1 H),6.65(s,1H),6.49(t,J=2.8Hz,1H),5.07-4.97(m,1H),3.71(s,3H),3.70(d,J=2.0Hz,1H),3 .57(d,J=11.6Hz,1H),3.22(d,J=11.6Hz,1H),2.71(s,1H),2.62-2.59(m,1H),2.42(d,J=6.8Hz ,6H),2.26(t,J=12.4Hz,1H),1.76-1.69(m,2H),1.55(d,J=12.4Hz,1H),1.43(d,J=13.2Hz,1H).

[0466] Step 9: Synthesis of compound 33-P2

[0467] NaOH (46 mg, 1.14 mmol) was added to a solution of compound 33h-P2 (65 mg, 0.11 mmol) in methanol / tetrahydrofuran / water (0.6 mL / 0.6 mL / 0.6 mL). The reaction was stirred at 40°C for 16 hours. After completion, the reaction solution was adjusted to pH 5 with AcOH and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-55%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to afford compound 33h-P2 (34.3 mg, yield: 65.9%). MS m / z (ESI): 455.2 [M+1] + . 1H NMR (400MHz, DMSO-d6): δ10.81(s,1H),7.84(q,J=18.8Hz,2H),7.76(s,1H),7.26(t,J=2.8Hz,1 H),6.65(s,1H),6.49(t,J=2.8Hz,1H),5.07-4.97(m,1H),3.71(s,3H),3.70(d,J=2.0Hz,1H),3 .57(d,J=11.6Hz,1H),3.22(d,J=11.6Hz,1H),2.71(s,1H),2.62-2.59(m,1H),2.42(d,J=6.8Hz ,6H),2.26(t,J=12.4Hz,1H),1.76-1.69(m,2H),1.55(d,J=12.4Hz,1H),1.43(d,J=13.2Hz,1H).

[0468] Example 12 (Compound 34-1)

[0469] Step 1: Synthesis of compound 34b

[0470] (-)-1,2-Bis((2R,5R)-2,5-diphenylphosphino)ethane (0.20 g, 0.39 mmol) and bis(ethylene)rhodium acetylacetonate (0.10 g, 0.39 mmol) were added sequentially to a mixture of compound 34a (5.02 g, 23.36 mmol) and benzyl 4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (1.80 g, 7.79 mmol) in tert-amyl alcohol and water (30 mL / 3 mL). The reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, ethyl acetate (50 mL) was added to the reaction solution, which was then washed with water (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to afford compound 34b (2.90 g). MS m / z(ESI):402.1[M+1] + .

[0471] Step 2: Synthesis of compound 34c

[0472] Under nitrogen, potassium tert-butoxide (1.21 g, 10.85 mmol) was slowly added to a mixture of trimethylsulfoxide iodide (2.38 g, 10.85 mmol) in tetrahydrofuran and dimethylsulfoxide (15 mL / 15 mL). The mixture was stirred at room temperature for 0.5 hour, followed by the addition of a solution of compound 34b (2.90 g, 7.23 mmol) in DMSO (5 mL). The reaction mixture was stirred at 26°C for 16 hours. After completion of the reaction, the reaction mixture was poured into ice water (150 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to afford compound 34c (1.20 g). MS m / z (ESI): 416.1 [M+1]. + .

[0473] Step 3: Synthesis of compound 34d

[0474] Tris(pentafluorophenyl)borane (1.48 g, 2.89 mmol) was added to a solution of compound 34c (1.20 g, 2.89 mmol) in toluene (20 mL) at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After completion, the reaction solution was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to obtain compound 34d (1.50 g, crude product). MS m / z (ESI): 416.1 [M+1] + .

[0475] Step 4: Synthesis of compound 34e

[0476] (Triphenylphosphonium) difluoroacetic acid inner salt (1.85 g, 5.20 mmol) was added to a solution of compound 34d (1.08 g, 2.60 mmol) in N-methylpyrrolidone (30 mL). The reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to obtain compound 34e (250 mg). MS m / z (ESI): 450.1 [M+1] + .

[0477] Step 5: Synthesis of compound 34f

[0478] Iodotrimethylsilane (444.7 mg, 2.22 mmol) was added to a solution of compound 34e (250 mg, 0.56 mmol) in dichloromethane (5 mL) at 0°C, and the reaction mixture was stirred at 0°C for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the pH was adjusted to 4-5 with dilute hydrochloric acid. The mixture was washed with petroleum ether (50 mL). The aqueous phase was adjusted to pH 8-9 with saturated sodium bicarbonate solution, and extracted with dichloromethane (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield compound 34f (70 mg). MS m / z (ESI): 316.0 [M+1]. + .

[0479] Step 6: Synthesis of compound 34g

[0480] Compound 34f (60 mg, 0.19 mmol), compound A2 (236.2 mg, 0.76 mmol), cesium carbonate (185.7 mg, 0.57 mmol), and potassium iodide (94.6 mg, 0.57 mmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was quenched with water (5 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases were 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 silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 8:1) to obtain compound 34-1 (50 mg, yield 44.7%). MS m / z (ESI): 589.2 [M+1] + .

[0481] Step 7: Synthesis of compound 34-1

[0482] Sodium hydroxide (47.8 mg, 1.19 mmol) was added to a solution of compound 34g (47 mg, 0.079 mmol) in methanol / tetrahydrofuran / water (1 mL / 1 mL / 1 mL). The reaction mixture was stirred at 40°C for 16 hours. After completion, the reaction solution was adjusted to pH 5 with acetic acid and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gemini 5μm C18 150*21.2 mm; 150*21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonia solution); gradient: 30-60%; column temperature: 25°C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 70 bar) to afford compound 34-1 (5.68 mg). MS m / z (ESI): 475.35 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ10.84(s,1H),7.98-7.86(m,3H),7.26-7.25(m,1H),6.66(s,1H),6.51-6.44(m,1H),4.99-4.37(m,1H),3.92-3. 75(m,1H),3.72(s,3H),3.61–3.56(m,1H),3.24(d,J=11.6Hz,1H),2.79–2.60(m,2H),2.42(s,3H),2.33–2.27(m,1H),1.71–1.28(m,4H).

[0483] Example 13 (Compound 35-P1)

[0484] Step 1: Synthesis of compound 35b

[0485] (-)-1,2-Bis((2R,5R)-2,5-diphenylphosphino)ethane (0.17 g, 0.32 mmol) and bis(ethylene)rhodium acetylacetonate (0.08 g, 0.32 mmol) were added sequentially to a mixture of compound 35a (4.18 g, 19.47 mmol), benzyl 4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (1.5 g, 6.49 mmol), and triethylamine (1.97 g, 19.47 mmol) in tert-amyl alcohol and water (50 mL / 5 mL). The reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate (150 mL), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 5 / 1) to afford compound 35b (2.80 g, crude product). MS m / z(ESI):402.2[M+1] + .

[0486] Step 2: Synthesis of compound 35c

[0487] Under nitrogen, potassium tert-butoxide (0.94 g, 8.37 mmol) was slowly added to a mixture of trimethylsulfoxide iodide (1.85 g, 8.37 mmol) in THF and DMSO (20 mL / 20 mL). The mixture was stirred at room temperature for 0.5 hour, followed by the addition of a solution of compound 35b (2.80 g, 6.98 mmol) in DMSO (5 mL). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was poured into ice water (40 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 20 / 1 to 3 / 1) to afford compound 35c (1.80 g). MS m / z (ESI): 416.2 [M+1]. + .

[0488] Step 3: Synthesis of compound 35d

[0489] Tris(pentafluorophenyl)borane (2.20 g, 4.33 mmol) was added to a solution of compound 35c (1.80 g, 4.33 mmol) in toluene (20 mL) at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 20 / 1 to 3 / 1) to obtain compound 35d (0.90 g). MS m / z (ESI): 416.2 [M+1] + .

[0490] Step 4: Synthesis of compound 35e

[0491] Compound 35d (900 mg, 2.16 mmol) was added to a solution of (triphenylphosphonium) difluoroacetic acid inner salt (1.54 g, 4.32 mmol) in NMP (20 mL). The reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to obtain compound 35e (400 mg). MS m / z (ESI): 450.2 [M+1] + .

[0492] Step 5: Synthesis of compound 35f

[0493] Iodotrimethylsilane (498.8 mg, 3.55 mmol) was added to a solution of compound 35e (400 mg, 0.89 mmol) in dichloromethane (10 mL) at 0°C, and the reaction mixture was stirred at 0°C for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, the pH was adjusted to 4-5 with dilute hydrochloric acid, and the mixture was washed with petroleum ether (10 mL x 2). The aqueous phase was adjusted to pH 8-9 with saturated sodium bicarbonate solution, and extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 35f (200 mg). The crude product was used directly in the next step without purification. MS m / z (ESI): 316.1 [M+1] + .

[0494] Step 6: Synthesis of compound 35g

[0495] At room temperature, sodium triacetoxyborohydride (402.6 mg, 1.90 mmol) was added to a solution of compound 35f (200 mg, 0.63 mmol) and compound A1 (derived from Meiyue) (275.8 mg, 0.95 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at 40°C for 16 hours. After completion of the reaction, the reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were 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 silica gel column chromatography (PE / EA = 1 / 0 to 3 / 1) to obtain compound 35g (95 mg). MS m / z (ESI): 589.3 [M+1] + .

[0496] Step 7: Synthesis of compound 35-P1

[0497] Sodium hydroxide (54.2 mg, 1.35 mmol) was added to a mixture of compound 35g (80 mg, 0.13 mmol) in methanol / tetrahydrofuran / water (3 mL / 3 mL / 3 mL). The reaction mixture was stirred at 40°C for 16 hours. After completion, the reaction mixture was adjusted to pH 5 with acetic acid and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 5%-45%; column temperature: 25°C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to afford 35-P1 (42.5 mg). MS m / z (ESI): 475.3 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ13.25(s,1H),10.84(s,1H),7.79(d,J=8.0Hz,1H),7.72(s,1H),7.53(d ,J=8.4Hz,1H),7.33–7.20(m,1H),6.66(s,1H),6.51–6.38(m,1H),5.06–4.86(m,1H),3.74(s,3H ),3.63(d,J=11.2Hz,1H),3.57–3.44(m,1H),3.30–3.23(m,1H),2.72–2.62(m,1H),2.61–2.53( m,1H),2.42(s,3H),2.33–2.20(m,1H),1.86–1.72(m,1H),1.71–1.53(m,2H),1.49–1.37(m,1H).

[0498] Example 14 (Compound 36-P1)

[0499] Step 1: Synthesis of compound 36b

[0500] (-)-1,2-Bis((2R,5R)-2,5-diphenylphosphino)ethane (0.27 g, 0.54 mmol) and acetylacetonatobis(ethylene)rhodium (0.14 g, 0.54 mmol) were added sequentially to a mixed solution of 4-oxo-3,4-dihydropyridine-1(2H)-carboxylic acid benzyl ester (2.50 g, 10.81 mmol), compound 36a (5.67 g, 27.03 mmol) and triethylamine (3.28 g, 32.43 mmol) in tert-amyl alcohol and water (25 mL / 2.5 mL), and the reaction mixture was stirred at 80 ° C for 10 hours. After the reaction was complete, ethyl acetate (50 mL) was added to the reaction solution, which was then washed with water (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 3 / 1) to obtain compound 36b (4.50 g, crude product). MS m / z (ESI): 397.8 [M+1] + .

[0501] Step 2: Synthesis of compound 36c

[0502] Under nitrogen, potassium tert-butoxide (1.87 g, 16.65 mmol) was slowly added to a mixture of trimethylsulfoxide iodide (3.66 g, 16.65 mmol) in tetrahydrofuran and dimethylsulfoxide (20 mL / 20 mL). The mixture was stirred at room temperature for 1 hour, followed by the addition of a solution of compound 36b (4.40 g, 11.08 mmol) in DMSO (10 mL). The reaction mixture was stirred at room temperature for another 4 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to afford compound 36c (3.70 g). MS m / z (ESI): 411.9 [M+1]. + .

[0503] Step 3: Synthesis of compound 36d

[0504] Tris(pentafluorophenyl)borane (4.90 g, 9.57 mmol) was added to a solution of compound 36c (3.60 g, 8.76 mmol) in toluene (36 mL) at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 5 / 1 to 2 / 1) to give compound 36d (2.45 g). MS m / z (ESI): 411.9 [M+1] + .

[0505] Step 4: Synthesis of compound 36e

[0506] Compound 36d (2.40 g, 5.83 mmol) was added to a solution of (triphenylphosphonium) difluoroacetic acid inner salt (4.13 g, 11.66 mmol) in N-methylpyrrolidone (24 mL). The reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to obtain compound 36e (1.60 g). MS m / z (ESI): 445.9 [M+1]. + .

[0507] Step 5: Synthesis of compound 36f

[0508] Iodotrimethylsilane (2.38 g, 11.90 mmol) was added to a solution of compound 36e (1.50 g, 3.37 mmol) in dichloromethane (16 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction solution was concentrated under reduced pressure at room temperature and the pH was adjusted to 4-5 with dilute hydrochloric acid. The aqueous phase was washed with petroleum ether (30 mL x 2) and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 36f (0.86 g). MS m / z (ESI): 311.7 [M+1]. + .

[0509] Step 6: Synthesis of compound 36g

[0510] Cesium carbonate (1.26 g, 3.85 mmol) and potassium iodide (319.9 mg, 1.92 mmol) were added to a solution of compound 36f (300 mg, 0.96 mmol) and compound A2 (598.9 mg, 1.92 mmol) in N,N-dimethylformamide (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, it was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to obtain compound 36g (150 mg). MS m / z (ESI): 585.1 [M+1] + .

[0511] Step 7: Synthesis of compound 36-P1

[0512] Sodium hydroxide (95.6 mg, 2.39 mmol) was added to a solution of compound 36g (140 mg, 0.24 mmol) in methanol / tetrahydrofuran / water (1 mL / 1 mL / 1 mL). The reaction mixture was stirred at 40°C for 16 hours. After completion, the reaction solution was adjusted to pH 5 with acetic acid and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Xbridge-C18; 19×150 mm, 5 μm; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 20-30%; column temperature: 25°C; flow rate: 25 mL / min; wavelength: 214 nm; column pressure: 50 bar) to afford compound 36-P1 (50.4 mg). MS m / z (ESI): 471.0 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ12.41(s,1H),10.82(s,1H),7.65(d,J=7.6Hz,1H),7.30–7.23(m,2 H),7.15(d,J=7.6Hz,1H),6.65(s,1H),6.56–6.51(m,1H),5.03–4.90(m,1H),3.85(s,3H),3 .70(s,3H),3.63(d,J=12.0Hz,1H),3.49–3.44(m,1H),3.38–3.34(m,1H),2.61–2.54(m,2H ),2.41(s,3H),2.27–2.21(m,1H),1.96–1.82(m,1H),1.71–1.59(m,2H),1.48–1.40(m,1H).

[0513] Example 15 (Compound 37-P1)

[0514] Step 1: Synthesis of compound 37b

[0515] Vinylmagnesium bromide (1.0 M, 86.9 mL, 86.93 mmol) was slowly added dropwise to a solution of compound 37a (5 g, 21.73 mmol) in tetrahydrofuran (100 mL) at -78°C. The reaction mixture was stirred at 0°C for 2 hours. After completion of the reaction, the reaction solution was quenched with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (200 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 80 / 20) to obtain compound 37b (2 g). MS m / z (ESI): 223.9 [M+1] + .

[0516] Step 2: Synthesis of compound 37c

[0517] Di-tert-butyl dicarbonate (7.30 g, 33.47 mmol) and 4-dimethylaminopyridine (0.27 g, 2.23 mmol) were added sequentially to a solution of compound 37b (5 g, 22.31 mmol) in dichloromethane (50 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to afford compound 37c (4.50 g). 1H NMR (400MHz, CDCl3) δ7.51 (d, J = 4.0 Hz, 1H), 6.71 (s, 1H), 6.56 (d, J = 4.0 Hz, 1H), 3.89 (s, 3H), 2.57 (s, 3H), 1.59 (s, 9H).

[0518] Step 3: Synthesis of compound 37d

[0519] Under nitrogen, tributyltinmethanol (1.48 g, 4.61 mmol) and X-Phos Pd G2 (241.6 mg, 0.30 mmol, CAS: 1310584-14-5) were added to a solution of compound 37c (1 g, 3.07 mmol) in 1,4-dioxane (15 mL). The reaction mixture was stirred at 80°C under nitrogen for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 37d (0.40 g). MS m / z (ESI): 258.1 [M-OH] + .

[0520] Step 4: Synthesis of compound 37e

[0521] (Chloromethylene)dimethylammonium chloride (370.5 mg, 2.89 mmol) was added to a dichloromethane solution (10 mL) of compound 37d (400 mg, 1.45 mmol) at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was quenched with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 37e (300 mg, crude product). MS m / z (ESI): 258.1 [M-Cl] + .

[0522] Step 5: Synthesis of compound 37f

[0523] Compound 32d (150 mg, 0.53 mmol), cesium carbonate (694.9 mg, 2.13 mmol), and potassium iodide (177.0 mg, 1.06 mmol) were added to a solution of compound 37e (314.4 mg, 1.06 mmol) in N,N-dimethylformamide (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases were 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 silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 10:1) to obtain compound 37f (100 mg). MS m / z (ESI): 539.2 [M+1] + .

[0524] Step 6: Synthesis of compound 37-P1

[0525] Sodium hydroxide (37.1 mg, 0.93 mmol) was added to a mixture of compound 37f (50 mg, 0.093 mmol) in methanol / tetrahydrofuran / water (1 mL / 1 mL / 1 mL). The reaction mixture was stirred at 40°C for 16 hours. After completion, the reaction solution was adjusted to pH 5 with acetic acid and concentrated under reduced pressure. The residue was purified using a Biotage-Flash instrument (column: C18 reverse phase column, acetonitrile-water (0.1% ammonium bicarbonate); gradient: 5%-35%) to obtain product 37-P1 (25.7 mg). MS m / z (ESI): 425.1 [M+1] + Supercritical fluid chromatography (SFC): retention time = 4.451 min, UV = 254 nm. 1 HNMR (400MHz, DMSO-d6) δ12.79(s,1H),10.84(s,1H),7.95(d,J=8.8Hz,2H),7.63(d,J=8.0 Hz,2H),7.22(t,J=3.0Hz,1H),6.64(s,1H),6.58–6.50(m,1H),5.07–4.88(m,1H),3.59(d, J=12.0Hz,1H),3.55–3.48(m,1H),3.29–3.22(m,1H),2.73–2.60(m,1H),2.48–2.41(m,1H) ,2.36(s,3H),2.30–2.19(m,4H),2.00–1.87(m,1H),1.69–1.55(m,2H),1.49–1.36(m,1H).

[0526] Example 16 (Compound 38-P1)

[0527] Step 1: Synthesis of compound 38b

[0528] Potassium nitrate (7.99 g, 79.57 mmol) was slowly added portionwise to a solution of compound 38a (25 g, 113.76 mmol) in concentrated sulfuric acid (120 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. After the reaction, the reaction mixture was poured into ice water (200 mL), resulting in the precipitation of a precipitate. The mixture was filtered, and the filter cake was washed with water and dried to yield compound 38b (12 g, crude product). 1 H NMR (400MHz, CDCl3) δ8.26 (s, 1H), 6.98 (s, 1H), 3.99 (s, 3H).

[0529] Step 2: Synthesis of compound 38c

[0530] Vinylmagnesium bromide (1.0 M, 108.7 mL, 108.71 mmol) was slowly added dropwise to a solution of compound 38b (7.20 g, 27.17 mmol) in tetrahydrofuran (240 mL) at -78°C. The reaction mixture was stirred at 0°C for 2 hours. After completion, the reaction solution was quenched with water (300 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (200 mL x 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 85 / 15) to obtain compound 38c (1.40 g). MS m / z (ESI): 259.9 [M+1]. + .

[0531] Step 3: Synthesis of compound 38d

[0532] Di-tert-butyl dicarbonate (1.77 g, 8.10 mmol) and 4-dimethylaminopyridine (0.07 g, 0.54 mmol) were added sequentially to a solution of compound 38c (1.40 g, 5.40 mmol) in dichloromethane (20 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 9 / 1) to afford compound 38d (1.80 g). 1 H NMR (400MHz, CDCl3) δ7.58 (d, J = 3.6 Hz, 1H), 6.97 (s, 1H), 6.63 (d, J = 3.6 Hz, 1H), 3.93 (s, 3H), 1.64 (s, 9H).

[0533] Step 4: Synthesis of compound 38e

[0534] Under nitrogen, tributyltinmethanol (2.26 g, 7.10 mmol) and tetrakis(triphenylphosphine)palladium (1.09 g, 0.94 mmol) were added to a solution of compound 38d (1.70 g, 4.73 mmol) in 1,4-dioxane (30 mL). The reaction mixture was stirred at 100°C under nitrogen for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 4:1) to obtain compound 38e (0.65 g). MS m / z (ESI): 294.0 [M-OH] + .

[0535] Step 5: Synthesis of compound 38f

[0536] Under nitrogen, (chloromethylene)dimethylammonium chloride (392.8 mg, 3.07 mmol) was added to a dichloromethane solution (15 mL) of compound 38e (640 mg, 2.05 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was quenched with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 38f (600 mg, crude product). MS m / z (ESI): 293.9 [M-Cl] + .

[0537] Step 6: Synthesis of compound 38g

[0538] Compound 32d (180 mg, 0.64 mmol), cesium carbonate (416.9 mg, 1.28 mmol), and potassium iodide (212.4 mg, 1.28 mmol) were added to a solution of compound 38f (423.9 mg, 1.28 mmol) in N,N-dimethylformamide (15 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a Biotage-Flash instrument (column: C18 reverse phase column, acetonitrile-water (0.1% formic acid), gradient: 5-50%) to afford compound 38g (190 mg). MS m / z (ESI): 575.2 [M+1] + .

[0539] Step 7: Synthesis of compound 38-P1

[0540] Sodium hydroxide (128.4 mg, 3.21 mmol) was added to a solution of compound 38g (185 mg, 0.32 mmol) in methanol / tetrahydrofuran / water (3 mL / 3 mL / 3 mL). The reaction mixture was stirred at 40°C for 16 hours. After completion, the reaction solution was adjusted to pH 5 with acetic acid and concentrated under reduced pressure. The residue was purified using a Biotage-Flash instrument (column: C18 reverse phase column, acetonitrile-water (0.1% ammonium bicarbonate); gradient: 5%-35%) to afford compound 38-P1 (133.7 mg). MS m / z (ESI): 461.0 [M+1] + Supercritical fluid chromatography (SFC): retention time 4.337 min, UV = 214 nm. 1 H NMR (400MHz, DMSO-d6) δ12.83 (s, 1H), 11.20 (s, 1H), 7.95 (d, J = 8.4Hz, 2H), 7.63 (d,J=7.9Hz,2H),7.35(t,J=2.8Hz,1H),6.94(s,1H),6.61-6.60(m,1H),5.04–4 .94(m,1H),3.74(s,3H),3.59-3.50(m,2H),3.34–3.31(m,2H),2..72-2.64(m,1 H),2.30-2.24(m,1H),1.89-1.83(m,1H),1.67-1.59(m,2H),1.46-1.42(m,1H).

[0541] Example 17 (Compound 39-P1)

[0542] Step 1: Synthesis of Compound A3-1

[0543] Boron tribromide (12.08 g, 48.22 mmol) was added to a solution of compound A3 (7 g, 24.11 mmol) in dichloromethane (140 mL) at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. After completion, the reaction solution was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with dichloromethane (100 mL x 2). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 2 / 1) to obtain compound A3-1 (1 g). MS m / z (ESI): 176.2 [M+1] + .

[0544] Step 2: Synthesis of Compound A3-2

[0545] At room temperature, deuterated iodomethane (893.6 mg, 6.16 mmol) and potassium carbonate (1.06 g, 7.70 mmol) were added to a solution of compound A3-1 (900 mg, 5.13 mmol) in DMF (18 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 5 / 1) to obtain compound A3-2 (950 mg). MS m / z (ESI): 193.1 [M+1] + .

[0546] Step 3: Synthesis of Compound A3

[0547] At room temperature, di-tert-butyl dicarbonate (1.18 g, 5.43 mmol), triethylamine (0.75 g, 7.41 mmol), and 4-dimethylaminopyridine (60.4 mg, 0.49 mmol) were added sequentially to a solution of compound A3-2 (0.95 g, 4.94 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 9 / 1) to obtain compound A3 (1.20 g). MS m / z (ESI): 293.3 [M+1] + .

[0548] Step 4: Synthesis of compound 39a

[0549] Sodium acetate borohydride (1.20 g, 5.68 mmol) was added to a solution of compound 32d (400 mg, 1.42 mmol) and compound A3 (625.7 mg, 2.13 mmol) in tetrahydrofuran (10 mL) at room temperature. The reaction mixture was stirred at 40°C for 16 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate (50 mL) and washed with saturated sodium bicarbonate solution (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to obtain compound 39a (0.60 g). MS m / z (ESI): 558.5 [M+1] + .

[0550] Step 5: Synthesis of compound 39-P1

[0551] Sodium hydroxide (143.2 mg, 3.58 mmol) was added to a solution of compound 39a (200 mg, 0.36 mmol) in methanol / tetrahydrofuran / water (2 mL / 2 mL / 2 mL). The reaction mixture was stirred at 40°C for 16 hours. After completion, the reaction solution was adjusted to pH 5 with acetic acid and concentrated under reduced pressure. The residue was purified using a Biotage-Flash instrument (column: C18 reverse phase column, acetonitrile-water (0.1% ammonium bicarbonate); gradient: 5%-35%) to obtain compound 39-P1 (94.6 mg). MS m / z (ESI): 444.4 [M+1] + Supercritical fluid chromatography (SFC): retention time = 2.462 min, UV = 214 nm. 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.95(d,J=8.0Hz,2H),7.63(d,J=8.0Hz,2H),7.25 (t,J=2.6Hz,1H),6.64(s,1H),6.51–6.47(m,1H),5.04–4.91(m,1H),3.58(d,J=12.0Hz, 1H),3.51–3.47(m,1H),3.29(d,J=11.6Hz,1H),2.71–2.65(m,1H),2.60–2.55(m,1H),2.4 1(s,3H),2.24(t,J=11.6Hz,1H),1.90–1.80(m,1H),1.72–1.57(m,2H),1.48–1.39(m,1H).

[0552] Example 18 (Compound 40-P1)

[0553] Step 1: Synthesis of compound 40a

[0554] Boron tribromide (1.0 M, 8.4 mL, 8.35 mmol) was added dropwise to a solution of compound 36f (260 mg, 0.83 mmol) in dichloromethane (3 mL) at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. After completion, the reaction solution was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield compound 40a (130 mg, crude product). MS m / z (ESI): 298.1 [M+1] + .

[0555] Step 2: Synthesis of compound 40b

[0556] Potassium carbonate (113.2 mg, 0.80 mmol) and potassium iodide (134 mg, 0.80 mmol) were added to a solution of compound 40a (120 mg, 0.40 mmol) and compound A2 (188.2 mg, 0.60 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was quenched with water (5 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 10 / 1) to obtain compound 40b (120 mg). MS m / z (ESI): 571.0 [M+1] + .

[0557] Step 3: Synthesis of compound 40-P1

[0558] Sodium hydroxide (76.9 mg, 1.92 mmol) was added to a solution of compound 40b (110 mg, 0.19 mmol) in methanol / tetrahydrofuran / water (1 mL / 1 mL / 1 mL). The reaction mixture was stirred at 40°C for 16 hours. After completion, the reaction solution was adjusted to pH 5 with acetic acid and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gemini-C18; 150 x 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% trifluoroacetic acid); gradient: 20-40%; column temperature: 25°C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 50 bar) to afford compound 40-P1 (41.3 mg). MS m / z (ESI): 456.9 [M+1] + Supercritical fluid chromatography (SFC): retention time = 1.933 min, UV = 214 nm. 1 H NMR (400MHz, DMSO-d6) δ11.20(s,1H),8.96(s,1H),7.97(d,J=8.0Hz,1H),7.48–7.40(m,1H),7.36 (s,1H),7.21(d,J=8.4Hz,1H),6.79(s,1H),6.40(s,1H),5.31–5.19(m,1H),4.68(t,J=10.6Hz,1H ),4.28–4.13(m,2H),3.75(s,3H),3.53–3.45(m,1H),3.16(d,J=12.0Hz,1H),2.92–2.86(m,1H),2 .40(s,3H),2.32–2.22(m,1H),2.21–2.08(m,1H),1.84(d,J=15.2Hz,1H),1.65(d,J=14.8Hz,1H).

[0559] Example 19 (Compound 41-P1)

[0560] Step 1: Synthesis of compound 41a

[0561] Under nitrogen, potassium tert-butoxide solution (1.0 M, 7.9 mL, 7.86 mmol) was slowly added to a solution of (3-bromopropyl)triphenylphosphonium bromide (1.83 g, 3.93 mmol) in THF (10 mL). The mixture was stirred at 70°C for 1 hour, followed by the addition of a solution of compound 32b (1 g, 2.62 mmol) in THF (10 mL). The reaction mixture was stirred at 70°C for 3 hours. After completion of the reaction, the reaction mixture was poured into ice water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to afford compound 41a (0.60 g). MS m / z (ESI): 406.3 [M+1]. + .

[0562] Step 2: Synthesis of compound 41b

[0563] Iodotrimethylsilane (814.2 mg, 4.07 mmol) was added to a solution of compound 41a (550 mg, 1.35 mmol) in dichloromethane (10 mL) at 0°C, and the reaction mixture was stirred at 0°C for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure at room temperature and adjusted to pH 4-5 with 1N dilute hydrochloric acid. The aqueous phase was washed with petroleum ether (20 mL x 2) and then adjusted to pH 8-9 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to yield compound 41b (350 mg). MS m / z (ESI): 272.2 [M+1] + .

[0564] Step 3: Synthesis of compound 41c

[0565] At room temperature, cesium carbonate (1.20 g, 3.68 mmol) and potassium iodide (305.8 mg, 1.84 mmol) were added to a solution of compound 41b (250 mg, 0.92 mmol) and compound A2 (572.6 mg, 1.84 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, it was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 0-10 / 1) to give compound 41c (350 mg). MS m / z (ESI): 545.5 [M+1] + .

[0566] Step 4: Synthesis of compound 41-P1

[0567] Sodium hydroxide (183.2 mg, 4.58 mmol) was added to a solution of compound 41c (250 mg, 0.46 mmol) in methanol / tetrahydrofuran / water (2.5 mL / 2.5 mL / 2.5 mL). The reaction mixture was stirred at 40°C for 16 hours. After completion, the reaction solution was adjusted to pH 5 with acetic acid and concentrated under reduced pressure. The residue was purified using a Biotage-Flash instrument (column: C18 reverse phase column, acetonitrile-water (0.1% ammonium bicarbonate), gradient: 10%-30%) to afford compound 41-P1 (152.8 mg). MS m / z (ESI): 431.4 [M+1] + Supercritical fluid chromatography (SFC): retention time = 3.101 min, UV = 214 nm. 1 HNMR(400MHz,DMSO-d6)δ12.80(s,1H),10.80(s,1H),7.95(d,J=8.4Hz,2H),7.65(d,J=8.0Hz,2H), 7.25(t,J=2.8Hz,1H),6.64(s,1H),6.48–6.44(m,1H),5.99–5.94(m,1H),3.70(s,3H),3.55(d,J=12 .0Hz,1H),3.47–3.40(m,1H),3.22(d,J=12.0Hz,1H),2.70–2.63(m,1H),2.61–2.54(m,1H),2.41(s, 3H),2.26–2.16(m,1H),1.95–1.80(m,2H),1.73–1.58(m,2H),1.22–1.13(m,1H),1.12–1.02(m,3H).

[0568] Example 20 (Comparative Example 1)

[0569] The preparation of Comparative Example 1 was carried out with reference to the preparation of the reference compound of WO2022028527A1. MS m / z (ESI): 423.1 [M+1] + . 1 H NMR (400MHz, DMSO) δ10.74(s,1H),7.89(d,J=8.4Hz,2H),7.58(d,J=7.9Hz,2H),7.18( t,J=2.7Hz,1H),6.58(s,1H),6.41–6.35(m,1H),3.64(s,3H),3.55–3.42(m,3H),3.36 (t,J=7.0Hz,2H),3.16(d,J=11.8Hz,1H),2.41–2.38(m,1H),2.35(s,3H),2.29–2.19( m,1H),1.81–1.71(m,1H),1.68–1.58(m,2H),1.46–1.35(m,1H),1.10(t,J=7.0Hz,3H).

[0570] Example 21 (Compound 60-P1)

[0571] Step 1: Synthesis of compound 60b

[0572] [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (8.12 g, 9.95 mmol) was added to a mixture of compound 60a (23 g, 99.50 mmol), cyclopropylboronic acid (12.82 g, 149.25 mmol), and potassium phosphate (63.36 g, 298.50 mmol) in 1,4-dioxane and water (300 mL / 100 mL). The reaction mixture was stirred at 90°C for 16 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate (500 mL). The combined organic phases were washed with saturated brine (200 mL x 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain compound 60b (15 g). MS m / z (ESI): 193.2 [M+1] + .

[0573] Step 2: Synthesis of compound 60c

[0574] At 0°C, tert-butyl nitrite (16.09 g, 156.17 mmol) was slowly added to a solution of compound 60b (15 g, 78.09 mmol) in acetonitrile (300 mL). The mixture was stirred at 0°C for 0.5 hours before copper bromide (34.84 g, 156.17 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to afford compound 60c (15 g). 1 H NMR (400MHz, CDCl3) δ8.22(s,1H),6.79(s,1H),2.53(s,3H),2.24–2.18(m,1H),1.17–1.11(m,2H),0.79–0.74(m,2H).

[0575] Step 3: Synthesis of compound 60d

[0576] Vinylmagnesium bromide (1.0 M, 312.4 mL, 312.4 mmol) was slowly added dropwise to a solution of compound 60c (20 g, 78.43 mmol) in tetrahydrofuran (400 mL) at -78°C. The reaction mixture was stirred at 0°C for 2 hours. After completion, the reaction solution was quenched with water (100 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 80 / 20) to obtain compound 60d (5 g). MS m / z (ESI): 248.1 [M-1]. + .

[0577] Step 4: Synthesis of compound 60e

[0578] Di-tert-butyl dicarbonate (6.54 g, 29.98 mmol) and 4-dimethylaminopyridine (0.24 g, 1.99 mmol) were added sequentially to a solution of compound 60d (5 g, 19.98 mmol) in dichloromethane (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to afford compound 60e (6.50 g). 1H NMR (400MHz, CDCl3) δ7.52(d,J=3.6Hz,1H),6.66(s,1H),6.63(d,J=3.6Hz,1H),2 .55(s,3H),2.24–2.16(m,1H),1.62(s,9H),1.03–0.98(m,2H),0.71–0.67(m,2H).

[0579] Step 5: Synthesis of compound 60f

[0580] Under nitrogen, tributyltin carbinol (548.4 mg, 1.71 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (96.3 mg, 0.11 mmol) were added to a solution of compound 60e (400 mg, 1.13 mmol) in 1,4-dioxane (8 mL). The reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 60f (200 mg). MS m / z (ESI): 284.3 [M-OH] + .

[0581] Step 6: Synthesis of compound 60g

[0582] (Chloromethylene)dimethylammonium chloride (127.0 mg, 0.99 mmol) was added to a dichloromethane solution (4 mL) of compound 60f (200 mg, 0.66 mmol) at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was quenched with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 60g (200 mg, crude product). MS m / z (ESI): 284.2 [M-Cl] + .

[0583] Step 7: Synthesis of compound 60h

[0584] Compound 60g (200 mg, 0.71 mmol), cesium carbonate (926.6 mg, 2.84 mmol), and potassium iodide (236.1 mg, 1.42 mmol) were added to a solution of compound 32d (456.2 mg, 1.42 mmol) in N,N-dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 10:1) to obtain compound 60h (200 mg). MS m / z (ESI): 565.5 [M+1] + .

[0585] Step 8: Synthesis of compound 60-P1

[0586] Sodium hydroxide (127.3 mg, 3.18 mmol) was added to a mixture of compound 60h (180 mg, 0.32 mmol) in methanol, tetrahydrofuran, and water (3 mL / 3 mL / 3 mL). The reaction mixture was stirred at 40°C for 16 hours. After completion, the reaction solution was adjusted to pH 5 with acetic acid and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (0.05% ammonia solution); gradient: 50-90%; column temperature: 25°C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to afford compound 60-P1 (44.3 mg). MS m / z (ESI): 451.4 [M+1] + Supercritical fluid chromatography (SFC): retention time = 3.164 min, UV = 254 nm. 1H NMR (400MHz, DMSO-d6) δ10.83(s,1H),7.91(d,J=8.0Hz,2H),7.57(d,J=8.0Hz,2H),7.23(t,J=2.8Hz,1 H),6.64–6.54(m,1H),6.44(s,1H),5.06–4.89(m,1H),3.79(d,J=12.0Hz,1H),3.54–3.44(m,2H),2.72 –2.65(m,1H),2.57–2.52(m,1H),2.41–2.25(m,4H),2.24–2.15(m,1H),2.02–1.90(m,1H),1.73–1.56( m,2H),1.50–1.38(m,1H),0.89–0.77(m,1H),0.73–0.61(m,1H),0.60–0.50(m,1H),0.25–0.14(m,1H).

[0587] Example 22 (Compound 61-P1)

[0588] Step 1: Synthesis of compound 61b

[0589] Vinylmagnesium bromide (1.0 M, 143 mL, 143.28 mmol) was slowly added dropwise to a solution of compound 61a (9.70 g, 38.72 mmol) in tetrahydrofuran (200 mL) at -78°C. The reaction mixture was stirred at 0°C for 2 hours. After completion, the reaction solution was quenched with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (200 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 80 / 20) to obtain compound 61b (4.55 g). MS m / z (ESI): 244.0 [M+1] + .

[0590] Step 2: Synthesis of compound 61c

[0591] At room temperature, di-tert-butyl dicarbonate (6.09 g, 27.91 mmol) and 4-dimethylaminopyridine (0.23 g, 1.86 mmol) were added sequentially to a solution of compound 61b (4.55 g, 18.60 mmol) in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to obtain compound 61c (3.60 g). MS m / z (ESI): 243.6 [M-100] +.

[0592] Step 3: Synthesis of compound 61d

[0593] Under nitrogen, tributyltin carbinol (4.87 g, 15.19 mmol) and tetrakis(triphenylphosphine)palladium (2.34 g, 2.02 mmol) were added to a solution of compound 61c (3.50 g, 10.12 mmol) in 1,4-dioxane (30 mL). The reaction mixture was stirred at 100°C under nitrogen for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to obtain compound 61d (0.63 g). MS m / z (ESI): 278.0 [M-OH] + .

[0594] Step 4: Synthesis of compound 61e

[0595] (Chloromethylene)dimethylammonium chloride (355.8 mg, 2.78 mmol) was added to a dichloromethane solution (10 mL) of compound 61d (550 mg, 1.85 mmol) at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was quenched with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 61e (500 mg, crude product). MS m / z (ESI): 278.0 [M-Cl] + .

[0596] Step 5: Synthesis of compound 61f

[0597] Compound 32d (200.8 mg, 0.71 mmol), cesium carbonate (930.3 mg, 2.85 mmol), and potassium iodide (473.9 mg, 2.85 mmol) were added to a solution of compound 61e (450 mg, 1.43 mmol) in N,N-dimethylformamide (6 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was quenched with water (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases were 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 silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 10:1) to obtain compound 61f (165 mg). MS m / z (ESI): 559.3 [M+1] + .

[0598] Step 6: Synthesis of compound 61-P1

[0599] Sodium hydroxide (110.7 mg, 2.77 mmol) was added to a solution of compound 61f (155 mg, 0.28 mmol) in methanol / tetrahydrofuran / water (1 mL / 1 mL / 1 mL). The reaction mixture was stirred at 40°C for 16 hours. After completion, the reaction solution was adjusted to pH 5 with acetic acid and concentrated under reduced pressure. The crude residue was purified by preparative HPLC (column: Gemini-C18; 150 x 21.2 mm, 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 25-50%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to afford compound 61-P1 (75 mg). MS m / z (ESI): 445.1 [M+1] + Supercritical fluid chromatography (SFC): retention time = 2.824 min, UV = 254 nm. 1 HNMR (400MHz, DMSO-d6) δ12.83 (s, 1H), 11.20 (s, 1H), 8.14 (s, 0.25H), 7.94 (d, J = 8.4Hz, 2H), 7. 66(d,J=8.0Hz,2H),7.36(t,J=2.6Hz,1H),6.87(s,1H),6.73–6.60(m,1H),5.07–4.87(m,1H),3. 68(d,J=12.0Hz,1H),3.63–3.55(m,1H),3.50(d,J=12.4Hz,1H),2.74–2.63(m,1H),2.57–2.52( m,1H),2.41(s,3H),2.37–2.29(m,1H),2.03–1.87(m,1H),1.73–1.58(m,2H),1.54–1.41(m,1H).

[0600] Biological Examples

[0601] 1. Complement hemolytic activity detection

[0602] The hemolysis experiment was described in Xuan Yuan et al., Haematologica. (2017) 102: 466-475. 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 (obtained from healthy volunteers) was added to GVB containing 10mM Mg-EGTA. 0The cells were diluted in a buffer (0.1% gelatin, 5 mM Veronal, 145 mM NaCl, 0.025% NaN3, pH 7.3, Complement technology) and incubated with various concentration gradients of the test compound at 37°C for 15 minutes. 0 RE (from healthy Japanese white rabbits) was added to the buffer solution to reach 1×10 8 The final concentration of cells / ml was 100 μg / ml and incubated at 37°C for 30 minutes. The positive control (100% lysis) consisted of GVB containing 10 mM Mg-EGTA with NHS and RE but without test compound. 0 Buffer composition; negative control (0% lysis) consisted of GVB 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 test compound 0 Buffer composition. Samples were centrifuged at 2000 g for 5 minutes and the supernatant was collected. The absorbance at 415 nm (A415) was measured using a microplate reader (Molecular Devices, SpectraMax i3X). 50 The values ​​were calculated by nonlinear regression from the percentage of hemolysis as a function of the concentration of the test compound. The test results are shown in Table 1.

[0603] Table 1

[0604] 2. Wieslab complement alternative pathway activation inhibition experiment

[0605] The monkey serum complement alternative pathway activity test was performed using the Wieslab assay kit ( Complement system alternative pathway, AP330RUO). Remove the 96-well plate from the kit as needed and equilibrate at room temperature for 30 minutes. Seal the remaining plates and store at 4°C. Add 100 μL / well of the positive control (untreated monkey serum) diluted 18-fold with Diluent AP from the kit, a negative control (100 μL of untreated monkey serum heated in a 56°C waterbath for 30 minutes), and the test sample to the plate. Seal the plate with transparent sealing film, cover, and incubate at 37°C for 65 minutes. Pour out the liquid and add 300 μL / well of 1X wash buffer. Repeat three times, patting the plate dry for the final step. Add 100 μL of conjugate to each well and incubate at room temperature (20-25°C) for 30 minutes, then repeat the plate wash. Add 100 μL of substrate solution per well, protect from light, and incubate at room temperature (20-25°C) for 30 minutes. Read the OD405 value immediately, or stop the reaction by adding 5 mM EDTA and read the OD405 value within 60 minutes. Calculate complement activity using the formula: % complement activity = (Sample-NC) / (PC-NC) * 100.

[0606] 3.TR-FRET binding assay

[0607] Competitive binding experiments using Cy5 fluorescently labeled small molecule inhibitors as probes were performed to screen the degree of inhibition of the binding of compounds to human complement factor B. TM The reaction was terminated by adding 1M Tris (pH 7.5) after incubation of Sulfo-NHS-LC-LC-Biotin at a ratio of 1:2 on ice for 1 hour. TM Biotin-labeled complement factor B was obtained by purification twice using a desalt spin column (EZ-LinkTM Sulfo-NHS-LC-Biotin instructions). During the experiment, biotin-labeled complement factor B with a final concentration of 10 nM was pre-incubated with different concentrations of compounds in a buffer solution at room temperature for 1 hour. Cy5 fluorescent-labeled probes and europium chelate-labeled streptavidin (PerkinElmer, #AD0060) were added at final concentrations of 75 nM and 5 nM, respectively, to start the reaction. Kinetic readings were performed on a microplate 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 .

[0608] 4. Optical surface plasmon resonance (SPR) binding force detection

[0609] SPR experiments were performed at 25°C using PBS supplemented with 0.05% (v / v) P20 and 5% DMSO. The analyzer was a GE Healthcare Biacore 8K. A CM7 chip (GE Healthcare) was activated for 420 seconds with 400 mM EDC and 100 mM NHS at a flow rate of 30 μL / min. Complement factor B was covalently immobilized to the detection chip (protein immobilization level: 25,000 RU) by dilution with 10 mM sodium acetate (pH 4.0) for 1200 seconds at a flow rate of 10 μL / min. The chip was then blocked with 1 M ethanolamine hydrochloride at a flow rate of 10 μL / min for 300 seconds. The test compound concentration was 500 μM, with an association time of 120 seconds and a dissociation time of 300 seconds. Data analysis used a 1:1 binding model (Biacore Insight Evalution Software, Version 2.0.15.12933).

[0610] Conclusion: The binding affinity of the compound of the present invention has a significant advantage over that of the comparative example as determined by optical surface plasmon resonance binding affinity.

[0611] 5. Evaluation of the inhibitory effect of the test substance on the alternative pathway of the human serum complement system

[0612] The test compound was tested at a starting concentration of 10 μM, diluted 3-fold, 8 concentration points, and a final DMSO concentration of 0.1%. The test was repeated. A Human Serum (Complement Technology, NHS) was taken out from the -80°C ultra-low temperature freezer, and after it was completely thawed on ice, it was gently pipetted to mix. Diluent AP ( COMPLEMENT SYSTEM ALTERNATIVE PATHWAY AP330RUO) was diluted into 1.25x Human Serum working solution. At the same time, an appropriate amount of Human Serum was taken out and heated in a 56°C water bath for 30 minutes to inactivate it. It was also diluted into 1.25x inactivated working solution as the NC control. 25 μL of compound working solution and 100 μL of 1.25x Human Serum working solution were added to the 96-well plate in sequence. 25 μL of 5‰ DMSO and 100 μL of 1.25x Human Serum working solution were added to the PC control wells. 25 μL of 5‰ DMSO and 100 μL of 1.25x Human Serum inactivated working solution were added to the negative control wells. The mixture was gently mixed on a microplate constant temperature shaker. After incubation at room temperature for 15 minutes, 100 μL of the above mixture was taken out and gently transferred to the pre-coated well plate (containing LPS) provided in the kit ( In a COMPLEMENT SYSTEM ALTERNATIVE PATHWAY AP330RUO (provided by RT-PCR), add 100 μL of Diluent AP as a blank control, avoiding the formation of bubbles, and incubate at 37°C for 65 minutes. Pour off the liquid in the wells and add 300 μL of 1X wash buffer per well. Repeat four times, patting the plate dry for the final step. Add 100 μL of conjugate to each well and incubate at room temperature (20-25°C) for 30 minutes, then repeat the wash cycle. Add 100 μL of substrate solution per well, protect from light, and incubate at room temperature (20-25°C) for 30 minutes. Read the OD405 value immediately, or stop the reaction by adding 5 mM EDTA and read the OD405 value within 60 minutes. Calculate complement activity using the formula: % complement activity = (Sample-NC) / (PC-NC) * 100, and analyze the data. The test results are shown in Table 2.

[0613] Table 2

[0614] 6. Liver Microsome Stability Test

[0615] (1) Preparation of buffer solution

[0616] Take a 0.1 M dipotassium hydrogen phosphate distilled water solution (containing 1 mM ethylenediaminetetraacetic acid), and then use a 0.1 M potassium dihydrogen phosphate distilled water solution (containing 1 mM ethylenediaminetetraacetic acid) to adjust the pH to 7.4.

[0617] (2) Microsome source and preparation of working solution

[0618] Microsome Source:

[0619] Mouse: ICR / CD-1 Liver Microsomes, Cat. No.: M00501, Bioreclamation IVT.

[0620] Rat: SD Rat Liver Microsomes, Cat. No.: LM-DS-02M, RILD Liver Disease Research (Shanghai) Co., Ltd.

[0621] Dog: Beagle Dog Liver Microsomes, Cat. No.: M00201, BioreclamationIVT.

[0622] Monkey: Cynomolgus Monkey Liver Microsomes, Cat. No.: LM-SXH-02M, RILD Liver Disease Research (Shanghai) Co., Ltd.

[0623] Human: Pooled Human Liver Microsomes (Mongolian), Cat. No.: LM-R-02M, RILD Liver Disease Research (Shanghai) Co., Ltd.

[0624] Preparation of working fluid

[0625] Prepare a 10 mM solution of each test compound in DMSO. Then, add 10 μL of the solution to 190 μL of acetonitrile to create a 0.5 mM stock solution. Add 1.5 μL of the 0.5 mM stock solution to 18.75 μM of 20 mg / mL liver microsomes and 479.75 μL of buffer. (The actual volume can be adjusted based on usage.)

[0626] (3) Experimental process

[0627] Prepare 10 mg / mL NADPH in buffer. Place a 96-well plate on ice. Set up 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 0-min well, add 155 μL of glacial acetonitrile (internal standard concentration: 1 μM), mix thoroughly with a pipette, and then add 15 μL of NADPH (10 mg / mL). Before initiating the reaction, preincubate the 96-well plate on a thermostatted microplate shaker (37°C) for 5 minutes. Then, add 15 μL of NADPH (10 mg / mL) to each well to initiate the metabolic reaction. After 10, 30, 60, and 90 minutes, terminate the reaction by adding 155 μL of glacial acetonitrile (internal standard concentration: 1 μM) to the corresponding wells. For the non-NADPH system, terminate the reaction after 90 minutes by adding 155 μL of glacial acetonitrile (internal standard concentration: 1 μM). After the reaction, the 96-well plate was shaken for 10 minutes using a microplate shaker (600 rpm) and 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, followed by 300 μL of deionized water. The supernatant was analyzed using an AB SCIEX ExionLC-Triple Quad 5500 high-performance liquid chromatography-mass spectrometry instrument, using Analyst 1.6.3 software.

[0628] 7. Hepatocyte Stability Experiment

[0629] (1) Reagent information

[0630] Williams E Medium: Gibco, Lot No.: 2336217.

[0631] GlutaMAX (100x): Gibco, Lot No.: 22777239.

[0632] Dexamethasone: NICPBP.

[0633] Human-insulin: Gibco, 12585-014.

[0634] FBS: Corning, 35-076-CV.

[0635] DPBS: Gibco, 2224922.

[0636] HEPES: Sigma, RNBH8969.

[0637] Isotonic percoll: Cytiva, 10303640.

[0638] (2) Cell source and preparation of working solution

[0639] Cell source

[0640] Person: BioIVT, Product No.: X008001;

[0641] Monkey: Cynomolgus, RILD, Product No.: HP-SXH-02M;

[0642] Dog: Beagle, TPCS, Product No.: CDH-100BE-SQ;

[0643] Rat: SD, BioIVT, Product No.: M00005;

[0644] Mouse: CD-1, TPCS, Product No.: CMH-100CD-SQ.

[0645] Preparation of working fluid

[0646] The compound was diluted to 10 mM with DMSO and then diluted to 100 μM with 50% acetonitrile in water.

[0647] (3) Experimental process

[0648] Preheat the incubation medium and thawing medium at 37°C for 15 minutes. Remove the hepatocytes from the liquid nitrogen tank, thaw at 37°C, transfer to thawing medium, centrifuge briefly, and transfer to a safety cabinet. Detect cell number and cell viability using AO / PI staining and dilute with incubation medium to a working concentration of 0.5×10 6 / mL. Add 2μL of compound working solution to 198μL of liver cell fluid. After mixing, incubate under 5% CO2 and 37℃. Samples were taken at reaction time points of 0.5, 15, 30, 60, 90 and 120min. At each time point, 25μL of reaction solution was added to 150μL of ACN containing internal standard (100nM alprazolam, 200nM caffeine and 100nM tolbutamide) and vortexed for 5min. All samples were centrifuged at 3,220g for 45min. Take 100μL of supernatant and add 100μL of deionized water and mix well. LC / MS / MS analysis was performed using Triple Quad TM The samples were analyzed using a 5500 high performance liquid chromatography-mass spectrometer, and the software used was Analyst 1.6.3.

[0649] 8. Protein binding rate experiment

[0650] Buffer preparation

[0651] Phosphate buffer: Cat. No.: E607008-0500, BBI.

[0652] (1) Plasma source and working solution preparation

[0653] Plasma Source:

[0654] Human plasma was purchased from Wuhan Purity Biotechnology Co., Ltd.

[0655] Animal plasma, collected or obtained from CRO.

[0656] (2) Preparation of working fluid:

[0657] Preparation of compound working solution 1: Pipette 1 μL of the compound DMSO stock solution (10 mM) into 99 μL of ACN acetonitrile to prepare a 200 μM working solution 1. Add an appropriate amount of compound working solution 1 to an appropriate volume of plasma (or serum) and mix thoroughly to obtain a final concentration of 1 μM working solution 2.

[0658] (3) Experimental process

[0659] Insert the equilibrium dialysis system into the corresponding wells of a RED Devices plate. Add 100 μL of working solution 2 to the red plasma chamber and 350 μL of PBS to the buffer chamber. Cover the equilibrium dialysis plate with a sealing film and incubate at 37°C on a constant-temperature shaker at 250 rpm for approximately 4 hours. After incubation, remove a predetermined volume (usually multiples of 25 μL) from each of the buffer chamber and plasma buffer and transfer it to a centrifuge tube or deep-well plate (stored at -20°C) for later use. Transfer 25 μL each of the dialyzed plasma sample and buffer sample to a 96-well plate. Add 25 μL of PBS to the removed plasma sample, and 25 μL of plasma to the buffer sample. Add 300 μL of pre-prepared ice-cold precipitant containing an internal standard (toluyflavone, final concentration 1 μM) and shake at 400 rpm for 5 minutes. Preparation of samples at time point T0: Add 25 μL of working solution 2 prepared in 2.2.2 to a 96-well plate. Add 25 μL of PBS and mix thoroughly. Add 300 μL of ice-cold precipitant containing the internal standard (toluene xanthocyanide) and shake at 400 rpm for 5 minutes. Repeat in duplicate. Centrifuge the precipitated sample at 4000 rpm for 15 minutes at 4°C. Dilute the supernatant 4-fold with ultrapure water, load the sample, and analyze on an AB SCIEX ExionLC-Triple Quad 5500 high-performance liquid chromatography-mass spectrometer using Analyst 1.6.3 software.

[0660] 9. Caco-2 permeability test

[0661] (1) Source and preparation of buffer and cell culture medium

[0662] HBSS: Sigma-Aldrich, Cat#: H8264;

[0663] FBS: Gibco, Cat#: 10091148;

[0664] Hepes: Gibco, Cat#: 15630106;

[0665] DMEM: Gibco, Cat#: 11995-065;

[0666] Trypsin: Gibco, Cat#: 25200-056;

[0667] DPBS: Gibco, Cat#: 14190-144;

[0668] MEM NEAA: Gibco, Cat#: 11140050;

[0669] Pen Strep: Gibco, Cat#: 15140-122;

[0670] 24-Multiwell insert system: corning, Cat#: 351181;

[0671] 24-Multiwell cell plate: corning, Cat#: 353047.

[0672] Preparation of cell culture medium: Add 50 mL of FBS, 5 mL of Pen Strep, and 5 mL of MEM NEAA to DMEM medium (500 mL / bottle). Mix well.

[0673] HBSS (containing Hepes) was prepared as follows: 12.5 mL of Hepes was added to 487.5 mL of HBSS and the pH was adjusted to 7.4.

[0674] (2) Cell culture and preparation of working solution

[0675] Aspirate the culture medium in the culture flask with a sterile pipette tip, draw 10mL DPBS into the culture flask to rinse, and repeat the wash with DPBS once. Aspirate 1mL 0.25% Trypsin, rinse the cells once, then aspirate 2mL 0.25% Trypsin, gently shake the culture flask, cover it with a lid and place it in the incubator, and enzymatically hydrolyze until the cells fall off. Aspirate 8mL of culture medium, mix it with the cells, and aspirate it into a 15mL centrifuge tube, centrifuge at 1000rpm for about 5 minutes. Pour out the upper culture medium. Add 10mL of culture medium and mix it by pipetting. Take out about 1mL of enzymatically hydrolyzed cells and put it into a 1.5mL centrifuge tube, take 20μL of cell fluid and mix it with 20μL of trypan blue solution, then take 10μL into the cell counting plate, the cell counter will give the data, and record the data. According to the number of living cells obtained, dilute with DMEM culture medium to 3.2*10 4 Cells were plated at a density of 100 μL / mL. 400 μL of cell solution was added to each well. Gently tap the plate. 30 mL of MEM medium was added to the bottom layer. Wipe the plate with alcohol wipes and transfer to an incubator. Culture the plate at 37°C in 5% CO2. The medium should be changed every 3-4 days. Cell resistance was measured using a Millipore resistance meter to determine cell status. Cells with resistance greater than 600 Ω were suitable for the next experiment. The number of cells at each cell generation, as well as the date of plating, was recorded and archived for future reference.

[0676] The compound was diluted to 10 mM with DMSO, and 5 μL of 10 mM compound solution was added to 5 mL of HBSS (containing Hepes) to prepare the compound working solution.

[0677] (3) Experimental process

[0678] Preheat HBSS (containing Hepes) to 37°C. Measure and record the cell plate resistance. Remove the cell plate culture medium and rinse once with HBSS (containing Hepes). Add the compound working solution to the donor end and the HBSS (containing Hepes) solution to the receiver end. Equilibrate the cell plate at 5% CO₂ and 37°C for 10 min. Remove 100 μL of each of the equilibrated solutions from the donor and receiver ends as the 0-min sample. Equilibrate the cell plate at 5% CO₂ and 37°C for another 90 min. Remove 100 μL of each of the 0-min and 90-min samples and add 300 μL of ACN solution (containing 10 ng / mL toluylurea as an internal standard) to the sample. Vortex to mix. Centrifuge at 4,000 rpm and 4°C for 10 min. Take 100 μL of each of the 0-min and 90-min samples and add 100 μL of deionized water to the sample. Mix thoroughly before analysis. The samples were analyzed using an AB SCIEX ExionLC-Triple Quad 5500 high performance liquid chromatography-mass spectrometry instrument, and the software used was Analyst 1.6.3.

[0679] Conclusion: Compared with the comparative example, the permeability of the compound of the present invention has significant advantages.

[0680] 10. Single-dose PK experiment in mice

[0681] ICR male mice weighing ~25g (Shanghai Bikekoji Biotechnology Co., Ltd.) were fasted overnight, with 3 mice in each group, and administered by gavage. The test compound was administered at a volume of 10mL / kg. Blood was collected through the eye socket, 30μL at each time point, anticoagulated with EDTA-K2, and immediately centrifuged at 4000rpm*5min at 4°C to obtain the supernatant. Blood collection time points: 15min, 30min, 1h, 2h, 4h, 7h, 24h. The animal status was observed at any time after administration. After completing blood collection at all time points, the animals were euthanized. Plasma samples were measured by LC-MS / MS, and the data were calculated using WinNonlin software for kinetic parameter calculation. The results are shown in Table 3:

[0682] Table 3

[0683] 11. Single-dose PK experiment in rats

[0684] Experimental methods:

[0685] 6-9 week old SD male rats (Shanghai Bikekeji Biotechnology Co., Ltd.) were fasted overnight, 3 rats per group, and administered by gavage. The test compounds were administered at a volume of 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 4000 rpm*5 min at 4 ° C to obtain the supernatant. Blood collection time points: 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, 24 h. The animal status was observed at any time after administration. After completing blood collection at all time points, the animals were euthanized. Plasma samples were measured by LC-MS / MS, and the data were calculated using WinNonlin software for kinetic parameter calculation. The results are shown in Table 4:

[0686] Conclusion: Compared with the comparative example, the compound of the present invention has significant pharmacokinetic advantages in rats after single administration. In addition, the compound of the present invention also has significant pharmacokinetic advantages in other species, such as dogs.

[0687] The above is an exemplary description of the implementation methods of the technical solution of the present invention. It should be understood that the scope of protection of the present invention is not limited to the above implementation methods. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention shall be included in the scope of protection of the claims of this application.

Claims

1. A compound represented by formula (IE) or a pharmaceutically acceptable salt thereof, in: Ring A is selected from phenyl, 5-10 membered heteroaryl and Ring B is selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; G' is CR 7 or N; R 0 Selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, deuterated C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl and 3-8 membered cycloalkyl; Each R 1 the same or different, each independently selected from H, D, halogen, CN, NH2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl and 3-8 membered cycloalkyl; R 2 Selected from H, D, halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 2-6 Alkynyl and 3-8 membered cycloalkyl; Each R 3 the same or different, each independently selected from H, D, halogen, CN, NH2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl and 3-8 membered cycloalkyl; Each R 4 are the same or different, each independently selected from H, halogen, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkynyl and 3-8 membered cycloalkyl; R 7 and R 8 are the same or different, each independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; or R 7 and R 8 The carbon atoms connected thereto form a 3-8 membered cycloalkyl or a 3-8 membered heterocycloalkyl, wherein the 3-8 membered cycloalkyl or the 3-8 membered heterocycloalkyl is optionally substituted by one or more halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 substituted by a haloalkoxy substituent; m is 0, 1 or 2; n is 0, 1, 2 or 3; r is 0, 1, 2, 3 and 4.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Selected from: Ring B, R 4 and r as defined in claim 1; Preferably, ring B is selected from 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl and 6 membered heteroaryl; Preferably, ring B is selected from phenyl, pyridyl, cyclopentenyl and dihydrofuranyl.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, which is a compound of formula (IIG) or a pharmaceutically acceptable salt thereof: in: X and Y are the same or different and are each independently selected from CH or N; G', R 1 , R 2 , R 3 , R 4 , R 8 , m and n are as defined in claim 1 or 2; Preferably, R 7 and R 8 are the same or different, each independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; Each R 1 The same or different, each independently selected from H, D, CN, NH2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl and 3-8 membered cycloalkyl; R 2 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy and 3-8 membered cycloalkyl; Each R 3 The same or different, each independently selected from H, D, CN, NH2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl and 3-8 membered cycloalkyl; Each R 4 are the same or different, each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy.

4. A compound of formula (I) or formula (III) or a pharmaceutically acceptable salt thereof, in, X and Y are the same or different and are each independently selected from CH or N; G is CR 5 or N; R 5 and R 6 are the same or different, each independently selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; Each R 3 The same or different, each independently selected from H, D, CN, NH2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl and 3-8 membered cycloalkyl; Or, 2 R 3 The carbon atom to which it is attached forms a C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, the C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 substituted with a haloalkoxy group; R 1 , R 2 , R 4 , m and n are as defined in any one of claims 1-3.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, which is a compound of formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof: in, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m and n as defined in claim 4; Preferably, wherein R 5 and R 6 are the same or different, each independently selected from H, halogen, CN, C 1-6 Alkyl and C 1-6 Preferably, R 5 and R 6 The same or different, each independently selected from H, F, CN and methyl; Preferably, R 6 C 1-6 Alkoxy.

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, which is a compound or pharmaceutically acceptable salt thereof represented by formula (IVG): in, X, Y, G', R 1 , R 2 , R 3 , R 4 , R 8 , m and n are as defined in any one of claims 1-3.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 or 6, which is a compound or pharmaceutically acceptable salt thereof represented by formula (IVG-1) or formula (IVG-2): in, X, Y, R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , m and n are as defined in any one of claims 1-3 or 6.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, 6 or 7, which is a compound or pharmaceutically acceptable salt thereof represented by formula (IVG-3): in, X, Y, R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , m and n are as defined in any one of claims 1-3, 6 or 7.

9. The compound according to any one of claims 1 to 3 or 6 to 8 or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 are the same or different, each independently selected from H, halogen, CN, C 1-6 Alkyl and C 1-6 Preferably, R 7 and R 8 are the same or different, each independently selected from H, F, CN, methyl and -CHF2; Or, R 7 and R 8 Together with the carbon to which it is attached, it forms a 3-6 membered cycloalkyl group; Preferably, R 7 and R 8 Together with the carbon to which it is attached it forms a cyclopropyl group.

10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein X and Y are both CH; Alternatively, X is N and Y is CH; and / or, R 2 is selected from methyl, methoxy, deuterated methoxy, cyclopropyl, halogen and ethynyl; preferably, R 2 is selected from methyl, methoxy, deuterated methoxy and cyclopropyl, preferably, R 2 is methoxy; and / or, R 4 Selected from H, OH, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkynyl and 3-8 membered cycloalkyl; preferably, R 4 H, OH, halogen, C 1-6 Alkyl or C 1-6 Alkoxy.

11. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, selected from the following compounds: Preferably, the compound or its pharmaceutically acceptable salt is selected from the following compounds:

12. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

13. Use of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, in the preparation of a medicament for modulating the activity of the complement alternative pathway in a subject; preferably, use of a medicament for the prevention and / or treatment of a disease or condition affected by the modulation of the complement alternative pathway; Preferably, its use in the preparation of a medicament for inhibiting complement factor B; preferably, its use in the preparation of a medicament for preventing and / or treating a disease mediated by complement factor B; Preferably, the invention relates to a use of the invention in the preparation of a medicament for preventing and / or treating autoimmune diseases, inflammatory diseases, cardiovascular diseases or respiratory diseases; preferably, the invention relates to a use of the invention in the preparation of a medicament for preventing and / or treating paroxysmal nocturnal hemoglobinuria (PNH), primary glomerulonephritis (IgAN), membranous nephropathy (MN), diabetic nephropathy (DKD), C3 glomerulonephritis (C3G), lupus nephritis (LN), proliferative nephritis, systemic lupus erythematosus (SLE), 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, psoriatic arthritis, hepatitis, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), Guillain-Barré syndrome (GBS), neuromyelitis optica spectrum disorder (NMOSD), uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, sympathetic ophthalmia, ocular pemphigoid, ocular pemphigus, nonarteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, tarda macular dystrophy, North Carolina macular dystrophy, Stargardt disease, corneal inflammatory disease, neutrophil resistance Use in drugs for diseases such as angiotensin-converting antigen-associated vasculitis (ANCA-AAV), Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-cardiopulmonary bypass or renal bypass pump syndrome, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, and mesenteric artery reperfusion after aortic reconstruction.

14. A compound represented by formula (IEA) or a salt thereof, in, R w C 1-6 alkyl; R p is an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl (Fmoc) or trifluoroacetyl; Ring A, G', R 0 , R 1 , R 2 , R 3 , R 4 , R 8 , r, m and n are as defined in formula (IE); Preferably, the compound represented by formula (IEA) or a salt thereof is selected from the following compounds:

15. A method for preparing the compound of formula (IE) according to claim 1, comprising subjecting the compound of formula (IEA) according to claim 14 to hydrolysis and deprotection to obtain the compound of formula (IE), in, R w C 1-6 alkyl; R p is an amino protecting group, preferably benzyl, tert-butyloxycarbonyl (Boc), 2-biphenyl-2-propoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl (Fmoc) or trifluoroacetyl; Ring A, G', R 0 , R 1 , R 2 , R 3 , R 4 , R 8 , r, m and n are as defined in claim 1.

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