Piperidinyl indole derivatives, processes for their preparation and use thereof

Abstract

The present application provides a piperidinyl indole derivative, a preparation method and application thereof, in particular, the present application provides a compound with structural formula A and I or a pharmaceutically acceptable form thereof, which can be used for preparing a drug for treating a disease or disorder mediated by a disorder of a complement bypass pathway, in particular, a drug for treating a disease or disorder mediated by complement factor B.

Description

Piperidinyl indole derivatives, their preparation methods and applications Technical field The present invention relates to a piperidinyl indole derivative and its application, specifically to a piperidinyl indole derivative and its preparation method, and its application in the treatment of diseases or disorders related to the activation of the alternative complement pathway, especially complement factor B. Background technology The complement system is mainly composed of a variety of proteins synthesized by the liver, circulates in the blood and tissues, accounting for about 10% of the globulins in serum, and is an important part of the innate immune system. In normal host cells, the complement is strictly controlled by many cell surface proteins, avoiding damage to its own tissues; while foreign pathogens and damaged host cells are vulnerable to this attack. When the complement system is abnormally activated or over-activated, it can cause cell and tissue damage, leading to autoimmune diseases and inflammatory diseases. The complement system mainly consists of complement activation factors, regulatory factors and complement receptors. Under physiological conditions, complement activation factors exist in the form of inactive enzyme precursors; when the complement system is activated, a membrane attack complex is generated, which acts on the cell membrane to form small pores, ultimately leading to the death of target cells. Complement regulatory factors can finely regulate all aspects of complement activation. Complement receptors are mainly expressed on the surface of immune cell membranes and are a class of membrane proteins. Complement receptors can bind to activated complement components to play roles such as recruiting white blood cells to the inflammation site, promoting the phagocytosis of pathogenic microorganisms, and clearing immune complexes generated in the blood system. The complement system is mainly activated by three pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP). The classical pathway and the lectin pathway are initiated by recognizing signals on the cell surface. In these two pathways, C4 and C2 molecules are cleaved and form C4b2a. This reaction of the classical pathway is achieved through the C1 complex, while the lectin pathway is through some pathogen-associated molecular patterns (PAMPs) to activate the zymogen of serine protease (MASPs), and MASP-1 and MASP-2 further form a complex to promote the cleavage of C4 and C2, ultimately forming C3 convertase (C4b2a). The alternative pathway is different from the above two pathways. It involves the hydrolysis of C3, exposing the thioester domain, and under the action of complement factor B (CFB) and complement factor D (CFD), binding to the activated Bb molecule to form an active C3 convertase (C3(H2O)Bb). Under the action of the C3 convertase, the C3 molecule is further cleaved into C3a and C3b. The deposited C3b can, under the action of CFB, form a new C3 convertase (C3bBb), thus forming a reaction loop of C3. In addition, excess C3b molecules can bind to the C3 convertase to form C5 convertases (including C4b2aC3b and C3bBbC3b), which cleave the C5 molecule into C5a and C5b. C5b binds to C6, C7, C8, and C9 to form the membrane attack complex (C5b9), ultimately causing damage to the target cells. Current research has found that various diseases such as hematological, autoimmune, inflammatory, and neurodegenerative diseases are associated with abnormal regulation of the complement system, such as paroxysmal nocturnal hemoglobinuria (PNH), immunoglobulin A nephropathy (IgAN), atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), age-related macular degeneration (AMD), systemic lupus erythematosus (SLE), dense deposit disease (DDD), ANCA-associated vasculitis (AAV), immune thrombocytopenia (ITP), cold agglutinin disease (CAD), etc. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal disease of hematopoietic stem cells, with clinical manifestations including episodic intravascular hemolysis of varying degrees, paroxysmal hemoglobinuria, bone marrow hematopoietic failure, and the formation of venous thrombosis. The deficiency of complement decay-accelerating factor CD55 and membrane attack complex inhibitor CD59 is considered the main mechanism of intravascular hemolysis in PNH patients. CD55 and CD59 are physiologically expressed on the cell surface. CD55 inhibits complement activation by accelerating the decay of C3 and C5 convertases, while CD59 directly inhibits the formation of the membrane attack complex (MAC) by preventing C9 from inserting into the C5b-8 complex during the assembly of the MAC, thus inhibiting the terminal complement attack reaction. IgAN nephropathy refers to primary glomerular disease with predominant IgA deposition in the glomerular mesangial region, with or without the deposition of other immunoglobulins in the glomerular mesangial region. IgA nephropathy is caused by multiple factors. Currently, it is widely recognized internationally that factors such as genetics or the environment lead to an increase in galactose-deficient IgA1 (Gd-IgA1); the production of specific antibodies against Gd-IgA1; the binding of Gd-IgA1 to antibodies to form pathogenic immune complexes containing IgA; and these immune complexes cause glomerular damage. Complement activation is one of the most common downstream events after the deposition of Gd-IgA1 immune complexes in the mesangial region of the kidneys of IgAN patients, suggesting that abnormal activation of the alternative complement pathway is related to the degree of clinical and pathological changes. C3 glomerulopathy (C3G) is a group of diseases caused by genetic or acquired regulatory defects in the alternative complement pathway, resulting in abnormal deposition of complement C3 in the glomeruli. It can present as asymptomatic hematuria and / or proteinuria, or acute nephritic syndrome, nephrotic syndrome, rapidly progressive nephritic syndrome, etc. Dysregulation of the alternative complement pathway is the main driving factor in the pathogenesis of C3G. Atypical hemolytic uremic syndrome (aHUS) is a rare and critical clinical syndrome characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ damage, especially acute kidney injury. Congenital abnormalities of alternative complement pathway proteins, or autoantibodies against complement factors or complement pathway regulatory proteins, leading to continuous activation of the alternative complement pathway, are the main pathogenic mechanisms of aHUS. Age-related macular degeneration (AMD) is a degenerative disease caused by multiple factors and is the main cause of low vision and blindness in the elderly population. It is estimated that the number of global AMD patients will reach 288 million in 2040. Currently, large-scale studies have confirmed that complement activation plays an important role in the pathogenesis of AMD. Inhibiting the complement system is one of the methods involved in inhibiting complement proteins to downregulate the alternative pathway and form the membrane attack complex, and it is a potential treatment method for dAMD. ANCA-associated vasculitis (AAV) is a group of systemic diseases characterized by small-vessel immune necrotizing inflammation. AAV is characterized by the presence of antibodies against neutrophil protease 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). These antibodies can activate neutrophils and the complement system, leading to vascular wall inflammation and damage. The interaction between the complement activation product C5a and its related receptor C5aR1 (CD88) has become a recognized key link in inducing inflammatory responses and also a key target for therapeutic intervention. Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease involving multiple organs, characterized by the production of various pathogenic autoantibodies and the extensive deposition of immune complexes (ICs). 50% - 60% of SLE patients develop lupus nephritis (LN) within 10 years after the onset. LN is one of the main reasons for the poor prognosis of SLE patients. Research has found that the formation, deposition of a large number of immune complexes and the over-activation or regulatory imbalance of the complement system are closely related to the onset and progression of LN. Complement activation is an important marker for the activity and recurrence of LN. Immune thrombocytopenia (ITP) is a disease characterized by platelet reduction caused by increased platelet destruction and decreased platelet production. A large number of experimental and clinical evidences have shown that the production of autoantibodies that accelerate platelet clearance is the core of the pathogenesis of ITP, and these IgM and some IgG antiplatelet antibodies activate complement in vivo, thereby leading to the aggravation of the complement cascade reaction and the progression of the disease. Early studies have shown that inhibiting the activation of the terminal complement C5 can improve platelet count and rapidly reduce the occurrence of thromboembolic complications. Cold agglutinin disease (CAD) is an autoimmune hemolytic anemia (AIHA) affected by lower temperatures and caused by cold agglutinins (CAs). In this disease, the complement system in the immune system mistakenly attacks healthy human red blood cells and causes the rupture of red blood cells (hemolysis). CAD patients may experience chronic anemia, severe fatigue, acute hemolytic crisis and other potential complications, including an increased risk of thromboembolic events and early death. Currently, the treatment for CAD includes non-drug treatment and drug treatment. Drug treatment includes general treatment, treatment targeting B cells, and treatment with complement inhibitors. Complement inhibitors have a rapid onset of action and can be used for acute hemolysis, but long-term maintenance treatment is required to avoid the occurrence of hemolysis. Summary of the Invention One object of the present invention is to provide a new compound as a regulator of the alternative pathway activation factor of complement. Another object of the present invention is to provide a preparation method of the compound. Another object of the present invention is to provide a composition containing the compound. Another object of the present invention is to provide the application of the compound. Technical Solution 1: The present invention provides a compound having the structural formula A or a pharmaceutically acceptable form thereof: Preferably, the compound is a stereoisomer shown in Formula I: According to some specific embodiments of the present invention, the pharmaceutically acceptable forms of the compound of formula A or formula I are selected from pharmaceutically acceptable salts, deuterated compounds, prodrugs, polymorphs or solvates. The pharmaceutically acceptable salts generally refer to any salts that are physiologically tolerable when used in an appropriate manner for treatment (especially when applied or used in humans and / or mammals). Generally speaking, this means that it is non-toxic, especially non-toxic as a result of the counterion. These physiologically acceptable salts can be formed by the compound with a cation or a base, or with an anion or an acid. Specifically, it may include salts formed with alkali metals, alkaline earth metals or ammonium cations (NH4 + ), and salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid. The chemical structural formulas of exemplary pharmaceutically acceptable salts of the compound of formula I are as follows: The deuterated compound refers to a compound obtained by substituting any H in the compound of formula I with deuterium, which may provide certain therapeutic advantages due to greater metabolic stability, such as an increase in the in vivo half-life or a decrease in the dose requirement or an improvement in the therapeutic index. According to some specific embodiments of the present invention, the deuterated compound is selected from one of the following structures: The prodrug refers to those derivatives that can be converted into the compound of formula I in vivo to improve the bioavailability or delivery efficiency of the compound. The polymorph refers to any crystalline form of the compound, which can exist alone as one crystal or coexist as multiple crystals. The solvate generally refers to any substance obtained by the active compound according to the present invention being combined with another molecule (usually a polar solvent) through non-covalent bonds, specifically including but not limited to hydrates and alcoholates, such as methanolates. Technical solution two: The present invention provides a preparation method of the compound of formula A, comprising the following steps: (1) 4-Bromo-3-methylbenzonitrile, 4-methoxypyridine and benzyl chloroformate react under the catalysis of a Grignard reagent to form benzyl 2-(4-cyano-2-methylphenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate; (2) The benzyl 2-(4-cyano-2-methylphenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate is subjected to a hydrogenation reaction to obtain benzyl 2-(4-cyano-2-methylphenyl)-4-oxopiperidine-1-carboxylate; (3) Reduce the carbonyl group in benzyl 2-(4-cyano-2-methylphenyl)-4-oxopiperidine-1-carboxylate to obtain benzyl 2-(4-cyano-2-methylphenyl)-4-hydroxypiperidine-1-carboxylate; (4) React benzyl 2-(4-cyano-2-methylphenyl)-4-hydroxypiperidine-1-carboxylate with a silylating agent in the presence of an acid-binding agent to protect the hydroxyl group, obtaining 4-((tert-butyldiphenylsilyl)oxy)-2-(4-cyano-2-methylphenyl)piperidine-1-carboxylate; (5) Remove the hydroxyl protecting group from 4-((tert-butyldiphenylsilyl)oxy)-2-(4-cyano-2-methylphenyl)piperidine-1-carboxylate to obtain 2-(4-cyano-2-methylphenyl)-4-hydroxypiperidine-1-carboxylate; (6) Carry out a nucleophilic substitution reaction of 2-(4-cyano-2-methylphenyl)-4-hydroxypiperidine-1-carboxylate with a halogenated hydrocarbon to obtain 2-(4-cyano-2-methylphenyl)-4-ethoxypiperidine-1-carboxylate; (7) React 2-(4-cyano-2-methylphenyl)-4-ethoxypiperidine-1-carboxylate with an acid and an alkyl alcohol to obtain methyl 4-(4-ethoxypiperidin-2-yl)-3-methylbenzoate; (8) React methyl 4-(4-ethoxypiperidin-2-yl)-3-methylbenzoate with tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate to obtain tert-butyl 4-(4-ethoxy-2-(4-(alkoxycarbonyl)-2-methylphenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate; (9) Hydrolyze tert-butyl 4-(4-ethoxy-2-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate to obtain Compound A, 4-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3-methylbenzoic acid. Compound I can be prepared by separating Compound A by SFC, and the specific preparation method is as follows: (1) React 4-bromo-3-methylbenzonitrile, 4-methoxypyridine, and benzyl chloroformate under the catalysis of a Grignard reagent to generate benzyl 2-(4-cyano-2-methylphenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate; (2) Carry out a hydrogenation reaction of benzyl 2-(4-cyano-2-methylphenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate to obtain benzyl 2-(4-cyano-2-methylphenyl)-4-oxopiperidine-1-carboxylate; (3) Reduce the carbonyl group in benzyl 2-(4-cyano-2-methylphenyl)-4-oxopiperidine-1-carboxylate to obtain benzyl 2-(4-cyano-2-methylphenyl)-4-hydroxypiperidine-1-carboxylate; (4) React benzyl 2-(4-cyano-2-methylphenyl)-4-hydroxypiperidine-1-carboxylate with a silylating agent in the presence of an acid-binding agent to protect the hydroxyl group, and purify to obtain trans-4-((tert-butyldiphenylsilyl)oxy)-2-(4-cyano-2-methylphenyl)piperidine-1-carboxylate; (5) Remove the hydroxyl protecting group from trans-4-((tert-butyldiphenylsilyl)oxy)-2-(4-cyano-2-methylphenyl)piperidine-1-carboxylate to obtain trans-2-(4-cyano-2-methylphenyl)-4-hydroxypiperidine-1-carboxylate; (6) Perform a nucleophilic substitution reaction of trans-2-(4-cyano-2-methylphenyl)-4-hydroxypiperidine-1-carboxylate with a halogenated hydrocarbon to obtain trans-2-(4-cyano-2-methylphenyl)-4-ethoxypiperidine-1-carboxylate; (7) React trans-2-(4-cyano-2-methylphenyl)-4-ethoxypiperidine-1-carboxylate with an acid and an alkyl alcohol to obtain trans-4-(4-ethoxypiperidin-2-yl)-3-methylbenzoate; (8) React trans-4-(4-ethoxypiperidin-2-yl)-3-methylbenzoate with tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate to obtain tert-butyl trans-4-(4-trans-ethoxy-2-(4-(alkoxycarbonyl)-2-methylphenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate; (9) Purify tert-butyl trans-4-(4-trans-ethoxy-2-(4-(alkoxycarbonyl)-2-methylphenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate by SFC to obtain tert-butyl 4-((2S,4S)-4-ethoxy-2-(4-(alkoxycarbonyl)-2-methylphenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate; (10) Hydrolyze tert-butyl 4-((2S,4S)-4-ethoxy-2-(4-(alkoxycarbonyl)-2-methylphenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate to obtain the compound of formula I: 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3-methylbenzoic acid. As a specific embodiment of the above preparation method, the Grignard reagent in step (1) is magnesium isopropyl bromide or magnesium isopropyl chloride. As a specific embodiment of the above preparation method, the silylating agent in step (4) is tert-butyldiphenylchlorosilane, and the acid-binding agent is imidazole. As a specific embodiment of the above preparation method, the halogenated hydrocarbon in step (6) is iodoethane. As a specific embodiment of the above preparation method, the acid in step (7) is sulfuric acid, and the alkyl alcohol is methanol. Technical solution three: The present invention also provides a composition, which comprises a compound of formula I or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, excipient and / or one or more other therapeutic agents. The carrier refers to a material that can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug, and deliver the drug to the target organ, which has no obvious irritation to the human body and will not eliminate the biological activity of the drug. The excipient refers to a material that forms a specific dosage form with the drug to facilitate drug administration, which should have no incompatibility with the drug, no side effects, and no influence on the efficacy. The other therapeutic agent refers to other drugs that can be co-administered with the compound of formula I and do not have adverse reactions with it. Technical solution four: The present invention also provides the use of a compound of formula A or formula I, a pharmaceutically acceptable form thereof or a pharmaceutical composition containing the same, for the preparation of a drug for treating a disease or disorder mediated by complement alternative pathway dysregulation. According to some specific embodiments of the present invention, the disease or disorder mediated by complement alternative pathway dysregulation is mediated by complement factor B. According to some specific embodiments of the present invention, the disease or disorder is a blood-related, autoimmune, inflammatory and / or neurodegenerative-related disease or disorder. According to some specific embodiments of the present invention, the disease or disorder is paroxysmal nocturnal hemoglobinuria, immunoglobulin A nephropathy, atypical hemolytic uremic syndrome, age-related macular degeneration, ANCA-associated vasculitis, systemic lupus erythematosus, immune thrombocytopenia, cold agglutinin disease and other diseases mediated by complement alternative pathway dysregulation and / or C3 glomerulopathy. Specific embodiments The technical solutions of the present invention will be described in detail below with reference to specific examples. For those not specified in the examples, they are carried out according to conventional conditions or conditions recommended by the manufacturer. For reagents or instruments whose manufacturers are not specified, they are all conventional products that can be obtained through commercial purchase. Unless otherwise specified, column chromatography generally uses silica gel with 200-300 meshes as the carrier, and the reaction temperature is room temperature (20-30 °C). Abbreviations and Their Meanings CbzCl Benzyl chloroformate EA Ethyl acetate PE Petroleum ether MTBE Methyl tert-butyl ether TBDPSCl tert-Butyldiphenylchlorosilane SFC Supercritical fluid chromatography Example 1 This example provides a compound of formula I, and its preparation method is as follows: Synthetic route: 1. At 10 - 15°C, isopropylmagnesium chloride (THF, 1.3 M, 112 mL) was slowly added dropwise to a solution of 4-bromo-3-methylbenzonitrile (27 g, 138 mmol) in tetrahydrofuran (108 mL). After the addition was complete, tetrahydrofuran (108 mL) was added, and the temperature was lowered to -5°C. 4-Methoxypyridine (15 g, 138 mmol) and CbzCl (23.5 g, 138 mmol) were added to the reaction solution, and the mixture was stirred at -5°C for 10 h. After the reaction was completed, the reaction was quenched with HCl (5 M, 60 mL), and the mixture was extracted with EA (200 ml). The organic phase was washed with saturated sodium chloride solution (100 ml), dried over anhydrous sodium sulfate, the solvent was removed, and the crude product was purified by silica gel column chromatography, EA / PE (1 / 2), to obtain benzyl 2-(4-cyano-2-methylphenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (28.8 g, yield 60.4%). LCMS (ESI, m / z): [M + H] + = 347.1 2. Under nitrogen protection at room temperature, zinc powder (13.2 g, 202 mmol) was added to a solution of benzyl 2-(4-cyano-2-methylphenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (28.0 g, 80.8 mmol) in acetic acid (100 m), and the mixture was reacted at 80°C for 1 h. After the reaction was completed, the filter cake was removed by filtration, the filtrate was concentrated by evaporation, and the crude product was dissolved in MTBE (150 mL) and water (80 mL). The organic phase was separated, washed with saturated sodium chloride solution (80 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain benzyl 2-(4-cyano-2-methylphenyl)-4-oxopiperidine-1-carboxylate (18.2 g). LCMS (ESI, m / z): [M + H] + = 349.0 3. Under nitrogen protection, at -45 °C, a solution of lithium borohydride in tetrahydrofuran (2 M, 36.9 mL) was added dropwise to a solution of benzyl 2-(4-cyano-2-methylphenyl)-4-oxopiperidine-1-carboxylate (19.5 g, 55.9 mmol) in tetrahydrofuran (195 mL). The reaction was carried out at -45 °C for 1 h. After the reaction was completed, the reaction was quenched by adding a saturated aqueous solution of potassium bisulfate (100 mL). MTBE (300 mL) and saturated sodium chloride solution (300 mL) were added, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate and then evaporated to dryness to obtain benzyl 2-(4-cyano-2-methylphenyl)-4-hydroxypiperidine-1-carboxylate (19.0 g, yield 96.8%). LCMS(ESI,m / z):[M+H] + = 351.0。 4. Benzyl 2-(4-cyano-2-methylphenyl)-4-hydroxypiperidine-1-carboxylate (19 g, 54.2 mmol, 1.0 equiv) was dissolved in DMF (190 mL). At room temperature, TBDPSCl (19.4 g, 70.5 mmol, 1.3 equiv) and imidazole (5.02 g, 73.7 mmol, 1.36 equiv) were added, and the mixture was stirred at room temperature for 12 h. After the reaction was completed, saturated brine (150 mL) and MTBE (200 mL) were added at room temperature, and the layers were separated. The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (EA / PE = 1 / 10) gave trans-4-((tert-butyldiphenylsilyl)oxy)-2-(4-cyano-2-methylphenyl)piperidine-1-carboxylate (4 g, yield 12.5%). LCMS(ESI,m / z):[M+H] + = 589.2。 5. Trans-4-((tert-butyldiphenylsilyl)oxy)-2-(4-cyano-2-methylphenyl)piperidine-1-carboxylate (3 g, 5.1 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (30 mL). At room temperature, tetrabutylammonium fluoride (2.41 g, 7.64 mmol) was added, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, saturated brine (20 mL) and MTBE (10 mL) were added at room temperature. After stirring, the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the crude product by column chromatography (EA / PE = 1 / 10 to 1 / 2) gave trans-2-(4-cyano-2-methylphenyl)-4-hydroxypiperidine-1-carboxylate (1.75 g, yield 98.02%). LCMS(ESI,m / z):[M+H] + = 351.1。 6. Sodium hydride (499 mg, 12.5 mmol, 60% purity) was dissolved in DMF (9 mL), and the temperature was lowered to -5 °C. Trans-2-(4-cyano-2-methylphenyl)-4-hydroxypiperidine-1-carboxylate (1.75 g, 4.99 mmol) was added to the reaction solution, and the mixture was stirred at -5 to 0 °C for 30 min. Iodoethane (2.65 g, 17 mmol) was added dropwise, and the mixture was stirred at -5 to 0 °C for 1 h. After the reaction was completed, the reaction was quenched by adding a saturated solution of potassium bisulfate (30 mL). Ethyl acetate (80 mL) was added for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (EA / PE = 1 / 5) to obtain trans-2-(4-cyano-2-methylphenyl)-4-ethoxypiperidine-1-carboxylate (1.3 g, yield 68.8%). LCMS (ESI, m / z): [M+H] + = 379.1. 7. Trans-2-(4-cyano-2-methylphenyl)-4-ethoxypiperidine-1-carboxylate (1.3 g, 3.43 mmol) was dissolved in methanol (13 mL) and water (13 mL), sulfuric acid (23.9 g, 243 mmol) was added, and the reaction was carried out at 80 °C for 12 h. After the reaction was completed, saturated sodium carbonate solution was added to adjust the pH to 8 - 9. Ethyl acetate (40 mL) was added for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH = 5 / 1) to obtain methyl trans-4-(4-ethoxypiperidin-2-yl)-3-methylbenzoate (600 mg, yield 62.9%). LCMS (ESI, m / z): [M+H] + = 278.0. 8. Under nitrogen protection at room temperature, magnesium sulfate (796 mg, 6.62 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (1.26 g, 4.37 mmol) were added to a solution of methyl trans-4-(4-ethoxypiperidin-2-yl)-3-methylbenzoate (600 mg, 2.16 mmol) in 1,2-dichloroethane (12 mL), and the reaction was carried out at room temperature for 4 h. Sodium triacetoxyborohydride (1.63 g, 7.68 mmol) was added to the reaction solution, and the reaction was carried out at room temperature for 12 h. After the reaction was completed, the filtrate was obtained by filtration, and the solvent was removed to obtain the crude product. Purification by preparative liquid chromatography gave tert-butyl trans-4-(4-trans-ethoxy-2-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (500 mg, yield 41.9%). Conditions are as follows (column type: Welch Ultimate XB-CN 250*50*10 μm; mobile phase: n-hexane:ethanol = 97:3 by volume, isocratic elution, flow rate: 60 mL / min; wavelength: 254 nm / 220 nm, RT = 8.5 min). LCMS(ESI,m / z):[M+H] + = 551.3. 9. Tert-butyl trans-4-(4-trans-ethoxy-2-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (500 mg) was purified by SFC to give tert-butyl 4-((2R,4R)-4-ethoxy-2-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (210 mg, yield 42%) and tert-butyl 4-((2S,4S)-4-ethoxy-2-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (165 mg, yield 33%). SFC conditions: column type: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: CO2:MeOH = 7:3 by volume, isocratic elution, wavelength: 254 / 220 nm; flow rate: 40 mL / min; the retention times of the two products are RT1 = 10.2 min and RT2 = 16.5 min respectively. LCMS(ESI,m / z):[M+H] + = 551.3. 10. tert-Butyl 4-((2R,4R)-4-ethoxy-2-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (210 mg, 0.381 mmol) and lithium hydroxide (101 mg, 4.19 mmol) were dissolved in tetrahydrofuran (2.3 mL) and water (2.3 mL), and the reaction was carried out at 50 - 55 °C for 5.5 h. After the reaction was completed, it was neutralized to pH = 7 - 8 with HCl (1 M), and the solvent was removed to obtain the crude product. Purification by preparative liquid chromatography gave 4-((2R,4R)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3-methylbenzoic acid (Compound II, 68.8 mg, yield 41.2%). Preparation conditions, column type: Waters xbridge 150*25 mm 10 μm; mobile phase A: water (0.1% NH4HCO3), mobile phase B: acetonitrile; gradient: 16% B to 46% B in 10 min; flow rate: 40 mL / min; wavelength: 254 / 220 nm; RT = 12 min. LCMS(ESI,m / z):[M+H] + = 437.2. 1 H NMR(400MHz,CDCl3)δ9.75 - 9.25(broad,1H),8.25(s,1H),7.95(s,1H),7.75 - 7.45(broad,1H),7.01(s,1H),6.55(s,1H),6.34(s,1H),4.50 - 4.45(m,2H),3.72 - 3.55(m,7H),3.52 - 3.30(m,4H),3.01(s,1H),2.41(s,6H),2.05 - 1.75(m,2H),1.22(s,3H). 11. tert-Butyl 4-((2S,4S)-4-ethoxy-2-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (163 mg, 0.296 mmol) and lithium hydroxide (77.9 mg, 3.26 mmol) were dissolved in tetrahydrofuran (1.4 mL) and water (1.4 mL), and the reaction was carried out at 50 - 55 °C for 5.5 h. After the reaction was completed, it was neutralized to pH = 7 - 8 with HCl (1 M), and the solvent was removed to obtain the crude product. Purification by preparative liquid chromatography gave 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3-methylbenzoic acid (Compound I, 88.4 mg, yield 68.1%). Preparation conditions: column type: Waters xbridge 150*25 mm 10um; mobile phase A: water (0.1% NH4HCO3), mobile phase B: acetonitrile; gradient: 15% B to 45% B in 10 min; flow rate: 40 mL / min; wavelength: 254 / 220 nm; RT = 12 min. LCMS(ESI,m / z):[M+H] + = 437.2. 1 H NMR(400MHz,CDCl3)δ9.75 - 9.25(broad,1H),8.25(s,1H),7.95(s,1H),7.75 - 7.45(broad,1H),7.01(s,1H),6.55(s,1H),6.34(s,1H),4.50 - 4.45(m,2H),3.72 - 3.55(m,7H),3.52 - 3.30(m,4H),3.01(s,1H),2.41(s,6H),2.05 - 1.75(m,2H),1.22(s,3H). Example 2 Reaction route: Experimental operation: 1: Compound S1 (46.9 g, 138 mmol) was added to anhydrous tetrahydrofuran (500 mL). The reaction temperature was lowered to 0 °C, and LiAlD4 (3.46 g, 4.71 mL) was added dropwise. The reaction was carried out at 25 °C for 1 hour. Thin-layer chromatography (ethyl acetate: petroleum ether = 20:1) was used to monitor the complete consumption of the starting material. The reaction mixture was slowly added dropwise with water (50.0 mL) at 0 - 10 °C, and extracted with ethyl acetate (100 mL × 2). The organic phase was directly concentrated and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10:1 to 3:1) to obtain Compound 1 (19.0 g, yield: 43.8%). 2: Compound 1 (17.9 g, 56.8 mmol) was added to ethylene glycol dimethyl ether (200 mL). The reaction temperature was lowered to 0 °C, and boron tribromide (9.23 g, 34.1 mmol) was added. The reaction was carried out at 45 °C for 4 hours. Thin-layer chromatography (ethyl acetate: petroleum ether = 20:1) was used to monitor the complete consumption of the starting material. The reaction mixture was slowly added dropwise with saturated sodium bicarbonate solution (100 mL) and water (50.0 mL) at 0 - 10 °C, and extracted with ethyl acetate (100 mL × 3). The organic phase was directly concentrated to obtain Compound 2 (21.0 g, yield: 97.7%). 3: Compound 2 (21.0 g, 55.5 mmol) was added to anhydrous tetrahydrofuran (220 mL). The temperature was lowered to 0 °C, and LiAlD4 (1.87 g, 44.4 mmol) was added dropwise. The reaction was carried out at 25 °C for 0.5 hour, and then heated to 66 °C for 3 hours. Thin-layer chromatography (ethyl acetate: petroleum ether = 0:1) was used to monitor the complete consumption of the starting material. The reaction mixture was slowly added dropwise with water (20.0 mL) at 0 °C, and extracted with ethyl acetate (100 mL × 2). The organic phase was directly concentrated and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100:1 to 10:1) to obtain Compound 3 (19.0 g, crude product). 4: 3 (16.5 g, 55.0 mmol) was added to anhydrous tetrahydrofuran (170 mL), and the temperature was lowered to -70 to -60 °C. Isopropylmagnesium chloride-lithium chloride complex (1.30 M, 46.5 mL) was added dropwise. After reacting at this temperature for 1 hour, 4-methoxypyridine (6.60 g, 60.5 mmol) and benzyl chloroformate (10.3 g, 60.5 mmol) were added, and then the system was reacted at -70 to -60 °C for 1 hour. Thin-layer chromatography (ethyl acetate: petroleum ether = 5:1) monitored the complete consumption of the starting materials; hydrochloric acid (5 M, 50.0 mL) was added to the reaction solution, and it was extracted with ethyl acetate (200 mL * 3), washed with saturated sodium bicarbonate solution (500 mL * 2), and the organic phase was dried over anhydrous sodium sulfate. The dried organic phase was directly filtered and concentrated, and was separated and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100:1 to 3:1) to obtain compound 4 (20.0 g, yield: 87.8%). LCMS(ESI,m / z):[M+H] + = 404.9。 5: Compound 4 (7.20 g, 17.8 mmol) was added to acetic acid (30.0 mL), the reaction temperature was raised to 30 - 40 °C, zinc powder (3.57 g, 49.1 mmol) was added, and the reaction was carried out at 80 °C for 1 hour. 1 1H NMR monitored the complete consumption of the starting materials. The reaction solution was filtered, the filter cake was washed with ethyl acetate (100 mL * 1), the filtrate was diluted with ethyl acetate (300 mL), the organic phases were combined, washed with saturated sodium bicarbonate solution (500 mL * 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 5 (6.68 g, yield: 92.3%). 6: Compound 5 (6.68 g, 16.4 mmol) was added to anhydrous tetrahydrofuran (70.0 mL), the reaction temperature was lowered to -40 °C, lithium borohydride in tetrahydrofuran solution (2 M, 10.7 mL) was added dropwise, and the reaction was carried out at -40 °C for 1 hour. Thin-layer chromatography (ethyl acetate: petroleum ether = 5:1) monitored the complete consumption of the starting materials. The reaction solution was slowly added dropwise with ammonium chloride aqueous solution (50.0 mL) at 0 °C, the reaction solution was extracted with ethyl acetate (100 mL * 3), and the organic phase was directly concentrated and separated and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100:1 to 50:1) to obtain compound 6 (5.70 g, yield 84.8%). LCMS(ESI,m / z):[M+H] + = 409。 7: 6 (2.00 g, 4.91 mmol) was added to 1-methyl-2-pyrrolidone (20.0 mL). Sodium hydride (490 mg, 12.2 mmol, 60% purity) was added under a nitrogen atmosphere at 0 °C. The reaction was carried out at 25 °C for 1 hour, and then iodoethane (2.68 g, 17.1 mmol) was added under a nitrogen atmosphere at 0 - 5 °C. The reaction was carried out at 25 °C for 3 hours. Thin layer chromatography (ethyl acetate: petroleum ether = 5:1) showed that the raw materials were completely consumed. At 0 °C, an aqueous ammonium chloride solution (10.0 mL) was added to the reaction solution. The reaction solution was extracted with ethyl acetate (50 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 7 (1.66 g, yield: 77.6%) was obtained by column chromatography separation and purification. LCMS (ESI, m / z): [M+H] + = 391.1. 8: Bis(triphenylphosphine)palladium(II) dichloride (311 mg, 381 μmol) was added to anhydrous methanol (40.0 mL) and acetonitrile (10.0 mL). Compound 7 (1.66 g, 3.81 mmol) and triethylamine (1.54 g, 15.2 mmol) were added successively. The system was purged with Ar three times and then with CO three times. The system was heated to 125 °C under a CO (2 Mpa) atmosphere and reacted for 12 hours. TLC (petroleum ether / ethyl acetate = 5:1) showed that the raw materials were completely consumed. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. Compound 8 (1.11 g, yield: 70.3%) was obtained by column chromatography (SiO2, petroleum ether / ethyl acetate = 100:1 to 3:1) separation and purification. LCMS (ESI, m / z): [M+H] + = 415.3. 9: Compound 8 (1.10 g, 2.65 mmol) was dissolved in anhydrous ethanol (10.0 mL) and tetrahydrofuran (10.0 mL). Palladium on carbon (2.82 g, 10.0%) was added under an argon atmosphere. Then the system was purged with argon three times and then with hydrogen three times. The reaction was carried out at 25 °C for 12 hours under a hydrogen (15 Psi) atmosphere. The formation of compound 9 was monitored by LCMS. The reaction solution was filtered and concentrated under reduced pressure to obtain compound 9 (700 mg, yield: 97.0%). LCMS (ESI, m / z): [M+H] + = 281.0. 10: Compound 9 (700 mg, 2.50 mmol) was dissolved in N,N-dimethylformamide (10.0 mL). Potassium iodide (414 mg, 2.50 mmol), potassium carbonate (6.90 mg, 4.99 mmol) and compound 12 (1.16 g, 3.74 mmol) were added successively, and the reaction was carried out at room temperature for 2 hours. The formation of compound 10 was monitored by TLC (petroleum ether / ethyl acetate = 3:1). Water (20.0 mL) was added to the reaction system, and the reaction solution was extracted with ethyl acetate (10.0 mL * 3). The organic phase was washed with brine (20.0 mL * 1), separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 10 (500 mg, yield: 91.7%) was obtained by separation and purification through column chromatography (SiO2, petroleum ether / ethyl acetate = 100:1 to 4:1). LCMS (ESI, m / z): [M+H] + = 554.7 11: Compound 10 was subjected to chiral resolution by the following method (which was further separated by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); mobile phase: [CO2 - isopropanol]; B%: 25%, isocratic elution, column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); mobile phase: [CO2 - EtOH]; B%: 35%, isocratic elution and column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); mobile phase: [CO2 - isopropanol]; B%: 30%, isocratic elution).) to obtain Compound 11_Peak 1 (30.0 mg, yield: 6.00%, retention time 3.5 min); Compound 11_Peak 2 (30.0 mg, yield: 6.00%, retention time 5.5 min); Compound 11_Peak 3 (180 mg, yield: 36.0%, retention time 12.5 min); Compound 11_Peak 4 (200 mg, yield: 40.0%, retention time 15.5 min). LCMS (ESI, m / z): [M+H] + = 554.3 12: Compound 11_Peak 1 (30.0 mg, 54.1 μmol) was added to anhydrous methanol (0.50 mL) and water (0.10 mL). Lithium hydroxide monohydrate (11.3 mg, 270 μmol) was added successively. The reaction system was heated to 60 °C and reacted for 12 hours. LCMS showed that the raw material was completely consumed. Methanol was removed by concentration under reduced pressure. The pH of the aqueous phase was adjusted to 7 with hydrochloric acid (0.5 M), and the aqueous phase was extracted with ethyl acetate (10.0 mL * 3). The combined organic phases were directly concentrated under reduced pressure. Purification was carried out by neutral reversed-phase high-performance liquid chromatography (column: CD24-WePure Biotech XPT C18 150*25*7um; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 12%-42% B over 11.0 min). Compound LB220-D01-1 (6.86 mg, yield: 28.6%) was obtained. LCMS (ESI, m / z): [M+H] + = 440.3. 1 H NMR: EC19837-666-P1A1 (400 MHz, CHLOROFORM-d) δ = 9.93 - 8.92 (m, 1H), 8.38 - 8.12 (m, 1H), 7.97 - 7.86 (m, 1H), 7.80 - 7.49 (m, 1H), 7.05 - 6.92 (m, 1H), 6.59 - 6.48 (m, 1H), 6.35 (br s, 1H), 4.51 - 4.36 (m, 1H), 4.30 - 4.16 (m, 1H), 3.78 - 3.71 (m, 1H), 3.66 (br s, 3H), 3.50 - 3.44 (m, 2H), 3.36 (br s, 1H), 2.98 (br d, J = 2.0 Hz, 1H), 2.39 (br s, 5H), 2.00 (br d, J = 12.5 Hz, 1H), 1.84 - 1.75 (m, 1H), 1.31 - 1.17 (m, 4H). 13: Compound 11_Peak2 (30.0 mg, 54.1 μmol) was added to anhydrous methanol (0.50 mL) and water (0.10 mL), and lithium hydroxide monohydrate (11.3 mg, 270 μmol) was added successively. The temperature of the system was raised to 60 °C and the reaction was carried out for 12 hours. LCMS showed that the raw material was completely consumed. Methanol was removed by concentration under reduced pressure, and the pH of the aqueous phase was adjusted to 7 with hydrochloric acid (0.5 M). The aqueous phase was extracted with ethyl acetate (10.0 mL * 3), and the combined organic phases were directly concentrated under reduced pressure. Purification was carried out by neutral reversed-phase high-performance liquid chromatography (column: CD24-WePure Biotech XPT C18 150 * 25 * 7 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 12%-42% B over 11.0 min). Compound LB220-D01-2 (9.81 mg, yield: 40.0%) was obtained. LCMS (ESI, m / z): [M + H] + = 440.3. 1 H NMR: EC19837-668-P1A2 (400 MHz, DMSO-d6) δ = 7.93 - 7.79 (m, 2H), 7.78 - 7.70 (m, 1H), 7.27 - 7.19 (m, 1H), 6.68 - 6.61 (m, 1H), 6.45 - 6.35 (m, 1H), 3.89 (br d, J = 10.8 Hz, 1H), 3.70 - 3.65 (m, 3H), 3.64 - 3.53 (m, 2H), 3.47 - 3.36 (m, 2H), 3.31 (br d, J = 11.4 Hz, 1H), 2.55 (br d, J = 12.0 Hz, 2H), 2.39 (s, 3H), 1.82 (br d, J = 12.1 Hz, 1H), 1.69 - 1.54 (m, 2H), 1.25 - 1.18 (m, 1H), 1.16 - 0.99 (m, 3H). 14: Compound 11_Peak 3 (180 mg, 325 μmol) was added to anhydrous methanol (1.00 mL) and water (0.50 mL). Lithium hydroxide monohydrate (68.2 mg, 1.63 mmol) was added successively. The temperature of the system was raised to 60 °C and the reaction was carried out for 12 hours. LCMS showed that the raw material was completely consumed. Methanol was removed by concentration under reduced pressure. The pH of the aqueous phase was adjusted to 7 with hydrochloric acid (0.5 M), and the aqueous phase was extracted with ethyl acetate (10.0 mL * 3). The combined organic phases were directly concentrated under reduced pressure. Purification was carried out by neutral reverse-phase high-performance liquid chromatography (column: CD24-WePure Biotech XPT C18 150*25*7um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 12%-42% B over 11.0 min). Compound LB220-D01-3 (52.4 mg, yield: 36.0%) was obtained. LCMS (ESI, m / z): [M+H] + = 440.3. 1 H NMR: EC19837-665-P1A (400 MHz, DMSO-d6) δ = 10.85 - 10.77 (m, 1H), 7.90 - 7.80 (m, 2H), 7.80 - 7.73 (m, 1H), 7.28 - 7.22 (m, 1H), 6.68 - 6.61 (m, 1H), 6.43 - 6.36 (m, 1H), 3.69 (s, 3H), 3.55 - 3.51 (m, 1H), 3.47 (br s, 1H), 3.45 - 3.39 (m, 3H), 3.15 (br d, J = 11.8 Hz, 1H), 2.79 (br d, J = 12.1 Hz, 1H), 2.44 - 2.38 (m, 3H), 2.10 - 2.01 (m, 1H), 1.97 (br d, J = 11.0 Hz, 1H), 1.88 - 1.80 (m, 1H), 1.40 - 1.30 (m, 1H), 1.25 - 1.15 (m, 1H), 1.07 - 1.01 (m, 3H). 15: Compound 11_Peak 4 (200 mg, 331 μmol) was added to anhydrous methanol (1.00 mL) and water (0.50 mL). Lithium hydroxide monohydrate (75.7 mg, 1.81 mmol) was added successively. The reaction system was heated to 60 °C and reacted for 12 hours. LCMS showed that the raw materials were completely consumed. Methanol was removed by concentration under reduced pressure. The pH of the aqueous phase was adjusted to 7 with hydrochloric acid (0.5 M), and the aqueous phase was extracted with ethyl acetate (10.0 mL * 3). The combined organic phases were directly concentrated under reduced pressure. Purification was performed by neutral reversed-phase high-performance liquid chromatography (column: CD24-WePure Biotech XPT C18 150*25*7um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 12%-42% B over 11.0 min). Compound LB220-D01-4 (59.8 mg, yield: 37.5%) was obtained. LCMS (ESI, m / z): [M+H] + = 440.3. 1 H NMR: EC19837-665-P1A (400 MHz, CHLOROFORM-d) δ = 8.05-7.97 (m, 2H), 7.94 (br s, 1H), 7.91 (s, 1H), 7.21-7.17 (m, 1H), 6.70-6.68 (m, 1H), 6.65 (br s, 1H), 3.78 (s, 4H), 3.51 (q, J = 7.0 Hz, 3H), 3.44-3.37 (m, 1H), 3.29 (br d, J = 12.4 Hz, 1H), 3.05 (br d, J = 11.8 Hz, 1H), 2.46 (s, 3H), 2.15 (br d, J = 12.6 Hz, 1H), 2.09-2.04 (m, 1H), 1.92 (br d, J = 12.1 Hz, 1H), 1.64-1.50 (m, 2H), 1.17 (t, J = 7.0 Hz, 3H). Example 3 Reaction route: Experimental operation: 1: Compound 1 (2.00 g, 8.43 mmol, 1.00 eq) was dissolved in MeCN (20.0 mL). At 25 °C, Boc2O (5.52 g, 25.3 mmol, 5.81 mL, 3.00 eq) and DMAP (412 mg, 3.37 mmol, 0.40 eq) were added. The reaction mixture was stirred at 25 °C for 8 h. Thin-layer chromatography (TLC, SiO2, petroleum ether / ethyl acetate = 10:1) showed complete consumption of the starting material. At 25 °C, saturated aqueous NH4Cl solution (20.0 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2, petroleum ether / ethyl acetate = 20:1 to 10:1) gave compound 2 (2.80 g, yield: 98.5%). 2: Compound 2 (2.80 g, 8.30 mmol, 1.00 eq) was dissolved in EtOH (25.0 mL). At 25 °C, Pd / C (883 mg, 830 μmol, purity 10.0%, 0.10 eq) and HCOONH4 (549 mg, 8.71 mmol, 1.05 eq) were added. The reaction mixture was stirred at 45 °C for 3 h. TLC (SiO2, petroleum ether / ethyl acetate = 10:1) showed complete consumption of the starting material. The reaction mixture was filtered through celite. The cake was washed with MeOH (50.0 mL). The combined organic phases were concentrated under reduced pressure to give compound 3 (2.10 g, crude product). 3: Compound 3 (1.60 g, 6.47 mmol, 1.00 eq) was dissolved in THF (30.0 mL). At 20 - 25 °C, MeMgBr (3.00 M, 2.26 mL, 1.05 eq) was slowly added dropwise. The reaction mixture was stirred at 45 °C for 0.5 h, then paraformaldehyde (640 mg, 19.4 mmol, 3.00 eq) was added. The reaction mixture was stirred at 65 °C for 1 h. TLC (SiO2, petroleum ether / ethyl acetate = 10:1, R f = 0.66) showed complete consumption of the starting material. At 25 °C, saturated aqueous NH4Cl solution (20.0 mL) was slowly added dropwise to the reaction mixture. The mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 100:1) gave yellow solid compound 4 (640 mg, yield: 35.9%). 4: Compound 4 (640 mg, 2.32 mmol, 1.00 eq) and K2CO3 (643 mg, 4.65 mmol, 2.00 eq) were dissolved in MeCN (7.00 mL). CD3I (674 mg, 4.65 mmol, 289 μL, 2.00 eq) was added at 25 °C, and the reaction mixture was stirred at 25 °C for 8 h. Thin-layer chromatography plate detection (SiO2, petroleum ether / ethyl acetate = 20:1) monitored that the raw materials were completely consumed. Water (10.0 mL) was added to the reaction mixture at 25 °C, and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification was carried out by column chromatography (SiO2, petroleum ether / ethyl acetate = 20:1). Compound 5 (600 mg, yield: 88.3%) was obtained. 5: Compound 6 (600 mg, 2.05 mmol, 1.00 eq) and 5 (569 mg, 2.05 mmol, 1.00 eq) were dissolved in DCE (10.0 mL). MgSO4 (741 mg, 6.16 mmol, 3.00 eq) was added at 25 °C, and the reaction mixture was stirred at 25 °C for 12 h. Then, NaBH(OAc)3 (1.52 g, 7.18 mmol, 3.50 eq) was added at 25 °C, and the reaction mixture was stirred at 25 °C for 12 h. LCMS showed that the raw materials were completely consumed. The reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with EtOAc (20.0 mL). The combined organic phases were washed with saturated aqueous NaHCO3 solution (15.0 mL), washed with water (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification was carried out by normal-phase reversed-phase high-performance liquid chromatography (column: Phenomenex luna C18 100*40 mm*3 um; mobile phase: [H2O(0.05% HCl)-ACN]; gradient: 38%-68% B over 15.0 min). Compound 7_Peak1 (170 mg, yield: 15.0%, retention time 4.8 min) was obtained. Compound 7_Peak2 (209 mg, yield: 16.7%, retention time 8.5 min) was obtained. Compound LB220-D05-7_Peak3 (32.0 mg, yield: 2.82%, retention time 13.4 min) was obtained. LCMS (ESI, m / z): [M+H] + = 554.4. 6: Compound 7_Peak1 (170 mg, 307 μmol, 1.00 eq) was dissolved in MeOH (5.00 mL) and H2O (1.00 mL), and lithium hydroxide monohydrate (129 mg, 3.07 mmol, 10.0 eq) was added. The reaction mixture was reacted at 60 °C for 8 hours. LCMS showed that the raw material was completely consumed. The reaction mixture was adjusted to pH 7 - 8 with hydrochloric acid (2.00 M) and then concentrated under reduced pressure. It was separated and purified by neutral reversed-phase high-performance liquid chromatography (column: CD07-Daisogel SP-100-8-ODS-PK 150*25*10um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 15% - 45% B over 10.0 min). Compound LB220-D05-1 (40.53 mg, yield: 29.1%) was obtained. 1 1H NMR: (400 MHz, MeOD) δ 8.02 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 3.2 Hz, 1H), 6.75 (s, 1H), 6.32 (d, J = 2.8 Hz, 1H), 4.59 - 4.64 (m, 2H), 4.24 - 4.27 (m, 1H), 4.00 - 4.03 (m, 1H), 3.72 - 3.78 (m, 1H), 3.55 - 3.60 (m, 2H), 3.47 - 3.50 (m, 1H), 2.55 (s, 3H), 2.50 (s, 3H), 2.30 - 2.34 (m, 1H), 2.17 - 2.20 (m, 1H), 1.83 - 1.93 (m, 1H), 1.69 - 1.77 (m, 1H), 1.16 (t, J = 7.0 Hz, 3H). LCMS (ESI, m / z): [M + H] + = 440.2. 7: Compound 7_Peak2 (209 mg, 3.77 μmol, 1.00 eq) was dissolved in MeOH (5.00 mL) and H2O (1.00 mL), and lithium hydroxide monohydrate (158 mg, 3.77 mmol, 10.0 eq) was added. The reaction mixture was stirred at 60 °C for 8 h. LCMS analysis showed complete consumption of the starting material. The reaction mixture was adjusted to pH 7 - 8 with hydrochloric acid (2.00 M) and then concentrated under reduced pressure. The product was purified by neutral reversed-phase high-performance liquid chromatography (column: CD07-Daisogel SP-100-8-ODS-PK 150*25*10um; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 15% - 45% B over 10.0 min). Compound LB220-D05-2 (64.40 mg, yield: 38.8%) was obtained. 1 H NMR: (400 MHz, MeOD) δ 8.02 (d, J = 8.0 Hz, 1H), 7.91 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 3.2 Hz, 1H), 6.75 (s, 1H), 6.40 (d, J = 2.4 Hz, 1H), 4.59 (s, 1H), 4.29 - 4.32 (m, 1H), 4.16 - 4.19 (m, 1H), 3.80 (s, 1H), 3.59 - 3.64 (m, 2H), 3.53 - 3.56 (m, 1H), 3.36 (s, 1H), 2.53 (s, 3H), 2.50 (s, 3H), 2.10 - 2.21 (m, 2H), 1.98 - 2.06 (m, 2H), 1.31 (t, J = 7.0 Hz, 3H). LCMS (ESI, m / z): [M+H] + = 440.2. 8: Compound 7_Peak3 (32 mg, 57.8 μmol, 1.00 eq) was dissolved in MeOH (5.00 mL) and H2O (1.00 mL), and lithium hydroxide monohydrate (24.3 mg, 578 μmol, 10.0 eq) was added. The reaction mixture was reacted at 60 °C for 8 hours. LCMS showed that the raw material was completely consumed. The reaction mixture was adjusted to pH 7 - 8 with hydrochloric acid (2.00 M) and then concentrated under reduced pressure. It was separated and purified by neutral reversed-phase high-performance liquid chromatography (column: CD02-Waters Xbidge BEH C18 150*25*10um; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 15% - 45% B over 10.0 min). Compound LB220-D05-3 (64.40 mg, yield: 38.8%) was obtained. 1 H NMR: (400 MHz, MeOD) δ 8.01 (d, J = 8.0 Hz, 1H), 7.90 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 3.2 Hz, 1H), 6.74 (s, 1H), 6.40 (d, J = 3.2 Hz, 1H), 4.60 (s, 1H), 4.25 - 4.29 (m, 1H), 4.12 - 4.15 (m, 1H), 3.79 (s, 1H), 3.56 - 3.63 (m, 2H), 3.49 - 3.56 (m, 1H), 3.34 (s, 1H), 2.52 (s, 3H), 2.49 (s, 3H), 2.08 - 2.18 (m, 2H), 1.98 - 2.05 (m, 2H), 1.30 (t, J = 7.0 Hz, 3H). LCMS (ESI, m / z): [M + H] + = 440.2. Example 4 Reaction route: Experimental operation: 1. Sodium hydride (600.00 mg, 15.00 mmol, purity 60%, 4.63 eq) was dissolved in N-methylpyrrolidone (12 mL), and compound LB220-2-7 (1.2 g, 3.24 mmol, 1 eq) was dissolved in N-methylpyrrolidone (3 mL). The solution was added to the reaction mixture at 0 - 5 °C, and the reaction mixture was reacted at 0 - 5 °C for 0.5 h. Then, iodoethane-d (1 g, 6.21 mmol, 1.92 eq) was added to the reaction mixture at 0 - 5 °C, and the mixture was stirred at 15 - 25 °C for 4 h. LCMS showed the formation of compound LB220-D06-1. Saturated ammonium chloride aqueous solution was added to the reaction mixture at 0 - 15 °C to adjust the pH to 6 - 7, and then the mixture was stirred for 0.5 h. The reaction mixture was extracted with ethyl acetate (30 mL × 2), and the combined organic phases were concentrated to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:0 to 20:1) to obtain compound LB220-D06-1 (0.95 g, yield 72%). LCMS(ESI,m / z):[M+H] + = 403.1. 2. Triethylamine (790 mg, 7.82 mmol, 1.09 mL, 3.32 eq) was dissolved in methanol (10 mL) and acetonitrile (20 mL). Pd(dppf)Cl2 (633 mg, 775 μmol, 3.29e-1 eq) and compound LB220-D06-1 (950 mg, 2.36 mmol, 1 eq) were added at 20 - 30 °C. Then, the reaction was carried out at 125 - 135 °C for 12 h under a carbon monoxide (3 Mpa) atmosphere. LCMS showed that the raw materials were completely consumed. The reaction mixture was cooled to 20 - 25 °C, and methanol and acetonitrile were removed by concentration. Then, ethyl acetate (10 mL) and water (10 mL) were added, and the mixture was filtered. The filtrate was separated. The aqueous phase was extracted with ethyl acetate (10 mL × 2), and the combined organic phases were concentrated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 50:0 to 30:1) to obtain compound LB220-D06-2 (710 mg, yield 78.8%). LCMS(ESI,m / z):[M+H] + = 383.2. 3. Compound LB220-D06-2 (710 mg, 1.86 mmol, 1.00 eq) was dissolved in ethyl acetate (1.4 mL), hydrochloric acid / ethyl acetate (2 M, 3.5 mL) was added, and then the mixture was stirred at 30 - 40 °C for 4 hours. LCMS showed that the raw material was completely consumed. The reaction solution was concentrated to remove ethyl acetate to obtain compound LB220-D06-3 (550 mg, crude hydrochloride). LCMS (ESI, m / z): [M+H] + = 283.2. 4. Compound LB220-D06-3 (200 mg, 627 μmol, 1.00 eq, HCl) was dissolved in N,N-dimethylformamide (2.00 mL). Potassium iodide (100 mg, 602 μmol, 1.06 eq), potassium carbonate (260 mg, 1.88 μmol, 3.00 eq) and compound LB220-D06-S2 (200 mg, 645 μmol, 1.03 eq) were added successively, and the reaction was carried out at 10 - 20 °C for 4 hours. LCMS showed that the raw material was completely consumed. Water (10.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10.0 mL * 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by thin layer chromatography plate (SiO2, petroleum ether / ethyl acetate = 3:1) gave compound LB220-D06-4 (234 mg, yield 67.1%). LCMS (ESI, m / z): [M+H] + = 556.3. 5. Compound LB220-D06-4 (234 mg, 421 μmol, 1.00 eq) was dissolved in methanol (2 mL) and water (0.5 mL). Lithium hydroxide monohydrate (177 mg, 4.21 mmol, 10 eq) was added at 15 - 25 °C. Then the mixture was stirred at 55 - 65 °C for 1 hour. LCMS showed that the raw material was completely consumed. The pH of the reaction solution was adjusted to 6 - 7 with hydrochloric acid (0.1 M), and then concentrated under reduced pressure to obtain the crude product. Purification by reverse phase preparation (CD20-Waters Xbidge BEH C18 250*25*10um; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 15% - 45% B over 10.0 min) gave compound LB220-D06 (48 mg, 99.9% purity). LCMS (ESI, m / z): [M+H]+ = 442.2. 1H NMR: EC20710-463-P1F (400 MHz, DMSO-d6), δ ppm: 10.81 (s, 1H), 7.95 - 7.89 (m, 1H), 7.88 - 7.82 (m, 1H), 7.76 (s, 1H), 7.25 (t, J = 2.80 Hz, 1H), 6.65 (s, 1H), 6.49 - 6.40 (m, 1H), 3.78 - 3.72 (m, 1H), 3.70 (s, 3H), 3.59 - 3.53 (m, 2H), 3.17 (d, J = 11.6 Hz, 1H), 2.54 - 2.51 (m, 1H), 2.43 (s, 3H), 2.41 (s, 3H), 2.39 - 2.30 (m, 1H), 1.84 - 1.80 (m, 1H), 1.72 - 1.62 (m, 1H), 1.61 - 1.43 (m, 2H). Example 5 Reaction route: Experimental procedure: 1: Add compound 1 (2.3 g, 5.77 mmol), zinc powder (1.38 g, 21.1 mmol) and zinc cyanide (3.68 g, 31.3 mmol) to N,N-dimethylformamide (23 mL). Under a nitrogen atmosphere, add 1,1-bis(diphenylphosphino)ferrocene palladium chloride (422 mg, 577 μmol), then heat the reaction solution to 130 - 135 °C and react at 130 - 135 °C for 4 hours. TLC (petroleum ether:ethyl acetate = 3:1) shows that the raw materials are completely consumed. Dilute the reaction solution with water (50 mL), extract the aqueous phase with ethyl acetate (50 mL × 2), wash the organic phase with saturated brine (50 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify by column chromatography (petroleum ether:ethyl acetate = 100:20 to 100:30) to obtain compound 2 (610 mg, crude product). LCMS (ESI, m / z): [M - 99] + = 245.1. 2: Compound 2 (200 mg, 580 μmol) was dissolved in anhydrous tetrahydrofuran (4 mL), and the temperature was lowered to -70 to -60 °C. Then, n-butyllithium (2.5 M, 301 μL) was added dropwise under a nitrogen atmosphere, and the reaction was carried out at -70 to -60 °C for 1 hour. Methanol-d (41.9 mg, 1.16 mmol) was added dropwise at -70 to -60 °C, and the reaction was carried out at -70 to -60 °C for 1 hour. LCMS showed that the starting material was completely consumed. The reaction solution was diluted with water (5 mL), and the aqueous phase was extracted with ethyl acetate (5 mL × 2). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether:ethyl acetate = 100:20 to 100:30) gave compound 3 (670 mg, yield: 47.8%). LCMS (ESI, m / z): [M - 99] + = 246.1 3: Compound 3 (730 mg, 2.11 mmol) was dissolved in water (7.3 mL) and sulfuric acid (7.3 mL), methanol (7.3 mL) was added, and the reaction was carried out at 75 - 80 °C for 24 hours. LCMS showed that the starting material was completely consumed. The pH was adjusted to 8 - 9 with saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 4 (520 mg, yield: 88.4%). LCMS (ESI, m / z): [M + H] + = 279.1 5: Compound 4 (520 mg, 1.87 mmol) and 5-methoxy-7-methyl-T-BOC-1H-indole-4-carbaldehyde (1.08 g, 3.74 mmol) were dissolved in 1,2-dichloroethane (10 mL), anhydrous magnesium sulfate (674 mg, 5.60 mmol) was added, and the mixture was stirred at 15 - 25 °C for 12 hours. Sodium triacetoxyborohydride (1.39 g, 6.54 mmol) was added, and the mixture was stirred at 15 - 25 °C for 12 hours. The mixture was filtered, and the filtrate was diluted with saturated aqueous sodium bicarbonate (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether:ethyl acetate = 100:20 to 100:30) gave compound 5 (690 mg, yield: 66.9%). LCMS (ESI, m / z): [M + H] + = 552.4 6: Compound 5 (670 mg, 1.21 mmol) was dissolved in methanol (10 mL), and lithium hydroxide monohydrate (2 M, 3.04 mL) was added. The reaction was carried out at 60 - 65 °C for 1 hour. LCMS showed that the raw material was completely consumed. The pH of the reaction solution was adjusted to 6 - 7 with hydrochloric acid (2 M), and then concentrated under reduced pressure. Purification was carried out by reversed-phase high-performance liquid chromatography (column: CD18 - Welch Utimate C18 150*40*7um; mobile phase: [H2O(0.05%HCl)-ACN]; gradient: 7% - 37% B over 10.0 min) and reversed-phase high-performance liquid chromatography (column: CD09 - Phenomenex Gemini C18 150*30*5um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 16% - 46% B over 13.0 min) to obtain compound 6 (55 mg, yield: 10.3%). LCMS(ESI,m / z):[M+H] + = 438.3. 7: Compound 6 (250 mg) was purified by SFC (column: SFC - IK - 30 - DAICEL CHIRAL IK(250mm*30mm,10um); mobile phase: [CO2 - MeOH(0.1%NH3H2O). Compounds LB220 - D08 - 1 (15 mg), LB220 - D08 - 3 (10 mg), LB220 - D08 (150 mg) and compound LB220 - D08 - 4 (15 mg) were obtained. LCMS(ESI,m / z):[M+H] + = 438.3. Example 6 - 10 With reference to the previous examples (the starting materials are different from those in the previous examples, and the preparation steps can refer to the previous examples), the following compounds were further synthesized. The LCMS data of each compound are shown in the following table: Comparative Example This comparative example provides compounds D1 and D2, and their structural formulas are as follows: Among them, D1 was purchased from MCE Company, and D2 was self - made. Its preparation method is as follows: 1. Under nitrogen protection, at room temperature, to a solution of (4-(methoxycarbonyl)-2-methylphenyl)boronic acid (500 mg, 2.58 mmol, 1 equiv) and 2-iodopyridine (600 mg, 2.93 mmol, 1.14 equiv) in 1,4-dioxane (4 mL) and water (1 mL), Pd(dppf)Cl2 (100 mg, 137 μmol, 0.05 equiv) and sodium carbonate (550 mg, 5.19 mmol, 2 equiv) were added respectively. Under nitrogen protection, the reaction was carried out at 100 °C for 2 hours. After the reaction was completed, it was diluted with water (5 mL), and extracted with EA (3×5 mL). The organic phases were combined, washed with saturated sodium chloride solution (2×30 mL), dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography, EA / PE (1 / 3), to obtain methyl 3-methyl-4-(pyridin-2-yl)benzoate (375 mg, yield 64%). LCMS(ESI,m / z):[M+H] + = 228.0. 2. At room temperature, to a solution of methyl 3-methyl-4-(pyridin-2-yl)benzoate (370 mg, 1.63 mmol, 1 equiv) in methanol (10 mL), HCl (261 μL, 12 M) and platinum dioxide (37 mg, 163 μmol, 0.1 equiv) were added respectively. It was replaced with argon three times and then with hydrogen three times, and reacted overnight at 60 °C under a hydrogen (2.0 MPa) atmosphere. The filter cake was removed by filtration, and after the filtrate was evaporated to dryness, methyl 3-methyl-4-(piperidin-2-yl)benzoate hydrochloride (430 mg) was obtained. LCMS(ESI,m / z):[M+H] + = 234.1. 3. Under nitrogen protection, at room temperature, potassium carbonate (750 mg, 5.43 mmol, 3.4 equiv) and potassium iodide (300 mg, 1.81 mmol, 1.13 equiv) were added to a solution of methyl 3-methyl-4-(piperidin-2-yl)benzoate (430 mg, 1.59 mmol, 1 equiv) and tert-butyl 4-(chloromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (750 mg, 2.42 mmol, 1.52 equiv) in DMF (10 mL) respectively. The reaction was carried out at room temperature for 2 h under nitrogen protection. After the reaction was completed, it was diluted with water (10 mL), and extracted with EA (3×10 mL). The organic phases were combined, washed with saturated sodium chloride solution (2×30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography, EA / PE (1 / 40~1 / 10), to give tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (610 mg, yield 75.5%). LCMS(ESI,m / z):[M+H] + = 507.3. 4. At room temperature, lithium hydroxide monohydrate (500 mg, 11.9 mmol, 10.1 equiv) was added to a solution of tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (600 mg, 1.18 mmol, 1.0 equiv) in methanol (6 mL) and water (2 mL). The reaction was carried out at 50 °C for 10 h under nitrogen protection. The obtained residue was concentrated under reduced pressure. The crude product was purified by preparative liquid phase to give 4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3-methylbenzoic acid (100 mg, yield 21.4%), with the following conditions (column type: CD20-Waters Xbidge BEH C18 250*25*10um; mobile phase: mobile phase A: water (0.1% NH4HCO3), mobile phase B: acetonitrile; gradient: 15 min 10% B - 40% B; flow rate: 40 mL / min; wavelength: 254 nm / 220 nm, RT = 12.5 min). LCMS(ESI,m / z):[M+H] + = 393.2. 11H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.85 (s, 2H), 7.75 (s, 1H), 7.25 (s, 1H), 6.64 (s, 1H), 6.45 (s, 1H), 3.96 (s, 3H), 3.54 (d, J = 12.0 Hz, 1H), 3.39 (m, 2H), 3.15 (d, J = 12.0 Hz, 1H), 2.80 (d, J = 11.2 Hz, 1H), 2.44 (s, 3H), 2.41 (s, 3H), 2.05 - 1.95 (m, 3H), 1.70 - 1.35 (m, 5H). Test Example The pharmacological activities of the compounds prepared in the examples of the present invention were investigated. Referring to the preclinical experimental data of the comparative example D1 of eculizumab, affinity experiments, in vitro enzyme activity experiments (CVF-Bb experiment, AP-deposition experiment, PNH-Like hemolysis experiment), and pharmacokinetic experiments in rats and mice were carried out respectively, and a parallel comparison was made with the comparative example D1 of eculizumab at the same time. In the preclinical experimental data of eculizumab, it was proved through the CVF-Bb experiment and the AP-deposition experiment that this drug has the potential to treat complement pathway-related nephropathies such as IgA nephropathy and blood diseases by targeting the complement pathway. The inventors investigated the compounds provided by the present invention using the same experimental items, and proved the pharmacological activities of the compounds of the present invention by comparing them with eculizumab. Test Example 1 Affinity Experiment Detect the affinity of the examples and comparative examples with complement factor B, and evaluate the binding strength of the compound with factor B. Experimental Materials: CFB (Sino Biological Inc.), NTA sensor (Sartorius), compound I of Example 1, and comparative compounds D1 and D2. Experimental Method: 1) Divide 8 NTA sensors into 2 groups, and pre-wet them in PBST for more than 10 min. Among them, 4 sensors are immobilized, and the other 4 sensors are used as reference sensors and do not need to be immobilized with protein. Add PBST to the first column of the 96-well sample plate, and add 50 μg / mL CFB to the second column. Set the baseline for 60 s and the loading for 3000 s to make the immobilization height reach more than 4 nm, and then perform baseline for 60 s for equilibration. 2) Take a new 96-well plate and set the Buffer and Sample wells. Add PBST + 0.1% DMSO buffer to the Buffer well, and add compound I, D1, and D2 to the Sample wells respectively. The drug concentrations are 2.47, 7.41, 22.22, 66.67, 200, 400 nM from left to right. 3) After curing is completed, first set a relatively long equilibration step (more than 10 minutes), and then enter the baseline / association / dissociation cycle. The Assay Definition is set as follows: baseline 60s, association 120s, dissociation 360s. 4) After setting the curing sensor cycle, add a set of reference sensor cycles, and this cycle program is consistent with the curing sensor cycle program. 5) After setting, set the position of the sensor in Sensor Assignment. The sensors are divided into two columns, one set of curing sensors and one set of reference sensors, with 4 sensors in each column. After checking the Review Experiment without errors, set the save path, file name, temperature, etc. in Run Experiment, and click GO to run. 6) Use the Octet analysis software Data Analysis software to perform kinetic and steady-state analysis on the raw data after double subtraction processing. Experimental results: The affinities of three compounds for complement factor B are shown in Table 1. Table 1 Affinity data As can be seen from the results in Table 1, the affinity of Compound I for complement factor B is higher than that of Comparative Examples D1 and D2, indicating that Compound I has a stronger binding to complement factor B and has the potential to treat related kidney diseases (such as IgA nephropathy) and blood diseases caused by abnormal complement alternative pathway by targeting CFB. Test Example 2 CVF-Bb experiment Cobra venom factor (CVF) is an anti-complement factor isolated from cobra venom. It is closely related to the complement system and has a similar function to the C3 degradation product C3b fragment. It can reversibly bind to factor B in serum at a ratio of 1:1 in vivo and in vitro to form a stable C3 cleavage complex CVF-B. Under the hydrolytic activation of factor D, the CVF-B complex is cleaved into CVF-Bb with C3 convertase function. Subsequently, CVF-Bb can cleave C3 to generate two fragments, C3b and C3a, further activating the alternative pathway of complement, thereby triggering a cascade amplification reaction, resulting in a large amount of activation and depletion of complement. Experimental materials: Purified human factor B, purified human factor D (complement technology), cobra venom factor, C3 protein (quidel), Anti-C3a / C3a des Arg antibody

[2991] , Goat Anti-Mouse IgG H&L (HRP) (Abcam), QuantaBlu Fluorogenic Peroxidase Substrate Kit, Thermo Scientific TM StartingBlock TM T20 (PBS) 1X (thermofisher), Compound I of Example 1, and Comparative Compounds D1 and D2. Experimental method: 1) Factor B, Factor D, and CVF were added to the experimental wells respectively. After mixing, they were incubated at 37 °C for 3 hours. 2) 100 mM solutions of Compound I, D1, and D2 were prepared with DMSO respectively and serially diluted 100-fold to prepare 1 mM working solutions. The working solutions were serially diluted in a 3-fold gradient to prepare each series of working solutions. During the experiment, 1 μL of each series of working solutions was added to each reaction well respectively, so that the final concentrations were 10000, 3333.33, 1111.11, 370.37, 123.45, 41.15, 13.72, 4.57, 1.52 nM respectively. After shaking evenly, they were incubated at 37 °C for 1 hour. 3) Human complement factor C3 protein was added to the reaction wells. After mixing, they were incubated at 37 °C for 2 hours to prepare C3 reaction samples. 4) 97 μL of coating buffer and 3 μL of reaction samples were added to a 96-well black adsorption plate respectively. After mixing, the plate was sealed and incubated at 4 °C overnight. 5) Washed 3 times with 300 μL of washing solution, 300 μL of startingBlock blocking buffer was added, and incubated at room temperature for 15 minutes. 6) Washed 3 times with 300 μL of washing solution, 100 μL of Anti-C3a / C3a des Arg antibody was added and incubated at 37 °C for 1 hour. 7) Washed 3 times with 300 μL of washing solution, 100 μL of Goat Anti-Mouse IgG H&L (HRP) was added and incubated at 37 °C for 30 minutes. 8) Washed 3 times with 300 μL of washing solution, 100 μL of Quantablu substrate solution was added and incubated at room temperature for 20 minutes. 9) 100 μL of Quantablu stop solution was added. 10) The absorbance values at 320 nm and 420 nm were measured using a microplate reader. Experimental results: The inhibitory effects of the three compounds on the enzyme activity of C3 cleavage products are shown in Table 2. Table 2 CVF-Bb enzyme activity data As can be seen from the results in Table 2, Compound I has an inhibitory IC on the enzyme activity of C3 cleavage products50 It is basically the same as Comparative Example D1, indicating that Compound I has a significant inhibitory effect on the alternative complement pathway and has the potential to treat related kidney diseases (such as IgA nephropathy) and blood diseases caused by abnormal alternative complement pathway by targeting CFB. Experimental Example 3 AP-deposition experiment In this experiment, lipopolysaccharide (LPS) was used as the activation initiator to activate the alternative complement pathway. LPS can directly bind to C3b and form C3 convertase with the participation of factors such as Factor B and Factor D. C3 convertase can cleave C3 into C3a and C3b fragments, and then bind to the cleaved C3b to form C5 convertase. C5 convertase cleaves C5 into C5a and C5b fragments, and C5b reacts with C6, C7, C8, and C9 in sequence in the liquid phase to finally form the terminal complement complex (TCC, SC5b-9), thereby exerting the effect of lysing cells. Experimental materials: Normal Human Serum (Complement Technology), WIESLAB Complement System Alternative Pathway (Svarlifescience), Compound I of Example 1, and Comparative Compound D1. Experimental method: 1) Prepare 100 mM solutions of Compound I, D1, and D2 with DMSO respectively, and perform 1000-fold dilution to prepare 100 μM working solutions. Perform 3-fold serial dilution on the working solutions to prepare each series of working solutions. During the experiment, add 95 μL of human serum and 5 μL of each series of working solutions to each sample well respectively, so that their final concentrations are 5000, 1666.67, 555.55, 185.185, 61.728, 20.576, 6.858 nM respectively. Add 100 μL of Diluent AP as a blank control, positive control NHS as a positive control, and negative control NHS as a negative control to the control wells respectively. After mixing, incubate at 37 °C for 1 hour. 2) Wash 3 times with 300 μL of washing solution, and finally pat the plate dry. Add 100 μL of C5b-9 conjugate and incubate at room temperature for 30 minutes. 3) Wash 3 times with 300 μL of washing solution, and finally pat the plate dry. Add 100 μL of substrate solution and incubate at room temperature for 30 minutes. 4) Use an enzyme-linked immunosorbent assay reader to measure the absorbance value at 405 nm. Experimental results: The AP-deposition enzyme activity data of the two compounds are shown in Table 3. Table 3 AP-deposition enzyme activity data As can be seen from Table 3, the IC of compound I against AP-deposition enzyme activity 50 is basically the same as that of Comparative Example D1, indicating that compound I has significant inhibitory activity against the alternative complement pathway and has the potential to treat related kidney diseases (such as IgA nephropathy) and blood diseases caused by abnormal alternative complement pathway by targeting CFB. Test Example 4 PNH-like hemolysis experiment Under acidic conditions (pH 6.4 - 6.5), the complement system in serum is easily activated. Since the red blood cells of PNH patients lack CD55 and CD59, they cannot effectively prevent the attack of the terminal complement complex, resulting in hemolysis; while normal red blood cells can resist this attack, so hemolysis does not occur. In this experiment, CD55 and CD59 antibodies were used to neutralize CD55 and CD59 on the surface of normal red blood cells to simulate the characteristics of PNH red blood cells, and EGTA was used to chelate Ca2+ in serum to block the classical complement pathway and lectin pathway, leaving only the activity of the alternative complement pathway. Experimental materials: C5B-9 ANTIBODY, CD55 antibody, EDTA (Thermo), Anti-CD59 antibody [MEM-43] (abcam), PIPES (Macklin), EGTA (Solarbio), whole blood and serum of healthy individuals, compound I of Example 1, and comparative compounds D1 and D2. Experimental method: 1) Collect 1 ml of fresh blood from healthy volunteers using a heparin anticoagulant tube and 15 ml of blood using a clot-promoting tube. 2) Centrifuge at 2000 rpm for 5 min at room temperature to remove the upper layer solution such as plasma, and wash 3 times with 10 times the volume of sodium chloride solution. 3) Dilute RBCs to 2×10^9 cells / ml with PBS solution. 4) Take 100 ul of 2×10^9 cells / ml red blood cells, and add 1 ul of 1 mg / ml mouse anti-human CD 55 and 3 ul of 1 mg / ml CD 59 monoclonal antibody respectively, and incubate with shaking at 37℃ for 30 min. 5) Wash RBCs three times with PIPES-GVBR solution to remove excess antibodies. 6) Dilute RBCs to 1×10^8 cells / ml with PIPES-GVBR solution. 7) Collect serum from the same healthy individual (NHS) as the complement source. Collect blood using a coagulation-promoting tube and centrifuge to obtain serum at 4°C, 3000g for 15 min. 8) Add EGTA and MgCl2 to the serum to block the activation of the classical complement pathway (final concentrations are 8 mM and 2.85 mM respectively); acidify it with 0.25 M HCl to a pH of 6.4 to activate the AP system. 9) Prepare serial concentrations of each drug with the acidified serum and pre-incubate on ice for 10 min; simultaneously set up a baseline group (final concentration of 10 mM EDTA group) and a maximum hemolysis group (pure water group). 10) Drug incubation: Take 200 ul of the acidified serum containing the drug and mix it with 20 ul of erythrocytes at 1×10^8 cells / ml, and incubate with shaking at 37°C for 6 h. 11) Terminate the reaction: Add 200 ul of E-GVBR solution (final concentration of EDTA is 15 mM) to each tube, and centrifuge at 4000 rpm for 5 min at room temperature. 12) Hemolysis detection: Take 100 ul of the supernatant and add it to a 96-well plate for OD 405 nm detection. Experimental results: The hemolysis inhibition IC of the three compounds 50 As shown in Table 4. Table 4 Serum hemolysis data As can be seen from the results in Table 4, the hemolysis inhibition IC of Compound I 50 is about 2 times better than that of Comparative Example D1, indicating that Compound I has stronger potential pharmacological activity against paroxysmal nocturnal hemoglobinuria. Test Example 5 Pharmacokinetics experiment in mice This experiment investigated the bioavailability of Compound I, D1, and D2 after intragastric administration to mice at a dose of 1 mg / kg, and explored the pharmacokinetic characteristics of Compound I, D1, and D2 in mice. Experimental materials: BALB / c mice (Vital River), acetonitrile, methanol, isopropanol (chromatographically pure Merck), formic acid (Maclean), PEG400 (Solarbio), DMSO (Aladdin), Compound I of Example 1, and Comparative Compounds D1 and D2. Experimental method: 1) After administration, take 0.1 mL of blood from the test animals at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h, add it to a disposable anticoagulation tube, centrifuge at 4000 rpm for 10 min, and store the supernatant at -20°C in the refrigerator for future measurement. 2) The plasma sample treatment method is as follows: Take 20 μL of plasma sample in a 1.5 mL centrifuge tube, add 180 μL of internal standard working solution (internal standard acetonitrile solution at 10 ng / mL), vortex at level 5 for 5 min, then centrifuge at 12000 rpm in a high-speed centrifuge for 10 min. Take the supernatant, add it to the injector vial for LC / MS analysis, and record the chromatogram. Experimental results: The bioavailability and pharmacokinetic parameters of the three compounds are shown in Table 5. Among them, D1-iv-1 is intravenous administration, and D1-po-1 is intragastric administration. Table 5 Mouse pharmacokinetic data Experimental conclusion: After BALB / c mice were intragastrically administered 1 mg / kg of Compound I, D1, and D2 respectively, the bioavailability was relatively high. Compared with the intragastric administration group of Compound I, the systemic exposure level (AUC) of the prototype drug in the intragastric administration groups of the comparative examples D1 and D2 was lower; the AUCINF_obs of the D2 intragastric administration group was about 22.7% of that of the Compound I intragastric administration group, the Cmax was about 44.8% of that of the Compound I intragastric administration group, and the plasma clearance rate was faster and the half-life was shorter. In summary, on BALB / c mice, the PK characteristics of Compound I were superior to those of D1 and D2. Test Example 6 Rat pharmacokinetic experiment This experiment investigated the bioavailability of rats after intragastric administration of 1 mg / kg of Compound I and the comparative example D1 respectively, and explored the pharmacokinetic characteristics of Compound I and the comparative example D1 in rats. Experimental materials: SD rats (Beijing Huafukang), acetonitrile, methanol, isopropanol (chromatographic grade, Merck), formic acid (Maclean), PEG400 (Solarbio), DMSO (Aladdin), Compound I and D1. Experimental method: 1) After dosing, 0.1 mL of blood was collected from the test animals at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h, added to a disposable anticoagulation tube, centrifuged at 4000 rpm for 10 min, and the supernatant was stored in a -20 °C refrigerator for later measurement. 2) The plasma sample treatment method is as follows: Take 20 μL of plasma sample in a 1.5 mL centrifuge tube, add 180 μL of internal standard working solution ((internal standard acetonitrile solution at 1 ng / mL)), vortex at level 5 for 10 min, then centrifuge at 12000 rpm in a high-speed centrifuge for 10 min. Take the supernatant, add it to the injector vial for LC-MS / MS analysis, and record the chromatogram. Experimental results: The bioavailability and pharmacokinetic parameters of the two compounds are shown in Table 6. Table 6 Pharmacokinetic data of rats Experimental conclusion: After SD rats were intragastrically administered with 1 mg / kg of Compound I and Comparative Example D1 respectively, both had relatively high bioavailability. The systemic exposure levels (AUC, Cmax) of the prototype drug in the intragastric administration group of Compound I were higher than those in the intragastric administration group of Comparative Example D1. In summary, on SD rats, the PK characteristics of Compound I are superior to those of D1. Test Example 7 LPS-induced complement activation test in mice Lipopolysaccharide LPS, as an activator of the alternative pathway, can rapidly activate the alternative pathway after being injected into mice, inducing a series of cascade reactions, resulting in a significant increase in the level of C3b and further amplifying the alternative pathway effect. In this experiment, by detecting the change in the level of C3b, the effects of Comparative Example D1 and Compound I in inhibiting the alternative pathway were evaluated. Experimental materials: C57BL / 6J mice (Vital River), LPS (Sigma), C3b Elisa Kit (Huamei Bio); Compound I and D1 (Yiling Pharmaceutical) Experimental method: After the animal quarantine ended, the animals in the model control group and each dosing group were intraperitoneally injected with approximately 0.1 ml / animal (concentration 0.5 mg / ml, dose 2.5 mg / kg) of LPS (prepared with normal saline), and the animals in the normal control group were intraperitoneally injected with an equal volume of normal saline. Approximately 1.5 h after the mice were modeled, the dosing groups were intragastrically administered with the corresponding test drugs, and the normal control group (blank control group without LPS injection) and the model control group (control group only injected with LPS) were intragastrically administered with the corresponding volume of solvent. Approximately 6 h after dosing, the mice were bled by eye socket enucleation (using EDTA anticoagulant tubes). The blood was centrifuged at 3500 rpm at 4 °C for 10 min, and the supernatant was stored at -80 °C to detect the content of the C3b index. Experimental results: Compared with the model control group, the plasma C3b content in the D1-120 mg / kg group was significantly decreased (P<0.05), and the plasma C3b content in the D1-60 mg / kg group had a decreasing trend (P>0.05); the plasma C3b content in the Compound I-60 mg / kg group and the Compound I-120 mg / kg group was significantly decreased (P<0.01). Compared with the D1-60 mg / kg group, the plasma C3b content in the Compound I-60 mg / kg group was significantly decreased (P<0.01); compared with the D1-120 mg / kg group, the plasma C3b content in the Compound I-120 mg / kg group was significantly decreased (P<0.05). Experimental conclusion: At doses of 60 mg / kg and 120 mg / kg, Compound I can significantly inhibit the activation of the alternative pathway induced by LPS, and the inhibitory effect is better than that of Comparative Example D1. The C3b content data are shown in Table 7 below: Table 7 Note: # Compared with the normal control group, # P < 0.05, ## P < 0.01; * compared with the model control group, *P < 0.05, **P < 0.01; △ Compared with the D1-60 mg / kg group, △ P < 0.05, △△ P < 0.01; $ Compared with the D1-120 mg / kg group, $ P < 0.05, $$ P < 0.01. To stabilize the chiral centers of Compound I that are prone to racemization and improve its stability, a series of deuterated molecules were designed based on Compound I to achieve the goal of "same activity, high stability". Affinity experiments, in vitro enzyme activity experiments (CVF-Bb experiment, AP-deposition experiment, rabbit red blood cell hemolysis experiment), canine pharmacokinetic experiments and stability experiments were carried out on the deuterated molecules and racemic molecules of Compound I, and parallel comparisons were made with Compound I at the same time. As follows: Test Example 8 Rabbit Red Blood Cell Hemolysis Experiment 2% non-sensitized rabbit red blood cells can activate the complement pathway in serum. Add EGTA to the rat serum to chelate Ca in the serum 2+ , to block the classical pathway and lectin pathway of complement, while the binding ability of EGTA to Mg 2+ is very weak and can be used to activate the alternative pathway of complement. According to the hemolysis degree of rabbit red blood cells, the complement activity of the alternative pathway of complement can be measured. Experimental materials: Rat serum, EGTA (Solarbio), EDTA (Thermo), 2% rabbit red blood cells (Nanjing Senbeijia Biology), Compound I, LB220-D01, LB220-D05-1, LB220-D05-2, LB220-D05-3, LB220-D06, LB220-D08, LB220-D08-1, LB220-D08-3, LB220-D08-4, Compound II (isomeric molecule of Compound I, Yiling Pharmaceutical). Experimental method: 1) Preparation of rabbit red blood cell suspension: Take 10 ml of commercially available 2% rabbit red blood cells for hemolysis, centrifuge at 2500 rpm at room temperature for 5 min to remove the upper layer solution, add 10 ml of normal saline and wash twice until the supernatant is a clear solution. Pour out the supernatant and re-add 10 ml of normal saline to prepare a 2% rabbit red blood cell solution. 2) Drug pretreatment: Take 10 ml of rat serum as the reaction system, add EGTA and MgCl2 to the serum to block the activation of the classical complement pathway (the final concentrations are 8 mM (62.5x) and 2.85 mM (200X) respectively). Prepare each drug series concentration with the treated serum (the final drug concentrations are: 2500 nM, 1000 nM, 333.33 nM, 111.11 nM, 37.04 nM, 12.35 nM), and incubate at room temperature for 10 min; at the same time, set up a negative control group (serum group containing 10 mM EDTA) and a positive maximum hemolysis group (serum group without drug). 3) Drug incubation: Take 0.2 ml of drug-containing, negative and positive control (i.e., positive maximum hemolysis group) rat serum and mix them with 0.2 ml of 2% red blood cell suspension (1:1 mixing). After mixing, immediately place them in an incubator at 37 ± 0.5 °C for oscillatory incubation (150 rpm) and continuously oscillate and incubate for 3 hours. 4) Terminate the reaction: After the reaction is completed, add 200 μl of normal saline containing EDTA with a final concentration of 15 mM to each tube and centrifuge at 4000 rpm at room temperature for 5 min. 12) Hemolysis detection: Take 100 μl of the supernatant and add it to a 96-well plate for OD 405 nm detection. Experimental results: The rabbit red blood cell hemolysis inhibition IC of LB220-D05-2, LB220-D05-3, LB220-D06 and LB220-D08 50 is basically consistent with the hemolysis inhibition IC of Compound I 50 The remaining deuterated molecules LB220-D05-1, LB220-D01, LB220-D08-1, LB220-D08-3, LB220-D08-4 and the isomeric molecule of Compound I, Compound II, have no inhibitory effect on rabbit red blood cell hemolysis. The rabbit red blood cell hemolysis data is shown in Table 8 below: Table 8 Test Example 9 Affinity Experiment Based on the results of in vitro rabbit red blood cell hemolysis test, the affinity of Compound I and its deuterated compounds (Compound LB220-D05-2 and LB220-D05-3 in Example 3, Compound LB220-D06 in Example 4, and Compound LB220-D08 in Example 5) with complement factor B was detected to evaluate the binding strength of the compounds with factor B. Experimental materials: CFB (Sino Biological Inc.), NTA sensor (Sartorius), Compound I in Example 1, Compound LB220-D05-2 and LB220-D05-3 in Example 3, Compound LB220-D06 in Example 4, and Compound LB220-D08 in Example 5 (Yiling Pharmaceutical Co., Ltd.). Experimental methods: 1) Divide 12 NTA sensors into 2 groups and pre-wet them in PBST for more than 10 min. Among them, 6 sensors are immobilized, and the other 6 sensors are used as reference sensors without protein immobilization. Add PBST to the first column and 50 μg / mL CFB to the second column in a 96-well sample plate. Set baseline for 60 s and loading for 3000 s to make the immobilization height reach more than 4 nm, and then perform baseline for 60 s for equilibration. 2) Take a new 96-well plate and set Buffer and Sample wells. Add PBST + 0.1% DMSO buffer to the Buffer well, and add Compound I, LB220-D05-2, LB220-D05-3, LB220-D06, and LB220-D08 to the Sample wells respectively, with drug concentrations of 2.47, 7.41, 22.22, 66.67, 200, 400 nM from left to right. 3) After immobilization is completed, first set a relatively long equilibration step (more than 10 min), and then enter the baseline / association / dissociation cycle. The Assay Definition is set as follows: baseline 60 s, association 120 s, dissociation 360 s. 4) After setting the immobilized sensor cycle, add a set of reference sensor cycles, and this cycle program is consistent with the immobilized sensor cycle program. 5) After setting, set the positions of the sensors in Sensor Assignment. The sensors are divided into two columns, one group of immobilized sensors and one group of reference sensors, with 6 sensors in each column. After checking the Review Experiment without errors, set the save path, file name, temperature, etc. in Run Experiment, and click GO to run. 6) The original data is subjected to double subtraction processing using the Octet analysis software Data Analysis software, followed by kinetic and steady-state analysis. Experimental results: The affinities of 5 compounds for complement factor B are shown in Table 9. Table 9 Affinity data As can be seen from the results in Table 9, the compound LB220-D08 of Example 5 has the highest affinity for CFB, and the binding strength to CFB is ranked in descending order: LB220-D08 > LB220-D06 > I > LB220-D05-2 > LB220-D05-3. Test Example 10 CVF-Bb experiment Experimental materials: Purified human factor B, purified human factor D (Complement Technology), cobra venom factor, C3 protein (quidel), Anti-C3a / C3a des Arg protein

[2991] , goat anti-mouse IgG H&L (HRP) (Abcam), QuantaBlu fluorescent peroxidase substrate kit, Thermo Scientific TM StartingBlock TM T20 (PBS) 1X (thermofisher), compound I of Example 1, compounds LB220-D05-2 and LB220-D05-3 of Example 3, compound LB220-D06 of Example 4, and compound LB220-D08 of Example 5 (Yiling Pharmaceutical). Experimental method: 1) Factor B, factor D, and CVF are respectively added to the experimental wells, and after mixing, they are incubated at 37°C for 3 hours. 2) 100 mM solutions of compound I, LB220-D05-2, LB220-D05-3, LB220-D06, and LB220-D08 are respectively prepared with DMSO and diluted 100-fold to prepare 1 mM working solutions. The working solutions are serially diluted in a 3-fold gradient to prepare each series of working solutions. During the experiment, 1 μL of each series of working solutions is added to each reaction well, so that their final concentrations are 10000, 3333.33, 1111.11, 370.37, 123.45, 41.15, 13.72, 4.57, 1.52 nM respectively. After shaking evenly, they are incubated at 37°C for 1 hour. 3) Human complement factor C3 protein is added to the reaction wells, and after mixing, they are incubated at 37°C for 2 hours to prepare C3 reaction samples. 4) Add 97 μL of coating buffer and 3 μL of reaction sample into a 96-well black adsorption plate respectively. After mixing evenly, seal the plate and incubate overnight at 4°C. 5) Wash 3 times with 300 μL of washing solution, add 300 μL of startingBlock blocking buffer, and incubate at room temperature for 15 minutes. 6) Wash 3 times with 300 μL of washing solution, add 100 μL of Anti-C3a / C3a des Arg antibody and incubate at 37°C for 1 hour. 7) Wash 3 times with 300 μL of washing solution, add 100 μL of Goat anti-mouse IgG H&L (HRP) and incubate at 37°C for 30 minutes. 8) Wash 3 times with 300 μL of washing solution, add 100 μL of Quantablu substrate solution and incubate at room temperature for 20 minutes. 9) Add 100 μL of Quantablu stop solution. 10) Use a microplate reader to measure the absorbance values at 320 nm and 420 nm. Experimental results: The inhibitory effects of 5 compounds on the enzyme activity of C3 spliceosome are shown in Table 10. Table 10 CVF-Bb enzyme activity data As can be seen from the results in Table 10, the compound LB220-D08 in Example 5 has an IC of inhibitory effect on the enzyme activity of C3 spliceosome 50 which is basically the same as that of compound I in Example 1. The enzyme activity inhibitory activities are ranked in order of magnitude: LB220-D08 > LB220-D06 > I > LB220-D05-2 > LB220-D05-3. Test Example 11 AP-deposition experiment Experimental materials: Normal Human Serum (Complement Technology), WIESLAB Complement System Alternative Pathway (Svarlifescience), compound I in Example 1, compounds LB220-D05-2 and LB220-D05-3 in Example 3, compound LB220-D06 in Example 4, and compound LB220-D08 in Example 5 (Yiling Pharmaceutical). Experimental method: 1) Prepare 100 mM solutions of Compound I, LB220-D05-2, LB220-D05-3, LB220-D06, and LB220-D08 in DMSO respectively, and perform a 1000-fold dilution to prepare 100 μM working solutions. Perform a 3-fold serial dilution on the working solutions to prepare each series of working solutions. During the experiment, add 95 μL of human serum and 5 μL of each series of working solutions to each sample well, so that the final concentrations are 5000, 1666.67, 555.55, 185.185, 61.728, 20.576, 6.858 nM respectively. Add 100 μL of Diluent AP to the control wells as a blank control, positive control NHS as a positive control, and negative control NHS as a negative control. After mixing, incubate at 37 °C for 1 hour. 2) Wash 3 times with 300 μL of washing solution, and pat the plate dry for the last time. Add 100 μL of C5b-9 conjugate and incubate at room temperature for 30 minutes. 3) Wash 3 times with 300 μL of washing solution, and pat the plate dry for the last time. Add 100 μL of substrate solution and incubate at room temperature for 30 minutes. 4) Measure the absorbance value at 405 nm using a microplate reader. Experimental results: The AP-deposition enzyme activity data of the two compounds are shown in Table 11. Table 11 AP-deposition enzyme activity data As can be seen from Table 11, the compounds LB220-D05-2 and LB220-D05-3 in Example 3, the compound LB220-D06 in Example 4, and the compound LB220-D08 in Example 5 have an inhibitory IC on AP-deposition enzyme activity 50 which is basically consistent with that of Compound I in Example 1, indicating that the above compounds all have significant inhibitory activity on the alternative complement pathway and have the potential to treat related kidney diseases (such as IgA nephropathy) and blood diseases caused by abnormal alternative complement pathway by targeting CFB. Test Example 9 Pharmacokinetics PK Test of Beagle Dogs Experimental purpose: Based on the comprehensive affinity and in vitro enzyme activity results, investigate the pharmacokinetic characteristics in beagle dogs after intragastric administration of 1 mg / kg of Compound I, LB220-D06 in Example 4, and LB220-D08 in Example 5 respectively. Experimental materials: SD rats (Huafukang, Beijing), acetonitrile, methanol, isopropanol (chromatographically pure, Merck), formic acid (Maclean), PEG400 (Solarbio), DMSO (Aladdin), Compound I, LB220-D06, LB220-D08 (Yiling Pharmaceutical). Experimental methods: 1) At 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, and 48 h after dosing, 0.1 mL of blood was collected from the test animals, placed in a disposable anticoagulation tube, centrifuged at 4000 rpm for 10 min, and the supernatant was stored at -20°C in a refrigerator for later measurement. 2) The plasma sample treatment method is as follows: Take 20 μL of plasma sample in a 1.5 mL centrifuge tube, add 180 μL of internal standard working solution (1 ng / mL internal standard acetonitrile solution), vortex at level 5 for 10 min, then centrifuge at 12000 rpm in a high-speed centrifuge for 10 min. Take the supernatant and add it to an injector vial for LC-MS / MS analysis, and record the chromatogram. Experimental results: 1) After male beagle dogs were administered 1 mg / kg of Compound I by gavage, AUCINF_obs was 8568.02 h*ng / mL, Tmax was 0.42 h, Cmax was 1473.27 ng / mL, and T1 / 2 was 5.92 h. 2) After male beagle dogs were administered 1 mg / kg of LB220-D06 by gavage, AUCINF_obs was 8478.75 h*ng / mL, Tmax was 0.83 h, Cmax was 1249.67 ng / mL, T1 / 2 was 6.46 h, and the oral relative bioavailability was 98.96%. 3) After male beagle dogs were administered 1 mg / kg of LB220-D08 by gavage, AUCINF_obs was 9328.75 h*ng / mL, Tmax was 0.50 h, Cmax was 1250.78 ng / mL, T1 / 2 was 7.03 h, and the oral relative bioavailability was 108.88%. Experimental conclusion: After male beagle dogs were administered 1 mg / kg of Compound LB220-D06 and LB220-D08 by gavage respectively, the systemic exposure levels of the prototype drugs in each gavage group were ranked from high to low as follows: LB220-D08 > I > LB220-D06, but there was no significant difference among the three. The pharmacokinetic data of dogs are shown in Table 12 below: Table 12 Test Example 10 Stability experiment: Under the conditions of 4N concentration HCl, 50 °C, and 12 h, both the chiral purity and chemical purity of LB220-D08 can be maintained without a decrease in purity; for the comparative example (LNP023) and other deuterated compounds, there are varying degrees of decrease in chemical purity and chiral purity (as shown in Table 13 below). Table 13 The above content is only a specific implementation manner of the present invention, which is for explaining and illustrating the present invention, rather than a limitation on the protection scope of the present invention. Any improvement made without departing from the principle of the present invention should also be included in the protection scope of the present invention.

Claims

1. A compound of formula A or a pharmaceutically acceptable form thereof, wherein the pharmaceutically acceptable form is selected from pharmaceutically acceptable stereoisomers, salts, deuterated compounds, prodrugs, polymorphs or solvates:

2. A compound of formula I or a pharmaceutically acceptable form thereof, wherein, The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, deuterated compounds, prodrugs, polymorphs or solvates:

3. The compound according to claim 2 or a pharmaceutically acceptable form thereof, wherein, The deuterated compound is selected from one of the following structures:

4. A process for preparing the compound according to claim 1, wherein, It includes the following steps: (1) 4-Bromo-3-methylbenzonitrile, 4-methoxypyridine and benzyl chloroformate react under the catalysis of a Grignard reagent to form benzyl 2-(4-cyano-2-methylphenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate; (2) The benzyl 2-(4-cyano-2-methylphenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate undergoes a hydrogenation reaction to obtain benzyl 2-(4-cyano-2-methylphenyl)-4-oxopiperidine-1-carboxylate; (3) The carbonyl group in the benzyl 2-(4-cyano-2-methylphenyl)-4-oxopiperidine-1-carboxylate is reduced to obtain benzyl 2-(4-cyano-2-methylphenyl)-4-hydroxypiperidine-1-carboxylate; (4) The benzyl 2-(4-cyano-2-methylphenyl)-4-hydroxypiperidine-1-carboxylate reacts with a silylating reagent in the presence of an acid-binding agent to protect the hydroxyl group, obtaining 4-((tert-butyldiphenylsilyl)oxy)-2-(4-cyano-2-methylphenyl)piperidine-1-carboxylate; (5) The 4-((tert-butyldiphenylsilyl)oxy)-2-(4-cyano-2-methylphenyl)piperidine-1-carboxylate is deprotected to obtain 2-(4-cyano-2-methylphenyl)-4-hydroxypiperidine-1-carboxylate; (6) The 2-(4-cyano-2-methylphenyl)-4-hydroxypiperidine-1-carboxylate undergoes a nucleophilic substitution reaction with a halogenated hydrocarbon to obtain 2-(4-cyano-2-methylphenyl)-4-ethoxypiperidine-1-carboxylate; (7) The 2-(4-cyano-2-methylphenyl)-4-ethoxypiperidine-1-carboxylate reacts with an acid and an alkyl alcohol to obtain 4-(4-ethoxypiperidin-2-yl)-3-methylbenzoate; (8) The methyl 4-(4-ethoxypiperidin-2-yl)-3-methylbenzoate reacts with tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate to obtain tert-butyl 4-(4-ethoxy-2-(4-(alkoxycarbonyl)-2-methylphenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate; (9) The tert-butyl 4-(4-ethoxy-2-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate is hydrolyzed to obtain Compound A, 4-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3-methylbenzoic acid.

5. A process for preparing the compound according to claim 4, wherein, It includes the following steps: (1) 4-Bromo-3-methylbenzonitrile, 4-methoxypyridine and benzyl chloroformate react under the catalysis of a Grignard reagent to form benzyl 2-(4-cyano-2-methylphenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate; (2) The hydrogenation reaction of benzyl 2-(4-cyano-2-methylphenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate gives benzyl 2-(4-cyano-2-methylphenyl)-4-oxopiperidine-1-carboxylate; (3) The carbonyl group in benzyl 2-(4-cyano-2-methylphenyl)-4-oxopiperidine-1-carboxylate is reduced to give benzyl 2-(4-cyano-2-methylphenyl)-4-hydroxypiperidine-1-carboxylate; (4) Benzyl 2-(4-cyano-2-methylphenyl)-4-hydroxypiperidine-1-carboxylate reacts with a silylating agent in the presence of an acid-binding agent to protect the hydroxyl group, and after purification, trans-4-((tert-butyldiphenylsilyl)oxy)-2-(4-cyano-2-methylphenyl)piperidine-1-carboxylate is obtained; (5) The hydroxyl protecting group of trans-4-((tert-butyldiphenylsilyl)oxy)-2-(4-cyano-2-methylphenyl)piperidine-1-carboxylate is removed to give trans-2-(4-cyano-2-methylphenyl)-4-hydroxypiperidine-1-carboxylate; (6) The trans-2-(4-cyano-2-methylphenyl)-4-hydroxypiperidine-1-carboxylate undergoes a nucleophilic substitution reaction with a halogenated hydrocarbon to give trans-2-(4-cyano-2-methylphenyl)-4-ethoxypiperidine-1-carboxylate; (7) The trans-2-(4-cyano-2-methylphenyl)-4-ethoxypiperidine-1-carboxylate reacts with an acid and an alkyl alcohol to give trans-4-(4-ethoxypiperidin-2-yl)-3-methylbenzoate; (8) The trans-4-(4-ethoxypiperidin-2-yl)-3-methylbenzoate reacts with tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate to give tert-butyl trans-4-(4-trans-ethoxy-2-(4-(alkoxycarbonyl)-2-methylphenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate; (9) The tert-butyl trans-4-(4-trans-ethoxy-2-(4-(alkoxycarbonyl)-2-methylphenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate is purified by SFC to give tert-butyl 4-((2S,4S)-4-ethoxy-2-(4-(alkoxycarbonyl)-2-methylphenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate; (10) The tert-butyl 4-((2S,4S)-4-ethoxy-2-(4-(alkoxycarbonyl)-2-methylphenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate is hydrolyzed to give the compound of formula I, 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3-methylbenzoic acid.

6. The preparation method according to claim 4 or 5, wherein The Grignard reagent described in step (1) is isopropylmagnesium chloride; and / or: The silanization reagent described in step (4) is tert-butyldiphenylchlorosilane, and the acid-binding agent is imidazole; and / or: The halogenated hydrocarbon described in step (6) is iodoethane; and / or: The acid described in step (7) is sulfuric acid, and the alkyl alcohol is methanol.

7. A pharmaceutical composition, wherein, Comprising the compound according to claim 1, 2 or 3 or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier, excipient and / or one or more other therapeutic agents.

8. Use of the compound according to claim 1, 2 or 3 or a pharmaceutically acceptable form thereof in the preparation of a medicament for treating a disease or disorder mediated by complement alternative pathway dysregulation.

9. Use of the compound according to claim 1, 2 or 3 or a pharmaceutically acceptable form thereof in the preparation of a medicament for treating a disease or disorder mediated by complement factor B.

10. Use of the compound according to claim 1, 2 or 3 or a pharmaceutically acceptable form thereof in the preparation of a medicament for treating a disease or disorder related to hematologic, autoimmune, inflammatory and / or neurodegenerative diseases.

11. Use of the compound according to claim 1, 2 or 3 or a pharmaceutically acceptable form thereof in the preparation of a medicament for treating diseases mediated by complement alternative pathway dysregulation such as paroxysmal nocturnal hemoglobinuria, immunoglobulin A nephropathy, C3 glomerulopathy, atypical hemolytic uremic syndrome, age-related macular degeneration, ANCA-associated vasculitis, systemic lupus erythematosus, immune thrombocytopenia, cold agglutinin disease, etc.

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