Indole compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of chemical drugs, and relates to a compound as shown in a general formula (I), or a racemate thereof, or an isomer thereof, or a pharmaceutically acceptable salt thereof, # imgabs0 as a complement factor B inhibitor, and a method for treating various specific diseases or symptoms by using the complement factor B inhibitor.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical drugs, and relates to an indole compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt, and its preparation method and application as a complement factor B inhibitor, and a method of using the same to treat a variety of specific diseases or symptoms. Background Art

[0002] Complement is a class of soluble pattern recognition molecules in the immune system that can perform a variety of effector functions. Currently known complement activation pathways mainly include three: the classical pathway, the lectin pathway, and the alternative pathway. Complement factor B (CFB) is a trypsin-like serine protease that circulates in human blood in the form of a potential zymogen. The alternative pathway is a magnesium-dependent cascade that is activated by the deposition and activation of C3 on certain susceptible surfaces (such as cell wall polysaccharides of yeast and bacteria, and certain biopolymer materials).

[0003] Paroxysmal nocturnal hemoglobinuria (PHN) is a rare, life-threatening blood disorder characterized by complement-driven hemolysis, thrombosis, and impaired bone marrow function, leading to anemia, fatigue, and other debilitating symptoms that can severely impact patients' quality of life. Despite treatment with current anti-C5 standard-of-care therapies, a large proportion of PNH patients remain anemic and transfusion-dependent.

[0004] Other diseases associated with the complement cascade include membranous nephropathy (MN), C3 glomerulonephritis (C3G), age-related macular degeneration (AMD), geographic atrophy (GA), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), complications of hemodialysis, hemolytic anemia or hemodialysis, neuromyelitis (NMO), hepatic inflammation, inflammatory bowel disease, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), respiratory diseases and cardiovascular diseases.

[0005] Inflammation and immune-related diseases are diverse and difficult to cure. The only drug on the market for PNH is eculizumab, but due to its price, it imposes a heavy burden on patients. At the same time, many patients still experience anemia after treatment with eculizumab, and many patients still need continuous blood transfusions. In addition, eculizumab requires intravenous injection. Some diseases do not have specific therapeutic drugs so far, such as IgA nephropathy. There are unmet clinical needs in these areas, and new small molecule drugs need to be developed for medical treatment.

[0006] Prior art, for example, WO2022028527A1 and CN104603127B disclose small molecule compounds as complement factor B inhibitors, and methods of using the same to treat a variety of specific diseases or conditions. Summary of the invention

[0007] In view of the problems existing in the prior art, the present application provides a compound represented by general formula (A), or its isomer, or its racemate, or its pharmaceutically acceptable salt, and its preparation method and application as a small molecule inhibitor of complement factor B, and methods of using the same to treat a variety of specific diseases or conditions.

[0008] In a first aspect, the present application provides a compound represented by general formula (A), or an isomer, a racemate, or a pharmaceutically acceptable salt thereof:

[0010]

[0011] In a second aspect, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of any one of the above compounds or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0012] In a third aspect, the present invention also provides a use of a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease condition, wherein the disease is a complement factor B inhibitor-related disease, specifically, the disease condition is selected from PNH and the like.

[0013] Specifically, the present invention is achieved through the following technical solutions:

[0014] A compound represented by general formula (A), or its isomer, racemate, or pharmaceutically acceptable salt, comprising:

[0015]

[0016] Wherein, m = 1 or 2;

[0017] When m=1, as shown in formula (I),

[0018] When m=2, as shown in formula (II)

[0019] X is selected from O, S or NH;

[0020] The R is selected from: substituted or unsubstituted alkyl, alkoxy, alkylalkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, a bicyclic ring consisting of aryl and cycloalkyl, wherein the substitution is selected from halogen, hydroxyl, alkyl, alkoxy, alkylalkoxy, cycloalkyl, heterocycloalkyl, and the number of the substitution is one or more;

[0021] The R 1 , R 2 independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or R 1 , R 2 Cyclize together to form a heterocycloalkyl;

[0022] Wherein K is selected from a positive integer of 5-30, said R 3 , R 4 , R 5 is selected from hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl;

[0023] m1, n, p, q, r, s, t are integers of 1-10 selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0024] As a preferred technical solution of the present invention, the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt, is selected from the compound represented by formula (Ia) or formula (Ib), wherein R is as defined above.

[0025] As a preferred technical solution of the present invention, the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt, is selected from the compound represented by formula (IIa), wherein R is as defined above.

[0026] As a preferred technical solution of the present invention, the alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, 1-ethylbutyl, n-heptyl, isoheptyl;

[0027] The alkoxy group is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1,2-dimethylpropoxy, isopentoxy, neopentoxy, n-hexoxy, isohexoxy, sec-hexoxy, tert-hexoxy, neohexoxy, 2-methylpentoxy, 1,2-dimethylbutoxy, 1-ethylbutoxy, n-heptoxy, isoheptoxy;

[0028] The alkoxyalkyl group is selected from methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, ethoxyhexyl, propoxymethyl, propoxyethyl, propoxybutyl, propoxypentyl, propoxyhexyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, butoxyhexyl, pentyloxymethyl, pentyloxyethyl, pentyloxypropyl, pentyloxybutyl, pentyloxypentyl, pentyloxyhexyl, hexyloxymethyl, hexyloxyethyl, hexyloxypropyl, hexyloxybutyl, hexyloxypentyl, hexyloxyhexyl; the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, The heterocycloalkyl group refers to a cycloalkane group in which at least one carbon atom is substituted by a heteroatom.

[0029] Wherein, the heterocycloalkyl group includes:

[0030] As a preferred technical solution of the present invention, the aromatic group is selected from a five-membered ring, a six-membered ring, a seven-membered ring, an eight-membered ring, a nine-membered ring, and a ten-membered ring. The aromatic group is a monocyclic ring or a bicyclic ring, and the bicyclic ring means that two rings share two carbon atoms; the heteroaryl group means that at least one carbon atom on the aromatic ring is replaced by a heteroatom.

[0031] Specifically, the aryl group is selected from phenyl; the heteroaryl group is selected from 5 to 12 membered heteroaryl groups, and the 5 to 12 membered heteroaryl groups are selected from

[0032] Bicyclic rings composed of aryl and cycloalkyl include:

[0033] As a preferred technical solution of the present invention, the halogen is selected from fluorine, chlorine, bromine and iodine.

[0034] As a preferred technical solution of the present invention, the heteroatom is selected from nitrogen, oxygen, and sulfur, and the heteroatom is one or more.

[0035] As a preferred technical solution of the present invention, when m=1, the R is selected from ethyl, isopropyl,

[0036]

[0037] Or when m=2, R is selected from As a preferred technical solution of the present invention, the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt is selected from:

[0038]

[0039]

[0040]

[0041] As a preferred technical solution of the present invention, the pharmaceutically acceptable salt refers to the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt prepared with a pharmaceutically acceptable acid or base.

[0042] As a preferred technical solution of the present invention, at least one hydrogen atom of the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt is substituted by deuterium isotope.

[0043] The present invention further provides a pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

[0044] The present invention further provides the medical use of the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt, specifically, the use in the preparation of a drug for treating a disease, wherein the disease is a complement factor B inhibitor-related disease, specifically selected from proteinuria and the like.

[0045] For the sake of clarity, general terms used in the description of the compounds are defined herein.

[0046] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood in accordance with the ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" used here refers to those compounds, materials, compositions and / or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0047] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, which are prepared from the compounds having specific substituents discovered in the present invention and pharmaceutically acceptable acids or bases.

[0048] The compounds described herein are readily chemically transformed under physiological conditions to form Compound 42A. Additionally, prodrugs can be converted to compounds by chemical or biochemical methods in an in vivo environment.

[0049] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present invention.

[0050] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, atropisomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present invention.

[0051] Optically active (R)- and (S)-isomers, as well as D and L isomers, atropisomers, etc., can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (for example, a carbamate is generated from an amine).

[0052] The atoms of the molecules of the compounds of the present invention are isotopes, and isotope derivatization can generally extend the half-life, reduce the clearance rate, stabilize metabolism, and improve the in vivo activity. In addition, an embodiment is included in which at least one atom is replaced by an atom with the same atomic number (proton number) and a different mass number (proton and neutron sum). Examples of isotopes included in the compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, which respectively include 2 H. 3 H. 13 C. 14 C. 15 N. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F.36 In particular, radioactive isotopes that emit radiation as they decay, such as 3 H or 14 C can be used for local anatomy inspection of pharmaceutical preparations or compounds in vivo. Stable isotopes neither decay or change with their amount nor have radioactivity, so they can be used safely. When the atoms constituting the molecules of the compounds of the present invention are isotopes, the isotopes can be converted according to general methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0053] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0054] Furthermore, the compounds of the present invention may have one or more hydrogen atoms deuterated with isotopes of deuterium ( 2 After deuteration, the compounds of the present invention have the effects of extending half-life, reducing clearance rate, stabilizing metabolism and improving in vivo activity.

[0055] The preparation method of the isotopic derivative generally includes: a phase transfer catalytic method. For example, a preferred deuteration method uses a phase transfer catalyst (e.g., a tetraalkylammonium salt, NBu4HSO4). The use of a phase transfer catalyst to exchange the methylene protons of the diphenylmethane compound results in a higher deuterium introduction than reduction with deuterated silane (e.g., triethyldeuterated monosilane) or with a Lewis acid such as aluminum trichloride using sodium deuterated borate in the presence of an acid (e.g., methanesulfonic acid).

[0056] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity enhancers, transdermal enhancers, etc. Their preparations are well known to those skilled in the art of cosmetics or topical drugs. For other information about the carrier, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0057] The term "excipient" generally refers to a carrier, diluent and / or vehicle required to formulate an effective pharmaceutical composition.

[0058] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. For oral dosage forms of the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0059] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0060] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0061] Indicates the connection location.

[0062] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 Schematic diagram of the crystal structure of intermediate I;

[0064] Figure 2 It is the crystal parameter diagram of the crystal structure of intermediate I;

[0065] Figure 3 The atomic coordinates and isotropic displacement parameter diagram of the crystal structure of intermediate I;

[0066] Figure 4 This is the XRPD pattern of the crystal structure of intermediate I. DETAILED DESCRIPTION

[0067] The present application is further described in detail below in conjunction with examples, but the implementation methods of the present application are not limited thereto.

[0068] THF tetrahydrofuran, Zn zinc, HOAc acetic acid, Dioxane 1,4-dioxane, NaOH sodium hydroxide, i-PrOH isopropanol, rt room temperature, K3PO4 potassium phosphate, SOCl2 thionyl chloride, MeOH methanol, DCM dichloromethane, DMAP4-dimethylaminopyridine, DCE 1,2-dichloroethane, K2CO3 potassium carbonate, NaBH4 sodium borohydride, DMF N,N-dimethylformamide, EA / EtOAc ethyl acetate, Acetone acetone, NaIO4 sodium periodate, Py pyridine, HBr hydrobromic acid, H2 hydrogen.

[0069] Compound Z

[0070]

[0071] The specific synthetic route is as follows:

[0072]

[0073] Step A: Synthesis of (S)-6-((4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0074] At room temperature, 2-bromopyrazine (348 mg, 2.20 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (214 mg, 0.29 mmol), potassium phosphate (634 mg, 2.92 mmol) and water (3 ml) were added to 1,4-dioxane (15 ml) containing (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (700 mg, 1.47 mmol) and 1,4-dioxane (15 ml), and nitrogen was replaced and the temperature was raised to 95°C for 5 hours. After the reaction was completed, the mixture was filtered, washed with ethyl acetate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1:5) to obtain 380 mg of light yellow oily liquid (S)-6-((4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 60%). LC-MS: RT = 2.10 min, [M+H] + =430.25.

[0075] Step B: Synthesis of (S)-2-(4-methoxycarbonyl)phenyl)-4-(pyrazine-2-yl)piperidine-1-carboxylic acid

[0076] (S)-Benzyl 6-((4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (380 mg, 0.89 mmol) was dissolved in ethyl acetate (10 ml), palladium carbon (150 mg) was added, hydrogen was replaced, and the mixture was reacted at room temperature for 3 hours.

[0077] After the reaction was completed, the mixture was filtered, washed with methanol, and concentrated to obtain 310 mg of light yellow oily liquid (S)-2-((4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylic acid. LC-MS: RT = 2.13 min, [M+H] + =297.19.

[0078] Step C: Synthesis of (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0079] To a solution of (S)-2-((4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylic acid (310 mg, 1.04 mmol) in 1,2-dichloroethane (5 ml) was added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (452 ​​mg, 1.57 mmol) and sodium triacetoxyborohydride (881 mg, 4.16 mmol), and the mixture was heated to 40°C and reacted overnight. After the reaction was completed, methanol was added and the mixture was concentrated to dryness. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1:1) to give 178 mg of white solid (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield: 30%).

[0080] The diastereoisomers were separated by chiral HPLC (Agilent prep C18) using 25% CH3CN (+0.05% NH3·H2O) solution to obtain 107 mg of absolute configuration intermediate I (yield: 18%) and 178 mg of absolute configuration intermediate II (yield: 30%). LC-MS: RT = 2.02 min, [M+H] + =571.34. Confirmation of the absolute configuration of intermediate I:

[0081] The crystal structure of intermediate I was successfully determined by MicroED method. The crystal structure belongs to the orthorhombic system and the space group is P212121 (No.19). The unit cell constant measured by MicroED is α=90°,β=90°,γ=90°,unit cell volume The Z' of the system is 1, and the asymmetric unit of the crystal consists of 1 API molecule. The absolute configuration of intermediate I was determined as follows: Figure 1 As shown, the crystal parameters of the crystal structure of intermediate I are shown in Figure 2 As shown, the atomic coordinates and isotropic displacement parameters of the crystal structure of intermediate I are shown in Figure 3 As shown, the XRPD pattern of the crystal structure of intermediate I is as follows Figure 4 shown.

[0082] Step D: Compound Z

[0083]

[0084] To a solution of (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (178 mg, 0.31 mmol) in methanol (15 ml), potassium carbonate (174 mg, 1.25 mmol) was added, the mixture was heated to 70°C for 5 hours, and water (3 ml) was added and the reaction was continued for 4 hours.

[0085] After the reaction was completed, the product was concentrated and purified by silica gel column chromatography (eluent: dichloromethane: methanol = 10:1) to obtain a crude product. The diastereomers were separated by chiral HPLC (Agilent prep C18) and eluted with 25% CH3CN (+0.05% NH3·H2O) solution to obtain 19 mg of absolute configuration diastereomer Z (yield: 13%).

[0086] Compound Z: HPLC: RT = 9.6 min, LC-MS: RT = 1.62 min, [M + H] + =457.26. (MeOH, Rudolph Autopol I rotator).

[0087] 1HNMR(400MHz,DMSO-d6)δ10.86(s,1H),8.72(d,J=1.8Hz,1H),8.67(dd,J=2.4,1.8Hz,1H),8.50 (d,J=2.4Hz,1H),7.82(d,J=7.8Hz,2H),7.40(d,J=7.8Hz,2H),7.25(t,J=2.8Hz,1H),6.63(s,1H ),6.47(t,J=2.5Hz,1H),3.67(s,3H),3.69-3.65(m,1H),3.51(dd,J=9.6,3.3Hz,1H),3.31-3.23 (m,2H),2.67-2.59(m,1H),2.44-2.39(m,1H),2.41(s,3H),2.21-2.08(m,3H),1.85-1.75(m,1H).

[0088] Example 1 Synthesis of Compound 1

[0089]

[0090] The specific synthetic route is as follows:

[0091] Step A: Synthesis of ethyl 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoate

[0092] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (200 mg, 0.43 mmol), potassium carbonate (178.0 mg, 1.29 mmol) were dissolved in acetonitrile (10 ml), dimethyl sulfoxide (2 ml) and N,N-dimethylformamide (1 ml), iodoethane (134.0 mg, 0.86 mmol) was added, and the reaction was carried out at room temperature for 12 hours. After the reaction was completed, The reaction solution was poured into water and extracted with ethyl acetate (10 ml x 3 times). The organic phases were combined, dried and spin-dried to obtain a crude product. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain 7.8 mg of ethyl 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoate (yield: 3.7%). Compound 1: LCMS: RT = 1.73 min, [M+H] + =485.29. 1H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.74-8.65(m,2H),8.51(d,J=2.5Hz,1H),7.97(d,J=8.3Hz,2H), 7.70(d,J=8.1Hz,2H),7.26(t,J=2.8Hz,1H),6.65(s,1H),6.45(dd,J=3.1,1.9Hz,1H),4.31(q,J=7.1Hz ,2H),3.71(d,J=9.4Hz,1H),3.69(s,3H),3.67(s,1H),3.38-3.35(m,1H),3.22(t,J=4.8Hz,1H),2.68- 2.60(m,1H),2.48-2.39(m,4H),2.30-2.04(m,3H),1.80(dt,J=15.1,7.5Hz,1H),1.32(t,J=7.1Hz,3H).

[0093] Example 2 Synthesis of Compound 2

[0094]

[0095] The specific synthetic route is as follows:

[0096] Step A: Synthesis of isopropyl 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoate

[0097] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (70 mg, 0.15 mmol) and potassium carbonate (41.4 mg, 0.3 mmol) were dissolved in N,N-dimethylformamide (1 ml), and 2-iodopropane (38.2 mg, 0.22 mmol) was added and reacted at room temperature for 12 hours. After the reaction was completed, the reaction solution was poured into water and ethyl acetate was used. The organic phases were combined, dried and spin-dried to give a crude product. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 34 mg of white solid 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid isopropyl ester (yield: 45.5%). Compound 2: LCMS: RT = 1.77 min, [M+H] + =499.30. 1H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.72(d,J=1.5Hz,1H),8.68(dd,J=2.5,1.5Hz,1H),8.52(d,J=2.6Hz,1H ),7.96(d,J=8.1Hz,2H),7.70(d,J=8.0Hz,2H),7.26(t,J=2.8Hz,1H),6.65(s,1H),6.46(dd,J=3.1,1.9Hz,1H) ,5.14(m,1H),3.70-3.67(m,5H),3.37(d,J=12.0Hz,1H),3.22(t,J=5.0Hz,1H),2.64(d,J=13.1Hz,1H),2.42( s,3H),2.24(q,J=12.7,11.7Hz,1H),2.16(s,2H),2.10(m,1H),1.85-1.77(m,1H),1.32(dd,J=6.2,1.1Hz,6H).

[0098] Example 3 Synthesis of Compound 3

[0099]

[0100] The specific synthetic route is as follows:

[0101] Step A: Synthesis of compound 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid ((isopropoxycarbonyl)oxy)methyl ester

[0102] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoic acid (60 mg, 0.13 mmol) and potassium carbonate (36 mg, 0.26 mmol) were dissolved in N,N-dimethylformamide (1 ml), and chloromethyl isopropyl carbonate (29 mg, 0.19 mmol) was added and reacted at 50°C for 4 hours. After the reaction was completed, the reaction solution was poured into water and washed with ethyl acetate. The organic phases were combined, dried and spin-dried to give a crude product. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 30 mg of 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid ((isopropoxycarbonyl)oxy)methyl ester (yield: 40.3%). Compound 3: LCMS: RT = 1.79 min, [M+H] + =573.29. 1HNMR (400MHz, DMSO-d6) δ8.64(d,J=2.4Hz,2H),8.48(d,J=2.3Hz,1H),8.12(d,J=8.2Hz,2H),7.98(s,1H),7.75(d,J=8.1Hz ,2H),7.25(t,J=2.8Hz,1H),6.75-6.69(m,2H),6.04(s,2H),4.98(m,1H),3.93(d,J=12.2Hz,1H),3.83-3.82(d,J=2Hz,1H), 3.81(s,3H),3.53(d,J=12.2Hz,1H),3.29(t,J=4.9Hz,1H),2.88(dt,J=12.6,4.7Hz,1H),2.57-2.51(d,J=12Hz,1H),2.42( dd,J=12.5,9.5Hz,1H),2.23(ddd,J=13.9,9.2,4.9Hz,2H),2.06(tt,J=10.1,5.0Hz,1H),1.63(s,3H)1.36(d,J=6.2Hz,6H).

[0103] Example 4 Synthesis of Compound 4

[0104]

[0105] The specific synthetic route is as follows:

[0106] Step A: Synthesis of 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (2,3-dihydroxy)propyl ester

[0107] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (40 mg, 0.087 mmol) and potassium carbonate (29 mg, 0.21 mmol) were dissolved in N,N-dimethylacetamide (0.4 ml), 3-chloro-1,2-propanediol (19.1 mg, 0.087 mmol) was added, and the mixture was reacted at 80°C for 12 hours.

[0108] After the reaction, the reaction solution was poured into water and extracted with ethyl acetate (10 ml x 5 times). The organic phases were combined, dried and spin-dried to obtain a crude product. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain 13.5 mg of white solid 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (2,3-dihydroxy)propyl ester (yield: 29.2%). Compound 4: LCMS: RT = 1.63 min, [M+H] + =531.34. 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.74-8.65(m,2H),8.51(d,J=2.5Hz,1H),7.97(d,J=8.3Hz,2H), 7.70(d,J=8.1Hz,2H),7.26(t,J=2.8Hz,1H),6.65(s,1H),6.45(dd,J=3.1,1.9Hz,1H),4.31(q,J=7.1Hz ,2H),3.71(d,J=9.4Hz,1H),3.69(s,3H),3.67(s,1H),3.38-3.35(m,1H),3.22(t,J=4.8Hz,1H),2.68- 2.60(m,1H),2.48-2.39(m,4H),2.30-2.04(m,3H),1.80(dt,J=15.1,7.5Hz,1H),1.32(t,J=7.1Hz,3H).

[0109] Example 5 Synthesis of Compound 5

[0110]

[0111] The specific synthetic route is as follows:

[0112] Step A: Synthesis of 2-methoxyethyl-4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoate To a solution of 4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoic acid (80 mg, 0.175 mmol) in dichloromethane (5 ml) were added 4-dimethylaminopyridine (25.66 mg, 0.21 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.32 mg, 0.2625 mmol), and 2-methoxyethane-1-ol (13.35 mg, 0.175 mmol) at room temperature and the mixture was reacted overnight at room temperature. After the reaction, the reaction solution was poured into water and extracted with dichloromethane (50 ml × 3 times). The organic phase was washed with saturated sodium chloride solution (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by preparative HPLC (chromatographic column: Agilent 5 Prep-C18 100 mm × 30 mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water + 0.05% saturated ammonia water) to obtain 38 mg of white solid 2-methoxyethyl-4-((2S, 4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoate (yield: 42%). Compound 5: LCMS: RT = 1.75 min, [M + H] + =515.32. 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.73(s,1H),8.71-8.65(m,1H),8.52(d,J=2.5Hz,1H),7.98(d,J= 8.0Hz,2H),7.72(d,J=8.0Hz,2H),7.27(t,J=2.8Hz,1H),6.66(s,1H),6.47(d,J=2.6Hz,1H),4.40(dd,J= 5.8,3.6Hz,2H),3.69(q,J=6.4,4.9Hz,7H),3.39(d,J=12.0Hz,1H),3.31(s,3H),3.23(t,J=5.0Hz,1H), 2.65(dt,J=11.7,4.4Hz,1H),2.42(m,4H),2.32-2.22(m,1H),2.21-2.06(m,2H),1.81(t,J=12.3Hz,1H).

[0113] Example 6 Synthesis of Compound 6

[0114]

[0115] The specific synthetic route is as follows:

[0116] Step A: Synthesis of 2-morpholino-2-oxoethyl-4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoate To a solution of 4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoic acid (80 mg, 0.175 mmol) in N,N-dimethylformamide (5 ml) were added potassium carbonate (60.5 mg, 0.438 mmol) and 2-chloro-1-morpholinoethane-1-one (28.63 mg, 0.175 mmol) at room temperature, and the temperature was raised to 50°C and the reaction was allowed to react overnight. After the reaction, the reaction solution was poured into water and extracted with dichloromethane (50 ml × 3 times). The organic phase was washed with saturated sodium chloride solution (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by preparative HPLC (chromatographic column: Agilent 5Prep-C18 100 mm × 30 mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water + 0.05% saturated ammonia water) to obtain 24 mg of white solid 2-morpholino-2-oxoethyl-4-((2S, 4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoate (yield: 23%). Compound 6: LCMS: RT = 1.68 min, [M+H] + =584.35. 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),8.73(d,J=1.5Hz,1H),8.71-8.65(m,1H),8.53(d,J=2.5Hz,1H ),8.01(d,J=8.0Hz,2H),7.74(d,J=8.1Hz,2H),7.27(t,J=2.8Hz,1H),6.66(s,1H),6.46(t,J=2.4Hz ,1H),5.07(s,2H),3.70(m,5H),3.61(dt,J=17.6,4.7Hz,4H),3.52-3.37(m,5H),3.28-3.20(m,2H), 2.65(dd,J=11.5,6.3Hz,1H),2.43(s,3H),2.32-2.23(m,1H),2.23-2.07(m,2H),1.87-1.73(m,1H).

[0117] Example 7 Synthesis of Compound 7

[0118]

[0119] The specific synthetic route is as follows:

[0120] Step A: Synthesis of 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (pivaloyloxy)methyl ester

[0121] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (100 mg, 0.21 mmol) and potassium carbonate (43.0 mg, 0.31 mmol) were dissolved in N,N-dimethylformamide (3 ml), and chloromethyl pivalate (94.8 mg, 0.63 mmol) was added and reacted at 50°C for 2 hours. After the reaction, the reaction solution was poured into water and washed with ethyl acetate ( 5 ml × 3 times) extraction, the organic phases were combined, dried and spin-dried to obtain a crude product, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 2) to obtain 45 mg of a white solid 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (pivaloyloxy)methyl ester (yield: 37.6%). Compound 7: LCMS: RT = 1.82 min, [M+H] + =571.35. 1 H NMR (400MHz, DMSO-d6) δ10.83(d,J=2.3Hz,1H),8.72(d,J=1.6Hz,1H),8.67(dd,J=2.6Hz,1H),8.51(d,J=2. 5Hz,1H),7.98(d,J=8.1Hz,2H),7.73(d,J=8.1Hz,2H),7.25(t,J=2.8Hz,1H),6.65(s,1H),6.45(dd,J=3.0,1 .9Hz,1H),5.96(s,2H),3.68(m,5H),3.38(d,J=11.9Hz,1H),3.21(t,J=5.0Hz,1H),2.70-2.59(m,1H),2.46 (s,1H),2.41(s,3H),2.26(t,J=10.7Hz,1H),2.18(d,J=13.6Hz,1H),2.10(m,1H),1.80(m,1H),1.15(s,9H).

[0122] Example 8 Synthesis of Compound 8

[0123]

[0124] The specific synthetic route is as follows:

[0125] Step A: Synthesis of compound 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (1-((isopropoxycarbonyl)oxy))ethyl ester

[0126] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoic acid (100 mg, 0.21 mmol) and potassium carbonate (43 mg, 0.31 mmol) were dissolved in N,N-dimethylformamide (5 ml), 1-chloroethyl isopropyl carbonate (104.9 mg, 0.63 mmol) was added, and the mixture was reacted at 50°C for 2 hours. After the reaction was completed, the reaction solution was poured into water and ethyl acetate was used to remove the residue. The mixture was extracted with ester (5 ml x 3 times), the organic phases were combined, dried and spin-dried to give a crude product, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 2) to give 100 mg of a white solid 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (1-((isopropoxycarbonyl)oxy))ethyl ester (yield: 81.3%). Compound 8: LCMS: RT = 1.84 min, [M+H] + =587.37. 1 H NMR (400MHz, DMSO-d6) δ10.83(t,J=2.3Hz,1H),8.72(s,1H),8.68(t,J=2.0Hz,1H),8.52(d,J=2.6Hz,1H),7.98(d,J=8.1Hz,2H ),7.73(d,J=8.1Hz,2H),7.25(q,J=2.5Hz,1H),6.87(q,J=5.4Hz,1H),6.65(s,1H),6.45(dt,J=3.6,1.9Hz,1H),4.82-4.75(m, 1H),3.75-3.64(m,5H),3.37(dd,J=11.9,2.6Hz,1H),3.22(t,J=5.0Hz,1H),2.62(s,1H),2.41(s,4H),2.26(t,J=11.4Hz,1H), 2.17(d,J=12.8Hz,1H),2.09(ddd,J=13.7,8.9,4.8Hz,1H),1.86-1.74(m,1H),1.63-1.53(m,3H),1.22(dd,J=6.3,1.4Hz,6H).

[0127] Example 9 Synthesis of Compound 9

[0128]

[0129] The specific synthetic route is as follows:

[0130] Step A: Synthesis of methyl ((R)-1,4-dioxan-2-yl)methyl-4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoate

[0131] To a solution of 4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoic acid (80 mg, 0.175 mmol) in dichloromethane (5 ml) were added 4-dimethylaminopyridine (25.66 mg, 0.21 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (50.32 mg, 0.2625 mmol) and (R)-(1,4-dioxan-2-yl)methanol (20.67 mg, 0.175 mmol) at room temperature and the mixture was reacted overnight at room temperature.

[0132] After the reaction, the reaction solution was poured into water and extracted with dichloromethane (50 ml × 3 times). The organic phase was washed with saturated sodium chloride solution (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (chromatographic column: Agilent 5Prep-C18 100 mm × 30 mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water + 0.05% saturated ammonia water) to obtain 24 mg of white solid ((R)-1,4-dioxane-2-yl)methyl-4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoic acid methyl ester (yield: 23%). Compound 9: LCMS: RT = 1.75 min, [M + H] + =557.33. 1H NMR (400MHz, DMSO-d6) δ10.85(s,1H),8.73(d,J=1.5Hz,1H),8.68(dd,J=2.5,1.5Hz,1H),8.52(d,J=2.6H z,1H),7.98(d,J=8.0Hz,2H),7.72(d,J=8.0Hz,2H),7.27(t,J=2.8Hz,1H),6.66(s,1H),6.49-6.44(m,1H ),4.27(d,J=4.9Hz,2H),3.90-3.84(m,1H),3.83-3.69(m,8H),3.67-3.57(m,1H),3.55-3.38(m,3H),3.2 6-3.19(m,1H),2.69-2.61(m,1H),2.42(m,4H),2.31-2.19(m,1H),2.19-2.06(m,2H),1.87-1.75(m,1H).

[0133] Example 10 Synthesis of Compound 10

[0134]

[0135] The specific synthetic route is as follows:

[0136] Step A: Synthesis of 2,3-dihydro-1H-indene-5-yl-4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoate

[0137] 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (100 mg, 0.22 mmol), 2,3-dihydro-1H-inden-5-ol (59 mg, 0.44 mmol), 4-dimethylaminopyridine (5 mg, 0.044 mmol) and N,N-diisopropylethylamine (57 mg, 0.44 mmol) were dissolved in dichloromethane (10 ml) at room temperature. After the solution was clarified, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg, 0.44 mmol) was added and reacted at room temperature for 12 hours.

[0138] After the reaction, the reaction solution was concentrated to obtain a crude product. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to obtain a crude product. Preparative chromatography was performed to obtain 54.1 mg of 2,3-dihydro-1H-inden-5-yl-4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoate (yield: 42.9%). Compound 10: LCMS: RT = 1.89 min, [M+H] + =573.3. 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.73(s,1H),8.68(d,J=4.0Hz,1H),8.52(d,J=2.4Hz,1H),8.12 (d,J=8.0Hz,2H),7.78(d,J=8.0Hz,2H),7.28(d,J=8.4Hz,2H),7.11(d,J=2.0Hz,1H),6.99(d,J=8.0Hz ,1H),6.66(s,1H),6.48(s,1H),3.80-3.66(m,4H),3.44-3.36(m,1H),3.24(t,J=4.0Hz,1H),3.17(s,2 H),2.88(q,J=7.2Hz,4H),2.72-2.61(m,1H),2.47-2.38(m,4H),2.35-2.01(m,4H),1.88-1.76(m,1H).

[0139] Example 11 Synthesis of Compound 11

[0140]

[0141] The specific synthetic route is as follows:

[0142] Step A: Pyridin-3-ylmethyl-4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoate

[0143] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (100 mg, 0.22 mmol), pyridin-3-ylmethanol (48 mg, 0.44 mmol), 4-dimethylaminopyridine (53 mg, 0.44 mmol) and N,N-diisopropylethylamine (57 mg, 0.44 mmol) were dissolved in dichloromethane (10 ml). After the solution was clarified, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg, 0.44 mmol), reacted at room temperature for 12 hours. After the reaction, the reaction solution was concentrated to obtain a crude product, and the residue was purified by silica gel column chromatography (eluent: 100% ethyl acetate) to obtain a crude product, which was separated by preparative chromatography to obtain 50.1 mg of pyridin-3-ylmethyl-4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoate (yield: 41.5%). Compound 11: LCMS: RT = 1.68 min, [M+H] + =548.32. 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.71(d,J=2.8Hz,2H),8.69-8.63(m,1H),8.57(dd,J=4.8,1.6Hz,1H ),8.51(d,J=2.4Hz,1H),8.01(d,J=8.0Hz,2H),7.91(d,J=8.0Hz,1H),7.71(d,J=8.0Hz,2H),7.44(dd,J=8. 0,4.8Hz,1H),7.25(t,J=2.8Hz,1H),6.64(s,1H),6.51-6.40(m,1H),5.39(s,2H),3.68(s,5H),3.38(d,J=1 2.0Hz,1H),3.25-3.18(m,1H),2.69-2.60(m,1H),2.47-2.37(m,4H),2.30-2.05(m,3H),1.86-1.74(m,1H).

[0144] Example 12 Synthesis of Compound 12

[0145]

[0146] The specific synthetic route is as follows:

[0147] Step A: Synthesis of compound 1-(pyridin-3-yl)ethyl-4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoate

[0148] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (100 mg, 0.22 mmol), 1-(pyridin-3-yl)ethane-1-ol (54 mg, 0.44 mmol), 4-dimethylaminopyridine (53 mg, 0.44 mmol) and N,N-diisopropylethylamine (57 mg, 0.44 mmol) were dissolved in dichloromethane (10 ml). After the solution was clarified, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg, 0.44 mmol) was added and reacted at room temperature for 12 hours.

[0149] After the reaction, the reaction solution was concentrated to obtain a crude product. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to obtain a crude product. The residue was purified by preparative HPLC (chromatographic column: Agilent 5Prep-C18 100 mm × 30 mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water + 0.05% saturated ammonia water) to obtain 20.1 mg of 1-(pyridin-3-yl)ethyl-4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoate (yield: 16.2%) Compound 12: LCMS: RT = 1.73 min, [M+H] + =562.33. 1HNMR (400MHz, DMSO-d6) δ10.82(s,1H),8.71(s,2H),8.67(t,J=2.0Hz,1H),8.56-8.48(m,2H),8.02(d,J=7.2H z,2H),7.91(dt,J=8.0,2.0Hz,1H),7.71(d,J=8.0Hz,2H),7.41(dd,J=8.0,4.8Hz,1H),7.25(d,J=3.2Hz,1H), 6.65(s,1H),6.47(q,J=2.4Hz,1H),6.10(q,J=6.4Hz,1H),3.75-3.64(m,5H),3.42-3.35(m,1H),3.24-3.17(m ,1H),2.69-2.60(m,1H),2.47-2.38(m,4H),2.34-2.05(m,3H),1.86-1.74(m,1H),1.64(dd,J=6.4,2.0Hz,3H).

[0150] Example 13 Synthesis of Compound 13

[0151]

[0152] The specific synthetic route is as follows:

[0153] Step A: Synthesis of compound (2,2-dimethyl-1,3-dioxolan-4-yl)-4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoic acid methyl ester

[0154] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (100 mg, 0.22 mmol), (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (60 mg, 0.44 mmol), 4-dimethylaminopyridine (53 mg, 0.44 mmol) and N,N-diisopropylethylamine (57 mg, 0.44 mmol) were dissolved in dichloromethane (10 ml). After the solution was clarified, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg, 0.44 mmol) was added and reacted at room temperature for 12 hours.

[0155] After the reaction was completed, the reaction solution was concentrated to obtain a crude product, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to obtain 25.3 mg of (2,2-dimethyl-1,3-dioxolan-4-yl)-4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoic acid methyl ester (yield: 20.1%). Compound 13: LCMS: RT = 2.05 min, [M+H] + =571.33. 1 HNMR (400MHz, DMSO-d6) δ10.82(s,1H),8.72(s,1H),8.70-8.65(m,1H),8.51(d,J=2.4Hz,1H),7.99(d,J=8. 0Hz,2H),7.71(d,J=8.0Hz,2H),7.25(q,J=2.4Hz,1H),6.65(s,1H),6.51-6.41(m,1H),4.44-4.32(m,2H),4 .30-4.24(m,1H),4.12-4.05(m,1H),3.84-3.78(m,1H),3.74-3.65(m,5H),3.4-3.36(m,1H),3.26-3.18(m, 1H),2.70-2.60(m,1H),2.48-2.39(m,4H),2.35-2.05(m,3H),1.85-1.74(m,1H),1.34(s,3H),1.29(s,3H).

[0156] Example 14 Synthesis of Compound 14

[0157]

[0158] The specific synthetic route is as follows:

[0159] Step A: Synthesis of 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (1,3-dioxolan-2-yl)methyl ester

[0160] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (100 mg, 0.22 mmol), 2-bromomethyl-1,3-dioxolane (54.8 mg, 0.33 mmol), potassium carbonate (60.7 mg, 0.44 mmol) were dissolved in N,N-dimethylformamide (5 ml) and reacted at 65 degrees Celsius for 4 hours. After the reaction was completed The reaction solution was poured into water and extracted with ethyl acetate (10 ml x 3 times). The organic phases were combined, dried and spin-dried to give a crude product. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 48 mg of 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (1,3-dioxolan-2-yl)methyl ester (yield: 40.3%).

[0161] Compound 14: LCMS: RT = 2.04 min, [M+H] + =543.30.

[0162] Example 15 Synthesis of Compound 15

[0163]

[0164] The specific synthetic route is as follows:

[0165] Step A: Synthesis of 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)tetrahydro-2H-pyran-4-ylbenzoate

[0166] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (100 mg, 0.22 mmol), tetrahydropyran-4-ol (26.5 mg, 0.26 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (63.2 mg, 0.33 mmol), 4-dimethylaminopyridine (40.3 mg, 0.33 mmol) were dissolved in dichloromethane (5 ml) and reacted at 40 degrees Celsius for 6 hours. After the reaction was completed, the reaction solution was poured into water and extracted with dichloromethane (8 ml × 3 times). The organic phases were combined, dried and spin-dried to obtain a crude product. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain 55 mg of white solid 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)tetrahydro-2H-pyran-4-ylbenzoate (yield: 46.6%). Compound 15: LCMS: RT = 2.13 min, [M+H] + =541.31. 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.72(d,J=1.5Hz,1H),8.69-8.65(m,1H),8.51(d,J=2.6Hz,1H),7.97(d,J=8 .1Hz,2H),7.72(d,J=8.1Hz,2H),7.26(t,J=2.8Hz,1H),6.65(s,1H),6.45(dd,J=3.0,1.9Hz,1H),5.21(t,J=3.8Hz ,1H),4.30(d,J=3.8Hz,2H),4.03-3.92(m,2H),3.91-3.82(m,2H),3.71(s,1H),3.69(s,3H),3.38(d,J=12.0Hz,1H ),3.25-3.19(m,1H),2.70-2.60(m,1H),2.41(s,3H),2.28(d,J=11.2Hz,1H),2.22-2.05(m,2H),1.86-1.76(m,1H).

[0167] Example 16 Synthesis of Compound 16

[0168]

[0169] The specific synthetic route is as follows:

[0170] Step A: Synthesis of compound 1-methoxypropan-2-yl-4-(2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoate

[0171] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (100 mg, 0.22 mmol), 1-methoxypropan-2-ol (40 mg, 0.44 mmol), 4-dimethylaminopyridine (53 mg, 0.44 mmol) and N,N-diisopropylethylamine (57 mg, 0.44 mmol) were dissolved in dichloromethane (10 ml). After the solution was clarified, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg, 0.44 mmol) was added and reacted at room temperature for 12 hours.

[0172] After the reaction, the reaction solution was concentrated to obtain a crude product. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to obtain a crude product. The residue was purified by preparative HPLC (chromatographic column: Agilent 5Prep-C18 100 mm × 30 mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water + 0.05% saturated ammonia water) to obtain 34.9 mg of 1-methoxypropan-2-yl-4-(2S, 4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoate (yield: 30.0%) Compound 16: LCMS: RT = 1.79 min, [M+H] + =529.33. 1 HNMR(400MHz,DMSO-d6)δ10.82(s,1H),8.72(s,1H),8.70-8.65(m,1H),8.51(d,J=2 .4Hz,1H),7.99(d,J=8.0Hz,2H),7.71(d,J=8.0Hz,2H),7.25(s,1H),6.65(s,1H),6 .46(s,1H),5.28-5.16(m,2H),3.75-3.65(m,5H),3.59-3.45(m,3H),3.30-3.17(m, 4H),2.70-2.60(m,1H),2.48-2.39(m,4H),2.35-2.04(m,3H),1.26(d,J=6.4Hz,3H).

[0173] Example 17 Synthesis of Compound 17

[0174]

[0175] The specific synthetic route is as follows:

[0176] Step A: Synthesis of compound 1-(1,3-dioxolan-4-yl)ethyl-4-(2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoate

[0177] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (100 mg, 0.22 mmol), 1-(1,3-dioxolan-4-yl)ethane-1-ol (52 mg, 0.44 mmol), 4-dimethylaminopyridine (53 mg, 0.44 mmol) and N,N-diisopropylethylamine (57 mg, 0.44 mmol) were dissolved in dichloromethane (10 ml). After the solution was clarified, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg, 0.44 mmol) was added and reacted at room temperature for 12 hours.

[0178] After the reaction was completed, the reaction solution was concentrated to obtain a crude product, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to obtain 20.1 mg of (2,2-dimethyl-1,3-dioxolan-4-yl)-4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoic acid methyl ester (yield: 16.4%). Compound 17: LCMS: RT = 1.80 min, [M+H] + =557.33. 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.71(s,1H),8.67(s,1H),8.51(d,J=2.4Hz,1H),7.97(d,J=8.0Hz,2H) ,7.72(d,J=8.0Hz,2H),7.25(q,J=2.4Hz,1H),6.65(s,1H),6.46(s,1H),4.97(d,J=6.4Hz,1H),4.70-4.60(m, 2H),4.24-4.17(m,1H),3.90-3.80(m,1H),3.75-3.65(m,5H),3.58-3.48(m,1H),3.42-3.35(m,1H),3.25-3. 16(m,1H),2.70-2.60(m,1H),2.48-2.37(m,4H),2.34-2.03(m,3H),1.85-1.74(m,1H),1.23(d,J=6.4Hz,3H).

[0179] Example 18 Synthesis of Compound 18

[0180]

[0181] Example 18 can be synthesized by referring to the synthetic route of Examples 1-17, Compound 18: LCMS: RT = 1.73 min, [M+H] + =569.24. 1 H NMR (400MHz, DMSO-d6) δ10.82 (s, 1H), 8.78-8.62 (m, 2H), 8.51 (d, J = 2.5Hz, 1H), 7 .99(d,J=8.1Hz,2H),7.72(d,J=8.0Hz,2H),7.25(t,J=2.7Hz,1H),6.65(s,1H),6 .45(dd,J=3.0,1.8Hz,1H),5.21(s,2H),3.79-3.65(m,5H),3.22(m,3H),2.70-2. 59(m,1H),2.41(s,4H),2.27(m,1H),2.22(s,3H),2.14(m,1H),1.91-1.71(m,1H).

[0182] Example 19 Synthesis of Compound 19

[0183]

[0184] Example 19 can be synthesized by referring to the synthetic route of Examples 1-17, Compound 19: LCMS: RT = 1.73 min, [M+H] + =527.30. 1H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.73(d,J=1.5Hz,1H),8.68(t,J=2.1Hz,1H),8.52(d,J=2.6Hz,1H),7.9 8(d,J=8.0Hz,2H),7.71(d,J=8.0Hz,2H),7.27(t,J=2.7Hz,1H),6.65(s,1H),6.47(q,J=2.0Hz,1H),5.46(d,J= 5.7Hz,1H),3.94-3.84(m,3H),3.80(dq,J=8.4,4.1Hz,1H),3.70(s,4H),3.40(s,1H),3.31(s,1H),3.23(t,J=4 .9Hz,1H),2.69-2.61(m,1H),2.42(m,4H),2.26(dt,J=14.5,7.6Hz,2H),2.18-2.02(m,3H),1.86-1.75(m,1H).

[0185] Example 20 Synthesis of Compound 20

[0186]

[0187] The specific synthetic route is as follows:

[0188] Step A: Synthesis of compound 2-methyl-1,3-dioxane-5-yl-4-(2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoate

[0189] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (100 mg, 0.22 mmol), 2-methyl-1,3-dioxane-5-ol (52 mg, 0.44 mmol), 4-dimethylaminopyridine (53 mg, 0.44 mmol) and N,N-diisopropylethylamine (57 mg, 0.44 mmol) were dissolved in dichloromethane (10 ml). After the solution was clarified, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg, 0.44 mmol) was added and reacted at room temperature for 12 hours.

[0190] After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to obtain a crude product. Preparative chromatography was performed to obtain 26.1 mg of 2-methyl-1,3-dioxane-5-yl-4-(2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoate (yield: 21.3%). Compound 20: LCMS: RT = 1.81 min, [M+H] + =557.32. 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.72(s,1H),8.67(s,1H),8.52(d,J=2.4Hz,1H),7.98(d,J=6. 0Hz,2H),7.72(d,J=8.0Hz,2H),7.26(s,1H),6.65(s,1H),6.46(s,1H),5.13-4.95(m,1H),4.46-4.32 (m,2H),4.29-4.11(m,1H),4.05-3.82(m,1H),3.78-3.62(m,5H),3.45-3.38(m,2H),3.26-3.18(m,2H ),2.73-2.60(m,1H),2.46-2.39(m,3H),2.34-2.04(m,3H),1.86-1.73(m,1H),1.27(t,J=5.2Hz,3H).

[0191] Example 21 Synthesis of Compound 21

[0192]

[0193] The specific synthetic route is as follows:

[0194] Step A: Synthesis of compound 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)-2-methoxypropyl benzoate

[0195] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (100 mg, 0.22 mmol), 2-methoxy-1-propanol (23.4 mg, 0.26 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (63.2 mg, 0.33 mmol), and 4-dimethylaminopyridine (40.3 mg, 0.33 mmol) were dissolved in dichloromethane (5 ml) and reacted at 40 °C for 6 hours.

[0196] After the reaction, the reaction solution was poured into water and extracted with dichloromethane (8 ml × 3 times). The organic phases were combined, dried and spin-dried to obtain a crude product. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain 39 mg of white solid 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)-2-methoxypropyl benzoate (yield: 33.6%). Compound 21: LCMS: RT = 1.77 min, [M+H] + =529.30. 1 HNMR (400MHz, DMSO-d6) δ10.83(t,J=2.3Hz,1H),8.73(d,J=1.5Hz,1H),8.71-8.65(m,1H),8.52(d,J=2.5Hz,1H),7.98( d,J=8.1Hz,2H),7.72(d,J=8.1Hz,2H),7.26(t,J=2.5Hz,1H),6.66(s,1H),6.47(dd,J=3.1,1.8Hz,1H),4.31(dt,J=11. 5,3.9Hz,1H),4.21(ddd,J=11.5,5.8,4.1Hz,1H),3.76–3.61(m,5H),3.39(d,J=12.1Hz,1H),3.32(d,J=7.6Hz,3H),3.2 3(p,J=5.1Hz,1H),2.73-2.63(m,2H),2.42(s,3H),2.32-2.23(m,1H),2.22-2.06(m,1H),1.80(td,J=10.0,4.8Hz,1H).

[0197] Example 22 Synthesis of Compound 22

[0198]

[0199] Example 22 can be synthesized by referring to the synthetic route of Example 1-17, Compound 22: LCMS: RT = 1.73 min, [M + H] + =543.30. 1H NMR (400MHz, DMSO-d6) δ10.84(d,J=2.5Hz,1H),8.73(d,J=1.5Hz,1H),8.69(t,J=2.0Hz,1H),8.52(d,J=2.6 Hz,1H),8.02(d,J=8.0Hz,2H),7.74(d,J=8.1Hz,2H),7.27(t,J=2.6Hz,1H),6.66(s,1H),6.47(t,J=2.5Hz,1 H),4.10(dd,J=12.7,2.6Hz,2H),3.97(dd,J=12.6,3.2Hz,2H),3.71(m,5H),3.38(m,1H),3.24(q,J=4.9Hz, 1H),2.71-2.61(m,2H),2.42(s,3H),2.28(d,J=11.5Hz,1H),2.22-2.11(m,2H),1.81(td,J=9.9,5.0Hz,1H).

[0200] Example 23 Synthesis of Compound 23

[0201]

[0202] Example 23 can be synthesized by referring to the synthetic route of Example 1-17, compound 23: LCMS: RT = 1.75min, [M+H] + =569.30. 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.73(d,J=1.5Hz,1H),8.68(t,J=2.1Hz,1H),8.52(d,J=2.6Hz,1H),7.99(d,J= 8.1Hz,2H),7.73(d,J=8.1Hz,2H),7.26(t,J=2.6Hz,1H),6.66(s,1H),6.48(t,J=2.4Hz,1H),5.68(d,J=5.2Hz,1H),5 .38(dt,J=8.3,6.0Hz,1H),4.11-3.99(m,1H),3.95-3.75(m,2H),3.70(s,3H),3.40(d,J=12.7Hz,1H),3.26-3.11(m, 2H),2.71-2.61(m,2H),2.42(s,3H),2.27(d,J=10.6Hz,1H),2.23-2.06(m,2H),2.05-1.95(m,1H),1.85-1.78(m,2H).

[0203] Example 24 Synthesis of Compound 24

[0204]

[0205] The specific synthetic route is as follows:

[0206] Step A: Synthesis of compound 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)3R,3aR,6S,6aR-hexahydrofuran[3,2-b]furan-3,6-diylbis(4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid).

[0207] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (100 mg, 0.22 mmol), isosorbide (16.1 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (63.2 mg, 0.33 mmol), 4-dimethylaminopyridine (40.3 mg, 0.33 mmol) were dissolved in dichloromethane (5 ml) and reacted at 40 degrees Celsius for 10 hours. After the reaction, the reaction solution was poured into water and extracted with dichloromethane (8 ml × 3 times). The organic phases were combined, dried and spin-dried to obtain a crude product. The residue was purified by preparative HPLC (chromatographic column: Agilent 5Prep-C18 100 mm × 30 mm 5 μm, mobile phase A: acetonitrile, mobile phase B: water + 0.05% saturated ammonia water) to give 48 mg of a white solid 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)3R,3aR,6S,6aR-hexahydrofuran[3,2-b]furan-3,6-diylbis(4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid) (yield: 21.3%). Compound 24: LCMS: RT = 2.12 min, [M+H] + =1023.6. 1H NMR (400MHz, DMSO-d6) δ10.83(d,J=2.5Hz,2H),8.73(dd,J=4.8,1.5Hz,2H),8.70-8.66(m,2H),8.52(t,J=2.4Hz,2H),7.99(dd,J=1 6.0,8.1Hz,4H),7.73(t,J=8.0Hz,4H),7.27(q,J=2.7Hz,2H),6.65(d,J=2.5Hz,2H),6.47(dt,J=5.2,2.3Hz,2H),5.44-5.33(m,2H) ,5.00(t,J=5.3Hz,1H),4.64(d,J=4.9Hz,1H),4.07-3.94(m,4H),3.70(d,J=3.7Hz,10H),3.39(dd,J=11.9,7.0Hz,2H),3.21(dd,J= 11.6, 6.2Hz, 2H), 2.66 (dt, J = 12.3, 5.1Hz, 2H), 2.42 (d, J = 1.6Hz, 6H), 2.32-2.23 (m, 2H), 2.18-2.08 (m, 4H), 1.79 (d, J = 14.8Hz, 2H).

[0208] Example 25 Synthesis of Compound 25

[0209]

[0210] Example 25 can be synthesized by referring to the synthetic route of Example 24, compound 25: LCMS: RT = 1.84 min, [M+H] + = 967.49. 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 2H), 8.67 (dd, J = 18.1, 1.9 Hz, 4H), 8.50 (d, J = 2.6 Hz, 2H), 7.97 (d, J = 8.1 Hz, 4H), 7.67 (d, J = 8.1 Hz, 4H), 7.25 (t, J = 2.8 Hz,2H),6.64(s,2H),6.45(t,J=2.5Hz,2H),4.32(d,J=6.0Hz,4H),3.67(d,J=3.4Hz,10H),3.37(d,J=12.0Hz, 4H),3.24-3.13(m,2H),2.73-2.58(m,2H),2.41(s,8H),2.30-2.05(m,6H),1.78(s,2H),1.11(d,J=6.9Hz,3H).

[0211] Example 26 Synthesis of Compound 26

[0212]

[0213] Example 26 can be synthesized by referring to the synthetic route of Example 24. Compound 26: LCMS: RT = 1.81 min, [M+H] + =925.44. 1 H NMR (400MHz, DMSO-d6) δ10.81 (s, 2H), 8.80-8.60 (m, 4H), 8.50 (d, J = 2.6Hz, 2H), 8.01 (d, J = 8. 1Hz, 4H), 7.73 (d, J = 8.1Hz, 4H), 7.24 (t, J = 2.8Hz, 2H), 6.63 (s, 2H), 6.44 (t, J = 2.5Hz, 2H), 6. 21(s,2H),3.69(d,J=13.5Hz,10H),3.37(d,J=12.2Hz,4H),3.25-3.18(m,2H),2.63(d,J=11. 2Hz, 2H), 2.40 (s, 8H), 2.25 (t, J = 11.2Hz, 2H), 2.12 (d, J = 18.6Hz, 2H), 1.80 (d, J = 10.8Hz, 2H).

[0214] Example 27 Synthesis of Compound 27

[0215]

[0216] Example 27 can be synthesized by referring to the synthetic route of Example 24, compound 27: LCMS: RT = 1.73 min, [M + H] + =939.54. 1 H NMR(400MHz,DMSO-d6)δ10.80(t,J=2.4Hz,2H),8.76-8.62(m,4H),8.50(d,J=2.6Hz,2H),7 .97(d,J=8.1Hz,4H),7.68(d,J=8.1Hz,4H),7.24(t,J=2.8Hz,2H),6.61(s,2H),6.43(t,J= 2.4Hz,2H),4.63(s,4H),3.71-3.62(m,10H),3.32-3.36(m,4H),3.21-3.16(m,2H),2.71-2 .57(m,2H),2.39(s,8H),2.24(t,J=11.2Hz,2H),2.17-2.07(m,2H),1.78(t,J=6.6Hz,2H).

[0217] Example 28 Synthesis of Compound 28

[0218]

[0219] Example 28 can be synthesized by referring to the synthetic route of Example 24, compound 28: LCMS: RT = 1.81 min, [M + H] + =939.47. 1 H NMR (400MHz, DMSO-d6) δ10.81(s,2H),8.68(d,J=16.5Hz,4H),8.50(s,2H),7.99(d,J=8. 0Hz,4H),7.72(d,J=8.0Hz,4H),7.24(d,J=4.2Hz,3H),6.64(d,J=3.5Hz,2H),6.54-6.36( m,2H),3.78-3.63(m,11H),3.28-3.42(m,4H),3.21(s,2H),2.63(d,J=11.0Hz,4H),2.41( d,J=2.8Hz,8H),2.26(s,2H),2.16(d,J=11.8Hz,2H),1.79(s,2H),1.71(d,J=5.4Hz,3H).

[0220] Example 29 Synthesis of Compound 29

[0221]

[0222] Example 29 can be synthesized by referring to the synthetic route of Example 1-17, compound 29: LCMS: RT = 2.08 min, [M + H] + =541.2. 1 H NMR (400MHz, DMSO-d6) δ10.82(t,J=2.3Hz,1H),8.80-8.65(m,2H),8.51(d,J=2.6Hz,1H),8.01(d,J=8.1 Hz,2H),7.74(d,J=8.1Hz,2H),7.26(t,J=2.8Hz,1H),6.65(s,1H),6.46(td,J=3.0,1.9Hz,1H),5.79(t, J=9.2Hz,1H),4.48(td,J=8.9,2.2Hz,1H),4.36(ddd,J=10.0,8.7,6.4Hz,1H),3.69(s,5H),3.39(d,J=1 1.9Hz,1H),3.22(q,J=5.0Hz,1H),2.69-2.62(m,1H),2.42(s,5H),2.33-2.06(m,4H),1.89-1.73(m,1H).

[0223] Example 30 Synthesis of Compound 30

[0224]

[0225] Example 30 can be synthesized by referring to the synthetic route of Example 1-17, compound 30: LCMS: RT = 2.01 min, [M + H] + =557.20. 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.70(dt,J=20.8,1.7Hz,2H),8.52(d,J=2.5Hz,1H),7.96(d,J=8.0Hz,2H),7.73 (d,J=8.1Hz,2H),7.26(q,J=2.5Hz,1H),6.65(s,1H),6.46(ddd,J=6.7,3.0,1.9Hz,1H),5.19(s,1H),4.65(t,J=8.6Hz ,1H),4.61-4.54(m,1H),4.53-4.49(m,1H),4.47(ddd,J=7.5,4.4,2.9Hz,1H),3.77-3.66(m,5H),3.39(dd,J=11.9,7. 6Hz, 1H), 3.21 (s, 1H), 2.64 (d, J = 5.3Hz, 1H), 2.42 (s, 4H), 2.28 (t, J = 10.8Hz, 1H), 2.14 (d, J = 21.9Hz, 2H), 1.80 (s, 1H).

[0226] Example 31 Synthesis of Compound 31

[0227]

[0228] Example 31 can be synthesized by referring to the synthetic route of Example 1-17, compound 31: LCMS: RT = 2.13 min, [M + H] + =571.2. 1H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.72(d,J=1.6Hz,1H),8.67(dd,J=2.5,1.5Hz,1H),8.51(d,J=2.5Hz,1H),7.96(d ,J=8.1Hz,2H),7.70(d,J=8.1Hz,2H),7.25(t,J=2.8Hz,1H),6.65(s,1H),6.46(dd,J=3.1,1.9Hz,1H),4.34(t,J=6.9Hz ,2H),3.95-3.85(m,4H),3.69(s,5H),3.38(d,J=11.9Hz,1H),3.22(t,J=5.0Hz,1H),2.69-2.60(m,1H),2.46(s,1H),2. 41(s,3H),2.26(t,J=11.0Hz,1H),2.20-2.10(m,2H),2.06(t,J=6.9Hz,2H),1.80(dt,J=14.5,7.5Hz,1H),1.32(s,3H).

[0229] Example 32 Synthesis of Compound 32

[0230]

[0231] Example 32 can be synthesized by referring to the synthetic route of Example 24. Compound 32: LCMS: RT = 1.75 min, [M+H] + =983.21.

[0232] Example 33 Synthesis of Compound 33

[0233]

[0234] Example 33 can be synthesized by referring to the synthetic route of Example 1-17, compound 33: LCMS: RT = 1.98 min, [M + H] + =629.19. 1H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.72(s,1H),8.70-8.64(m,1H),8.52(d,J=2.4Hz,1H),8.00(d,J=8. 0Hz,2H),7.74(d,J=8.0Hz,2H),7.25(t,J=2.8Hz,1H),6.65(s,1H),6.49-6.40(m,1H),6.01-5.89(m,2H), 4.14(t,J=6.4Hz,2H),3.76-3.64(m,5H),3.41-3.36(m,2H),3.26-3.18(m,1H),2.69-2.60(m,1H),2.47-2 .38(m,4H),2.30-2.02(m,3H),1.85-1.74(m,1H),1.64-1.53(m,2H),1.33-1.15(m,7H),0.89-0.75(m,3H).

[0235] Example 34 Synthesis of Compound 34

[0236]

[0237] Example 34 can be synthesized by referring to the synthetic route of Example 1-17, compound 34: LCMS: RT = 1.73min, [M+H] + =585.21. 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),8.70(dt,J=19.1,1.8Hz,2H),8.52(d,J=2.5Hz,1H),7.98(d,J=8.0Hz,2H),7.71(dd, J=8.4,2.2Hz,2H),7.25(q,J=2.7Hz,1H),6.65(s,1H),6.45(dt,J=5.0,2.5Hz,1H),5.10(dt,J=11.3,6.3Hz,1H),4.31-4.18 (m,1H),4.06(ddd,J=18.0,8.5,6.8Hz,1H),3.90(dd,J=8.5,5.8Hz,1H),3.83-3.63(m,5H),3.37(s,1H),3.27-3.18(m,1H) ,2.64(d,J=13.8Hz,1H),2.41(s,4H),2.25(t,J=11.8Hz,1H),2.19-2.04(m,2H),1.79(d,J=14.3Hz,1H),1.49-1.12(m,9H).

[0238] Example 35 Synthesis of Compound 35

[0239]

[0240] Example 35 can be synthesized by referring to the synthetic route of Example 1-17, Compound 35: LCMS: RT = 1.79 min, [M + H] + =557.18. 1 H NMR (400MHz, DMSO-d6) δ10.84(t,J=2.3Hz,1H),8.73(d,J=1.5Hz,1H),8.68(dd,J=2.6,1.5Hz,1H),8.52(d,J=2.6Hz,1H),7.99(d,J= 8.1Hz,2H),7.72(d,J=8.0Hz,2H),7.25(t,J=2.8Hz,1H),6.65(s,1H),6.44(dd,J=3.1,1.9Hz,1H),4.43-4.31(m,2H),4.31-4.21(m,1 H),4.02(dd,J=8.5,6.6Hz,1H),3.78(dd,J=8.5,5.7Hz,1H),3.72-3.63(m,5H),3.37(s,1H),3.26-3.19(m,1H),2.69-2.59(m,1H),2. 46(s,1H),2.41(s,3H),2.28-2.24(m,2H),2.21-2.14(m,2H),2.14-2.06(m,1H),1.80(dd,J=13.7,9.3Hz,1H),1.58(p,J=7.9Hz,2H).

[0241] Example 36 Synthesis of Compound 36

[0242]

[0243] Example 36 can be synthesized by referring to the synthetic route of Examples 1-17, Compound 36: LCMS: RT = 1.77 min, [M+H] + =583.18.

[0244] Example 37 Synthesis of Compound 37

[0245]

[0246] Example 37 can be synthesized by referring to the synthetic route of Example 1-17, compound 37: LCMS: RT = 1.72 min, [M + H] + =541.13.

[0247] Example 38 Synthesis of Compound 38

[0248]

[0249] Example 38 can be synthesized by referring to the synthetic route of Example 1-17, compound 38: LCMS: RT = 1.85 min, [M + H] + =547.71.

[0250] Example 39 Synthesis of Compound 39

[0251]

[0252] Example 39 can be synthesized by referring to the synthetic route of Example 1-17, compound 39: LCMS: RT = 1.88 min, [M + H] + =561.16. 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),8.73(d,J=1.5Hz,1H),8.68(dd,J=2.5,1.5Hz,1H),8.52(d,J=2 .5Hz,1H),7.99(d,J=8.1Hz,2H),7.72(d,J=8.0Hz,2H),7.27(t,J=2.8Hz,1H),6.66(s,1H),6.47(dd, J=3.0,1.9Hz,1H),4.34(d,J=6.0Hz,2H),3.69(s,5H),3.42(m,2H),3.23(t,J=4.9Hz,1H),2.81-2.65 (m,2H),2.64-2.57(m,2H),2.42(s,3H),2.27(t,J=11.4Hz,1H),2.21-2.04(m,2H),1.85-1.74(m,1H).

[0253] Example 40 Synthesis of Compound 40

[0254]

[0255] Example 40 can be synthesized by referring to the synthetic route of Example 1-17, Compound 40: LCMS: RT = 1.82 min, [M+H] + =539.12. 1H NMR (400MHz, DMSO-d6) δ10.84(s,1H),8.73(d,J=1.6Hz,1H),8.69(dd,J=2.6,1.5Hz,1H),8.53(d,J=2.6 Hz,1H),8.02(d,J=8.1Hz,2H),7.77(d,J=8.1Hz,2H),7.27(t,J=2.8Hz,1H),6.66(s,1H),6.46(dd,J=3. 0,1.9Hz,1H),5.01(q,J=9.0Hz,2H),3.70(s,5H),3.39(d,J=12.1Hz,2H),3.23(t,J=5.0Hz,1H),2.66(d d,J=11.4,6.2Hz,1H),2.42(s,3H),2.29(q,J=11.8,11.3Hz,1H),2.22-2.06(m,2H),1.87-1.75(m,1H).

[0256] Example 41 Synthesis of Compound 41

[0257]

[0258] Example 41 can be synthesized by referring to the synthetic route of Example 1-17. Compound 41: LCMS: RT = 1.81 min, [M+H] + =557.14. 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.72(s,1H),8.68(s,1H),8.52(d,J=2.4Hz,1H),7.98(d,J=6. 0Hz,2H),7.72(d,J=8.0Hz,2H),7.26(s,1H),6.65(s,1H),6.45(s,1H),5.17-4.94(m,1H),4.50-4.3 0(m,2H),4.29-4.12(m,1H),3.98-3.81(m,1H),3.74-3.62(m,5H),3.46-3.36(m,2H),3.26-3.17(m, 1H),2.68-2.58(m,1H),2.47-2.36(m,4H),2.34-2.05(m,3H),1.85-1.66(m,1H),1.32-1.24(m,3H).

[0259] Example 42 Synthesis of Compound 42

[0260]

[0261] The specific synthetic route is as follows:

[0262] Step A: Synthesis of Compound Oxiran-2-yl Methyl Palmitate

[0263] Oxiran-2-ylmethanol (4 g, 54 mmol) and pyridine (5.1 g, 64.8 mmol) were dissolved in dichloromethane (100 ml), and palmitoyl chloride (16.3 g, 59.4 mmol) was added and reacted at room temperature overnight.

[0264] After the reaction was completed, the reaction solution was poured into water, a large amount of solid precipitated, a large amount of dichloromethane and methanol were added until it was clarified, the layers were separated, and the organic phase was dried over anhydrous sodium sulfate. The filtrate was concentrated and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / dichloromethane = 10 / 1 / 1) to obtain 3.7 g of light yellow oily oxirane-2-ylmethyl palmitate (yield 22%). 1 HNMR (400MHz, CDCl3) δ4.41(dd,J=12.4,3.2Hz,1H),3.91(dd,J=12.4,6.4Hz,1H),3.21(dt,J=6.4,3.2Hz,1H),2.84( t,J=4.8Hz,1H),2.69-2.58(m,1H),2.35(t,J=7.6Hz,2H),1.63(t,J=7.2Hz,2H),1.25(s,24H),0.88(t,J=6.8Hz,3H).

[0265] Step B: Synthesis of compound 2-hydroxypropane-1,3-diyldipalmitate

[0266] Oxiran-2-ylmethyl palmitate (3.7 g, 11.8 mmol) and palmitic acid (3.64 g, 14.21 mmol) were mixed evenly, tetrabutylammonium bromide (191 mg, 0.59 mmol) was added, and the mixture was heated to 100 degrees Celsius for reaction for 24 hours.

[0267] The reaction mixture was cooled to room temperature, methanol and n-hexane (ratio 1 / 3) were added, stirred at 45°C until clear, and left at room temperature overnight. A large amount of solid precipitated, which was filtered to obtain 1.5 g of 2-hydroxypropane-1,3-diyldipalmitate (yield 70%). 1 H NMR (400MHz, CDCl3) δ4.22-4.03(m,5H),2.57(d,J=4.8Hz,1H),2.33(t,J=7.6Hz,4H),1.67-1.56(m,4H),1.36-1.18(m,48H),0.87(t,J=6.8Hz,6H).

[0268] Step C: Synthesis of compound 6-((tert-butyldiphenylsilyl)oxy)ethyl hexanoate

[0269] Ethyl 6-hydroxyhexanoate (9.13 g, 57 mmol) and imidazole (5.04 g, 74.1 mmol) were dissolved in dichloromethane (100 ml), tert-butyldiphenylsilyl chloride (18.8 g, 68.4 mmol) was added, and the mixture was reacted at room temperature overnight.

[0270] After the reaction was completed, ethyl acetate was added for dilution, filtered, and the filtrate was concentrated. Purification by silica gel column chromatography (eluent: n-hexane / ethyl acetate / dichloromethane = 10 / 1 / 1) gave 22 g of ethyl 6-((tert-butyldiphenylsilyl)oxy)hexanoate (yield 97%).

[0271] Step D: Synthesis of compound 6-((tert-butyldiphenylsilyl)oxy)hexanoic acid

[0272] Ethyl 6-((tert-butyldiphenylsilyl)oxy)hexanoate (22 g, 55.2 mmol) was dissolved in methanol (200 ml), and an aqueous solution (100 ml) of lithium hydroxide monohydrate (7 g, 165.6 mmol) was added, and the mixture was reacted at 50 degrees Celsius for 1 hour.

[0273] After the reaction is completed, the majority of methanol is removed by concentration. The residue is diluted with water, and the pH is adjusted to 5-6 with a 2M hydrochloric acid aqueous solution under ice-water cooling, extracted with ethyl acetate, washed and dried, and concentrated to obtain 20.8 g of 6-((tert-butyldiphenylsilyl)oxy)hexanoic acid (crude product), which is directly used in the next step. 1HNMR (400MHz, CDCl3) δ7.70-7.62 (m, 4H), 7.44-7.35 (m, 6H), 3.66 (t, J = 6.4Hz, 2H), 2.33 (t, J = 7.6Hz, 2H), 1.68-1.52 (m, 4H), 1.46-1.36 (m, 2H), 1.05 (s, 9H).

[0274] Step E: Synthesis of compound 2-((6-((tert-butyldiphenylsilyl)oxy)hexanoyl)oxypropane-1,3-diyldipalmitate

[0275] 6-((tert-Butyldiphenylsilyl)oxy)hexanoic acid (130 mg, 0.36 mmol), 2-hydroxypropane-1,3-diyldipalmitate (100 mg, 0.18 mmol), 4-dimethylaminopyridine (43 mg, 0.36 mmol) and N,N-diisopropylethylamine (45 mg, 0.36 mmol) were dissolved in dichloromethane (10 ml). After the solution was clarified, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (75 mg, 0.44 mmol) was added and reacted at room temperature for 12 hours.

[0276] After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 20 / 1) to obtain 200 mg of 2-((6-((tert-butyldiphenylsilyl)oxy)hexanoyl)oxypropane-1,3-diyl dipalmitate (crude product). 1 H NMR (400MHz, CDCl3) δ7.65(d,J=6.0Hz,4H),7.44-7.35(m,6H),5.26(q,J=5.2Hz,1H),4.29(dd,J=12.0,4.4Hz,2H),4.14(dd,J=12.0,6.0Hz, 2H),3.65(t,J=6.4Hz,2H),2.33-2.26(m,6H),1.64-1.59(m,6H),1.44 -1.37(m,2H),1.33-1.22(m,50H),1.04(s,9H),0.88(t,J=6.8Hz,6H).

[0277] Step F: Synthesis of Compound 2-((6-hydroxyhexanoyl)oxy)propane-1,3-diyldipalmitate

[0278] 2-((6-((tert-butyldiphenylsilyl)oxy)hexanoyl)oxypropane-1,3-diyl dipalmitate (200 mg, 0.22 mmol) was dissolved in tetrahydrofuran (5 ml). After the solution was clarified, tetrabutylammonium fluoride (2.2 ml, 2.2 mmol) was added and reacted at room temperature for 2 hours.

[0279] After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to obtain 90 mg of 2-((6-hydroxyhexanoyl)oxy)propane-1,3-diyl dipalmitate (crude product), which was directly used in the next step reaction.

[0280] Step G: Synthesis of compound 2-((6-((4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)hexanoyl)oxy)propane-1,3-diyl dipalmitate

[0281] At room temperature, 2-((6-hydroxyhexanoyl)oxy)propane-1,3-diyl dipalmitate (100 mg, 0.15 mmol), 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (70 mg, 0.15 mmol), and 4-dimethylaminopyridine (38 mg, 0.3 mmol) were dissolved in dichloromethane (10 ml). After the solution was clarified, diisopropylcarbodiimide (97 mg, 0.75 mmol) was added and reacted at room temperature for 12 hours.

[0282] After the reaction was completed, the reaction solution was concentrated to obtain a crude product, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to obtain 13.1 mg of 2-((6-((4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)hexanoyl)oxy)propane-1,3-diyl dipalmitate (yield: 7.8%). Compound 42: 1 H NMR (400MHz, CDCl3) δ8.65-8.55(m,2H),8.43(d,J=2.4Hz,1H),8.03(d,J=8.0Hz,2H),7.95(s,1H),7.68(d,J=8.0Hz,2H),7.2 0(s,1H),6.69(d,J=5.2Hz,2H),5.25(q,J=5.2Hz,1H),4.37-4.25(m,4H),4.14(dd,J=12.0,6.0Hz,2H),3.82-3.71(m,5H),3. 50 (d, J = 12.0 Hz, 1H), 3.31-3.19 (m, 1H), 2.88-2.79 (m, 1H), 2.55-2.44 (m, 4H), 2.41-2.26 (m, 7H), 2.25-2.15 (m, 2H), 2.06-1.96 (m, 1H), 1.84-1.76 (m, 2H), 1.74-1.66 (m, 2H), 1.53-1.46 (m, 2H), 1.34-1.20 (m, 50H), 0.87 (t, J = 6.8 Hz, 6H). Example 43 Synthesis of Compound 43

[0283]

[0284] The specific synthetic route is as follows:

[0285] Step A: Synthesis of (R)-2-((5-((tert-butoxycarbonyl)amino)pentanoyl)oxy)-3-(stearoyloxy)propyl(2-(trimethylammonio)ethyl)phosphate.

[0286] At room temperature, 5-((tert-Butyloxycarbonyl)amino)pentanoic acid (332 mg, 1.53 mmol) was dissolved in dichloromethane (25 ml), and 4-dimethylaminopyridine (93 mg, 0.76 mmol), N,N-diisopropylethylamine (289 mg, 2.29 mmol), (R)-2-hydroxy-3-(stearoyloxy)propyl(2-(trimethylammonio)ethyl)phosphate (200 mg, 0.38 mmol) were added, and the reaction was carried out at room temperature for 48 hours.

[0287] After the reaction was completed, the crude product was concentrated to dryness and purified by preparative liquid phase to obtain 190 mg of a colorless oily substance (R)-2-((5-((tert-butoxycarbonyl)amino)pentanoyl)oxy)-3-(stearoyloxy)propyl(2-(trimethylammonio)ethyl)phosphate (yield: 68.8%).

[0288] Step B: Synthesis of (R)-2-((5-aminopentanoyl)oxy)-3-(stearoyloxy)propyl(2-(trimethylammonio)ethyl)phosphate hydrochloride.

[0289] At room temperature, (R)-2-((5-((tert-butoxycarbonyl)amino)pentanoyl)oxy)-3-(stearoyloxy)propyl(2-(trimethylammonio)ethyl)phosphate (95 mg, 0.13 mmol) was added to dichloromethane (2 ml), and 4N hydrogen chloride / dioxane solution (0.13 ml, 0.52 mmol) was added, and the reaction was carried out at room temperature for 1.5 hours.

[0290] After the reaction was completed, the mixture was concentrated to dryness to obtain 87 mg of white solid (R)-2-((5-aminopentanoyl)oxy)-3-(stearoyloxy)propyl(2-(trimethylammonio)ethyl)phosphate hydrochloride (yield: 100.0%).

[0291] Step C: Synthesis of (R)-2-((5-(4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoylamino)pentanoyl)oxy)-3-(stearoyloxy)propyl(2-(trimethylammonio)ethyl)phosphate.

[0292] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (40 mg, 0.087 mmol) and (R)-2-((5-aminopentanoyl)oxy)-3-(stearoyloxy)propyl(2-(trimethylammonio)ethyl)phosphate hydrochloride (63.5 mg, 0.96 mmol) were added to dichloromethane (2 ml), and 1-hydroxybenzotriazole (23.6 mg, 0.17 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (33.5 g, 0.17 mmol) and N,N-diisopropylethylamine (38.5 mg, 0.29 mmol) were added, and the mixture was reacted at room temperature for 12 hours.

[0293] After the reaction, the crude product was concentrated to dryness and purified by preparative liquid phase to give 31.2 mg of off-white solid (R)-2-((5-(4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoylamino)pentanoyl)oxy)-3-(stearoyloxy)propyl(2-(trimethylammonio)ethyl)phosphate (yield: 33.5%).

[0294] Compound 43: LCMS: RT = 2.68 min, [M+H] + =1061.8. 1 H NMR (400MHz, Methanol-d4) δ8.69(s,2H),8.48(s,1H),7.90(d,J=8.1Hz,2H),7.70(d,J=7.9Hz,2H),7.21(d,J=3.1Hz,1H),6.69(s, 1H),6.44(d,J=3.2Hz,1H),5.27(s,1H),4.43(dd,J=12.0,3.4Hz,1H),4.26(s,2H),4.19(dd,J=12.0,6.8Hz,1H),4.03(q,J=5.9,5.4 Hz,2H),3.87(d,J=11.9Hz,1H),3.77(s,4H),3.61(t,J=4.7Hz,2H),3.47-3.40(m,3H),3.19(s,9H),2.90(d,J=12.3Hz,1H),2.47(d, J=8.9Hz,7H),2.28(q,J=12.6,10.0Hz,4H),1.80-1.66(m,4H),1.55(d,J=7.9Hz,2H),1.26(d,J=8.4Hz,30H),0.90(t,J=6.7Hz,3H).

[0295] Example 44 Synthesis of Compound 44

[0296]

[0297] Example 44 can be synthesized by referring to the synthetic routes of Examples 42 and 43, compound 44: 1 H NMR(400MHz,Chloroform-d)δ8.62(d,J=2.6Hz,2H),8.46(d,J=2.3Hz,1H),8.09(d,J=8.0Hz,2H),7.99(s,1H),7.73(d,J=8.1Hz,2H),7.22(t,J=2.9Hz,1 H),6.74-6.67(m,2H),6.02(s,2H),5.31-5.24(m,1H),4.30(ddd,J=12.0,4. 4,2.0Hz,2H),4.14(dd,J=11.9,6.0Hz,2H),3.90(d,J=12.2Hz,1H),3.79(s, 3H),3.50(d,J=12.2Hz,1H),3.27(p,J=5.1Hz,1H),2.86(dt,J=12.6,4.6Hz, 1H),2.55-2.47(m,6H),2.43(d,J=5.8Hz,1H),2.40-2.28(m,7H),2.21(ddd, J=13.8,9.3,4.8Hz,2H),2.04(ddd,J=14.2,9.6,4.7Hz,1H),1.60(d,J=7.0H z, 5H), 1.28 (d, J = 7.3Hz, 56H), 1.05 (d, J = 6.1Hz, 3H), 0.90 (t, J = 6.7Hz, 6H).

[0298] Example 45 Synthesis of Compound 45

[0299] Example 45 can be synthesized by referring to the synthetic route of Example 42 or 43, Compound 45: 1H NMR (400 MHz, Chloroform-d) δ8.67-8.58 (m, 2H), 8.46 (d, J = 2.5 Hz, 1H), 8.06 (d, J = 8.1 Hz, 2H), 7.97 (s, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.22 (t, J = 2.9 Hz, 1H), 6.71 (d, J = 3.2 Hz, 2H), 5.36-5.25 (m, 1H), 4.34 (dt, J = 11.8, 4.8 Hz, 4H), 4.17 (dd, J = 12.0, 5.9 Hz, 2H), 3.96 -3.88(m,1H),3.79(s,4H),3.52(d,J=12.2Hz,1H),3.27(t,J=5.0Hz,1H), 2.87(dt,J=12.7,4.7Hz,1H),2.48(s,3H),2.33(t,J=7.6Hz,4H),2.23(dq, J=14.0,5.0Hz,2H),2.04(dd,J=17.1,8.5Hz,1H),1.83(dd,J=6.5,3.6Hz, 3H), 1.62 (d, J = 6.0Hz, 10H), 1.27 (d, J = 3.5Hz, 48H), 0.90 (t, J = 6.8Hz, 6H).

[0300] Example 46 Synthesis of Compound 46

[0301]

[0302] Example 46 can be synthesized by referring to the synthetic route of Example 42 or 43. Compound 46: 1H NMR (400 MHz, Chloroform-d) δ8.69-8.57 (m, 2H), 8.45 (d, J = 2.4 Hz, 1H), 8.05 (d, J = 8.0 Hz, 2H), 7.99 (s, 1H), 7.71 (d, J = 7.9 Hz, 2H), 7.22 (t, J = 2.8 Hz, 1H), 6.71 (d, J = 4.2 Hz, 2H), 5.31 (p, J = 5.3 Hz, 1H), 4.39 (dt, J = 6.9, 3.3 Hz, 2H), 4.37-4.29 (m, 2H), 4.16 (dd, J = 11.9, 6.0 Hz, 2H), 3.92 (d ,J=12.3Hz,1H),3.79(s,4H),3.52(d,J=12.3Hz,1H),3.27(p,J=5.1Hz,1H),2.87(dt,J=12.8,4.6Hz,1H),2.58-2.36(m,6H),2.32(t,J=7.4Hz ,4H),2.23(dq,J=14.0,5.2,4.2Hz,3H),1.96(ddq,J=60.4,12.7,6.5,5.8Hz,3H),1.27(s,48H),1.08(d,J=6.2Hz,3H),0.90(t,J=6.7Hz,6H).

[0303] Example 47 Synthesis of Compound 47

[0304]

[0305] The specific synthetic route is as follows:

[0306] Step A: Synthesis of 2-oxypropane distearate-1,3-diol

[0307] At room temperature, stearic acid (6.5 g, 22.84 mmol) and 4-dimethylaminopyridine (0.24 g, 1.96 mmol) were dissolved in dichloromethane (60 ml), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.3 g, 32.86 mmol) and 1,3-dihydroxyacetone (1.0 g, 11.10 mmol) were added and reacted at room temperature for 12 hours.

[0308] After the reaction, the reaction solution was poured into water and extracted with dichloromethane (100 ml x 2 times). The organic phases were combined, dried, filtered, and concentrated to precipitate a large amount of solids. 6.4 g of white solid 2-oxypropane-1,3-diester of distearic acid was obtained by filtration (yield: 88.1%).

[0309] Step B: Synthesis of 2-hydroxypropane-1,3-distearate

[0310] At room temperature, 2-oxopropane-1,3-diester distearate (400 mg, 0.64 mmol) and water (0.4 ml) were added to tetrahydrofuran (18 ml), cooled to 0°C, sodium borohydride (36 mg, 0.96 mmol) was added, and the mixture was reacted for 0.5 hour.

[0311] After the reaction, the reaction solution was poured into an ammonium chloride solution (15 ml), extracted with dichloromethane (30 ml x 1 time), and the organic phase was dried, filtered, and concentrated to obtain 400 mg of white solid 2-hydroxypropane-1,3-diester distearate (yield: 99.6%).

[0312] Step C: Synthesis of 2-((5-bromovaleryl)oxy)propane-1,3-diol Distearate

[0313] At room temperature, 5-bromovaleric acid (86.9 mg, 0.48 mmol) and 4-dimethylaminopyridine (8 mg, 0.064 mmol) were dissolved in dichloromethane (5 ml), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (123 mg, 0.64 mmol) and 2-hydroxypropane-1,3-diester distearate (200 mg, 0.32 mmol) were added and reacted at room temperature for 12 hours.

[0314] After the reaction, the mixture was concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1) to obtain 226 mg of white solid 2-((5-bromovaleryl)oxy)propane-1,3-diester distearate (yield: 89.6%).

[0315] Step D: Synthesis of 2-((5-((4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)pentanoyl)oxy)propane-1,3-diyl distearate

[0316] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (30 mg, 0.065 mmol), 2-((5-bromovaleryl)oxy)propane-1,3-diester distearate (77.7 mg, 0.098 mmol), potassium carbonate (18.1 mg, 0.13 mmol) and tetrabutylammonium iodide (2.4 mg, 0.0065 mmol) were added to N,N-dimethylformamide (3 ml) and heated to react for 12 hours.

[0317] After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate (80 ml) was added, and the mixture was washed with water (80 ml × 3 times). The organic phase was dried, filtered, and concentrated to obtain a crude product. The crude product was purified by thin layer chromatography on a silica gel precast plate (developing solvent: dichloromethane / methanol = 10 / 1) to obtain 58 mg of a yellow oily substance 2-((5-((4-((2S, 4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)pentanoyl)oxy)propane-1,3-diyl distearate (yield: 76.3%). Compound 47: 1 H NMR(400MHz,Chloroform-d)δ8.62(d,J=5.3Hz,2H),8.45(d,J=2.4Hz,1H),8.06(d,J=8.0Hz,2H),7.98(s,1H),7.71(d,J=8.0Hz,2H),7. 22(d,J=5.8Hz,1H),6.71(s,2H),5.29(p,J=5.4Hz,1H),4.39-4.30(m,4H),4.17(dd,J=11.9,5.9Hz,2H),3.92(d,J=12.2Hz,1H),3.79(s, 3H),3.52(d,J=12.2Hz,1H),3.27(p,J=4.9Hz,1H),2.87(dt,J=12.6,4.6Hz,1H),2.46(d,J=14.8Hz,7H),2.33(t,J=7.5Hz,4H),2.23(ddd ,J=13.7,8.6,4.7Hz,2H),2.04(tt,J=9.6,4.6Hz,1H),1.85(s,4H),1.61(d,J=6.1Hz,5H),1.27(d,J=3.4Hz,56H),0.90(t,J=6.7Hz,6H).

[0318] Example 48 Synthesis of Compound 48

[0319]

[0320] The specific synthetic route is as follows:

[0321] Step A: Synthesis of 2-((5-((4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)pentanoyl)oxy)propane-1,3-diyl dioleate

[0322] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (30 mg, 0.065 mmol), 2-((5-bromovaleryl)oxy)propane-1,3-diethioate (77 mg, 0.098 mmol, prepared according to the synthetic method of steps AC of Example 5), potassium carbonate (18.1 mg, 0.13 mmol) and tetrabutylammonium iodide (2.4 mg, 0.0065 mmol) were added to N,N-dimethylformamide (3 ml) and heated to react for 12 hours.

[0323] After the reaction, the temperature was lowered to room temperature, ethyl acetate (80 ml) was added, and the mixture was washed with water (80 ml × 3 times). The organic phase was dried, filtered, and concentrated to give a crude product, which was purified by thin layer chromatography on a silica gel precast plate (developing solvent: dichloromethane / methanol = 10 / 1) to give 49 mg of a yellow oily substance, 2-((5-((4-((2S, 4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)pentanoyl)oxy)propane-1,3-diyl dioleate (yield: 64.3%).

[0324] Compound 48: 1 H NMR (400MHz, Chloroform-d) δ8.62(d,J=5.0Hz,2H),8.45(d,J=2.4Hz,1H),8.06(d,J=8.0Hz,2H),7.98(s,1H),7.71(d,J=8.0Hz,2H),7.22(t, J=2.8Hz,1H),6.71(d,J=4.2Hz,2H),5.48-5.33(m,4H),5.30(d,J=8.1Hz,1H),4.43-4.29(m,4H),4.17(dd,J=11.9,5.9Hz,2H),3.92(d,J=12. 3Hz,1H),3.79(s,3H),3.52(d,J=12.2Hz,1H),3.27(t,J=5.0Hz,1H),2.87(dt,J=12.0,4.5Hz,1H),2.46(d,J=15.1Hz,7H),2.33(t,J=7.6Hz,4 H), 2.23 (ddd, J=13.7, 8.9, 4.8Hz, 2H), 2.03 (p, J=7.1, 6.4Hz, 9H), 1.83 (dq, J=6.7, 3.1Hz, 4H), 1.30 (d, J=10.0Hz, 40H), 0.90 (t, J=6.7Hz, 6H).

[0325] Example 49 Synthesis of Compound 49

[0326]

[0327] Example 49 can be synthesized by referring to the synthetic routes of Examples 42, 43, 47, and 48, compound 49: 1 H NMR(400MHz,Chloroform-d)δ8.69-8.59(m,2H),8.46(d,J=2.5Hz,1H),8.06( d,J=8.0Hz,2H),7.98(s,1H),7.71(d,J=8.0Hz,2H),7.22(t,J=2.8Hz,1H),6. 71(d,J=3.3Hz,2H),5.28(p,J=5.1Hz,1H),4.38-4.29(m,4H),4.16(dd,J=12. 0,5.9Hz,2H),3.92(d,J=12.3Hz,1H),3.79(s,3H),3.52(d,J=12.2Hz,1H),3.2 8(q,J=5.0Hz,1H),2.87(dt,J=12.6,4.4Hz,1H),2.53(d,J=13.9Hz,1H),2.48 (s,3H),2.40(q,J=7.8Hz,3H),2.33(t,J=7.5Hz,4H),2.23(tt,J=8.9,4.8Hz,2 H),2.09-1.99(m,1H),1.82(p,J=6.9Hz,2H),1.73(q,J=7.7Hz,2H),1.59(d,J =7.4Hz,3H),1.57-1.47(m,2H),1.28(d,J=9.6Hz,58H),0.90(t,J=6.7Hz,6H).

[0328] Example 50 Synthesis of Compound 50

[0329]

[0330] The specific synthetic route is as follows:

[0331] Step A: Synthesis of 5-((1,3-bis(palmitoyloxy)prop-2-yl)oxy)-5-oxopentanoic acid

[0332] At room temperature, 2-hydroxypropane-1,3-diyldipalmitate (1.0 g, 1.755 mmol, prepared by the synthesis method AB in step 35) was dissolved in dichloromethane (30 ml), and glutaric anhydride (0.40 g, 3.51 mmol) and 4-dimethylaminopyridine (0.22 g, 1.75 mmol) were added with stirring, and the reaction was carried out at room temperature for 48 hours.

[0333] After the reaction, the crude product was concentrated and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to obtain 1.1 g of white solid 5-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-5-oxopentanoic acid (yield: 80.3%).

[0334] Step B: Synthesis of 1,3-bis(palmitoyloxy)propan-2-yl(chloromethyl)glutarate

[0335] At room temperature, 5-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-5-oxopentanoic acid (60.0 mg, 0.087 mmol) was dissolved in dichloromethane (2 ml), water (2 ml) was added, and the mixture was cooled in an ice bath. Tetrabutylammonium hydrogen sulfate (3.0 mg, 0.0087 mmol), sodium bicarbonate (29.0 mg, 0.35 mmol), and chloromethyl chlorosulfonate (17.4 mg, 0.10 mmol) were added, and the temperature was raised to room temperature for reaction for 12 hours.

[0336] After the reaction, water (10 ml) was added, extracted with dichloromethane (30 ml x 1 time), the organic phases were combined, dried, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1) to obtain 64 mg of white solid 1,3-bis(palmitoyloxy)propan-2-yl(chloromethyl)glutarate (yield: 99.6%).

[0337] Step C: Synthesis of 1,3-bis(palmitoyloxy)propan-2-yl((4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)methyl)glutarate

[0338] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (20 mg, 0.044 mmol), 1,3-bis(palmitoyloxy)propan-2-yl(chloromethyl)glutarate (49 mg, 0.065 mmol), potassium carbonate (12.1 mg, 0.087 mmol) and potassium iodide (3.6 mg, 0.022 mmol) were added to N,N-dimethylformamide (3 ml) and heated to react for 12 hours.

[0339] After the reaction was completed, the temperature was lowered to room temperature, ethyl acetate (80 ml) was added, and the mixture was washed with water (80 ml x 3 times). The organic phase was dried, filtered, and concentrated to obtain a crude product. The crude product was purified by thin layer chromatography on a silica gel precast plate (developing solvent: dichloromethane / methanol = 10 / 1) to obtain 29 mg of a yellow oily substance 1,3-bis(palmitoyloxy)propan-2-yl((4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)methyl)pentanedioate (yield: 57.4%). Compound 50: 1 H NMR (400MHz, Chloroform-d) δ8.62(d,J=2.6Hz,2H),8.46(d,J=2.3Hz,1H),8.09(d,J=8.0Hz,2H),7.98(s,1H),7.73(d,J=8.1Hz,2H ),7.22(t,J=2.8Hz,1H),6.70(d,J=3.8Hz,2H),6.02(s,2H),5.32-5.22(m,1H),4.31(dd,J=11.9,4.3Hz,2H),4.14(dd,J=11.9,5.9 Hz,2H),3.91(d,J=12.2Hz,1H),3.80(s,3H),3.51(d,J=12.2Hz,1H),3.27(t,J=4.9Hz,1H),2.87(dt,J=13.0,4.8Hz,1H),2.61-2.3 7(m,11H),2.32(t,J=7.5Hz,5H),2.21(tt,J=9.3,4.8Hz,2H),2.12-1.92(m,4H),1.58(s,1H),1.27(s,48H),0.90(t,J=6.7Hz,6H).

[0340] Example 51 Synthesis of Compound 51

[0341]

[0342] The specific synthetic route is as follows:

[0343] Step A: Synthesis of 2-((6-((4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)hexanoyl)oxy)propane-1,3-diyl dioleate

[0344] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (20 mg, 0.044 mmol), 2-((6-bromohexanoyl)oxy)propane-1,3-diester (52.4 mg, 0.065 mmol, prepared according to the synthetic method of steps AC of Example 5), potassium carbonate (12.1 mg, 0.087 mmol) and tetrabutylammonium iodide (1.6 mg, 0.0044 mmol) were added to N,N-dimethylformamide (3 ml) and heated to react for 12 hours.

[0345] After the reaction, the temperature was lowered to room temperature, ethyl acetate (80 ml) was added, and the mixture was washed with water (80 ml × 3 times). The organic phase was dried, filtered, and concentrated to give a crude product. The crude product was purified by thin layer chromatography on a silica gel precast plate (developing solvent: dichloromethane / methanol = 10 / 1) to give 37 mg of a yellow oily substance, 2-((6-((4-((2S, 4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)hexanoyl)oxy)propane-1,3-diyl dioleate (yield: 71.9%).

[0346] Compound 51: 1 H NMR(400MHz,Chloroform-d)δ8.70-8.60(m,2H),8.45(d,J=2.5Hz,1H),8.05(d,J=8.0Hz,2H),7.98(s,1H),7.71(d,J=8.0Hz,2H),7.22(t,J=2.8Hz,1H), 6.71(d,J=2.9Hz,2H),5.42-5.32(m,4H),5.32-5.24(m,1H),4.37-4.28(m,4 H),4.16(dd,J=11.9,5.9Hz,2H),3.91(d,J=12.3Hz,1H),3.79(s,3H),3.52( d,J=12.2Hz,1H),3.30-3.24(m,1H),2.87(dt,J=12.7,4.6Hz,1H),2.48(s,4 H),2.40(q,J=7.8Hz,3H),2.33(t,J=7.5Hz,4H),2.23(tt,J=8.9,4.7Hz,2H) ,2.02(q,J=6.6,5.7Hz,9H),1.82(p,J=6.9Hz,2H),1.73(t,J=7.7Hz,2H),1. 63(s,3H),1.56-1.49(m,2H),1.31(t,J=10.7Hz,42H),0.90(t,J=6.6Hz,6H).

[0347] Example 52 Synthesis of Compound 52

[0348]

[0349] The specific synthetic route is as follows:

[0350] Step A: Synthesis of 1-(1,3-bis(palmitoyloxy)propan-2-yl)5-(((4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)methyl)3-methylpentanoate

[0351] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (20 mg, 0.044 mmol), 1-(1,3-bis(palmitoyloxy)propan-2-yl) 5-(chloromethyl) 3-methylglutarate (49 mg, 0.065 mmol, prepared according to the synthetic method of steps AC of Example 8), potassium carbonate (12.1 mg, 0.087 mmol) and potassium iodide (3.6 mg, 0.022 mmol) were added to N,N-dimethylformamide (3 ml) and heated to react for 12 hours.

[0352] After the reaction, the temperature was lowered to room temperature, ethyl acetate (80 ml) was added, and the mixture was washed with water (80 ml x 3 times). The organic phase was dried, filtered, and concentrated to give a crude product, which was purified by thin layer chromatography on a silica gel precast plate (developing solvent: dichloromethane / methanol = 10 / 1) to give 27 mg of a yellow oily substance, 1-(1,3-bis(palmitoyloxy)propan-2-yl)5-(((4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)methyl)3-methylpentanoate (yield: 52.8%).

[0353] Compound 52: 1H NMR (400MHz, Chloroform-d) δ8.62(d,J=2.9Hz,2H),8.46(d,J=2.4Hz,1H),8.09(d,J=8.1Hz,2H),7.99(s,1H),7.73(d,J=8.1Hz,2H),7.22(t, J=2.8Hz,1H),6.76-6.66(m,2H),6.02(s,2H),5.32-5.24(m,1H),4.31(ddd,J=12.1,4.4,2.1Hz,2H),4.14(dd,J=12.0,6.0Hz,2H),3.91(d,J=1 2.3Hz,1H),3.79(d,J=2.4Hz,3H),3.51(d,J=12.2Hz,1H),3.27(t,J=5.0Hz,1H),2.87(dt,J=12.5,4.4Hz,1H),2.58-2.27(m,15H),2.21(tt,J= 9.3, 4.7Hz, 2H), 2.05 (dq, J = 13.4, 9.1, 6.9Hz, 1H), 1.58 (d, J = 7.1Hz, 4H), 1.28 (d, J = 6.7Hz, 48H), 1.06 (d, J = 6.0Hz, 3H), 0.90 (t, J = 6.7Hz, 6H).

[0354] Example 53 Synthesis of Compound 53

[0355]

[0356] The specific synthetic route is as follows:

[0357] Step A: Synthesis of 4,4,5,7-tetramethylchroman-2-one

[0358] 3,5-Dimethylphenol (1.0 g, 8.18 mmol) and 3,3-dimethylacrylic acid (0.82 g, 8.18 mmol) were added to methanesulfonic acid (8 ml) at room temperature, and the mixture was heated to 87° C. and reacted for 4 hours.

[0359] After the reaction, the temperature was lowered to room temperature, ethyl acetate (80 ml) was added, and the mixture was washed with water (60 ml × 1 time) and sodium bicarbonate solution (60 ml × 1 time) in sequence. The organic phase was dried, filtered, and concentrated to obtain 2.0 g of yellow liquid 4,4,5,7-tetramethylchroman-2-one (yield: 100.0%).

[0360] Step B: Synthesis of 2-(4-hydroxy-2-methylbutan-2-yl)-3,5-dimethylphenol

[0361] At room temperature, lithium aluminum hydride (1.85 g, 48.74 mmol) was added to tetrahydrofuran (40 ml), cooled in an ice bath, and 4,4,5,7-tetramethylchroman-2-one (2.0 g, 9.79 mmol) was added. After the addition, the mixture was reacted at room temperature for 1 hour.

[0362] After the reaction was completed, the mixture was cooled in an ice bath, quenched by adding ammonium chloride solution (50 ml), and adjusted to acidity with dilute hydrochloric acid.

[0363] Dichloromethane (150 ml x 1 time) was added for extraction, and the organic phase was dried, filtered, and concentrated to obtain 2.1 g of yellow liquid 2-(4-hydroxy-2-methylbutan-2-yl)-3,5-dimethylphenol (yield: 100.0%).

[0364] Step C: Synthesis of 2-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-3,5-dimethylphenol

[0365] At room temperature, 2-(4-hydroxy-2-methylbutan-2-yl)-3,5-dimethylphenol (2.1 g, 10.08 mmol) was added to dichloromethane (40 ml), cooled in an ice bath, tert-butyldimethylsilyl chloride (1.8 g, 12.09 mmol) was added, and triethylamine (4.1 g, 40.32 mmol) was added dropwise. After the addition, the temperature was raised to room temperature and the reaction was allowed to react for 12 hours.

[0366] After the reaction, dichloromethane (100 ml) was added, washed with water (100 ml × 1 time), the organic phase was dried, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: n-hexane / dichloromethane = 3 / 2) to obtain 2.08 g of white solid 2-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-3,5-dimethylphenol (yield: 64.0%).

[0367] Step D: Synthesis of 1,3-bis(palmitoyloxy)propan-2-yl(2-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-3,5-dimethylphenyl)glutarate

[0368] At room temperature, 5-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-5-oxopentanoic acid (936 mg, 1.37 mmol) and 4-dimethylaminopyridine (159 mg, 1.30 mmol) were dissolved in dichloromethane (60 ml), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (375 mg, 1.95 mmol) and 2-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-3,5-dimethylphenol (421 mg, 1.30 mmol) were added, and the mixture was reacted at room temperature for 12 hours.

[0369] After the reaction, the crude product was concentrated to dryness and purified by silica gel column chromatography (eluent: n-hexane / dichloromethane = 1 / 1) to obtain 1.17 g of yellow oily 1,3-bis(palmitoyloxy)propan-2-yl(2-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-3,5-dimethylphenyl)pentanedioate (yield: 90.6%).

[0370] Step E: Synthesis of 1,3-bis(palmitoyloxy)propan-2-yl(2-(4-hydroxy-2-methylbutan-2-yl)-3,5-dimethylphenyl)glutarate

[0371] At room temperature, 1,3-bis(palmitoyloxy)propan-2-yl(2-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-3,5-dimethylphenyl)pentanedioate (1.17 g, 1.18 mmol) was dissolved in dichloromethane (11 ml) and methanol (11 ml), 10-camphorsulfonic acid (41.2 mg, 0.17 mmol) was added, and the reaction was carried out at room temperature for 40 minutes.

[0372] After the reaction, dichloromethane (150 ml) was added, and the mixture was washed with sodium bicarbonate solution (50 ml × 1 time). The organic phase was dried, filtered, and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to obtain 0.9 g of yellow liquid 1,3-bis(palmitoyloxy)propan-2-yl(2-(4-hydroxy-2-methylbutan-2-yl)-3,5-dimethylphenyl)pentanedioate (yield: 85.7%).

[0373] Step F: Synthesis of 1,3-bis(palmitoyloxy)propan-2-yl(3,5-dimethyl-2-(2-methyl-4-oxobutan-2-yl)phenyl)glutarate

[0374] At room temperature, 1,3-bis(palmitoyloxy)propan-2-yl(2-(4-hydroxy-2-methylbutan-2-yl)-3,5-dimethylphenyl)pentanedioate (445 mg, 0.51 mmol) was dissolved in dichloromethane (20 ml), celite (198 mg) was added, the mixture was cooled in an ice bath, pyridinium chlorochromate (197.7 mg, 0.91 mmol) was added, and the reaction was carried out at room temperature for 1.5 hours.

[0375] After the reaction, the mixture was filtered through celite pad, and the filtrate was washed with water (30 ml × 1 time) and sodium bicarbonate solution (30 ml × 1 time) in sequence. The organic phase was dried, filtered, and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to obtain 400 mg of yellow liquid 1,3-bis(palmitoyloxy)propan-2-yl(3,5-dimethyl-2-(2-methyl-4-oxobutan-2-yl)phenyl)pentanedioate (yield: 90.0%).

[0376] Step G: Synthesis of 3-(2-((5-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-5-oxopentanoyl)oxy-4,6-dimethylphenyl)-3-methylbutanoic acid

[0377] At room temperature, 1,3-bis(palmitoyloxy)propan-2-yl(3,5-dimethyl-2-(2-methyl-4-oxobutan-2-yl)phenyl)pentanedioate (200 mg, 0.23 mmol) was dissolved in acetone (8 ml) and water (4 ml), potassium permanganate (54 mg, 0.34 mmol) was added, and the mixture was reacted at room temperature for 12 hours.

[0378] After the reaction, water (30 ml) was added, and the mixture was adjusted to acidity with dilute hydrochloric acid. Dichloromethane (370 ml) was added, and the mixture was filtered through celite. The filtrate was separated into an organic phase, which was dried, filtered, and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 6 / 1) to obtain 146 mg of a yellow oily substance, 3-(2-((5-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-5-oxopentanoyl)oxy-4,6-dimethylphenyl)-3-methylbutanoic acid (yield: 71.7%).

[0379] Step H: Synthesis of 1,3-bis(palmitoyloxy)propan-2-yl(2-(4-(chloromethoxy)-2-methyl-4-oxobutan-2-yl)-3,5-dimethylphenyl)glutarate

[0380] At room temperature, 3-(2-((5-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-5-oxopentanoyl)oxy-4,6-dimethylphenyl)-3-methylbutanoic acid (146 mg, 0.16 mmol) was dissolved in dichloromethane (4 ml) and water (4 ml), cooled in an ice bath, tetrabutylammonium hydrogen sulfate (5.6 mg, 0.0164 mmol), sodium bicarbonate (55 mg, 0.65 mmol), and chloromethyl chlorosulfonate (32.6 mg, 0.19 mmol) were added, and the mixture was reacted at room temperature for 3 hours.

[0381] After the reaction, water (10 ml) was added, and the mixture was extracted with dichloromethane (40 ml × 1 time). The organic phase was dried, filtered, and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1) to obtain 103 mg of a yellow oily substance, 1,3-bis(palmitoyloxy)propan-2-yl(2-(4-(chloromethoxy)-2-methyl-4-oxobutan-2-yl)-3,5-dimethylphenyl)pentanedioate (yield: 66.8%).

[0382] Step I: Synthesis of 1,3-bis(palmitoyloxy)propan-2-yl(2-(4-((4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)-methoxy)-2-methyl-4-oxobutan-2-yl)-3,5-dimethylphenyl)glutarate

[0383] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (20 mg, 0.044 mmol), 1,3-bis(palmitoyloxy)propan-2-yl(2-(4-(chloromethoxy)-2-methyl-4-oxobutan-2-yl)-3,5-dimethylphenyl)glutarate (61 mg, 0.065 mmol), potassium carbonate (12.1 mg, 0.087 mmol) and potassium iodide (3.6 mg, 0.022 mmol) were added to N,N-dimethylformamide (3 ml) and heated to react for 1.5 hours.

[0384] After the reaction, the temperature was lowered to room temperature, ethyl acetate (80 ml) was added, and the mixture was washed with water (80 ml x 3 times). The organic phase was dried, filtered, and concentrated to obtain a crude product. The crude product was purified by thin layer chromatography on a silica gel precast plate (developing solvent: dichloromethane / methanol = 10 / 1) to obtain 47 mg of a yellow oily substance, 1,3-bis(palmitoyloxy)propan-2-yl(2-(4-((4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)-methoxy)-2-methyl-4-oxobutan-2-yl)-3,5-dimethylphenyl)pentanedioate (yield: 79.1%)

[0385] Compound 53: 1H NMR(400MHz,Chloroform-d)δ8.63(d,J=3.2Hz,2H),8.46(d,J=2.3Hz,1H),8.03(t,J=6.9Hz,3H),7.72(d,J=8.0Hz,2H),7.23(t,J=2.8Hz,1H), 6.82-6.67(m,3H),6.51(d,J=2.0Hz,1H),5.90(s,2H),5.30(p,J=5.1Hz,1H),4.33(dd,J=11.9,4.3Hz,2H),4.17(dd,J=12.0,5.8Hz,2H),3.91(d ,J=12.2Hz,1H),3.79(s,3H),3.51(d,J=12.2Hz,1H),3.28(q,J=5.1Hz,1H),2.91(s,2H),2.86(dd,J=11.1,6.5Hz,1H),2.65(t,J=7.4Hz,2H),2. 60-2.45(m,9H),2.45-2.30(m,5H),2.27-2.13(m,5H),2.06(p,J=7.5Hz ,3H),1.63(d,J=8.6Hz,11H),1.33-1.24(m,48H),0.90(t,J=6.7Hz,6H).

[0386] Example 54 Synthesis of Compound 54

[0387]

[0388] The specific synthetic route is as follows:

[0389] Step A: Synthesis of 1-(1,3-bis(palmitoyloxy)propan-2-yl)5-(2-(4-((4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)-2-methyl-4-oxobutan-2-yl)-3,5-dimethylphenyl)3-methylpentanoate

[0390] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (20 mg, 0.044 mmol), 1-(1,3-bis(palmitoyloxy)propan-2-yl)5-(2-(4-(chloromethoxy)-2-methyl-4-oxobutan-2-yl)-3,5-dimethylphenyl)3-methylglutarate (62 mg, 0.065 mmol, prepared according to the synthetic method of Step A in Example 8 and Step DH in Example 11), potassium carbonate (12.1 mg, 0.087 mmol) and potassium iodide (3.6 mg, 0.022 mmol) were added to N,N-dimethylformamide (3 ml) and heated to react for 2 hours.

[0391] After the reaction, the temperature was lowered to room temperature, ethyl acetate (80 ml) was added, and the mixture was washed with water (80 ml x 3 times). The organic phase was dried, filtered, and concentrated to obtain a crude product. The crude product was purified by thin layer chromatography on a silica gel precast plate (developing solvent: dichloromethane / methanol = 10 / 1) to obtain 38 mg of a yellow oily substance 1-(1,3-bis(palmitoyloxy)propan-2-yl)5-(2-(4-((4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)-2-methyl-4-oxobutan-2-yl)-3,5-dimethylphenyl)3-methylpentanoate (yield: 60.0%)

[0392] Compound 54: 1H NMR (400MHz, Chloroform-d) δ8.63(d,J=3.3Hz,2H),8.46(d,J=2.3Hz,1H),8.03(t,J=7.1Hz,3H),7.72(d,J=8.0Hz,2H),7.22(t,J=2.8Hz,1H),6.78 -6.67(m,3H),6.52(d,J=2.0Hz,1H),5.90(s,2H),5.31(p,J=5.2Hz,1H),4 .33(ddd,J=11.9,4.4,2.0Hz,2H),4.17(dd,J=11.9,6.0Hz,2H),3.91(d,J =12.2Hz,1H),3.79(s,3H),3.51(d,J=12.2Hz,1H),3.28(q,J=5.0Hz,1H), 2.91(s,3H),2.72-2.46(m,11H),2.34(dt,J=14.9,7.1Hz,6H),2.22(ddd, J=14.1,9.0,4.8Hz,5H),2.05(tt,J=9.7,4.7Hz,1H),1.63(d,J=13.0Hz,1 1H), 1.28 (d, J = 11.7Hz, 48H), 1.12 (d, J = 6.2Hz, 3H), 0.90 (t, J = 6.7Hz, 6H).

[0393] Example 55 Synthesis of Compound 55

[0394]

[0395] Step A: Synthesis of compound 2-(10-(4-(2S,4S)-1-(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)decanoyl)oxy)propane-1,3-diyl dioleate

[0396] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (20 mg, 0.044 mmol), 2-((10-bromocarnoyl)oxy)propane-1,3-diyl dioleate (55.4 mg, 0.065 mmol, prepared according to the synthetic method of Example 5), potassium carbonate (12.1 mg, 0.087 mmol) and tetrabutylammonium iodide (1.6 mg, 0.0044 mmol) were added to N,N-dimethylformamide (3 ml) and heated to react for 12 hours.

[0397] After the reaction, the temperature was lowered to room temperature, ethyl acetate (80 ml) was added, and the mixture was washed with water (80 ml x 3 times). The organic phase was dried, filtered, and concentrated to give a crude product, which was purified by thin layer chromatography on a silica gel precast plate (developing solvent: dichloromethane / methanol = 10 / 1) to give 28 mg of a yellow oily substance 2-(10-(4-(2S,4S)-1-(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)decanoyl)oxy)propane-1,3-diyl dioleate (yield: 51.8%).

[0398] Compound 55: 1 H NMR(400MHz,Chloroform-d)δ8.62(d,J=1.6Hz,2H),8.49(s,1H),8.11(d,J=8.3Hz,3H),7.80(s,2H),7.22(t,J=2.8Hz,1H ),6.66(d,J=19.9Hz,2H),5.36(td,J=5.7,3.3Hz,3H),5.34-5.22(m,2H),4.40-4.26(m,4H),4.16(dd,J=11.9,5.9Hz,2H) ,3.81(s,3H),3.35(s,1H),2.94(d,J=29.2Hz,1H),2.48(s,4H),2.33(td,J=7.5,3.6Hz,6H),2.18(s,2H),2.03(q,J=6.4H z,8H),1.79(p,J=6.7Hz,5H),1.63(d,J=7.0Hz,6H),1.47(d,J=8.1Hz,3H),1.31(t,J=11.2Hz,48H),0.90(t,J=6.7Hz,6H).

[0399] Example 56 Synthesis of Compound 56

[0400]

[0401] The specific synthetic route is as follows:

[0402] Step A: Synthesis of 2-((7-((4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)heptanoyl)oxy)propane-1,3-diyl dioleate

[0403] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (20 mg, 0.044 mmol), 2-((7-bromoheptanoyl)oxy)propane-1,3-diethioate (53 mg, 0.065 mmol, prepared according to the synthetic method of steps AC of Example 5), potassium carbonate (12.1 mg, 0.087 mmol) and tetrabutylammonium iodide (1.6 mg, 0.0044 mmol) were added to N,N-dimethylformamide (3 ml) and heated to react for 12 hours.

[0404] After the reaction, the temperature was lowered to room temperature, ethyl acetate (80 ml) was added, and the mixture was washed with water (80 ml × 3 times). The organic phase was dried, filtered, and concentrated to give a crude product, which was purified by thin layer chromatography on a silica gel precast plate (developing solvent: dichloromethane / methanol = 15 / 1) to give 30 mg of a yellow oily substance, 2-((7-((4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)heptanoyl)oxy)propane-1,3-diyl dioleate (yield: 57.6%).

[0405] Compound 56: 1 H NMR (400MHz, Chloroform-d) δ8.63(dt,J=4.1,1.7Hz,2H),8.46(d,J=2.5Hz,1H),8.03(s,2H),7.99(d,J=2.5Hz,1H),7.71(d,J=8.1Hz,2H),7.22( t,J=2.8Hz,1H),6.71(d,J=2.8Hz,2H),5.43-5.24(m,5H),4.39-4.27(m, 4H), 4.16 (dd, J=11.9, 5.9Hz, 2H), 3.91 (d, J=12.2Hz, 1H), 3.79 (s, 3H), 3. 51(d,J=12.2Hz,1H),3.28(q,J=5.0Hz,1H),2.87(dt,J=12.6,4.6Hz,1H) ,2.48(s,4H),2.35(dt,J=13.1,7.5Hz,7H),2.23(tt,J=9.3,4.9Hz,2H), 2.02(q,J=6.8Hz,9H),1.80(p,J=6.8Hz,2H),1.65(s,7H),1.47(dq,J=20 .0,7.4,6.8Hz,4H),1.31(dd,J=13.9,9.1Hz,40H),0.90(t,J=6.7Hz,6H).

[0406] Example 57 Synthesis of Compound 57

[0407]

[0408] The specific synthetic route is as follows:

[0409] Step A: Synthesis of 2-((8-((4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)octanoyl)oxy)propane-1,3-diyl dioleate

[0410] At room temperature, 4-((2S,4S)-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-piperidin-2-yl)benzoic acid (20 mg, 0.044 mmol), 2-((8-bromooctanoyl)oxy)propane-1,3-diester (54 mg, 0.065 mmol, prepared according to the synthetic method of steps AC of Example 5), potassium carbonate (12.1 mg, 0.087 mmol) and tetrabutylammonium iodide (1.6 mg, 0.0044 mmol) were added to N,N-dimethylformamide (3 ml) and heated to react for 12 hours.

[0411] After the reaction, the temperature was lowered to room temperature, ethyl acetate (80 ml) was added, and the mixture was washed with water (80 ml × 3 times). The organic phase was dried, filtered, and concentrated to give a crude product. The crude product was purified by thin layer chromatography on a silica gel precast plate (developing solvent: dichloromethane / methanol = 15 / 1) to give 37 mg of a yellow oily substance, 2-((8-((4-((2S, 4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoyl)oxy)octanoyl)oxy)propane-1,3-diyl dioleate (yield: 70.3%).

[0412] Compound 57: 1H NMR(400MHz,Chloroform-d)δ8.77-8.57(m,2H),8.46(d,J=2.4Hz,1H),8.03(s,2H),7.99(s,1H),7.71(d,J=8.0Hz,2H),7.23(t,J=2 .8Hz,1H),6.71(d,J=3.1Hz,2H),5.52-5.32(m,4H),5.32-5.23(m,1H),4.41-4.27(m,4H),4.16(dd,J=11.9,5.9Hz,2H),3.91(d,J=12 .3Hz,1H),3.79(s,3H),3.51(d,J=12.2Hz,1H),3.27(p,J=5.0Hz,1H),2.87(dt,J=12.7,4.4Hz,1H),2.48(s,4H),2.34(q,J=7.5Hz,7 H),2.23(tt,J=9.3,4.8Hz,2H),2.03(q,J=6.6Hz,9H),1.79(p,J=6.7Hz,3H),1.65(s,6H),1.53-1.20(m,46H),0.90(t,J=6.7Hz,6H).

[0413] Example 58 Synthesis of Compound 58

[0414]

[0415] Example 25 can be synthesized by referring to the synthetic routes of Examples 42, 43, 47, 48, 50-57, Compound 58: 1H NMR(400MHz,Chloroform-d)δ8.62(d,J=2.6Hz,2H),8.46(d,J=2.3Hz,1H),8.09(d,J=8.0Hz,2H),7.99(s,1H),7.73(d,J=8.0Hz,2H),7 .23(t,J=2.8Hz,1H),6.70(d,J=4.2Hz,2H),6.02(s,2H),5.26(p,J=5.1Hz,1H),4.31(dd,J=11.9,4.4Hz,2H),4.15(dd,J=11.9,5.9Hz, 2H),3.90(d,J=12.2Hz,1H),3.79(s,3H),3.51(d,J=12.2Hz,1H),3.27(t,J=5.0Hz,1H),2.86(dt,J=12.7,4.5Hz,1H),2.58-2.29(m,16 H), 2.22 (dq, J = 8.9, 4.4Hz, 2H), 2.04 (ddt, J = 14.1, 9.1, 4.1Hz, 2H), 1.74-1.68 (m, 5H), 1.29 (d, J = 12.3Hz, 56H), 0.90 (t, J = 6.7Hz, 6H).

[0416] Comparative Examples 1A, 1B and 2

[0417]

[0418] For the synthetic routes of Comparative Examples 1A and 1B, refer to the synthetic route of the compound of Example 2 in the specification of WO2022143940A1. For the synthetic route of Comparative Example 2, refer to the synthetic route of the compound of Example 26 in the specification of WO2015009616A1.

[0419] Example 59 Pharmacokinetics Experiment in Rats

[0420] (1) Experimental Materials

[0421] SD rats: male, 180-250 g, purchased from Guangdong Weitonglihua Experimental Animal Technology Co., Ltd. / Beijing Weitonglihua Experimental Animal Technology Co., Ltd.

[0422] Reagents: DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), normal saline, EDTA-K2, acetonitrile, formic acid, propranolol (internal standard) are all commercially available.

[0423] Instrument: AB SCIEX QTRAP 5500+ / Thermo Fisher LC-MS (U300 UPLC, TSQ QUANTUMN ULTRA triple quadrupole mass spectrometer).

[0424] (2) Experimental methods

[0425] Weigh the compound and dissolve it in DMSO-PEG-400-normal saline (5:60:35, v / v / v) system. After intravenous or oral administration to rats, collect 200μL of venous blood in EDTA-K2 anticoagulation EP tubes at 15min, 30min, 1h, 2h, 5h, 7h, and 24h (5min for iv group), centrifuge at 12000rpm for 2min, and freeze the plasma at -80℃ for testing. Accurately weigh a certain amount of the test sample and dissolve it in DMSO to 2mg / mL as the stock solution. Accurately draw an appropriate amount of the compound stock solution, add acetonitrile to dilute and prepare a standard series of solutions. Accurately draw 10μL of each of the above standard series solutions, add 90μL of blank plasma, vortex and mix, and prepare plasma samples equivalent to plasma concentrations of 1, 3, 5, 10, 30, 100, 300, 1000, and 3000ng / mL. Perform double sample analysis for each concentration to establish a standard curve. Take 30 μL of plasma (5 min, 15 min, and 30 min plasma diluted 5 times / 10 times after intravenous administration), add 150 μL of acetonitrile solution of internal standard propranolol (50 ng / mL), vortex mix, add 100 μL of purified water, vortex mix again, centrifuge at 4000 rpm for 5 min, and take the supernatant for LC-MS analysis. LC-MS detection conditions are as follows:

[0426] Chromatographic column: YMC Triart C18, 50*3.0mm, 2.1μm / Thermo Fisher HYPERSIL GOLD C-18 UPLC column, 100*2.1mm, 1.7μm.

[0427] Mobile phase: water (0.1% formic acid)-acetonitrile for gradient elution as shown in Table 1.

[0428] Table 1

[0429]

[0430]

[0431] (3) Data processing

[0432] After LC-MS detection of blood drug concentration, WinNonlin 6.1 software was used to calculate the pharmacokinetic parameters using the non-compartmental model method. The results are shown in Table 2.

[0433] Table 2: Pharmacokinetic parameters of the compounds of the present invention in SD rats (ig administration)

[0434]

[0435] As shown in Table 2, the rat PK of the compound of the present invention has a higher Cmax and oral exposure compared with compound Z, comparative example 1A and comparative example 1B.

[0436] Example 60 Complement System Alternative Pathway Inhibitory Activity Test

[0437] Commercial kits ( COMPLAP330 RUO, Svar life science) was used to evaluate the inhibitory effect of compounds on the alternative complement pathway of human serum. The initial test concentration of the test compound was 10 μM, 3-fold gradient dilution, 8 concentration points were set, and single-well detection was performed.

[0438] The test compound was diluted with DMSO to a gradient concentration solution of 720 times the final concentration. 0.5 μL of the compound solution was added to 340 μL Diluent, and then 20 μL human serum was added to mix. 100 μL of the mixture was added to the pre-coated reaction plate; 20 μL of the negative control or positive control solution was added to 340 μL Diluent and 0.5 μL DMSO, and 100 μL of the mixture was added to the reaction plate as a negative control well or a positive control well. After incubation at 37°C for 60 minutes, the liquid in the well was discarded, and 300 μL of washing solution was added to each well for washing 3 times. 100 μL Conjugate was added to each well, incubated at room temperature for 30 minutes, the liquid in the well was discarded, and 300 μL of washing solution was added for washing 3 times. Then 100 μL of substrate was added to each well and incubated at room temperature for 15 minutes. The OD405 value was read using an ELISA reader (FLUOstarOmega, BMG LRBTECH). The test results are shown in Table 3.

[0439] Table 3:

[0440] Compound No. <![CDATA[IC 50 (nM)]]> Z <![CDATA[A # ]]> Comparative Example 1A <![CDATA[B # ]]> Comparative Example 1B <![CDATA[C # ]]>

[0441] Among them, A # Indicates <200nM, B # Indicates greater than 200nM and less than 500nM, C # Indicates greater than 500nM.

[0442] It can be seen from the experimental results in Table 3 that, compared with Comparative Examples 1A and 1B, the compound Z of the present invention has better inhibitory activity on the complement system bypass.

[0443] Example 61 Enzyme induction test study of compound

[0444] (1) Experimental materials and instruments

[0445] Materials: Williams'Medium E (without phenol red) was purchased from Sigma-Aldrich Trading Co., Ltd.; Williams'Medium E, human recombinant insulin, GlutaMAX and HEPES were purchased from Life Technologies; Isotonic Percoll was purchased from General Electric; Fetal bovine serum was purchased from Corning; Dexamethasone was commercially available; CellTiter-Fluor TM Cell Viability Assay kit was purchased from Promega; Taqman Gene Expression Assay probe (20×, CYP3A4, FAM labeled) and Taqman Gene Expression Assay probe (20×, ACTB, VIC labeled) were purchased from AB (Applied biosystems); human primary hepatocytes were purchased from BioIVT.

[0446] Instrument: AB Sciex5500+.

[0447] (2) Experimental design

[0448] Accurately weigh the test substance (Compound Z and Comparative Example 2), positive inducer, negative inducer, and internal standard to prepare the corresponding concentration stock solution. Prepare the cell recovery solution and incubation solution; CellTiter-Fluor TM Detection kits for cell viability tests, reagents and consumables for mRNA extraction, reverse transcription and fluorescence quantitative PCR.

[0449] The frozen primary human hepatocytes were revived and seeded on appropriate cell culture plates at a certain density for monolayer cell culture to meet the cell growth requirements.

[0450] Add freshly prepared and preheated dosing solutions containing positive / negative inducers or test substances at different concentrations to the corresponding wells. Incubate for 3 consecutive days and change the solution every day. Perform the operation in parallel in two replicate wells for each compound or concentration.

[0451] For enzyme activity test, the corresponding substrate is added and incubated for a certain period of time, and semi-quantitative analysis is performed using LC-MS / MS. TM The cell viability assay kit is used to detect intracellular protease activity.

[0452] The extraction, reverse transcription and fluorescence quantitative PCR of mRNA were carried out according to the instructions of relevant kits.

[0453] (3) Test results

[0454] The test results of the induction effect of Example Z and Comparative Example 2 on the mRNA level of CYP3A4 are shown in Table 4 below.

[0455] Table 4 Experimental results

[0456]

[0457] It can be seen from the experimental results in Table 4 that the compound Z of the present application reduces the induction risk compared with the comparative example 2.

[0458] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A compound represented by general formula (A), or an isomer, a racemate, or a pharmaceutically acceptable salt thereof, characterized in that: Wherein, m = 1 or 2; When m=1, as shown in formula (I): When m=2, as shown in formula (II): X is selected from O, S or NH; The R is selected from: substituted or unsubstituted alkyl, alkoxy, alkylalkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, a bicyclic ring consisting of aryl and cycloalkyl, wherein the substitution is selected from halogen, hydroxyl, alkyl, alkoxy, alkylalkoxy, cycloalkyl, heterocycloalkyl, and the number of the substitution is one or more; The R 1 , R 2 independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or R 1 , R 2 Cyclize together to form a heterocycloalkyl; Wherein K is selected from a positive integer of 5-30, said R 3 , R 4 , R 5 is selected from hydrogen, halogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; m1, n, p, q, r, s, t are integers of 1-10 selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

2. The compound according to claim 1, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: A compound selected from the group consisting of compounds represented by formula (Ia) or formula (Ib), wherein R is as defined above.

3. The compound according to claim 1, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: is selected from the compounds represented by formula (IIa), wherein R is as defined above.

4. The compound according to claim 1, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: The alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, 1-ethylbutyl, n-heptyl, isoheptyl; The alkoxy group is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1,2-dimethylpropoxy, isopentyl, neopentoxy, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentoxy, 1,2-dimethylbutoxy, 1-ethylbutoxy, n-heptyl, isoheptyl; The alkoxyalkyl group is selected from methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, ethoxyhexyl, propoxymethyl, propoxyethyl, propoxybutyl, propoxypentyl, propoxyhexyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, butoxyhexyl, pentyloxymethyl, pentyloxyethyl, pentyloxypropyl, pentyloxybutyl, pentyloxypentyl, pentyloxyhexyl, hexyloxymethyl, hexyloxyethyl, hexyloxypropyl, hexyloxybutyl, hexyloxypentyl, and hexyloxyhexyl; The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, The heterocycloalkyl group refers to a cycloalkane group in which at least one carbon atom is substituted by a heteroatom.

5. The compound according to claim 1, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: The aromatic group is selected from a five-membered ring, a six-membered ring, a seven-membered ring, an eight-membered ring, a nine-membered ring, and a ten-membered ring. The aromatic group is a monocyclic ring or a bicyclic ring, wherein the bicyclic ring means that two rings share two carbon atoms; the heteroaryl group means that at least one carbon atom on the aromatic ring is replaced by a heteroatom.

6. The compound according to claim 1, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: The halogen is selected from fluorine, chlorine, bromine and iodine, the heteroatoms of the heterocycloalkyl and heteroaryl are selected from nitrogen, oxygen and sulfur, the heteroatoms are one or more, and K is selected from a positive integer of 10-20.

7. The compound according to claim 1, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: When m=1, the R is selected from ethyl, isopropyl, Or when m=2, R is selected from 8. The compound according to claim 1, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: Selected from:

9. A pharmaceutical composition, characterized in that The invention comprises a therapeutically effective amount of the compound according to any one of claims 1 to 8, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. The medical use of the compound according to any one of claims 1 to 8, or its isomer, racemate, or pharmaceutically acceptable salt, specifically, use in the preparation of a medicament for treating a disease, wherein the disease is a complement factor B inhibitor-related disease, specifically selected from proteinuria and the like.

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