Indole-phenylpiperidine 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, as a complement factor B inhibitor, and a method for treating various specific diseases or symptoms by using the complement factor B inhibitor. # imgabs0 #

Description

Indole-phenylpiperidine compound and its preparation method and application Technical Field

[0001] The present invention belongs to the field of chemical pharmaceutical technology and relates to an indole-phenylpiperidine compound, or an isomer, racemate, or pharmaceutically acceptable salt thereof, as well as a preparation method and application thereof as a complement factor B inhibitor, and methods of using the same to treat various specific diseases or conditions. 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 latent 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] PNH 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 significant 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), hemodialysis complications, hemolytic anemia or hemodialysis, neuromyelitis (NMO), hepatitis, inflammatory bowel disease, dermatomyositis and amyotrophic lateral sclerosis, myasthenia gravis (MG), respiratory diseases and cardiovascular diseases.

[0005] Inflammatory and immune-related diseases are diverse and difficult to cure. The only marketed treatment for paronychia nodosa (PNH) is eculizumab, but its price puts a heavy burden on patients. Furthermore, many patients continue to experience anemia after treatment with eculizumab, and many still require continuous blood transfusions. Furthermore, eculizumab requires intravenous administration. Some diseases, such as IgAN, currently have no specific treatments. These areas present unmet clinical needs, necessitating the development of new small molecule therapeutics.

[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.

[0007] Summary of the Invention

[0008] In view of the problems existing in the prior art, the present application provides a compound represented by general formula (I), or an isomer, racemate, or pharmaceutically acceptable salt thereof, as well as a preparation method and use thereof as a small molecule inhibitor of complement factor B, and methods of using the same to treat various specific diseases or conditions.

[0009] In a first aspect, the present application provides a compound represented by general formula (I), or an isomer, a racemate, or a pharmaceutically acceptable salt thereof:

[0010] In a second aspect, the present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of any one of the above-mentioned compounds or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0011] 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 condition, wherein the disease is a complement factor B inhibitor-related disease, specifically, the condition is selected from PNH and other diseases.

[0012] Specifically, the present invention is achieved through the following technical solutions:

[0013] A compound represented by general formula (I), or its isomer, racemate, or pharmaceutically acceptable salt, comprising:

[0014] Where n is 0, 1 or 2;

[0015] R 1 is selected from hydrogen, halogen, hydroxy, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, the substituent is selected from halogen, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy, the substituent may be one or more;

[0016] R 2 is selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, the substituent is hydroxyl, halogen, and the substituent may be one or more;

[0017] R3 is selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, the substituent is hydroxyl, halogen, and the substituent may be one or more;

[0018] R 4 、R 5 are independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein the substituent is selected from hydroxyl, halogen, C3-6 heterocycloalkyl, -(CH2) m -C(O)OH, m is 0, 1 or 2, and the substituent may be one or more;

[0019] R 6 independently selected from hydrogen, alkyl;

[0020] R 7 independently selected from hydrogen or hydroxy;

[0021] Ring A is independently selected from aryl or heteroaryl, wherein the aryl and heteroaryl groups are optionally substituted with one or more R 8 Substitute, where R 8 are independently selected from hydrogen, cyano, sulfone, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-6 Epoxyalkyl, substituted or unsubstituted C 3-6 Cycloalkoxy, wherein the substituent is selected from halogen, C 1-6 Alkoxy, cyano, C 3-6 In the case of a cycloalkyl group, the substituent may be one or more.

[0022] As a preferred technical solution of the present invention, the C 1-6 The alkyl group is selected from the group consisting of methyl, ethyl, 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, and 1-ethylbutyl;

[0023] The C 1-6Alkoxy is selected from methoxy, ethoxy, 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;

[0024] The C 3-6 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the C 3-6 The alkylene oxide group refers to a cycloalkane group in which one or more carbon atoms are replaced by oxygen atoms.

[0025] The C 3-6 Cycloalkoxy is where x is 1, 2, 3, or 4, For the connection key.

[0026] 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, and the aromatic group is a monocyclic or bicyclic ring; the heteroaryl group refers to one or more carbon atoms on the aromatic ring being replaced by a heteroatom.

[0027] As a preferred technical solution of the present invention, the halogen is selected from fluorine, chlorine, bromine and iodine.

[0028] 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.

[0029] As a preferred technical solution of the present invention, wherein the A ring is selected from a benzene ring, The C 3-6 The heterocycloalkyl group is selected from

[0030] As a preferred technical solution of the present invention, R 8 The substituted A ring is selected from

[0031] R 1 is selected from methoxy, cyclopropyl;

[0032] R 2 selected from methyl;

[0033] R 3 selected from hydrogen;

[0034] R 4 Selected from

[0035] R 5 selected from hydrogen;

[0036] R 6 selected from hydrogen;

[0037] R 7 selected from hydrogen or hydroxy;

[0038] For the connection key.

[0039] 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:

[0040] 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.

[0041] As a preferred technical solution of the present invention, one or more hydrogen atoms of the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt are substituted with deuterium isotope.

[0042] 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.

[0043] The present invention further provides the medical use of the compound, or its isomer, or its racemate, or its pharmaceutically acceptable salt, specifically, its 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.

[0044] For the sake of clarity, general terms used in the description of the compounds are defined herein.

[0045] 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 as undefined or unclear in the absence of a specific definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0046] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is prepared by reacting a compound having a specific substituent discovered in the present invention with a pharmaceutically acceptable acid or base.

[0047] In addition to the form of salts, the compounds provided by the present invention also exist in prodrug form. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to be converted into the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0048] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrates. In general, the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present invention.

[0049] 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 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 such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0050] 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 resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0051] The atoms of the molecules of the compounds of the present invention are isotopes, and isotope derivatization can generally extend half-life, reduce clearance, stabilize metabolism, and increase in vivo activity. In addition, an embodiment is included in which at least one atom is replaced by an atom having the same atomic number (number of protons) and a different mass number (protons and neutrons). 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, 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 testing of pharmaceutical preparations or compounds in vivo. Stable isotopes neither decay nor change with their amount nor are they radioactive, 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.

[0052] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute 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 encompassed within the scope of the present invention.

[0053] Furthermore, one or more hydrogen atoms of the compounds of the present invention are replaced by the isotope deuterium (2H). After deuteration, the compounds of the present invention have the effects of extending half-life, reducing clearance rate, metabolic stability and improving in vivo activity.

[0054] 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 incorporation than reduction with a deuterated silane (e.g., triethyldeuterated monosilane) in the presence of an acid (e.g., methanesulfonic acid) or with a Lewis acid such as aluminum trichloride using sodium deuterated borate.

[0055] 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, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity increasers, transdermal enhancers, etc. Their preparation is well known to those skilled in the field of cosmetics or topical medicine. For additional information on carriers, 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.

[0056] The term "excipient" generally refers to a carrier, diluent and / or vehicle required to formulate an effective pharmaceutical composition.

[0057] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0058] 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.

[0059] "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.

[0060] represents the connection key, "abs" indicates the absolute configuration.

[0061] 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 examples of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Figure 1 is a schematic diagram of the crystal structure of intermediate I;

[0063] FIG2 is a crystal parameter diagram of the crystal structure of intermediate I;

[0064] FIG3 is a diagram showing the atomic coordinates and isotropic displacement parameters of the crystal structure of intermediate I;

[0065] FIG4 is an XRPD pattern of the crystal structure of intermediate I. DETAILED DESCRIPTION

[0066] The present application is further described in detail below with reference to examples, but the implementation methods of the present application are not limited thereto.

[0067] 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.

[0068] Example 1 Synthesis of Compounds 1A and 1B

[0069] The specific synthetic route is as follows:

[0070] Step A: Synthesis of 2-(4-cyanophenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0071] To a solution of 4-bromobenzonitrile (36.7 g, 201.5 mmol) in tetrahydrofuran (180 mL) was added a solution of isopropylmagnesium chloride lithium chloride complex (i-PrMgCl.LiCl) (1.3 M in THF, 155 mL) dropwise at room temperature, followed by stirring for 2 hours. To a solution of 4-methoxypyridine (20 g, 183 mmol) in tetrahydrofuran (THF, 100 mL) at -5 to -10°C was added the above reaction solution and benzyl chloroformate (CbzCl, 27 mL, 192 mmol) dropwise in this order. The mixture was stirred at 0°C for 1.5 hours, then at room temperature for 16 hours.

[0072] After the reaction was complete, the mixture was quenched with 5M HCl (40 ml) and stirred at room temperature for 0.5 hours. The mixture was concentrated under reduced pressure, extracted with ethyl acetate (50 ml x 3 times), washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 3) to obtain 21 g of light yellow solid 2-(4-cyanophenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylic acid benzyl ester (yield: 34%). LC-MS: RT = 1.98 min, [M+H] + =333.14.

[0073] Step B: Synthesis of (S)-2-(4-cyanophenyl)-4-oxopiperidine-1-carboxylic acid benzyl ester

[0074] Benzyl 2-(4-cyanophenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (5.0 g, 15 mmol) was added to acetic acid (HOAc, 100 ml) at room temperature and heated to 100°C. Zinc powder (Zn, 3.0 g, 45 mmol) was added in batches and reacted overnight.

[0075] After the reaction was completed, the mixture was cooled to room temperature, diluted with ethyl acetate (50 ml), filtered, and the filtrate was washed with water, neutralized with saturated sodium bicarbonate, washed with saturated brine, dried, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1). 3.0 g of light yellow solid 2-(4-cyanophenyl)-4-oxopiperidine-1-carboxylic acid benzyl ester was obtained (yield 59%). By chiral SFC, using AS-H column with 55% MeOH in CO2 containing 5 mM NH4OH gave 1.3 g of benzyl (S)-2-(4-cyanophenyl)-4-oxopiperidine-1-carboxylate as a white solid.

[0076] Step C: Synthesis of (S)-benzyl 6-(4-cyanophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate

[0077] Benzyl (S)-2-(4-cyanophenyl)-4-oxopiperidine-1-carboxylate (200 mg, 0.60 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (PhN(Tf)2, 320 mg, 0.90 mmol) were dissolved in tetrahydrofuran (THF, 10 ml) at room temperature and the temperature was lowered to -60°C. Lithium bis(trimethylsilylamide) (LiHMDS, 1.8 ml, 1.8 mmol) was added, stirred for 0.5 hour, and then warmed to room temperature for 1 hour.

[0078] After the reaction was complete, the reaction mixture was poured into water (40 ml) and extracted with ethyl acetate (50 ml x 3 times). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1). 190 mg of (S)-benzyl 6-(4-cyanophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate was obtained as a yellow oil (yield 68%).

[0079] Step D: Synthesis of (S)-6-(4-cyanophenyl)-4-phenyl-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0080] At room temperature, compound (S)-6-(4-cyanophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (190 mg, 0.41 mmol), phenylboronic acid (100 mg, 0.82 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2, 30 mg, 0.04 mmol), and potassium phosphate (K3PO4, 180 mg, 0.82 mmol) were added to 1,4-dioxane (10 ml). Under nitrogen protection, the temperature was raised to 90°C and the reaction was carried out overnight.

[0081] After the reaction was complete, ethyl acetate (30 ml) was added to dilute the mixture, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1). 230 mg of (S)-6-(4-cyanophenyl)-4-phenyl-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester was obtained as a light yellow oil. LC-MS: RT = 2.28 min, [M+H] + =395.14.

[0082] Step E: Synthesis of (S)-4-(1-((benzyloxy)carbonyl)-4-phenyl-1,2,5,6-tetrahydropyridin-2-yl)benzoic acid

[0083] At room temperature, compound (S)-6-(4-cyanophenyl)-4-phenyl-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (230 mg, 0.58 mmol) was dissolved in isopropanol (i-PrOH, 10 ml), water (10 ml) and sodium hydroxide (NaOH, 120 mg, 2.92 mmol) were added, and the mixture was heated to 100°C and reacted overnight.

[0084] After the reaction was complete, water (30 ml) was added for dilution. The pH was adjusted to 5-6 with 6N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. 250 mg of (S)-4-(1-((benzyloxy)carbonyl)-4-phenyl-1,2,5,6-tetrahydropyridin-2-yl)benzoic acid (crude) was obtained as a yellow oil. LC-MS: RT = 2.13 min, [M+H] + =412.17.

[0085] Step F: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-phenyl-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0086] At room temperature, compound (S)-4-(1-((benzyloxy)carbonyl)-4-phenyl-1,2,5,6-tetrahydropyridin-2-yl)benzoic acid (230 mg, 0.55 mmol) was dissolved in methanol (MeOH, 10 ml), thionyl chloride (SOCl2, 330 mg, 2.78 mmol) was added, and the mixture was heated to 80°C for 3 hours.

[0087] After the reaction was complete, ethyl acetate (30 ml) was added to dilute the mixture, which was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1). 120 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-phenyl-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (crude) was obtained as a pale yellow oil. LC-MS: RT = 2.30 min, [M+H] + =428.21.

[0088] Step G: Synthesis of methyl 4-((2S)-4-phenylpiperidin-2-yl)benzoate

[0089] At room temperature, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-phenyl-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (100 mg, 0.23 mmol) was dissolved in methanol (MeOH, 10 ml), the pH was adjusted to 5-6 with 6N hydrochloric acid, ammonium formate (HCOONH4, 300 mg, 4.68 mmol) and palladium / carbon (Pd / C, 50 mg) were added, and the mixture was heated to 80°C and reacted for 2 hours.

[0090] After the reaction was complete, the mixture was filtered and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 10 / 1). 50 mg of methyl 4-((2S)-4-phenylpiperidin-2-yl)benzoate was obtained as a light yellow oil (yield 60%). LC-MS: RT = 1.68 min, [M+H] +=296.19.

[0091] Step H: Synthesis of tert-butyl 5-methoxy-7-methyl-1H-indole-1-carboxylate

[0092] 5-Methoxy-7-methyl-1H-indole (10.0 g, 62.0 mmol), di-tert-butyl dicarbonate (Boc2O, 16.2 g, 74.4 mmol), and 4-dimethylaminopyridine (DMAP, 9.1 g, 74.4 mmol) were dissolved in dichloromethane (DCM, 100 ml) at room temperature and reacted for 1 hour.

[0093] After the reaction was complete, water was added and extracted with dichloromethane (30 ml x 4). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 10) to obtain 15.6 g of tert-butyl 5-methoxy-7-methyl-1H-indole-1-carboxylate as a light yellow solid (yield: 96.0%). LC-MS: RT = 2.21 min, [M+H] + =262.20.

[0094] Step I: Synthesis of tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0095] To a solution of N-methyl-N-phenylformamide (5.2 g, 38.7 mmol) in dichloromethane (80 mL) was slowly added oxalyl chloride (COCl2, 4.9 g, 38.7 mmol) at 0°C and allowed to warm to room temperature for 12 hours. The temperature was then lowered to -10°C, and a solution of tert-butyl 5-methoxy-7-methyl-1H-indole-1-carboxylate (7.8 g, 29.8 mmol) in dichloromethane (DCM, 30 mL) was added. The temperature was then raised to 0°C for 1 hour, and then allowed to react at room temperature for 3 hours.

[0096] After the reaction was complete, saturated aqueous sodium bicarbonate (150 ml) was added under ice-cooling, and the mixture was extracted with dichloromethane (50 ml x 3 times). The organic phases were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 20) to obtain 5.5 g of tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate as a white solid (yield: 63.8%). LC-MS: RT = 2.25 min, [M+H] + =290.21.

[0097] Step J: Synthesis of tert-butyl 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-phenylpiperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0098] At room temperature, the compound methyl 4-((2S)-4-phenylpiperidin-2-yl)benzoate (50 mg, 0.17 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (98 mg, 0.34 mmol) were dissolved in 1,2-dichloroethane (DCE, 10 ml), and sodium triacetoxyborohydride (NaBH(OAc)3, 180 mg, 0.85 mmol) was added and stirred overnight.

[0099] After the reaction was completed, methanol was added and the mixture was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1). 68 mg of tert-butyl 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-phenylpiperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate was obtained as a yellow oil (yield 62%). LC-MS: RT = 1.96 min, [M+H] + =569.30.

[0100] Step K: Synthesis of Compounds 1A and 1B

[0101] At room temperature, the compound 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-phenylpiperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (65 mg, 0.11 mmol) was dissolved in methanol (MeOH, 10 ml), potassium carbonate (K2CO3, 160 mg, 1.1 mmol) was added, and the mixture was heated to 70°C for overnight. Water (5 ml) was added and the reaction was continued for 2 hours.

[0102] After the reaction was completed, a 10% aqueous solution of citric acid was added to adjust the pH to neutral, and the mixture was extracted with dichloromethane (10 ml x 4 times). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 5 / 1) to give a crude product. The diastereomers were separated by chiral HPLC (Agilent prep C18) using 25% CH3CN (+0.05% NH3·H2O) solution to give 2 mg of the absolute configuration diastereomer 1A (yield: 3.8%) and 7.3 mg of the absolute configuration diastereomer 1B (yield: 14%).

[0103] Compound 1A: HPLC: RT = 8.5 min, LC-MS: RT = 1.77 min, [M+H]+ =455.25.

[0104] Compound 1B: HPLC: RT = 9.7 min, LC-MS: RT = 1.77 min, [M+H] + =455.28.

[0105] Example 2 Synthesis of Compounds 2A and 2B

[0106] The specific synthetic route is as follows:

[0107] Step A: Synthesis of (S)-benzyl 6-(4-(methoxycarbonyl)phenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate

[0108] Benzyl (S)-2-(4-cyanophenyl)-4-oxopiperidine-1-carboxylate (1.3 g, 3.68 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.2 g, 6.02 mmol) were dissolved in tetrahydrofuran (THF, 20 ml) at room temperature and cooled to -60°C in a cryostat. Lithium bistrimethylsilylamide (LiHMDS, 6 ml, 6 mmol) was added, and the mixture was stirred for 30 minutes, then warmed to room temperature and stirred for 1 hour.

[0109] After the reaction was complete, the reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (50 ml x 3 times). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1). 1.4 g of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester was obtained as a light yellow oil (yield 79%).

[0110] Step B: Synthesis of (S)-6′-(4-(methoxycarbonyl)phenyl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylic acid benzyl ester

[0111] Under nitrogen protection, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (700 mg, 1.4 mmol), 2-pyridineboronic acid (348 mg, 2.8 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2, 102 mg, 0.14 mmol), and potassium phosphate (K3PO4, 594 mg, 2.8 mmol) were added to 1,4-dioxane (30 ml), and the temperature was raised to 105°C for 24 hours.

[0112] After the reaction was complete, the mixture was cooled to room temperature, diluted with ethyl acetate (30 ml), filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1). 210 mg of (S)-6'-(4-(methoxycarbonyl)phenyl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid benzyl ester was obtained as a yellow oil (yield 35%). LC-MS: RT = 2.13 min, [M+H] + =429.20.

[0113] Step C: Synthesis of methyl 4-((2S)-4-(pyridin-2-yl)piperidin-2-yl)benzoate

[0114] At room temperature, compound (S)-6′-(4-(methoxycarbonyl)phenyl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylic acid benzyl ester (180 mg, 0.42 mmol) was dissolved in methanol (MeOH, 10 ml), the pH was adjusted to 4-5 with 6N hydrochloric acid, ammonium formate (HCOONH4, 265 mg, 4.2 mmol) and palladium / carbon (Pd / C, 50 mg) were added, and the mixture was heated to 80°C for 2 hours.

[0115] After the reaction was complete, the mixture was filtered, sodium carbonate was added to the filtrate, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 10 / 1). 150 mg of methyl 4-((2S)-4-(pyridin-2-yl)piperidin-2-yl)benzoate was obtained as a light yellow solid. LC-MS: RT = 1.49 min, [M+H] + =297.19.

[0116] Step D: Synthesis of tert-butyl 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0117] Under ice-cooling conditions, sodium borohydride (NaBH4, 257.2 mg, 6.8 mmol) was slowly added to tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (1.0 g, 3.4 mmol) in methanol (MeOH, 20 ml) and reacted at room temperature for 1 hour.

[0118] After the reaction was complete, the mixture was quenched with saturated aqueous ammonium chloride (45 mL) under ice-cooling conditions and extracted with ethyl acetate (20 mL x 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1) to afford 830.0 mg of tert-butyl 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate as a white solid (yield 84%). LC-MS: RT = 1.95 min, [M-18+H] + =174.18.

[0119] Step E: Synthesis of tert-butyl 4-(chloromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0120] Compound 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (250 mg, 0.86 mmol) was dissolved in dichloromethane (DCM, 6 ml), cooled in an ice-water bath, and (chloromethylene)dimethylammonium chloride (181 mg, 1.46 mmol) was added. The mixture was warmed to room temperature and reacted for 1 hour.

[0121] After the reaction was complete, the mixture was cooled in an ice-water bath and quenched by the addition of 5% sodium bicarbonate. The mixture was extracted with dichloromethane (20 ml x 3 times). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 200 mg of crude tert-butyl 4-(chloromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate as a brown oil, which was used directly in the next reaction.

[0122] Step F: Synthesis of tert-butyl 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(pyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0123] At room temperature, the compound 4-((2S)-4-(pyridin-2-yl)piperidin-2-yl)benzoic acid methyl ester (80 mg, 0.27 mmol) and 4-(chloromethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (167 mg, 0.54 mmol) were dissolved in N,N-dimethylformamide (DMF, 6 ml), and sodium carbonate (Na2CO3, 85 mg, 0.81 mmol) was added and stirred overnight.

[0124] After the reaction was complete, the product was quenched with water and extracted with ethyl acetate (20 ml x 4 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 10 / 1). 145 mg of dark yellow oily 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(pyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was obtained (yield 56%). LC-MS: RT = 1.86 min, [M+H] + =570.25.

[0125] Step G: Synthesis of compounds 2A and 2B

[0126] At room temperature, the compound 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(pyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (145 mg, 0.15 mmol) was dissolved in methanol (MeOH, 5 ml), potassium carbonate (K2CO3, 211 mg, 1.5 mmol) was added, and the mixture was heated to 70°C and stirred overnight. Water (1 ml) was added and the reaction was continued for 2 hours.

[0127] After the reaction was completed, a 10% aqueous solution of citric acid was added to adjust the pH to neutral, and the mixture was extracted with dichloromethane (10 ml × 4 times). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 1 / 1) to give a crude product. The diastereomers were separated by chiral HPLC (Agilent prep C18) using 25% CH3CN (+0.05% NH3·H2O) solution for elution to give 2.9 mg of the absolute configuration diastereomer 2A (yield: 2.5%) and 8.7 mg of the absolute configuration diastereomer 2B (yield: 7.5%).

[0128] Compound 2A: HPLC: RT = 7.5 min, LC-MS: RT = 1.62 min, [M+H] + =456.19.

[0129] Compound 2B: HPLC: RT = 10.2 min, LC-MS: RT = 1.62 min, [M+H] + =456.22.

[0130] Example 3 Synthesis of Compounds 3A and 3B

[0131] The specific synthetic route is as follows:

[0132] Step A: Synthesis of (S)-6-((4-methoxycarbonyl)phenyl)-4-(thiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0133] To a solution of benzyl (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.42 mmol) in dioxane (10 ml) at room temperature were added 2-bromothiazole (104 mg, 0.63 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl2, 61 mg, 0.08 mmol), potassium phosphate (K3PO4, 182 mg, 0.84 mmol), and water (2 ml). The atmosphere was replaced with nitrogen, and the temperature was raised to 90°C for 5 hours.

[0134] After the reaction was complete, the product was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to afford 120 mg of (S)-benzyl 6-((4-methoxycarbonyl)phenyl)-4-(thiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate as a pale yellow oily liquid (yield: 66%). LC-MS: RT = 2.16 min, [M+H] + =435.23.

[0135] Step B: Synthesis of (S)-methyl 4-(4-thiazol-2-yl)piperidin-2-ylbenzoate

[0136] At room temperature, benzyl (S)-6-((4-methoxycarbonyl)phenyl)-4-(thiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.24 mmol) was dissolved in ethyl acetate solution (EA, 10 ml), palladium on carbon (Pd / C, 20 mg) was added to replace the hydrogen, and the temperature was raised to 60°C to react overnight.

[0137] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated to obtain 55 mg of a light yellow oily liquid (S)-methyl 4-(4-thiazol-2-yl)piperidin-2-ylbenzoate (yield: 66%). LC-MS: RT = 1.65 min, [M+H] + =303.19.

[0138] Step C: Synthesis of (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(thiazol-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0139] To a solution of (S)-methyl 4-(4-thiazol-2-yl)piperidin-2-ylbenzoate (55 mg, 0.18 mmol) in 1,2-dichloroethane (DCE, 5 ml) at room temperature were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (79 mg, 0.27 mmol) and sodium triacetoxyborohydride (NaBH(OAc)3, 76 mg, 0.36 mmol), and the mixture was heated to 40°C and reacted overnight.

[0140] After the reaction was completed, a small amount of methanol was added and the solvent was directly evaporated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to obtain 44 mg of (S)-tert-butyl 5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(thiazol-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate as a white solid (yield: 42%). LC-MS: RT = 1.97 min, [M+H] + =576.27.

[0141] Step D: Synthesis of compounds 3A and 3B

[0142] To a solution of tert-butyl (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(thiazol-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (44 mg, 0.08 mmol) in methanol (MeOH, 5 ml) at room temperature was added potassium carbonate (K2CO3, 42 mg, 0.30 mmol), the mixture was heated to 70°C for 5 hours, and water (1 ml) was added and the reaction was continued for 4 hours.

[0143] After the reaction was completed, a 10% aqueous solution of citric acid was added to adjust the pH to neutral, and the mixture was extracted with dichloromethane (10 ml x 4 times). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give a crude product. The diastereomers were separated by chiral HPLC (Agilent prep C18) using 25% CH3CN (+0.05% NH3·H2O) solution to give 9 mg of the absolute configuration diastereomer 3A (yield: 24%) and 15 mg of the absolute configuration diastereomer 3B (yield: 41%).

[0144] Compound 3A: HPLC: RT = 10.1 min, LC-MS: RT = 1.66 min, [M+H] + =462.24.

[0145] Compound 3B: HPLC: RT = 14.2 min, LC-MS: RT = 1.66 min, [M+H] + =462.22.

[0146] Example 4

[0147] Synthesis of 4-((2S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(1H-pyrazol-1-yl)piperidin-2-yl)benzoic acid

[0148] The specific synthetic route is as follows:

[0149] Step A: Synthesis of (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

[0150] Under nitrogen protection at room temperature, compound (S)-benzyl 6-(4-cyanophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (500 mg, 1.0 mmol), pinacol diboron (760 mg, 3.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2, 150 mg, 0.2 mmol), and potassium acetate (KOAc, 400 mg, 4.0 mmol) were added to 1,4-dioxane (15 ml), and the temperature was raised to 105°C for 24 hours.

[0151] After the reaction was complete, ethyl acetate (30 ml) was added to dilute the mixture, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1). 400 mg of (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 was obtained as a yellow oil (yield 80%). LC-MS: RT = 2.30 min, [M+H] + =478.17. 1 H NMR (400MHz, CDCl3) δ8.04-7.86 (m, 2H), 7.55-7.22 (m, 7H), 5.77-5.48 (m, 1H), 5.29-5.03 (m, 2H,), 4.54-4 .28(m, 1H), 3.98-3.85(m, 3H), 3.58-3.47(m, 1H), 3.03-2.65(m, 2H), 2.40-2.22(m, 1H), 1.29-1.26(m, 12H)

[0152] Step B: Synthesis of (S)-(1-((benzyloxy)carbonyl)-6-(4-(methoxycarbonyl)phenyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid

[0153] At room temperature, compound (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 (400 mg, 0.84 mmol) was dissolved in acetone (10 ml), and water (10 ml), ammonium acetate (NH4OAc, 200 mg, 2.52 mmol) and sodium periodate (NaIO4, 540 mg, 2.52 mmol) were added in sequence and the reaction was allowed to proceed overnight.

[0154] After the reaction was complete, water (50 mL) was added for dilution, and the mixture was extracted with ethyl acetate (20 mL x 3 times). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. 310 mg of (S)-(1-((benzyloxy)carbonyl)-6-(4-(methoxycarbonyl)phenyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid was obtained as a yellow oil (yield 93%). LC-MS: RT = 1.95 min, [M+H] + =396.14.

[0155] Step C: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-1-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0156] Compound (S)-(1-((benzyloxy)carbonyl)-6-(4-(methoxycarbonyl)phenyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (260 mg, 0.66 mmol), copper acetate (360 mg, 1.97 mmol), and pyrazole (135 mg, 1.97 mmol) were dissolved in dichloromethane (DCM, 10 ml) at room temperature, and pyridine (Py, 1 ml) was added and the reaction was carried out for 48 hours.

[0157] After the reaction was complete, ethyl acetate (30 ml) was added to dilute the mixture and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1). 180 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-1-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester was obtained as a light yellow gum (yield 65%). LC-MS: RT = 2.14 min, [M+H] + =418.16.

[0158] Step D: Synthesis of methyl 4-((2S)-4-(1H-pyrazol-1-yl)piperidin-2-yl)benzoate

[0159] Under hydrogen protection at room temperature, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-1-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (150 mg, 0.36 mmol) was dissolved in methanol (MeOH, 10 ml), the pH was adjusted to 2 with 6N hydrochloric acid, and palladium / carbon (Pd / C, 50 mg) was added to react for 10 hours.

[0160] After the reaction was complete, the mixture was filtered, concentrated, and diluted with ethyl acetate and water. Ammonia was added to adjust the pH to greater than 13. Extraction was performed with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. 95 mg of methyl 4-((2S)-4-(1H-pyrazol-1-yl)piperidin-2-yl)benzoate was obtained as a light yellow oil (yield 90%). LC-MS: RT = 1.56 min, [M+H] + =286.15.

[0161] Step E: Synthesis of tert-butyl 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0162] At room temperature, methyl 4-((2S)-4-(1H-pyrazol-1-yl)piperidin-2-yl)benzoate (90 mg, 0.32 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (183 mg, 0.64 mmol) were dissolved in 1,2-dichloroethane (DCE, 6 ml), and sodium triacetoxyborohydride (NaBH(OAc)3, 334 mg, 1.58 mmol) was added and the mixture was reacted overnight.

[0163] After the reaction was complete, methanol was added to dissolve until clear and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1). 86 mg of tert-butyl 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate was obtained as a yellow oil (yield 48%). LC-MS: RT = 1.86 min, [M+H] + =559.24.

[0164] Step F: Synthesis of 4-((2S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(1H-pyrazol-1-yl)piperidin-2-yl)benzoic acid

[0165] At room temperature, the compound 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-1-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (86 mg, 0.15 mmol) was dissolved in methanol (MeOH, 5 ml), potassium carbonate (K2CO3, 213 mg, 1.5 mmol) was added, and the mixture was heated to 70°C and stirred overnight. Water (1 ml) was added and the reaction was continued for 2 hours.

[0166] After the reaction was complete, the purification method described in Step D of Example 3 was used to isolate 40.4 mg of 4-((2S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(1H-pyrazol-1-yl)piperidin-2-yl)benzoic acid. LC-MS: RT = 1.63 min, [M+H] + =445.18.

[0167] Example 5

[0168] Synthesis of 4-((2S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(thiophen-3-yl)piperidin-2-yl)benzoic acid

[0169] Synthesis route:

[0170] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0171] Under nitrogen protection at room temperature, compound (S)-6-(4-cyanophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (940 mg, 1.88 mmol), 3-thiopheneboronic acid (482 mg, 3.76 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2, 137 mg, 0.188 mmol), and potassium phosphate (K3PO4, 1.2 g, 5.65 mmol) were added to 1,4-dioxane (15 ml), and the temperature was raised to 95°C for 24 hours.

[0172] After the reaction was complete, ethyl acetate (50 ml) was added to dilute the mixture, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1). 610 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester was obtained as a yellow semi-solid (yield 74%). LC-MS: RT = 2.27 min, [M+H] + =434.28.

[0173] Step B: Synthesis of benzyl (2S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidine-1-carboxylate

[0174] At room temperature, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (300 mg, 0.69 mmol) was dissolved in methanol (MeOH, 10 ml), the pH was adjusted to 2 with 6N hydrochloric acid, ammonium formate (HCOONH4, 692 mg, 13.84 mmol) and palladium / carbon (Pd / C, 100 mg) were added, and the reaction was heated to 75°C for 3 hours.

[0175] After the reaction was complete, the mixture was filtered and concentrated. Ethyl acetate was added for dilution, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. 200 mg of (2S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidine-1-carboxylic acid benzyl ester was obtained as a light yellow oil (yield 66%). LC-MS: RT = 2.27 min, [M+H] + =436.12.

[0176] Step C: Synthesis of methyl 4-((2S)-4-(thiophen-3-yl)piperidin-2-yl)benzoate

[0177] At room temperature, compound (2S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidine-1-carboxylic acid benzyl ester (150 mg, 0.34 mmol) was dissolved in ethyl acetate (EA, 5 ml), cooled in an ice-water bath, and 33% hydrobromic acid / acetic acid solution (HBr / HOAc, 2 ml) was added. The temperature was raised to room temperature and the reaction was carried out for 2 hours.

[0178] After the reaction was complete, methanol was added to quench the reaction, and the mixture was adjusted to alkaline with aqueous ammonia. The mixture was concentrated under reduced pressure to remove most of the methanol. The resulting residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1). 100 mg of brown solid methyl 4-((2S)-4-(thiophen-3-yl)piperidin-2-yl)benzoate was obtained (yield 72%). LC-MS: RT = 1.65 min, [M+H] + =302.14.

[0179] Step D: Synthesis of tert-butyl 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0180] Methyl 4-((2S)-4-(thiophen-3-yl)piperidin-2-yl)benzoate (100 mg, 0.33 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (192 mg, 0.66 mmol) were dissolved in 1,2-dichloroethane (DCE, 10 ml) at room temperature, and sodium triacetoxyborohydride (NaBH(OAc)3, 352 mg, 1.66 mmol) was added to the mixture and the reaction was allowed to proceed overnight.

[0181] After the reaction was complete, methanol was added and the mixture was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1). 210 mg of crude tert-butyl 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate was obtained as a yellow oil. LC-MS: RT = 1.95 min, [M+H] + =575.24.

[0182] Step E: Synthesis of 4-((2S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(thiophen-3-yl)piperidin-2-yl)benzoic acid

[0183] At room temperature, the compound 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (210 mg, 0.146 mmol, purity 40%) was dissolved in methanol (MeOH, 5 ml), potassium carbonate (K2CO3, 202 mg, 1.46 mmol) was added, and the mixture was heated to 70°C and stirred overnight. Water (2 ml) was added and the reaction was continued for 2 hours.

[0184] After the reaction was complete, the product was purified using the method described in Step D of Example 3 to yield 47.8 mg of 4-((2S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(thiophen-3-yl)piperidin-2-yl)benzoic acid. LC-MS: RT = 1.69 min, [M+H] + =461.15.

[0185] Example 6 Synthesis of Compounds 6A and 6B

[0186] The specific synthetic route is as follows:

[0187] Step A: Synthesis of (S)-benzyl 4-(isothiazol-5-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0188] At room temperature, compound (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 (200 mg, 0.5 mmol), 5-bromoisothiazole (100 mg, 0.6 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2, 37 mg, 0.05 mmol), and potassium phosphate (K3PO4, 215 mg, 1.0 mmol) were added to 1,4-dioxane (10 ml). Under nitrogen protection, the temperature was raised to 95°C and the reaction was carried out for 24 hours.

[0189] After the reaction was complete, ethyl acetate (50 ml) was added to dilute the mixture, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1). 170 mg of (S)-benzyl 4-(isothiazol-5-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate was obtained as a yellow oil (yield 77%). LC-MS: RT = 2.16 min, [M+H] + =435.12.

[0190] Step B: Synthesis of benzyl (2S)-4-(isothiazol-5-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate

[0191] At room temperature, compound (S)-4-(isothiazol-5-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (170 mg, 0.39 mmol) was dissolved in ethyl acetate (EA, 10 ml), palladium / carbon (Pd / C, 100 mg) was added, and the mixture was heated to 60°C under a hydrogen atmosphere and reacted overnight.

[0192] After the reaction was complete, the mixture was filtered and concentrated to yield 150 mg of (2S)-4-(isothiazol-5-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid benzyl ester (crude) as a pale yellow gum. This crude product was used directly in the next step without purification. LC-MS: RT = 2.12 min, [M+H] + =437.07.

[0193] Step C: Methyl 4-((2S)-4-(isothiazol-5-yl)piperidin-2-yl)benzoate

[0194] At room temperature, compound (2S)-4-(isothiazol-5-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid benzyl ester (150 mg, 0.34 mmol) was dissolved in ethyl acetate (EtOAc, 5 ml) and cooled in an ice-water bath. 33% hydrobromic acid / acetic acid solution (HBr / HOAc, 0.6 ml) was added and the mixture was warmed to room temperature and stirred for 2 hours.

[0195] After the reaction was complete, the mixture was quenched with methanol, adjusted to alkalinity with aqueous ammonia, and concentrated. The residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1). 50 mg of methyl 4-((2S)-4-(isothiazol-5-yl)piperidin-2-yl)benzoate was obtained as a yellow gum (yield 48%). LC-MS: RT = 1.58 min, [M+H] + =303.10.

[0196] Step D: Synthesis of tert-butyl 4-(((2S)-4-(isothiazol-5-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0197] At room temperature, the compound 4-((2S)-4-(isothiazol-5-yl)piperidin-2-yl)benzoic acid methyl ester (50 mg, 0.16 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (96 mg, 0.33 mmol) were dissolved in 1,2-dichloroethane (DCE, 5 ml) and stirred for 1 hour. Sodium triacetoxyborohydride (NaBH(OAc)3, 175 mg, 0.83 mmol) was added and the reaction was allowed to proceed overnight.

[0198] After the reaction was complete, methanol was added to dissolve until clear and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1). 160 mg of yellow oily tert-butyl 4-(((2S)-4-(isothiazol-5-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (crude product) was obtained and used directly in the next reaction. LC-MS: RT = 1.90 min, [M+H] + =576.18.

[0199] Step E: Synthesis of compounds 6A and 6B

[0200] At room temperature, the compound 4-(((2S)-4-(isothiazol-5-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (160 mg, 0.16 mmol, crude product) was dissolved in methanol (MeOH, 10 ml), potassium carbonate (K2CO3, 384 mg, 2.7 mmol) was added, and the mixture was heated to 70°C and stirred overnight. Water (2 ml) was added and the reaction was continued for 2 hours.

[0201] After the reaction was completed, the purification and chiral separation methods described in Step D of Example 3 were used to obtain 4 mg of the absolute configuration diastereomer 6A (yield: 3.1%) and 13.5 mg of the absolute configuration diastereomer 6B (yield: 8.0%).

[0202] Compound 6A: HPLC: RT = 14.8 min, LC-MS: RT = 1.66 min, [M+H] + =462.14.

[0203] Compound 6B: HPLC: RT = 16.7 min, LC-MS: RT = 1.66 min, [M+H] + =462.12.

[0204] Example 7 Synthesis of Compounds 7A and 7B

[0205] The specific synthetic route is as follows:

[0206] Step A: Synthesis of (S)-benzyl 4-(isothiazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0207] At room temperature, compound (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 (200 mg, 0.5 mmol), 4-bromoisothiazole (100 mg, 0.6 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2, 37 mg, 0.05 mmol), and potassium phosphate (K3PO4, 215 mg, 1.0 mmol) were added to 1,4-dioxane (10 ml), and the temperature was raised to 95°C under nitrogen protection for 24 hours.

[0208] After the reaction was complete, ethyl acetate (50 ml) was added to dilute the mixture, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1). 100 mg of (S)-benzyl 4-(isothiazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate was obtained as a yellow oil (yield 55%). LC-MS: RT = 2.16 min, [M+H] + =435.12.

[0209] Step B: Synthesis of benzyl (2S)-4-(isothiazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate

[0210] Under hydrogen protection, compound (S)-4-(isothiazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (100 mg, 0.23 mmol) was dissolved in ethyl acetate (10 ml), palladium / carbon (100 mg) was added, and the mixture was heated to 60°C overnight.

[0211] After the reaction was complete, the mixture was filtered and concentrated to yield 100 mg of crude (2S)-4-(isothiazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate as a yellow gum. This crude product was used directly in the next step without further purification. LC-MS: RT = 2.13 min, [M+H] + =437.08.

[0212] Step C: Methyl 4-((2S)-4-(isothiazol-4-yl)piperidin-2-yl)benzoate

[0213] Under ice-water cooling, compound (2S)-4-(isothiazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid benzyl ester (100 mg, 0.23 mmol) was dissolved in ethyl acetate (EtOAc, 5 ml), and 33% hydrobromic acid / acetic acid solution (HBr / HOAc, 0.6 ml) was added, and the mixture was warmed to room temperature and stirred for 2 hours.

[0214] After the reaction was complete, the mixture was quenched with methanol, adjusted to alkalinity with aqueous ammonia, and concentrated. The residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1). 60 mg of methyl 4-((2S)-4-(isothiazol-4-yl)piperidin-2-yl)benzoate (yield 86%) was obtained as a yellow gum. LC-MS: RT = 1.58 min, [M+H] + =303.10.

[0215] Step D: Synthesis of tert-butyl 4-(((2S)-4-(isothiazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0216] At room temperature, the compound 4-((2S)-4-(isothiazol-4-yl)piperidin-2-yl)benzoic acid methyl ester (60 mg, 0.2 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (115 mg, 0.4 mmol) were dissolved in 1,2-dichloroethane (DCE, 5 ml), and sodium triacetoxyborohydride (NaBH(OAc)3, 210 mg, 1.0 mmol) was added and the reaction was allowed to proceed overnight.

[0217] After the reaction was complete, methanol was added to dissolve until clear, and the mixture was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1). 210 mg of yellow oily tert-butyl 4-(((2S)-4-(isothiazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (crude product, purity 30%) was obtained and used directly in the next reaction. LC-MS: RT = 1.88 min, [M+H] + =576.17.

[0218] Step E: Synthesis of compounds 7A and 7B

[0219] At room temperature, the compound 4-(((2S)-4-(isothiazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (210 mg, 0.11 mmol, crude product) was dissolved in methanol (MeOH, 5 ml), potassium carbonate (K2CO3, 150 mg, 1.1 mmol) was added, and the mixture was heated to 70°C and stirred overnight. Water (2 ml) was added and the reaction was continued for 2 hours.

[0220] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 6 mg of the absolute configuration diastereomer 7A (yield: 3.5%) and 12.4 mg of the absolute configuration diastereomer 7B (yield: 7.4%).

[0221] Compound 7A: HPLC: RT = 11.2 min, LC-MS: RT = 1.69 min, [M+H] + =462.15.

[0222] Compound 7B: HPLC: RT = 13.8 min, LC-MS: RT = 1.69 min, [M+H] + =462.12.

[0223] Example 8 Synthesis of Compounds 8A and 8B

[0224] The specific synthetic route is as follows:

[0225] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0226] Under nitrogen protection, a mixed solution of 1,4-dioxane and water (12 ml, 1,4-dioxane:water=5:1) containing benzyl (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200.0 mg, 0.42 mmol), 4-bromothiazole (103.7 mg, 0.62 mmol), [1,1′-bis(triphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2, 61.0 mg, 0.08 mmol) and potassium phosphate (K3PO4, 182.0 mg, 0.84 mmol) was heated to 95°C for 12 hours.

[0227] After the reaction was complete, water was added and the mixture was extracted with ethyl acetate (20 ml x 4). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to obtain 57.0 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester as a pale yellow solid (yield: 31.2%). LC-MS: RT = 2.11 min, [M+H] + =435.08.

[0228] Step B: Synthesis of benzyl (2S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiazol-4-yl)piperidine-1-carboxylate

[0229] At room temperature, palladium on carbon (30 mg) was added to ethyl acetate (EtOAc, 10 ml) containing benzyl (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (57.0 mg, 0.13 mmol) to replace the hydrogen. Under hydrogen protection, the temperature was raised to 60°C and the reaction was carried out for 12 hours.

[0230] After the reaction was complete, the mixture was cooled to room temperature, filtered, and concentrated to dryness to obtain 57.0 mg of a pale yellow solid (2S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiazol-4-yl)piperidine-1-carboxylic acid benzyl ester (yield: 100%). LC-MS: RT = 2.09 min, [M+H] + =437.09.

[0231] Step C: Synthesis of (S)-methyl 4-(4-(thiazol-4-yl)piperidin-2-yl)benzoate

[0232] Under ice-bath conditions, to a solution of benzyl (2S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiazol-4-yl)piperidine-1-carboxylate (57.0 mg, 0.13 mmol) in ethyl acetate (EtOAc, 5.0 ml) was added dropwise a solution of hydrobromic acid in acetic acid (0.3 ml, hydrobromic acid concentration of 30%), and the mixture was heated to room temperature to react for 2 hours.

[0233] After the reaction was complete, the mixture was quenched with saturated aqueous sodium bicarbonate solution under ice-cooling conditions and extracted with ethyl acetate (20 ml x 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 2) to yield 28.0 mg of (S)-methyl 4-(4-(thiazol-4-yl)piperidin-2-yl)benzoate as a pale yellow oily liquid. LC-MS: RT = 1.61 min, [M+H] + =303.09.

[0234] Step D: Synthesis of (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(thiazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0235] Under nitrogen protection, (S)-methyl 4-(4-(thiazol-4-yl)piperidin-2-yl)benzoate (28.0 mg, 0.09 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (65.0 mg, 0.22 mmol) were dissolved in 1,2-dichloroethane (DCE, 3.0 ml). The temperature was raised to 40° C. and the reaction was carried out for 1 hour. Sodium triacetoxyborohydride (NaBH(OAc)3, 57.2 mg, 0.27 mmol) was added and the reaction was continued for 12 hours.

[0236] After the reaction was complete, methanol was added, the sample was spin-dried, and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 2) to obtain 34.0 mg of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(thiazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield: 66.6%) as a yellow solid. LC-MS: RT = 1.91 min, [M+H] + =576.19.

[0237] Step E: Synthesis of compounds 8A and 8B

[0238] To a methanol solution (MeOH, 5.0 ml) containing tert-butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(thiazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (44.0 mg, 0.06 mmol) was added potassium carbonate (K2CO3, 33.1 mg, 0.24 mmol) at room temperature. The temperature was raised to 70°C for 5 hours, and water (1.0 ml) was added and the reaction was continued for 12 hours.

[0239] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 10.0 mg of the absolute configuration diastereomer 8A (yield: 28.4%) and 15.0 mg of the absolute configuration diastereomer 8B (yield: 44.1%).

[0240] Compound 8A: HPLC: RT = 12.2 min, LC-MS: RT = 1.66 min, [M+H] + =462.16.

[0241] Compound 8B: HPLC: RT = 14.5 min, LC-MS: RT = 1.66 min, [M+H] + =462.16.

[0242] Example 9 Synthesis of Compounds 9A and 9B

[0243] The specific synthetic route is as follows:

[0244] Step A: Synthesis of (S)-6-((4-methoxycarbonyl)phenyl)-4-(thiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0245] To a solution of benzyl (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.42 mmol) in dioxane (10 ml) at room temperature were added 5-bromothiazole (104 mg, 0.63 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2, 61 mg, 0.08 mmol) and potassium phosphate (K3PO4, 182 mg, 0.84 mmol), followed by water (2 ml), nitrogen replacement, and the reaction mixture was heated to 90°C for 5 hours.

[0246] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 5) to obtain 160 mg of (S)-6-((4-methoxycarbonyl)phenyl)-4-(thiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester as a pale yellow oily liquid (yield: 88%). LC-MS: RT = 2.12 min, [M+H] + =435.25.

[0247] Step B: Synthesis of (S)-benzyl 2-(4-methoxycarbonyl)phenyl)-4-(thiazol-5-yl)piperidine-1-carboxylate

[0248] At room temperature, benzyl (S)-6-((4-methoxycarbonyl)phenyl)-4-(thiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (150 mg, 0.35 mmol) was dissolved in methanol solution (MeOH, 10 ml), palladium on carbon (Pd / C, 30 mg) was added, and the hydrogen was replaced and the reaction was continued for 0.5 hour.

[0249] After the reaction was complete, the mixture was filtered, washed with methanol, and concentrated to give 110 mg of (S)-2-((4-methoxycarbonyl)phenyl)-4-(thiazol-5-yl)piperidine-1-carboxylic acid benzyl ester as a light yellow oil. LC-MS: RT = 2.13 min, [M+H] + =437.19.

[0250] Step C: Synthesis of (S)-methyl 4-(4-thiazol-5-yl)piperidin-2-ylbenzoate

[0251] Under ice cooling, benzyl (S)-2-((4-methoxycarbonyl)phenyl)-4-(thiazol-5-yl)piperidine-1-carboxylate (110 mg, 0.25 mmol) was dissolved in ethyl acetate solution (6 ml), and a solution of hydrobromic acid in acetic acid (HBr / AcOH, 0.4 ml) was added, and the temperature was raised to room temperature to react for 2 hours.

[0252] After the reaction was complete, the mixture was quenched with ammonia water, the pH was adjusted to approximately 5, and the mixture was extracted with ethyl acetate, dried, filtered, and concentrated to obtain 95 mg of (S)-methyl 4-(4-thiazol-5-yl)piperidin-2-ylbenzoate as a light yellow oily liquid. LC-MS: RT = 1.67 min, [M+H] + =303.21.

[0253] Step D: Synthesis of (S)-tert-butyl 5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(thiazol-5-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0254] To a solution of (S)-methyl 4-(4-thiazol-5-yl)piperidin-2-ylbenzoate (60 mg, 0.20 mmol) in dichloroethane (DCE, 5 ml) at room temperature were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (86 mg, 0.30 mmol) and sodium triacetoxyborohydride (NaBH(OAc)3, 76 mg, 0.36 mmol), and the mixture was heated to 40°C and reacted overnight.

[0255] After the reaction was complete, methanol was added and the mixture was concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to afford 25 mg of (S)-tert-butyl 5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(thiazol-5-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate as a white solid (yield: 21%). LC-MS: RT = 1.98 min, [M+H] + =576.27.

[0256] Step E: Synthesis of compounds 9A and 9B

[0257] To a solution of tert-butyl (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(thiazol-5-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (25 mg, 0.04 mmol) in methanol (5 ml) at room temperature was added potassium carbonate (K2CO3, 24 mg, 0.17 mmol), the mixture was heated to 70°C for 5 hours, and water (1 ml) was added and the reaction was continued for 4 hours.

[0258] After the reaction was completed, the purification and chiral separation methods described in Step D of Example 3 were used to obtain 5 mg of the absolute configuration diastereomer 9A (yield: 26%) and 10 mg of the absolute configuration diastereomer 9B (yield: 52%).

[0259] Compound 9A: HPLC: RT = 12.2 min, LC-MS: RT = 1.71 min, [M+H] + =462.26.

[0260] Compound 9B: HPLC: RT = 14.6 min, LC-MS: RT = 1.71 min, [M+H] + =462.28.

[0261] Example 10 Synthesis of Compounds 10A and 10B

[0262] The specific synthetic route is as follows:

[0263] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0264] Under nitrogen protection, compound (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 (1.0 g, 2.09 mmol), 4-bromo-1-methyl-1H-pyrazole (675 mg, 4.18 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl2, 154 mg, 0.21 mmol), and potassium phosphate (K3PO4, 890 mg, 4.18 mmol) were added to 1,4-dioxane (15 ml) and water (2 ml), and the temperature was raised to 95°C for 24 hours.

[0265] After the reaction was complete, ethyl acetate (50 ml) was added to dilute the mixture, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1). 570 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester was obtained as a dark yellow solid (yield 63%). LC-MS: RT = 2.05 min, [M+H] + =432.23.

[0266] Step B: Synthesis of methyl 4-((2S)-4-(1-methyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate

[0267] Under hydrogen protection, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (520 mg, 1.21 mmol) was dissolved in ethyl acetate (EtOAc, 25 ml), palladium / carbon (130 mg) was added, and the reaction was carried out at room temperature for 5 hours.

[0268] After the reaction was complete, the mixture was filtered and concentrated to obtain 390 mg of methyl 4-((2S)-4-(1-methyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate (crude product) as a yellow oil, which was used directly in the next step without purification. LC-MS: RT = 1.50 min, [M+H] + =300.21.

[0269] Step C: Synthesis of tert-butyl 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0270] At room temperature, the compound 4-((2S)-4-(1-methyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoic acid methyl ester (390 mg, 1.3 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (754 mg, 2.6 mmol) were dissolved in 1,2-dichloroethane (DCE, 20 ml), and sodium triacetoxyborohydride (NaBH(OAc)3, 159 mg, 0.75 mmol) was added and the reaction was carried out overnight.

[0271] After the reaction was complete, methanol was added to dissolve until clear, and the mixture was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1). 480 mg of light yellow gum 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (yield 64%) was obtained and used directly in the next reaction. LC-MS: RT = 1.88 min, [M+H] + =573.34.

[0272] Step D: Synthesis of compounds 10A and 10B

[0273] At room temperature, the compound 5-methoxy-4-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (40 mg, 0.07 mmol, crude) was dissolved in methanol (MeOH, 5 ml), potassium carbonate (K2CO3, 100 mg, 0.7 mmol) was added, and the mixture was heated to 70°C and stirred overnight. Water (2 ml) was added and the reaction was continued for 2 hours.

[0274] After the reaction was completed, the purification and chiral separation methods described in Step D of Example 3 were used to obtain 1.2 mg of the absolute configuration diastereomer 10A (yield: 3.8%) and 2.1 mg of the absolute configuration diastereomer 10B (yield: 6.5%).

[0275] Compound 10A: HPLC: RT = 7.0 min, LC-MS: RT = 1.65 min, [M+H] + =459.29.

[0276] Compound 10B: HPLC: RT = 10.4 min, LC-MS: RT = 1.65 min, [M+H] + =459.27.

[0277] Example 11 Synthesis of Compounds 11A and 11B

[0278] The specific synthetic route is as follows:

[0279] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0280] To a solution of benzyl (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.42 mmol) in dioxane (10 ml) at room temperature were added 3-bromo-1-methylpyrazole (101 mg, 0.63 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2, 61 mg, 0.08 mmol) and potassium phosphate (K3PO4, 182 mg, 0.84 mmol), followed by water (2 ml), nitrogen replacement, and the mixture was heated to 90°C for 5 hours.

[0281] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 5) to obtain 165 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester as a pale yellow oily liquid (yield: 90%). LC-MS: RT = 2.12 min, [M+H] + =432.25.

[0282] Step B: Synthesis of (S)-methyl 4-(4-(1-methyl-1H-pyrazol-3-yl)piperidin-2-yl)benzoate

[0283] At room temperature, benzyl (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (165 mg, 0.38 mmol) was dissolved in ethyl acetate solution (10 ml), palladium on carbon (30 mg) was added to replace the hydrogen atmosphere, and the temperature was raised to 60°C to react overnight.

[0284] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated to give 110 mg of colorless oily liquid (S)-methyl 4-(4-(1-methyl-1H-pyrazol-3-yl)piperidin-2-yl)benzoate. LC-MS: RT = 1.60 min, [M+H] + =300.19.

[0285] Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0286] To a solution of (S)-methyl 4-(4-(1-methyl-1H-pyrazol-3-yl)piperidin-2-yl)benzoate (50 mg, 0.17 mmol) in dichloroethane (5 ml) at room temperature were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (72 mg, 0.25 mmol) and sodium triacetoxyborohydride (50 mg, 0.24 mmol), and the mixture was heated to 40°C and reacted overnight.

[0287] After the reaction was completed, a small amount of methanol was added and the solvent was directly evaporated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to obtain 45 mg of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester as a white solid (yield: 46%). LC-MS: RT = 1.90 min, [M+H] + =573.35.

[0288] Step D: Synthesis of compounds 11A and 11B

[0289] To a solution of tert-butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (45 mg, 0.08 mmol) in methanol (5 ml) was added potassium carbonate (44 mg, 0.31 mmol) at room temperature, the mixture was heated to 70°C for 5 hours, and water (1 ml) was added and the reaction was continued for 4 hours.

[0290] After the reaction was completed, the purification and chiral separation methods of Step D of Example 3 were used to obtain 5 mg of the absolute configuration diastereomer 11A (yield: 14%) and 25 mg of the absolute configuration diastereomer 11B (yield: 69%).

[0291] Compound 11A: HPLC: RT = 11.0 min, LC-MS: RT = 1.65 min, [M+H] + =459.22.

[0292] Compound 11B: HPLC: RT = 14.4 min, LC-MS: RT = 1.65 min, [M+H] + =459.26.

[0293] Example 12

[0294] Synthesis of (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(1-methyl-1H-pyrazol-5-yl)piperidin-2-yl)benzoic acid

[0295] The specific synthetic route is as follows:

[0296] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0297] To a solution of benzyl (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.42 mmol) in dioxane (10 ml) at room temperature were added 5-bromo-1-methylpyrazole (101 mg, 0.63 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (61 mg, 0.08 mmol) and potassium phosphate (182 mg, 0.84 mmol). Water (2 ml) was added, the atmosphere was replaced with nitrogen, and the temperature was raised to 90°C for reaction for 5 hours.

[0298] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 5) to obtain 120 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester as a pale yellow oily liquid (yield: 66%). LC-MS: RT = 2.15 min, [M+H] + =432.25.

[0299] Step B: Synthesis of (S)-methyl 4-(4-(1-methyl-1H-pyrazol-5-yl)piperidin-2-yl)benzoate

[0300] At room temperature, benzyl (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (120 mg, 0.28 mmol) was dissolved in ethyl acetate solution (10 ml), palladium on carbon (30 mg) was added, the hydrogen atmosphere was replaced, and the temperature was raised to 60°C for reaction overnight.

[0301] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated to give 75 mg of colorless oily liquid (S)-methyl 4-(4-(1-methyl-1H-pyrazol-5-yl)piperidin-2-yl)benzoate. LC-MS: RT = 1.60 min, [M+H] + = 300.19.

[0302] Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0303] To a solution of (S)-methyl 4-(4-(1-methyl-1H-pyrazol-5-yl)piperidin-2-yl)benzoate (50 mg, 0.17 mmol) in dichloroethane (5 ml) at room temperature were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (72 mg, 0.25 mmol) and sodium triacetoxyborohydride (50 mg, 0.24 mmol), and the mixture was heated to 40°C and reacted overnight.

[0304] After the reaction was completed, a small amount of methanol was added and the solvent was directly evaporated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to obtain 40 mg of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester as a white solid (yield: 41%). LC-MS: RT = 1.93 min, [M+H] + =573.35.

[0305] Step D: Synthesis of (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(1-methyl-1H-pyrazol-5-yl)piperidin-2-yl)benzoic acid

[0306] To a solution of tert-butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (40 mg, 0.07 mmol) in methanol (5 ml) at room temperature was added potassium carbonate (39 mg, 0.28 mmol), the mixture was heated to 70°C for 5 hours, and water (1 ml) was added and the reaction was continued for 4 hours.

[0307] After the reaction was complete, the purification method described in Step D of Example 3 was used to isolate 23 mg of (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(1-methyl-1H-pyrazol-5-yl)piperidin-2-yl)benzoic acid (yield: 72%). LC-MS: RT = 1.62 min, [M+H] +=459.26.1H NMR (400MHz, DMSO-d6) δ10.82 (s, 1H), 7.83 (d, J = 8.4Hz, 2H), 7.42 (d, J = 7.7Hz, 2H), 7.25 (t , J=2.8Hz, 1H), 7.22 (d, J=1.9Hz, 1H), 6.66 (s, 1H), 6.44 (t, J=2.5Hz, 1H), 6.00 (d, J=1.9Hz, 1H), 3.74 (d, J=8.1Hz, 6H), 3.60 (d, J=11.7Hz, 1H), 3.31-3.17 (m, 3H), 2.94-2.80 (m, 2H), 2. 42(s, 3H), 2.22-2.10(m, 1H), 1.86(d, J=12.7Hz, 1H), 1.79-1.65(m, 2H), 1.48-1.33(m, 1H).

[0308] Examples 13A and 13B

[0309] Synthesis of compounds 13A and 13B

[0310] The specific synthetic route is as follows:

[0311] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0312] At room temperature, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (940 mg, 1.88 mmol), 2-thiopheneboronic acid (482 mg, 3.76 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (137 mg, 0.188 mmol), and potassium phosphate (1.2 g, 5.65 mmol) were added to 1,4-dioxane (15 ml). Under nitrogen protection, the temperature was raised to 90°C and the reaction was carried out for 12 hours.

[0313] After the reaction was complete, ethyl acetate (30 ml) was added to dilute the mixture, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1). 402 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester were obtained as a yellow semisolid (yield 47.6%). LC-MS: RT = 2.20 min, [M+H] + =434.19.

[0314] Step B: Synthesis of (S)-methyl 4-(4-(thiophen-2-yl)piperidin-2-yl)benzoate

[0315] At room temperature, benzyl (S)-6-(4-methoxycarbonyl)phenyl)-4-(thiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (400 mg, 0.41 mmol) was dissolved in ethyl acetate (15 ml), palladium on carbon (60 mg) was added, the hydrogen atmosphere was replaced, and the temperature was raised to 60°C for reaction overnight.

[0316] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated to obtain 80 mg of colorless oily liquid (S)-methyl 4-(4-(thiophen-2-yl)piperidin-2-yl)benzoate. LC-MS: RT = 1.70 min, [M+H] + =302.20.

[0317] Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0318] To a solution of (S)-methyl 4-(4-(thiophen-2-yl)piperidin-2-yl)benzoate (80 mg, 0.27 mmol) in 1,2-dichloroethane (5 ml) at room temperature were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (118 mg, 0.41 mmol) and sodium triacetoxyborohydride (115 mg, 0.54 mmol), and the mixture was heated to 40°C and reacted overnight.

[0319] After the reaction was completed, methanol was added and the mixture was concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 1) to obtain 68 mg of (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(thien-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate as a white solid (yield: 44%). LC-MS: RT = 1.95 min, [M+H] + =575.24.

[0320] Step D: Synthesis of compounds 13A and 13B

[0321] To a solution of tert-butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (68 mg, 0.12 mmol) in methanol (5 ml) at room temperature was added potassium carbonate (82.8 mg, 0.6 mmol), the mixture was heated to 70°C and reacted for 5 hours. Water (1 ml) was added and the reaction was continued for 4 hours.

[0322] After the reaction was completed, the purification and chiral separation methods described in Step D of Example 3 were used to obtain 6 mg of the absolute configuration diastereomer 13A (yield: 14%) and 15 mg of the absolute configuration diastereomer 13B (yield: 36%).

[0323] Compound 13A: HPLC: RT = 11.7 min, LC-MS: RT = 1.66 min, [M+H] + =423.24.

[0324] Compound 13B: HPLC: RT = 14.9 min, LC-MS: RT = 1.24 min, [M+H] + =423.24.

[0325] Examples 14A and 14B

[0326] Synthesis of compounds 14A and 14B

[0327] The specific synthetic route is as follows:

[0328] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0329] At room temperature, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (940 mg, 1.88 mmol), 3-thiopheneboronic acid (482 mg, 3.76 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (137 mg, 0.188 mmol) and potassium phosphate (1.2 g, 5.65 mmol) were added to 1,4-dioxane (15 ml), and the temperature was raised to 90°C under nitrogen protection for 14 hours.

[0330] After the reaction was complete, ethyl acetate (30 ml) was added to dilute the mixture, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1). 610 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester was obtained as a yellow semisolid (yield 74%). LC-MS: RT = 2.27 min, [M+H] + =434.08.

[0331] Step B: Synthesis of (S)-methyl 4-(4-hydroxy-4-(thiophen-3-yl)piperidin-2-yl)benzoate

[0332] At room temperature, compound (S)-benzyl 6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (170 mg, 0.39 mmol) was dissolved in ethyl acetate (5 ml), cooled in an ice-water bath, and HBr / HOAc solution (2 ml) was added, and the reaction was carried out at room temperature for 1 hour.

[0333] After the reaction was complete, the mixture was cooled in an ice-water bath and quenched with ice. The pH was adjusted to 12-13 with aqueous ammonia. The mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 10 / 1). 85 mg of (S)-methyl 4-(4-hydroxy-4-(thiophen-3-yl)piperidin-2-yl)benzoate was obtained as a light yellow oil (yield 72%). LC-MS: RT = 1.58 min, [M+H] + =318.12. 1 H NMR (400MHz, CDCl3) δ8.02 (d, J=8.0Hz, 2H), 7.52 (d, J=8.0Hz, 2H), 7.33-7.30 (m, 1H), 7.26-7.22 (m, 1H), 7.19-7.16 (m, 1H), 4.32-4.27 (m, 1H), 3.92 (s, 3H), 3.39-3.32 (m, 1H), 3.21-3.16 (m, 1H), 2.23-2.15 (m, 1H), 2.01-1.90 (m, 4H).

[0334] Step C: Synthesis of (S)-tert-butyl 4-((4-hydroxy-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0335] To a solution of (S)-methyl 4-(4-hydroxy-4-(thiophen-3-yl)piperidin-2-yl)benzoate (85 mg, 0.268 mmol) in 1,2-dichloroethane (5 ml) was added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (155 mg, 0.536 mmol) at room temperature and the mixture was allowed to react for 4 hours. Then, sodium triacetoxyborohydride (284 mg, 1.34 mmol) was added and the reaction was allowed to proceed overnight.

[0336] After the reaction was completed, methanol was added and the mixture was concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to afford 55 mg of (S)-tert-butyl 4-((4-hydroxy-2-(4-(methoxycarbonyl)phenyl)-4-(thien-3-yl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate as a yellow oil (yield: 34%). LC-MS: RT = 1.89 min, [M+H] + =591.17.

[0337] Step D: Synthesis of compounds 14A and 14B

[0338] To a solution of tert-butyl (S)-4-((4-hydroxy-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (55 mg, 0.09 mmol) in methanol (5 ml) at room temperature was added potassium carbonate (130 mg, 0.9 mmol), the mixture was heated to 70°C and reacted overnight, and water (2 ml) was added and the reaction was continued for 2 hours.

[0339] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 16.4 mg of the absolute configuration diastereomer 14A (yield: 37%) and 3.9 mg of the absolute configuration diastereomer 14B (yield: 8.8%).

[0340] Compound 14A: HPLC: RT = 14.3 min, LC-MS: RT = 1.66 min, [M+H] + =477.17.

[0341] Compound 14B: HPLC: RT = 15.2 min, LC-MS: RT = 1.66 min, [M+H] + =477.17.

[0342] Example 15

[0343] Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthien-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid

[0344] The specific synthetic route is as follows:

[0345] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0346] At room temperature, compound (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 (400 mg, 0.84 mmol), 3-bromo-2-methylthiophene (178 mg, 1.01 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (62 mg, 0.83 mmol), and potassium carbonate (231 mg, 1.68 mmol) were added to 1,4-dioxane (10 ml), and water (5 ml) was added. Under nitrogen protection, the temperature was raised to 90°C and the reaction was carried out for 5 hours.

[0347] After the reaction was complete, ethyl acetate (50 ml) was added to dilute the mixture, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1). 208 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester were obtained as a yellow oil (yield 43%). LC-MS: RT = 2.29 min, [M+H] + =448.25.

[0348] Step B: Synthesis of (S)-methyl 4-(4-(2-methylthiophen-3-yl)piperidin-2-yl)benzoate

[0349] At room temperature, compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (110 mg, 0.25 mmol) was dissolved in ethyl acetate (10 ml), palladium / carbon (50 mg) was added, and the mixture was heated to 60°C under a hydrogen atmosphere and reacted overnight.

[0350] After the reaction was complete, the mixture was filtered and concentrated to obtain 60 mg of (S)-methyl 4-(4-(2-methylthiophen-3-yl)piperidin-2-yl)benzoate (crude product) as a pale yellow gum. This crude product was used directly in the next step without purification. LC-MS: RT = 1.73 min, [M+H] + =316.18.

[0351] Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0352] At room temperature, compound (S)-methyl 4-(4-(2-methylthiophen-3-yl)piperidin-2-yl)benzoate (60 mg, 0.15 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (132 mg, 0.45 mmol) were dissolved in 1,2-dichloroethane (5 ml) and stirred for 6 hours. Sodium triacetoxyborohydride (161 mg, 0.76 mmol) was added and the reaction was allowed to react overnight.

[0353] After the reaction was complete, methanol was added and the mixture was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1). 100 mg of (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthien-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (crude product) was obtained as a yellow oil and used directly in the next reaction. LC-MS: RT = 2.05 min, [M+H] + =589.29.

[0354] Step D: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid

[0355] At room temperature, compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (100 mg, 0.16 mmol, crude product) was dissolved in methanol (10 ml), potassium carbonate (235 mg, 1.7 mmol) was added, and the mixture was heated to 70°C for 3 hours. Water (2 ml) was added and the reaction was continued for 3 hours.

[0356] After the reaction was completed, the purification method in Step D of Example 3 was used to isolate 1.3 mg of a white solid (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid (yield: 1.1%).

[0357] Compound 15: HPLC: RT = 3.554 min, LC-MS: RT = 1.78 min, [M+H] + =475.25.

[0358] Example 16

[0359] Synthesis of compound (S)-4-((4-(5-bromo-2-methylthiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid

[0360] The specific synthetic route is as follows:

[0361] Step A: Synthesis of (S)-benzyl 2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)piperidine-1-carboxylate

[0362] Compound (S)-benzyl 6-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.45 mmol) was dissolved in ethyl acetate (15 ml), palladium / carbon (50 mg) was added, and the mixture was heated to 60°C under a hydrogen atmosphere for 5 hours.

[0363] After the reaction was complete, the mixture was filtered and concentrated to yield 190 mg of (S)-2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)piperidine-1-carboxylic acid benzyl ester (crude product) as a pale yellow gum. This crude product was used directly in the next step without purification. LC-MS: RT = 2.29 min, [M+H] + =450.25.

[0364] Step B: Synthesis of (S)-benzyl 4-(5-bromo-2-methylthiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate

[0365] Benzyl (S)-2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)piperidine-1-carboxylate (100 mg, 0.22 mmol) was dissolved in N,N-dimethylformamide (5 ml) at room temperature, and NBS (40 mg) was added to react overnight.

[0366] After the reaction was complete, the mixture was added to water (30 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 9 / 1) to provide 80 mg of (S)-benzyl 4-(5-bromo-2-methylthiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate as a yellow gum (yield 68%).

[0367] Step C: (S)-methyl 4-(4-(5-bromo-2-methylthiophen-3-yl)piperidin-2-yl)benzoate

[0368] Compound (S)-benzyl 4-(5-bromo-2-methylthiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (80 mg, 0.15 mmol) was dissolved in ethyl acetate (5 ml), cooled in an ice-water bath, and 33% hydrobromic acid / acetic acid solution (0.6 ml) was added. The mixture was warmed to room temperature and reacted for 2 hours.

[0369] After the reaction was complete, water was added to quench the reaction, and the mixture was adjusted to alkalinity with aqueous ammonia. The mixture was concentrated, and the resulting residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1). 30 mg of (S)-methyl 4-(4-(5-bromo-2-methylthiophen-3-yl)piperidin-2-yl)benzoate was obtained as a yellow gum (yield 50%). LC-MS: RT = 1.77 min, [M+H] + =394.05.

[0370] Step D: Synthesis of (S)-tert-butyl 4-((4-(5-bromo-2-methylthiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0371] At room temperature, compound (S)-methyl 4-(4-(5-bromo-2-methylthiophen-3-yl)piperidin-2-yl)benzoate (30 mg, 0.076 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (88 mg, 0.3 mmol) were dissolved in 1,2-dichloroethane (5 ml) and reacted overnight. Sodium triacetoxyborohydride (80 mg, 0.38 mmol) was added and reacted for 3 hours.

[0372] After the reaction was complete, methanol was added and the mixture was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1). 80 mg of (S)-tert-butyl 4-((4-(5-bromo-2-methylthiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (crude product) was obtained as a yellow oil and used directly in the next reaction. LC-MS: RT = 2.05 min, [M+H] + =669.05.

[0373] Step E: Synthesis of compound (S)-4-((4-(5-bromo-2-methylthiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid

[0374] At room temperature, compound (S)-tert-butyl 4-((4-(5-bromo-2-methylthiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (80 mg, 0.11 mmol, crude product) was dissolved in methanol (5 ml), potassium carbonate (165 mg, 1.2 mmol) was added, and the mixture was heated to 70°C for overnight. Water (2 ml) was added and the reaction was continued for 2 hours.

[0375] After the reaction was completed, the purification method in Step D of Example 3 was used to isolate 6.1 mg of a white solid (S)-4-((4-(5-bromo-2-methylthiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid (yield: 9%).

[0376] Compound 16: HPLC: RT = 11.2 min, LC-MS: RT = 1.84 min, [M+H] + =553.17.

[0377] Examples 17A and 17B

[0378] Synthesis of compounds 17A and 17B

[0379] The specific synthetic route is as follows:

[0380] Step A: Synthesis of (S)-6-(4-methoxycarbonyl)phenyl)-4-(5-methylthiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0381] To a solution of benzyl (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (300 mg, 0.63 mmol) in 1,4-dioxane (10 ml) at room temperature were added 5-methyl-3-bromothiophene (110 mg, 0.94 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (92 mg, 0.13 mmol), potassium phosphate (273 mg, 1.26 mmol) and water (2 ml). The atmosphere was replaced with nitrogen and the temperature was raised to 90°C for 5 hours.

[0382] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to obtain 200 mg of (S)-6-(4-methoxycarbonyl)phenyl)-4-(5-methylthiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester as a pale yellow oily liquid (yield: 71%). LC-MS: RT = 2.22 min, [M+H] + =448.21.

[0383] Step B: Synthesis of (S)-methyl 4-(4-(5-methylthiophen-3-yl)piperidin-2-yl)benzoate

[0384] Benzyl (S)-6-(4-methoxycarbonyl)phenyl)-4-(5-methylthiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.41 mmol) was dissolved in ethyl acetate (15 ml), palladium on carbon (70 mg) was added, the hydrogen atmosphere was replaced, and the temperature was raised to 60°C for reaction overnight.

[0385] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated to obtain 50 mg of colorless oily liquid (S)-methyl 4-(4-(5-methylthiophen-3-yl)piperidin-2-yl)benzoate. LC-MS: RT = 1.67 min, [M+H] + =316.21.

[0386] Step C: Synthesis of (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-methylthiophen-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0387] To a solution of (S)-methyl 4-(4-(5-methylthiophen-3-yl)piperidin-2-yl)benzoate (50 mg, 0.16 mmol) in 1,2-dichloroethane (5 ml) were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (69 mg, 0.24 mmol) and sodium triacetoxyborohydride (67 mg, 0.32 mmol), and the mixture was heated to 40°C and reacted overnight.

[0388] After the reaction was completed, methanol was added and the mixture was concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 1) to obtain 50 mg of (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-methylthien-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate as a white solid (yield: 53%). LC-MS: RT = 2.03 min, [M+H] + =589.33.

[0389] Step D: Synthesis of compounds 17A and 17B

[0390] To a solution of tert-butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-methylthiophen-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (50 mg, 0.09 mmol) in methanol (5 ml) was added potassium carbonate (47 mg, 0.34 mmol), the mixture was heated to 70°C for 5 hours, and water (1 ml) was added and the reaction was continued for 4 hours.

[0391] After the reaction was completed, the purification and chiral separation methods described in Step D of Example 3 were used to obtain 6 mg of the absolute configuration diastereomer 17A (yield: 14%) and 15 mg of the absolute configuration diastereomer 17B (yield: 36%).

[0392] Compound 17A: HPLC: RT = 10.7 min, LC-MS: RT = 1.79 min, [M+H] + =475.29. 1 H NMR (400MHz, DMSO-d6) δ10.80 (s, 1H), 7.81 (d, J=7.8Hz, 2H), 7.40 (d, J=7.8Hz, 2H), 7.24 (t, J =2.7Hz, 1H), 7.01 (d, J = 1.5Hz, 1H), 6.79 (s, 1H), 6.63 (s, 1H), 6.48 (dd, J = 3.0, 1.7Hz, 1H), 3.6 8 (s, 3H), 3.61 (d, J=11.9Hz, 1H), 3.45-3.41 (m, 1H), 3.25 (s, 1H), 2.96 (t, J=4.5Hz, 1H), 2.60- 2.54 (m, 1H), 2.43 (d, J=14.9Hz, 6H), 2.23-1.98 (m, 3H), 1.92-1.89 (m, 1H), 1.79-1.73 (m, 1H).

[0393] Compound 17B: HPLC: RT = 15.9 min, LC-MS: RT = 1.79 min, [M+H] + =475.31. 1H NMR (400MHz, DMSO-d6) δ10.83 (d, J=2.4Hz, 1H), 7.88 (d, J=7.9Hz, 2H), 7.49 (d, J=7.8Hz, 2H), 7.25 (t, J=2 .8Hz, 1H), 6.84 (d, J=1.4Hz, 1H), 6.72 (s, 1H), 6.65 (s, 1H), 6.47 (t, J=2.5Hz, 1H), 3.72 (s, 3H), 3.60 (d, J =11.8Hz, 1H), 3.22 (dd, J = 14.3, 10.3Hz, 2H), 2.85 (dt, J = 11.7, 3.4Hz, 1H), 2.68 (td, J = 10.4, 8.8, 6.1Hz, 1H), 2.39 (d, J=25.5Hz, 6H), 2.15-2.04 (m, 1H), 1.92-1.83 (m, 1H), 1.80-1.62 (m, 2H), 1.48-1.38 (m, 1H).

[0394] Example 18

[0395] Synthesis of (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(3-methylisothiazol-5-yl)piperidin-2-yl)benzoic acid

[0396] The specific synthetic route is as follows:

[0397] Step A: Synthesis of (S)-6-(4-methoxycarbonyl)phenyl)-4-(3-methylisothiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0398] To a solution of benzyl (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.42 mmol) in 1,4-dioxane (10 ml) at room temperature were added 3-methyl-5-bromoisothiazole (113 mg, 0.63 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (61 mg, 0.08 mmol), potassium phosphate (182 mg, 0.84 mmol) and water (2 ml). The atmosphere was replaced with nitrogen and the temperature was raised to 90°C for 5 hours.

[0399] After the reaction was complete, the product was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to afford 110 mg of (S)-benzyl (6-(4-methoxycarbonyl)phenyl)-4-(3-methylisothiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate as a pale yellow oily liquid (yield: 61%). LC-MS: RT = 2.13 min, [M+H] + =449.21.

[0400] Step B: Synthesis of (S)-methyl 4-(4-(3-methylisothiazol-5-yl)piperidin-2-yl)benzoate

[0401] Benzyl (S)-6-(4-methoxycarbonyl)phenyl)-4-(3-methylisothiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (110 mg, 0.25 mmol) was dissolved in ethyl acetate (10 ml), palladium carbon (50 mg) was added to replace hydrogen, and the temperature was raised to 60°C for reaction overnight.

[0402] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated to give 31 mg of colorless oily liquid (S)-methyl 4-(4-(3-methylisothiazol-5-yl)piperidin-2-yl)benzoate. LC-MS: RT = 1.67 min, [M+H] + =317.19.

[0403] Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(3-methylisothiazol-5-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0404] To a solution of (S)-methyl 4-(4-(3-methylisothiazol-5-yl)piperidin-2-yl)benzoate (31 mg, 0.10 mmol) in 1,2-dichloroethane (5 ml) were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (43 mg, 0.15 mmol) and sodium triacetoxyborohydride (42 mg, 0.2 mmol), and the mixture was heated to 40°C and reacted overnight.

[0405] After the reaction was completed, methanol was added and the mixture was concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to afford 18 mg of (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(3-methylisothiazol-5-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate as a white solid (yield: 31%). LC-MS: RT = 1.95 min, [M+H] + =590.33.

[0406] Step D: Synthesis of (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(3-methylisothiazol-5-yl)piperidin-2-yl)benzoic acid

[0407] To a solution of tert-butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(3-methylisothiazol-5-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (18 mg, 0.03 mmol) in methanol (5 ml) was added potassium carbonate (17 mg, 0.12 mmol), the mixture was heated to 70°C for 5 hours, and water (1 ml) was added and the reaction was continued for 4 hours.

[0408] After the reaction was complete, the purification method described in Step D of Example 3 was used to isolate 5 mg of (S)-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(3-methylisothiazol-5-yl)piperidin-2-yl)benzoic acid as a white solid (yield: 35%). LC-MS: RT = 1.70 min, [M+H] + =476.21.

[0409] Examples 19A and 19B

[0410] Synthesis of compounds 19A and 19B

[0411] The specific synthetic route is as follows:

[0412] Step A: Synthesis of (S)-6-(4-methoxycarbonyl)phenyl)-4-(2-methylthiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0413] To a solution of (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 (200 mg, 0.42 mmol) in 1,4-dioxane (10 ml) at room temperature were added 2-methyl-4-bromothiazole (113 mg, 0.63 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (61 mg, 0.08 mmol), potassium phosphate (182 mg, 0.84 mmol) and water (2 ml). The atmosphere was replaced with nitrogen and the temperature was raised to 90°C for 5 hours.

[0414] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 140 mg of (S)-6-(4-methoxycarbonyl)phenyl)-4-(2-methylthiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester as a pale yellow oily liquid (yield: 74%). LC-MS: RT = 2.10 min, [M+H] + =449.21.

[0415] Step B: Synthesis of (S)-methyl 4-(4-(2-methylthiazol-4-yl)piperidin-2-yl)benzoate

[0416] Benzyl (S)-6-(4-methoxycarbonyl)phenyl)-4-(2-methylthiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (120 mg, 0.27 mmol) was dissolved in ethyl acetate (10 ml), palladium carbon (50 mg) was added, the hydrogen atmosphere was replaced, and the temperature was raised to 60°C for reaction overnight.

[0417] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated to give 90 mg of (S)-methyl 4-(4-(2-methylthiazol-4-yl)piperidin-2-yl)benzoate as a light yellow oily liquid. LC-MS: RT = 1.63 min, [M+H] + =317.17.

[0418] Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0419] To a solution of (S)-methyl 4-(4-(2-methylthiazol-4-yl)piperidin-2-yl)benzoate (90 mg, 0.28 mmol) in 1,2-dichloroethane (5 ml) at room temperature were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (123 mg, 0.43 mmol) and sodium triacetoxyborohydride (118 mg, 0.56 mmol), and the mixture was heated to 40°C and reacted overnight.

[0420] After the reaction was completed, methanol was added and the mixture was concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to afford 45 mg of (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate as a white solid (yield: 42%). LC-MS: RT = 1.91 min, [M+H] + =589.31.

[0421] Step D: Synthesis of compounds 19A and 19B

[0422] To a solution of tert-butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (45 mg, 0.08 mmol) in methanol (5 ml) at room temperature was added potassium carbonate (42 mg, 0.31 mmol), the mixture was heated to 70°C for 5 hours, and water (1 ml) was added and the reaction was continued for 4 hours.

[0423] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 5.8 mg of the absolute configuration diastereomer 19A (yield: 15%) and 17.3 mg of the absolute configuration diastereomer 19B (yield: 46%).

[0424] Compound 19A: HPLC: RT = 13.6 min, LC-MS: RT = 1.72 min, [M+H] + =476.23.

[0425] Compound 19B: HPLC: RT = 18.5 min, LC-MS: RT = 1.72 min, [M+H] + =476.22.

[0426] Examples 20A and 20B

[0427] Synthesis of compounds 20A and 20B

[0428] The specific synthetic route is as follows:

[0429] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-difluoromethyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0430] To a solution of benzyl (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (700 mg, 1.47 mmol) in 1,4-dioxane (20 ml) at room temperature were added 4-bromo-1-difluoromethylpyrazole (433 mg, 2.20 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (214 mg, 0.29 mmol), potassium phosphate (637 mg, 2.93 mmol) and water (4 ml). The atmosphere was replaced with nitrogen and the temperature was raised to 90° C. for reaction overnight.

[0431] After the reaction was complete, the product was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1:5) to obtain 450 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-difluoromethyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester as a pale yellow oily liquid (yield: 65%). LC-MS: RT = 2.17 min, [M+H] + =468.23.

[0432] Step B: Synthesis of (S)-methyl 4-(4-(1-difluoromethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate

[0433] At room temperature, benzyl (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-difluoromethyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (450 mg, 0.96 mmol) was dissolved in ethyl acetate (20 ml), palladium on carbon (200 mg) was added to replace the hydrogen atmosphere, and the reaction was carried out at room temperature for 3 hours.

[0434] After the reaction, the mixture was filtered, washed with ethyl acetate, and the liquid phase was directly concentrated under reduced pressure to obtain 330 mg of colorless oily liquid (S)-methyl 4-(4-(1-difluoromethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate. LC-MS: RT = 1.68 min, [M+H] + =336.21.

[0435] Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-difluoromethyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0436] To a solution of (S)-methyl 4-(4-(1-difluoromethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate (330 mg, 0.98 mmol) in 1,2-dichloroethane (5 ml) at room temperature were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (427 mg, 1.48 mmol) and sodium triacetoxyborohydride (848 mg, 4.00 mmol), and the mixture was heated to 40°C and reacted overnight.

[0437] After the reaction was completed, methanol was added and the mixture was concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane = 1:1) to afford 310 mg of (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-difluoromethyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate as a white solid (yield: 52%). LC-MS: RT = 1.97 min, [M+H] + =608.34

[0438] Step D: Synthesis of compounds 20A and 20B

[0439] To a solution of tert-butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-difluoromethyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (310 mg, 0.51 mmol) in methanol (15 ml) at room temperature was added potassium carbonate (284 mg, 2.04 mmol), the mixture was heated to 70°C for 5 hours, and water (3 ml) was added and the reaction was continued for 4 hours.

[0440] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate and obtain 38 mg of the absolute configuration diastereomer 20A (yield: 15%) and 120 mg of the absolute configuration diastereomer 20B (yield: 48%).

[0441] Compound 20A: HPLC: RT = 8.5 min, LC-MS: RT = 1.63 min, [M+H] + =495.27. 1 H NMR (400MHz, DMSO-d6) δ10.80 (s, 1H), 8.16 (s, 1H), 7.84-7.77 (m, 3H), 7.40 (d, J= 7.8Hz, 2H), 7.24 (t, J=2.7Hz, 1H), 6.63 (s, 1H), 6.48 (dd, J=3.1, 1.7Hz, 1H), 3.68 (s, 3H), 3.58 (d, J=11.9Hz, 1H), 3.19 (d, J=11.9Hz, 1H), 3.03 (s, 1H), 2.56 (dd, J= 9.7, 6.0Hz, 1H), 2.52 (s, 2H), 2.41 (s, 3H), 2.17-2.02 (m, 3H), 1.90-1.75 (m, 2H).

[0442] Compound 20B: HPLC: RT = 13.6 min, LC-MS: RT = 1.63 min, [M+H] + =495.27.1 H NMR (400MHz, DMSO-d6) δ10.85 (t, J=2.2Hz, 1H), 8.00 (s, 1H), 7.88 (d, J=7.9Hz, 2H), 7.68 (d, J=7.1Hz, 2H) , 7.54-7.45 (m, 2H), 7.25 (t, J=2.8Hz, 1H), 6.66 (s, 1H), 6.47 (t, J=2.5Hz, 1H), 3.72 (s, 3H), 3.60 (d, J=11. 8Hz, 2H), 3.23 (dd, J=15.8, 10.1Hz, 2H), 2.85 (dt, J=11.7, 3.3Hz, 1H), 2.73-2.63 (m, 1H), 2.43 (s, 3H), 2.1 5-2.06 (m, 1H), 1.95 (d, J=12.6Hz, 1H), 1.79 (d, J=13.0Hz, 1H), 1.66 (q, J=12.2Hz, 1H), 1.50-1.35 (m, 1H).

[0443] Examples 21A and 21B

[0444] Synthesis of compounds 21A and 21B

[0445] The specific synthetic route is as follows:

[0446] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-ethyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0447] To a solution of benzyl (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, 2.10 mmol) in 1,4-dioxane (20 ml) at room temperature were added 4-bromo-1-ethylpyrazole (546 mg, 3.14 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (306 mg, 0.42 mmol), potassium phosphate (910 mg, 4.19 mmol) and water (4 ml). The atmosphere was replaced with nitrogen and the temperature was raised to 90°C for reaction overnight.

[0448] After the reaction was complete, the product was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 5) to obtain 550 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-ethyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester as a pale yellow oily liquid (yield: 59%). LC-MS: RT = 2.20 min, [M+H] + =446.25.

[0449] Step B: Synthesis of (S)-methyl 4-(4-(1-ethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate

[0450] At room temperature, benzyl (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-ethyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (550 mg, 1.23 mmol) was dissolved in ethyl acetate (20 ml), palladium on carbon (105 mg) was added to replace the hydrogen, and the temperature was raised to 60°C for reaction for 3 hours.

[0451] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated to give 450 mg of colorless oily liquid (S)-methyl 4-(4-(1-ethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate. LC-MS: RT = 1.65 min, [M+H] + =314.23.

[0452] Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-ethyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0453] To a solution of (S)-methyl 4-(4-(1-ethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate (450 mg, 1.42 mmol) in 1,2-dichloroethane (10 ml) at room temperature were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (617 mg, 2.14 mmol) and sodium triacetoxyborohydride (602 mg, 2.84 mmol), and the mixture was heated to 40°C and reacted overnight.

[0454] After the reaction was completed, methanol was added and the mixture was concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to obtain 410 mg of (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-ethyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate as a white solid (yield: 46%). LC-MS: RT = 2.00 min, [M+H] + =587.37.

[0455] Step D: Synthesis of compounds 21A and 21B

[0456] To a solution of tert-butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-ethyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (350 mg, 0.59 mmol) in methanol (15 ml) at room temperature was added potassium carbonate (330 mg, 2.38 mmol), the mixture was heated to 70°C for 5 hours, and water (3 ml) was added and the reaction was continued for 4 hours.

[0457] After the reaction was completed, the purification method and chiral separation method in Step D of Example 3 were used to separate and obtain 19 mg of the absolute configuration diastereomer 21A (yield: 7%) and 198 mg of the absolute configuration diastereomer 21B (yield: 70%).

[0458] Compound 21A: HPLC: RT = 12.4 min, LC-MS: RT = 1.70 min, [M+H] + =473.33.

[0459] Compound 21B: HPLC: RT = 16.7 min, LC-MS: RT = 1.70 min, [M+H] + =473.34.

[0460] Examples 22A and 22B

[0461] Synthesis of compounds 22A and 22B

[0462] The specific synthetic route is as follows:

[0463] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-isopropyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0464] To a solution of benzyl (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, 2.10 mmol) in 1,4-dioxane (20 ml) at room temperature were added 4-bromo-1-isopropylpyrazole (546 mg, 3.14 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (306 mg, 0.42 mmol), potassium phosphate (910 mg, 4.19 mmol), water (4 ml), the atmosphere was replaced with nitrogen, and the temperature was raised to 90°C for reaction overnight.

[0465] After the reaction was complete, the product was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1:5) to obtain 570 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-isopropyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester as a pale yellow oily liquid (yield: 59%). LC-MS: RT = 2.15 min, [M+H] + =460.27.

[0466] Step B: Synthesis of (S)-methyl 4-(4-(1-isopropyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate

[0467] At room temperature, benzyl (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-isopropyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (570 mg, 1.24 mmol) was dissolved in ethyl acetate (20 ml), palladium on carbon (200 mg) was added to replace the hydrogen atmosphere, and the reaction was carried out at room temperature for 3 hours.

[0468] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated to obtain 330 mg of colorless oily liquid (S)-methyl 4-(4-(1-isopropyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate. LC-MS: RT = 1.64 min, [M+H] + =328.23.

[0469] Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-isopropyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0470] To a solution of (S)-methyl 4-(4-(1-isopropyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate (330 mg, 1.01 mmol) in 1,2-dichloroethane (5 ml) at room temperature were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (438 mg, 1.51 mmol) and sodium triacetoxyborohydride (856 mg, 4.04 mmol), and the mixture was heated to 40°C and reacted overnight.

[0471] After the reaction was completed, methanol was added and the mixture was concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane = 1:1) to afford 400 mg of (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-isopropyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate as a white solid (yield: 46%). LC-MS: RT = 1.97 min, [M+H] + =601.37

[0472] Step D: Synthesis of compounds 22A and 22B

[0473] To a solution of tert-butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-isopropyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (400 mg, 0.67 mmol) in methanol (15 ml) at room temperature was added potassium carbonate (371 mg, 2.67 mmol), the mixture was heated to 70°C for 5 hours, and water (3 ml) was added and the reaction was continued for 4 hours.

[0474] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate and obtain 23 mg of the absolute configuration diastereomer 22A (yield: 7%) and 217 mg of the absolute configuration diastereomer 22B (yield: 66%).

[0475] Compound 22A: HPLC: RT = 9.2 min, LC-MS: RT = 1.65 min, [M+H] + =487.24. 1H NMR (400MHz, DMSO-d6) δ10.79 (s, 1H), 7.80 (d, J=8.1Hz, 2H), 7.64 (s, 1H), 7.39 (d, J=7.8Hz, 2H), 7. 35 (s, 1H), 7.24 (t, J = 2.7Hz, 1H), 6.63 (s, 1H), 6.49 (dd, J = 3.1, 1.7Hz, 1H), 4.49 (p, J = 6.6Hz, 1H), 3 .68 (s, 3H), 3.58 (d, J = 11.9Hz, 1H), 3.39 (d, J = 4.5Hz, 2H), 3.20 (d, J = 12.0Hz, 1H), 2.98 (d, J = 4.5Hz , 1H), 2.41 (s, 3H), 2.19-2.10 (m, 1H), 2.05-1.98 (m, 2H), 1.81-1.73 (m, 2H), 1.44 (d, J=6.7Hz, 6H).

[0476] Compound 22B: HPLC: RT = 15.6 min, LC-MS: RT = 1.65 min, [M+H] + =487.24. 1 H NMR (400MHz, DMSO-d6) δ10.84 (t, J=2.3Hz, 1H), 7.93-7.85 (m, 2H), 7.53 (d, J=11.1Hz, 3H), 7.29-7.1 9 (m, 2H), 6.66 (s, 1H), 6.48 (dd, J=3.1, 1.9Hz, 1H), 4.36 (p, J=6.6Hz, 1H), 3.72 (s, 3H), 3.60 (d, J=11. 8Hz, 1H), 3.23 (dd, J=18.1, 10.1Hz, 2H), 2.84 (dt, J=11.9, 3.3Hz, 1H), 2.67-2.56 (m, 1H), 2.42 (s, 3H) , 2.16-2.05(m, 1H), 1.95-1.87(m, 1H), 1.80-1.72(m, 1H), 1.61(q, J=12.2Hz, 1H), 1.45-1.25(m, 7H).

[0477] Examples 23A and 23B

[0478] Synthesis of compounds 23A and 23B

[0479] The specific synthetic route is as follows:

[0480] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0481] To a solution of benzyl (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (900 mg, 1.89 mmol) in 1,4-dioxane (20 ml) at room temperature were added 4-bromo-1-cyclopropylpyrazole (534 mg, 2.83 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (276 mg, 0.38 mmol), potassium phosphate (821 mg, 3.78 mmol) and water (4 ml). The atmosphere was replaced with nitrogen and the temperature was raised to 90°C for reaction overnight.

[0482] After the reaction was complete, the product was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane = 1:5) to afford 700 mg of (S)-benzyl 6-(4-(methoxycarbonyl)phenyl)-4-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate as a pale yellow oily liquid (yield: 81%). LC-MS: RT = 2.18 min, [M+H] + =458.26.

[0483] Step B: Synthesis of (S)-methyl 4-(4-(1-cyclopropyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate

[0484] At room temperature, benzyl (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (700 mg, 1.53 mmol) was dissolved in ethyl acetate (20 ml), palladium on carbon (200 mg) was added to replace the hydrogen atmosphere, and the reaction was carried out at room temperature for 3 hours.

[0485] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated to obtain 500 mg of colorless oily liquid (S)-methyl 4-(4-(1-cyclopropyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate. LC-MS: RT = 1.63 min, [M+H] + =326.23.

[0486] Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-cyclopropyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0487] To a solution of (S)-methyl 4-(4-(1-cyclopropyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate (550 mg, 1.53 mmol) in 1,2-dichloroethane (10 ml) at room temperature were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (665 mg, 2.30 mmol) and sodium triacetoxyborohydride (661 mg, 3.12 mmol), and the mixture was heated to 40°C and reacted overnight.

[0488] After the reaction was complete, 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 afford 350 mg of (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-cyclopropyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate as a white solid (yield: 38%). LC-MS: RT = 1.98 min, [M+H] + =599.36.

[0489] Step D: Synthesis of compounds 23A and 23B

[0490] To a solution of tert-butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-cyclopropyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (350 mg, 0.58 mmol) in methanol (15 ml) at room temperature was added potassium carbonate (325 mg, 2.34 mmol), the mixture was heated to 70°C for 5 hours, and water (3 ml) was added and the reaction was continued for 4 hours.

[0491] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate and obtain 30 mg of the absolute configuration diastereomer 23A (yield: 11%) and 140 mg of the absolute configuration diastereomer 23B (yield: 50%).

[0492] Compound 23A: HPLC: RT = 9.7 min, LC-MS: RT = 1.65 min, [M+H] + =485.34. 1H NMR (400MHz, DMSO-d6) δ10.79 (s, 1H), 7.81 (d, J = 7.8Hz, 2H), 7.68 (s, 1H), 7.39 (d, J = 7.8Hz, 2H), 7.33 (s, 1H), 7.24 (t, J=2.7Hz, 1H), 6.63 (s, 1H), 6.48 (t, J=2.3Hz, 1H), 3.73 (dt, J=7.4, 3.6Hz, 1H), 3.68 ( s, 3H), 3.57 (d, J=12.0Hz, 1H), 3.19 (d, J=11.9Hz, 1H), 2.95 (t, J=4.2Hz, 1H), 2.55 (s, 2H), 2.41 (s, 3H ), 2.13 (d, J=9.5Hz, 1H), 2.04-1.96 (m, 2H), 1.79-1.72 (m, 2H), 1.11-1.02 (m, 2H), 0.97-0.93 (m, 2H).

[0493] Compound 23B: HPLC: RT = 14.3 min, LC-MS: RT = 1.65 min, [M+H] + =485.34. 1 H NMR (400MHz, DMSO-d6) δ10.83 (t, J=2.3Hz, 1H), 7.93 (d, J=7.9Hz, 2H), 7.58 (d, J=7.8Hz, 2H), 7.53 (s, 1H) , 7.30-7.20 (m, 2H), 6.66 (s, 1H), 6.47 (t, J=2.5Hz, 1H), 3.72 (s, 3H), 3.59 (d, J=3.9Hz, 1H), 3.30-3.17 (m, 3H), 2.83 (dt, J=11.6, 3.3Hz, 1H), 2.59 (td, J=10.2, 8.3, 6.0Hz, 1H), 2.17-2.02 (m, 1H), 1.95-1.86 (m, 1H) , 1.74 (d, J=12.4Hz, 1H), 1.59 (q, J=12.2Hz, 1H), 1.42-1.30 (m, 1H), 0.99-0.90 (m, 2H), 0.87-0.82 (m, 2H).

[0494] Examples 24A and 24B

[0495] Synthesis of compounds 24A and 24B

[0496] The specific synthetic route is as follows:

[0497] Step A: Synthesis of (S)-benzyl 6-(4-(methoxycarbonyl)phenyl)-4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0498] At room temperature, compound (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 (1.0 g, 2.1 mmol), 4-bromo-1-(2-methoxyethyl)-1H-pyrazole (648.3 mg, 3.1 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (307 mg, 0.4 mmol) and potassium phosphate (912 mg, 4.2 mmol) were added to 1,4-dioxane (30 ml) and water (6 ml), and the temperature was raised to 95° C. under nitrogen protection for 12 hours.

[0499] After the reaction was complete, ethyl acetate (50 ml) was added to dilute the mixture, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1). 532 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester were obtained as a yellow oil (yield 53.3%). LC-MS: RT = 2.05 min, [M+H] + =476.25.

[0500] Step B: Synthesis of (S)-methyl 4-(4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)piperidin-2-yl)benzoate

[0501] At room temperature, compound (S)-benzyl 6-(4-(methoxycarbonyl)phenyl)-4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (532 mg, 1.12 mmol) was dissolved in ethyl acetate (20 ml), palladium / carbon (600 mg) was added, and the reaction was carried out at room temperature under a hydrogen atmosphere overnight.

[0502] After the reaction was complete, the mixture was filtered and concentrated to obtain 300 mg of a pale yellow oily product, methyl (S)-4-(4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)piperidin-2-yl)benzoate (crude product), which was used directly in the next reaction. LC-MS: RT = 1.56 min, [M+H] + =344.25.

[0503] Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0504] At room temperature, compound (S)-methyl 4-(4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)piperidin-2-yl)benzoate (300 mg, 0.87 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (502 mg, 1.74 mmol) were dissolved in 1,2-dichloroethane (5 ml). The mixture was stirred at room temperature for 1 hour, and sodium triacetoxyborohydride (553.1 mg, 2.61 mmol) was added. The temperature was raised to 40°C and the reaction was allowed to proceed overnight.

[0505] After the reaction was complete, methanol was added and the mixture was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1). 350 mg of brown solid (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was obtained (yield 65.3%). LC-MS: RT = 1.89 min, [M+H] + =617.41.

[0506] Step D: Synthesis of compounds 24A and 24B

[0507] At room temperature, compound (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)piperidin-1-yl))methyl)-7-methyl-1H-indole-1-carboxylate (350 mg, 0.56 mmol) was dissolved in methanol (10 ml), potassium carbonate (313 mg, 2.2 mmol) was added, and the mixture was heated to 70°C for overnight. Water (2 ml) was added and the reaction was continued for 2 hours.

[0508] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 22 mg of the absolute configuration diastereomer 24A (yield: 7.8%) and 118 mg of the absolute configuration diastereomer 24B (yield: 41.9%).

[0509] Compound 24A: HPLC: RT = 3.214 min, LC-MS: RT = 1.63 min, [M+H] + =503.35.

[0510] 1H NMR (400MHz, DMSO-d6) δ10.81 (s, 1H), 7.81 (d, J=7.8Hz, 2H), 7.63 (s, 1H), 7.42-7.34 (m, 3H), 7 .24(t, J=2.7Hz, 1H), 6.63(s, 1H), 6.47(dd, J=3.0, 1.8Hz, 1H), 4.32-4.23(m, 2H), 3.76-3.65( m, 5H), 3.57 (d, J = 11.9Hz, 1H), 3.26 (s, 3H), 3.17 (d, J = 11.9Hz, 1H), 2.98 (d, J = 5.7Hz, 1H), 2.5 5 (s, 2H), 2.41 (s, 3H), 2.15 (dt, J=12.3, 7.2Hz, 1H), 2.05-1.93 (m, 2H), 1.77 (d, J=5.0Hz, 2H).

[0511] Compound 24B: HPLC: RT = 3.217 min, LC-MS: RT = 1.63 min, [M+H] + =503.35

[0512] 1 H NMR (400MHz, DMSO-d6) δ10.81 (t, J=2.3Hz, 1H), 7.83 (d, J=7.8Hz, 2H), 7.47-7.38 (m, 3H), 7.27-7.20 (m, 2H), 6.64 (s, 1H), 6.47 (dd, J=3.1, 1.9Hz, 1H), 4.11 (t, J=5.4Hz, 2H), 3.71 (s, 3H), 3.64-3.54 (m, 3H), 3.20 (t, J=5.6Hz, 1H), 3.17 (s, 4H), 2.85-2.77 (m, 1H), 2.62-2.56 (m, 1H) 2.41 (s, 3H), 2.07 (t, J =11.9Hz, 1H), 1.88 (d, J = 12.6Hz, 1H), 1.82-1.70 (m, 1H), 1.59 (q, J = 12.2Hz, 1H), 1.42-1.28 (m, 1H).

[0513] Examples 25A and 25B

[0514] Synthesis of compounds 25A and 25B

[0515] The specific synthetic route is as follows:

[0516] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0517] To a solution of benzyl (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, 2.1 mmol) in 1,4-dioxane (10 ml) at room temperature were added 4-bromo-1-methyl-1H-pyrazole (514 mg, 3.15 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (154 mg, 0.21 mmol), potassium phosphate (1.11 g, 5.25 mmol) and water (2 ml). The atmosphere was replaced with nitrogen and the temperature was raised to 90°C for reaction overnight.

[0518] After the reaction was complete, the product was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1) to afford 560 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester as a pale yellow oily liquid (yield: 62%). LC-MS: RT = 2.04 min, [M+H] + =432.22.

[0519] Step B: Synthesis of (S)-methyl 4-(1-methyl-1H-pyrazol-4-yl)piperidin-2-ylbenzoate

[0520] At room temperature, benzyl (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (560 mg, 1.30 mmol) was dissolved in ethyl acetate (10 ml), palladium on carbon (50 mg) was added to replace the hydrogen atmosphere, and the reaction was carried out at room temperature for 4 hours.

[0521] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated to obtain 350 mg of a light yellow oily liquid (S)-methyl 4-(1-methyl-1H-pyrazol-4-yl)piperidin-2-ylbenzoate (yield: 90%). LC-MS: RT = 1.52 min, [M+H] + =300.23.

[0522] Step C: Synthesis of tert-butyl 5-cyclopropyl-4-((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0523] To a solution of (S)-methyl 4-(1-methyl-1H-pyrazol-4-yl)piperidin-2-ylbenzoate (200 mg, 0.67 mmol) in 1,2-dichloroethane (5 ml) were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (215 mg, 1.01 mmol) and sodium triacetoxyborohydride (284 mg, 1.34 mmol), and the mixture was heated to 40°C and reacted overnight.

[0524] After the reaction was complete, methanol was added and the mixture was concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to afford 95 mg of tert-butyl 5-cyclopropyl-4-((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate as a pale yellow oil (yield: 24%). LC-MS: RT = 1.91 min, [M+H] + =583.38.

[0525] Step D: Synthesis of compounds 25A and 25B

[0526] To a solution of tert-butyl 5-cyclohexyl-4-((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (95 mg, 0.16 mmol) in methanol (5 ml) was added potassium carbonate (88 mg, 0.64 mmol), the mixture was heated to 70°C for 5 hours, and water (1 ml) was added and the reaction was continued for 4 hours.

[0527] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 12.3 mg of the absolute configuration diastereomer 25A (yield: 16%) and 30.9 mg of the absolute configuration diastereomer 25B (yield: 41%).

[0528] Compound 25A: HPLC: RT = 3.285 min, LC-MS: RT = 1.66 min, [M+H] + =469.30.

[0529] Compound 25B: HPLC: RT = 3.303 min, LC-MS: RT = 1.66 min, [M+H] + =469.30. 1H NMR (400MHz, DMSO-d6) δ10.83 (s, 1H), 7.82-7.75 (m, 2H), 7.45 (s, 1H), 7.35 (d, J=7.7Hz, 2H), 7.23 (s, 1H), 7.22 (d, J=2.7Hz, 1H), 6.55 (dd, J=3.1, 1.7Hz, 1H), 6.43 (s, 1H), 3.81 (d, J=12.0Hz, 1H), 3.72 (s, 3H), 3.27 (d, J=11.9Hz, 2H), 3.21 (dd, J=11.2, 2.7Hz, 1H), 2.79-2.72(m, 1H), 2.65-2.55(m, 1H), 2.35(s, 3H), 2.25-2.17(m, 1H), 2.15-2.05(m, 1H), 1.88(d, J=12.8Hz, 1H), 1.72-1.62 (m, 1H), 1.37 (dd, J=12.6, 3.4Hz, 1H), 0.84-0.75 (m, 1H), 0.72-0.64 (m, 1H), 0.60-0.52 (m, 1H), 0.19-0.11 (m, 1H).

[0530] Examples 26A and 26B

[0531] Synthesis of compounds 26A and 26B

[0532] The specific synthetic route is as follows:

[0533] Step A: Synthesis of 4-bromo-1-(deuterated methyl)-1H-pyrazole

[0534] Compound 4-bromo-1H-pyrazole (1.0 g, 6.8 mmol) and deuterated iodomethane (1.1 g, 7.53 mmol) were dissolved in N,N-dimethylformamide (10 ml), cooled to 0°C, sodium hydride (324 mg, 8.1 mmol) was added, and the mixture was heated to room temperature for 12 hours.

[0535] After the reaction was complete, ice water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10 / 1). 530 mg of 4-bromo-1-(deuterated methyl)-1H-pyrazole was obtained as a yellow oil (yield 48.1%). LC-MS: RT = 1.66 min, [M+H] + =164.04.

[0536] Step B: Synthesis of (S)-benzyl 6-(4-(methoxycarbonyl)phenyl)-4-(1-(deuterated methyl)-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0537] Compound (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 (900 mg, 1.89 mmol), 4-bromo-1-(deuterated methyl)-1H-pyrazole (463 mg, 2.8 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (276 mg, 0.38 mmol), and potassium phosphate (820 mg, 3.8 mmol) were added to 1,4-dioxane (20 ml) and water (4 ml), and the temperature was raised to 95° C. under nitrogen protection for 12 hours.

[0538] After the reaction was complete, ethyl acetate (50 ml) was added to dilute the mixture, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1). 400 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-(deuterated methyl)-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester was obtained as a yellow oil (yield 48.7%). LC-MS: RT = 2.04 min, [M+H] + =435.28.

[0539] Step C: Synthesis of (S)-methyl 4-(4-(1-(deuterated methyl)-1H-pyrazol-4-yl)piperidin-2-yl)benzoate

[0540] Compound (S)-benzyl 6-(4-(methoxycarbonyl)phenyl)-4-(1-(deuterated methyl)-1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (400 mg, 0.92 mmol) was dissolved in ethyl acetate (20 ml), palladium / carbon (400 mg) was added, and the mixture was reacted at room temperature under a hydrogen atmosphere overnight.

[0541] After the reaction was complete, the mixture was filtered and concentrated to obtain 250 mg of a pale yellow oily product, methyl (S)-4-(4-(1-(deuterated methyl)-1H-pyrazol-4-yl)piperidin-2-yl)benzoate (crude product), which was used directly in the next step without purification. LC-MS: RT = 1.54 min, [M+H] + =303.24.

[0542] Step D: Synthesis of (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-(deuterated methyl)-1H-pyrazol-4-yl)piperidin-1-yl))methyl)-7-methyl-1H-indole-1-carboxylate

[0543] Compound (S)-methyl 4-(4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)piperidin-2-yl)benzoate (250 mg, 0.82 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (578 mg, 2.0 mmol) were dissolved in 1,2-dichloroethane (5 ml), stirred at room temperature for 1 hour, sodium triacetoxyborohydride (343.3 mg, 1.64 mmol) was added, and the temperature was raised to 40°C and the reaction was continued overnight.

[0544] After the reaction was complete, methanol was added and the mixture was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 2). 280 mg of brown solid (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-(deuterated methyl)-1H-pyrazol-4-yl)piperidin-1-yl))methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was obtained (yield 59.3%). LC-MS: RT = 1.88 min, [M+H] + =576.42.

[0545] Step E: Synthesis of compounds 26A and 26B

[0546] Compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)piperidin-1-yl))methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (280 mg, 0.48 mmol) was dissolved in methanol (12 ml), potassium carbonate (268.7 mg, 1.9 mmol) was added, and the mixture was heated to 70°C for overnight reaction. Water (2 ml) was added and the reaction was continued for 2 hours.

[0547] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 25 mg of the absolute configuration diastereomer 26A (yield: 11.3%) and 160 mg of the absolute configuration diastereomer 26B (yield: 72.3%).

[0548] Compound 26A: HPLC: RT = 3.160 min, LC-MS: RT = 1.61 min, [M+H] + =462.30.

[0549] 1H NMR (400MHz, DMSO-d6) δ10.79 (s, 1H), 7.80 (d, J=7.9Hz, 2H), 7.60 (s, 1H), 7.38 (d, J=7.7H z, 2H), 7.32 (s, 1H), 7.23 (t, J=2.7Hz, 1H), 6.62 (s, 1H), 6.50-6.44 (m, 1H), 3.67 (s, 3H), 3 .56(d, J=11.9Hz, 1H), 3.16(d, J=11.9Hz, 1H), 3.00-2.94(m, 1H), 2.55(s, 2H), 2.40(s, 3H ), 2.13 (dt, J=12.0, 7.2Hz, 1H), 1.98 (td, J=13.9, 12.1, 6.8Hz, 2H), 1.75 (p, J=3.9Hz, 2H).

[0550] Compound 26B: HPLC: RT = 3.190 min, LC-MS: RT = 1.61 min, [M+H] + =462.30.

[0551] 1 H NMR (400MHz, DMSO-d6) δ10.83 (t, J=2.3Hz, 1H), 7.82 (d, J=7.8Hz, 2H), 7.45-7.36 (m, 3H), 7.26-7.20 ( m, 2H), 6.64 (s, 1H), 6.46 (dd, J=3.1, 1.9Hz, 1H), 3.71 (s, 3H), 3.58 (d, J=11.8Hz, 1H), 3.18 (dd, J=11. 4, 2.9Hz, 2H), 2.81 (dt, J=11.6, 3.3Hz, 1H), 2.65-2.52 (m, 1H), 2.41 (s, 3H), 2.07 (dd, J=13.2, 10.7Hz , 1H), 1.88 (d, J=12.7Hz, 1H), 1.73 (dd, J=14.2, 4.5Hz, 1H), 1.60 (q, J=12.2Hz, 1H), 1.42-1.29 (m, 1H).

[0552] Examples 27A and 27B

[0553] Synthesis of compounds 27A and 27B

[0554] The specific synthetic route is as follows:

[0555] Step A: Synthesis of (S)-4-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0556] Compound (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 (1.0 g, 2.1 mmol), 4-bromo-1,3-dimethyl-1H-pyrazole (550 mg, 3.1 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (307 mg, 0.4 mmol), and potassium phosphate (912 mg, 4.2 mmol) were added to 1,4-dioxane (30 ml) and water (6 ml), and the temperature was raised to 95°C under nitrogen protection for 12 hours.

[0557] After the reaction was complete, ethyl acetate (50 ml) was added to dilute the mixture, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1). 400 mg of (S)-benzyl 4-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate was obtained as a yellow oil (yield 42.8%). LC-MS: RT = 2.05 min, [M+H] + =446.27.

[0558] Step B: Synthesis of (S)-methyl 4-(4-(1,3-dimethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate

[0559] Compound (S)-benzyl 4-(1,3-dimethyl-1H-pyrazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (400 mg, 0.9 mmol) was dissolved in ethyl acetate (20 ml), palladium / carbon (400 mg) was added, and the mixture was reacted at room temperature under a hydrogen atmosphere overnight.

[0560] After the reaction was complete, the mixture was filtered and concentrated to obtain 270 mg of (S)-methyl 4-(4-(1,3-dimethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate (crude product) as a pale yellow oil, which was used directly in the next step without purification. LC-MS: RT = 1.54 min, [M+H] + =314.24.

[0561] Step C: Synthesis of (S)-tert-butyl 4-((4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0562] Compound (S)-methyl 4-(4-(1,3-dimethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate (270 mg, 0.86 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (500 mg, 1.72 mmol) were dissolved in 1,2-dichloroethane (5 ml), stirred at room temperature for 1 hour, sodium triacetoxyborohydride (546.8 mg, 2.58 mmol) was added, and the temperature was raised to 40°C to react overnight.

[0563] After the reaction was complete, methanol was added and the mixture was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1). 290 mg of (S)-tert-butyl 4-((4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate was obtained as a brown solid (yield 57.5%). LC-MS: RT = 1.89 min, [M+H] + =587.41.

[0564] Step D: Synthesis of compounds 27A and 27B

[0565] Compound (S)-tert-butyl 4-((4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (290 mg, 0.5 mmol) was dissolved in methanol (10 ml), potassium carbonate (276 mg, 2.0 mmol) was added, and the mixture was heated to 70°C for overnight reaction. Water (2 ml) was added and the reaction was continued for 2 hours.

[0566] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 20 mg of the absolute configuration diastereomer 27A (yield: 8.4%) and 100 mg of the absolute configuration diastereomer 27B (yield: 42.3%).

[0567] Compound 27A: HPLC: RT = 13.1 min, LC-MS: RT = 1.63 min, [M+H] + =473.30.

[0568] 1H NMR (400MHz, DMSO-d6) δ10.80 (s, 1H), 7.79 (d, J=7.9Hz, 2H), 7.66 (s, 1H), 7.41 (d, J=7.8Hz, 2H), 7 .24 (t, J=2.7Hz, 1H), 6.63 (s, 1H), 6.51 (dd, J=3.0, 1.8Hz, 1H), 3.78 (s, 3H), 3.69 (s, 3H), 3.66 (d, J =11.9Hz, 1H), 3.53 (dd, J = 10.1, 3.1Hz, 1H), 2.89 (d, J = 4.8Hz, 1H), 2.61-2.53 (m, 2H), 2.41 (s, 3H) , 2.21 (t, J=10.9Hz, 1H), 2.02 (s, 4H), 1.85 (d, J=13.5Hz, 1H), 1.70 (s, 1H), 1.60 (d, J=13.1Hz, 1H).

[0569] Compound 27B: HPLC: RT = 13.58 min, LC-MS: RT = 1.63 min, [M+H] + =473.30.

[0570] 1 H NMR (400MHz, DMSO-d6) δ10.82 (t, J=2.3Hz, 1H), 7.84 (d, J=7.9Hz, 2H), 7.44 (d, J=7.7Hz, 2H), 7.31 (s, 1H), 7.24 (t, J=2.8Hz, 1H), 6.64 (s, 1H), 6.46 (dd, J=3.1, 1.9Hz, 1H), 3.71 (s, 3H), 3. 62(s, 4H), 3.25-3.15(m, 3H), 2.85-2.77(m, 1H), 2.41(s, 3H), 2.14-2.07(m, 1H), 2.05(s, 3H) , 1.82-1.73 (m, 1H), 1.64 (dd, J=12.0, 6.2Hz, 1H), 1.57 (d, J=12.2Hz, 1H), 1.39-1.25 (m, 1H).

[0571] Examples 28A and 28B

[0572] Synthesis of compounds 28A and 28B

[0573] The specific synthetic route is as follows:

[0574] Step A: Synthesis of (S)-4-(1,5-dimethyl-1H-pyrazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0575] A mixed solution of 1,4-dioxane and water (35 ml, 1,4-dioxane:water=6:1) containing benzyl (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.0 g, 2.09 mmol), 4-bromo-1,5-dimethyl-1H-pyrazole (550.0 mg, 3.14 mmol), [1,1′-bis(triphenylphosphino)ferrocene]dichloropalladium (154.0 mg, 0.21 mmol) and potassium phosphate (890.0 mg, 4.19 mmol) was heated to 90°C under nitrogen protection for 12 hours.

[0576] After the reaction was complete, water was added and the mixture was extracted with ethyl acetate (20 ml x 4). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to obtain 500 mg of (S)-benzyl 4-(1,5-dimethyl-1H-pyrazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate as a yellow gum (yield: 54%). LC-MS: RT = 2.05 min, [M+H] + =446.23.

[0577] Step B: Synthesis of (S)-methyl 4-(4-(1,5-dimethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate

[0578] At room temperature, palladium on carbon (150 mg) was added to ethyl acetate (20 ml) containing (S)-4-(1,5-dimethyl-1H-pyrazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (500 mg, 1.12 mmol), and the hydrogen was replaced three times. The reaction was carried out at room temperature under hydrogen protection for 8 hours.

[0579] After the reaction was complete, the mixture was filtered and the filtrate was dried to give 350 mg of yellow-brown oily (S)-methyl 4-(4-(1,5-dimethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate (yield: 100%). LC-MS: RT = 1.55 min, [M+H] + =314.25.

[0580] Step D: Synthesis of (S)-tert-butyl 4-((4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0581] Methyl (S)-4-(4-(1,5-dimethyl-1H-pyrazol-4-yl)piperidin-2-yl)benzoate (350.0 mg, 1.12 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (650.0 mg, 2.24 mmol) were dissolved in 1,2-dichloroethane (15 ml) and reacted at room temperature overnight. Sodium triacetoxyborohydride (710 mg, 3.35 mmol) was added and reacted for 5 hours.

[0582] After the reaction was complete, methanol was added, the sample was spin-dried, and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 2) to obtain 390.0 mg of (S)-tert-butyl 4-((4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate as a yellow gum (yield: 59%). LC-MS: RT = 1.88 min, [M+H] + =587.42.

[0583] Step E: Synthesis of compounds 28A and 28B

[0584] To a solution of (S)-tert-butyl 4-((4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (390 mg, 0.665 mmol) in methanol (15.0 ml) at room temperature was added potassium carbonate (919 mg, 6.65 mmol), the mixture was heated to 70°C and reacted overnight, and water (5.0 ml) was added and the reaction was continued for 2 hours.

[0585] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 31 mg of the absolute configuration diastereomer 28A (yield: 9.8%) and 135.8 mg of the absolute configuration diastereomer 28B (yield: 43.2%).

[0586] Compound 28A: HPLC: RT = 12.2 min, LC-MS: RT = 1.63 min, [M+H] + =473.29. 1H NMR (400MHz, DMSO-d6) δ10.81 (s, 1H), 7.79 (d, J=8.0Hz, 2H), 7.45 (s, 1H), 7.40 (d, J=8 .0Hz, 2H), 7.27-7.23(m, 1H), 6.65(s, 1H), 6.51-6.47(m, 1H), 3.75-3.64(m, 7H), 3.59- 3.53(m, 1H), 3.39-3.34(m, 1H), 2.92-2.85(m, 1H), 2.65-2.57(m, 1H), 2.42(s, 3H), 2. 35-2.25(m, 1H), 2.12(s, 3H), 2.07-1.97(m, 1H), 1.93-1.85(m, 1H), 1.75-1.59(m, 2H).

[0587] Compound 28B: HPLC: RT = 14.5 min, LC-MS: RT = 1.63 min, [M+H] + =473.29. 1 H NMR (400MHz, DMSO-d6) δ10.83 (s, 1H), 7.90 (d, J=8.0Hz, 2H), 7.54 (d, J=8.0Hz, 2H), 7.27 -7.23(m, 1H), 7.13(s, 1H), 6.65(s, 1H), 6.48-6.45(m, 1H), 3.72(s, 3H), 3.64(s, 3H), 3. 62-3.56(m, 1H), 3.30-3.24(m, 1H), 3.23-3.17(m, 1H), 2.87-2.79(m, 1H), 2.59-2.53(m, 1H), 2.42(s, 3H), 2.15(s, 3H), 2.13-2.07(m, 1H), 1.77-1.55(m, 3H), 1.48-1.36(m, 1H).

[0588] Examples 29A and 29B

[0589] Synthesis of compounds 29A and 29B

[0590] The specific synthetic route is as follows:

[0591] Step A: Synthesis of 4-bromo-1-(2-fluoroethyl)-1H-pyrazole

[0592] At room temperature, 2-fluoroethyl 4-methylbenzenesulfonate (4.5 g, 20.41 mmol) and cesium carbonate (6.7 g, 20.41 mmol) were added to N,N-dimethylformamide (30 ml) containing 4-bromo-1H-pyrazole (2.0 g, 13.61 mmol). Under nitrogen protection, the mixture was heated to 100°C and reacted overnight.

[0593] After the reaction was complete, water was added and the mixture was extracted with ethyl acetate (20 ml x 4). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to obtain 1.3 g of 4-bromo-1-(2-fluoroethyl)-1H-pyrazole as a colorless oil (yield: 49%). LC-MS: RT = 1.74 min, [M+H] + =193.04.

[0594] Step B: Synthesis of (S)-benzyl 4-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0595] Compound (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 (1.0 g, 2.09 mmol), 4-bromo-1-(2-fluoroethyl)-1H-pyrazole (605 mg, 3.13 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (154 mg, 0.21 mmol), and potassium phosphate (890 mg, 4.18 mmol) were added to 1,4-dioxane (30 ml), and water (6 ml) was added. The mixture was heated to 90°C under nitrogen protection and reacted overnight.

[0596] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 2) to obtain 670 mg of (S)-benzyl 4-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate as a pale yellow gummy liquid (yield: 69%). LC-MS: RT = 2.05 min, [M+H] + =464.30.

[0597] Step C: Synthesis of (S)-methyl 4-(4-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)piperidin-2-yl)benzoate

[0598] Benzyl (S)-4-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (670 mg, 1.45 mmol) was dissolved in ethyl acetate (20 ml), and palladium on carbon (300 mg) was added to replace the hydrogen atmosphere. The mixture was reacted at room temperature for 4 hours.

[0599] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated to give 450 mg of (S)-methyl 4-(4-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)piperidin-2-yl)benzoate as a light yellow oily liquid (yield: 93%). LC-MS: RT = 1.54 min, [M+H] + =332.24.

[0600] Step D: Synthesis of (S)-tert-butyl 4-((4-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0601] Methyl (S)-4-(4-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)piperidin-2-yl)benzoate (450 mg, 1.36 mmol) was dissolved in 1,2-dichloroethane (20 ml) at room temperature, and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (784 mg, 2.72 mmol) was added and the mixture was reacted overnight. Sodium triacetoxyborohydride (863 mg, 4.07 mmol) was then added and the reaction was carried out for 5 hours.

[0602] After the reaction was completed, methanol was added and the mixture was concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to afford 550 mg of (S)-tert-butyl 4-((4-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate as a light yellow gum (yield: 67%). LC-MS: RT = 1.84 min, [M+H] + =605.40.

[0603] Step E: Synthesis of compounds 29A and 29B

[0604] To a solution of tert-butyl (S)-4-((4-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (550 mg, 0.91 mmol) in methanol (20 ml) was added potassium carbonate (1.26 g, 9.1 mmol), the mixture was heated to 70°C for overnight, and water (5 ml) was added and the reaction was continued for 3 hours.

[0605] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 46.3 mg of the absolute configuration diastereomer 29A (yield: 10.3%) and 257.3 mg of the absolute configuration diastereomer 29B (yield: 57.6%).

[0606] Compound 29A: HPLC: RT = 12.2 min, LC-MS: RT = 1.61 min, [M+H] + =491.42. 1 H NMR (400MHz, DMSO-d6) δ10.81 (s, 1H), 7.81 (d, J=8.0Hz, 2H), 7.69 (s, 1H), 7.44-7.34 (m, 3H), 7.26- 7.20 (m, 1H), 6.63 (s, 1H), 6.50-6.46 (m, 1H), 4.88-4.82 (m, 1H), 4.76-4.70 (m, 1H), 4.50-4.45 (m, 1H ), 4.43-4.38(m, 1H), 3.68(s, 3H), 3.61-3.54(m, 1H), 3.40-3.38(m, 1H), 3.21-3.13(m, 1H), 3.03-2. 95(m, 1H), 2.59-2.53(m, 1H), 2.41(s, 3H), 2.21-2.10(m, 1H), 2.08-1.95(m, 2H), 1.83-1.72(m, 2H).

[0607] Compound 29B: HPLC: RT = 14.6 min, LC-MS: RT = 1.61 min, [M+H] + =491.42. 1H NMR (400MHz, DMSO-d6) δ10.84 (s, 1H), 7.89 (d, J=8.0Hz, 2H), 7.58-7.44 (m, 3H), 7.32 (s, 1H), 7.27-7.22 (m, 1H), 6.66 (s, 1H), 6.51-6.44 (m, 1H), 4.78-4.72 (m, 1H), 4.67-4.60 (m, 1H), 4.36-4.31 (m, 1H), 4.29-4 .23(m,1H),3.72(s,3H),3.62-3.57(m,1H),3.28-3.16(m,2H),2.87-2.80(m,1H),2.68-2.57(m,1H),2.4 2(s, 3H), 2.14-2.03(m, 1H), 1.97-1.87(m, 1H), 1.81-1.72(m, 1H), 1.67-1.55(m, 1H), 1.45-1.31(m, 1H).

[0608] Examples 30A and 30B

[0609] Synthesis of compounds 30A and 30B

[0610] The specific synthetic route is as follows:

[0611] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0612] To a solution of benzyl (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.5 g, 3.14 mmol) in 1,4-dioxane (25 ml) at room temperature were added tert-butyl 4-bromo-1H-pyrazole-1-carboxylate (1.16 g, 4.71 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (460 mg, 0.63 mmol), potassium phosphate (1.37 g, 6.28 mmol) and water (4 ml). The atmosphere was replaced with nitrogen and the temperature was raised to 95° C. for reaction overnight.

[0613] After the reaction was complete, the product was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1:5) to obtain 800 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester as a pale yellow oily liquid (yield: 61%). LC-MS: RT = 1.98 min, [M+H]+ =418.23.

[0614] Step B: Synthesis of (S)-methyl 4-(4-(1H-pyrazol-4-yl)piperidin-2-yl)benzoate

[0615] Benzyl (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (800 mg, 1.92 mmol) was dissolved in ethyl acetate (20 ml), and palladium carbon (300 mg) was added to replace the hydrogen atmosphere. The mixture was reacted at room temperature for 3 hours.

[0616] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated to obtain 550 mg of colorless oily liquid (S)-methyl 4-(4-(1H-pyrazol-4-yl)piperidin-2-yl)benzoate. LC-MS: RT = 1.61 min, [M+H] + =286.23.

[0617] Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0618] To a solution of (S)-methyl 4-(4-(1H-pyrazol-4-yl)piperidin-2-yl)benzoate (400 mg, 0.96 mmol) in 1,2-dichloroethane (5 ml) were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (416 mg, 1.44 mmol) and sodium triacetoxyborohydride (815 mg, 3.84 mmol), and the mixture was heated to 40°C and reacted overnight.

[0619] After the reaction was completed, methanol was added and the mixture was concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane = 1:1) to afford 400 mg of (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate as a white solid (yield: 75%). LC-MS: RT = 1.85 min, [M+H] + =559.34

[0620] Step D: Compounds 30A and 30B

[0621] To a solution of tert-butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1H-pyrazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (200 mg, 0.36 mmol) in methanol (10 ml) was added potassium carbonate (200 mg, 1.43 mmol), the mixture was heated to 70°C for 5 hours, and water (2 ml) was added and the reaction was continued for 4 hours.

[0622] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate and obtain 5 mg of the absolute configuration diastereomer 30A (yield: 3%) and 80 mg of the absolute configuration diastereomer 30B (yield: 50%).

[0623] Compound 30A: HPLC: RT = 10.1 min, LC-MS: RT = 1.63 min, [M+H] + =445.27.

[0624] Compound 30B: HPLC: RT = 15.6 min, LC-MS: RT = 1.63 min, [M+H] + =445.27. 1 H NMR (400MHz, DMSO-d6) δ10.80 (t, J=2.3Hz, 1H), 7.83 (d, J=7.8Hz, 2H), 7.40 (d, J=8.5Hz, 4H), 7.24 (t, J=2.7Hz, 1H), 6.65 (s, 1H), 6.48 (dd, J=3.2, 1.7Hz, 1H), 3.72 (s, 3H), 3.60 (d, J=11.9Hz, 1H), 3.20 (dd, J=11.5, 3.2Hz, 2H), 2.88-2.78 (m, 1H), 2.64 (td, J=12.1, 6.2Hz, 1H), 2.42 (s, 3H), 2.09 (dd, J=13.2, 1 0.7Hz, 1H), 1.91 (d, J=12.8Hz, 1H), 1.75 (d, J=12.8Hz, 1H), 1.63 (q, J=12.1Hz, 1H), 1.45-1.33 (m, 1H).

[0625] Examples 31A and 31B

[0626] Synthesis of compounds 31A and 31B

[0627] The specific synthetic route is as follows:

[0628] Step A: Synthesis of 2,3-dihydropyrazolo[5,1-b]oxazole

[0629] At room temperature, 1,2-dihydro-3H-pyrazol-3-one (3.00 g, 35.7 mmol) was dissolved in acetonitrile (30 ml), 1,2-dibromoethane (20.21 g, 107.1 mmol) and potassium carbonate (14.78 g, 107.1 mmol) were added, and the temperature was raised to 80°C and the reaction was carried out overnight.

[0630] After the reaction was complete, the mixture was filtered and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 800 mg of 2,3-dihydropyrazolo[5,1-b]oxazole as a light yellow oil (yield: 20%). LC-MS: RT = 0.72 min, [M+H] + =111.13.

[0631] Step B: Synthesis of 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole

[0632] To a solution of 2,3-dihydropyrazolo[5,1-b]oxazole (1 g, 9.08 mmol) in acetonitrile (10 ml) was added N-bromosuccinimide (1.78 g, 9.99 mmol) at 0°C and the mixture was allowed to warm to room temperature for 2 hours.

[0633] After the reaction was complete, the mixture was filtered and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 1.4 g of white solid 2,3-dihydropyrazolo[5,1-b]oxazole (yield: 82%). LC-MS: RT = 1.66 min, [M+H] + =189.04 / 191.00.

[0634] Step C: Synthesis of (S)-4-(2,3-dihydropyrazolo[5,1-b]oxazol-7-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0635] To a solution of benzyl (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (800 mg, 1.68 mmol) in 1,4-dioxane (10 ml) at room temperature were added 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole (476 mg, 2.52 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (124 mg, 0.17 mmol), potassium phosphate (892 mg, 4.20 mmol) and water (2 ml). The atmosphere was replaced with nitrogen and the temperature was raised to 90°C for reaction overnight.

[0636] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to obtain 230 mg of (S)-benzyl 4-(2,3-dihydropyrazolo[5,1-b]oxazol-7-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate as a pale yellow oily liquid (yield: 30%). LC-MS: RT = 2.02 min, [M+H] + =460.23.

[0637] Step D: Synthesis of (S)-methyl 4-(4-(2,3-dihydropyrazolo[5,1-b]oxazol-7-yl)piperidin-2-yl)benzoate

[0638] (S)-benzyl 4-(2,3-dihydropyrazolo[5,1-b]oxazol-7-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (230 mg, 0.50 mmol) was dissolved in ethyl acetate (10 ml), palladium on carbon (100 mg) was added to replace the hydrogen, and the temperature was raised to 50°C for reaction for 3 hours.

[0639] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated to afford 110 mg of (S)-methyl 4-(4-(2,3-dihydropyrazolo[5,1-b]oxazol-7-yl)piperidin-2-yl)benzoate as a light yellow oil (yield: 68%). LC-MS: RT = 1.54 min, [M+H] + =328.21.

[0640] Step E: Synthesis of (S)-tert-butyl 4-(4-(2,3-dihydropyrazolo[5,1-b]oxazol-7-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[0641] To a solution of (S)-methyl 4-(4-(2,3-dihydropyrazolo[5,1-b]oxazol-7-yl)piperidin-2-yl)benzoate (110 mg, 0.34 mmol) in 1,2-dichloroethane (5 ml) was added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (246 mg, 0.85 mmol) and sodium triacetoxyborohydride (144 mg, 0.68 mmol), and the mixture was heated to 40°C and reacted overnight.

[0642] After the reaction was completed, methanol was added and the mixture was concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to afford 100 mg of a pale yellow oily substance, (S)-tert-butyl 4-(4-(2,3-dihydropyrazolo[5,1-b]oxazol-7-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (yield: 50%). LC-MS: RT = 1.86 min, [M+H] + =601.36.

[0643] Step F: Synthesis of compounds 31A and 31B

[0644] To a solution of (S)-tert-butyl 4-(4-(2,3-dihydropyrazolo[5,1-b]oxazol-7-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (100 mg, 0.17 mmol) in methanol (5 ml) was added potassium carbonate (94 mg, 0.68 mmol), the mixture was heated to 70°C for 5 hours, and water (1 ml) was added and the reaction was continued for 4 hours.

[0645] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 9.5 mg of the absolute configuration diastereomer 31A (yield: 11%) and 26.9 mg of the absolute configuration diastereomer 31B (yield: 32%).

[0646] Compound 31A: HPLC: RT = 3.171 min, LC-MS: RT = 1.65 min, [M+H] + =487.29.

[0647] Compound 31B: HPLC: RT = 3.174 min, LC-MS: RT = 1.65 min, [M+H] + =487.29. 1H NMR (400MHz, DMSO-d6) δ10.80 (t, J=2.3Hz, 1H), 7.87 (d, J=7.9Hz, 2H), 7.49 (d, J=7.7Hz, 2H), 7.2 4(t, J=2.8Hz, 1H), 7.12 (s, 1H), 6.64 (s, 1H), 6.47 (t, J=2.5Hz, 1H), 4.96 (t, 2H), 4.13 (t, J=7.9H z, 2H), 3.71 (s, 3H), 3.57 (d, J=11.9Hz, 1H), 3.25-3.14 (m, 3H), 2.80 (dt, J=11.8, 3.4Hz, 1H), 2.4 1 (s, 3H), 2.05 (dd, J=13.3, 10.7Hz, 1H), 1.90-1.81 (m, 1H), 1.73-1.52 (m, 2H), 1.46-1.31 (m, 1H).

[0648] Examples 32A and 32B

[0649] Synthesis of compounds 32A and 32B

[0650] The specific synthetic route is as follows:

[0651] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0652] To a solution of benzyl (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (800 mg, 1.68 mmol) in 1,4-dioxane (10 ml) at room temperature were added 4-bromo-1-methyl-1H-imidazole (411 mg, 2.52 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (124 mg, 0.17 mmol), potassium phosphate (892 mg, 4.2 mmol) and water (2 ml). The atmosphere was replaced with nitrogen and the temperature was raised to 90°C for 2 hours.

[0653] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain 250 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester as a pale yellow oily liquid (yield: 42%). LC-MS: RT = 1.70 min, [M+H] + =432.24.

[0654] Step B: Synthesis of (S)-methyl 4-(4-(1-methyl-1H-imidazol-4-yl)piperidin-2-yl)benzoate

[0655] (S)-benzyl 6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (250 mg, 0.58 mmol) was dissolved in ethyl acetate solution (10 ml), palladium carbon (130 mg) was added, hydrogen was replaced, and the temperature was raised to 50°C for reaction for 4 hours.

[0656] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated to give 130 mg of (S)-methyl 4-(4-(1-methyl-1H-imidazol-4-yl)piperidin-2-yl)benzoate as a light yellow oil (yield: 74%). LC-MS: RT = 0.26 min, [M+H] + =300.25.

[0657] Step C: Synthesis of (S)-5-methoxy-4-(2-(4-(methoxycarbonyl(phenyl)-4-(1-methyl-1H-imidazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate tert-butyl ester

[0658] To a solution of (S)-methyl 4-(4-(1-methyl-1H-imidazol-4-yl)piperidin-2-yl)benzoate (130 mg, 0.43 mmol) in 1,2-dichloroethane (5 ml) were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (312 mg, 1.08 mmol) and sodium triacetoxyborohydride (182 mg, 0.86 mmol), and the mixture was heated to 40°C and reacted overnight.

[0659] After the reaction was completed, methanol was added and the mixture was concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give 86 mg of a pale yellow oily substance (S)-5-methoxy-4-(2-(4-(methoxycarbonyl(phenyl)-4-(1-methyl-1H-imidazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate tert-butyl ester (yield: 35%). LC-MS: RT = 1.73 min, [M+H] + =573.34.

[0660] Step D: Synthesis of compounds 32A and 32B

[0661] To a solution of tert-butyl (S)-5-methoxy-4-(2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-imidazol-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (86 mg, 0.15 mmol) in methanol (5 ml) was added potassium carbonate (83 mg, 0.60 mmol), the mixture was heated to 70°C for 5 hours, and water (1 ml) was added and the reaction was continued for 4 hours.

[0662] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 10 mg of the absolute configuration diastereomer 32A (yield: 15%) and 17 mg of the absolute configuration diastereomer 32B (yield: 25%).

[0663] Compound 32A: HPLC: RT = 0.988 min, LC-MS: RT = 1.66 min, [M+H] + =462.24.

[0664] Compound 32B: HPLC: RT = 0.672 min, LC-MS: RT = 1.66 min, [M+H] + =455.22.

[0665] Examples 33A and 33B

[0666] Synthesis of compounds 33A and 33B

[0667] The specific synthetic route is as follows:

[0668] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-1,2,3-triazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0669] Compound (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 (750 mg, 1.57 mmol), 4-bromo-1-methyl-1H-1,2,3-triazole (381.4 mg, 2.35 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (229.5 mg, 0.3 mmol), and potassium phosphate (682 mg, 3.1 mmol) were added to a mixture of 1,4-dioxane (25 ml) and water (5 ml), and the mixture was heated to 95° C. under nitrogen protection and reacted for 12 hours.

[0670] After the reaction was complete, ethyl acetate (50 ml) was added to dilute the mixture, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1). 470 mg of (S)-benzyl 6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-1,2,3-triazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate were obtained (yield 53.3%). LC-MS: RT = 1.97 min, [M+H] + =433.24.

[0671] Step B: Synthesis of (S)-methyl 4-(4-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-2-yl)benzoate

[0672] At room temperature, compound (S)-benzyl 6-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-1,2,3-triazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (420 mg, 0.97 mmol) was dissolved in ethyl acetate (20 ml), palladium / carbon (420 mg) was added, and the reaction was carried out under a hydrogen atmosphere overnight.

[0673] After the reaction was complete, the mixture was filtered and concentrated to obtain 300 mg of a pale yellow oily product, methyl (S)-4-(4-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-2-yl)benzoate (crude product), which was used directly in the next step without purification. LC-MS: RT = 1.49 min, [M+H] + =301.22.

[0674] Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-1)-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0675] The compound ((S)-methyl 4-(4-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-2-yl)benzoate (300 mg, 1.0 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (578 mg, 2.0 mmol) were dissolved in 1,2-dichloroethane (5 ml), stirred at room temperature for 1 hour, sodium triacetoxyborohydride (635.8 mg, 3.0 mmol) was added, and the temperature was raised to 40°C for reaction overnight.

[0676] After the reaction was complete, methanol was added and the mixture was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1). 387 mg of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-1)-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was obtained as a brown solid (yield 67.5%). LC-MS: RT = 1.84 min, [M+H] + =574.34.

[0677] Step D: Synthesis of compounds 33A and 33B

[0678] Compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-1,2,3-triazol-4-yl)piperidin-1)-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (387 mg, 0.67 mmol) was dissolved in methanol (15 ml), potassium carbonate (372.8 mg, 2.7 mmol) was added, and the mixture was heated to 70°C for overnight reaction. Water (2 ml) was added and the reaction was continued for 2 hours.

[0679] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 10 mg of the absolute configuration diastereomer 33A (yield: 3.2%) and 102 mg of the absolute configuration diastereomer 33B (yield: 33.1%).

[0680] Compound 33A: HPLC: RT = 3.055 min, LC-MS: RT = 1.61 min, [M+H] + =460.27.

[0681] Compound 33B: HPLC: RT = 2.961 min, LC-MS: RT = 1.61 min, [M+H] + =460.27.

[0682] 1H NMR (400MHz, DMSO-d6) δ10.82 (d, J=2.7Hz, 1H), 7.86-7.80 (m, 2H), 7.79 (s, 1H), 7.41 (d, J=7.7H z, 2H), 7.24 (t, J=2.7Hz, 1H), 6.65 (s, 1H), 6.48 (dd, J=3.1, 1.8Hz, 1H), 3.93 (s, 3H), 3.72 (s, 3H) , 3.60 (d, J=11.8Hz, 1H), 3.27-3.17 (m, 2H), 2.89-2.77 (m, 2H), 2.42 (s, 3H), 2.11 (dd, J=13.2, 10 .7Hz, 1H), 1.99-1.90 (m, 1H), 1.81 (d, J=12.9Hz, 1H), 1.71 (q, J=12.3Hz, 1H), 1.52-1.38 (m, 1H).

[0683] Examples 34A and 34B

[0684] Synthesis of compounds 34A and 34B

[0685] The specific synthetic route is as follows:

[0686] Step A: Synthesis of (S)-6′-(4-(methoxycarbonyl)phenyl)-6-methyl-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylic acid benzyl ester

[0687] To a solution of benzyl (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (800 mg, 1.68 mmol) in 1,4-dioxane (10 ml) at room temperature were added 2-bromo-6-methylpyridine (433 mg, 2.52 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (124 mg, 0.17 mmol), potassium phosphate (892 mg, 4.2 mmol) and water (2 ml). The atmosphere was replaced with nitrogen and the temperature was raised to 90°C for reaction overnight.

[0688] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to obtain 120 mg of (S)-6'-(4-(methoxycarbonyl)phenyl)-6-methyl-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid benzyl ester as a pale yellow oily liquid (yield: 58%). LC-MS: RT = 2.09 min, [M+H] + =443.24.

[0689] Step B: Synthesis of (S)-methyl 4-(4-(6-methylpyridin-2-yl)piperidin-2-yl)benzoate

[0690] (S)-benzyl 6′-(4-(methoxycarbonyl)phenyl)-6-methyl-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate (430 mg, 0.97 mmol) was dissolved in ethyl acetate (10 ml), and palladium carbon (250 mg) was added to replace the hydrogen atmosphere. The mixture was reacted at room temperature overnight.

[0691] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain 150 mg of (S)-methyl 4-(4-(6-methylpyridin-2-yl)piperidin-2-yl)benzoate as a light yellow oily liquid (yield: 49%). LC-MS: RT = 1.41 min, [M+H] + =311.23.

[0692] Step C: Synthesis of (S)-5-methoxy-4-(2-(4-(methoxycarbonyl)phenyl)-4-(6-methylpyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0693] To a solution of (S)-methyl 4-(4-(6-methylpyridin-2-yl)piperidin-2-yl)benzoate (150 mg, 0.48 mmol) in 1,2-dichloroethane (5 ml) was added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (347 mg, 1.2 mmol) and sodium triacetoxyborohydride (203 mg, 0.96 mmol), and the mixture was heated to 40°C and reacted overnight.

[0694] After the reaction was complete, methanol was added and the mixture was concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1) to afford 120 mg of a pale yellow oily substance (S)-tert-butyl 5-methoxy-4-(2-(4-(methoxycarbonyl)phenyl)-4-(6-methylpyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (yield: 44%). LC-MS: RT = 1.98 min, [M+H] + =584.37.

[0695] Step D: Synthesis of compounds 34A and 34B

[0696] To a solution of tert-butyl (S)-5-methoxy-4-(2-(4-(methoxycarbonyl)phenyl)-4-(6-methylpyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (120 mg, 0.21 mmol) in methanol (5 ml) was added potassium carbonate (116 mg, 0.84 mmol), the mixture was heated to 70°C for 5 hours, and water (1 ml) was added and the reaction was continued for 4 hours.

[0697] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 23.8 mg of the absolute configuration diastereomer 34A (yield: 24%) and 30.2 mg of the absolute configuration diastereomer 34B (yield: 31%).

[0698] Compound 34A: HPLC: RT = 0.971 min, LC-MS: RT = 1.57 min, [M+H] + =470.30. 1 H NMR (400MHz, DMSO-d6) δ10.81 (s, 1H), 7.88 (d, J=7.9Hz, 2H), 7.58-7.49 (m, 3H), 7.26 (t, J= 2.8Hz, 1H), 7.01 (t, J=8.0Hz, 2H), 6.66 (s, 1H), 6.50 (dd, J=3.1, 1.9Hz, 1H), 3.72 (s, 3H), 3 .61(d, J=11.9Hz, 1H), 3.32-3.19(m, 2H), 2.93-2.86(m, 1H), 2.85-2.75(m, 1H), 2.42(s, 3H ), 2.39 (s, 3H), 2.18-2.08 (m, 1H), 1.91-1.76 (m, 2H), 1.75-1.68 (m, 1H), 1.67-1.56 (m, 1H).

[0699] Compound 34B: HPLC: RT = 2.239 min, LC-MS: RT = 1.57 min, [M+H] + =470.30. 1H NMR (400MHz, DMSO-d6) δ10.80 (s, 1H), 7.93 (d, J=8.1Hz, 2H), 7.69-7.60 (m, 3H), 7.25 (t, J=2.8H z, 1H), 7.20 (d, J=7.8Hz, 1H), 7.08 (d, J=7.6Hz, 1H), 6.64 (s, 1H), 6.47 (dd, J=3.1, 1.9Hz, 1H), 3 .75-3.70(m, 1H), 3.69(s, 3H), 3.40-3.32(m, 2H), 3.06-2.99(m, 1H), 2.69-2.58(m, 1H), 2.49(s , 1H), 2.41 (s, 3H), 2.29-2.19 (m, 1H), 2.19-2.10 (m, 1H), 2.10-1.98 (m, 1H), 1.81-1.71 (m, 1H).

[0700] Examples 35A and 35B

[0701] Synthesis of compounds 35A and 35B

[0702] The specific synthetic route is as follows:

[0703] Step A: Synthesis of (S)-6′-(4-(methoxycarbonyl)phenyl)-5-methyl-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylic acid benzyl ester

[0704] To a solution of benzyl (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (800 mg, 1.68 mmol) in 1,4-dioxane (10 ml) at room temperature were added 2-bromo-5-methylpyridine (433 mg, 2.52 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (124 mg, 0.17 mmol), potassium phosphate (892 mg, 4.2 mmol) and water (2 ml). The atmosphere was replaced with nitrogen and the temperature was raised to 90°C for reaction overnight.

[0705] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 600 mg of (S)-6'-(4-(methoxycarbonyl)phenyl)-5-methyl-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid benzyl ester as a pale yellow oily liquid (yield: 85%). LC-MS: RT = 2.11 min, [M+H] + =443.24.

[0706] Step B: Synthesis of (S)-methyl 4-(4-(5-methylpyridin-2-yl)piperidin-2-yl)benzoate

[0707] (S)-benzyl 6′-(4-(methoxycarbonyl)phenyl)-5-methyl-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate (600 mg, 1.36 mmol) was dissolved in ethyl acetate (10 ml), palladium carbon (300 mg) was added, the hydrogen atmosphere was replaced, and the reaction was carried out at room temperature overnight.

[0708] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain 180 mg of (S)-methyl 4-(4-(5-methylpyridin-2-yl)piperidin-2-yl)benzoate as a light yellow oily liquid (yield: 43%). LC-MS: RT = 1.50 min, [M+H] + =311.23.

[0709] Step C: Synthesis of (S)-5-methoxy-4-(2-(4-(methoxycarbonyl)phenyl)-4-(5-methylpyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0710] To a solution of (S)-methyl 4-(4-(5-methylpyridin-2-yl)piperidin-2-yl)benzoate (180 mg, 0.58 mmol) in 1,2-dichloroethane (5 ml) was added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (419 mg, 1.45 mmol) and sodium triacetoxyborohydride (246 mg, 1.16 mmol), and the mixture was heated to 40°C and reacted overnight.

[0711] After the reaction was completed, methanol was added and the mixture was concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1) to afford 250 mg of a pale yellow oily substance (S)-tert-butyl 5-methoxy-4-(2-(4-(methoxycarbonyl)phenyl)-4-(5-methylpyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (yield: 74%). LC-MS: RT = 1.89 min, [M+H] + =584.41.

[0712] Step D: Synthesis of compounds 35A and 35B

[0713] To a solution of tert-butyl (S)-5-methoxy-4-(2-(4-(methoxycarbonyl)phenyl)-4-(5-methylpyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (250 mg, 0.43 mmol) in methanol (5 ml) was added potassium carbonate (237 mg, 1.72 mmol), the mixture was heated to 70°C for 5 hours, and water (1 ml) was added and the reaction was continued for 4 hours.

[0714] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 23 mg of the absolute configuration diastereomer 35A (yield: 11%) and 144 mg of the absolute configuration diastereomer 35B (yield: 53%).

[0715] Compound 35A: HPLC: RT = 3.038 min, LC-MS: RT = 1.72 min, [M+H] + =470.31. 1 H NMR (400MHz, DMSO-d6) δ10.79 (s, 1H), 8.42 (d, J = 2.3Hz, 1H), 7.79 (d, J = 7.9Hz, 2H), 7.57 (dd, J = 8.1, 2.4Hz, 1H), 7.36 (d, J=7.8Hz, 2H), 7.31 (d, J=8.0Hz, 1H), 7.24 (t, J=2.8Hz, 1H), 6.62 (s, 1H), 6.46 (dd, J=3.0, 1.8Hz, 1H), 3. 66 (s, 3H), 3.63 (d, J = 11.9Hz, 1H), 3.46 (dt, J = 9.8, 4.6Hz, 1H), 3.23 (d, J = 11.9Hz, 2H), 3.07 (t, J = 4.7Hz, 1H), 2. 62-2.55 (m, 1H), 2.41 (s, 3H), 2.37 (s, 1H), 2.30 (s, 3H), 2.19-2.13 (m, 1H), 2.13-2.00 (m, 1H), 1.80-1.70 (m, 1H).

[0716] Compound 35B: HPLC: RT = 0.974 min, LC-MS: RT = 1.72 min, [M+H] + =470.31. 1H NMR (400MHz, DMSO-d6) δ10.82 (s, 1H), 8.27 (d, J = 2.3Hz, 1H), 7.86 (d, J = 8.2Hz, 2H), 7.51-7. 43 (m, 3H), 7.25 (t, J=2.8Hz, 1H), 7.14 (d, J=8.0Hz, 1H), 6.65 (s, 1H), 6.50 (dd, J=3.1, 1.9Hz , 1H), 3.72 (s, 3H), 3.61 (d, J=11.9Hz, 1H), 3.31-3.19 (m, 2H), 2.91-2.78 (m, 2H), 2.42 (s, 3H ), 2.21 (s, 3H), 2.18-2.08 (m, 1H), 1.89-1.80 (m, 2H), 1.74-1.67 (m, 1H), 1.65-1.55 (m, 1H).

[0717] Examples 36A and 36B

[0718] Synthesis of compounds 36A and 36B

[0719] The specific synthetic route is as follows:

[0720] Step A: Synthesis of (S)-6-((4-methoxycarbonyl)phenyl)-4-(4-methylpyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0721] To a solution of benzyl (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1000 mg, 2.09 mmol) in 1,4-dioxane (30 ml) at room temperature were added 2-bromo-4-methylpyridine (541 mg, 3.14 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (152 mg, 0.21 mmol), potassium phosphate (1100 mg, 5.24 mmol) and water (6 ml). The atmosphere was replaced with nitrogen and the temperature was raised to 90°C for reaction for 5 hours.

[0722] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 8 / 1) to obtain 470 mg of (S)-6-((4-methoxycarbonyl)phenyl)-4-(4-methylpyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester as a pale yellow oily liquid (yield: 51%). LC-MS: RT = 1.97 min, [M+H] + =443.23.

[0723] Step B: Synthesis of (S)-methyl 4-(4-(4-methylpyridin-2-yl)piperidin-2-ylbenzoate

[0724] Benzyl (S)-6-((4-methoxycarbonyl)phenyl)-4-(4-methylpyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (470 mg, 1.06 mmol) was dissolved in ethyl acetate (20 ml), palladium on carbon (47 mg) was added, the hydrogen atmosphere was replaced, and the temperature was raised to 60°C for reaction overnight.

[0725] After the reaction was completed, the mixture was filtered, washed with ethyl acetate, and concentrated to give 290 mg of (S)-methyl 4-(4-(4-methylpyridin-2-yl)piperidin-2-ylbenzoate as a light yellow oily liquid (yield: 88%). LC-MS: RT = 1.47 min, [M+H] + =311.23.

[0726] Step C: Synthesis of (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(4-methylpyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0727] To a solution of (S)-methyl 4-(4-(4-methylpyridin-2-yl)piperidin-2-ylbenzoate (290 mg, 0.93 mmol) in 1,2-dichloroethane (20 ml) were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (405 mg, 1.40 mmol) and sodium triacetoxyborohydride (396 mg, 1.87 mmol), and the mixture was heated to 40°C and reacted overnight.

[0728] After the reaction was complete, methanol was added and the mixture was concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1) to afford 240 mg of (S)-tert-butyl 5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(4-methylpyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate as a white solid (yield: 44%). LC-MS: RT = 1.91 min, [M+H] + =584.38.

[0729] Step D: Synthesis of compounds 36A and 36B

[0730] To a solution of tert-butyl (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(4-methylpyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (240 mg, 0.41 mmol) in methanol (15 ml) was added potassium carbonate (568 mg, 4.10 mmol), the mixture was heated to 70°C for 5 hours, and water (1 ml) was added and the reaction was continued for 4 hours.

[0731] After the reaction was completed, the product was filtered, rinsed with methanol, and concentrated. The chiral separation method in Step D of Example 3 was used to separate 26 mg of the absolute configuration diastereomer 36A (yield: 13%) and 153 mg of the absolute configuration diastereomer 36B (yield: 79%).

[0732] Compound 36A: HPLC: RT = 1.875 min, LC-MS: RT = 1.54 min, [M+H] + =470.34. 1 H NMR (400MHz, DMSO-d6) δ10.80 (d, J=2.5Hz, 1H), 8.44 (d, J=5.0Hz, 1H), 7.81 (d, J=7.8Hz, 2H), 7.39 (d, J=8.0Hz, 2H), 7.24 (dd, J=6.3, 3.6Hz, 2H), 7.06 (d, J=5.0Hz, 1H), 6.64 (s, 1H), 6.49 (t, J=2.3Hz, 1H), 3.68 (s, 3H), 3.54 (dd, J=9.2, 3.3Hz, 1H), 3.40-3.30 (s, 2H), 3.06 (t, J=4.9Hz, 1H), 2.64-2.58 (m, 1H) , 2.42 (s, 3H), 2.34 (s, 3H), 2.28-2.13 (m, 3H), 2.07 (ddd, J=13.8, 9.1, 4.9Hz, 1H), 1.80-1.69 (m, 1H).

[0733] Compound 36B: HPLC: RT = 0.968 min, LC-MS: RT = 1.54 min, [M+H] + =470.34. 1H NMR (400MHz, DMSO-d6) δ10.84 (s, 1H), 8.29 (d, J = 5.0Hz, 1H), 7.84 (d, J = 7.8Hz, 2H), 7.43 (d, J = 7.7Hz , 2H), 7.26 (t, J=2.8Hz, 1H), 7.09 (s, 1H), 6.98 (d, J=5.0Hz, 1H), 6.66 (s, 1H), 6.52 (t, J=2.5Hz, 1H), 3 .73(s, 3H), 3.63(d, J=11.9Hz, 1H), 3.28-3.20(m, 3H), 2.93-2.75(m, 2H), 2.43(s, 3H), 2.25(s, 3H), 2.18-2.07 (m, 1H), 1.88 (q, J=10.6, 8.2Hz, 2H), 1.72 (d, J=12.4Hz, 1H), 1.61 (qd, J=12.2, 3.6Hz, 1H).

[0734] Examples 37A and 37B

[0735] Synthesis of compounds 37A and 37B

[0736] The specific synthetic route is as follows:

[0737] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyridazin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0738] Compound (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 (0.8 g, 1.68 mmol), 3-bromopyridazine (675 mg, 4.18 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (123 mg, 0.168 mmol), and potassium phosphate (713 mg, 3.36 mmol) were added to a mixture of 1,4-dioxane (20 ml) and water (4 ml). Under nitrogen protection, the temperature was raised to 80°C and the reaction was carried out overnight.

[0739] After the reaction was complete, ethyl acetate (50 ml) was added to dilute the mixture, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 2). 560 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyridazin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester was obtained as a brown gum (yield 77%). LC-MS: RT = 1.98 min, [M+H] + =430.22.

[0740] Step B: Synthesis of (S)-methyl 4-(4-(pyridazin-3-yl)piperidin-2-yl)benzoate

[0741] Compound (S)-benzyl 6-(4-(methoxycarbonyl)phenyl)-4-(pyridazin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (560 mg, 1.3 mmol) was dissolved in ethyl acetate (20 ml), palladium / carbon (280 mg) was added, and the mixture was reacted at room temperature under hydrogen protection overnight.

[0742] After the reaction was complete, the mixture was filtered and concentrated to obtain 350 mg of crude (S)-methyl 4-(4-(pyridazin-3-yl)piperidin-2-yl)benzoate as a yellow oil, which was used directly in the next step without purification. LC-MS: RT = 1.49 min, [M+H] + =298.26.

[0743] Step C: Synthesis of (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridazin-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0744] Compound (S)-methyl 4-(4-(pyridazin-3-yl)piperidin-2-yl)benzoate (350 mg, 1.18 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (681 mg, 2.35 mmol) were dissolved in 1,2-dichloroethane (20 ml), stirred at room temperature overnight, and sodium triacetoxyborohydride (750 mg, 3.53 mmol) was added to react for 4 hours.

[0745] After the reaction was complete, methanol was added and the mixture was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 3). 430 mg of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridazin-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was obtained as a light yellow solid (yield 64%). LC-MS: RT = 1.86 min, [M+H] + =571.40.

[0746] Step D: Synthesis of compounds 37A and 37B

[0747] Compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridazin-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (430 mg, 0.75 mmol) was dissolved in methanol (20 ml), potassium carbonate (1.04 g, 7.5 mmol) was added, and the mixture was heated to 70°C for overnight reaction. Water (5 ml) was added and the reaction was continued for 4 hours.

[0748] After the reaction was completed, the product was concentrated and purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to give a crude product. The diastereomers were separated by chiral HPLC (Agilent prep C18) using 25% CH3CN (+0.05% NH3·H2O) solution to give 39.4 mg of the absolute configuration diastereomer 37A (yield: 8.6%) and 170.8 mg of the absolute configuration diastereomer 37B (yield: 37.3%).

[0749] Compound 37A: HPLC: RT = 7.0 min, LC-MS: RT = 1.59 min, [M+H] + =457.30. (MeOH, Rudolph Autopol I rotator). 1 H NMR (400MHz, DMSO-d6) δ10.82 (s, 1H), 9.13 (d, J = 8.0Hz, 1H), 7.82 (d, J = 8.0Hz, 2H) ,7.76-7.70(m,1H),7.69-7.63(m,1H),7.40(d,J=8.0Hz,2H),7.27-7.23(m,1H),6 .64(s, 1H), 6.50-6.45(m, 1H), 3.71-3.63(m, 4H), 3.56-3.49(m, 1H), 3.29-3.22(m , 2H), 2.69-2.61(m, 1H), 2.48-2.39(m, 4H), 2.27-2.12(m, 3H), 1.90-1.79(m, 1H).

[0750] Compound 37B: HPLC: RT = 10.4 min, LC-MS: RT = 1.59 min, [M+H] + =457.30. (MeOH, Rudolph Autopol I rotator). 1H NMR (400MHz, DMSO-d6) δ10.85 (s, 1H), 9.05 (d, J=8.0Hz, 1H), 7.91 (d, J=8.0Hz, 2H), 7.6 6-7.49(m, 4H), 7.29-7.29(m, 1H), 6.67(s, 1H), 6.54-6.47(m, 1H), 3.74(s, 3H), 3.68-3. 60(m, 1H), 3.40-3.32(m, 1H), 3.29-3.21(m, 1H), 3.16-3.05(m, 1H), 2.97-2.89(m, 1H), 2.43(s, 3H), 2.26-2.15(m, 1H), 2.00-1.90(m, 2H), 1.85-1.78(m, 1H), 1.76-1.64(m, 1H)

[0751] Example 38

[0752] Synthesis of compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid

[0753] The specific synthetic route is as follows:

[0754] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0755] Compound (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 (0.8 g, 1.68 mmol), 4-chloropyrimidine hydrochloride (380 mg, 2.52 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (123 mg, 0.168 mmol), and sodium bicarbonate (283 mg, 3.36 mmol) were added to 1,4-dioxane (20 ml) and water (5 ml), and the reaction was carried out at 80°C under nitrogen protection overnight.

[0756] After the reaction was complete, ethyl acetate (50 ml) was added to dilute the mixture, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 2). 450 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester was obtained as a light yellow oil (yield 62%). LC-MS: RT = 2.06 min, [M+H] + =430.19.

[0757] Step B: Synthesis of (S)-methyl 4-(4-(pyrimidin-4-yl)piperidin-2-yl)benzoate

[0758] Compound (S)-benzyl 6-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (450 mg, 1.05 mmol) was dissolved in ethyl acetate (20 ml), palladium / carbon (230 mg) was added, and the mixture was reacted at room temperature under hydrogen protection overnight.

[0759] After the reaction was complete, the mixture was filtered and concentrated to obtain 300 mg of yellow oily (S)-methyl 4-(4-(pyrimidin-4-yl)piperidin-2-yl)benzoate (crude product), which was used directly in the next step without purification. LC-MS: RT = 1.53 min, [M+H] + =298.19.

[0760] Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0761] Compound (S)-methyl 4-(4-(pyrimidin-4-yl)piperidin-2-yl)benzoate (300 mg, 1.01 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (584 mg, 2.02 mmol) were dissolved in 1,2-dichloroethane (20 ml), stirred at room temperature overnight, and sodium triacetoxyborohydride (642 mg, 3.53 mmol) was added to react for 4 hours.

[0762] After the reaction was complete, methanol was added and the mixture was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 9). 500 mg of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was obtained as a light yellow solid (yield 87%). LC-MS: RT = 1.86 min, [M+H] + =571.34.

[0763] Step D: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid

[0764] Compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (500 mg, 0.87 mmol) was dissolved in methanol (20 ml), potassium carbonate (1.21 g, 8.7 mmol) was added, and the mixture was heated to 70°C for overnight reaction. Water (5 ml) was added and the reaction was continued for 4 hours.

[0765] After the reaction was completed, the purification method in Step D of Example 3 was used to isolate 238.9 mg of a white solid (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid (yield: 59.6%).

[0766] Compound 38: HPLC: RT = 7.0 min, LC-MS: RT = 1.59 min, [M+H] + =457.30. 1 H NMR (400MHz, DMSO-d6) δ10.86 (s, 1H), 9.05 (d, J = 8.0Hz, 1H), 8.64 (d, J = 8.0Hz, 1H), 7.85 (d, J=8.0Hz, 2H), 7.49-7.35 (m, 3H), 7.28-7.23 (m, 1H), 6.66 (s, 1H), 6 .53-6.47(m, 1H), 3.73(s, 3H), 3.66-3.59(m, 1H), 3.29-3.20(m, 2H), 2.94-2.8 3(m, 2H), 2.43(s, 3H), 2.19-2.10(m, 1H), 1.94-1.72(m, 3H), 1.68-1.55(m, 1H).

[0767] Examples 39A and 39B

[0768] Synthesis of compounds 39A and 39B

[0769] The specific synthetic route is as follows:

[0770] Step A: Synthesis of (S)-6-((4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0771] To a solution of (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) in 1,4-dioxane (15 ml) at room temperature were added 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). The atmosphere was replaced with nitrogen and the temperature was raised to 95°C for 5 hours.

[0772] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1:5) to obtain 380 mg of (S)-6-((4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester as a pale yellow oily liquid (yield: 60%). LC-MS: RT = 2.10 min, [M+H] + =430.25.

[0773] Step B: Synthesis of (S)-2-(4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylic acid

[0774] Benzyl (S)-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), and palladium carbon (150 mg) was added to replace the hydrogen atmosphere. The mixture was reacted at room temperature for 3 hours.

[0775] After the reaction was complete, the mixture was filtered, washed with methanol, and concentrated to obtain 310 mg of (S)-2-((4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylic acid as a light yellow oil. LC-MS: RT = 2.13 min, [M+H] + =297.19.

[0776] Step D: Synthesis of (S)-tert-butyl 5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0777] 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.

[0778] After the reaction was complete, methanol was added and the mixture was concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane = 1:1) to afford 178 mg of (S)-tert-butyl 5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate as a white solid (yield: 30%). LC-MS: RT = 2.02 min, [M+H] + =571.34.

[0779] Step E: Compounds 39A and 39B

[0780] To a solution of tert-butyl (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (178 mg, 0.31 mmol) in methanol (15 ml) was added potassium carbonate (174 mg, 1.25 mmol), the mixture was heated to 70°C for 5 hours, and water (3 ml) was added and the reaction was continued for 4 hours.

[0781] After the reaction was completed, the product was concentrated and purified by silica gel column chromatography (eluent: dichloromethane: methanol = 10:1) to give a crude product. The diastereomers were separated by chiral HPLC (Agilent prep C18) using 25% CH3CN (+0.05% NH3·H2O) solution to give 19 mg of the absolute configuration diastereomer 39A (yield: 13%) and 71 mg of the absolute configuration diastereomer 39B (yield: 50%).

[0782] Compound 39A: HPLC: RT = 9.6 min, LC-MS: RT = 1.62 min, [M+H] + =457.26. (MeOH, Rudolph Autopol I spinometer). 1H NMR (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).

[0783] Compound 39B: HPLC: RT = 13.5 min, LC-MS: RT = 1.62 min, [M+H] + =457.26. 1 H NMR (400MHz, DMSO-d6) δ10.83 (t, J=2.4Hz, 1H), 8.59 (d, J=1.5Hz, 1H), 8.54-8.49 (m, 1H), 8.44 (d, J=2.5Hz, 1H), 7.83 (d, J=7.9Hz, 2H), 7.43 (d, J=7.7Hz, 2H), 7.26 (t, J=2.7Hz, 1H), 6.66 (s, 1H), 6.50 (dd, J=3.0, 1.8Hz, 1H), 3.73 (s, 3H), 3.62 (d, J=11.9Hz, 1H), 3.25 (dd, J=12.0, 8.4Hz , 2H), 3.02-2.86(m, 2H), 2.43(s, 3H), 2.21-2.10(m, 1H), 1.98-1.86(m, 2H), 1.81-1.61(m, 2H).

[0784] The diastereomers 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 were resolved by chiral HPLC (Agilent prep C18) using 25% CH3CN (+0.05% NH3·H2O) solution for elution to afford 107 mg of the absolute configuration of intermediate I (yield: 18%) and 178 mg of the absolute configuration of intermediate II (yield: 30%).

[0785] Confirmation of the absolute configuration of intermediate I:

[0786] 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=24,β=24,γ=24.,unit cell volume The z′ of the system is 1, and the asymmetric unit of the crystal consists of one API molecule. The absolute configuration of Intermediate I was determined as shown below, specifically in Figure 1. The crystal parameter diagram of the crystal structure of Intermediate I is shown in Figure 2. The atomic coordinates and isotropic displacement parameter diagram of the crystal structure of Intermediate I are shown in Figure 3. The XRPD pattern of the crystal structure of Intermediate I is shown in Figure 4:

[0787] Therefore, the structure of intermediate II is

[0788] To a solution of tert-butyl intermediate I (5-methoxy-4-(((2S,4S)-(2-(4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (80 mg, 0.14 mmol) in methanol (15 ml) was added potassium carbonate (193 mg, 1.4 mmol). The mixture was heated to 70°C for 5 hours, and then water (3 ml) was added and the reaction continued for 4 hours. After the reaction was complete, the product was concentrated and purified by silica gel column chromatography (eluent: dichloromethane:methanol = 10:1) to give 29 mg of 4-((2S,4S)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoic acid. NMR data were the same as those of 39A (yield: 45%).

[0789] To a solution of the intermediate II, tert-butyl 5-methoxy-4-(((2S,4R)-(2-(4-methoxycarbonyl)phenyl)-4-(pyrazin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (160 mg, 0.28 mmol) in methanol (15 ml), potassium carbonate (386 mg, 2.8 mmol) was added, and the mixture was heated to 70°C for 5 hours. Water (3 ml) was then added and the reaction continued for 4 hours. After the reaction was complete, the mixture was concentrated and purified by silica gel column chromatography (eluent: dichloromethane:methanol = 10:1) to give 69 mg of 4-((2S,4R)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-(pyrazin-2-yl)piperidin-2-yl)benzoic acid. NMR data were the same as those of 39B (yield: 54%).

[0790] Therefore, compounds 39A and 39B are:

[0791] Examples 40A and 40B

[0792] Synthesis of compounds 40A and 40B

[0793] The specific synthetic route is as follows:

[0794] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0795] Compound (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 (800 mg, 1.7 mmol), 2-bromopyrimidine (333.9 mg, 2.5 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (244.1 mg, 0.33 mmol), and potassium phosphate (725.6 mg, 3.3 mmol) were added to 1,4-dioxane (30 ml) and water (6 ml), and the temperature was raised to 95°C under nitrogen protection for 12 hours.

[0796] After the reaction was complete, ethyl acetate (50 ml) was added to dilute the mixture, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1). 600 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester was obtained as a yellow oil (yield 83.7%). LC-MS: RT = 2.10 min, [M+H] + =430.21.

[0797] Step B: Synthesis of (S)-methyl 4-(4-(pyrimidin-2-yl)piperidin-2-yl)benzoate

[0798] Under a hydrogen atmosphere, benzyl (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (600 mg, 1.4 mmol) was dissolved in ethyl acetate (20 ml), and palladium / carbon (600 mg) was added, and the mixture was reacted at room temperature overnight.

[0799] After the reaction was complete, the mixture was filtered and concentrated to obtain 370 mg of a pale yellow oily product, (S)-methyl 4-(4-(pyrimidin-2-yl)piperidin-2-yl)benzoate (crude product), which was used directly in the next step without purification. LC-MS: RT = 1.52 min, [M+H] + =298.22.

[0800] Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0801] Compound (S)-methyl 4-(4-(pyrimidin-2-yl)piperidin-2-yl)benzoate (370 mg, 1.2 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (717.6 mg, 2.4 mmol) were dissolved in 1,2-dichloroethane (7 ml), stirred at room temperature for 1 hour, sodium triacetoxyborohydride (762.9 mg, 3.6 mmol) was added, and the temperature was raised to 40°C for reaction overnight.

[0802] After the reaction was complete, methanol was added and the mixture was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1). 330 mg of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was obtained as a brown solid (yield 48.2%). LC-MS: RT = 1.84 min, [M+H] + =571.36.

[0803] Step D: Synthesis of compounds 40A and 40B

[0804] Compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (330 mg, 0.57 mmol) was dissolved in methanol (10 ml), potassium carbonate (317 mg, 2.3 mmol) was added, and the mixture was heated to 70°C for overnight reaction. Water (2 ml) was added and the reaction was continued for 2 hours.

[0805] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 2.4 mg of the absolute configuration diastereomer 40A (yield: 0.9%) and 47 mg of the absolute configuration diastereomer 40B (yield: 18.1%).

[0806] Compound 40A: HPLC: RT=11.2min, LC-MS: RT=1.61min, [M+H] + =457.23.

[0807] Compound 40B: HPLC: RT = 13.8 min, LC-MS: RT = 1.61 min, [M+H] + =457.23.

[0808] 1 H NMR (400MHz, DMSO-d6) δ10.81 (t, J=2.3Hz, 1H), 8.69 (d, J=4.9Hz, 2H), 7.85-7.77 (m, 2H), 7.41 (d, J=7.7 Hz, 2H), 7.32-7.25 (m, 1H), 7.25 (d, J=2.7Hz, 1H), 6.65 (s, 1H), 6.51 (dd, J=3.1, 1.8Hz, 1H), 3.72 (s, 3H), 3.68-3.58(m, 1H), 3.28-3.22(m, 2H), 3.04-2.94(m, 1H), 2.92-2.85(m, 1H), 2.42(s, 3H), 2.1 3 (dd, J=13.1, 10.6Hz, 1H), 1.94 (q, J=12.4Hz, 2H), 1.84 (d, J=14.3Hz, 1H), 1.71-1.58 (m, 1H).

[0809] Examples 41A and 41B

[0810] Synthesis of compounds 41A and 41B

[0811] The specific synthetic route is as follows:

[0812] Step A: Synthesis of (S)-6′-(4-(methoxycarbonyl)phenyl)-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylic acid benzyl ester

[0813] Under nitrogen protection, compound (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 (800 mg, 1.67 mmol), 3-bromopyridine (395.0 mg, 2.5 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (244.1 mg, 0.33 mmol), potassium phosphate (725 mg, 3.3 mmol) were added to 1,4-dioxane (30 ml) and water (6 ml), and the temperature was raised to 95° C. to react for 12 hours.

[0814] After the reaction was complete, ethyl acetate (50 ml) was added to dilute the mixture, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1). 550 mg of (S)-6'-(4-(methoxycarbonyl)phenyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid benzyl ester was obtained as a yellow oil (yield 76.9%). LC-MS: RT = 1.91 min, [M+H] + =429.22.

[0815] Step B: Synthesis of (S)-methyl 4-(4-(pyridin-3-yl)piperidin-2-yl)benzoate

[0816] Under a hydrogen atmosphere, compound (S)-6′-(4-(methoxycarbonyl)phenyl)-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylic acid benzyl ester (550 mg, 1.28 mmol) was dissolved in ethyl acetate (20 ml), palladium / carbon (600 mg) was added, and the reaction was carried out at room temperature overnight.

[0817] After the reaction was complete, the mixture was filtered and concentrated to obtain 360 mg of a pale yellow oily product, (S)-methyl 4-(4-(pyridin-3-yl)piperidin-2-yl)benzoate (crude product), which was used directly in the next step without purification. LC-MS: RT = 0.49 min, [M+H] + =297.24.

[0818] Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridin-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0819] Compound (S)-methyl 4-(4-(pyridin-3-yl)piperidin-2-yl)benzoate (360 mg, 1.2 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (693 mg, 2.4 mmol) were dissolved in 1,2-dichloroethane (7 ml), stirred at room temperature for 1 hour, sodium triacetoxyborohydride (762.9 mg, 3.6 mmol) was added, and the temperature was raised to 40°C to react overnight.

[0820] After the reaction was complete, methanol was added and the mixture was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 2). 560 mg of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridin-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was obtained as a brown solid (yield 81.9%). LC-MS: RT = 1.82 min, [M+H] + =570.37.

[0821] Step D: Synthesis of compounds 41A and 41B

[0822] Compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridin-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (560 mg, 0.98 mmol) was dissolved in methanol (10 ml), potassium carbonate (543 mg, 3.93 mmol) was added, and the mixture was heated to 70°C for overnight reaction. Water (2 ml) was added and the reaction was continued for 2 hours.

[0823] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 55 mg of the absolute configuration diastereomer 41A (yield: 12.3%) and 270 mg of the absolute configuration diastereomer 41B (yield: 60.5%).

[0824] Compound 41A: HPLC: RT = 0.895 min, LC-MS: RT = 1.50 min, [M+H] + =456.30.

[0825] 1H NMR (400MHz, DMSO-d6) δ10.83 (d, J=2.7Hz, 1H), 8.58 (d, J=2.4Hz, 1H), 8.43 (dd, J=4.7, 1.6Hz, 1H), 7.80 (d, J=7.9 Hz, 3H), 7.43-7.34 (m, 3H), 7.25 (t, J=2.7Hz, 1H), 6.65 (s, 1H), 6.49 (dd, J=3.1, 1.8Hz, 1H), 3.75 (d, J=12.0Hz, 1H) , 3.69 (s, 3H), 3.58 (dd, J=8.4, 3.6Hz, 1H), 3.45 (d, J=12.0Hz, 1H), 3.06 (t, J=5.3Hz, 1H), 2.71-2.62 (m, 1H), 2.42 ( s, 3H), 2.28 (d, J=11.3Hz, 2H), 2.14 (ddd, J=13.5, 8.3, 4.8Hz, 1H), 2.05-1.97 (m, 1H), 1.75 (td, J=9.3, 4.5Hz, 1H).

[0826] Compound 41B: HPLC: RT = 0.800 min, LC-MS: RT = 1.50 min, [M+H] + =456.30.

[0827] 1 H NMR (400MHz, DMSO-d6) δ10.85 (t, J=2.3Hz, 1H), 8.46 (d, J=2.3Hz, 1H), 8.36 (dd, J=4.7, 1.6Hz, 1H), 7.88-7 .82 (m, 2H), 7.66 (dt, J=8.0, 2.0Hz, 1H), 7.46 (d, J=7.7Hz, 2H), 7.30-7.22 (m, 2H), 6.65 (s, 1H), 6.47 (dd, J= 3.1, 1.9Hz, 1H), 3.72 (s, 3H), 3.62 (d, J=11.8Hz, 1H), 3.29-3.25 (m, 1H), 3.23 (d, J=6.0Hz, 1H), 2.89 (dt, J=11.8, 3.3Hz, 1H ), 2.76 (s, 1H), 2.42 (s, 3H), 2.21-2.10 (m, 1H), 1.80 (t, J=9.7Hz, 2H), 1.68 (d, J=12.1Hz, 1H), 1.57 (qd, J=12.4, 3.5Hz, 1H).

[0828] Examples 42A and 42B

[0829] Synthesis of compounds 42A and 42B

[0830] The specific synthetic route is as follows:

[0831] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydro-[4,4′-bipyridine]-1(2H)-carboxylic acid benzyl ester

[0832] Under nitrogen protection, compound (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 (650 mg, 1.45 mmol), 4-bromopyridine (343.3 mg, 2.1 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (211.9 mg, 0.29 mmol), potassium phosphate (630 mg, 2.9 mmol) were added to 1,4-dioxane (20 ml) and water (4 ml), and the temperature was raised to 95° C. for 12 hours.

[0833] After the reaction was complete, ethyl acetate (50 ml) was added to dilute the mixture, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1). 390 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydro-[4,4′-bipyridine]-1(2H)-carboxylic acid benzyl ester was obtained as a yellow oil (yield 62.8%). LC-MS: RT = 1.81 min, [M+H] + =429.22.

[0834] Step B: Synthesis of (S)-methyl 4-(4-(pyridin-4-yl)piperidin-2-yl)benzoate

[0835] Under hydrogen atmosphere, compound (S)-benzyl 6-(4-(methoxycarbonyl)phenyl)-3,6-dihydro-[4,4′-bipyridine]-1(2H)-carboxylate (390 mg, 0.91 mmol) was dissolved in ethyl acetate (20 ml), palladium / carbon (400 mg) was added, and the reaction was carried out at room temperature overnight.

[0836] After the reaction was complete, the mixture was filtered and concentrated to obtain 230 mg of a pale yellow oily product, (S)-methyl 4-(4-(pyridin-4-yl)piperidin-2-yl)benzoate (crude product), which was used directly in the next step without purification. LC-MS: RT = 0.494 min, [M+H] + =297.23.

[0837] Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridin-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0838] Compound (S)-methyl 4-(4-(pyridin-4-yl)piperidin-2-yl)benzoate (230 mg, 0.77 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (450 mg, 1.55 mmol) were dissolved in 1,2-dichloroethane (5 ml), stirred at room temperature for 1 hour, sodium triacetoxyborohydride (490 mg, 2.3 mmol) was added, and the temperature was raised to 40°C for reaction overnight.

[0839] After the reaction was complete, methanol was added and the mixture was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 2). 320 mg of brown solid (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridin-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester was obtained (yield 72.9%). LC-MS: RT = 1.79 min, [M+H] + =570.33.

[0840] Step D: Synthesis of compounds 42A and 42B

[0841] Compound (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridin-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (320 mg, 0.56 mmol) was dissolved in methanol (15 ml), potassium carbonate (310 mg, 2.24 mmol) was added, and the mixture was heated to 70°C for overnight reaction. Water (2 ml) was added and the reaction was continued for 2 hours.

[0842] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 40 mg of the absolute configuration diastereomer 42A (yield: 15.6%) and 170 mg of the absolute configuration diastereomer 42B (yield: 66.7%).

[0843] Compound 42A: HPLC: RT = 0.993 min, LC-MS: RT = 1.50 min, [M+H] + =456.29.

[0844] 1H NMR (400MHz, DMSO-d6) δ10.82 (s, 1H), 8.56-8.50 (m, 2H), 7.80 (d, J=7.9Hz, 2H), 7.43-7.36 (m, 4 H), 7.25 (t, J=2.7Hz, 1H), 6.64 (s, 1H), 6.48 (dd, J=3.0, 1.7Hz, 1H), 3.68 (s, 3H), 3.49 (dd, J=8.6 , 3.3Hz, 1H), 3.37 (s, 2H), 3.02 (t, J=5.1Hz, 1H), 2.64 (dd, J=11.6, 6.3Hz, 1H), 2.41 (s, 3H), 2.2 7 (d, J=14.2Hz, 1H), 2.22-2.07 (m, 2H), 2.02 (d, J=13.4Hz, 1H), 1.77 (td, J=9.6, 9.1, 5.0Hz, 1H).

[0845] Compound 42B: HPLC: RT = 0.786 min, LC-MS: RT = 1.50 min, [M+H] + =456.29.

[0846] 1 H NMR (400MHz, DMSO-d6) δ10.85 (t, J=2.4Hz, 1H), 8.448.38 (m, 2H), 7.85 (d, J=7.9Hz, 2H), 7.45 (d, J=7.7H z, 2H), 7.28-7.22 (m, 3H), 6.65 (s, 1H), 6.46 (dd, J=3.0, 1.9Hz, 1H), 3.72 (s, 3H), 3.61 (d, J=11.8Hz, 1H), 3.28-3.20(m, 2H), 2.89(dt, J=11.8, 3.3Hz, 1H), 2.74(tt, J=12.0, 3.8Hz, 1H), 2.42( s, 3H), 2.14 (td, J=11.9, 2.3Hz, 1H), 1.88-1.65 (m, 3H), 1.54 (qd, J=12.4, 3.5Hz, 1H).

[0847] Examples 43A and 43B

[0848] Synthesis of compounds 43A and 43B

[0849] The specific synthetic route is as follows:

[0850] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0851] To a solution of benzyl (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (400 mg, 0.84 mmol) in 1,4-dioxane (5 ml) at room temperature were added 5-bromopyrimidine (200 mg, 1.26 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (61 mg, 0.08 mmol), potassium phosphate (446 mg, 2.10 mmol) and water (1 ml). The atmosphere was replaced with nitrogen and the temperature was raised to 90°C for reaction overnight.

[0852] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to afford 150 mg of (S)-benzyl 6-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate as a pale yellow oily liquid (yield: 42%). LC-MS: RT = 1.97 min, [M+H] + =430.22.

[0853] Step B: Synthesis of (S)-methyl 4-(4-(pyrimidin-5-yl)piperidin-2-yl)benzoate

[0854] Benzyl (S)-6-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (250 mg, 0.58 mmol) was dissolved in ethyl acetate solution (10 ml), palladium carbon (100 mg) was added, the hydrogen atmosphere was replaced, and the temperature was raised to 60°C for reaction overnight.

[0855] After the reaction was complete, the mixture was filtered, washed with ethyl acetate, and concentrated to obtain 100 mg of a light yellow oily liquid (S)-methyl 4-(4-(pyrimidin-5-yl)piperidin-2-yl)benzoate (yield: 59%). LC-MS: RT = 1.49 min, [M+H] + =298.22.

[0856] Step C: Synthesis of (S)-5-methoxy-4-(2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-5-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate tert-butyl ester

[0857] To a solution of (S)-methyl 4-(4-(pyrimidin-5-yl)piperidin-2-yl)benzoate (100 mg, 0.34 mmol) in 1,2-dichloroethane (5 ml) were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (246 mg, 0.85 mmol) and sodium triacetoxyborohydride (144 mg, 0.68 mmol), and the mixture was heated to 40°C and reacted overnight.

[0858] After the reaction was complete, methanol was added and the mixture was concentrated to dryness. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to afford 145 mg of a pale yellow oily substance: (S)-tert-butyl 5-methoxy-4-(2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-5-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (yield: 74%). LC-MS: RT = 1.84 min, [M+H] + =571.31.

[0859] Step D: Synthesis of compounds 43A and 43B

[0860] To a solution of tert-butyl (S)-5-methoxy-4-(2-(4-(methoxycarbonyl)phenyl)-4-(pyrimidin-5-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (145 mg, 0.25 mmol) in methanol (5 ml) was added potassium carbonate (138 mg, 1.00 mmol), the mixture was heated to 70°C for 5 hours, and water (1 ml) was added and the reaction was continued for 4 hours.

[0861] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 16.8 mg of the absolute configuration diastereomer 43A (yield: 15%) and 56.4 mg of the absolute configuration diastereomer 43B (yield: 49%).

[0862] Compound 43A: HPLC: RT = 12.8 min, LC-MS: RT = 1.59 min, [M+H] + =457.29.

[0863] Compound 43B: HPLC: RT = 13.4 min, LC-MS: RT = 1.59 min, [M+H] + =457.29. 1H NMR (400MHz, DMSO-d6) δ10.81 (s, 1H), 8.99 (s, 1H), 8.71 (s, 2H), 7.83 (d, J=7.9Hz, 2H), 7.43 (d, J=7.7Hz, 2H), 7.24 (t, J=2.7Hz, 1H), 6.65 (s, 1H), 6.45 (dd, J=3.1, 1.7Hz, 1H), 3.72 (s, 3H), 3.6 1(d, J=11.8Hz, 1H), 3.28-3.23(m, 2H), 3.21(d, J=11.7Hz, 1H), 2.93-2.86(m, 1H), 2.42(s, 3H), 2.20-2.10 (m, 1H), 1.85 (t, J=8.9Hz, 2H), 1.71 (d, J=12.3Hz, 1H), 1.62 (dd, J=12.3, 3.6Hz, 1H).

[0864] Examples 44A and 44B

[0865] The specific synthetic route is as follows:

[0866] Step A: Synthesis of (S)-4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0867] To a solution of benzyl (S)-6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, 2.09 mmol) in dioxane (10 ml) was added 2-bromo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (587 mg, 3.14 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (154 mg, 0.21 mmol) and potassium phosphate (1.11 g, 5.23 mmol) at room temperature. Water (2 ml) was then added, the reaction atmosphere was replaced with nitrogen, and the temperature was raised to 90° C. for 5 hours.

[0868] After completion of the reaction, the mixture was filtered and washed with ethyl acetate, and the organic phase was directly concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1) to obtain 540 mg of (S)-benzyl 4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate as a pale yellow oily liquid (yield: 57%). LCMS: RT = 1.77 min, [M+H] + =458.29.

[0869] Step B: Synthesis of (S)-methyl 4-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)piperidin-2-yl)benzoate

[0870] (S)-4-(6,7-Dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (540 mg, 1.18 mmol) was dissolved in ethyl acetate solution (20 ml), palladium carbon (300 mg) was added, and after the reaction replaced hydrogen, the temperature was raised to 50°C and the reaction was carried out for 2 hours.

[0871] After the reaction, the mixture was filtered and washed with ethyl acetate. The organic phase was directly concentrated under reduced pressure to obtain 240 mg of (S)-methyl 4-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)piperidin-2-yl)benzoate as a light yellow oil (yield: 63%). LCMS: RT = 0.26 min, [M+H] + =326.30.

[0872] Step C: Synthesis of (S)-4-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0873] To a solution of (S)-methyl 4-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)piperidin-2-yl)benzoate (240 mg, 0.74 mmol) in 1,2-dichloroethane (10 ml) were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (535 mg, 1.85 mmol) and sodium triacetoxyborohydride (314 mg, 1.48 mmol), and the mixture was reacted at 40°C overnight.

[0874] After the reaction was completed, a small amount of methanol was added and the solvent was directly evaporated. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain 158 mg of (S)-tert-butyl 4-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate as a light yellow oily liquid (yield: 35%). LCMS: RT = 1.70 min, [M+H] + =599.34.

[0875] Step D: Synthesis of compounds 44A and 44B

[0876] To a solution of (S)-tert-butyl 4-(4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (158 mg, 0.26 mmol) in methanol (5 mL) was added potassium carbonate (144 mg, 1.04 mmol), and the solution was heated to 70° C. for 5 hours. Water (1 mL) was then added, and heating at 70° C. was continued for 4 hours.

[0877] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 4.4 mg of the absolute configuration diastereomer 44A (yield: 3%) and 8.7 mg of the absolute configuration diastereomer 44B (yield: 7%).

[0878] Compound 44A: HPLC: RT = 3.707 min, LCMS: RT = 1.52 min, [M+H] + =485.31.

[0879] Compound 44B: HPLC: RT = 3.995 min, LCMS: RT = 1.52 min, [M+H] + =485.31.

[0880] 1 H NMR (400MHz, DMSO-d6) δ10.80 (s, 1H), 7.81 (d, J = 7.8Hz, 2H), 7.38 (d, J = 7.7Hz, 2H), 7.23 (t, J = 2.7Hz, 1H), 6. 68 (s, 1H), 6.64 (s, 1H), 6.47 (t, J = 2.4Hz, 1H), 3.80 (t, J = 7.0Hz, 2H), 3.71 (s, 3H), 3.58 (d, J = 11.9Hz, 1H), 3. 22-3.14 (m, 2H), 2.81 (dt, J=11.7, 3.4Hz, 1H), 2.65-2.58 (m, 2H), 2.58-2.52 (m, 1H), 2.46-2.35 (m, 5H), 2.05 (t, J=11.9Hz, 1H), 1.89 (d, J=12.7Hz, 1H), 1.74 (d, J=12.7Hz, 1H), 1.64 (q, J=12.3Hz, 1H), 1.45-1.31 (m, 1H).

[0881] Example 45

[0882] The synthetic route of compound 45 is as follows:

[0883] Step A: Synthesis of (S)-6-methoxy-6′-(4-(methoxycarbonyl)phenyl)-3′,6′-dihydro-[2,4′-bipyridine]-1(2H)-carboxylic acid benzyl ester

[0884] Compound (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 (700.0 mg, 1.46 mmol), 2-bromo-6-methoxypyridine (258.4 mg, 2.2 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (213.4 mg, 0.29 mmol), and potassium phosphate (634.4 mg, 2.92 mmol) were added to 1,4-dioxane (20 ml) and water (4 ml), and the reaction was carried out at 95°C under nitrogen protection for 12 hours.

[0885] After the reaction was completed, ethyl acetate (50 ml) was added to dilute the mixture, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1). 500.0 mg of (S)-6-methoxy-6'-(4-(methoxycarbonyl)phenyl)-3',6'-dihydro-[2,4'-bipyridine]-1(2H)-carboxylic acid benzyl ester was obtained as a dark yellow solid (yield 74.7%). LCMS: RT = 2.29 min, [M+H] + =459.24.

[0886] Step B: Synthesis of (S)-methyl 4-(4-(6-methoxypyridin-2-yl)piperidin-2-yl)benzoate

[0887] Compound (S)-6-methoxy-6′-(4-(methoxycarbonyl)phenyl)-3′,6′-dihydro-[2,4′-bipyridine]-1(2H)-carboxylic acid benzyl ester (500 mg, 1.1 mmol) was dissolved in ethyl acetate (20 ml), palladium / carbon (500 mg) was added, and the mixture was reacted at room temperature under hydrogen protection for 12 hours.

[0888] After the reaction was complete, the mixture was filtered and concentrated under reduced pressure to obtain 340 mg of methyl (S)-4-(4-(6-methoxypyridin-2-yl)piperidin-2-yl)benzoate as a yellow oil, which was used directly in the next step without purification. LCMS: RT = 1.65 min, [M+H] + =327.26.

[0889] Step C: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(6-methoxypyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0890] Compound (S)-methyl 4-(4-(6-methoxypyridin-2-yl)piperidin-2-yl)benzoate (340.0 mg, 1.0 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (578.0 mg, 2.0 mmol) were dissolved in 1,2-dichloroethane (7 ml), stirred at room temperature for 12 hours, and then sodium triacetoxyborohydride (635.8 mg, 3.0 mmol) was slowly added and reacted at 40°C for 4 hours.

[0891] After the reaction is completed, methanol is added to dissolve until clear, and finally concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1). 300 mg of light yellow solid (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(6-methoxypyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester are obtained (yield 50.0%). LCMS: RT = 1.95 min, [M+H] + =600.34.

[0892] Step D: Synthesis of compound 45

[0893] Compound (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(6-methoxypyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (300 mg, 0.5 mmol) was dissolved in methanol (20 ml), potassium carbonate (276.0 mg, 2.0 mmol) was added, and the mixture was heated to 70°C and stirred overnight. Water (1 ml) was then added, and the mixture was reacted at 70°C for 12 hours.

[0894] After the reaction was completed, the purification and chiral separation method described in Step D of Example 3 were used to obtain 25.0 mg of the absolute configuration diastereomer 45 (yield: 10.3%).

[0895] Compound 45: HPLC: RT = 3.489 min, LCMS: RT = 1.70 min, [M+H] + =486.27.

[0896] 1H NMR (400MHz, DMSO-d6) δ10.82 (d, J=2.7Hz, 1H), 7.82 (d, J=7.8Hz, 2H), 7.60-7.52 (m, 1H), 7.41 (d, J=7.6Hz, 2 H), 7.25 (t, J=2.8Hz, 1H), 6.81 (d, J=7.3Hz, 1H), 6.65 (s, 1H), 6.57 (d, J=8.2Hz, 1H), 6.46 (dd, J=3.1, 1.8Hz, 1H), 3.79 (s, 3H), 3.72 (s, 3H), 3.61 (d, J=11.8Hz, 1H), 3.28-3.17 (m, 2H), 2.92-2.85 (m, 1H), 2.82-2.71 (m, 1 H), 2.42 (s, 3H), 2.18-2.07 (m, 1H), 1.84 (dt, J=24.2, 13.2Hz, 2H), 1.74 (d, J=12.9Hz, 1H), 1.69-1.55 (m, 1H).

[0897] Compounds 46A and 46B

[0898] The specific synthetic route is as follows:

[0899] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(5-methylthiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0900] Compound (S)-benzyl 6-(4-(methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (800.0 mg, 1.67 mmol), 2-bromo-5-methylthiophene (445.0 mg, 2.5 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (244.0 mg, 0.33 mmol), and potassium phosphate (725.0 mg, 3.34 mmol) were added to 1,4-dioxane (20 ml) and water (4 ml). The mixture was reacted at 95° C. under nitrogen protection for 12 hours.

[0901] After the reaction was completed, ethyl acetate (50 ml) was added to dilute the mixture, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1). 390.0 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(5-methylthiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester was obtained as a dark yellow solid (yield 52.2%). LCMS: RT = 2.30 min, [M+H] +=448.22.

[0902] Step B: Synthesis of methyl 4-((2S)-4-(5-methylthiophen-2-yl)piperidin-2-yl)benzoate

[0903] Compound (S)-benzyl 6-(4-(methoxycarbonyl)phenyl)-4-(5-methylthiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (390.0 mg, 0.87 mmol) was dissolved in ethyl acetate (25 ml), palladium / carbon (390 mg) was added, and the mixture was reacted at 60°C under hydrogen protection for 36 hours.

[0904] After the reaction was complete, the mixture was filtered and concentrated under reduced pressure to obtain 210.0 mg of methyl 4-((2S)-4-(5-methylthiophen-2-yl)piperidin-2-yl)benzoate as a yellow oil, which was used directly in the next step without purification. LCMS: RT = 1.73 min, [M+H] + =316.19.

[0905] Step C: Synthesis of tert-butyl 5-methoxy-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(5-methylthiophen-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0906] Compound 4-((2S)-4-(5-methylthiophen-2-yl)piperidin-2-yl)benzoic acid methyl ester (210.0 mg, 0.66 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (381.4 mg, 1.32 mmol) were dissolved in 1,2-dichloroethane (6 ml), stirred at room temperature for 12 hours, and then sodium triacetoxyborohydride (420 mg, 1.98 mmol) was slowly added and reacted at 40°C for 4 hours.

[0907] After the reaction is completed, methanol is added to dissolve until clear, and finally concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1). 240 mg of light yellow gum 5-methoxy-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(5-methylthiophen-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester is obtained (yield 61.7%). LCMS: RT = 1.97 min, [M+H] + =589.33.

[0908] Step D: Synthesis of compounds 46A and 46B

[0909] Tert-butyl 5-methoxy-(((2S)-2-(4-(methoxycarbonyl)phenyl)-4-(5-methylthiophen-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (240 mg, 0.53 mmol) was dissolved in methanol (5 ml), potassium carbonate (292.5 mg, 2.1 mmol) was added, and the mixture was heated to 70°C and stirred overnight. Water (2 ml) was then added, and the mixture was reacted at 70°C for 2 hours.

[0910] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 25.0 mg of the absolute configuration diastereomer 46A (yield: 10.0%) and 35.0 mg of the absolute configuration diastereomer 46B (yield: 13.9%).

[0911] Compound 46A: HPLC: RT = 3.587 min, LCMS: RT = 1.75 min, [M+H] + =475.26.

[0912] Compound 46B: HPLC: RT = 3.590 min, LCMS: RT = 1.75 min, [M+H] + =475.26.

[0913] 1 H NMR (400MHz, DMSO-d6) δ10.82 (d, J=2.9Hz, 1H), 7.88 (d, J=7.9Hz, 2H), 7.50 (d, J=7.7Hz, 2H), 7.25 (t, J=2.8Hz, 1H ), 6.65 (s, 1H), 6.59 (d, J = 3.5Hz, 1H), 6.55 (d, J = 3.6Hz, 1H), 6.45 (t, J = 2.5Hz, 1H), 3.71 (s, 3H), 3.57 (d, J = 11.8H z, 1H), 3.27 (dd, J=11.1, 2.7Hz, 1H), 3.20 (d, J=11.8Hz, 1H), 2.95-2.79 (m, 2H), 2.41 (s, 3H), 2.33 (s, 3H), 2.11 (t , J=11.8Hz, 1H), 1.98-1.86 (m, 1H), 1.80 (d, J=12.7Hz, 1H), 1.66 (q, J=12.1Hz, 1H), 1.44 (tt, J=13.7, 7.0Hz, 1H).

[0914] Example 47

[0915] The specific synthetic route is as follows:

[0916] Step A: Synthesis of (S)-4-(3,6-dichloropyridazin-4-yl)-6-(4-methoxycarbonyl)phenyl-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0917] Compound (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), 4-bromo-3,6-dichloropyridazine (335 mg, 1.47 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (108 mg, 0.147 mmol), and sodium bicarbonate (247 mg, 2.94 mmol) were added to 1,4-dioxane (20 ml), and 5 ml of water were added, and the mixture was reacted at 80°C under nitrogen protection for 12 hours.

[0918] After the reaction was completed, ethyl acetate (50 ml) was added to dilute the mixture, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1). 500 mg of (S)-4-(3,6-dichloropyridazin-4-yl)-6-(4-methoxycarbonyl)phenyl-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester was obtained as a yellow oil (yield 68%). LCMS: RT = 2.16 min, [M+H] + =498.17.

[0919] Step B: Synthesis of (S)-methyl 4-(4-(pyridazin-4-yl)piperidin-2-yl)benzoate

[0920] Compound (S)-4-(3,6-dichloropyridazin-4-yl)-6-(4-methoxycarbonyl)phenyl-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (110 mg, 0.25 mmol) was dissolved in isopropanol (20 ml) / ethyl acetate (2 ml), and palladium / carbon (200 mg) and sodium bicarbonate (168 mg, 2 mmol) were added, and the mixture was reacted at room temperature under a hydrogen atmosphere for 5 hours.

[0921] After the reaction was complete, the mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 10 / 1) to afford 150 mg of (S)-methyl 4-(4-(pyridazin-4-yl)piperidin-2-yl)benzoate as a yellow gum (yield 63%). LCMS: RT = 1.49 min, [M+H] + =298.22.

[0922] Step C: Synthesis of (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridazin-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0923] Compound (S)-methyl 4-(4-(pyridazin-4-yl)piperidin-2-yl)benzoate (150 mg, 0.5 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (292 mg, 1.0 mmol) were dissolved in 1,2-dichloroethane (8 ml) and stirred at room temperature for 4 hours. Sodium triacetoxyborohydride (320 mg, 1.5 mmol) was then added and the reaction was continued overnight.

[0924] After the reaction is completed, methanol is added to dissolve until clear, and finally concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1). 240 mg of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridazin-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester is obtained as a yellow oil (yield 83%). LCMS: RT = 1.81 min, [M+H] + =571.35.

[0925] Step D: Synthesis of compound 47

[0926] Compound (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(pyridazin-4-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (240 mg, 0.42 mmol) was dissolved in methanol (10 ml), potassium carbonate (580 mg, 4.2 mmol) was added, and the mixture was heated to 60°C and stirred overnight. Water (2 ml) was then added, and the mixture was reacted at 60°C for 4 hours.

[0927] After the reaction was completed, the solution was concentrated under vacuum and the purification and chiral separation method in Step D of Example 3 were used to separate 162.8 mg of the absolute configuration diastereomer 47 (yield: 84%).

[0928] Compound 47: HPLC: RT = 3.554 min, LCMS: RT = 1.57 min, [M+H] + =475.28.

[0929] 1H NMR (400MHz, DMSO-d6) δ10.85 (s, 1H), 9.18 (s, 1H), 9.05 (d, J=8.0Hz, 2H), 7.84 (d, J=8.0Hz, 2H), 7.60-7.53(m, 1H), 7.44(d, J=8.0Hz, 2H), 7.28-7.22(m, 1H), 6.66(s , 1H), 6.48-6.43(m, 1H), 3.73(s, 3H), 3.64-3.58(m, 1H), 3.30-3.17(m, 2H), 2.94- 2.76(m, 2H), 2.43(s, 3H), 2.21-2.11(m, 1H), 1.91-1.68(m, 3H), 1.63-1.51(m, 1H).

[0930] Examples 48A and 48B

[0931] The specific synthetic route is as follows:

[0932] Step A: Synthesis of (S)-6-((4-methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0933] To a solution of benzyl (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (700 mg, 1.47 mmol) in dioxane (10 ml) at room temperature were added 2-bromo-5-(trifluoromethyl)thiophene (374 mg, 1.62 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (110 mg, 0.15 mmol) and potassium phosphate (624 mg, 2.94 mmol). Water (2 ml) was then added, and the reaction atmosphere was replaced with nitrogen. The temperature was then raised to 95° C. for overnight reaction.

[0934] After the reaction, the mixture was filtered and washed with ethyl acetate. The organic phase was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to afford 306 mg of (S)-benzyl 6-((4-methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate as a pale yellow oil (yield: 41%). LCMS: RT = 2.29 min, [M+H] + =502.21.

[0935] Step B: Synthesis of (S)-methyl 4-(4-(5-trifluoromethyl)thiophen-2-yl)piperidin-2-ylbenzoate

[0936] Benzyl (S)-6-((4-methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (306 mg, 0.61 mmol) was dissolved in ethyl acetate solution (20 ml), and palladium carbon (300 mg) was added. After the reaction replaced hydrogen, the temperature was raised to 50°C and the reaction was carried out for 6 hours.

[0937] After the reaction, the mixture was filtered and washed with ethyl acetate. The organic phase was directly concentrated under reduced pressure to obtain 200 mg of a light yellow oily liquid (S)-methyl 4-(4-(5-trifluoromethyl)thiophen-2-yl)piperidin-2-ylbenzoate (yield: 89%). LCMS: RT = 0.26 min, [M+H] + =326.30.

[0938] Step C: Synthesis of (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0939] To a solution of (S)-methyl 4-(4-(5-trifluoromethyl)thiophen-2-yl)piperidin-2-ylbenzoate (200 mg, 0.74 mmol) in 1,2-dichloroethane (10 ml) were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (390 mg, 1.35 mmol) and sodium triacetoxyborohydride (229 mg, 1.08 mmol), and the mixture was reacted at 40°C overnight.

[0940] After the reaction, a small amount of methanol was added and the solvent was directly evaporated. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain 187 mg of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester as a light yellow oily liquid (yield: 54%). LCMS: RT = 2.04 min, [M+H] + =643.29.

[0941] Step D: Synthesis of compounds 48A and 48B

[0942] To a solution of tert-butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (187 mg, 0.29 mmol) in methanol (5 ml) was added potassium carbonate (160 mg, 1.16 mmol), the mixture was heated to 70°C for 5 hours, and water (1 ml) was added and the reaction was continued for 4 hours.

[0943] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 17.2 mg of the absolute configuration diastereomer 48A (yield: 3%) and 4.8 mg of the absolute configuration diastereomer 48B (yield: 7%).

[0944] Compound 48A: HPLC: RT = 3.663 min, LCMS: RT = 1.82 min, [M+H] + =529.23.

[0945] Compound 48B: HPLC: RT = 3.672 min, LCMS: RT = 1.82 min, [M+H] + =529.23.

[0946] Examples 49A and 49B

[0947] The synthetic routes of compounds 49A and 49B are as follows:

[0948] Step A: Synthesis of (S)-6-(4-cyanophenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0949] At room temperature, to a solution of (S)-6-(4-cyanophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (3 g, 6.74 mmol) in dioxane (20 ml) were added 2-bromopyrazine (1.60 g, 10.11 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (740 mg, 1.01 mmol) and potassium phosphate (3.93 g, 13.48 mmol). Water (4 ml) was then added, the reaction mixture was purged with nitrogen, and the temperature was raised to 95°C for 5 hours.

[0950] After the reaction, the mixture was filtered, washed with ethyl acetate, and the liquid phase was directly concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1:5) to obtain 2.5 g of (S)-6-(4-cyanophenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester as a pale yellow oily liquid (yield: 93%). LCMS: RT = 2.06 min, [M+H] + =397.21.

[0951] Step B: Synthesis of (S)-6-(4-(2H-tetrazol-5-yl)phenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0952] To a solution of (S)-6-(4-cyanophenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (2.20 g, 5.54 mmol) in N,N-dimethylformamide (15 ml) at room temperature were added trimethylsilyl azide (1.30 g, 11.08 mmol) and 2M tetrabutylammonium fluoride (1.1 ml). The mixture was protected with nitrogen and the temperature was raised to 80°C for reaction.

[0953] After completion of the reaction, the product was quenched with water and extracted with ethyl acetate. The organic phase was dried and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1:3) to afford 900 mg of (S)-6-(4-(2H-tetrazol-5-yl)phenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester as a pale yellow oily liquid (yield: 37%). LCMS: RT = 1.90 min, [M+H] + =440.27.

[0954] Step C: Synthesis of (S)-2-(2-(4-(2H-tetrazol-5-yl)phenylpiperidin-4-ylpyrazine

[0955] (S)-6-(4-(2H-tetrazol-5-yl)phenyl-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (900 mg, 2.05 mmol) was dissolved in a mixed solvent of ethyl acetate solution (10 ml) and methanol (20 ml), and palladium carbon (450 mg) was added. After the reaction replaced hydrogen, the reaction was allowed to react at room temperature for 0.5 hour.

[0956] After the reaction, the mixture was filtered and washed with methanol. The liquid phase was directly concentrated under reduced pressure to obtain 750 mg of a light yellow oily liquid (S)-2-(2-(4-(2H-tetrazol-5-yl)phenylpiperidin-4-ylpyrazine. LCMS: RT = 1.60 min, [M+H] + =308.19.

[0957] Step D: Synthesis of (S)-5-methoxy-4-(2-(4-(2H-tetrazol-5-yl)phenyl-4-(pyrazin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0958] To a solution of (S)-2-(2-(4-(2H-tetrazol-5-yl)phenylpiperidin-4-ylpyrazine (350 mg, 1.14 mmol) in methanol (10 ml) were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (494 mg, 1.71 mmol) and sodium cyanoborohydride (350 mg), and the mixture was reacted at 40°C overnight.

[0959] After the reaction was completed, a small amount of methanol was added and the solvent was directly evaporated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1:1) to obtain 230 mg of (S)-5-methoxy-4-(2-(4-(2H-tetrazol-5-yl)phenyl-4-(pyrazin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester as a white solid (yield: 35%). LCMS: RT = 1.82 min, [M+H] + =581.32.

[0960] Step E: Compounds 49A and 49B

[0961] To a solution of (S)-tert-butyl 5-methoxy-4-(2-(4-(2H-tetrazol-5-yl)phenyl-4-(pyrazin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (230 mg, 0.40 mmol) in methanol (15 mL) and (3 mL) water was added sodium hydroxide (64 mg, 1.59 mmol) and the solution was heated to 80°C for 3 hours. The solution was concentrated under vacuum and separated using the purification and chiral resolution methods of Example 3, Step D to give 5 mg of the absolute configuration of diastereomer 49A and 5 mg of the absolute configuration of diastereomer 49B.

[0962] Compound 49A: HPLC: RT = 9.8 min, LCMS: RT = 1.63 min, [M+H] + =481.27.

[0963] Compound 49B: HPLC: RT = 11.5 min, LCMS: RT = 1.63 min, [M+H] + =481.27.

[0964] Example 50

[0965] The synthetic route of compound 50 is as follows:

[0966] Step A: Synthesis of (S)-6-((4-methoxycarbonyl)phenyl)-4-(5-fluoropyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0967] To a solution of benzyl (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (700 mg, 1.47 mmol) in dioxane (30 ml) at room temperature were added 2-bromo-5-fluoropyridine (387 mg, 2.20 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (106 mg, 0.15 mmol) and potassium phosphate (778 mg, 3.67 mmol). Water (6 ml) was then added, the reaction atmosphere was replaced with nitrogen, and the temperature was raised to 90° C. for 5 hours.

[0968] After completion of the reaction, the mixture was filtered and washed with ethyl acetate. The organic phase was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 6 / 1) to afford 330 mg of (S)-benzyl 6-((4-methoxycarbonyl)phenyl)-4-(5-fluoropyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate as a pale yellow oily liquid (yield: 50%). LCMS: RT = 2.18 min, [M+H] + =447.22.

[0969] Step B: Synthesis of (S)-methyl 4-(4-(5-fluoropyridin-2-yl)piperidin-2-ylbenzoate

[0970] Benzyl (S)-6-((4-methoxycarbonyl)phenyl)-4-(5-fluoropyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (330 mg, 0.74 mmol) was dissolved in ethyl acetate solution (15 ml), and palladium carbon (33 mg) was added. After the reaction replaced hydrogen, the temperature was raised to 60°C and the reaction was carried out overnight.

[0971] After the reaction, the mixture was filtered and washed with ethyl acetate. The organic phase was directly concentrated under reduced pressure to obtain 215 mg of colorless oily liquid (S)-4-(4-(5-fluoropyridin-2-yl)piperidin-2-ylbenzoic acid methyl ester (yield: 92%). LCMS: RT = 1.59 min, [M+H] + =315.22.

[0972] Step C: Synthesis of (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(5-fluoropyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[0973] To a solution of (S)-methyl 4-(4-(5-fluoropyridin-2-yl)piperidin-2-ylbenzoate (215 mg, 0.68 mmol) in 1,2-dichloroethane (15 ml) were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (495 mg, 1.71 mmol) and sodium triacetoxyborohydride (580 mg, 2.74 mmol), and the mixture was reacted at 40° C. overnight.

[0974] After the reaction was completed, a small amount of methanol was added and the solvent was directly evaporated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to obtain 270 mg of (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(5-fluoropyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester as a yellow oil (yield: 69%). LCMS: RT = 1.95 min, [M+H] + =588.35.

[0975] Step D: Synthesis of Compound 50

[0976] To a solution of tert-butyl (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(5-fluoropyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (277 mg, 0.47 mmol) in methanol (15 ml) was added potassium carbonate (651 mg, 4.71 mmol), the mixture was heated to 70°C for 5 hours, and water (1 ml) was added and the reaction was continued for 4 hours.

[0977] After the reaction was completed, the mixture was filtered through diatomaceous earth, the filter cake was washed with methanol, and the filtrate was concentrated and the chiral separation method in step D of Example 3 was used to separate 147 mg of the absolute configuration diastereomer 50 (yield: 66%).

[0978] Compound 50: HPLC: RT = 3.35 min, LCMS: RT = 1.66 min, [M+H] + =474.27.

[0979] 1H NMR (400MHz, DMSO-d6) δ10.85 (t, J=2.3Hz, 1H), 8.43 (d, J=3.0Hz, 1H), 7.92 (d, J=7.9Hz, 2H), 7.59 (ddt , J=8.6, 5.8, 2.9Hz, 3H), 7.35 (dd, J=8.7, 4.5Hz, 1H), 7.27 (t, J=2.8Hz, 1H), 6.66 (s, 1H), 6.49 (t, J=2. 5Hz, 1H), 3.73 (s, 3H), 3.33 (dd, J=10.2, 3.8Hz, 2H), 3.24 (d, J=11.8Hz, 2H), 2.90 (dd, J=9.7, 5.9Hz, 2H ), 2.42 (s, 3H), 2.20-2.10 (m, 1H), 1.93-1.80 (m, 2H), 1.77-1.70 (m, 1H), 1.62 (tt, J=13.9, 6.9Hz, 1H).

[0980] Example 51

[0981] The synthetic route of compound 51 is as follows:

[0982] Step A: Synthesis of 4-bromo-2-(difluoromethyl)thiophene

[0983] Under ice-cooling, diethylaminosulfur trifluoride (4.19 g, 13.1 mmol) was added to dichloromethane (30 ml) containing 4-bromothiophene-2-carboxaldehyde (2.0 g, 10.4 mmol). After the addition was complete, the temperature was raised to 40°C and the mixture was reacted for 12 hours.

[0984] After the reaction, the reaction solution was poured into an ice-cold saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (10 ml x 3 times). The organic phases were combined, dried, and spin-dried. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane) to obtain 1.7 g of colorless liquid 4-bromo-2-(difluoromethyl)thiophene (yield: 76.9%).

[0985] Step B: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(5-(difluoromethyl)thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[0986] To a solution of benzyl (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.2 g, 2.51 mmol) in dioxane (20 ml) at room temperature were added 4-bromo-2-(difluoromethyl)thiophene (809.4 mg, 3.8 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (365.5 mg, 0.5 mmol) and potassium phosphate (1.1 g, 5.0 mmol), followed by the addition of water (4 ml). The reaction mixture was purged with nitrogen and heated to 95° C. for 12 hours.

[0987] After completion of the reaction, the mixture was filtered, washed with ethyl acetate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 700 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(5-(difluoromethyl)thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester as a pale yellow oily liquid (yield: 57.7%). LCMS: RT = 2.21 min, [M+H] + =484.20.

[0988] Step C: Synthesis of (S)-methyl 4-(4-(5-(difluoromethyl)thiophen-3-yl)piperidin-2-yl)benzoate

[0989] Benzyl (S)-6-(4-(methoxycarbonyl)phenyl)-4-(5-(difluoromethyl)thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (700 mg, 1.4 mmol) was dissolved in ethyl acetate solution (25 ml), and palladium carbon (600 mg) was added. After the reaction replaced hydrogen, the temperature was raised to 60°C and the reaction was carried out for 24 hours.

[0990] After the reaction, the mixture was filtered and washed with ethyl acetate. The liquid phase was directly concentrated under reduced pressure to obtain 300 mg of colorless oily liquid (S)-methyl 4-(4-(5-(difluoromethyl)thiophen-3-yl)piperidin-2-yl)benzoate. LCMS: RT = 1.70 min, [M+H] + =352.14.

[0991] Step D: Synthesis of (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-(difluoromethyl)thiophen-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[0992] To a solution of (S)-methyl 4-(4-(5-(difluoromethyl)thiophen-3-yl)piperidin-2-yl)benzoate (300 mg, 0.86 mmol) in dichloroethane (5 ml) was added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (495 mg, 1.71 mmol), and the mixture was stirred at room temperature for 12 hours. Then, sodium triacetoxyborohydride (546.8 mg, 2.58 mmol) was slowly added and the mixture was reacted at 40°C for 4 hours.

[0993] After the reaction was completed, a small amount of methanol was added and the solvent was directly evaporated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 9 / 1) to obtain 200 mg of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-(difluoromethyl)thiophen-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester as a white solid (yield: 41%). LCMS: RT = 1.95 min, [M+H] + =625.31.

[0994] Step E: Synthesis of Compound 51

[0995] To a solution of tert-butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (40 mg, 0.07 mmol) in methanol (5 ml) was added potassium carbonate (39 mg, 0.28 mmol), the mixture was heated to 70°C for 5 hours, and water (1 ml) was added and the reaction was continued for 4 hours.

[0996] After the reaction was completed, the product was concentrated and dried, and 20 ml of a 10 / 1 dichloromethane / methanol mixed solvent was added. The product was filtered and the filtrate was dried to give a crude product. The chiral separation method in Step D of Example 3 was used to separate the diastereomer 51 with an absolute configuration of 75.0 (yield: 50.0%).

[0997] Compound 51: HPLC: RT = 3.86 min, LCMS: RT = 1.75 min, [M+H] + =511.24.

[0998] 1H-NMR (400MHz, DMSO-d6) δ10.82 (t, J=2.3Hz, 1H), 7.82 (d, J=7.9Hz, 2H), 7.45-7 .37(m, 4H), 7.3-7.05(m, 2H), 6.65(s, 1H), 6.49-6.43(m, 1H), 3.71(s, 3H), 3.59( d, J=11.8Hz, 1H), 3.26-3.16 (m, 2H), 2.88-2.73 (m, 2H), 2.41 (s, 3H), 2.10 (dd, J= 13.0, 10.5Hz, 1H), 1.91 (d, J=12.7Hz, 1H), 1.81-1.63 (m, 2H), 1.52-1.38 (m, 1H).

[0999] Examples 52A and 52B

[1000] The synthetic routes of compounds 52A and 52B are as follows:

[1001] Step A: Synthesis of (S)-6-(4-cyanophenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[1002] To a solution of benzyl (S)-6-(4-cyanophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.0 g, 4.5 mmol) in dioxane (20 ml) at room temperature were added 2-bromopyrazine (1.06 g, 6.75 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (493.4 mg, 0.67 mmol) and potassium phosphate (1.95 g, 9 mmol). Water (4 ml) was then added, the reaction atmosphere was replaced with nitrogen, and the temperature was raised to 95° C. for 12 hours.

[1003] After the reaction, the mixture was filtered, washed with ethyl acetate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to obtain 1.3 g of (S)-6-(4-cyanophenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester as a brown oily liquid (yield: 72.9%). LCMS: RT = 2.04 min, [M+H] + =397.21.

[1004] Step B: Synthesis of (S)-4-(4-(2-pyrazinyl)piperidin-2-yl)benzonitrile

[1005] Benzyl (S)-6-(4-cyanophenyl)-4-(pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.3 g, 3.3 mmol) was dissolved in ethyl acetate solution (25 ml), palladium carbon (650 mg) was added, and the reaction was carried out at room temperature overnight after hydrogen was replaced by reaction.

[1006] After the reaction, the mixture was filtered, washed with ethyl acetate, and concentrated under reduced pressure to obtain 740 mg of a light yellow oily liquid (S)-4-(4-(2-pyrazinyl)piperidin-2-yl)benzonitrile (yield: 84.9%). LCMS: RT = 1.47 min, [M+H] + =265.21.

[1007] Step C: Synthesis of (S)-tert-butyl 2-(4-cyanophenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylate

[1008] (S)-4-(4-(2-pyrazinyl)piperidin-2-yl)benzonitrile (740 mg, 2.8 mmol), di-tert-butyl dicarbonate (916.6 mg, 4.2 mmol), and triethylamine (566.4 mg, 5.6 mmol) were dissolved in dichloromethane (15 ml), and 4-dimethylaminopyridine (17.1 mg, 0.14 mmol) was added, and the mixture was reacted at room temperature overnight.

[1009] After the reaction, the product was filtered and dried in a rotary evaporation cycle. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 1) to afford 400 mg of (S)-tert-butyl 2-(4-cyanophenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylate as a brown oil (yield: 39.2%). LCMS: RT = 1.98 min, [M-100+H] + =265.20.

[1010] Step D: Synthesis of (S)-tert-butyl 2-(4-(N-hydroxyaminoimidazolyl)phenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylate

[1011] (S)-tert-Butyl 2-(4-cyanophenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylate (400 mg, 1.1 mmol), hydroxylamine hydrochloride (114.6 mg, 1.65 mmol), and N,N-diisopropylethylamine (355.4 mg, 2.75 mmol) were dissolved in methanol (20 ml) and reacted at 75°C overnight.

[1012] After the reaction, the product was dried in spun-drying mode, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to afford 290 mg of (S)-tert-butyl 2-(4-(N-hydroxyaminoimidazolyl)phenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylate as a brown oil (yield: 66.5%). LCMS: RT = 1.63 min, [M+H] + =398.28.

[1013] Step E: Synthesis of (S)-tert-butyl 2-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylate

[1014] Dissolve (S)-tert-Butyl 2-(4-(N-hydroxyaminoimidazolyl)phenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylate (250 mg, 0.63 mmol) and pyridine (99.6 mg, 1.26 mmol) in tetrahydrofuran (10 ml), add trichloromethyl carbonate (74.7 mg, 0.252 mmol) at 0°C, react for 1 hour, and then raise the temperature to 60°C for overnight reaction.

[1015] After completion of the reaction, the product was spin-dried and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1) to afford 140 mg of (S)-tert-butyl 2-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylate as a brown oil (yield: 68.9%). LCMS: RT = 1.89 min, [M+H] + =324.24.

[1016] Step F: Synthesis of (S)-3-(4-(4-(2-pyrazinyl)piperidin-2-yl)phenyl)-1,2,4-oxadiazol-5(4H)-one

[1017] (S)-tert-Butyl 2-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-4-(pyrazin-2-yl)piperidine-1-carboxylate (140 mg, 0.33 mmol) was dissolved in dioxane hydrochloride solution (4 mol / L, 5 ml) and reacted at room temperature for 1 hour.

[1018] After the reaction, the mixture was dried by rotary evaporation, potassium carbonate solution was added to adjust the pH to 9, the mixture was dried by rotary evaporation, 5 ml of methanol was added, the mixture was filtered, and the filtrate was dried by rotary evaporation to obtain 109 mg of (S)-3-(4-(4-(2-pyrazinyl)piperidin-2-yl)phenyl)-1,2,4-oxadiazol-5(4H)-one as a white solid. LCMS: RT = 1.49 min, [M+H] + =324.21.

[1019] Step G: Synthesis of (S)-5-methoxy-7-methyl-4-((2-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-4-(pyrazin-2-yl)piperidin-1-yl)methyl)-1H-indole-1-carboxylic acid tert-butyl ester

[1020] (S)-3-(4-(4-(2-pyrazinyl)piperidin-2-yl)phenyl)-1,2,4-oxadiazol-5(4H)-one (109 mg, 0.33 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (190.7 mg, 0.66 mmol) were dissolved in dichloroethane (4 ml), stirred at room temperature for 12 hours, and then sodium triacetoxyborohydride (209.8 mg, 0.99 mmol) was slowly added and reacted at 40°C for 4 hours.

[1021] After the reaction was completed, a small amount of methanol was added and the solvent was directly evaporated. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain 160 mg of crude yellow oily product (S)-5-methoxy-7-methyl-4-((2-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-4-(pyrazin-2-yl)piperidin-1-yl)methyl)-1H-indole-1-carboxylic acid tert-butyl ester. LCMS: RT = 1.82 min, [M+H] + =597.37.

[1022] Step H: Synthesis of Compounds 52A and 52B

[1023] To a solution of (S)-tert-butyl 5-methoxy-7-methyl-4-((2-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)-4-(pyrazin-2-yl)piperidin-1-yl)methyl)-1H-indole-1-carboxylate (160 mg, 0.26 mmol) in methanol (10 ml) was added potassium carbonate (148 mg, 1.08 mmol), the mixture was heated to 70°C for 5 hours, and water (1 ml) was added and the reaction was continued for 4 hours.

[1024] After the reaction was completed, the product was concentrated and dried, and 10 ml of a 10 / 1 mixed solvent of dichloromethane and methanol was added. The product was filtered and the filtrate was dried to give a crude product. The chiral separation method in Step D of Example 3 was used to separate the product to give 3.3 mg of the absolute configuration diastereomer 52A (yield: 2.5%) and 13.8 mg of the absolute configuration diastereomer 52B (yield: 10.6%).

[1025] Compound 52A: HPLC: RT = 3.226 min, LCMS: RT = 1.66 min, [M+H] +=497.29.

[1026] 1 H NMR (400MHz, DMSO-d6) δ10.83 (s, 1H), 8.73 (d, J=1.5Hz, 1H), 8.71-8.65 (m, 1H ), 8.52 (d, J = 2.6Hz, 1H), 7.80 (d, J = 8.0Hz, 2H), 7.62 (d, J = 8.0Hz, 2H), 7.26 (t, J=2.8Hz, 1H), 6.65 (s, 1H), 6.45 (t, J=2.5Hz, 1H), 3.74-3.61 (m, 5H), 3.26-3.2 0 (m, 3H), 2.42 (s, 3H), 2.32-2.29 (m, 1H), 2.19 (d, J=15.3Hz, 3H), 1.83 (s, 1H).

[1027] Compound 52B: HPLC: RT = 3.153 min, LCMS: RT = 1.66 min, [M+H] + =497.29.

[1028] Examples 53A and 53B

[1029] The synthetic routes of compounds 53A and 53B are as follows:

[1030] Step A: Synthesis of (S)-6-((4-methoxycarbonyl)phenyl)-4-(5-chloropyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[1031] To a solution of benzyl (S)-6-((4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (500 mg, 1.05 mmol) in dioxane (15 ml) at room temperature were added 2-iodo-5-chloropyridine (376 mg, 1.57 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (76 mg, 0.10 mmol) and potassium phosphate (556 mg, 2.62 mmol), followed by the addition of water (3 ml). The reaction mixture was purged with nitrogen and heated to 90°C for 5 hours.

[1032] After the reaction, the mixture was filtered, washed with ethyl acetate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 258 mg of (S)-6-((4-methoxycarbonyl)phenyl)-4-(5-chloropyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester as a light yellow oily liquid (yield: 53%). LCMS: RT = 2.25 min, [M+H] + =463.19.

[1033] Step B: Synthesis of (S)-methyl 4-(4-(5-chloropyridin-2-yl)piperidin-2-ylbenzoate

[1034] Benzyl (S)-6-((4-methoxycarbonyl)phenyl)-4-(5-chloropyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (258 mg, 0.56 mmol) was dissolved in ethyl acetate solution (15 ml), and Wilkinson's catalyst (25 mg) was added. After hydrogen was replaced by reaction, the temperature was raised to 60°C and the reaction was carried out overnight.

[1035] After the reaction, the mixture was filtered, washed with ethyl acetate, and concentrated under reduced pressure to give 130 mg of (S)-methyl 4-(4-(5-chloropyridin-2-yl)piperidin-2-ylbenzoate as a light yellow oil (yield: 88%). LCMS: RT = 1.65 min, [M+H] + =331.19.

[1036] Step C: Synthesis of (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(5-chloropyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[1037] To a solution of methyl (S)-4-(4-(5-chloropyridin-2-yl)piperidin-2-ylbenzoate (130 mg, 0.39 mmol) in 1,2-dichloroethane (20 ml) were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (284 mg, 0.98 mmol) and sodium triacetoxyborohydride (333 mg, 1.57 mmol), and the mixture was reacted at 40° C. overnight.

[1038] After the reaction was completed, a small amount of methanol was added and the solvent was directly evaporated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 6 / 1) to obtain 87 mg of a light yellow solid (S)-tert-butyl (5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(5-chloropyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (yield: 36%). LCMS: RT = 2.00 min, [M+H] +=604.34.

[1039] Step D: Synthesis of compounds 53A and 53B

[1040] To a solution of tert-butyl (S)-5-methoxy-4-(2-(4-methoxycarbonyl)phenyl)-4-(5-chloropyridin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (87 mg, 0.14 mmol) in methanol (10 ml) was added potassium carbonate (199 mg, 1.40 mmol), the mixture was heated to 70°C for 5 hours, and water (0.3 ml) was added and the reaction was continued for 4 hours.

[1041] After the reaction was completed, the product was filtered with celite, the filter cake was washed with methanol, and the filtrate was concentrated. The chiral separation method described in Step D of Example 3 was used to separate the product to obtain 13.8 mg of the absolute configuration diastereomer 53A (yield: 19%) and 2.2 mg of the absolute configuration diastereomer 53B (yield: 3%).

[1042] Compound 53A: HPLC: RT = 3.563 min, LCMS: RT = 1.75 min, [M+H] + =490.21. (MeOH, Rudolph Autopol I rotator).

[1043] 1 HNMR (400MHz, DMSO-d6) δ10.84 (s, 1H), 8.65 (s, 1H), 7.95 (d, J=7.9Hz, 2H), 7.89 (dd, J=8.5, 2.6Hz, 1H), 7.65 ( d, J=7.9Hz, 2H), 7.49 (d, J=8.5Hz, 1H), 7.26 (d, J=2.8Hz, 1H), 6.65 (s, 1H), 6.46 (t, J=2.4Hz, 1H), 3.69 (m, 4H), 3.67 (s, 1H), 3.62 (dd, J = 9.1, 3.3 Hz, 2H), 3.34 (d, J = 11.9 Hz, 3H), 3.12 (t, J = 4.9 Hz, 2H), 2.63 (dt, J = 12.5, 4.4 Hz, 1H), 2.27-2.03 (m, 3H), 1.77 (tt, J = 10.1, 4.8 Hz, 1H). Compound 53B: HPLC: RT = 3.455 min, LCMS: RT = 1.73 min, [M+H] + =490.25.

[1044] Example 54

[1045] The synthetic route of compound 54 is as follows:

[1046] Step A: Synthesis of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester

[1047] Compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (940 mg, 1.88 mmol), 2-thiopheneboronic acid (482 mg, 3.76 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (137 mg, 0.188 mmol), and potassium phosphate (1.2 g, 5.65 mmol) were added to 1,4-dioxane (15 ml) and reacted at 90°C under nitrogen protection for 12 hours.

[1048] After the reaction was completed, ethyl acetate (30 ml) was added to dilute the mixture, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1). 402 mg of (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester was obtained as a yellow semisolid (yield 47.6%). LCMS: RT = 2.20 min, [M+H] + =434.19.

[1049] Step B: Synthesis of (S)-4-(thiophen-2-yl)-2-(4-(methoxycarbonyl)phenyl)pyridinecarboxylic acid benzyl ester

[1050] Benzyl (S)-4-(thiophen-2-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (400 mg, 0.94 mmol) was dissolved in ethyl acetate solution (15 ml), and palladium carbon (60 mg) was added. After the reaction replaced hydrogen, the temperature was raised to 60°C and the reaction was carried out overnight.

[1051] After the reaction, the mixture was filtered, washed with ethyl acetate, and concentrated under reduced pressure to obtain 355 mg of colorless oily liquid (S)-4-(thiophen-2-yl)-2-(4-(methoxycarbonyl)phenyl)pyridinecarboxylic acid benzyl ester (yield 86.6%). LCMS: RT = 2.15 min, [M+H] + =436.21.

[1052] Step C: Synthesis of (S)-4-(5-chlorothiophen-2-yl)-2-(4-(methoxycarbonyl)phenyl)pyridinecarboxylic acid benzyl ester

[1053] Benzyl (S)-4-(thiophen-2-yl)-2-(4-(methoxycarbonyl)phenyl)pyridinecarboxylate (355 mg, 0.82 mmol) was dissolved in 15 mL of acetic acid / N,N-dimethylformamide solution (1:2), and N-chlorosuccinimide (110 mg, 0.82 mmol) was added and reacted at room temperature for 1 hour.

[1054] After the reaction was completed, the reaction was quenched with ice and extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 5 / 1). 302 mg of (S)-4-(5-chlorothiophen-2-yl)-2-(4-(methoxycarbonyl)phenyl)pyridinecarboxylic acid benzyl ester was obtained as a light yellow oil (yield 79%). LCMS: RT = 2.32 min, [M+H] + =470.21.

[1055] Step D: Synthesis of (S)-methyl 4-(4-(5-chlorothiophen-2-yl)piperidin-2-yl)benzoate

[1056] Compound (S)-benzyl 4-(5-chlorothiophen-2-yl)-2-(4-(methoxycarbonyl)phenyl)pyridinecarboxylate (300 mg, 0.64 mmol) was dissolved in ethyl acetate (5 ml), cooled in an ice-water bath, and 33% hydrobromic acid / acetic acid solution (2 ml) was added and reacted at room temperature for 1 hour.

[1057] After the reaction is complete, the mixture is cooled in an ice-water bath and quenched with ice. The pH is then adjusted to 12-13 with aqueous ammonia. The mixture is extracted with ethyl acetate (20 ml x 3 times). The organic phases are combined, dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 10 / 1). 112 mg of (S)-methyl 4-(4-(5-chlorothiophen-2-yl)piperidin-2-yl)benzoate is obtained as a light yellow oil (yield 52%). LCMS: RT = 1.72 min, [M+H] + =336.13.

[1058] Step E: Synthesis of (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-chlorothien-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[1059] To a solution of (S)-methyl 4-(4-(5-chlorothien-2-yl)piperidin-2-yl)benzoate (110 mg, 0.33 mmol) in 1,2-dichloroethane (5 ml) were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (142 mg, 0.49 mmol) and sodium triacetoxyborohydride (174 mg, 0.82 mmol), and the mixture was reacted at 40°C overnight.

[1060] After the reaction was completed, a small amount of methanol was added and the solvent was directly evaporated. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 1) to obtain 109 mg of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-chlorothien-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester as a white solid (yield: 54%). LCMS: RT = 2.04 min, [M+H] + =609.26.

[1061] Step F: Synthesis of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-chlorothien-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid

[1062] To a solution of tert-butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-chlorothiophen-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (100 mg, 0.16 mmol) in methanol (5 ml) was added potassium carbonate (227 mg, 1.6 mmol), the mixture was heated to 70°C for 5 hours, and water (1 ml) was added and the reaction was continued for 4 hours.

[1063] After the reaction was completed, the purification method in Step D of Example 3 was used to isolate 13 mg of a white solid (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-chlorothien-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid (yield: 16.4%).

[1064] Compound 54: HPLC: RT = 4.98 min, LCMS: RT = 1.79 min, [M+H] + =495.17.

[1065] Examples 55A and 55B

[1066] The synthetic routes of compounds 55A and 55B are as follows:

[1067] Step A: Synthesis of (S)-benzyl 2-(4-methoxycarbonyl)phenyl)-4-(thiophen-2-yl)piperidine-1-carboxylate

[1068] To a solution of benzyl (S)-2-(4-methoxycarbonyl)phenyl)-4-(thiophen-2-yl)piperidine-1-carboxylate (300 mg, 0.69 mmol) in acetonitrile (10 ml) was added N-bromosuccinimide (123 mg, 0.69 mmol) at 0°C and the mixture was reacted at about 0°C for 4 hours.

[1069] After the reaction, the solvent was directly evaporated, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 159 mg of (S)-benzyl 2-(4-methoxycarbonyl)phenyl)-4-(thiophen-2-yl)piperidine-1-carboxylate as a pale yellow oily liquid (yield: 45%). LCMS: RT = 2.32 min, [M+H] + =514.10 / 516.06.

[1070] Step B: Synthesis of (S)-methyl 4-(4-(5-bromothiophen-2-yl)piperidin-2-methyl)benzoate

[1071] To a solution of benzyl (S)-2-(4-methoxycarbonyl)phenyl)-4-(thiophen-2-yl)piperidine-1-carboxylate in ethyl acetate (10 ml) was added 33% hydrobromic acid / acetic acid solution (0.5 ml) at 0°C, and the mixture was warmed to room temperature and reacted for 2 hours.

[1072] After the reaction, aqueous ammonia was added to adjust the pH to neutral, and the solvent was directly evaporated. The resulting residue was purified by silica gel column chromatography (eluent: 100% ethyl acetate) to obtain 23 mg of a light yellow oily substance (S)-methyl 4-(4-(5-bromothiophen-2-yl)piperidin-2-methyl)benzoate (yield: 22%). LCMS: RT = 1.73 min, [M+H] + =380.08 / 382.10.

[1073] Step C: Synthesis of (S)-tert-butyl 4-((4-(5-bromothiophen-2-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[1074] To a solution of (S)-methyl 4-(4-(5-bromothiophen-2-yl)piperidin-2-methyl)benzoate (52 mg, 0.14 mmol) in 1,2-dichloroethane (10 ml) were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (101 mg, 0.35 mmol) and sodium triacetoxyborohydride (59 mg, 0.28 mmol), and the mixture was reacted at 40°C overnight.

[1075] After the reaction, a small amount of methanol was added and the solvent was directly evaporated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5 / 1) to obtain 52 mg of (S)-tert-butyl 4-((4-(5-bromothiophen-2-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate as a light yellow oily liquid (yield: 57%). LCMS: RT = 2.02 min, [M+H] + =653.20.

[1076] Step D: Synthesis of compounds 55A and 55B

[1077] To a solution of (S)-tert-butyl 4-((4-(5-bromothiophen-2-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (52 mg, 0.08 mmol) in methanol (5 ml) was added potassium carbonate (44 mg, 0.32 mmol), the mixture was heated to 70°C for 5 hours, and water (1 ml) was added and the reaction was continued for 4 hours.

[1078] After the reaction was completed, the purification treatment and chiral separation method in Step D of Example 3 were used to separate 17.2 mg of the absolute configuration diastereomer 55A (yield: 1.6%) and 4.8 mg of the absolute configuration diastereomer 55B (yield: 3%).

[1079] Compound 55A: HPLC: RT = 3.663 min, LCMS: RT = 1.84 min, [M+H] + =539.16 / 541.16.

[1080] Compound 55B: HPLC: RT = 3.665 min, LCMS: RT = 1.84 min, [M+H] + =539.16 / 541.16.

[1081] Examples 56A and 56B

[1082] The synthetic routes of compounds 56A and 56B are as follows:

[1083] Step A: Synthesis of (S)-benzyl 2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidine-1-carboxylate

[1084] Compound (S)-6-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (1.5 g, 3.46 mmol) was dissolved in ethyl acetate (40 ml), palladium / carbon (600 mg) was added, and the mixture was heated to 60°C under a hydrogen atmosphere. The mixture was reacted overnight, filtered, and palladium / carbon (600 mg) was added, and the reaction was continued overnight.

[1085] After the reaction was complete, the mixture was filtered and concentrated under reduced pressure to obtain 780 mg of (S)-2-(4-(methoxycarbonyl)phenyl)-4-(thiophen-3-yl)piperidine-1-carboxylic acid benzyl ester (crude product) as a pale yellow gum. This crude product was used directly in the next step without purification. LCMS: RT = 2.21 min, [M+H] + =436.21.

[1086] Step B: Synthesis of (S)-benzyl 4-(2-chlorothiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate

[1087] Compound (S)-benzyl 2-(4-(methoxycarbonyl)phenyl)-4-(2-methylthiophen-3-yl)piperidine-1-carboxylate (630 mg, 1.45 mmol) was dissolved in N,N-dimethylformamide (20 ml), acetic acid (4 ml) was added, and the mixture was cooled in an ice-water bath. NCS (193 mg, 1.45 mmol) was added and the reaction was allowed to react at room temperature overnight.

[1088] After the reaction was completed, the reaction solution was poured into 100 ml of water and extracted with ethyl acetate (25 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 9 / 1) to obtain 450 mg of (S)-benzyl 4-(2-chlorothiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate as a yellow gum (yield 64%). LCMS: RT = 2.31 min, [M+H] + =470.16.

[1089] 1H NMR (400MHz, CDCl3) δ7.99 (d, J=8.0Hz, 2H), 7.42-7.28 (m, 5H), 7.18-7.09 (m, 2H), 7.05 (d, J=5.2Hz, 1H), 6.76 (d, J=5.2Hz, 1H), 5.13-5.05 (m, 2H) ,4.24-4.16(m,1H),3.94(s,3H),3.65-3.55(m,1H),3.25-3.13(m,1H),2 .37-2.25(m, 1H), 2.22-2.13(m, 1H), 2.09-1.94(m, 2H), 1.72-1.58(m, 2H)

[1090] Step C: (S)-methyl 4-(4-(2-chlorothiophen-3-yl)piperidin-2-yl)benzoate

[1091] Compound (S)-benzyl 4-(2-chlorothiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (450 mg, 0.96 mmol) was dissolved in ethyl acetate (10 ml), cooled in an ice-water bath, and 33% hydrobromic acid / acetic acid solution (1 ml) was added, followed by stirring at room temperature for 2 hours.

[1092] After the reaction was complete, the reaction was quenched with water, adjusted to alkalinity with aqueous ammonia, extracted with ethyl acetate (15 ml x 3 times), washed with saturated brine, dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1). 180 mg of (S)-methyl 4-(4-(2-chlorothiophen-3-yl)piperidin-2-yl)benzoate (yield 55%) was obtained as a yellow gum. LCMS: RT = 1.67 min, [M+H] + =336.15.

[1093] Step D: Synthesis of (S)-tert-butyl 4-((4-(2-chlorothiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

[1094] Methyl (S)-4-(4-(2-chlorothien-3-yl)piperidin-2-yl)benzoate (180 mg, 0.54 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (310 mg, 1.08 mmol) were dissolved in 1,2-dichloroethane (15 ml) and reacted at room temperature overnight. Sodium triacetoxyborohydride (340 mg, 1.61 mmol) was then added and the reaction continued for 4 hours.

[1095] After the reaction is completed, methanol is added to dissolve until clear, and finally concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 2 / 1). 610 mg of yellow oily (S)-4-((4-(2-chlorothiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (crude product) are obtained and used directly in the next reaction. LCMS: RT = 1.97 min, [M+H] + =609.28.

[1096] Step E: Synthesis of compounds 56A and 56B

[1097] Compound (S)-tert-butyl 4-((4-(2-chlorothiophen-3-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (610 mg, 0.3 mmol, crude product) was dissolved in methanol (20 ml). Potassium carbonate (415 mg, 3 mmol) was added, and the mixture was heated to 60°C and stirred overnight. Water (5 ml) was then added, and the reaction was continued for 5 hours.

[1098] After the reaction was completed, the solution was concentrated under vacuum and separated using the purification treatment and chiral resolution method in Step D of Example 3 to obtain 2.0 mg of the absolute configuration diastereomer 56A and 42.8 mg of the absolute configuration diastereomer 56B (yield: 29%).

[1099] Compound 56A: HPLC: RT = 10.2 min, LCMS: RT = 1.77 min, [M+H] + =495.17.

[1100] Compound 56B: HPLC: RT = 11.6 min, LCMS: RT = 1.77 min, [M+H] + =495.17.

[1101] 1H NMR (400MHz, DMSO-d6) δ10.83 (s, 1H), 7.98 (d, J = 8.0Hz, 2H), 7.71 (d, J = 8.0Hz, 2 H), 7.36 (d, J=4.0Hz, 1H), 7.28-7.24 (m, 1H), 7.02 (d, J=4.0Hz, 1H), 6.67 (s, 1H) , 6.49-6.44(m, 1H), 3.73(s, 3H), 3.63-3.56(m, 1H), 3.25-3.19(m, 2H), 2.95-2. 84(m, 2H), 2.43(s, 3H), 2.21-2.11(m, 1H), 1.82-1.70(m, 2H), 1.65-1.49(m, 2H).

[1102] Example 57

[1103] The synthetic route of compound 57 is as follows:

[1104] Step A: Synthesis of 4-bromo-2-(difluoromethyl)thiophene

[1105] Under ice-cooling, diethylaminosulfur trifluoride (5.6 g, 35 mmol) was added to a solution of 5-chloropyrazine-2-carboxaldehyde (2.0 g, 14.0 mmol) in dichloromethane (30 ml). After the addition was complete, the mixture was reacted at room temperature for 12 hours.

[1106] After the reaction, the reaction solution was poured into an ice-cold saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (10 ml x 3 times). The organic phases were combined, dried, and spin-dried. The resulting residue was purified by silica gel column chromatography and filtered through n-hexane to obtain 520 mg of colorless liquid 2-chloro-5-(difluoromethyl)pyrazine (yield: 23%).

[1107] Step B: Synthesis of (S)-benzyl 6-(4-(methoxycarbonyl)phenyl)-4-(5-(difluoromethyl)pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[1108] To a solution of benzyl (S)-6-(4-methoxycarbonyl)phenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (700 mg, 1.46 mmol) in dioxane (10 ml) at room temperature were added 2-chloro-5-(difluoromethyl)pyrazine (356.3 mg, 2.19 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (213.0 mg, 0.29 mmol) and potassium phosphate (634.4 mg, 2.92 mmol). Water (2 ml) was then added, the reaction atmosphere was replaced with nitrogen, and the temperature was raised to 95° C. for 12 hours.

[1109] After the reaction, the mixture was filtered, washed with ethyl acetate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to obtain 350 mg of (S)-benzyl 4-(5-(difluoromethyl)pyrazin-2-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate as a pale yellow oily liquid (yield: 50.1%). LCMS: RT = 2.14 min, [M+H] + =484.20.

[1110] Step C: Synthesis of (S)-methyl 4-(4-(5-(difluoromethyl)pyrazin-2-yl)piperidin-2-yl)benzoate

[1111] Benzyl (S)-4-(5-(difluoromethyl)pyrazin-2-yl)-6-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (350 mg, 0.73 mmol) was dissolved in ethyl acetate solution (20 ml), and palladium carbon (400 mg) was added. After hydrogen was replaced by the reaction, the reaction was allowed to react at room temperature for 24 hours.

[1112] After the reaction, the mixture was filtered, washed with ethyl acetate, and concentrated under reduced pressure to obtain 200 mg of colorless oily liquid (S)-methyl 4-(4-(5-(difluoromethyl)pyrazin-2-yl)piperidin-2-yl)benzoate (yield: 79.0%). LCMS: RT = 1.59 min, [M+H] + =348.21.

[1113] Step D: Synthesis of (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-(difluoromethyl)pyrazin-2-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[1114] To a solution of (S)-methyl 4-(4-(5-(difluoromethyl)pyrazin-2-yl)piperidin-2-yl)benzoate (200 mg, 0.57 mmol) in dichloroethane (5 ml) was added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (330 mg, 1.14 mmol), and the mixture was stirred at room temperature for 12 hours. Then, sodium triacetoxyborohydride (360.8 mg, 1.71 mmol) was slowly added and the mixture was reacted at 40°C for 4 hours.

[1115] After the reaction was completed, a small amount of methanol was added and the solvent was directly evaporated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to obtain 228 mg of (S)-tert-butyl 4-((4-(5-(difluoromethyl)pyrazin-2-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate as a white solid (yield: 64.5%). LCMS: RT = 1.93 min, [M+H] + =621.36.

[1116] Step E: Synthesis of Compound 57

[1117] To a solution of (S)-tert-butyl 4-((4-(5-(difluoromethyl)pyrazin-2-yl)-2-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (228 mg, 0.36 mmol) in methanol (10 ml) was added potassium carbonate (198.7 mg, 1.44 mmol). The mixture was heated to 70° C. for 5 hours, and then water (1 ml) was added and the reaction continued for 4 hours. After the reaction was complete, the purification and chiral resolution methods described in Step D of Example 3 were used to obtain 80.0 mg of the absolute configuration diastereomer 57 (yield: 50.0%).

[1118] Compound 57: HPLC: RT = 3.355 min, LCMS: RT = 1.66 min, [M+H] + =507.27.

[1119] 1 H NMR (400MHz, DMSO-d6) δ10.84 (d, J=2.4Hz, 1H), 8.83 (s, 1H), 8.73 (d, J=1.4Hz, 1H), 7.83 (d, J=7.9Hz , 2H), 7.43 (d, J=7.7Hz, 2H), 7.26 (t, J=2.8Hz, 1H), 7.19-6.92 (t, J=54Hz, 1H), 6.66 (s, 1H), 6.52-6.4 6 (m, 1H), 3.73 (s, 3H), 3.62 (d, J = 11.9Hz, 1H), 3.30-3.24 (m, 2H), 3.08 (d, J = 8.3Hz, 1H), 2.94-2.86 ( m, 1H), 2.42 (s, 3H), 2.22-2.11 (m, 1H), 1.98-1.89 (m, 2H), 1.79 (d, J=12.4Hz, 1H), 1.74-1.60 (m, 1H).

[1120] Example 58

[1121] The synthetic route of compound 58 is as follows:

[1122] Step A: Synthesis of (S)-benzyl (6-(4-methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[1123] To a solution of (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 (1.0 g, 2.09 mmol) in dioxane (10 ml) at room temperature were added 4-bromo-2-(trifluoromethyl)thiophene (580 mg, 2.51 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (153 mg, 0.21 mmol) and potassium phosphate (1.11 g, 5.23 mmol). Water (2 ml) was then added, the reaction atmosphere was replaced with nitrogen, and the temperature was raised to 95° C. for overnight reaction.

[1124] After completion of the reaction, the product was filtered, washed with ethyl acetate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 7 / 1) to obtain 640 mg of (S)-benzyl (6-(4-methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (yield: 61%). LCMS: RT = 2.30 min, [M+H] + =502.20.

[1125] Step B: Synthesis of (S)-methyl 4-(4-(5-(trifluoromethyl)thiophen-3-yl)piperidin-2-yl)benzoate

[1126] Benzyl (S)-6-(4-methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (640 mg, 1.28 mmol) was dissolved in ethyl acetate solution (20 ml), and palladium carbon (300 mg) was added. After the reaction replaced hydrogen, the temperature was raised to 50°C and the reaction was carried out overnight.

[1127] After the reaction, the mixture was filtered and washed with ethyl acetate. The organic phase was directly concentrated under reduced pressure to obtain 410 mg of (S)-methyl 4-(4-(5-(trifluoromethyl)thiophen-3-yl)piperidin-2-yl)benzoate as a light yellow oil (yield: 88%). LCMS: RT = 1.73 min, [M+H] + =370.19.

[1128] Step C: Synthesis of (S)-tert-butyl 5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate

[1129] To a solution of (S)-methyl 4-(4-(5-(trifluoromethyl)thiophen-3-yl)piperidin-2-yl)benzoate (410 mg, 1.11 mmol) in 1,2-dichloroethane (10 ml) were added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (390 mg, 1.35 mmol) and sodium triacetoxyborohydride (229 mg, 1.08 mmol), and the mixture was reacted at 40°C overnight.

[1130] After the reaction was completed, a small amount of methanol was added and the solvent was directly evaporated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4 / 1) to obtain 270 mg of (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester as a light yellow oily liquid (yield: 54%). LCMS: RT = 1.98 min, [M+H] + =643.31.

[1131] Step D: Synthesis of Compound 58

[1132] To a solution of tert-butyl (S)-5-methoxy-4-((2-(4-(methoxycarbonyl)phenyl)-4-(5-(trifluoromethyl)thiophen-3-yl)piperidin-1-yl)methyl)-7-methyl-1H-indole-1-carboxylate (270 mg, 0.42 mmol) in methanol (5 ml) was added potassium carbonate (232 mg, 1.68 mmol), the mixture was heated to 70°C for 5 hours, and water (1 ml) was added and the reaction was continued for 4 hours.

[1133] After the reaction was completed, a 10% aqueous solution of citric acid was added to adjust the pH to neutral, and the mixture was extracted with dichloromethane (10 ml x 4 times). The organic phases were combined, washed with saturated brine (20 ml), and then dried over anhyd...

Claims

1. A compound represented by general formula (I), or an isomer, a racemate, or a pharmaceutically acceptable salt thereof, characterized in that: Where n is 0, 1 or 2; R 1 is selected from hydrogen, halogen, hydroxy, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-6 Cycloalkyl, the substituent is selected from halogen, hydroxy, amino, C 1-6 Alkyl, C 1-6 Alkoxy, the substituent may be one or more; R 2 is selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, the substituent is hydroxyl, halogen, and the substituent may be one or more; R 3 is selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, the substituent is hydroxyl, halogen, and the substituent may be one or more; R 4 、R 5 are independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein the substituent is selected from hydroxy, halogen, C 3-6 Heterocycloalkyl, -(CH2) m -C(O)OH, m is 0, 1 or 2, and the substituent may be one or more; R 6 independently selected from hydrogen, alkyl; R 7 Selected from hydrogen or hydroxy; Ring A is independently selected from aryl or heteroaryl, wherein the aryl and heteroaryl groups are optionally substituted with one or more R 8 Substitute, where R 8 are independently selected from hydrogen, cyano, sulfone, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-6 Epoxyalkyl, substituted or unsubstituted C 3-6 Cycloalkoxy, wherein the substituent is selected from halogen, C 1-6 Alkoxy, cyano, C 3-6 In the case of a cycloalkyl group, the substituent may be one or more.

2. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt, characterized in that: The C 1-6 The alkyl group is selected from the group consisting of methyl, ethyl, 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, and 1-ethylbutyl; The C 1-6 Alkoxy is selected from methoxy, ethoxy, 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; The C 3-6 The cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the C 3-6 The epoxyalkyl group refers to a group in which one or more carbon atoms on a cycloalkane are replaced by oxygen atoms; The C 3-6 Cycloalkoxy is where x is 1, 2, 3, or 4, For the connection key.

3. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt, characterized in that: The aryl 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, and the aryl group is a monocyclic ring or a bicyclic ring; the heteroaryl group refers to a group in which one or more carbon atoms on the aromatic ring are replaced by heteroatoms.

4. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt, characterized in that: The halogen is selected from fluorine, chlorine, bromine and iodine.

5. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt, characterized in that: The heteroatom is selected from nitrogen, oxygen, and sulfur, and the heteroatom is one or more.

6. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt, characterized in that: in, The A ring is selected from a benzene ring, The C 3-6 The heterocycloalkyl group is selected from 7. The compound according to claim 1, or its isomer, racemate, or pharmaceutically acceptable salt, characterized in that: in, R 8 The substituted A ring is selected from R 1 is selected from methoxy, cyclopropyl; R 2 selected from methyl; R 3 selected from hydrogen; R 4 Selected from R 5 selected from hydrogen; R 6 selected from hydrogen; R 7 selected from hydrogen or hydroxy; For the connection key.

8. The compound according to claim 1, or its isomer, racemate, or 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, a racemate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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

Images